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semaj83

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48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 0.0-999.0, Severe Aortic Stenosis Subject must have co-morbidities such that Heart Team agrees predicted risk of operative mortality is ≥3% and <15% at 30 days (Intermediate Clinical Risk classification). Heart team evaluation of clinical surgical mortality risk for each patient includes the calculated STS score for predicted risk of surgical mortality augmented by consideration of the overall clinical status and co-morbidities unmeasured by the STS risk calculation Heart Team unanimously agree on treatment proposal and for randomization* based on their clinical judgement (including anatomy assessment, risk factors, etc.) Subject has severe aortic stenosis presenting with; 1. Critical aortic valve area defined as an initial aortic valve area of ≤1.0cm2 or aortic valve area index < 0.6cm2/m2 AND 2. Mean gradient > 40mmHg or Vmax > 4m/sec by resting echocardiogram or simultaneous pressure recordings at cardiac catherization [or with dobutamine stress, if subject has left ventricular ejection fraction (LVEF) <55%] or velocity ratio < 0.25 Subject is symptomatic from his/her aortic valve stenosis, as demonstrated by New York Heart Association (NYHA) Functional Class II or greater Subject and the treating physician agree that the subject will return for all required post-procedure follow-up visits Subject meets the legal minimum age to provide informed consent based on local regulatory requirements Subject has refused surgical aortic valve replacement (SAVR) as a treatment option; (not applicable for Single Arm) Any condition considered a contraindication for placement of a bioprosthetic valve (i.e., subject requires a mechanical valve) A known hypersensitivity or contraindication to all anticoagulation/antiplatelet regimens (or inability to be anticoagulated for the index procedure), nitinol, or sensitivity to contrast media which cannot be adequately pre-medicated Blood dyscrasias as defined: leukopenia (WBC <1000mm3), thrombocytopenia (platelet count <50,000 cells/mm3), history of bleeding diathesis or coagulopathy Ongoing sepsis, including active endocarditis Any condition considered a contraindication to extracorporeal assistance Any percutaneous coronary or peripheral interventional procedure performed within 30 days prior to randomization* (Subjects with recent placement of drug eluting stent(s) should be assessed for ability to safely proceed with SAVR within the protocol timeframe) Symptomatic carotid or vertebral artery disease or successful treatment of carotid stenosis within six weeks of randomization* Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical hemodynamic support Recent (within 6 months of randomization*) cerebrovascular accident (CVA) or transient ischemic attack (TIA)

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48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 20.0-75.0, Critical Stenosis of Aortic Valve Male or female Age: 20-75 years Moderate to severe aortic stenosis defined as a continuous wave Doppler determined peak aortic valve jet velocity of 3.0 5 m/s, mean pressure gradient of 25 mmHg, or aortic valve area of 0.76 5 cm2 Asymptomatic aortic stenosis patients, Stationary or minimum dyspnea on exertion (NYHA Fc ≤ I or II) will be included Patients who were prescribed ACEI or ARBs for treatment of hypertension will be enrolled after 2 weeks wash-out period SBP 120-140 mmHg with or without medication regardless of presence of hypertension or not Patients with BP > 140/90 mmHg with or without medication will be included after their BP is controlled with anti-hypertensive medication other than ACEI/ARBs Symptomatic aortic stenosis: presence of exertional dyspnea (≥ NYHA Fc III), angina or syncope Very severe aortic stenosis regardless of presence of symptoms. It was defined as a critical stenosis in the aortic valve area ≤ 0.75 cm2 accompanied by a peak aortic jet velocity ≥4.5 m/s or a mean transaortic pressure gradient ≥50 mm Hg on Doppler echocardiography Uncontrolled HTN (SBP > 160 or DBP >100) without ACEI or ARBs during 2-weeks wash out period in patients who were prescribed ACEI or ARBs for treatment of hypertension Patients with known history of coronary artery disease including myocardial infarction, regardless of the treatment (medication only, percutaneous coronary intervention, or coronary artery bypass grafting) Planned cardiac surgery or planned major non-cardiac surgery within the study period Stroke or resuscitated sudden death in the past 6 months Chronic disease requiring treatment with oral, intravenous, or intra-articular corticosteroids (use of topical, or nasal corticosteroids is permissible) Untreated hyperthyroidism or hypothyroidism with TSH levels more than 2 times upper limit of normal A diagnosis of cancer (other than superficial squamous or basal cell skin cancer) in the past 3 years or current treatment for the active cancer Female of child-bearing potential who do not use adequate contraception and women who are pregnant or breast-feeding

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48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-79.0, Congestive Heart Failure Left Ventricular (LV) Systolic Dysfunction Candidates for this study must meet ALL of the following Clinical Age ≥ 18 and ≤ 79 years Body Mass Index (BMI) ≤ 40 Symptomatic ischemic heart failure (New York Heart Association (NYHA) Class III or "ambulatory" Class IV as determined through the use of the SAS) post Myocardial Infarction (MI) in the Left Anterior Descending (LAD) territory at least 60 days prior to enrollment Patient is not hospitalized at the time of enrollment Receiving appropriate medical treatment for heart failure according to the current American College of Cardiology (ACC)/American Heart Association (AHA) Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult during the three months prior to enrollment The patient or the patient's legal representative has been informed of the nature of the study, agrees to its provisions, and has provided written informed consent as approved by the Institutional Review Board (IRB)/Ethics Committee (EC) of the respective clinical site The patient and the treating physician agree that the patient will return for all required post-procedure follow-up visits. based on Imaging ≤ Left Ventricular Ejection Fraction (LVEF) ≤ 35% by Transthoracic Echocardiogram (TTE) Post LV MI structural heart dysfunction represented by LV wall motion abnormality (WMA) by TTE Untreated clinically significant coronary artery disease requiring revascularization Cardiogenic shock within 72 hours of enrollment Patient has received a pacemaker, Implantable Cardioverter Defibrillator (ICD), or Cardiac Resynchronization Therapy (CRT) within 60 days of enrollment Excessive wall motion abnormalities outside the anteroapical region Recent (within 6 months) cerebrovascular accident (CVA) or transient ischemic attack (TIA) End stage renal disease requiring chronic dialysis Obstructive Sleep Apnea (OSA): unless compliant on CPAP therapy or successful surgery Hemoglobin < 10 g/dl (female), < 12 g/dl (male) or Creatinine > 2.5mg/dl Blood dyscrasia, history of bleeding diathesis or coagulopathy, or hypercoagulable states Active peptic ulcer or GI bleeding within the past 3 months

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48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 0.0-999.0, Aortic Valve Stenosis Subject must have co-morbidities such that one cardiologist and one cardiac surgeon agree that medical factors preclude operation, based on a conclusion that the probability of death or serious morbidity exceeds the probability of meaningful improvement. 2. Subject has senile degenerative aortic valve stenosis with: mean gradient > 40 mmHg or jet velocity greater than 4.0 m/s by either resting or dobutamine stress echocardiogram, or simultaneous pressure recordings at cardiac catheterization (either resting or dobutamine stress), AND an initial aortic valve area of ≤ 0.8 cm² (or aortic valve area index ≤ 0.5 cm²/m²) by resting echocardiogram. 3. Subject is symptomatic from his/her aortic valve stenosis, as demonstrated by NYHA Functional Class Class III or greater. If screening committee agrees the of a patient with class II , based on medical factors, he/she can be enrolled. 4. Patient has been informed of the nature of the trial and has signed an Informed Consent Form. 5. Patient agrees to comply with specified follow-up evaluations and to return to the same investigational site where the procedure was performed Evidence of an acute myocardial infarction ≤ 30 days prior to the intended treatment. 2. Any percutaneous coronary or peripheral interventional procedure performed within 30 days prior to the procedure. 3. Blood dyscrasias as defined Leukopenia (WBC count < 1,000 cells/mm³) Thrombocytopenia (platelet count <50,000 cells/mm³) History of bleeding diathesis or coagulopathy Hypercoagulable states 4. Untreated clinically significant coronary artery disease requiring revascularization. 5. Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical hemodynamic support. 6. Need for emergency surgery for any reason. 7. Severe ventricular dysfunction with left ventricular ejection fraction (LVEF) < 20% as measured by resting echocardiogram. 8. Recent (within 6 months) cerebrovascular accident (CVA) or transient ischemic attack(TIA). 9. End stage renal disease requiring chronic dialysis. 10. GI bleeding within the past 3 months. 11. A known hypersensitivity or contraindication to any of the following which cannot be adequately pre-medicated Aspirin Ticlopidine Heparin Contrast media Nitinol (titanium and nickel alloy) 12. Ongoing sepsis, including active endocarditis. 13. Subject refuses a blood transfusion. 14. Life expectancy < 12 months due to associated non-cardiac co-morbid conditions. 15. Other medical, social, or psychological conditions that in the opinion of an Investigator precludes the subject from appropriate consent. 16. Severe dementia (resulting in either inability to provide informed consent for the trial/procedure, prevents independent lifestyle outside of a chronic care facility, or will fundamentally complicate rehabilitation from the procedure or compliance with follow-up visits). 17. Currently participating in an investigational drug or another device trial. Note: Trials requiring extended follow-up for products that were investigational, but have since become commercially available, are not considered investigational trials. 18. Symptomatic carotid or vertebral artery disease. 19. Native aortic annulus size < 18 mm or > 20 mm per the screening diagnostic imaging. 20. Pre-existing prosthetic heart valve in any position. 21. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation). 22. Mitral regurgitation (moderate to severe) or severe tricuspid regurgitation. 23. Moderate to severe mitral stenosis. 24. Hypertrophic obstructive cardiomyopathy. 25. Echocardiographic evidence of intracardiac mass, thrombus or vegetation. 26. Severe basal septal hypertrophy with an outflow gradient. 27. Ascending aorta diameter > 34 mm 28. Congenital bicuspid or unicuspid valve verified by echocardiography. 29. For patients with native coronary artery dependent circulation

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48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Valve Stenosis Age ≥ 18 years Severe aortic stenosis (AS) based on overall clinical impression, with or without aortic valve mean gradient ≥ 40 mm Hg, EOA < 1.0 cm2, or EOA index < 0.6 cm2/m2 Scheduled for clinically indicated elective aortic valve replacement for a primary diagnosis of severe AS Less than moderate aortic regurgitation on preoperative testing Isolated aortic valve replacement; or aortic valve replacement with concomitant coronary artery bypass grafting, ascending aorta repair, or mitral and/or tricuspid annuloplasty for functional mitral regurgitation / tricuspid regurgitation Left ventricular ejection fraction ≥ 40% on preoperative testing Physically able and willing to pedal a recumbent bicycle Patient and surgeon agree that the patient will undergo valve replacement with a bioprosthesis Patient and surgeon agree that the use of one specific bioprosthesis manufacturer / model is not indicated based on clinical criteria Willing to undergo randomization to have implanted one of three bioprosthesis at the time of aortic valve replacement Age < 18 years AS felt by overall clinical impression to be less than severe Aortic valve replacement is urgent or emergent Moderate of more aortic regurgitation on preoperative testing Concomitant mitral or tricuspid valve replacement Left ventricular ejection fraction < 40% on preoperative testing Physically unable or unwilling to pedal a recumbent bicycle Planned aortic valve replacement with a mechanical prosthesis Operating surgeon believes that any one of the three protocol bioprosthetic devices is contraindicated based on clinical criteria Not willing to undergo randomization to have implanted one of three bioprosthesis

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Stenosis years of age or older Severe symptomatic aortic stenosis (estimated aortic valve area <1 cm2) 1,2 as documented on a transthoracic echocardiogram (ECG) performed within 4 months prior to enrollment Planned for AVR within 8 weeks after enrollment Able to have a cardiac MRI within 3 weeks prior to the AVR surgery A preoperative coronary angiography demonstrating the absence of hemodynamically-significant CAD in need of revascularization during AVR surgery Able to tolerate cardiac MRI with gadolinium contrast as required by protocol, to be performed at an ACRIN-qualified facility using an ACRIN-qualified MR scanner Willing and able to provide a written informed consent Not suitable to undergo cardiac MRI or use the contrast agent gadolinium because of Claustrophobia Presence of metallic objects or implanted medical devices in body (i.e., implanted cardiac pacemaker or defibrillator, central nervous system aneurysm clips, implanted neural stimulators, cochlear implant, ocular foreign body [e.g., metal shavings], other implanted medical devices [e.g., drug infusion port], insulin pump, surgical clips, prostheses, artificial hearts, valves with steel parts, metal fragments, shrapnel, tattoos near the eye, or steel implants) Weight greater than that allowable by the MRI table Known LV ejection fraction <50% Previous aortic valve surgery Planned additional valve repair/replacement Infective endocarditis Moderate or severe aortic valve regurgitation Rhythm other than sinus rhythm (i.e., atrial fibrillation) that results in an irregular heartbeat, compromising the quality of MRI and tonometry data acquisition, as documented on an ECG performed within 8 weeks prior to enrollment

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 0.0-999.0, Severe Aortic Stenosis Subject must have co-morbidities such that one cardiologist and two cardiac surgeons agree that medical factors preclude operation, based on a conclusion that the probability of death or serious morbidity exceeds the probability of meaningful improvement. Specifically, the predicted operative risk of death or serious, irreversible morbidity is ≥ 50% at 30 days Subjects must meet all of the under at least one of the sub-groups 2a-c: a. Senile degenerative aortic valve stenosis and i. At least one of the following co-morbid conditions: 1. Severe (≥3-4+) mitral valve regurgitation as measured by echocardiography 2. Severe (≥3-4+) tricuspid valve regurgitation as measured by echocardiography 3. End-stage renal disease requiring renal replacement therapy (Stage 5 of the KDOQI CKD Classification) or creatinine clearance <20cc/min but not requiring renal replacement therapy AND ii. mean gradient > 40 mmHg or jet velocity greater than 4.0 m/sec by either resting or dobutamine stress echocardiogram (if the LVEF < 50%), or simultaneous pressure recordings at cardiac catheterization either resting or with dobutamine stress (if the LVEF < 50%) AND iii. an initial aortic valve area of ≤ 0.8 cm2 (or aortic valve area index ≤0.5 cm2/m2) by resting echocardiogram or simultaneous pressure recordings at cardiac catheterization AND/OR b. Low gradient, low output aortic stenosis as defined by the presence of all three of the following i. In the presence of LVEF <50%, absence of contractile reserve, a mean gradient ≥25mmHg and <40mmHg AND jet velocity less than 4.0m/sec with dobutamine stress echocardiography or simultaneous pressure recordings at cardiac catheterization OR In the presence of LVEF ≥50%, a mean gradient ≥25mmHg and <40mmHg AND jet velocity less than 4.0 m/sec, by echocardiography or simultaneous pressure recordings at cardiac catheterization AND ii. an initial aortic valve area of ≤0.8 cm2 (or aortic valve area index ≤0.5 cm2/m2) by resting echocardiogram or simultaneous pressure recordings at cardiac catheterization AND iii. radiographic evidence of severe aortic valve calcification AND/OR c. Failed bioprosthetic surgical aortic valve Subject is symptomatic from his/her aortic valve stenosis, as demonstrated by New York Heart Association (NYHA) Functional Class II or greater The subject or the subject's legal representative has been informed of the nature of the study, agrees to its provisions and has provided written informed consent as approved by the IRB of the respective clinical site The subject and the treating physician agree that the subject will return for all required post-procedure follow-up visits Clinical Evidence of an acute myocardial infarction ≤30 days before the MCS TAVI procedure Any percutaneous coronary or peripheral interventional procedure performed within 30 days prior to the MCS TAVI procedure Blood dyscrasias as defined: leukopenia (WBC <1000mm3), thrombocytopenia (platelet count <50,000 cells/mm3), history of bleeding diathesis or coagulopathy Untreated clinically significant coronary artery disease requiring revascularization Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical hemodynamic support Need for emergency surgery for any reason Severe ventricular dysfunction with left ventricular ejection fraction (LVEF) <20% as measured by resting echocardiogram Recent (within 6 months) cerebrovascular accident (CVA) or transient ischemic attack (TIA) Active Gastrointestinal (GI) bleeding that would preclude anticoagulation

