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Patient is a 45-year-old man with a history of anaplastic astrocytoma of the spine complicated by severe lower extremity weakness and urinary retention s/p Foley catheter, high-dose steroids, hypertension, and chronic pain. The tumor is located in the T-L spine, unresectable anaplastic astrocytoma s/p radiation. Complicated by progressive lower extremity weakness and urinary retention. Patient initially presented with RLE weakness where his right knee gave out with difficulty walking and right anterior thigh numbness. MRI showed a spinal cord conus mass which was biopsied and found to be anaplastic astrocytoma. Therapy included field radiation t10-l1 followed by 11 cycles of temozolomide 7 days on and 7 days off. This was followed by CPT-11 Weekly x4 with Avastin Q2 weeks/ 2 weeks rest and repeat cycle.

eligible ages (years): 18.0-999.0, Solid Tumors Histologically confirmed selected recurrent or metastatic solid tumor types that have progressed after treatment with standard therapies and for which there are no curative intent surgery or chemoradiation Cohort 1: subjects with HNSCC (Head and neck squamous-cell carcinoma) who have not received prior PD-1/PD-L1 inhibitor therapy Cohort 2: subjects with HNSCC who have progressed on or after prior systemic therapy, at least one of which included a PD-1/PD-L1 inhibitor alone or in combination with chemotherapy Cohort 3: subjects with ESCC (Esophageal Squamous Cell Carcinoma) who progressed on or after platinum and/or fluoropyrimidine based regimen Cohort 4: subjects with PDAC (Pancreatic ductal adenocarcinoma) who have progressed on or after gemcitabine or fluoropyrimidine based regimens Cohort 5: subjects with BTC (Biliary tract carcinoma) (intrahepatic or extrahepatic cholangiocarcinoma or gall bladder cancer) who have progressed on gemcitabine or fluoropyrimidine or platinum therapy or a combination of these agents Cohort 6: subjects with Grade IV GBM (Glioblastoma multiforme) or Grade III AA (Anaplastic astrocytoma) (World Health Organization [WHO] criteria) with unequivocal first progression after surgery followed by radiotherapy and temozolomide Documented HPV (Human papilloma virus) / p16 status for oropharyngeal cancer Capable of giving signed informed consent, including compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol Adult participants of legal maturity (18 years or older) Presence of symptomatic central nervous system (CNS) metastases, leptomeningeal metastases or spinal cord compression. Previously-treated lesions should be stable for at least 6 weeks prior to study entry Participants with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment Prior therapy with PD-1/PD-L1 or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, or any form of immunotherapy to treat cancer (except cohort 2) Cohort 2: More than one prior therapy with PD-1/PD-L1 or CTLA-4 inhibitors, or any other form of immunotherapy to treat cancer ESCC patients with apparent tumor invasion on organs located adjacent to the esophageal disease (e.g., the aorta or respiratory tract) patients who have previously received taxane agents for recurrent/metastatic cancer GBM/AA Primary tumors localized to the brainstem or spinal cord Presence of diffuse leptomeningeal disease or extracranial disease

1

Patient is a 45-year-old man with a history of anaplastic astrocytoma of the spine complicated by severe lower extremity weakness and urinary retention s/p Foley catheter, high-dose steroids, hypertension, and chronic pain. The tumor is located in the T-L spine, unresectable anaplastic astrocytoma s/p radiation. Complicated by progressive lower extremity weakness and urinary retention. Patient initially presented with RLE weakness where his right knee gave out with difficulty walking and right anterior thigh numbness. MRI showed a spinal cord conus mass which was biopsied and found to be anaplastic astrocytoma. Therapy included field radiation t10-l1 followed by 11 cycles of temozolomide 7 days on and 7 days off. This was followed by CPT-11 Weekly x4 with Avastin Q2 weeks/ 2 weeks rest and repeat cycle.

eligible ages (years): 18.0-999.0, Advanced Malignancies Is willing and able to provide written informed consent for the trial. Is ≥18 years of age on the day of signing informed consent. Has a histologically confirmed advanced malignancy. Subjects with CTCL [MF or SS] who satisfy the Phase 2a, Cohort 3-specific may be enrolled into the Phase 1 part of the study. Is intolerant of, refuses, or is not eligible for standard antineoplastic therapy. Has at least 1 measurable disease lesion as defined by Is able to safely undergo a baseline tumor tissue biopsy prior to first dose of BI-1808 (on non previously irradiated lesions only). The biopsy must be performed at least 4 weeks following the last dose of tumor directed therapy. Has a life expectancy of ≥12 weeks. Phase 2: 1. Cohort 1 and Cohort 4 (NSCLC): 1. For subjects whose tumors have programmed death-ligand 1 (PD-L1) ≥50%: Required prior therapies will anti-PD-1 therapy as monotherapy. Prior standard of care chemotherapy will be allowed but not required. 2. For tumors with unknown PD-L1 or PD-L1 <50%, required prior therapies will anti PD 1/PD-L1 therapy and standard of care chemotherapy either combined with anti PD 1/PD-L1 therapy or given separately. 3. For subjects with known anaplastic lymphoma kinase, ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) or epidermal growth factor receptor sensitizing molecular rearrangements, 1 line of targeted therapy will be required in addition to anti-PD-1/PD-L1 therapy. Cohort 2 and Cohort 5 (OC): 1. Histologically confirmed and documented recurrent ovarian, fallopian tube, and peritoneal cancer. 2. Platinum-resistant OC (defined as relapsing within 6 months after the last administration of platinum-based chemotherapy) or platinum-refractory OC (defined as progressing while on a platinum-based chemotherapy). 3. At least treated with 1 line of platinum-based chemotherapy. 4. Prior treatment with poly-ADP ribose polymerase inhibitors is allowed. Cohort 3 (CTCL MF or SS) 1. Stage IB-IV MF or SS with failure of at least 1 systemic therapy. 2. No current large cell transformation. 3. Prior therapy No prior allo hematopoietic stem cell transplantation (HSCT); >90 days since auto HSCT; >4 weeks since systemic therapy and >2 weeks since skin-directed therapy. 4. Stable doses of systemic steroids (≤20 mg prednisone equivalent) and of low-to-medium potency topical steroids permitted (no change in preceding 4 weeks). 5. Prior lines with mogamulizumab or vorinostat are allowed Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Has adequate organ function as confirmed by laboratory values - Target population: Phase 1, Parts A and Part B of the trial will recruit subjects with all types of malignancies whose tumors have progressed after standard anticancer treatment. Phase 2a, Parts A and Part B of the trial will recruit patients with NSCLC, OC, and CTCL (specifically MF or SS). The following must be met for a subject to be eligible for in the trial: 1. Is willing and able to provide written informed consent for the trial. 2. Is ≥18 years of age on the day of signing informed consent. 3. Has a histologically confirmed advanced malignancy. Subjects with CTCL [MF or SS] who satisfy the Phase 2a, Cohort 3-specific may be enrolled into the Phase 1 part of the study. 4. Is intolerant of, refuses, or is not eligible for standard antineoplastic therapy. 5. Has at least 1 measurable disease lesion as defined by 6. Is able to safely undergo a baseline tumor tissue biopsy prior to first dose of BI-1808 (on non previously irradiated lesions only). The biopsy must be performed at least 4 weeks following the last dose of tumor directed therapy. 7. Has a life expectancy of ≥12 weeks. 8. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 9. Has adequate organ function as confirmed by laboratory values listed in the table below. Laboratory Test Value Required Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L (criteria must be met without erythropoietin dependency and without packed red blood cell transfusion within last 2 weeks) Absolute neutrophil count ≥1500/µL Platelet count ≥100,000/µL Total bilirubin ≤1.5 ×ULN or direct bilirubin ≤ULN for subjects with total bilirubin levels >1.5 × ULN ALT and AST ≤2.5 × ULN (≤5 × ULN for subjects with liver metastases) Creatinine or Measured or calculated creatinine clearance (per institutional standard [GFR can also be used in place of creatinine or creatinine clearance]) ≤1.5 × ULN or mL/min for subjects with creatinine levels >1.5 × institutional ULN INR or PT aPTT ≤1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants ALT=alanine aminotransferase (serum glutamic-pyruvic transaminase); aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase (serum glutamic-oxaloacetic transaminase); GFR=glomerular filtration rate; INR=international normalized ratio; PT=prothrombin time; ULN=upper limit of normal Phase 2a Expansion Cohort-Specific In addition to the general above, subjects must also meet the for the specific cohort. Additional requirements may be added or modified based on learnings from subjects enrolled in the Phase 1 portion of the trial. 1. Cohort 1 and Cohort 4 (NSCLC): 1. For subjects whose tumors have programmed death-ligand 1 (PD-L1) ≥50%: Required prior therapies will anti-PD-1 therapy as monotherapy. Prior standard of care chemotherapy will be allowed but not required. 2. For tumors with unknown PD-L1 or PD-L1 <50%, required prior therapies will anti PD 1/PD-L1 therapy and standard of care chemotherapy either combined with anti PD 1/PD-L1 therapy or given separately. 3. For subjects with known anaplastic lymphoma kinase, ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) or epidermal growth factor receptor sensitizing molecular rearrangements, 1 line of targeted therapy will be required in addition to anti-PD-1/PD-L1 therapy. 2. Cohort 2 and Cohort 5 (OC): a. Histologically confirmed and documented recurrent ovarian, fallopian tube, and peritoneal cancer. b. Platinum-resistant OC (defined as relapsing within 6 months after the last administration of platinum-based chemotherapy) or platinum-refractory OC (defined as progressing while on a platinum-based chemotherapy). c. At least treated with 1 line of platinum-based chemotherapy. d. Prior treatment with poly-ADP ribose polymerase inhibitors is allowed. 3. Cohort 3 (CTCL MF or SS) 1. Stage IB-IV MF or SS with failure of at least 1 systemic therapy. 2. No current large cell transformation. 3. Prior therapy No prior allo hematopoietic stem cell transplantation (HSCT); >90 days since auto HSCT; >4 weeks since systemic therapy and >2 weeks since skin-directed therapy. 4. Stable doses of systemic steroids (≤20 mg prednisone equivalent) and of low-to-medium potency topical steroids permitted (no change in preceding 4 weeks). 5. Prior lines with mogamulizumab or vorinostat are allowed Needs doses of prednisolone >10 mg daily (or equipotent doses of other corticosteroids) while on the trial other than as premedication. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Has known or suspected hypersensitivity to BI-1808 or pembrolizumab Has cardiac or renal amyloid light-chain amyloidosis. Has received the following: 1. Chemotherapy or small molecule products within 4 weeks of first dose of BI-1808. 2. Radiotherapy within 2 weeks of first dose of BI-1808. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) for non-CNS disease. Subjects who have previously had radiation pneumonitis are not allowed. 3. Immunotherapy within 4 weeks prior to the first dose of BI-1808. Has not recovered from AEs to at least Grade 1 by NCI CTCAE Has had Grade ≥3 autoimmune manifestations of previous immune checkpoint inhibitor treatments (eg, anti-PD-1, anti-PD-L1, or anti-CTLA-4). Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis. Has an active, known, or suspected autoimmune disease. Is a female subject and has the ability to become pregnant (or already pregnant or lactating/breastfeeding). However, those female subjects who have a negative serum or urine pregnancy test before enrollment and agree to use a highly effective method of birth control for 4 weeks before entering the trial, during the trial, and for 12 months after last dose of BI-1808, are considered eligible. Is a male subject with partner(s) of childbearing potential (unless he agrees to take measures not to father children by using 1 form of highly effective contraception [condom plus spermicide gel] during the trial and for 12 months after completing treatment) Has had major surgery from which the subject has not yet recovered. Is at high medical risk because of nonmalignant systemic disease including severe active infections on treatment with antibiotics, antifungals, or antivirals. Has presence of chronic graft versus host disease. Has had an allogenic tissue/solid organ transplant. Has known human immunodeficiency (HIV) and/or history of hepatitis B or C infections, or has a positive test for HIV antibody, hepatitis B antigen/hepatitis B virus DNA or hepatitis C antibody or RNA. A Has a history of active tuberculosis (Bacillus tuberculosis). Has received a live vaccine within 30 days before the first dose of study treatment. Has uncontrolled or significant cardiovascular disease. Has a known psychiatric or substance abuse disorder that would interfere with the subject's ability to cooperate with the requirements of the trial. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator. Is participating or planning to participate in another interventional clinical trial, or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to first dose of study drug. Has a known additional malignancy of another type, with the exception of adequately treated cone biopsied carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) and basal or squamous cell carcinoma of the skin. Male subjects with asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for >1 year prior to start of trial therapy are eligible. Has a diagnosis of primary or acquired immunodeficiency disorder or taking any other form of immunosuppressive therapy within 7 days prior the first dose of study drug

1

Patient is a 45-year-old man with a history of anaplastic astrocytoma of the spine complicated by severe lower extremity weakness and urinary retention s/p Foley catheter, high-dose steroids, hypertension, and chronic pain. The tumor is located in the T-L spine, unresectable anaplastic astrocytoma s/p radiation. Complicated by progressive lower extremity weakness and urinary retention. Patient initially presented with RLE weakness where his right knee gave out with difficulty walking and right anterior thigh numbness. MRI showed a spinal cord conus mass which was biopsied and found to be anaplastic astrocytoma. Therapy included field radiation t10-l1 followed by 11 cycles of temozolomide 7 days on and 7 days off. This was followed by CPT-11 Weekly x4 with Avastin Q2 weeks/ 2 weeks rest and repeat cycle.

eligible ages (years): 18.0-999.0, Grade III Astrocytoma Grade IV Astrocytoma Astrocytoma, Grade IV Astrocytoma, Grade III Histologically proven diagnosis of newly diagnosed supratentorial high-grade astrocytoma (WHO grade III-IV), excluding astrocytoma of brainstem and cerebellum. Gliosarcoma or other subvariants are allowed, including the newly defined "diffuse astrocytoma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV" (Brat et al., 2018) Must have recovered from the effects of surgery, postoperative infection, and other complications. -≥ 18 years of age Eligible for and planning to receive standard fractionated RT of 60 Gy with concurrent TMZ Karnofsky performance status ≥ 60 Available archival formalin-fixed paraffin-embedded (FFPE) tumor blocks Adequate organ and bone marrow function as defined below Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 Platelets ≥ 100,000 cells/mm3 Hemoglobin > 9.0 g/dL (Note: the use of transfusion or other intervention to achieve Hgb >9.0 g/dL is acceptable) Total bilirubin ≤ 1.5 upper limit of normal (ULN) Prior cranial RT or RT to the head and neck where potential field overlap may exist Gliomatosis, leptomeningeal, or metastatic involvement High-grade glioma with known IDH mutation. IDH status could be determined by either immunohistochemistry (IDH1-R132H mutation) or sequencing (including other uncommon variants of IDH1 and IDH2 mutations) as evaluated routinely for clinical diagnosis using a CLIA-approved assay Known severe hypersensitivity to tadalafil or other PDE5 inhibitors, including history of hypotension, priapism (painful erection > 4 hours duration), blindness, or hearing loss during prior treatment with tadalafil or other PDE5 inhibitors Concurrent nitrate, alpha-blocker, guanylate cyclase stimulators (eg, riociguat), or cytochrome P-450 3A4 (CYP3A4) inhibitor use. CYP3A4 inhibitors ketoconazole, itraconazole, and ritonavir Severe, active co-morbidity, defined as follows Unstable angina, angina requiring treatment with nitrates, positive cardiac stress test without evidence of subsequent effective cardiac intervention within 90 days of planned tadalafil administration Myocardial infarction, coronary artery bypass graft surgery, or percutaneous coronary angioplasty or stent within the 90 days of planned tadalafil administration New York Heart Association grade II or greater congestive heart failure within 6 months Serious and inadequately controlled arrhythmia