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 21.0-999.0, Aortic Valve Stenosis Age >21 years Presence of aortic stenosis defined as peak aortic jet velocity ≥2.5 m/s Symptomatic aortic stenosis Very severe aortic stenosis defined as an AVA≤0.6 cm2 Left ventricular ejection fraction < 50% More than mild aortic or mitral regurgitation, or mitral stenosis Atrial fibrillation or flutter Pregnant or lactating women Contraindications to gadolinium-enhanced MRI

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-80.0, Pain Thoracotomy Patients scheduled for thoracotomy who presented with contraindications to TEA. Contraindications to TEA are Patient's refusal after informations about advantages and risks of the technique Anti platelets treatment that can't be discontinued Anticoagulants at a curative dosage haemostasis and/or coagulation disorders: thrombopenia < 100.000/mm3, ACT > 1,5 / control, PTT < 75% Systemic or local infection of the puncture point and 3 grade atrio-ventricular heart block without pacing Severe aortic valve stenosis Kyphoscoliosis certain neurological disorders Patient's refusal to participate in the study Psychiatric disorder (impossibility to collect the informed consent) Patient under juridical protection On going an other study Pregnancy, breastfeeding Non balanced epilepsy grade auriculo-ventricular heart block without pacing Severe hepatocellular insufficiency Anti arrhythmic treatment : class III of the Vaughan William's classification Skin infection of the puncture point

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Valve Stenosis Aortic Valve Stenosis With Insufficiency Regurgitation, Aortic Valve Aortic Valve Incompetence Subjects will be required to meet all 1. Male or female, age 18 years or older 2. Has aortic stenosis or stenosis-insufficiency of an aortic valve requiring a planned replace-ment as indicated in the preoperative evaluation 3. Is scheduled to undergo planned aortic valve replacement with or without concomitant coronary bypass surgery 4. Provide written informed consent 5. Geographically stable and agrees to attend follow-up assessments until all subjects have completed 5 years of follow up Subjects will not be eligible for trial participation if any of the following are present: 1. Pure aortic insufficiency 2. Requires emergency surgery 3. Previous aortic valve replacement 4. Had prior mitral, tricuspid or pulmonic valve surgery, which included implant of a bioprosthetic valve, mechanical valve, or annuloplasty ring that will remain in situ 5. Requires multiple valve replacement/repair 6. Requires a surgical procedure outside of the cardiac area (e.g., vascular endarterectomy, vascular bypass, tumor removal) 7. Aneurysm of the aortic root and/or ascending aorta requiring surgical intervention 8. Active endocarditis/myocarditis or endocarditis/ myocarditis within 3 months prior to the scheduled AVR surgery 9. Myocardial infarction (MI) within thirty (30) days prior to valve replacement surgery 10. Renal insufficiency as determined by creatinine ≥ 2.5 mg/dL at screening or end-stage renal disease requiring chronic dialysis 11. Hyperparathyroidism 12. MRI or CT-scan confirmed cerebrovascular accident (CVA), or transient ischemic attack (TIA) within 6 months (180 days) of the procedure 13. Presence of non-cardiac disease limiting life expectancy to less than 12 months 14. Hypertrophic obstructive cardiomyopathy (HOCM) 15. Left ventricular ejection fraction ≤ 25% 16. Documented history of substance (drug or alcohol) abuse within the last 5 years 17. Echocardiographic evidence of an intra-cardiac mass, thrombus, or vegetation 18. Hemodynamic or respiratory instability requiring inotropic support, mechanical circulatory support, or mechanical ventilation within 30 days prior to the procedure 19. Pregnancy, lactation, or planning to become pregnant; 20. Currently incarcerated or unable to give voluntary informed consent 21. Leucopenia (WBC < 3.5x 103/µL), or acute anemia (Hgb < 10.0 gm/dL or 6 mmol/L), or thrombocytopenia (platelet count < 50x 103/µL), or history of bleeding diathesis or coagulopathy 22. History of myxomatous disease/connective tissue disorders (e.g., Marfan's Syndrome) 23. Current or recent participation (within 6 weeks prior to surgery) in an investigational drug or device trial Intra-operative Anatomic variances which contraindicate implant of the trial valve, such as: 1. anomalous coronary arteries 2. annular deformation or extensive calcification of the annulus or aortic root which cannot be removed 3. significant calcium on the anterior mitral leaflet 4. pronounced septal calcification 5. position of coronary ostia relative to Model 8300ACD valve that would result in obstruction of blood flow 25. Available devices are not suitably sized for the subject's annulus

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 14.0-55.0, Marfan Syndrome Diagnosis of MFS by Ghent and/or genetically proven Fibrillin-1 (FBN1) mutation 2. Age between 14 and 55 years 3. Beta-blocker treatment at least 3 months 4. subjects must not have been receiving chronic RAS inhibitor therapy (i.e. ARBs, or ACE inhibitors)>= 90days prior to screening 5. Written informed consent from the patients or authorized representatives must be obtained previous medical history of aortic surgery and/or dissection 2. significant valve disease requiring surgery 3. aortic root dimension > 5.5 cm 4. renal dysfunction (creatinine > upper normal limit) 5. pregnancy or planned pregnancy within 12 months of study entry or breast feeding women 6. Known renal artery stenosis 7. Hypersensitivity to the aliskiren or to any of the excipients 8. Elevation of serum creatinine during follow-up (> 30% than baseline) 9. Diarrhea, resulting severe dehydration 10. Development of gout or ureter stone 11. Symptomatic hypotension (SBP<90 with symptom) 12. Hyperkalemia 13. Concomitant use with ciclosporin A

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Valve Stenosis Aortic Valve Insufficiency Patient with aortic valve stenosis, aortic valve insufficiency or a combination of the two Patient requires replacement of his/her native aortic valve with a bioprosthesis with or without concomitant procedures Patient is above the minimum age as required by local regulations to be participating in a clinical study Patient is willing to return to the implant site for follow-up visits Patient has been adequately informed of this clinical study and is willing to sign the patient Data Release Form Patient requires replacement of two or more valves Patient who underwent previous aortic valve replacement (AVR) Patient with native bicuspid aortic valve Patient with active endocarditis or other systemic infection Patient dilatation of the ascending aorta, deformations or irregular aortic annulus or ascending aorta geometry as seen via preoperative imaging

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 16.0-999.0, Aortic Stenosis Hypoplastic Left Heart Syndrome Pregnant woman carrying a fetus with normal cardiac segmental anatomy and severe aortic stenosis as defined by Dysplastic/stenotic aortic valve with forward flow, with or without gradient, and no significant insufficiency If mitral insufficiency (incomplete closure of the mitral valve)is present, left ventricle systolic pressure calculation must be ≥ a normal systemic blood pressure (BP) for gestational age Retrograde aortic arch flow Left to right atrial shunting Left ventricle length no less than 90% the length of the right ventricle Maternal age ≥ 16 years of age Gestational age: 17 0/7-30 6/7 weeks' gestation as determined by clinical information and evaluation of first ultrasound. (Aortic valve dilation procedure cannot be performed until 18 0/7 weeks) Normal karyotype with written confirmation of results. Results by fluorescence in situ hybridization (FISH) for aneuploidy will be acceptable if the patient is at 24 weeks or more; non-invasive testing is acceptable (maternal serum testing for cell-free fetal DNA, currently commercially available) Singleton pregnancy Failure to meet all criteria Multi-fetal pregnancy Insulin dependent pregestational diabetes Fetal anomaly not related to aortic stenosis. A detailed fetal anatomic ultrasound will be conducted before consideration for the study and if the finding is abnormal, the patient will be excluded Current or planned cerclage or documented history of incompetent cervix Placenta previa or placental abruption Short cervix (< 20mm) measured by cervical ultrasound Previous spontaneous delivery prior to 37 weeks of a singleton pregnancy. If the study candidate had intact membranes and was induced, this is not considered spontaneous. Stillbirths prior to 37 weeks are not exclusionary Obesity as defined by body mass index of 35 or greater Maternal-fetal Rh isoimmunization, Kell sensitization or a history of neonatal alloimmune thrombocytopenia

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Bicuspid Aortic Valve Any patient over the age of 18 who is able/willing to give informed consent with the diagnosis of bicuspid aortic valve disease, a family history of this disease or an ascending aortic aneurysm that is idiopathic can be included in the registry Patients unable or unwilling to give informed consent

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-90.0, Turner Syndrome Bicuspid Aortic Valve Marfan Syndrome Turner syndrome (TS). A TS verified by genotyping Age > 18 years Awaiting operation due to aortic dilation B Previous aortic dissection or operation of the aorta (per-cutaneous or open surgery) Marfan syndrome (MS) A Females with MS verified clinically or by genotyping Age > 18 years Awaiting operation due to aortic dilation B Previous aortic dissection or operation of the aorta (per-cutaneous or open surgery) Bicuspid aortic valve A Females with Bicuspid aortic valve

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Stenosis (Group A) Asymptomatic patients with moderate to severe Aortic Stenosis Ejection fraction greater than 50% Not yet being considered for valve surgery (Group B) Severe Aortic Stenosis (as per ESC guidelines) Listed for immediate aortic valve replacement (Group A and B) Inability to provide informed consent Concurrent primary valve lesions greater than mild (as defined by ESC criteria) Previous myocardial infarction (regional wall motion abnormality on resting echo) Cardiomyopathy Congenital heart disease Previous cardiac surgery Renal failure (CKD stage 3, eGFR >30ml/min/1.73m2) Pregnancy, risk of pregnancy, breast feeding

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 0.0-999.0, Transcatheter Aortic Valve Implantation Existence of senile degenerative aortic stenosis with a transvalvular gradient by> 40 mmHg and / or maximum velocity> 4 m / sec and / or initial valve area <1 cm ² (indexed <0.6 cm ² / m²). The initial measurement of valve area must be obtained within 30 days prior to valve implantation 2 Presence of symptoms related to aortic stenosis (dyspnea, angina, syncope effort ...) demonstrated by Functional Classification for Congestive Heart Failure functional class> 2 or Class I, but with left ventricular dysfunction (ejection fraction <40% ) 3 A Score to "EuroSCORE" (Logistic European system for cardiac operative risk evaluation) > 20% and / or Society of Thoracic Surgeons' risk Calculator> 10. In case the "EuroSCORE" <20% or STS <10, confirmed that some comorbidities were not captured by these indices will be produced by the surgeon and cardiologist Some patients are in a situation against medical-cardiac surgery indicates heavy although this does not appear in the predictive risk assessment through the scores. In this regard, patients may be included in the following conditions: 3-1 ascending aorta very calcified ("porcelain") 3-2 Any other condition preventing cannulation for cardiopulmonary bypass, aortic clamping, or access mediastinal surgery: History of 3-2-1 against mediastinal irradiation indicating open-chest 3-2-2 thoracic deformity or history of mediastinitis-cons indicating the opening of the thorax 3-2-3 Other (eg, history of coronary bypass surgery may indicate against the opening of the thorax) 4 The patient accepts the scheduled evaluations at follow-up clinic 5 The patient or his legal representatives were informed of the nature of valve implantation and associated register and accept the conditions none

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Severe Symptomatic Aortic Stenosis years or older Primary indication is symptomatic primary severe aortic stenosis predicted to benefit from relief of valvular stenosis Aortic valve area less than 0.8 centimeters squared Mean aortic valve gradient greater than or equal to 40 mmHG Peak aortic jet velocity greater than or equal to 4.0 m per second Valve sheath access site is femoral, axillary, transapical, transaortic, subclavian or subaxillary Patient is judged by the local heart team to be inoperable for Aortic Valve Replacement due to severe chest wall deformities or radiation effects, severe peripheral or aortic vascular disease, or severe systemic disease prohibiting the safe conduct of Cardiopulmonary Bypass (CPB) Aortic valve annulus size is less than 18 mm or greater than 25 mm Active infectious endocarditis Valve in prosthetic valve procedure Patients considered by the heart team to be unlikely to receive meaningful or durable clinical benefit from the procedure

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Bicuspid Aortic Valve Unicuspid Aortic Valve At least 18 years of age Diagnosis of bicuspid or unicuspid aortic valve Less than 18 years of age Recognized syndrome or identified genetic mutation

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 40.0-999.0, Aortic Stenosis Fibrosis Neovascularization, Pathologic asymptomatic mild (peak valve velocity of 2-5-3.0 m/s; n=10), moderate (peak valve velocity of 3.0-4.0 m/s; n=10) or severe aortic stenosis (peak valve velocity of >4.0 m/s; n=10) and 10 patients with severe aortic stenosis proceeding to aortic valve replacement Healthy control subjects (n=10) will have no past medical history of ischaemic heart disease or valvular heart disease and have a structurally normal heart on echocardiography Atrial fibrillation Hepatic failure (Childs-Pugh grade B or C) Renal failure (estimated glomerular filtration rate <25 mL/min) Women of child-bearing potential Contraindication to magnetic resonance imaging Inability to undergo scanning Ochronosis and those with any form of collagen-vascular disease

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 71.0-999.0, Aortic Valve Stenosis Candidates for this study must meet all of the Indications and none of the Contraindications. (Indications): 1. Age > 70 years old 2. Severe aortic valve stenosis determined by echocardiogram and Doppler mean gradient >40 mmHg or peak jet velocity >4.0 m/s aortic valve area ≤0.8 cm2 or aortic valve area index ≤0.5 cm2/m2 3. Symptomatic aortic valve stenosis (angina, congestive heart failure, NYHA Functional Class ≥ II, or syncope). 4. Patient is an extreme risk candidate for open surgical aortic valve repair such that the site Investigators (interventional cardiologist and cardiothoracic surgeon) agree that medical factors preclude operation, based on the conclusion that the probability of death or serious morbidity exceeds the probability of meaningful improvement due to the patient's co-morbidities (such as, but not limited to, severe COPD, porcelain aorta, previous thorax irradiation) or logistic EuroSCORE ≥ 20 (Contraindications): The Direct Flow Medical device is contraindicated for post implant balloon valvuloplasty

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Type II Diabetes Age > 18 years Arm 1: Treated Type II diabetes, Arm 2: absence of type II diabetes Aortic valve stenosis LVEF > 50% with no kinetic abnormalities Non significant obstructive coronary artery disease Absence of gadolinium enhanced MRI contraindications Informed consent signed Patient affiliated to the French Social Security Chronic arrhythmia or absence of sinus rhythm Past history of cardiomyopathy or coronary insufficiency Significant coronaropathy seen during the coronary angiography with >50% degree stenosis prior to aortic valve replacement Hemodynamically significant valvular dysfunction other than aortic stenosis (grade 2 mitral or aortic insufficiency, mitral valve stenosis < 1.5 cm2) Systemic chronic inflammatory disease leading to cardiac injury (scleroderma) Renal insufficiency (clearance < 30 ml/min) Insufficient transthoracic echocardiography echogenicity Type I diabetes mellitus Uncontrolled hypertension (> 180/100 mm Hg)

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 13.0-25.0, B Thalassemia documented LVEF < 50% by echocardiography B thalassemia No decompensated heart failure for at least 4 weeks (hospitalization for CHF, worsening lower extremity edema, worsening dyspnea on exertion, , and orthopnea) have no evidence of acute myocarditis and hemoglobin level above 7 gr⁄dL pulse rate below 60/min systolic blood pressure less than 90 mmHg evidence of peripheral vascular disease major depression, history of asthma, PR interval more than 240 msec, second or third degree AV block major medical diseases including diabetes mellitus requiring insulin injection, hypothyroidism, hypoparathyroidism, chronic renal failure (glomerular filtration rate below 30 ml/min), hepatic cirrhosis, hepatitis-B and hepatitis-C, positive tests for human immunodeficiency virus, and other hemoglobinopathies

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-95.0, Heart Rate Control in ICD Patients With Heart Failure Age ≥ 18 years. Patients with stable chronic heart failure implanted with mono-cameral or bicameral ICD with a home monitoring remote control. Moderate to severe left ventricular dysfunction (FE ≤ 40%). Any cause of heart failure was allowed apart congenital heart disease. Bicameral ICD programmed in DDD or AAI/DDD with AV interval < 300 msec. Rest ECG heart rate ≥70 bpm; Sinus rhythm. In therapy with low-dose of beta-blocker (bisoprolol 1,25-2,5 mg) and with the maximum dose tolerated of angiotensin-converting enzyme inhibitor or blockade of angiotensin II receptor, mineralocorticoid antagonist, antiplatelet and lipid-lowering therapy, unless contraindicated Inability of providing informed consent; Age < 18 years. State of pregnancy or lactation. Recent (<2 months) myocardial infarction; Contraindications to beta-blockers and ivabradine; Rest ECG heart rate < 70 bpm; No sinus rhythm. Administration of non-dihydropyridinic calcium channels antagonists, digitalis, class I antiarrhythmic drugs, strong inhibitors of cytochrome P450 3A4 at the time of enrollment