1

Patient is a 45-year-old man with a history of anaplastic astrocytoma of the spine complicated by severe lower extremity weakness and urinary retention s/p Foley catheter, high-dose steroids, hypertension, and chronic pain. The tumor is located in the T-L spine, unresectable anaplastic astrocytoma s/p radiation. Complicated by progressive lower extremity weakness and urinary retention. Patient initially presented with RLE weakness where his right knee gave out with difficulty walking and right anterior thigh numbness. MRI showed a spinal cord conus mass which was biopsied and found to be anaplastic astrocytoma. Therapy included field radiation t10-l1 followed by 11 cycles of temozolomide 7 days on and 7 days off. This was followed by CPT-11 Weekly x4 with Avastin Q2 weeks/ 2 weeks rest and repeat cycle.

eligible ages (years): 40.0-999.0, Hypertension Systolic blood pressure of 120-159 mmHg or diastolic blood pressure of 80-99 mmHg, whether or not taking blood pressure medications Smartphone with a data plan Valid email address Willing and able to participate in online study videoconferencing visits (Zoom) Reads and writes in English Participating in another related research study Cardiovascular disease event (e.g. stroke, myocardial infarction) in prior 6 months Active cancer Recent hospitalization due to psychiatric condition or event Pregnancy or breastfeeding current or planned during the study period Documented dementia Prisoners Diabetes Diagnosis Heart Failure Diagnosis

0

Patient is a 45-year-old man with a history of anaplastic astrocytoma of the spine complicated by severe lower extremity weakness and urinary retention s/p Foley catheter, high-dose steroids, hypertension, and chronic pain. The tumor is located in the T-L spine, unresectable anaplastic astrocytoma s/p radiation. Complicated by progressive lower extremity weakness and urinary retention. Patient initially presented with RLE weakness where his right knee gave out with difficulty walking and right anterior thigh numbness. MRI showed a spinal cord conus mass which was biopsied and found to be anaplastic astrocytoma. Therapy included field radiation t10-l1 followed by 11 cycles of temozolomide 7 days on and 7 days off. This was followed by CPT-11 Weekly x4 with Avastin Q2 weeks/ 2 weeks rest and repeat cycle.

eligible ages (years): 40.0-999.0, Osteoarthritis, Hip Patients awaiting a total hip replacement Anyone above the age of 40 years Patients with neurologic conditions affecting mobility Patients with cognitive impairments Patients not willing to comply

0

Patient is a 45-year-old man with a history of anaplastic astrocytoma of the spine complicated by severe lower extremity weakness and urinary retention s/p Foley catheter, high-dose steroids, hypertension, and chronic pain. The tumor is located in the T-L spine, unresectable anaplastic astrocytoma s/p radiation. Complicated by progressive lower extremity weakness and urinary retention. Patient initially presented with RLE weakness where his right knee gave out with difficulty walking and right anterior thigh numbness. MRI showed a spinal cord conus mass which was biopsied and found to be anaplastic astrocytoma. Therapy included field radiation t10-l1 followed by 11 cycles of temozolomide 7 days on and 7 days off. This was followed by CPT-11 Weekly x4 with Avastin Q2 weeks/ 2 weeks rest and repeat cycle.

eligible ages (years): 18.0-80.0, Glioma • Patients with a new brain lesion interpreted as suspected infiltrating gliomas including but not limited to (diffuse astrocytoma WHO grade 2; oligodendroglioma WHO grade 2 and 3; anaplastic astrocytoma WHO grade 3; astrocytoma WHO grade 4), OR, patients with prior history of infiltrating glioma scheduled for surgery for tumor biopsy or resection Ages 18-80, including male and female Suitable to undergo contrast-enhanced MRI Negative serum pregnancy test Inability to undergo MRI scan Inability to receive IV contrast secondary to severe reaction or renal insufficiency

2

Patient is a 45-year-old man with a history of anaplastic astrocytoma of the spine complicated by severe lower extremity weakness and urinary retention s/p Foley catheter, high-dose steroids, hypertension, and chronic pain. The tumor is located in the T-L spine, unresectable anaplastic astrocytoma s/p radiation. Complicated by progressive lower extremity weakness and urinary retention. Patient initially presented with RLE weakness where his right knee gave out with difficulty walking and right anterior thigh numbness. MRI showed a spinal cord conus mass which was biopsied and found to be anaplastic astrocytoma. Therapy included field radiation t10-l1 followed by 11 cycles of temozolomide 7 days on and 7 days off. This was followed by CPT-11 Weekly x4 with Avastin Q2 weeks/ 2 weeks rest and repeat cycle.

eligible ages (years): 0.0-999.0, Prostate Hyperplasia Patients with benign prostatic hyperplasia with prostate size (60-100) grams Lower urinary tract symptoms (LUTS) not responding to medical treatment Recurrent prostatic bleeding Recurrent acute urinary retention Chronic urinary retention Patients with coagulation disorders Previous prostatic surgery Previous finasteride administration Bladder pathology (urinary bladder stones bladder mass) Suspected or proved cancer prostate Hepatic or renal impairment Patients unfit for operation eg. Decompensated heart failure, poor chest condition

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): 40.0-79.0, Cardiovascular Diseases Carotid Stenosis Cerebral Arteriosclerosis Cerebrovascular Disorders Heart Diseases Vascular Diseases Men and women with early carotid atherosclerosis and moderately elevated LDL cholesterol between the 60th and 90th percentiles

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, Coronary Disease Heart Diseases Patients undergoing evaluation for CAD who show at least two myocardial segments with wall motion abnormalities on a baseline echocardiogram will be offered to participate in this study. Patients will be adults older than 21 years of age. No pre-menopausal patients who are lactating, are pregnant or potentially pregnant as judged by history, physical examination, ultrasound or urine pregnancy test. No one with unstable angina. No subjects with recent myocardial infarction (less than 1 month). No one with frequent ectopy which precludes adequate imaging acquisition. No subjects with significant hypertension (systolic blood pressure greater than 170 mm Hg). No hypotension with basal sitting systolic arterial pressure less than 100 mm HG confirmed 30 minutes later. No subjects with sinus tachycardia greater than or equal to 100 beats/minute. No atrial fibrillation. No inadequate two-dimensional echocardiographic windows

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 Diseases Mitral Valve Stenosis Aortic Valve 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): 18.0-100.0, Cardiovascular Diseases Heart Diseases Hypertension for probands: Onset of hypertension by age 60 years and the presence of at least one additional hypertensive sibling who was willing to participate. Hypertension was defined according to systolic BP ≥140 or diastolic BP ≥90 in at least two different evaluations, or treatment for hypertension. Volunteers with type 1 diabetes or renal failure were excluded. for subsequent recruits: as indicated in Study Population Description (i.e., based on familial relationships, hypertension and antihypertensive medication status)

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, Atherosclerosis Cardiovascular Diseases Heart Diseases Hypercholesterolemia Hyperlipidemia, Familial Combined All participants related to a patient with familial combined hyperlipidemia

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): 0.0-100.0, Cardiovascular Diseases Heart Diseases Coronary Disease Hypertension Myocardial Ischemia Hypertrophy, Left Ventricular

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): 21.0-999.0, Heart Valve Diseases Patients a) 21 years old or older, with b) MR observed with color flow imaging, c) due to organic mitral valve disease demonstrated by Echocardiography (not normal valve as in functional or ischemic MR), c) isolated (no valve disease other than functional tricuspid regurgitation by Doppler-Echocardiography), d) pure (no mitral stenosis by Doppler-Echocardiography), e) quantifiable by Doppler-Echocardiography, f) of degree * moderate, defined as RVol * 30 mL/beat, g) occurring on native valves, h) with echocardiographic imaging allowing assessment of LA and LV, and i) asymptomatic (or mildly symptomatic but not considered as candidates for immediate surgery by their attending physician)