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Heart Failure Patient is 18 years or older Patients with moderate to severe ambulatory heart failure [American College of Cardiology/American Heart Association (ACC/AHA) Stage C; NYHA Class III/IV ambulatory], who are refractory to optimal medical therapy Patients who are non-responders to CRT pacemaker therapy Patient has signed and dated the investigation informed consent form Evidence of significant ascending aortic calcification on postero-anterior chest X-ray or CT scan Moderate or severe atherosclerotic aortic disease Ascending aorto-coronary artery bypass grafts Any history of aortic dissection Connective tissue disorder such as Marfans disease Aorta not conforming to specified dimensional constraints Patient has severe mitral valve incompetence, grade 4+ Patient has moderate to severe aortic valve incompetence, grade 2 Patient has systolic blood pressure less than 90 or greater than 140mmHg Presence of active systemic infection

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 40.0-70.0, Left Ventriclar Mass They had to have normal glucose tolerance They had to have either angiographically documented coronary artery disease or a previous history of myocardial infarction They were required to have an office BP < 130/80 mm Hg The presence of LVH on echocardiography (American Society of Echocardiography LVM index [LVMI] > 115 g/m2 for men and > 95 g/m2 for women) They were currently prescribed metformin They had renal and liver dysfunction, heart failure, or malignancy, or were unable to give informed consent Patients with contraindications to cardiac magnetic resonance (CMR) (pacemakers, claustrophobia) were also excluded, as were pregnant or lactating women

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-65.0, Healthy Healthy males and females, non-vegetarians, non-smokers, age 18-65 with BMI 18-35 kg m-2, taking no medication Diabetes Severe gastrointestinal disorders Kidney disease Thromboembolic or coagulation disease Hepatic disease Alcohol or any other substance abuse Gout Eating disorders Allergy Unregulated thyroid disease Asthma Eczema Hay fever Gluten/wheat intolerance Psychiatric disorder resulting in a perceived inability to give informed consent (including severe depression, lithium treatment, schizophrenia, severe behavioral disorders) Medication (Confirmed with GP) Orlistat (Xenical) Oral antidiabetics, insulin Digoxin, anti-arrhythmics Anti-inflammatories/anti-pyretics Tricyclic antidepressants, neuroleptics Antihistamines

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-90.0, Bicuspid Aortic Valve Bicuspid aortic valve Aortic measurement of 35 mm on prior imaging study Prior aortic valve or thoracic aortic surgery Prior aortic dissection Other condition associated with enlarged aorta including Coarctation, Marfans, Turner syndrome, Loeys-Dietz, etc Severe aortic stenosis or regurgitation Contraindication to MRI such as claustrophobia or implanted pacer/defibrillator Anticipated pregnancy, surgery, or move outside the area within 2 years

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 0.0-999.0, Acute Myocardial Infarction All patients with and STEMI prior intensive statin treatment contraindication to intensive statin therapy Time limit above 24 hours from hospital admission

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Mitral Valve Insufficiency Mitral Valve Regurgitation Mitral Valve Incompetence Mitral Regurgitation Mitral Insufficiency Patients screened in II Study will first be screened for high risk (HR) status and enrolled into the HR arm if they meet for this arm of the study. If they do not meet for the HR arm, patients will be further screened for for enrollment into the non-high risk (NHR) arm. Key The primary regurgitant jet originates from malcoaptation of the A2 and P2 scallops of the mitral valve (MV) Male or non-pregnant female Trans-septal catheterization is determined to be feasible by the treating physician High Risk Arm Predicted procedural mortality risk calculated using the STS surgical risk calculator of ≥12% or, in the judgment of a cardiac surgeon, the patient is considered a HR surgical candidate due to the presence of one of the following indications: 1. Porcelain aorta or mobile ascending aortic atheroma 2. Post-radiation mediastinum 3. Previous mediastinitis 4. Functional MR with EF <40 5. Over 75 years old with EF<40 6. Re-operation with patent grafts 7. Two or more prior chest surgeries 8. Hepatic cirrhosis 9. Three or more of the following STS high risk factors 9.1 Creatinine >2.5 mg/dL 9.2 Prior chest surgery 9.3 Age over 75 9.4 EF<35 Symptomatic moderate to severe (3+) or severe (4+) chronic MR and in the judgment of the investigator intervention to reduce MR is likely to provide symptomatic relief for the patient American Society of Anesthesiologists (ASA) physical status classification of ASA IV or lower Non-High Risk Arm Moderate to severe (3+) or severe (4+) chronic MV regurgitation and: 1. Symptomatic with >25% LVEF and LVESD ≤55mm or, 2. Asymptomatic with one or more of the following: i. Left Ventricular Ejection Fraction (LVEF) 25% to 60% ii. Left Ventricular End-Systolic Diameter (LVESD) ≥40 mm iii. New onset of Atrial fibrillation (AFib) iv. Pulmonary arterial systolic pressure (PASP) >50 mmHg at rest or >60 mmHg with exercise Candidate for MV repair or replacement surgery, including cardiopulmonary bypass Key Evidence of an Acute Myocardial Infarction (AMI) in the prior 12 weeks of the intended treatment In the judgment of the Investigator, the femoral vein cannot accommodate a 24 French scale (F) catheter or the presence of an inferior vena cava (IVC) filter would interfere with advancement of the catheter or ipsilateral Deep Venous Thrombus (DVT) is present MV orifice area <4.0 cm2 If leaflet flail is present: 1. Flail Width ≥15 mm, or 2. Flail Gap ≥10 mm If leaflet tethering is present: 1. Vertical coaptation length <2 mm Leaflet anatomy which may preclude clip implantation, proper clip positioning on the leaflets or sufficient reduction in MR. This may 1. Evidence of calcification in the grasping area of the A2 and/or P2 scallops 2. Presence of a significant cleft of A2 or P2 scallops 3. More than one anatomic dimensionally near the limits 4. Bileaflet flail or severe bileaflet prolapse 5. Lack of both primary and secondary chordal support Hemodynamic instability (systolic pressure <90 mmHg without afterload reduction or cardiogenic shock or the need for inotropic support or intra-aortic balloon pump) Need for emergency surgery for any reason Prior MV surgery or valvuloplasty or any currently implanted mechanical prosthetic valve or currently implanted Ventricular assist device (VAD) Echocardiographic evidence of intracardiac mass, thrombus or vegetation

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Coronary Artery Disease Patients of outpatient clinic presenting 12 months after introduction of the hs-TnT test in june 2009 none

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 8.0-90.0, Bicuspid Aortic Valve Disease Thoracic Aortic Disease in Patients With a Bicuspid Aortic Valve Patients diagnosed as having a bicuspid aortic valve All ages ≥8 years Able to provide fully informed consent None

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Heart Failure With Preserved Ejection Fraction (HFpEF) Clinical 1. Age >18 years 2. Written informed consent 3. HF with moderate to severe symptoms NYHA II or III 4. Hospitalization or emergency room visit for HF or symptom relief with diuretics within 12 months 5. Sinus rhythm or AF Echocardiographic 1. LVEF >40% 2. Left atrial size (volume ≥34 mL/m2 or LA parasternal diameter ≥45), or left ventricular hypertrophy (septal thickness or posterior wall thickness ≥11 mm) or LV diastolic dysfunction (E/e' ≥13 or mean e' septal and lateral wall <9 cm/s). Biomarker 1. BNP >100ng/L or NT-pro-BNP>400ng/L if sinus rhythm 2. BNP >300ng/L or NT-pro-BNP>1200ng/L if atrial fibrillation Patients unwilling or unable to sign informed consent 2. Patients with a pacemaker or ICD 3. Indication for ICD therapy according to the ESC guidelines 4. Life expectancy of less than one year 5. Significant coronary artery disease or myocardial infarction < 3 months 6. Complex congenital heart disease 7. Pregnancy

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 40.0-65.0, Adult Lymphoblastic Lymphoma Disease ALL in complete remission (CR) at the time of transplant. Remission is defined as "less than 5.0% bone marrow lymphoblasts by morphology," as determined by a bone marrow aspirate obtained within 2 weeks of study registration Philadelphia chromosome positive ALL is allowed Lymphoid blastic crisis of CML will be included (provided that patients achieve CR) Age Equal or above age 40 and up to 65 years. If younger than 40, there must be comorbidities which preclude the patient to undergo CyTBI conditioning regimen Organ Function All organ function testing should be done within 28 days of study registration Cardiac: Left ventricular ejection fraction (LVEF) ≥ 50% by MUGA (Multi Gated Acquisition) scan or echocardiogram Pulmonary: FEV1 (Forced expiratory volume in 1 second) and FVC (Forced vital capacity) ≥ 50% predicted, DLCO (alveolar diffusion capacity for carbon monoxide) (corrected for hemoglobin) ≥ 50% of predicted Renal: The estimated creatinine clearance (CrCl) must be equal or greater than 60 mL/min/1.73 m2 as calculated by the Cockcroft-Gault Formula: CrCl = (140-age) x weight (kg) x 0.85 (if female)/72 x serum creatinine (mg/dL) Hepatic Non-compliant to medications No appropriate caregivers identified HIV1 (Human Immunodeficiency Virus-1) or HIV2 positive Active life-threatening cancer requiring treatment other than ALL Uncontrolled medical or psychiatric disorders Uncontrolled infections, defined as positive blood cultures within 72 hours of study entry, or evidence of progressive infection by imaging studies such as chest CT scan within 14 days of registration Active central nervous system (CNS) leukemia Preceding allogeneic HSCT Receiving intensive chemotherapy within 21 days of registration. Maintenance type of chemotherapy will be allowed

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Breast Cancer Nos Metastatic Recurrent Women Aged 18 years and over With an invasive breast cancer diagnosed by cytology or histology Tumors cT0 to cT3, CN0-3 No clinical evidence of metastasis at the time of Untreated including scored for breast cancer surgery in progress Patient receiving a social security system Patient mastering the French language Free and informed consent for additional biological samples, different questionnaires and collecting information on resource usage Metastatic breast cancer Local recurrence of breast cancer History of cancer within 5 years prior to entry into the trial other than basal cell skin or carcinoma in situ of the cervix Already received treatment for breast cancer ongoing Blood transfusion performed for less than six months Persons deprived of liberty or under supervision (including guardianship)

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Thyroid Cancer Newly diagnosed with a first occurrence of thyroid cancer <2-4 weeks of diagnosis (i.e., histologically confirmed thyroid cancer (papillary, follicular, or medullary type; TNM classification system) Willing to participate in the EG meetings >18 years Alert and capable of giving free and informed consent Able to speak and read English or French Anaplastic thyroid cancer Karnofsky Performance Status (KPS) score <60 (rated by the Research Coordinator (RC) or referring physician) or expected survival <6 months according to clinical judgment

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-65.0, Chronic Pain Women Clinical diagnosis of chronic pelvic pain More than eighteen years Non-menstrual or noncyclic pelvic pain Duration of pain of at least 6 months Duration of pain less than 6 months Women who were pregnant in the last 12 months

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Coronary Artery Stenosis Age ≥ 18 years Patient with an indication for PCI including angina (stable or unstable), silent ischemia (in absence of symptoms a visually estimated target lesion diameter stenosis of ≥70%, a positive non-invasive stress test, or FFR ≤0.80 must be present), or recent STEMI. For STEMI the time of presentation to the first treating hospital, whether a transfer facility or the study hospital, must be >24 hours prior to randomization and enzyme levels (CK-MB or Troponin) demonstrating that either or both enzyme levels have peaked Non-target vessel PCI are allowed prior to randomization depending on the time interval and conditions as follows: a. During Baseline Procedure: i. PCI of non-target vessels performed during the baseline procedure itself immediately prior to randomization if successful and uncomplicated defined as: <50% visually estimated residual diameter stenosis, TIMI Grade 3 flow, no dissection ≥ NHLBI type C, no perforation, no persistent ST segment changes, no prolonged chest pain, no TIMI major or BARC type 3 bleeding. b. Less than 24 hours prior to Baseline Procedure: i. Not allowed (see #3). c. 24 hours-30 days prior to Baseline Procedure: i. PCI of non-target vessels 24 hours to 30 days prior to randomization if successful and uncomplicated as defined above. ii. In addition, in cases where non-target lesion PCI has occurred 24-72 hours prior to the baseline procedure, at least 2 sets of cardiac biomarkers must be drawn at least 6 and 12 hours after the non-target vessel PCI. If cardiac biomarkers are initially elevated above the local laboratory upper limit of normal, serial measurements must demonstrate that the biomarkers are falling. d. Over 30 days prior to Baseline Procedure: iii. PCI of non-target vessels performed greater than 30 days prior to procedure whether or not successful and uncomplicated Patient or legal guardian is willing and able to provide informed written consent and comply with follow-up visits and testing schedule. Angiographic (visual estimate) Treatment of up to three de novo target lesions, maximum of one de novo target lesion per vessel Target lesion(s) must be located in a native coronary artery with visually estimated diameter of ≥2.5 mm to ≤4.25 mm and diameter stenosis ≥50% to <100% Lesion must be ≤28 mm long and can be covered by a single study stent with maximum length of 33 mm (note: multiple focal stenoses may be considered as a single lesion and be enrolled if they can be completely covered with one stent) TIMI flow 2 or 3 If more than one target lesion will be treated, the RVD and lesion length of each must meet the above criteria Planned procedures after the baseline procedure in either the target or non-target vessels STEMI within 24 hours of initial time of presentation to the first treating hospital, whether at a transfer facility or the study hospital or in whom enzyme levels (either CK-MB or Troponin)have not peaked PCI within the 24 hours preceding the baseline procedure and randomization Non-target lesion PCI in the target vessel within 12 months of the baseline procedure History of stent thrombosis Cardiogenic shock (defined as persistent hypotension (systolic blood pressure <90 mm/Hg for more than 30 minutes) or requiring pressors or hemodynamic support, including IABP Known LVEF <30% Subject is intubated Relative or absolute contraindication to DAPT for 12 months (including planned surgeries that cannot be delayed, or subject is indicated for chronic oral anticoagulant treatment) Hemoglobin <10 g/dL

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 0.0-999.0, Aortic Valve Stenosis Adults with severe aortic stenosis referred for possible transcatheter aortic valve implantation with clinically indicated computed tomography imaging Inability or unwillingness to consent Inability to complete magnetic resonance imaging (MRI) study Contraindication to MRI Participation in another research study Non-diagnostic computed tomography scan

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-95.0, Aortic Stenosis Severe aortic stenosis defined as aortic valve area of less than 1 cm2 or index area of 0.6 cm2/m2 and low gradient (mean gradient across the aortic valve <40 mmHg) by echocardiography 2. Symptomatic patients with aortic stenosis referred for medically indicated AVR 3. Signed informed consent to participate in the study Pregnancy or breast feeding (women of childbearing potential will have a serum or urine pregnancy test). 2. Need for emergency surgery for any reason. 3. Any case in which the practicing physician asserts that enrollment in the protocol will adversely affect the patient treatment course

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Dilated Cardiomyopathy Autonomous ADULT patient, patient Marfan under their usual treatment(processing) (including ß blocking) diagnosis confirmed by the molecular biology (transfer(transformation) of the gene FBN1) Asymptomatic or Dilation of the aorta = 40 mm on the ascending aorta on an echocardiography or an imaging in cups(cuttings) dating less than 6 months. Aortic bicuspid Diagnosis confirmed by cardiac echography and/or imaging in cups(cuttings) Asymptomatic or Dilation of the aorta = 40 mm on the ascending aorta, and absence of valvulopathy aortic significant (IA of rank I in II, absence of significant RA), on the echocardiography or the imaging in cups(cuttings) dating less than 6 months. patients Insufficiency mitral organic moderated in severe asymptomatic SOR > 30 mm2, on an echocardiography or an imaging in cups(cuttings) dating less than 6 months Absence of ischemic or functional cause Patient recovering from a functional evaluation by echography of effort patients Insufficiency mitral organic severe surgical SOR > 40 mm2, on an echocardiography or an imaging in cups(cuttings) dating less than 6 months Patient claustrophobic patient refusing the protocol or the examination