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): 30.0-80.0, Hyperlipidemia Untreated dyslipidemic (LDL cholesterol >110 mg/dl) subjects with documented atherosclerosis in at least 1 vascular territory: at least moderate (≧4.0mm) aortic atherosclerosis by transesophageal echocardiography or CT/MRI, angiographically documented with coronary artery stenosis (≧50% luminal stenosis), ultrasonographically documented significant extracranial arterial stenosis (≧50%), history of ischemic stroke and transient ischemic attack (TIA), or documented peripheral vascular disease. Acute illness,infection, inflammation or major systemic diseases, T-Bil >3 mg/dl, or Creatinine >3 mg/dl

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 Septal Defects, Ventricular Aortic Valve Insufficiency ventricular septal defect patients receiving total repair from Jan, 1987 to Dec, 2002 follow up more than 1 year after operation complex cardiac lesions

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): 21.0-80.0, Aortic Valve Stenosis Age ≥ 21 years 2. Mild to moderate aortic stenosis 3. No symptoms caused by aortic stenosis 4. Written informed consent to participate in the study 5. Aortic valve leaflet thickening with reduced systolic opening 6. Reduced aortic valve area > 0,8 cm2 and < 1,5 cm2 7. Maximum aortic jet velocity at rest > 2,5 m/s Symptoms caused by aortic stenosis 2. Aortic valve area < 0,7 cm2 3. Severe aortic regurgitation 4. Reduced left ventricular ejection fraction (< 50%) 5. Any valve disease with indication for surgery 6. Coronary artery disease 7. Therapy refractory arterial hypertension 8. Comorbid noncardiac diseases or other reasons which make a regular follow-up impossible 9. Other indication for treatment with statins 10. Women of childbearing potential not using the contraception method(s) specified in this study (specify), as well as women who are breastfeeding 11. Known sensitivity to study drug(s) or class of study drug(s) 12. Patients with severe medical condition(s) that in the view of the investigator prohibits participation in the study (specify as required) 13. Use of any other investigational agent in the last 30 days

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 aortic valve stenosis - familial hypercholesterolemia. -

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, Brain Infarction Transient Ischemic Attack Embolism Patients of both sexes aged ≥ 18 years with the following 4 One of the 3 following ischemic events in the preceding 6 months Transient ischemic attack (TIA) Non-disabling brain infarcts within 6 months after onset Duration of symptoms and signs greater than 24 hours Neurological signs at the time of randomization with a Rankin Scale grade 3 or less With normal computed tomography (CT) scan or CT scan showing a brain infarct (even hemorrhagic infarct) Peripheral embolism Atherosclerotic plaque in the thoracic aorta is defined as wall thickness ≥ 4 mm where the protruding material is the largest, measured at transesophageal echocardiography with multiplane transducer or a plaque less than 4 mm but with mobile component Other causes of embolism Cardiac: endocarditis, atrial fibrillation, intra-cardiac thrombus, valvular prosthesis, rheumatic valvulopathy, left ventricular aneurysm, or ejection fraction less than 25% Atherosclerotic stenosis ipsilateral to the embolic territory: internal carotid artery stenosis greater than 70%, or severe (judgment of the investigator) intracranial stenosis, or scheduled carotid endarterectomy (in that case is possible 30 days after the procedure) Uncommon causes: dissection, vasculitis, procoagulant state, or sickle cell disease Other Intercurrent illness with life expectancy less than 36 months Pregnancy and non-menopausal women Unwillingness to participate Poor medication compliance expected Toxicomania

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, Stroke Coronary Artery Disease Arrhythmia Coronary artery stenosis >50% and either carotid or brain artery stenosis > 50% Creatinine > 2.0 mg/dL Co-morbidity A letter of authorization is not given

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 Patient requires, for the first time, isolated aortic valve replacement due to aortic stenosis or mixed aortic stenosis disease etiology when aortic stenosis is predominant and aortic regurgitation is mild Patient is of legal age in the host country Patient (or legal guardian) has signed a study specific informed consent form Patient was previously operated on with any heart surgery including heart valve replacement or coronary artery bypass graft (CABG); or underwent any form of myocardial revascularization in the past (including stents), etc Patient requires any concomitant heart surgery other than the isolated native aortic heart valve replacement and concomitant ascending aortic replacement (e.g not allowed are: multiple valve replacements or concomitant CABG, pacemaker insertions, or severe septal hypertrophy needing surgical excision, etc.) Patient has unstable angina Patient is in New York Heart Association functional class IV Patient has significant abnormality in wall motion Patient is affected by active endocarditis Patient has a cardiac pacemaker or automatic implanted cardiac defibrillator Patient is affected by acute aortic dissection Patient is in chronic and persistent atrial fibrillation Patient receives hemodialysis therapy

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 Disease Coronary Artery Disease Aortic valve replacement

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, Aortic Valve Stenosis Severe Aortic Stenosis NYHA Class 2-4 CHF Symptoms Age > 75 EuroSCORE > 7 Prohibitively High Risk for Aortic Valve Replacement Surgery as Designated by a Cardiac Surgeon

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, Stable Angina Pectoris Unstable Angina Pectoris Acute Myocardial Infarction unstable angina or acute myocardial infarction, or stable angina pectoris and scheduled for coronary angiography on accepted clinical reasons past coronary artery grafting

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 Left Ventricular Hypertrophy Atrial Fibrillation Symptomatic severe AVS referred for valve replacement (mechanic prosthesis or bioprosthesis) at Odense University Hospital 2. Signed informed consent Severe renal failure (s-creatinine >300 mmole/l) 2. Moderate or severe hepatic failure 3. Moderate or severe LV systolic dysfunction (LVEF<40%) 4. Patients already treated with ACE-I or ARB 5. Known intolerance for ARB 6. Unwilling to participate in the study 7. Poor echocardiographic window 8. Pregnant women

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 Patients >= 18 years of age with pulmonary embolism and cardiogenic shock, defined as a systolic arterial pressure <= 90 mmHg, a drop in systolic arterial pressure >= 40 mmHg for >= 15 minutes, or ongoing administration of catecholamines for systemic arterial hypotension 2. Subtotal or total filling defect in the left and/or right main pulmonary artery due to massive PE, as assessed by chest computed tomography or by conventional pulmonary angiography 3. Right ventricular dysfunction on echocardiography: RV systolic hypokinesis and/or RV dilation (optional) 4. Failed thrombolysis or at least one of the following contraindications to PE thrombolysis present Active bleeding History of intracranial bleeding Surgery, delivery, organ biopsy, puncture of a non-compressible vessel within 10 days History of stroke Gastrointestinal bleeding within 10 days Significant trauma within 15 days Head injury requiring hospitalization within 1 year Active cancer with known hemorrhagic risk Neurosurgery or ophthalmologic surgery within the past year Systemic (paradoxical) embolism in the presence of an atrial septal defect or patent foramen ovale 2. Free floating right heart thrombi, left heart thrombi 3. Life expectancy due to underlying disease less than one month