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 30.0-70.0, Hypertension Heart Failure persons (age 30-70 years old) will be included in the study, patients with stage I or II primary hypertension according to the European Society of Hypertension with coronary artery disease or a history of coronary artery disease (A, B) with unstable hypertension with a positive stress test with NYHA class III-IV heart failure after percutaneous or surgical revascularization with diabetes with GFR < 60 with hyperthyroidism and hypothyroidism active smokers with an implanted pacemaker

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 45.0-75.0, Hypertension Metabolic Disorder men and women, aged 45 to 75 years old verified diagnosis of hypertension by medical history or receiving antihypertensive drugs established diagnosis of CHD at least 3-month optimal treatment for hypertension moderate or severe OSA if they had secondary hypertension central sleep apneas history of significant chronic renal, or hepatic failure or severe pulmonary disease diagnosed with malignant cancer with a life expectancy of less than 2years regular use of medications that can affect BP(including corticosteroids or sedative drugs) severe psychiatric disease sustained excessive alcohol use current use of CPAP treatment for OSA or pharyngeal surgery for OSA New York Heart Association Class III-IV degree declined to participate or were unable to give informed consent

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-92.0, Aortic Stenosis Cardiac Death Patients with Aortic stenosis Control with aortic stenosis

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-60.0, Right Ventricular Outflow Tract Stenosis RVOT stenosis who have undergone transannular patch repair with moderate to severe pulmonary regurgitation Isotopic or CMR of and ≤160mL/m2 Age≥18 years and ≤60 years (Zhongshan Hospital age≥18 years and ≤60 years Body weight≥18 kg Pulmonary annular diameter between 14mm to 31mm RVOT length≥20mm The subject or his/her legal representative has provided written informed consent Subject will comply with protocol required follow-ups Add any of the following conditions Subject is symptomatic Subject presents with >30% pulmonary regurgitation fraction as defined by cardiac MRI Candidates will be excluded from the study if any of the following conditions are present Existing pulmonary artery branch stenosis or artificial pulmonary valve Severe chest wall deformity ADHF Active infection or endocarditis requiring antibiotic therapy Leukopenia (WBC<3000mm3) Acute or chronic anemia (Hb<9g/L) Platelet account <100,000 cells/mm3 In the judgment of the investigator, percutaneous introduction and delivery of the valve is not feasible A known hypersensitivity to aspirin or heparin

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Insufficiency The subject is 18 years of age or older 2. The subject has bi-leaflet aortic valve morphology 3. The subject has documented aortic valve disease which may or may not Aortic valve insufficiency Ascending aortic or aortic root pathology Other pathology of the ascending aorta that requires elective aortic replacement Associated stable one or two vessel coronary disease requiring concomitant coronary bypass Patients with recurrent severe AI (Grade 3 or 4) after prior bicuspid repair who are undergoing re-repair because of annular re-dilatation All bicuspid annular and leaflet configurations will be included 4. The subject needs correction of BAV annular dilatation in patients with chronic AI and dilated annulus restoration of a circular annular shape in patients with bicuspid valve and expansion of sinus to sinus dimensions stabilization of annular geometry long-term in rare bicuspid valve patients with severe AI and minimal annular dilatation 5. The is willing to comply with specified follow-up evaluations, including transesophageal echocardiography (TEE) if there are inadequate images by transthoracic echocardiography (TTE) to assess the aortic valve 6. The subject has reviewed and signed the written informed consent form 7. The subject agrees to return for all follow-up evaluations for the duration of the study (i.e. geographically stable) All patients will be excluded who require emergency surgery for any reason. 2. All the patients who have had a prior heart valve replacement 3. The subject's aortic valve morphology is not bicuspid. 4. The subject has active endocarditis 5. The subject has mixed stenosis and regurgitation of the aortic valve with predominant stenosis 6. Heavily calcified BAV valves, calcified aortic roots, or "porcelain aortas" 7. Leukopenia with a White Blood Cell (WBC) of less than 3000 8. Acute anemia with a Hgb less than 9mg% 9. Platelet count less than 100,000 cells/mm3 10. History of a defined bleeding diathesis or coagulopathy or the subject refuses blood transfusions 11. Active infection requiring antibiotic therapy (if temporary illness, subjects may enroll 2-4 weeks after discontinuation of antibiotics) 12. Subjects in whom transesophageal echocardiography (TEE) is contraindicated 13. Low Ejection Fraction (EF) < 35% 14. Life expectancy < 1 year, or severe comorbidities, such as dialysis or severe Chronic Obstructive Pulmonary Disease (COPD) 15. The subject is or will be participating in a concomitant research study of an investigational product or has participated in such a study within the 30 days prior to screening 16. The subject is a minor, an illicit drug user, alcohol abuser, prisoner, institutionalized, or is unable to give informed consent 17. The subject is pregnant or lactating 18. Recent (within 6 months) cerebrovascular accident (CVA) or a transient ischemic attack (TIA) 19. Myocardial Infarction (MI) within one month of trial 20. The subject has a known intolerance to titanium or polyester 21. The subject has documented unstable or > 2 vessel coronary disease 22. The subject requires additional valve replacement or valve repair

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 0.0-999.0, Cardiac Failure Congestive Heart Failure Patients discharged from the department of cardiology Discharge or death diagnosis involves diseases with I50 as the beginning of the International Classification of Diseases (ICD)-10 code, including congestive heart failure, congestive heart disease, cardiac failure, right side heart failure, right side ventricular failure, acute left side heart failure, chronic left side cardiac dysfunction, cardiac asthma, left side heart failure, left side heart failure with acute pulmonary edema, low cardiac output syndrome, cardiac dysfunction, acute heart failure, chronic heart failure, grade Ⅱ cardiac function class, grade Ⅲ cardiac function class, grade Ⅱ-Ⅲ cardiac function class, grade Ⅳ cardiac function class, heart failure, cardiac-renal failure, circulatory failure, and grade Ⅰcardiac function class (I51.903), pregnancy with heart failure (O99.408), pregnancy with cardiac dysfunction (O99.429), postpartum cardiac dysfunction (O99.434), post-operative heart failure with pulmonary edema (I97.104), and heart failure after cardiac surgery (I97.106) Agree to sign an informed consent form Refuse to sign an informed consent form Already involved in this study during previous hospitalization

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Valve Stenosis Adult patients with severe symptomatic native aortic valve stenosis scheduled for elective TAVI due to a prohibitive or high risk for surgical aortic valve replacement as judged by the institutional heart team based on risk scores and comorbidity assessment Written informed consent Life expectancy < 1 year Patients who are unlikely to gain improvement in their quality of life by TAVI procedure Unfavorable anatomy for TAVI (e.g. inadequate annulus size) Left-ventricular thrombus Active endocarditis Active infection Acute ST-segment elevation myocardial infarction Hemodynamic instability Preoperative troponin I concentration above the upper normal limit of 0.1 ng/ml Stroke within the last 6 weeks

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Dissection Age >18 years Presentation to the ED with any of the following symptoms: chest pain, back pain, abdominal pain, syncope or symptoms of perfusion deficit (central nervous system, mesenteric, myocardial, or limb ischemia) Aortic dissection considered among the differential diagnosis by the attending physician. Enrollment in the study will be decided by the attending physician during evaluation in the ED and before the establishment of a final diagnosis An alternative diagnosis to AD objectively established by the attending physician after the initial medical evaluation Clinical severity or other conditions not allowing complete evaluation/proper enrollment Lack of consent to participate to the study

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 30.0-85.0, Aortic Valve Disease Coronary Artery Disease (CAD) Patients >/= 30 and </= 85 years of age Male or female with aortic valve disease Able to understand character and individual consequences of the clinical trial and to provide written informed consent to participate in the study Women of childbearing potential (ie, those who have not undergone a hysterectomy or who have not been post-menopausal for at least 12 consecutive months) must test negative for pregnancy prior to bypass surgery History of recent (< 6 weeks) Q-wave myocardial infarction Left ventricular ejection fraction < 25% (as assessed by any one of the following: contrast ventriculography, multigated acquisition scanning [MUGA], or 2-D ECHO) Patients on intra-aortic balloon devices or with history of previous coronary artery bypass surgery Pregnant or lactating patients Patients who have participated in any other investigational studies within 30 days previous to enrollment Patients in cardiogenic shock (defined as a systolic BP < 90 mmHg for over one hour despite inotropic and chronotropic support) Patients with severe chronic obstructive lung disease (FEV1 < 50%) Previous cardiac valvular disease (clinical relevant) GFR <60 ml/min Planned Ross-procedure, Mitral valve surgery, Aortic valve reconstruction, double valve surgery, other concomitant operations excluding coronary artery bypass surgery or closing a patent foramen ovale

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 20.0-65.0, Chronic Smokers Hyperlipidemia Men > 20 years Chronic cigarette/ beedi smoker (2-3 packets/day since last 3 years or more) with mild to moderate hyperlipidemia (LDL ranging 160-189 mg/dL, TC >200 mg/dL and/or HDL-C <40 mg/dL) Being mentally competent and able to understand all study requirements and sign the informed consent form Patients with Chronic obstructive pulmonary disease (COPD) Women Patients with severe liver, renal, cardiac or brain diseases. Unable to complete follow up. Subjects on any medication like diuretics. Allergic to any medication. With a history of alcohol and/or drug abuse

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Organophosphate Poisoning Male (females usually wear national dresses considered to provide adequate protection (43) Age min. 18 years (implies being a legal worker) Grows crops in knee and abdomen height in given data collection period Willing to spend 1.5-3 hours working with organophosphates under normal working conditions Involved in farming minimum two years (implies being active) Usually sprays at least once in two weeks with organophosphates on average (implies being active) Uses a hand pressured backpack sprayer placed at home (necessary to complete non-intervention) Works with crops in 5-10 katha land (sufficient to apply organophosphates for given time) Has a mobile/landline number (necessary for easy contact) Has a helper during work with organophosphates (organophosphate exposure reduced)

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Valve Stenosis Adults over the age of 18 Any patient undergoing both TTE and CT scans within a one-week timeframe as a workup for aortic stenosis There are no specific for this retrospective review

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 0.0-999.0, Aortic Valve Stenosis Patient can be included if ALL of the following are met Patient with severe aortic valve stenosis requiring treatment Patient is an acceptable candidate for elective treatment with the Medtronic Engager Transcatheter Aortic Valve Implantation System and in conformity with the local regulatory requirements Patient is above the minimum age as required by local regulations to be participating in a clinical study The patient has been informed of the nature of the study and has consented to participate, and has authorized the collection and release of his/her medical information by signing a consent form (Patient Informed Consent Form or Data Release Form) Patient will not be included if any of the following conditions exist Known hypersensitivity or contraindication to aspirin, heparin, ticlopidine, clopidogrel, Nitinol of contrast medium that cannot be adequately controlled with pre-medication Intracardiac mass, thrombus, or vegetation Aortic aneurysm Sepsis or acute endocarditis Bleeding diathesis, or coagulopathy Cardiogenic shock, suspected cardiogenic shock Unicuspid or bicuspid aortic valve Pre-existing prosthetic heart valve in aortic position Patient is currently enrolled in another investigational device or drug trial

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 45.0-999.0, Myocardial Injury Patients > 45 years of age with 1 or more major cardiovascular risk factors: Congestive heart failure, peripheral artery disease (intermittent claudication, history of vascular surgery etc), diabetes mellitus type I or II, coronary artery disease (history of myocardial infarction, stable angina pectoris, history of ischemia or coronary artery disease on cardiac tests (electrocardiogram, scintigraphy, echocardiogram, coronary angiogram etc), cerebrovascular accident, renal insufficiency (creatinine > 150umol/l), aortic valve stenosis (valve area < 1 cm2) OR 2 or more minor cardiovascular risk factors: Age > 70, hypertension, high cholesterol, low functional capacity (4 metabolic equivalents or less), transient ischemic attack, chronic obstructive pulmonary disease AND undergoing abdominal surgery with an expected 30-day mortality rate > 2-3%: colorectal, gastric, pancreatic and liver surgery Age < 45 years of age, not scheduled for higher risk abdominal surgery, low cardiovascular risk profile

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 75.0-999.0, Severe Aortic Stenosis 75 years of age or older 2. Echocardiographic or hemodynamic based evidence of calcific (senile) aortic stenosis with one of the following: aortic valve EOA <1.0 cm2 or 0.6 cm2/m2 , mean aortic valve gradient >40 mmHg or peak aortic valve velocity >4 m/sec 3. Symptomatology due to aortic stenosis resulting in a New York Heart Association (NYHA) Functional Classification of II or greater 4. Aortic valve annular diameter ≥ 21 and ≤23mm measured by MSCT 5. An STS score ≥10; or Logistic EuroScore I ≥ 15; or a determination by one cardiovascular surgeon and one cardiologist that the co-morbidities not captured by the STS or EuroScore expected to increase the operative mortality risk to > 15%. 6. Geographically available, willing to comply with follow up and able to provide written informed consent Congenital unicuspid or bicuspid aortic valve, or noncalcified aortic valve; or valve eccentricity (calcific or otherwise) that in the opinion of the investigator could compromise procedural success. 2. Pre-existing prosthetic heart valve in any position, or prosthetic ring 3. Severe (Grade 3 to 4) aortic, mitral or tricuspid valve regurgitation 4. Moderate to severe mitral stenosis 5. Myocardial infarction within the past 30 days* 6. Echocardiographic evidence of intracardiac mass, thrombus or vegetation 7. LVEF < 30% 8. Uncontrolled hypertension (i.e. blood pressure at baseline > 140 mmHg systolic ; or in the opinion of the investigator cannot be controlled by medical therapy). 9. Severe pulmonary hypertension with pulmonary systolic pressure greater than two-thirds of systemic pressure 10. Hemodynamic instability requiring inotropic drug therapy within the past 14 days or mechanical support within the past 6 months* 11. Untreated clinically significant coronary artery disease requiring revascularization 12. Presence of significant aortic disease such as atheroma, thrombus, or aneurysm which, in the opinion of the investigator, precludes safe implant delivery 13. Blood dyscrasias defined as: acute leukopenia, acute anemia, acute thrombocytopenia, history of bleeding diathesis or coagulopathy 14. Patient ineligible for or refuses blood transfusions 15. Unfavorable peripheral vascular anatomy or disease (e.g. severe obstructive calcification, severe tortuosity or small vessels) that would preclude passage of catheters from the femoral arterial access to the aorta as evidenced by peripheral MSCT 16. Active peptic ulcer or gastrointestinal bleeding within the past 90 days* 17. Stroke or transient ischemic attack within past 6 months* 18. Renal insufficiency as demonstrated by a serum creatinine > 2.5 mg/dL or end stage renal disease requiring chronic dialysis 19. Active infection requiring ongoing treatment 20. Need for emergent surgery or intervention other than the investigational procedure 21. Any therapeutic invasive cardiac procedure performed or planned to perform within 30 days of the index procedure, (or 6 months for drug eluting coronary stent or biventricular pacemaker implantation)* 22. Hypersensitivity or contraindication to procedural medication and device materials (e.g. titanium, nickel, pork) which cannot be adequately pre-medicated 23. Life expectancy < 1 year due to non-cardiac co-morbid conditions 24. Currently participating in any investigational drug or device studies that may confound the results of this study 25. History of any cognitive or mental health status that would interfere with study participation * At the time of procedure, if a subject's medical status has changed since enrollment, the subject shall be re-evaluated for

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-65.0, Post Operative Pain Control Bone fracture Isolated injury Requires operative intervention pathological fractures inability to personally consent to participation due to cognitive impairment, intoxication or sedation severe head injury polytrauma patients with multiple fractures or other injuries pregnancy open fractures metabolic bone disease allergies or contraindications to the study medications, including sulfa medications prior or current drug or alcohol dependence or abuse liver or kidney disease