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): 18.0-70.0, Chagas Cardiomyopathy Chronic Heart Failure Males or females aged 18 to 70 years Heart failure symptoms NYHA functional class II to IV Left ventricular ejection fraction <40% determined by bi-dimensional echocardiography using modified Simpson's rule for ventricular volumes Subjects must be on standard and stable outpatient doses of ACEIs or angiotensin II receptor antagonist for at least four weeks Subjects receiving diuretics must be on a stable dose for at least two weeks Clinical Euvolemia:as evidenced by absence of rales, no pleural effusion or ascitis and no more than minimal peripheric edema CHF due to ischemic heart disease, valvular disease or any other etiology different than CD Severe aortic insufficiency Baseline advanced AV block defined as Mobitz type 2 or third degree AV block Serum creatinine >2.5 mg/dl Resting Heart rate less < 45 bpm Known malignancy and other severe disease which shorten life expectancy < 6 months Subjects with contraindications for beta-blockers: severe obstructive chronic pulmonary disease, asthma, severe pulmonary hypertension, type 1 diabetes mellitus or history of hypoglicemia Suspected or confirmed chronic infectious disease including HIV and hepatitis B History of active substance or alcohol abuse within the last year Clinically significant psychiatric illness which can negatively affect the subject compliance and participation in the 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): 0.0-18.0, Congenital Disorders Choa patients only. Data will be taken from the following patient groups Normal right ventricular (RV) EF with normal RV size and pulmonary insufficiency (PI) Normal RV EF with dilated RV and PI Reduced RV EF with dilated RV with PI Normal RV EF (pre-operatively) dilated RV and pulmonary valve replacement Reduced RV EF (pre-op) dilated RV and pulmonary valve replacement Those who do not conform with

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 Stenosis Aortic Sclerosis significant stenosis (more than 50% diameter stenosis) of one or more coronary arteries aortic sclerosis (group 1) or stenosis (AVA < 1cm2/m2, or mean gradient ≥ 30 mmHg) (group 2) or normal aortic valve (group 3) Rheumatic heart disease (defined as aortic stenosis with commissural fusion + rheumatic mitral valve disease) Status post aortic valve replacement Congenital complex heart disease (except bicuspid aortic valve) Moderate to severe aortic insufficiency (grade > 2/4) Marfan syndrome Infective endocarditis Hypertrophic obstruction cardiomyopathy Acute coronary syndrome within less than three months Severe heart failure, NYHA class IV Severe locomotion disability

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): 10.0-18.0, Congenital Heart Disease Bicuspid Aortic Valve diagnosed with Bicuspid Aortic Valve 15 with aortic root dilatation 15 without aortic root dilatation patients with congenital heart disease, but not bicuspid aortic valve meet for MRI 18 years of age under 10 years and over 19 years of age systemic hypertension for age and height Marfan syndrome on cardiac or vasoactive medications contra-indications to MRI such as metallic implants acquired heart disease require sedation

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, Coronary Artery Disease Left Ventricular Dysfunction Sudden Cardiac Death Randomized Arm 1. Evidence of Coronary Artery Disease (CAD)a. 2. Evidence of prior Myocardial Infarction defined by either: A. Clinical history of prior myocardial infarction OR B. Mild-moderate systolic LV dysfunction with an EF ≤50% 3. LVEF>35% by any current standard evaluation technique (e.g., echocardiogram, MUGA, angiography). • Patients who have an EF between 30-35% and NYHA Class I heart failure who do not have a history of ventricular tachyarrhythmias, or inducible ventricular tachycardia during electrophysiological (EP) testing can be enrolled (Target Population). 4. CE-MRI measure of infarct mass > 10% of LV mass (as measured by the MRI core lab) • If CE-MRI performed ≤ 40 days after myocardial infarction infarct mass must be ≥ 15% of the LV mass. 5. Patients aged 18 years or above 1. CAD will be confirmed by evidence of one of the following three (3) 1) Prior myocardial infarction, 2) Significant stenosis of a major epicardial vessel (>50% proximal or 70% distal) by coronary angiography, 3) Prior revascularization (percutaneous coronary intervention or coronary artery bypass surgery. Patients may not be randomized until 90 days after revascularization. 2. MI should be documented by the presence of two (2) of the following three (3) 1) Symptoms consistent with myocardial infarction (i.e. chest pain, shortness of breath), 2) Q-waves on electrocardiogram and 3) Elevated cardiac enzymes (CPK elevation > two times or troponin elevation > three times the upper limit of normal for the lab). Patients may not be randomized until 40 days after myocardial infarction History of cardiac arrest or spontaneous or inducible sustained VT (15 beats or more at a rate of 120 BPM or greater)* 2. Unexplained syncope 3. Need for revascularization based on investigator's clinical assessment within the next 12 months (patients may be reevaluated 90 days after revascularization) 4. Currently implanted permanent pacemaker and/or pacemaker/ICD lead 5. Contraindication to a ICD implant (i.e. inadequate venous access, bleeding disorder) 6. Acute or chronic severe renal insufficiency (< 30mL/min/1.73m2); acute renal insufficiency of any severity due to hepato-renal syndrome 7. Current or planned renal or liver transplant 8. End stage renal disease on hemodialysis or peritoneal dialysis 9. Contraindication to CE-MRI or history of allergy to gadolinium-based contrast dye 10. Metal fragments in the eyes or face, implantation of any electronic devices such as (but not limited to) cardiac pacemakers, cardiac defibrillators, cochlear implants or nerve stimulators, surgery on the blood vessels of the brain, body piercing 11. Recent MI (<40 days) or revascularization (<90 days) 12. CVA within 90 days 13. Antiarrhythmic drug therapy for ventricular arrhythmias 14. New York Heart Association CHF functional class IV at enrollment Non-Investigational Registry Evidence of CAD a with either a history of prior myocardial infarction OR any LV dysfunction Evidence of LV dysfunction (ejection fraction) as measured by any current standard screening technique (e.g., echocardiogram, MUGA, angiography).c Clinical CE-MRI within the past 12 months (scheduled or completed) Patients aged 18 years or above CAD will be confirmed by evidence of one of the following three (3) 1) Prior myocardial infarction, 2) Significant stenosis of a major epicardial vessel (>50% proximal or 70% distal) by coronary angiography, 3) Prior revascularization (percutaneous coronary intervention or coronary artery bypass surgery MI should be documented by the presence of two (2) of the following three (3) 1) Symptoms consistent with myocardial infarction (i.e. chest pain, shortness of breath), 2) Q-waves on electrocardiogram and 3) Elevated cardiac enzymes (CPK elevation > two times or troponin elevation > three times the upper limit of normal for the lab) Patients can be enrolled in the registry even if they have received or are about to receive an ICD for primary prevention History of cardiac arrest or spontaneous or inducible sustained VT (15 beats or more at a rate of 120BPM or greater)* Contraindication to CE-MRI or history of allergy to gadolinium-based contrast

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): 18.0-70.0, Angina Chest pain or anginal equivalent symptoms possibly suggestive of symptomatic coronary artery disease. 2. Low-intermediate risk (<75% pretest probability) for symptomatic coronary artery disease on basis of age, sex, and quality of reported symptom as classified by the Diamond and Forrester scheme6 3. Referred to Walter Reed Cardiology clinic for an exercise treadmill test as the initial diagnostic test of choice 4. Age equal to or greater than 18 years and less than 70 years 5. Ability to provide informed consent Abnormal baseline electrographic changes that would preclude proper diagnosis of ischemia including preexcitation (Wolff-Parkinson-White) syndrome, a paced ventricular rhythm, more than 1 mm of ST depression at rest, complete left bundle branch block, or for left ventricular hypertrophy, even if they have less than 1 mm of baseline ST depression 2. Presence of known pre-existing coronary artery disease (known prior myocardial infarction, EKG evidence of prior infarction, prior angiographic evidence of significant coronary artery disease, history of prior coronary revascularization). 3. Previous outpatient or inpatient evaluation for coronary artery disease to exercise treadmill testing, stress echocardiography or nuclear myocardial perfusion studies within the last three years. 4. Presence of signs or symptoms that are clearly compatible with non-cardiac chest pain, including musculoskeletal, gastrointestinal or neuropathic causes. 5. Renal insufficiency (creatinine >1.5mg/dl) or renal failure requiring dialysis. 6. Baseline heart rate > 100bpm, atrial fibrillation or other markedly irregular rhythm (frequent ectopy, multifocal atrial tachycardia) on baseline ECG. 7. Pregnancy or unknown pregnancy status. 8. Known allergy to iodinated contrast. 9. Inability to tolerate beta-blocking drugs, including patients with reactive airways disease requiring maintenance inhaled bronchodilators or steroids, complete heart block or second-degree atrioventricular block. 10. Patients with hyperthyroidism including Grave's disease and toxic multinodular goiter 11. Computed tomography imaging, or iodinated contrast administration over 50 ml, within the past 48 hours. 12. Unwillingness to withhold ingestion of metformin or commonly used erectile dysfunction medications (Viagra, Cialis, Levitra) for 48 hours prior to MSCT scan. 13. Previous history of radiation therapy to the thorax