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 20.0-75.0, Essential Hypertension, Dyslipidemia Patients who voluntarily signed informed consent for participating in this clinical trial 2. Male and female between 20 and 75 years old 3. Patients must have been confirmed essential hypertension and dyslipidemia at Screening visit (Visit1) 4. Patients who meet the following of fasting LDL-C and blood pressure at Baseline visit (Visit3) assessment after undergoing the therapeutic lifestyle change Low risk group: the case that does not have any other risk factor apart from hypertension / LDL-C (mg/dL): ≥160, ≤250, Mean SiSBP(mmHg): ≥140, <180 Moderate risk group: the case that has more than or equal to one risk factor apart from hypertension and has the 10-year risk of less than 10% / LDL-C (mg/dL): ≥160, ≤250, Mean SiSBP(mmHg): ≥140, <180 Moderate high risk group: the case that has more than or equal to one risk factor apart from hypertension and has the 10-year risk between 10% and 20% / LDL-C (mg/dL): ≥130, ≤250, Mean SiSBP(mmHg): ≥140, <180 High risk group: the case of CHD (Coronary heart disease) or CHD risk equivalents Risk factors cigarette smoking, hypertension (BP≥140/90 mmHg or on antihypertensive medication), low HDL cholesterol (<40mg/dL), family history of premature CHD(CHD in male first-degree relative <55 years of age; CHD in female first-degree relative < 65 years of age), and age (men≥45 years; women ≥55 years). in case of HDL-C ≥60mg/dL, reduce 1 from the total number of risk factors Electronic 10 year risk calculators are available at www.nhlbi.nih.gov/guidelines/cholesterol CHD includes history of myocardial infarction, unstable angina, coronary artery procedures (angioplasty or bypass surgery), or evidence of clinically significant myocardial ischemia CHD risk equivalents atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm and carotid artery disease [transient ischemic attacks or stroke of carotid origin or >50% obstruction of a carotid artery]), diabetes and 2+ risk factors with 10 year risk of over 20% 5. Subject must be able to understand the trial procedures and be willing to cooperate and complete the trial Severe hypertension patients with mean siSBP ≥ 180mmHg and/or SiDBP ≥110mmHg at the assessment of Screening visit (Visit1) and/or Baseline visit (Visit3). Or patients with postural hypotension with manifestation. 2. Patients with the mean SiSBP from 3 times of measurement of over 20mmHg. 3. Secondary hypertension patients, but not limited to the following disease (example: renovascular disease, adrenal medullary and cortical hyperfunctions, coarctation of the aorta, hyperaldosteronism, unilateral or bilateral renal artery stenosis, Cushing's syndrome, pheochromocytoma, polycystic kidney disease, etc) 4. Secondary dyslipidemia: nephrotic syndrome, dysproteinemia, obstructive hepatopathy or Cushing's syndrome. 5. Patients with fasting TG ≥ 400mg/dL at Pre-Baseline visit (Visit2) assessment 6. History of myopathy, rhabdomyolysis or/and CK ≥ 2 times upper normal limit. 7. Use of lipid modifying drug within 4 weeks prior to Pre-Baseline visit (Visit2) and/or antihypertensive drug within 2 weeks prior to Pre-Baseline visit(Visit2) 8. Clinically significant renal function abnormality in the laboratory results at Pre-Baseline visit (i.e. serum creatinine ≥ 1.5 times upper normal limit), liver function abnormality (ALT, AST ≥ 2 times upper normal limit), severe fatty liver disease that requires medication. 9. Clinically significant hypokalemia(less than 3.5 mmol/L) or hyperkalemia (exceeded 5.5 mmol/L) measured at Pre-Baseline visit (Visit2) 10. Subjects with following surgical and internal disease that may affect absorption, distribution, metabolism or excretion of drugs and have conditions which the following (but are not limited to): history of major gastrointestinal surgeries including gastrectomy, gastro-enterostomy or bowel resection, gastrointestinal bypass graft and stabling; current active gastritis, ulcer, gastrointestinal and rectal bleeding, presence of active inflammatory bowel syndrome or biliary obstruction with the past 12 months. 11. Subjects with depletion of body fluid or sodium ion not able to correct 12. Subjects with sever insulin-dependent Diabetes Mellitus(DM) or Chronic DM (HbA1c > 9% at Pre-Baseline visit, dosage of an oral hypoglycemic agent was modified within 12 weeks prior to screening visit , or currently use of active insulin treatment) or with hypothyroidism not able to correct.( TSH ≥ 1.5 times upper normal limit) 13. Subjects with severe heart disease (Heart failure New York Heart Association(NYHA) class 3 and 4), or history of any of the followings within the past 6 months; ischemic heart disease (e.g. angina pectoris, myocardial infarction), peripheral vascular disease, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft. 14. Subjects with clinically significant ventricular tachycardia, atrial fibrillation, atrial flutter or any other clinical significant arrhythmia conditions at discretion of investigator 15. Subjects with hypertrophic obstructive cardiomyopathy, severe obstructive coronary artery disease, aortic stenosis, hemodynamically significant aortic valve stenosis, or mitral valve stenosis. 16. Subjects with severe cerebrovascular disorder (e.g. stroke, cerebral infarction or cerebral hemorrhage within the past 6 months) 17. Subjects with chronic inflammatory disease requiring an chronic anti-inflammatory therapy, past or current medical history with wasting disease, autoimmune diseases (e.g. rheumatoid arthritis, systemic lupus erythematosus) or connective tissue disease. 18. Subjects with known moderate or malignant retinosis (e.g. retinal hemorrhage, visual disturbance or retinal microaneurysm in the past 6 months) 19. Subjects with hepatitis B (including positive test for HBsAg), hepatitis C-positive 20. Subjects with history or evidence of abusing drugs or alcohol within the past 2 years. 21. Medical history with hypersensitivity to angiotensin II antagonist based drugs or HMG-CoA reductase inhibitor based drugs or any ingredient contained in these 2 drugs. 22. Medical history with clinically significant hypersensitivity to any components or other drugs on the investigational product or additives (yellow 5) 23. Subjects with hereditary disorders of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. 24. Pregnant women and lactating female. 25. Subjects planning pregnancy or childbearing potential who are not using effective contraceptive methods (surgical sterilized, intrauterine (contraceptive) device/condom or the combination of diaphragm and spermicidal agents) 26. Subjects who are participating in another trial or took other investigational product within 12 weeks prior to Screening visit 27. Medical history of all kinds of malignant tumor including leukemia and lymphoma in the past 5 years 28. A subject with other reasons not specified above that, ineligible to participate in this clinical trial at discretion of study investigators

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 45.0-65.0, Osteoarthritis Patients with clinical hand OA defined according to the ACR (American College of Rheumatology) criteria Patients with radiographic hand OA defined according to the Kellgren Lawrence (≥ 2) Steady dose of statins for at least one month Subject affiliated to a social security scheme Written informed consent Rheumatoid arthritis, psoriatic arthritis or other inflammatory arthritis diseases History of arterial hypertension treated and / or uncontrolled (SBP > 140 mmHg and DBP (diastolic blood pressure) > 90 mmHg) Diabetes (fasting blood glucose > 7 mmol/L) Obesity (BMI > 35 kg/m²) Chronic renal failure defined by a glomerular filtration rate <60 ml/min/1,73m ² Patient with uncontrolled cardiovascular disease or a personal history of cardiovascular events (myocardial infarction and angina, occlusive arterial disease, stroke) Pregnant or breastfeeding, or premenopausal and not taking an effective contraception

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-90.0, Aortic Stenosis Severe aortic stenosis (1 or more of: aortic valve area < 1.0cm2, peak pressure gradient >64mmHg, or mean pressure gradient > 40mmHg) Symptomatic Age > 18 years and < 90 years Severe valvular disease other than AS Previous Valve surgery Severe renal impairment eGFR < 30ml/min Any absolute contraindication to CMR Other medical condition that limits life expectancy or precludes AVR Pregnancy

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 20.0-65.0, Chronic Smokers Hyperlipidemia Men > 20 years Chronic cigarette/ beedi smoker (2-3 packets/day since last 3 years or more) with mild to moderate hyperlipidemia (LDL ranging 160-189 mg/dL, TC >200 mg/dL and/or HDL-C <40 mg/dL) Being mentally competent and able to understand all study requirements and sign the informed consent form Patients with Chronic obstructive pulmonary disease (COPD) Women Patients with severe liver, renal, cardiac or brain diseases Unable to complete follow up Subjects on any medication like diuretics Allergic to any medication With a history of alcohol and/or drug abuse

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Severe Symptomatic Calcified Native Aortic Valve Stenosis Approved indications for commercially available Edwards Transcatheter Heart Valve, model 9000TFX or XT, model 9300TFX meeting one of the three sub-criteria below: 1. transfemoral delivery in subjects with severe symptomatic calcified native aortic valve stenosis without severe aortic insufficiency and with ejection fraction >20% who have been examined by a heart team including an experienced cardiac surgeon and a cardiologist and found to either be: 1. inoperable and in whom existing co-morbidities would not preclude the expected benefit from correction of the aortic stenosis; or 2. be operative candidates for aortic valve replacement but who have a Society of Thoracic Surgeons predicted operative risk score >8% or are judged by the heart team to be at a 15% risk of mortality for surgical aortic valve replacement. or 2. transapical delivery in subjects with severe symptomatic calcified native aortic valve stenosis without severe aortic insufficiency and with ejection fraction > 20% who have been examined by a heart team including an experienced cardiac surgeon and a cardiologist and found to be operative candidates for aortic valve replacement but who have a Society of Thoracic Surgeons operative risk score 8% or are judged by the heart team to be at a 15% risk of mortality for surgical aortic valve replacement. XT (Transfemoral or Transapical only) 3. in patients with symptomatic heart disease due to severe native calcific aortic stenosis (aortic valve area ≤ 1.0 cm2 or aortic valve area index ≤ 0.6 cm2/m2, a mean aortic valve gradient of ≥ 40 mmHg, or a peak aortic-jet velocity of ≥ 4.0 m/s), and with native anatomy appropriate for the 23, 26, or 29 mm valve system, who are judged by a heart team, including a cardiac surgeon, to be at high or greater risk for open surgical therapy (i.e., Society of Thoracic Surgeons operative risk score ≥8% or at a ≥15% risk of mortality at 30 days). 2. Compatible left common carotid artery (6.5 mm) and brachiocephalic artery (9 mm) diameters without significant stenosis (> 70%) as determined by Multi-Slice Computed Tomography (MSCT) scan or equivalent imaging modality 3. The subject and the treating physician agree that the subject will return for all required post-procedure follow-up visit 4. The subject or the subject's legal representative has been informed of the nature of the trial, agrees to its provisions and has provided written informed consent as approved by the IRB of the respective clinical site General 1. Vasculature in the right extremity precluding 6Fr sheath radial or brachial access 2. Inadequate circulation to the right extremity as evidenced by signs of artery occlusion (modified Allen's test) or absence of radial/brachial pulse 3. Hemodialysis shunt, graft, or arterio-venous fistula involving the upper extremity vasculature 4. Evidence of an acute myocardial infarction ≤ 1 month before the intended treatment 5. Aortic valve is a congenital unicuspid or bicuspid valve; or is non-calcified 6. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation >3+) 7. Any therapeutic invasive cardiac procedure resulting in a permanent implant that is performed within 30 days of the index procedure (unless part of planned strategy for treatment of concomitant coronary artery disease) 8. Pre-existing prosthetic heart valve in any position, prosthetic ring, or severe (greater than 3+) mitral insufficiency 9. Blood dyscrasias as defined: Leukopenia, acute anemia, thrombocytopenia, history of bleeding diathesis or coagulopathy 10. Hemodynamic instability requiring inotropic support or mechanical heart assistance. 11. Need for emergency surgery for any reason 12. Hypertrophic cardiomyopathy with or without obstruction 13. Severe ventricular dysfunction with LVEF ≤20% 14. Echocardiographic evidence of intracardiac or aortic mass, thrombus, or vegetation 15. Symptomatic or asymptomatic severe occlusive carotid disease requiring concomitant CEA/stenting 16. Subject has undergone carotid stenting or carotid endarterectomy within the previous 6 weeks 17. Active peptic ulcer or upper GI bleeding within the prior 3 months 18. A known hypersensitivity or contraindication to aspirin, heparin, ticlopidine, or clopidogrel, or sensitivity to contrast media, which cannot be adequately pre-medicated 19. Recent (within 6 months) CVA or a TIA 20. Renal insufficiency (creatinine > 3.0 mg/dL or GFR < 30) and/or renal replacement therapy at the time of screening 21. Life expectancy < 12 months due to non-cardiac co-morbid conditions 22. Subjects in whom anti-platelet and/or anticoagulant therapy is contraindicated, or who will refuse transfusion 23. Subjects who have active bacterial endocarditis or other active infections 24. Currently participating in an investigational drug or another device study 25. Subjects who have a planned treatment with any other investigational device or procedure during the study follow-up period (90 days) 26. Subject with planned concomitant surgical or transcatheter ablation for Atrial Fibrillation during the study follow-up period (90 days) 27. Any subject with a balloon valvuloplasty (BAV) within 30 days of the procedure Neurologic 28. Subject had active major psychiatric disease 29. Subject has severe visual, auditory, or learning impairment and who are unable to comprehend English and therefore unable to be consented for the study 30. Subjects with neurodegenerative or other progressive neurological disease or history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities Angiographic 31. Excessive tortuosity in the right radial/brachial/subclavian artery preventing Sentinel System access and insertion 32. Subject whose brachiocephalic or left carotid artery reveals significant stenosis, calcification, ectasia, dissection, or aneurysm at the ostium or within 3 cm of the ostium Magnetic Resonance Imaging 33. Subject Body Mass Index (BMI) precluding imaging in scanner 34. Contraindications to MRI (subjects with any implantable temporary or permanent pacemaker or defibrillator, metal implants in field of view, metallic fragments, clips, or devices in the brain or eye before TAVR procedure) 35. Planned implantation of a pacemaker or defibrillator implantation after TAVR 36. Claustrophobia 37. Known allergy to gadolinium or contrast agent

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Valve Disease Aortic Valve Stenosis Aortic Valve Calcification years or older, male or non pregnant women Senile degenerative aortic valve stenosis with echocardiography derived mean gradient ≥ 40 mmHg, or jet velocity ≥ 4.0 m/s, or an aortic valve area (AVA) of < 1.0 cm2 (or AVA index < 0.6 cm2/m2) Symptomatic due to aortic valve stenosis as demonstrated by NYHA (New York Heart Association) Functional Class ≥ II Expectation of life>12 months Calcific aortic stenosis, which is suitable for transcatheter aortic valve implantation anatomically is evaluated by at least two cardiovascular physicians, and they agreed that medical factors precluding operation suitable for surgery (the probability of death or serious, irreversible morbidity exceeded 50%) The subject agreed to comply follow-up evaluation Evidence of an acute myocardial infarction ≤ 1 month before the intended treatment aortic valve is a congenital unicuspid valve, or is non-calcified Any therapeutic invasive cardiac procedure resulting in a permanent implant that is performed within 30 days Implanted any heart valve prosthesis, prosthetic valve ring, severe（>3＋）mitral valve insufficiency Blood dyscrasia such as leukopenia (WBC < 3×109/L), acute anemia (Hgb < 90 g/L), thrombocytopenia (PLT < 50×109/L), bleeding diathesis, or history of coagulopathy Untreated clinically significant coronary artery disease requiring revascularization Hemodynamic instability requiring mechanical cardiac assist or mechanical hemodynamic support devices Need for emergency surgery for any reason Hypertrophic cardiomyopathy with or without obstruction Severe ventricular dysfunction with LVEF (Left ventricular ejection fraction) < 20%

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Valve Sclerosis Aortic Valve Stenosis Stenosis Progression Valvular Heart Disease Patient referred to routine clinical echocardiography Aortic sclerosis with or without stenosis Written informed consent Age <18 years Aortic valve replacement scheduled within 1 year after Any aortic valvular disease other than degenerative sclerotic, bi or unicuspid valves Known disease with expected survival <1 year Known malignant tumor Subvalvular obstruction (in left ventricular outflow tract) with mean pressure gradient >10mmHg