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): 5.0-999.0, Cystic Fibrosis Diagnosis of CF by clinical symptoms and positive sweat test or disease inducing mutation Age >5 yrs Proven ability to perform reproducible PFTs FEV1 >25% predicted Steady disease state for 3 months and no decrease in lung function exceeding 10% during that period Colonization Stable concomitant therapy >2 weeks prior to visit 1 and during the study Non-tobacco user of any kind Ability for sputum induction Written informed consent Severe CF with an FEV1 of <25% predicted History of lung transplant Active allergic bronchopulmonary aspergillosis (ABPA) Treatment with additional antibiotics (beyond standard CF treatment) for a period of 14 days before study entry (routine antibiotics permitted) Treatment with additional oral and/or IV steroids (beyond standard CF treatment) for a period of 14 days before study entry (screening day) Known hypersensitivity to plasma products IgA deficiency Uncontrolled hypertension Lung surgery in the previous two years Being on any thoracic surgery waiting list

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, Critical Aortic Stenosis Cohort A 1. Patients must have co-morbidities such that the surgeon and cardiologist Co-PIs concur that the predicted risk of operative mortality is ≥15% and/or a minimum STS score of 10 2. Patient has senile degenerative aortic valve stenosis with echocardiographically derived mean gradient >40 mmHg or jet velocity greater than 4.0 m/s or an initial aortic valve area of < 0.8 cm2 3. Patient is symptomatic from his/her aortic valve stenosis, as demonstrated by NYHA Functional Class II or greater 4. 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 5. The subject and the treating physician agree that the subject will return for all required post-procedure follow-up visits Cohort B All candidates for Cohort B of this study must meet #2, 3, 4, 5 of the above and 6. The subject, after formal consults by a cardiologist and two cardiovascular surgeons agree that medical factors preclude operation, based on a conclusion that the probability of death or serious, irreversible morbidity exceeds the probability of meaningful improvement. Specifically, the probability of death or serious, irreversible morbidity should exceed 50% Evidence of an acute myocardial infarction ≤ 1month before the intended treatment. 2. Aortic valve is a congenital unicuspid or bicuspid valve; or is non-calcified 3. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation >3+). 4. Any therapeutic invasive cardiac procedure performed within 30 days of the index procedure, (or 6 months if the procedure was a drug eluting coronary stent implantation). 5. Pre-existing prosthetic heart valve in any position, prosthetic ring, or severe (greater than 3+) mitral insufficiency

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 Severe aortic stenosis with ejection fraction less than 40% that is schedule to undergo aortic valve replacement Creatinine > 2 More than moderate mitral, tricuspid, or aortic regurgitation Endocarditis Emergent surgery Prior sternotimy

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, Mitral Regurgitation Patients years old or older, with Mitral regurgitation on the basis of Color flow imaging Due to organic disease of the mitral valve on the basis of two-dimensional echocardiography Isolated (no valve disease other than functional tricuspid regurgitation on the basis of Doppler-Echocardiography) Pure (no mitral stenosis by Doppler echocardiography) Quantifiable by Doppler-Echocardiographic methods Of more than mild degree, defined as regurgitant volume * 30 mL/beat Occurring on native valves With Two-dimensional echocardiographic imaging allowing assessment of LV remodeling, and Associated aortic valve disease (more than trace aortic regurgitation by color flow imaging or mean gradient *25 mmHg) Associated mitral stenosis (mean gradient* 5 mmHg, valve area < 1.5 cm2) Associated congenital or pericardial diseases on the basis of Doppler echocardiography Intolerance to either AII blockers or Angiotensin converting enzyme inhibitors Intolerance to iodine contrast material Intolerance to intravenous echographic contrast agents Renal failure with creatinine * 2 mg/dl Blood pressure below 100 mmHg Known renal artery stenosis Ongoing therapy with hydralazine, calcium-entry blocking drugs or angiotensin converting enzyme inhibitors

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 Mild to moderate calcific AS of a tricuspid or bicuspid aortic valve Echocardiographic derived mean pressure gradient >10 mmHg and an aortic valve area of 0.9 to 1.7 cm2 by continuity equation Laboratory evidence of LDL-c>70 mg/dl within 12 months prior to recruitment Left ventricular ejection fraction <50% Valvular area of 0.9 cm2 and a mean gradient >30 mmHg Rheumatic heart disease >Moderate (2+) aortic insufficiency Prior statin therapy to >10 mg of atorvastatin (Lipitor) or >20 mg of other HMG-CoA Reductase Inhibitors (statins) End-stage renal disease (ESRD) History of thoracic radiation Unable or unwilling to sign informed consent Unable to unwilling to return for follow-up Other clinically important renal, pulmonary, hepatic, neurological, endocrine, or hematological disorders, vasculitis, or any other situation or medical condition that, in the investigator's opinion, would make survival for the duration of the study unlikely, or would otherwise interfere with optimal participation in the study or produce a significant risk to the patient

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 Insufficiency Aortic Valve Stenosis > 18 years of age Isolated severe aortic stenosis Preserved left ventricular function CABG patients will have normal LV function and mass

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 Scheduled for surgery for aortic stenosis or aortic regurgitation Previous open heart surgery

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, Mitral Valve Insufficiency Heart Failure Symptomatic chronic heart failure, New York Heart Association (NYHA) class II to IIIb Left ventricular ejection fraction of 0.35 due to non-ischemic etiology Evidence by transthoracic echocardiography (TTE) of moderate or severe MR without obvious primary mitral valve pathology Peak VO2 less than or equal to 22 ml/kg/min, as obtained at study entry Optimal heart failure therapy for at least 6 months prior to study entry Significant coronary artery disease (greater than 75% lesion in any vessel) by coronary angiography or by a history of a prior heart attack Heart failure due to active myocarditis, congenital heart disease, or obstructive hypertrophic cardiomyopathy Significant ventricular arrhythmias not treated with an implantable defibrillator Primary MR due to significant chordal or leaflet abnormalities by TTE Other hemodynamically relevant stenotic or regurgitant valvular diseases Severe tricuspid regurgitation (TR) (moderate TR is allowed) Severe pulmonic regurgitation (PR) (moderate PR is allowed) Moderate to severe aortic regurgitation Any moderate to severe stenotic lesions using American Heart Association/American College of Cardiology (AHA/ACC) 31 Dependence on chronic inotropic therapy

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): 18.0-75.0, Aortic Regurgitation Moderate-to-severe aortic regurgitation identified by Standard echocardiography Chronic isolated aortic regurgitation Being asymptomatic ( Class 1 according to NYHA) Sinusal rhythm Ejection fraction < 50% Mitral valve disease accompanied to aortic regurgitation (patients with over mild degree of mitral regurgitation and stenosis Aortic stenosis Previous myocardial infarction, or the patients with >50% coronary occlusion in any of the coronary arteries Cardiomyopathies AV conduction disorders Chronic renal or hepatic insufficiency Malignities