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Pulmonary Embolism With Right Ventricle Enlargement Patients aged 18 years and over with 1. Symptomatic acute pulmonary embolism with first clinical symptoms within 15 days, and objectively confirmed by CT scan 2. RV dysfunction (≥1 criterion) confirmed by elevated BNP value or echocardiography or spiral computed tomography of the chest Echocardiography o Right/Left ventricular end diastolic diameter > 1(apical or subcostal 4-chamber view) Computed tomography o Right/Left short-axis diameter ratio>0.9 (transverse plane) Positive Nt-proBNP (>600) or BNP>200 pg/mL 3. One abnormal following PESI Heart Rate>110/min Systolic blood pressure<100mmHg Arterial oxyhemoglobin level<90% on room air or after 5 minutes of oxygen withdrawal Cardiogenic shock requiring thrombolysis Previous significant left ventricular insufficiency (LVEF<45%) Systolic blood pressure<90mmHg at admission Age ≤ 18 years Pregnancy No health insurance Patients deprived of liberty or under legal protection Creatinin clearance <30mL/min/m² hypersensibility to furosemide or its excipients functional renal insufficiency

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 20.0-75.0, Hyperlipidemias Subject signed the informed consent Male or female ≥18 to ≤75 years of age Fasting TG ≤400 mg/dL Fasting LDL-C as determined by central laboratory on admission and meeting the following LDL-C values based on risk factor status 1 Risk Factor Group: LDL-C ≥160 mg/dL Risk Factor Group: LDL-C ≥130 mg/dL CHD or CHD risk equivalents: LDL-C ≥100 mg/dL Major Risk factors: （1）Cigarette smoking;（2）Hypertension (BP ≥140/90 mmHg or on anti-hypertensive medication);（3）Low HDL cholesterol (HDL-C <40 mg/dL);（4）Family history of premature CHD (CHD in male first degree relative <55 years; CHD in female first degree relative <65 years);（5）Age (men ≥45 years; women ≥55 years) CHD and CHD equivalents:（1）Other clinical forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease);（2）Diabetes;（3）Multiple risk factors that confer a 10-year risk for CHD >20% CHD or CHD risk equivalent and not receiving statin therapy, with LDL-C at screening ≤99 mg/dL NYHA II, III or IV heart failure, or last known left ventricular ejection fraction <30% Uncontrolled cardiac arrhythmia, atrial fibrillation with rapid ventricular response, or not controlled supraventricular tachycardia in the past 3 months prior to randomization Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to randomization Planned cardiac surgery or revascularization Type 1 diabetes or newly diagnosed type 2 diabetes or poorly controlled type 2 diabetes Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) >160 mmHg or diastolic BP (DBP) >100 mmHg Subjects taken red yeast rice, niacin >200 mg/d, or omega-3 fatty acids >1000 mg/d or prescription lipid-regulating drugs other than statins or ezetimibe, such as fibrates and derivatives, or bile-acid sequestering resins in the last 6 weeks prior to LDL-C screening Subjects taken systemic cyclosporine, systemic steroids, vitamin A derivatives and retinol derivatives for the treatment of dermatologic conditions in the last 3 months prior to LDL-C screening Hyperthyroidism or hypothyroidism

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Bicuspid Aortic Valve Aortic Regurgitation Aortic Dilatation Men and women over 18 years-old and under the age of 60 (age selection will prevent from enrolling patient with age-related valve and aortic wall degeneration). For the BAV stenosis group there will be considered patients over 60 years-old: including the most frequent form of BAV disease and the commonest age, this group could be used as a control group compared to the outlier ones Echo diagnosis of BAV and indication to surgery: BAV with isolated regurgitation, BAV with normal valvular function but associated aorta dilatation, BAV with both valve regurgitation and aortic dilatation BAV with isolated stenosis Signed informed consent Patient with a previous cardiac or great vessels surgery coexistent coarctation of the aorta non-associated cardiac diseases: valve disease (other than aortic), ischemic disease, congenital heart disease Marfan syndrome or other connective tissue disorders involving aortic valve and aortic wall disease (history of disease or clinical signs) Other conditions/circumstances likely to lead to poor study adherence (e.g. psychological or organizational reasons) Serious disease other than aortic, severely limiting life expectancy Patients who refuse to give informed consent

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Endomyocardial Fibrosis Aortic Valve Stenosis Severe aortic valve stenosis (AVA ≤1cm2) Scheduled for aortic valve replacement Signed consent At least moderate mitral regurgitation or stenosis Primary aortic insufficiency Persistent or permanent atrial fibrillation/flutter CKD with e-GFR < 40 ml/kg/min Pacemaker or Implantable Cardioverter Defibrillator (ICD)

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Coronary Disease Aortic Valve Stenosis in cohort: Coronary Bypass Surgery: o presence of at least one coronary stenotic lesion above 50% with clinical indication for coronary bypass surgery in cohort: Coronary Stenting: o presence of at least one coronary stenotic lesion above 50% with indication for coronary vessel dilatation/stenting in cohort: Aortic Valve Replacement o presence of aortic valve disease (stenosis) with clinical indication for aortic valve replacement without coronary vessel stenosis above 50% for all three cohorts list of medication timely related to the procedure signed informed consent for all three cohorts intolerance to contrast agent multiple myeloma, pheochromocytoma, thyroid dysfunction, acute infection renal failure severe arrhythmia pregnancy reduction of cognitive capabilities to understand the purpose and the extent of the study participation in a medical-scientific study using X-rays in the last ten years lack of Russian knowledge to fill the forms lack of signed study agreement -

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 40.0-75.0, Dyslipidemia Arteriosclerotic cardiovascular disease: defined as acute coronary syndrome; history of myocardial infarction, stable or unstable angina, coronary revascularization, stroke, or transient ischemic attack presumed to be of atherosclerotic origin and revascularization Moderate-High CVD risk according to the WHO charts adapted by the National MoH (estimated 10-year CVD risk ≥ 20%) LDL-C level ≥ 190 mg/dL Type 2 diabetes in patients between 40 and 75 years of age Patients that are already receiving statins, pregnant women, bed-bound, and patients who cannot give informed consent End stage chronics kidney disease receiving dialysis ,HIV/AIDS, tuberculosis, alcohol or drugs abuse

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 0.0-999.0, Aortic Valve Stenosis Cardiovascular Diseases Heart Valve Diseases Bicuspid Patients with bicuspid aortic valve stenosis who are not candidates for surgical aortic valve replacement because of coexisting illnesses The patient or guardian agrees to the study protocol and the schedule of clinical follow-up, and provides informed, written consent, as approved by the appropriate Institutional Review Board/Ethics Committee of the respective clinical site

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Valve Stenosis Heart Failure Asymptomatic severe aortic stenosis (Vmax > 3.5 m/sec and aortic valve area < 1 cm2) Moderate LV systolic dysfunction (LVEF < 50%) Concomitant moderate-severe aortic valve regurgitation Concomitant moderate-severe mitral valve regurgitation Moderate to severe nephropathy Chronic or persistent atrial fibrillation Implanted pacemaker or cardio defibrillator Disability to exercise testing

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Heart Failure, Diastolic Aortic Valve Stenosis Monitoring, Physiologic Physiology Subject has aortic valve stenosis Subject is scheduled for open heart aortic valve replacement with or without simultaneous coronary artery bypass grafting Less than normal systolic function, defined as ejection fraction less than 0,5 Non-sinus rhythm Any major surgical complication Problems understanding the informed consent

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 0.0-999.0, Aortic Stenosis Heart Failure Syncope Angina Pectoris aortic stenosis detected by echocardiography / invasively acute coronary syndrome endocarditis

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Valve Stenosis Diameter of >5mm for Evolut R and >6mm for CoreValve of the vessel. 2. Aortic valve diameter of ≥20mm and ≤29mm as measured by echo. 3. Ascending aorta diameter ≤ 43mm at the sinotubular junction. 4. Severe aortic stenosis, defined as aortic valve area of < 1.0 cm2 (or aortic valve area index of < 0.6 cm2/m2) by the continuity equation, AND mean gradient > 40 mmHg or maximal aortic valve velocity > 4.0 m/sec by resting echocardiogram. 5. STS score of ≥ 8 OR LogEuroSCORE> 20%, OR years old OR years old with 1 or 2 (but not more than two) from the following Liver cirrhosis (Class A or B) Pulmonary insufficiency: VMS<1 liter Previous heart surgery (CABG, vascular surgery) Porcelain aorta Pulmonary artery systolic pressure >60 mmHg and high risk for heart surgery Relapsing pulmonary embolism Right ventricular insufficiency A known hypersensitivity or contraindication to any of the following which cannot be adequately pre-medicated: aspirin or heparin and bivalirudin, ticlopidine and clopidogrel, nitinol (titanium or nickel), contrast media 2. Ongoing sepsis, including active endocarditis. 3. Any percutaneous coronary or peripheral interventional procedure with a bare metal or drug eluting stent performed within 30 days prior to Heart Team assessment. 4. Echocardiographic evidence of LV or LA thrombus. 5. Mitral or tricuspid valve insufficiency (> grade II). 6. Previous aortic valve replacement (mechanical or bioprosthetic). 7. Recent (within 6 months of Heart Team assessment) cerebrovascular accident (CVA) or transient ischemic attack (TIA). 8. Patients with: Femoral, iliac or aortic vascular disease (stenosis etc) that precludes the insertion of a transcatheter sheath. OR Symptomatic carotid or vertebral artery disease (> 70% stenosis). 9. The patient has a bleeding diathesis, coagulopathy or denies blood transfusion. 10. Estimated life expectancy of less than 12 months due to associated non-cardiac co-morbid conditions. 11. Creatinine clearance < 20 ml/min. 12. Active gastritis or ulcer. 13. Pregnancy. 14. Severe left ventricular dysfunction with left ventricular ejection fraction (LVEF) < 20%. 15. Unicuspid or bicuspid aortic valve. 16. Mixed aortic valve disease (aortic stenosis and aortic regurgitation> 2+). 17. Liver failure (Child-Pugh class C). 18. Severe dementia (resulting in either inability to provide informed consent for the study/procedure, prevents independent lifestyle outside of a chronic care facility, or will fundamentally complicate rehabilitation from the procedure or compliance with follow-up visits). 19. Extreme aortic valve calcification and calcific asymmetry (if semiquantitively measured: grade 4, Agatston score: grade 4 AgS>5000 AU). 20. Aortic valve area of < 0.4 cm2

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-100.0, Coronary Artery Disease At least 18 years of age Subject is undergoing elective or urgent high risk PCI procedure and is hemodynamically stable Subject is indicated for a revascularization of at least one de novo or restenotic lesion in a native coronary vessel or bypass graft A heart team, including a cardiac surgeon, has determined high risk PCI is an acceptable therapeutic option Subject must provide written informed consent prior to any clinical investigation related procedure Imaging • The presence of complex coronary artery disease (CAD) makes hemodynamic instability resulting from repeat episodes of reversible myocardial ischemia during PCI likely. Complex CAD is defined as an ejection fraction of <50% by echocardiographic assessment AND at least one of the following intervention of the last patent coronary conduit, OR intervention of an unprotected left main artery, OR intervention on patient presenting with triple vessel disease defined as at least one significant stenosis (at least 50% diameter stenosis on visual assessment) in all three major epicardial territories Emergency PCI Any prior coronary revascularization within the last 6 months Any MI with elevated cardiac biomarker (creatinine kinase-MB (CK-MB) or troponin >1X upper limit of normal (ULN)) and no evidence of at least 1 consecutive CKMB or troponin value trending downward from previous value (at least 4 hours apart) OR ST Elevation MI (STEMI) within 72 hours prior to the index procedure regardless of the level of cardiac biomarker Cardiac arrest within 24 hours of procedure requiring cardiopulmonary resuscitation (CPR) or defibrillation Any use of a mechanical circulatory support device within 14 days prior to the index procedure (Note: Subjects must be hemodynamically stable without any hemodynamic support to be eligible for this clinical investigation.) Hemodynamic support with a mechanical circulatory support device (e.g.the HeartMate PHP, Impella, intra-aortic balloon pump (IABP), or extra-corporeal membrane oxygenation (ECMO)) post-PCI is anticipated Any condition that requires discontinuation of antiplatelet and/or anticoagulant therapy within 90 days following the index procedure (e.g. planned noncardiac surgery) Any use of vasopressors or inotropes within 24 hours prior to the index procedure Staged PCI is planned within 90 days following device removal Cardiogenic shock (SBP <90 mmHg for >1 hour with either cool clammy skin OR oliguria OR altered sensorium AND cardiac index <2.2 L/min/m2)

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 19.0-999.0, Coronary Artery Disease Stenosis Patients ≥ 19 years old Typical angina Stable or unstable angina pectoris At least one or more major epicardial coronary arteries with significant stenosis (>70% diameter stenosis by visual estimation on angiogram) confined to the proximal portion of left anterior descending artery, left circumflex artery, or right coronary artery Reference vessel diameter of target lesion ≥3.0 mm Normal LV ejection fraction (≥50%) without wall motion abnormality by echocardiography Previous myocardial infarction Previous coronary bypass graft surgery Cardiogenic shock Multiple lesions in the vessel of interest Contraindication or hypersensitivity to adenosine or contrast media Reduced coronary blood flow (TIMI flow grade <3) in the vessel of interest Heavy calcified (definite calcified lesions on angiogram) or extremely tortuous lesions Pregnant women or women with potential childbearing Inability to understand or read the informed content

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 0.0-999.0, Abdominal Aortic Aneurysms Diagnosed abdominal aortic aneurysm with indication for endovascular repair. 2. Intention to electively implant the Aorfix™ Stent Graft System Does not comply with the indications for Aorfix™ in the Instructions for Use (IFU). 2. Unwillingness or inability to comply with the recommended follow-up assessments according to the standards of care at the investigative site. 3. Unwillingness or inability to provide informed consent to both the Registry and the EVAR procedure. 4. Patients in whom Aorfix™ is being placed as a secondary procedure to a previous surgical or endovascular treatment of an AAA other than with another Aorfix™ graft

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Hypertrophic Cardiomyopathy The patient is adult (> or = 18 years) and informed He's agree for a 24-month follow-up The patient must be member or beneficiary of a health insurance system He must have a clear diagnosis of HCM defined by a left ventricular hypertrophy in tranthoracic echocardiography (superior to 15mm or 13mm if there is a familial history) without other causes of hypertrophy (severe hypertension, aortic stenosis, amyloidosis or fabry disease, ..) The patient is under safeguarding justice, tutorship or curatorship The patient formalizes his opposition It's impossible to give enlightened information The patient doesn't read French The patient is pregnant or breastfeeding Contraindication to the realization of a MRI (defibrillator, no-MRI compatible PMK, claustrophobia,..) Contraindication to the Persantine° injection (asthma, high degree block, ..) Contraindication or impossibility to realize a stress echocardiography Comorbidity that can be responsible of the studied anomalies: coronaropathy, myomectomy, multicomplicated diabetes, …

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-80.0, Anterior Myocardial Infarction Heart Failure Population Adult male or female patients aged < 80 years with acute myocardial infarction undergoing successful primary or rescue percutaneous recanalization of the infarct-related coronary artery, defined as TIMI 3 flow and residual stenosis <20%) within 24 hours of symptom onset and Left Ventricular Ejection Fraction (LVEF) ≤ 45% at 3-6 after revascularization, as documented by a two-dimensional echocardiogram. 1. Signed and dated informed consent 2. Men and women of any ethnic origin aged ≥ 18 years 3. Patients with acute ST-elevation myocardial infarction as defined by the universal definition of AMI. 4. Successful acute reperfusion therapy (residual stenosis visually <50% and TIMI flow ≥2) within 24 hours of symptom onset by successful percutaneous coronary intervention (PCI) or thrombolysis within 12 hours of symptom onset followed by successful PCI within 24 hours after thrombolysis 5. Left ventricular ejection fraction ≤ 45% at 24 hours after revascularization, as documented by a two-dimensional echocardiogram Participation in another clinical trial within 30 days prior to randomisation 2. Pregnant or nursing women or women in childbearing age not able to esclude the possibility of a pregnancy 3. Mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study or to follow the protocol 4. Necessity to revascularise additional vessels, outside the target coronary artery after investigational therapy/placebo administration (additional revascularisations after primary PCI and before investigational therapy/placebo administration are allowed) 5. Persistent cardiogenic shock 6. Known hematologic and neoplastic diseases 7. Severe impaired renal function, i.e. GFR<30 ml/min 8. Persistent fever or diarrhoea not responsive to treatment within 4 weeks prior screening or severe infection 9. Uncontrolled hypertension (systolic >180 mmHg and diastolic >120 mmHg) 10. Life expectancy of less than 2 years from any non-cardiac cause or neoplastic disease