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): 50.0-999.0, Heart Failure, Congestive Stage C Heart Failure,[34] which refers to past or current symptoms of heart failure with underlying structural heart disease. Indicated by chronic systolic dysfunction (left ventricle [LV] ejection fraction < 45%), diastolic dysfunction (with echo evidence of diminished compliance of the LV), or both. 2. The patient's cardiologist has recommended or initiated one of the following to prevent decompensation: continuing diuretic treatment, fluid restrictions, and/or restriction/reduction of dietary sodium intake. 3. A family member or members available for study participation with whom patient lives for at least 5 days a week. Emphasis will be given to the closest family members available (i.e., spouse). 4. Subjects are able to give informed consent (see below for due to well-documented dementia or evidence of cognitive impairment). 5. Patients will be age 50 or above. Younger patients may have a different family environment than the most common type of patient who is the target of the FPI intervention Patient has a well-documented diagnosis of dementia 2. Moderate or greater cognitive impairment, based on the Blessed Test of Orientation, Memory, and Concentration (BOMC)[26] score of 16. 3. Patient's family member has BOMC score of 10 (i.e., mild or greater cognitive impairment). 4. Inability to communicate verbally, major visual impairment, uncorrected hearing loss. 5. Patient and/or family member reports "frequent use" illicit substance abuse within the past year. Scores on the AUDIT-C 4 indicating alcohol abuse/dependence.[30] 6. Patient or family member has a current diagnosis of schizophrenia spectrum psychiatric disorder (e.g., schizophrenia, schizoaffective disorder). 7. Patient indicates active suicidal ideation and evaluated as a clinical risk. 8. Patient is in the Philadelphia VAMC home-telehealth program or some other incompatible intervention. 9. Patient has an unstable medical condition that would likely prevent the subject from completing 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): 18.0-999.0, Aortic Valve Stenosis Patients: Age >=18 years Pure isolated degenerative aortic valve stenosis Rheumatic, congenital or post-radiation aortic stenosis Severe renal insufficiency (clearance < 30 ml/min) Aortic insufficiency > or = grade 2/4 Other valve disease > or = grade 2/4 Controls Age >=18 years Known first degree relative with aortic valve stenosis Severe renal insufficiency (clearance < 30 ml/min) Any valve disease > or = grade 2/4

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): 1.0-55.0, Marfan Syndrome Diagnosis of MFS: Ghent and genetically proven defect of the FBN1 gene Age: 12 months to 55 years BSA-adjusted aortic z score = or >2 measured at the level of the sinuses of Valsalva at baseline according to Roman's method, or absolute aortic root diameter >38mm for females and >40 mm for males Prior aortic surgery and/or dissection Aortic root diameter at the level of the sinuses of Valsalva 5 cm Planned aortic surgery within 6 months of enrollment for a rate of ARD progression>5 mm/year even in pts with ARD less than 5 cm Clinical or molecular diagnosis of non-MFS connective tissue diseases sharing some features with MFS (Shprintzen-Goldberg syndrome or Loeys-Dietz syndromes) Un-renounceable therapeutic (systemic hypertension, arrhythmia, ventricular dysfunction, valve regurgitation) use of drugs such as ACE inhibitors, BBs, or calcium-channel blockers Known side-effects while taking an ARB or a BB Intolerance to ARB that resulted in termination of therapy Intolerance to BB that resulted in termination of therapy Renal dysfunction (creatinine level more than upper limit of age-related normal values) Diabetes mellitus

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 consecutive patients with clinically significant, symptomatic aortic stenosis referred to the Helsinki University Central Hospital for consideration of valve replacement surgery Individuals with past myocardial infarction, more than mild mitral valve disease, or previous cardiac surgery will be excluded Patients with heart failure who need urgent surgery or those with hypotension (systolic blood pressure below 110 mm Hg) will be excluded Patients already taking ACE inhibitors or AT-1R antagonists will be excluded from the study population Other the following Complicated diabetes Primary cardiomyopathy Pregnant women, women who are breast feeding, and women of childbearing potential who are not using chemical or mechanical contraception or have a positive serum pregnancy test History of malignancy (unless a documented disease free period exceeding 5-years is present) with the exception of basal cell or squamous cell carcinoma of the skin. Women with a history of cervical dysplasia would be permitted to enter the study provided they had 3 consecutive clear Papanicolaou (Pap) smears Hypothyroidism (TSH 1.5xULN)

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, Renal Artery Stenosis PAD and unilateral ostial >60% RAS and hypertension Conditions which imply RAS stenting (bilateral significant renal disease, single functioning kidney, or patients whose conditions cannot be managed medically or by intervention) Allergy to contrast agents or medication administered for best medical treatment (in particular ASA and statins)

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 Myocardial Infarction Atrial Fibrillation Aortic Stenosis Mitral Regurgitation Idiopathic Cardiomyopathy Candidates for this study must meet ALL of the following Age 18 years or older Be reliable, cooperative and willing to comply with all protocol-specified procedures and sub-study if consented Able to understand and grant informed consent Have at least one of the following (a-g): 1. Coronary Artery Disease (defined as) Coronary artery bypass surgery or Lesion >70% on cardiac or CT angiogram or Percutaneous Coronary Intervention 2. Myocardial infarction (defined as) Diagnosed by elevated troponin level or Diagnosed by ST segment elevations on EKG or Patients will be excluded if ANY of the following conditions apply Previously enrolled in The Genebank at Scripps Clinic Registry Any active bleeding (i.e. GI bleed) Has a significant medical condition which in the investigator's opinion may interfere with the patient's optimal participation in the study Treatment with any investigational agents or devices within 30 days preceding enrollment in the study Been administered or taken any CNS sedatives or depressants in the past 12 hours Been administered or taken any CNS sedatives or depressants in the past 12 hours Subject's qualifying diagnosis is Atrial fibrillation and they are known to have any one of the following: 1. Prior myocardial infarction, coronary artery bypass surgery, or percutaneous coronary intervention 2. EF < 45% at time of diagnosis (excluding tachycardia induced cardiomyopathy diagnosed by a cardiologist) 3. Elevated left atrial pressures (> 20 mmHg) 4. Dilated left atrium (> 4.0 cm or >2.0 cm/m2 body surface) 5. Mitral valve disease with significant valve pathology Mitral regurgitation/insufficiency greater than trace to mild on echo as determined by reading physician Rheumatic mitral valve disease 6. Congestive heart failure prior to diagnosis 7. Hypertrophic cardiomyopathy 8. Diagnosis following coronary artery bypass or valve replacement surgery 9. Post heart transplant 10. Congenital heart disease 11. Diagnosed in setting of hyperthyroid 12. COPD 13. Obstructive sleep apnea

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, Hypertension Females Or Males Over 18 Years Old Patients With Systemic Arterial Hypertension Grade I And II According With The European Society Of Cardiology Left Ventricular hypertrophy Demonstrated By Echocardiography Mild To Moderated hypercholesterolemia Willing To Participate And Sign The Informed Consent Form (ICF) Type 1 Or 2 Diabetes Mellitus Familiar hypercholesterolemia Low Density Lipoprotein-Cholesterol (LDL-C) > 190 mg/dl History Of Myocardial Infarction Or Stable Chronic Angina Triglycerides >250 mg/dl

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): 40.0-999.0, Aortic Valve Stenosis Coronary Disease Patients with aortic valve disease who were scheduled to undergo cardiac surgery Hemodynamic instability Renal insufficiency (serum creatinine level > 133umol/L) Known allergy to iodinated contrast agents Non-treated hyperthyreosis

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, Aortic Stenosis Subjects more than 18 yrs of age through 90 yrs of age Both male and female Patients with moderate or severe isolated Aortic Stenosis Patients who have been referred for both two-dimensional and three dimensional echocardiographies Poor acoustic windows h/o CAD and wall motion abnormality

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): 10.0-999.0, Marfan Syndrome Patients > 10 years Diagnosis of MFS, according to the Ghent and/or genetically proven FBN1 mutations or linkage Consent obtained (written) either for the patient and for his/her parents (<18y Z-score of the aorta at the level of the sinus of Valsalva ≥2 (BSA adjusted) ARB naïve patients Poor echocardiographic window,limiting the accurate measurement of the aortic root Contra-indication for ARB: Bilateral renal artery stenosis, renal function abnormalities (creatinine above normal for age), hyperkalemia Intolerance for ARB (eg angioedema) Pregnancy or breast feeding women Absence of effective contraception Liver function abnormalities Heart Failure Patients included in other clinical trial