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Diabetes Heart Disease Male or Female, aged 18 years or older; 2. Diabetes Mellitus (Type 1 or Type 2) undergoing treatment; 3. Multivessel disease involving the LAD + at least one other coronary territory (stenosis ≥ 70% in a 1.5 mm artery) in a patient referred for cCABG; 4. Angiographic lesion characteristics amenable to both PCI/DES and MICS CABG; 5. Indication for revascularization based upon objective ischemia Severe congestive heart failure (class III or IV NYHA) at enrollment; 2. Left ventricular ejection fraction less than 20%; 3. Prior CABG surgery; 4. Prior heart valve surgery; 5. Prior PCI within the previous 6 months; 6. Previous tuberculosis or trauma to the chest that may have caused adhesions or LITA damage; 7. Previous stroke within 6 months or patients with stroke at more than 6 months with significant residual neurologic involvement, as reflected by a Rankin Score > 1; 8. Prior history of significant bleeding that might be expected to recur with MICS CABG or PCI/DES related anticoagulation; 9. STEMI or Q-wave MI within 72 hours prior to enrollment; 10. Planned simultaneous surgical procedure unrelated to coronary revascularization (e.g. valve repair/replacement, aneurysmectomy, carotid endarterectomy or carotid stenting); 11. Contraindication to either cCABG, MICS CABG, or PCI/DES because of a coexisting clinical condition; 12. Significant leukopenia, neutropenia, thrombocytopenia, anemia, or known bleeding diathesis; 13. Intolerance or contraindication to aspirin or both clopidogrel and ticagrelor; 14. Dementia with a Mini Mental Status Examination (MMSE) score of < 20; 15. Extra-cardiac illness that is expected to limit survival to less than 5 years; 16. Suspected pregnancy. A pregnancy test (urine or serum) will be administered to all women not clearly menopausal; 17. Concurrent enrollment in another clinical trial; 18. Geographic inaccessibility for the follow-up visits required by protocol

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Valve Stenosis Clinically stable moderate aortic valve stenosis No evidence of acute cardiovascular disease Acute myocardial infarction in the last six months Pulmonary embolism in the last six months Hospitalisation for heart failure in the last six months Chronic kidney disease

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Femoracetabular Impingement Pain, Postoperative Any patient undergoing a hip arthroscopy procedure for femoracetabular impingement by the senior surgeon (M.T.) Morphine contraindication Clonidine contraindication Pregnant women Prisoners Adults unable to consent

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 40.0-80.0, Hypertension Hypertension Resistant to Conventional Therapy Angiographically Proven Grade III Unilateral or Bilateral Atherosclerotic Renal Artery Stenosis (ARAS) Greater Than or Equal to 60 Percent Age: 40 to 80 Years Men or women Supine office BP ≥ 140 and/or 90 mmHg at screening despite a stable medication regimen including full tolerated doses of 3 or more anti-hypertensive treatments of different classes, including a diuretic Unilateral or bilateral ARAS of a main renal artery ≥60% diagnosed by renal CT- angiogram (or MR-angiogram if there is a contraindication to perform CT) performed in the year before One or two functional kidney(s) ≥ 70 mm in pole-to-pole length eGFR ≥ 20 ml/min/1.73 m² (MDRD formula) Signed informed consent Social insurance coverage for the renal angiogram procedure RH confirmed by daytime ABPM ≥ 135 or 85 mmHg after 1 month treatment with SOMT at Visit V1. for the randomization Unilateral or bilateral ARAS of a main renal artery ≥ 60% confirmed on renal angiogram by Quantitative Vascular Analysis (QVA) Fibromuscular dysplasia of renal artery or other non-atherosclerotic renal artery stenosis Other secondary form of hypertension excluded on the basis of a clinical, hormonological and/or imaging work-up Restenosis after a previous renal angioplasty or stenting Only a stenosis of an accessory renal artery supplying <1/2 of the ipsilateral renal parenchyma Additional indication of ARAS stenting (Malignant hypertension, ≥ 30% increase in plasma creatinine after renin angiotensin system (RAS) blocker or after RAS blocker and diuretic administration, flash pulmonary edema) Kidney pole-to-pole length < 70 mm Vascular disease precluding access for stenting Abrupt vessel closure or dissection after diagnostic angiography Contraindication to renal artery stenting according the notice for use of the stents eGFR < 20 ml/min/1.73 m² (MDRD)

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 0.0-999.0, Heart Failure Patient with "de novo" heart Failure and LVEF <= 40% admitted in hospital, without contraindications for BB prescription with cardiologist up-titration prescription and without having achieved BB target dose previous discharge and signing informed consent Contraindications for BB Living in a nursing home Life expectancy < 6 months Unable to self-care or mental disease without caregiver Unable to weight Without phone Unable to go to clinic visit

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Valve Stenosis Severe symptomatic aortic valve stenosis undergoing TAVI Missing IC Pacemaker, internal cardioverter-defibrillator or cardiac resynchronization therapy (CRT) device at the time of screening Anatomic or clinical contraindications for TAVI or insertion Patient currently participating in another study evaluating a new transcatheter valve prosthesis or a new drug

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Coronary Artery Aneurysm (angiographic diagnosis) Coronary aneurysm: focal coronary dilatation which exceeds the diameter of normal adjacent segments or the diameter of the patient's largest coronary vessel by 1.5 times Patient ´s refusal to participate

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-80.0, Hypertrophic Cardiomyopathy Patients with a typical or atypical hypertrophic cardiomyopathy (HCM) confirmed by imaging modalities (echo and MRI) and/or genetic tests or a relative history of HCM Left ventricular obstruction during exercise on treadmill (above 50 mmHg) Positive response to leg lifting test (obstruction reduction above 20 mmHg) at rest or in early recovery phase Daily symptoms as shortness of breath during exercise (NYHA2-3), non coronary chest pain, dizziness Correct ultrasound windows quality Sinus rhythm Optimal medical treatment For women, pregnancy test or contraception Written consent form obtained Previous treatment by BX1514M Extra-cardiac pathology with life expectancy below than 1 year No capability of consent form written Pregnancy women Secondary hypertension hypertrophy, secondary valvular disease hypertrophy Permanent atrial fibrillation Severe ventricular arrhythmia without Implantable Cardioverter Defibrillator (ICD) Severe coronary disease Severe non stabilized hypertension Severe cardiopathy (ejection fraction below 40% or demonstrated elevated end diastolic pressure or pulmonary pressure above 60 mmHg)

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 0.0-999.0, Aortic Valve Stenosis Symptomatic native aortic valve stenosis or a stenosed, insufficient, or combined surgical bioprosthetic valve failure necessitating valve replacement Acceptable candidate for elective treatment with the Evolut R System and in conformity with the local regulatory and medico economic context Age ≥80 years OR considered to be at high or greater risk for surgical aortic valve replacement (AVR) where high risk is defined as Society of Thoracic Surgeons (STS) predicted risk of mortality ≥8% OR Documented heart team agreement of risk for AVR due to frailty or comorbidities Geographically stable and willing to return to the implanting site for all follow-up visits Of legal age to provide informed consent (patient Informed Consent or Data Release Form) in the country where they enroll in the trial The patient has been informed of the nature of the study, is able and willing to provide consent without assistance from a legal representative and has consented to participate, and has authorized the collection and release of his/her medical information by signing a Patient Informed Consent or Data Release Form Known hypersensitivity or contraindication to aspirin, heparin (HIT/HITTS) and bivalirudin, ticlopidine, clopidogrel, Nitinol (Titanium or Nickel), or sensitivity to contrast media, which cannot be adequately premedicated Preexisting mechanical heart valve in aortic position Ongoing sepsis, including active endocarditis Anatomically not suitable for the Evolut R system Estimated life expectancy of less than 1 year Participating in another trial that may influence the outcome of this trial Need for emergency surgery for any reason

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 40.0-999.0, Heart Failure Key Chronic symptomatic Heart Failure Ongoing stable GDMT HF management and management of potential comorbidities Age ≥ 40 years old LV ejection fraction ≥ 40% within the past 3 months, without previously documented ejection fraction <30% Elevated left atrial pressure with a gradient compared to right atrial pressure (RAP) documented by end-expiratory PCWP during supine ergometer exercise ≥ 25mm Hg, and greater than RAP by ≥ 5 mm Hg Key MI and/or percutaneous cardiac intervention within past 3 months; CABG in past 3 months, or current indication for coronary revascularization Cardiac Resynchronization Therapy initiated within the past 6 months Severe heart failure Inability to perform 6 minute walk test (distance < 50 m), OR 6 minute walk test > 600m History of stroke, transient ischemic attack (TIA), deep vein thrombosis (DVT), or pulmonary emboli within the past 6 months Presence of significant valve disease Known clinically significant untreated carotid artery stenosis Currently requiring dialysis; or estimated-GFR <25ml/min/1.73 m2 by CKD-Epi equation

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 30.0-85.0, Mitral Valve Insufficiency Presence of symptomatic severe MR (effective regurgitant orifice (ERO) ≥0.2 cm2 for Secondary MR, ERO ≥0.4 cm2 for Primary MR) The New York Heart Association Functional Class II, III or ambulatory IV Left Ventricular Ejection Fraction (LVEF) is ≥20% and ≤50% Creatine Kinase-MB (CK-MB) obtained within prior 14 days < local laboratory -Upper Limit of Normal (ULN) Left Ventricular End Systolic Dimension (LVESD) is ≤ 65 mm assessed by TTE obtained within 90 days -Untreated clinically significant coronary artery disease requiring revascularization. Presence of any of the following Estimated pulmonary artery systolic pressure (PASP) > 70 mmHg assessed by site based on echocardiography or right heart catheterization Hypertrophic cardiomyopathy, restrictive cardiomyopathy, constrictive pericarditis, or any other structural heart disease causing heart failure other than dilated cardiomyopathy of either ischemic or non-ischemic etiology Infiltrative cardiomyopathies (e.g., amyloidosis, hemochromatosis, sarcoidosis) Hemodynamic instability requiring inotropic support or mechanical heart assistance Hemodynamic instability defined as systolic pressure < 90 mmHg with or without afterload reduction, cardiogenic shock or the need for inotropic support or intra-aortic balloon pump or other hemodynamic support device Physical evidence of right-sided congestive heart failure with echocardiographic evidence of moderate or severe right ventricular dysfunction Coronary artery bypass grafting (CABG) within 30 days prior to subject's consent Percutaneous coronary intervention within 30 days prior to subject's consent Tricuspid valve disease requiring surgery

0

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Valve Stenosis Age 18 or greater Scheduled for Cardiac MRI Patients with known aortic valve area of less than 1 cm² on echocardiogram Able to provide informed consent Ambulatory and expected to be able to complete 6 minute walk test Other significant (moderate or severe) valvular heart disease Unable to complete 6 minute walk test (ex. Wheelchair bound)

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 0.0-999.0, Aortic Stenosis Severe, degenerative AS, defined as: 1. mean aortic valve gradient ≥40 mm Hg OR Vmax ≥4 m/sec AND 2. calculated aortic valve area ≤1.0 cm2 OR aortic valve area index ≤0.6 cm2/m2 2. Symptomatic AS, defined as a history of at least one of the following: 1. dyspnea that qualifies at New York Heart Association (NYHA) class II or greater 2. angina pectoris 3. cardiac syncope 3. The Heart Team, including at least one cardiothoracic surgeon and one interventional cardiologist, deem the patient to be reasonable for transfemoral TAVR with a commercially available bioprosthetic valve 4. The Heart Team agrees that the patient is low-risk, quantified by an estimated risk of ≤3% by the calculated STS score for operative mortality at 30 days; AND agrees that SAVR would be an appropriate therapy if offered. 5. The Heart Team agrees that transfemoral TAVR is anatomically feasible, based upon multislice CT measurements 6. Procedure status is elective 7. Expected survival is at least 24 months For the bicuspid cohort only: 8. Aortic Stenosis of a bicuspid aortic valve Concomitant disease of another heart valve or the aorta that requires either transcatheter or surgical intervention 2. Any condition that is considered a contraindication for placement of a bioprosthetic aortic valve (e.g. patient requires a mechanical aortic valve) 3. Aortic stenosis secondary to a bicuspid aortic valve (except for the bicuspid valve cohort) 4. Prior bioprosthetic surgical aortic valve replacement 5. Mechanical heart valve in another position 6. End-stage renal disease requiring hemodialysis or peritoneal dialysis, or a creatinine clearance <20 cc/min 7. Left ventricular ejection fraction <20% 8. Recent (<6 months) history of stroke or transient ischemic attack 9. Symptomatic carotid or vertebral artery disease, or recent (<6 weeks) surgical or endovascular treatment of carotid stenosis 10. Any contraindication to oral antiplatelet or anticoagulation therapy following the procedure, including recent or ongoing bleeding, or score >3 11. Severe coronary artery disease that is unrevascularized 12. Recent (<30 days) acute myocardial infarction 13. Patient cannot undergo transfemoral TAVR for anatomic reasons (as determined by supplemental imaging studies); this would inadequate size of iliofemoral access vessels or an aortic annulus size that is not accommodated by the commercially available valves 14. Any comorbidity not captured by the STS score that would make SAVR high risk, as determined by a cardiothoracic surgeon who is a member of the heart team; this includes: 1. porcelain or severely atherosclerotic aorta 2. frailty 3. hostile chest 4. IMA or other conduit either crosses midline of sternum or is adherent to sternum 5. severe pulmonary hypertension (PA systolic pressure > 2/3 of systemic pressure) 6. severe right ventricular dysfunction 15. Ongoing sepsis or infective endocarditis 16. Recent (<30 days) or ongoing bleeding that would preclude treatment with anticoagulant or antiplatelet therapy, including recent gastrointestinal bleeding 17. Uncontrolled atrial fibrillation (resting heart rate >120 beats per minute) 18. Severe chronic obstructive pulmonary disease, as demonstrated by forced expiratory volume (FEV1) <750 cc 19. Liver failure with Childs class C or D 20. Pre-procedure shock, inotropes, mechanical assist device, or cardiac arrest 21. Pregnancy or intent to become pregnant prior to completion of all protocol follow-up procedures 22. Known allergy to warfarin or aspirin

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Valve Stenosis All candidates for this study must meet all of the following 1. Age ≥18 years 2. NYHA class ≥ 2 3. NT-proBNP > 900pg/mL (or BNP > 200 pg/mL) or hospitalization for HF within the 2 years; Note: To account for the decrease in natriuretic peptide levels with overweight/obesity, NT-proBNP and BNP levels cutoff will be reduced by 4% for every increase of 1 kg/m2 in BMI above a reference BMI of 20 kg/m2). 4. Under appropriate and stable guideline-directed HF therapy for a minimum of 1 month. o Patients are expected to be on appropriate pharmacologic therapy and if indicated CRT for heart failure. (12, 13) Patients with aortic stenosis may not be able to tolerate maximal doses of heart failure medications and no specific guidelines exist for the medical treatment of heart failure in the setting of aortic stenosis. It is expected that the heart failure PI will review the medical therapy and confirm that it is appropriate for the patient's condition. 5. Moderate AS confirmed by the echo core lab. Moderate AS is defined as an aortic valve area (AVA) >1.0 cm2 and ≤1.5 cm2 on rest echo or if ≤1.0 cm2 at rest and low-flow AS is suspected when the an AVA > 1.0 cm2 with low dose dobutamine stress echo (DSE). Patients with AVA<1.0 cm2 but with an indexed AVA of >0.6 cm2/m2 on either rest or DSE are also eligible. Similarly, patients with AVA >1.5 cm2 but with indexed AVA<0.9 cm2/m2 on either rest of DSE are also eligible. Note: Typically such cases will demonstrate, • • Mean trans-aortic gradient (MG) ≥ 20 mmHg and < 40 mmHg at rest and aortic valve area (AVA) > 1.0 cm2 and ≤1.5 cm2 (or AVA < 1.0 cm2 but indexed AVA > 0.6 cm2) at rest OR Mean trans-aortic gradient (MG) ≥ 20 mmHg and < 40 mmHg and aortic valve area (AVA) ≤1.0 cm2 at rest AND MG < 40 mmHg and aortic valve area (AVA) >1.0 cm2 (or AVA < 1.0 cm2 but indexed AVA > 0.6 cm2) with low dose dobutamine stress echo (DSE). In atypical cases (for example mean gradient is below 20 mmHg but valve area is consistent with moderate AS, the final determination in regards to diagnosis of moderate AS will be made by the echocardiographic core lab. 6. Left ventricular (LV) ejection fraction (EF) < 50% at rest 7. Anatomically suitable for transfemoral TAVR with the 3 or 3 Ultra THV 8. Able to provide independent informed consent (i.e., not requiring a legally authorized representative) Candidates are excluded from the study if any of the following conditions are present: 1. LVEF < 20% or persistent need for intravenous inotropic support 2. Hospitalization for acute decompensated HF within 2 weeks prior to randomization 3. Cardiac resynchronization therapy (CRT) device implantation within 1 month prior to randomization 4. Coronary artery revascularization (PCI or CABG) within 1 month prior to randomization 5. In need and suitable for revascularization per heart team consensus 6. Severe aortic and/or mitral regurgitation 7. Congenital unicuspid or congenital bicuspid aortic valve 8. Concomitant non-aortic valvular disease with a formal indication for valve surgery per established guidelines (ESC/ACC/AHA) 9. Previous aortic valve replacement (mechanical or bioprosthetic) 10. Severe RV dysfunction 11. Previous stroke with permanent disability (modified Rankin score ≥ 2) 12. Severe lung disease as indicated by FEV1 <30% predicted or need for chronic daytime supplemental oxygen therapy 13. Severe chronic kidney disease: glomerular filtration rate (GFR) < 30 mL/min by MDRD or need for renal replacement therapy 14. Gastrointestinal (GI) bleeding within the past 3 months 15. Liver cirrhosis Child-Pugh C 16. Active systemic infection, including active endocarditis 17. Unwilling to accept blood transfusion 18. Evidence of intracardiac mass, thrombus or vegetation 19. Absence of minimum amount of aortic valve calcification necessary for TAVR with the 3 or 3 Ultra THV 20. Hypersensitivity or contraindication to clopidogrel, aspirin, or to oral anticoagulation if indicated (e.g. subject in atrial fibrillation) 21. Sensitivity to contrast media which cannot be adequately pre-medicated 22. Women of child-bearing potential 23. Clinical signs of dementia 24. Other medical, social, or psychological conditions that precludes appropriate consent and follow-up 25. Life expectancy < 2 years due to cancer or other non-cardiac chronic diseases 26. Unwillingness to undergo follow-up investigations 27. Currently participating in an investigational drug or another device trial that has not reached its primary endpoint (excluding registries)

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 21.0-99.0, Left Ventricular Hypertrophy Hypertension Myocardial Fibrosis 21 years and over 2. Physician diagnosed essential hypertension, on at least 1 medication for blood pressure control 3. Newly diagnosed hypertension: systolic blood pressure 140mmHg or greater (diastolic blood pressure 90mmHg or greater) on at least 2 office visits (Weber 2013) and not started on any anti hypertensive medications at time of ambulatory blood pressure monitoring 4. Resistant hypertension: persistent systolic blood pressure 140mmHg or greater (diastolic blood pressure 90mmHg or greater) despite on at least 3 anti-hypertensive medications (Jennings 2013; Weber 2013) Known secondary hypertension: renal causes (renal artery stenosis, chronic renal failure); endocrine causes (aldosterone excess, pheochromocytoma, cushing's syndrome, hyperthyroidism); cardiac causes (coarctation of the aorta) 2. Contraindications to cardiovascular magnetic resonance: implantable devices, cerebral aneurysm clips, cochlear implants, renal impairment (GRF <30ml/min/1.73m2), claustrophobia and women who are pregnant or breast-feeding 3. Limited life expectancy 4. On-going unstable medical conditions: hypertensive crisis, acute coronary syndromes or acute heart failure 5. History of coronary artery disease, ischemic heart disease 6. History of transient ischemic attacks or cerebrovascular events 7. History of atrial fibrillation 8. History of heart failure

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Valve Disease Aortic Stenosis adult male or female ≥18 years of age 2. symptomatic for aortic stenosis / mixed aortic stenosis and aortic insufficiency disease for which isolated surgical aortic valve replacement without concomitant procedures is planned 3. EuroSCORE <20 4. NYHA Class ≥II 5. Subject has signed and dated the investigation informed consent form prior to study specific procedures are performed 6. Subject is geographically stable and agrees to participate in follow-up assessments as specified in the protocol and informed consent (i.a.): 1. pure aortic insufficiency 2. previous cardiac surgery (involved FS or MIS approach) 3. congenital true bicuspid / unicuspid aortic valve 4. requires emergency surgery or has had emergency surgery for any reason ≤ 1 month before the intended treatment 5. LVEF <25% 6. active endocarditis ≤ 6 months before the intended treatment 7. acute MI ≤ 90 days before the intended treatment 8. had a stroke or transient ischemic attack within six months prior to scheduled aortic valve replacement surgery 9. oxygen or ventilator dependent 10. life expectancy < 12 months 11. substance abuser 12. Female subject is pregnant or lactating 13. documented leukopenia (WBC < 3.5x 103/μL), acute anemia (Hgb < 10.0 gm/dL or < 6.2 mmol/L), thrombocytopenia (platelet count < 100x 103/mL), or history of bleeding diathesis or coagulopathy 14. hemodynamic or respiratory instability requiring inotropic support, mechanical circulatory support, or mechanical ventilation within 30 days of procedure 15. documented echocardiographic evidence of intracardiac mass, thrombus or vegetation 16. renal insufficiency as determined by Serum creatinine ≥ 200 μmol/L (2.27 mg/dL) at screening or end-stage renal disease requiring chronic dialysis 17. documented hyperparathyroidism 18. currently participating in an investigational drug or device trial for which follow-up has not yet been completed 19. Minimally Invasive access to the heart is not possible due to anatomical constraints or any other pre-existing condition Intra-operative 1. has calcium on the anterior mitral leaflet which cannot be removed 2. has extensive calcification of the aortic root 3. Annular deformation which may or may not be caused by too extensive decalcification of the aortic annulus 4. has left atrial thrombus 5. The position of the coronary ostia relative to the Valve would result in obstruction of blood flow 6. hemodynamically unstable during the procedure requiring the procedure to be aborted prior to insertion of the study bioprosthesis and delivery system 7. Study device is not available in the correct size for the subject

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 0.0-999.0, Aortic Stenosis Severe, calcific aortic stenosis 2. NYHA Functional Class ≥ 2 OR exercise tolerance test that demonstrates a limited exercise capacity, abnormal BP response, or arrhythmia OR asymptomatic with LVEF <50% 3. Heart team agrees the patient has a risk of operative mortality and has an STS <4 4. The study patient has been informed of the nature of the study, agrees to its provisions and has provided written informed consent Native aortic annulus size unsuitable for sizes 20, 23, 26, or 29 mm THV 2. Iliofemoral vessel characteristics that would preclude safe passage of the introducer sheath 3. Evidence of an acute myocardial infarction ≤ 30 days before randomization 4. Aortic valve is unicuspid, bicuspid, or non-calcified 5. Severe aortic regurgitation (>3+) 6. Severe mitral regurgitation (>3+) ≥ moderate stenosis 7. Pre-existing mechanical or bioprosthetic valve in any position 8. Complex coronary artery disease: 1. Unprotected left main coronary artery 2. Syntax score > 32 3. Heart Team assessment that optimal revascularization cannot be performed 9. Symptomatic carotid or vertebral artery disease or successful treatment of carotid stenosis within 30 days of randomization 10. Leukopenia, anemia, thrombocytopenia, history of bleeding diathesis or coagulopathy, or hypercoagulable states 11. Hemodynamic or respiratory instability requiring inotropic support, mechanical ventilation or mechanical heart assistance within 30 days of randomization 12. Hypertrophic cardiomyopathy with obstruction 13. Ventricular dysfunction with LVEF < 30% 14. Cardiac imaging evidence of intracardiac mass, thrombus or vegetation 15. Inability to tolerate or condition precluding treatment with antithrombotic/anticoagulation therapy during or after the valve implant procedure 16. Stroke or transient ischemic attack within 90 days of randomization 17. Renal insufficiency and/or renal replacement therapy at the time of screening. 18. Active bacterial endocarditis within 180 days of randomization 19. Severe lung disease or currently on home oxygen 20. Severe pulmonary hypertension 21. History of cirrhosis or any active liver disease 22. Significant frailty as determined by the Heart Team 23. Significant abdominal or thoracic aortic disease that would preclude safe passage of the delivery system or cannulation and aortotomy for surgical AVR 24. Hostile chest or conditions or complications from prior surgery that would preclude safe reoperation 25. Patient refuses blood products 26. BMI > 50 kg/m2 27. Estimated life expectancy < 24 months 28. Absolute contraindications or allergy to iodinated contrast that cannot be adequately treated with pre-medication 29. Immobility that would prevent completion of study procedures 30. Patient is not a candidate for both arms of the study 31. Currently participating in an investigational drug or another device study

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Bicuspid Aortic Valve Patients ≥ 18 years old with BAV confirmed by transthoracic echocardiography (in case of doubts other techniques will be required: transesophageal echocardiography or CT to confirm diagnosis) Valve dysfunction only moderate: in case of aortic stenosis with average gradient < 30 mmHg and in case of aortic regurgitation a vena contracta < 7 mm or a jet with < 10 mm Aortic valve not show severe calcification by transthoracic echocardiography Ascending aortic diameter (Valsalva sinus or tubular ascending aorta) ≤ 50 mm The patient must give the consent form signed Patients younger than 18 Patients with uncontrolled hypertension and a history or risk of diabetes mellitus Patients who receive statins treatment or other lipid lowering drug or if they have indication to be treated according to the current clinical practice guidelines Previous cardiac surgery or any surgery of other segments of the aorta Previous aortic dissection and/or aortic coarctation NYHA functional class III or IV Presence or antecedent of liver failure (transaminase > 2 fold the superior limit of normal levels according to local laboratory), renal failure (creatinine clearance < 30ml/min or creatinine > 2.5mg/dl), myopathy or creatine kinase levels > 5 fold the superior limit of normality, or other gastrointestinal, hematologic or endocrine diseases or any other situation that according to the investigator could affect the study treatment evaluation Hypersensitivity, intolerance or contraindication to any component of the study drug or to the contrast used in CT Pregnancy, breastfeeding or desire for pregnancy during the study period. A negative pregnancy test (negative gonadotropin) will be required in all fertile women to participate in the study Participation in another drug study

2

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 18.0-999.0, Aortic Valve Disease Aortic Stenosis ≥18 years of age aortic stenosis / mixed aortic stenosis and aortic insufficiency SAVR+CABG (1-4 distal anastomoses) Log. EuroSCORE ≥6 NYHA Class ≥II (i.a.) pure aortic insufficiency pre-existing prosthetic heart valve or ring congenital true bicuspid / unicuspid aortic valve LVEF <20%

1

48 M with a h/o HTN hyperlipidemia, bicuspid aortic valve, and tobacco abuse who presented to his cardiologist on [**2148-10-1**] with progressive SOB and LE edema. TTE revealed severe aortic stenosis with worsening LV function. EF was 25%. RV pressure was 41 and had biatrial enlargement. Noted to have 2+ aortic insufficiency with mild MR. He was sent home from cardiology clinic with Lasix and BB (which he did not tolerate), continued to have worsening SOB and LE edema and finally presented here for evaluation. During this admission repeat echo confirmed critical aortic stenosis showing left ventricular hypertrophy with cavity dilation and severe global hypokinesis, severe aortic valve stenosis with underlying bicuspid aortic valve, dilated ascending aorta, mild pulmonary artery systolic hypertension. The patient underwent a preop workup for valvular replacement with preop chest CT scan and carotid US (showing moderate heterogeneous plaque with bilateral 1-39% ICA stenosis). He also underwent a cardiac cath with right heart cath to evaluate his pulm art pressures which showed no angiographically apparent flow-limiting coronary artery disease.

eligible ages (years): 0.0-999.0, Aortic Valve Stenosis Severe aortic stenosis, defined as follows: 1. For symptomatic patients: Aortic valve area ≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), OR mean gradient ≥40 mmHg, OR Maximal aortic valve velocity ≥4.0 m/sec by transthoracic echocardiography at rest 2. For asymptomatic patients Very severe aortic stenosis with an aortic valve area of ≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), AND maximal aortic velocity ≥5.0 m/sec , or mean gradient ≥60 mmHg by transthoracic echocardiography at rest, OR Aortic valve area of ≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), AND a mean gradient ≥40 mmHg or maximal aortic valve velocity ≥4.0 m/sec by transthoracic echocardiography at rest, AND an exercise tolerance test that demonstrates a limited exercise capacity, abnormal BP response, or arrhythmia OR Aortic valve area of ≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), AND mean gradient ≥40 mmHg, or maximal aortic valve velocity ≥4.0 m/sec by transthoracic echocardiography at rest, AND a left ventricular ejection fraction <50%. 2. Documented heart team agreement of low risk for SAVR, where low risk is defined as predicted risk of mortality for SAVR <3% at 30 days per multidisciplinary local heart team assessment. 3. The subject and the treating physician agree that the subject will return for all required post-procedure follow-up visits Any condition considered a contraindication for placement of a bioprosthetic valve (eg, subject is indicated for mechanical prosthetic valve). 2. A known hypersensitivity or contraindication to any of the following that cannot be adequately pre-medicated: 1. aspirin or heparin (HIT/HITTS) and bivalirudin 2. ticlopidine and clopidogrel 3. Nitinol (titanium or nickel) 4. contrast media 3. Blood dyscrasias as defined: leukopenia (WBC <1000 mm3), thrombocytopenia (platelet count <50,000 cells/mm3), history of bleeding diathesis or coagulopathy, or hypercoagulable states. 4. Ongoing sepsis, including active endocarditis. 5. Any percutaneous coronary or peripheral interventional procedure with a bare metal stent within 30 days prior to randomization, or drug eluting stent performed within 180 days prior to randomization. 6. Multivessel coronary artery disease with a Syntax score >22 and/or unprotected left main coronary artery. 7. Symptomatic carotid or vertebral artery disease or successful treatment of carotid stenosis within 10 weeks of Heart Team assessment. 8. Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical hemodynamic support. 9. Recent (within 2 months of Heart Team assessment) cerebrovascular accident (CVA) or transient ischemic attack (TIA). 10. Gastrointestinal (GI) bleeding that would preclude anticoagulation. 11. Subject refuses a blood transfusion. 12. Severe dementia (resulting in either inability to provide informed consent for the trial/procedure, prevents independent lifestyle outside of a chronic care facility, or will fundamentally complicate rehabilitation from the procedure or compliance with follow-up visits). 13. Estimated life expectancy of less than 24 months due to associated non-cardiac co-morbid conditions. 14. Other medical, social, or psychological conditions that in the opinion of the investigator precludes the subject from appropriate consent or adherence to the protocol required follow-up exams. 15. Currently participating in an investigational drug or another device trial (excluding registries). 16. Evidence of an acute myocardial infarction ≤30 days before the trial procedure due to unstable coronary artery disease (WHO criteria). 17. Need for emergency surgery for any reason. 18. Subject is pregnant or breast feeding. 19. Subject is less than legal age of consent, legally incompetent, or otherwise vulnerable 20. Pre-existing prosthetic heart valve in any position. 21. Severe mitral regurgitation amenable to surgical replacement or repair. 22. Severe tricuspid regurgitation amenable to surgical replacement or repair. 23. Moderate or severe mitral stenosis amenable to surgical replacement or repair. 24. Hypertrophic obstructive cardiomyopathy with left ventricular outflow gradient. 25. Bicuspid aortic valve verified by echocardiography, MDCT, or MRI. 26. Prohibitive left ventricular outflow tract calcification. 27. Sinus of Valsalva diameter unsuitable for placement of the self-expanding bioprosthesis. 28. Aortic annulus diameter of <18 or >30 mm. 29. Significant aortopathy requiring ascending aortic replacement. For transfemoral or transaxillary (subclavian) access: 30. Access vessel mean diameter <5.0 mm for Evolut 23R, 26R, or 29R mm TAV, or access vessel mean diameter <5.5 mm for Evolut 34R mm or Evolut PRO TAV. However, for transaxillary (subclavian) access in patients with a patent LIMA, access vessel mean diameter <5.5mm for Evolut 23R, 26R, or 29R mm TAV, or access vessel mean diameter <6.0 mm for the Evolut 34R or Evolut PRO TAV

1