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): 70.0-80.0, Aortic Valve Stenosis Ventricular Hypertrophy Age > or = 70 years and < 80 years Severe aortic valve stenosis Indication for aortic valve replacement by bioprothesis Ejection fraction > or = 50% Without treatment with statin No renal failure Informed consent signed Ischemic heart disaese Concomitant surgery to aortic valve replacement Emergency surgery Known intolerance for statin Pregnant woman

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, Vascular Disease Diabetes Hypertension Hyperlipidemia Patients aged 40 to 100 were referred to the hospital with a recent diagnosis of clinically evident arterial disease or a cardiovascular risk factor Those with connective tissue disease, congenital heart disease, cardiomyopathy, congestive heart failure,rheumatic arthritis, secondary causes of hypertension, or active cancer

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): 30.0-80.0, Healthy Volunteers Heart Failure Aortic Stenosis Ischemic Heart Disease Pulmonary Hypertension Symptomatic heart failure Severe valvular aortic stenosis Acute Coronary Syndrome Medically refractory chronic angina pectoris or pulmonary hypertension with preserved left ventricular function Pregnancy Drug abuse Malignant disease Significant disease of other organs including endocrine diseases

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 Recipient Day of Transplant Registered male or female primary heart transplant candidate ≥18 years old Signed, written informed consent document and authorization to use and disclose protected health information Donor Hearts <60 years old Mean systolic blood pressure >60 mmHg at the time of final heart assessment Satisfactory echocardiography assessment defined as Ejection fraction >40% Absence of severe segmental wall motion abnormalities Absence of left ventricular hypertrophy (inter ventricular septum and posterior wall thickness <1.3 cm) Recipient Day of Transplant >4 previous sternotomies Chronic renal failure as defined by chronic serum creatinine >3.0 mg/dL for more than 2 weeks and/or requiring hemodialysis (except for hemodialysis or hemofiltration for fluid overload) Ventilator dependence at the time of transplant Use of a ventricular assist device for > 30 days and the presence of any of the following: sepsis, intracranial hemorrhage or heparin induced thrombocytopenia Panel reactive antibodies > 40% with a positive prospective cross match and/or virtual cross match Use of an investigational drug or device, other than OCS, during the study Simultaneous transplant of non-heart allograft, except for concurrent kidney transplant Donor Hearts Abnormal coronary angiogram defined as >50% stenosis, requiring coronary bypass Donor-to-recipient body weight ratio of <0.6

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): 65.0-75.0, Valvular Aortic Stenosis Patients with severe valvular aortic stenosis and indication for valve replacement Coronary heart disease with indication for additional bypass surgery Leading insufficiency of the valve Age < 65 or > 75 Diseases or conditions leading to additional risks during physical activity (e.g. diabetes, arthrosis, obstructive pulmonary 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): 18.0-999.0, Cystic Fibrosis Diagnosis of CF based on the following: sweat chloride > 60 mEq/L and/or genotype with 2 identifiable mutations consistent with CF; (ΔF508 homozygote, or ΔF508 heterozygote with a second allele known to cause the disease, or two alleles known to cause a class I, II, or III mutation) and one or more clinical features consistent with CF Male and female subjects aged ≥18 years of age A female subject is eligible to participate if she is of Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<140 pmol/L) is confirmatory] Child-bearing potential and agrees to use one of the contraception methods listed in Section 8.1.1 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until one week after the last dose Patients are non-smokers or former smokers by history. Former smokers will be defined as those who have not smoked for ≥6 months. Subjects who only use chewing tobacco products may be enrolled at the discretion of the Investigator and after consultation with the GSK medical monitor In the judgement of the investigator the patient is clinically stable with no change in symptoms or medication, no admissions to hospital, and no intravenous antibiotic therapy for at least 1 month prior to dosing Able to perform lung function tests reliably FEV1 >40% and <110% predicted Excluding periods of exacerbation, FEV1 has not decreased by >15% over the past 12 months Any clinically relevant abnormality identified on the screening medical assessment, laboratory examination, or ECG, that is not associated with cystic fibrosis Neutrophil count <1.5x109 /L In the judgment of the PI, the patient suffers from clinically unstable pancreatic function has clinically significant weight loss( ≥5% after a previously stable period) has recent change in pancreatic enzyme requirements in the past 2 months Recent viral infection (within 4 weeks of dosing), with or without steroid or antibiotic treatment. Presumed viral infection will be determined according to the judgment of the Investigator and no specific testing for virus will be required Subjects unable to produce a technically acceptable sputum sample Clinically significant hepatic impairment Evidence of cirrhosis

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 Male or non-pregnant/non-breast feeding Female ≥ 18 years of age. Women of childbearing potential must have a negative pregnancy test (within 7 days of the procedure) Documented stable angina pectoris Canadian Cardiovascular Society Classification (CCSC) 1-4, unstable angina pectoris with documented ischemia (Braunwald I-II) or documented silent ischemia Left ventricular ejection fraction (LVEF) ≥ 25% Patient is an acceptable candidate for PTCA, stenting, and emergent coronary artery bypass grafting (CABG) Patient is willing to provide informed consent and comply with follow-up visits and testing schedule Target lesion is a de novo lesion in a native coronary artery vessel Initial stenosis is ≥ 50% and < 100% by visual estimate or quantitative coronary angiography (QCA) Reference Vessel Diameter (RVD) is ≥ 2.5 and ≤ 3.25 prior to predilation Target lesion is ≤18mm in length and can be treated in its entirety by no more than 1 single Lutonix Catheter balloon and 1 single BMS Guidewire is able to cross lesion and be placed in distal vessel prior to enrollment History of stroke within past 6 months History of myocardial infarction (MI) or thrombolysis within 72 hours of randomization Prior vascular brachytherapy Uncontrollable allergies to procedure medications, materials or contrast Angiographic evidence of thrombus or dissection within the target vessel Intervention of another coronary lesion ≤ 60 days before index procedure day or planned following index procedure Target lesion is planned to be treated with something other than PTCA and stent (i.e., cutting-balloon, atherectomy, vascular brachytherapy (VBT), etc.) Target lesion is in the Left Main and has excessive calcification or tortuosity or involves bifurcation disease of vessel ≥ 2.5mm Known sensitivity or has received paclitaxel or other antimitogenic agent within 12 months prior to target vessel treatment Patient has any previous intervention (PTCA, stent, etc.) of the target coronary vessel

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 FOR CT Adult patients age 18 years or older Having calcific aortic stenosis being considered for surgical or catheter-based treatment, determined on physical examination or noninvasive imaging such as echocardiography Undergoing diagnostic cardiac catheterization within 1 year Able to provide informed consent FOR OF DATA Adult patients age 18 years or older Having calcific aortic stenosis being considered for surgical or catheter-based treatment, determined on physical examination or noninvasive imaging such as echocardiography Undergoing diagnostic cardiac catheterization within 1 year Having undergone cardiac CT for medical indications meeting the technical requirements of this protocol Able to provide informed consent FOR CT Pregnant or lactating women Decompensated heart failure (unable to lie flat during CT) FOR BETA Advanced atrioventricular block (Mobitz Type II second degree or third degree atrioventricular heart block) Asthma or chronic obstructive pulmonary disease (emphysema) currently treated with beta adrenergic agonists FOR -Severe kidney disease (MDRD estimated Glomerular Filtration Rate < 30mL/min/l.73m(2)). -Request of referring physician or surgeon not to administer iodinated radiocontrast FOR OF DATA: -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, Myocardial Reperfusion Injury Cardiac Output, Low Hypertrophy, Left Ventricular Adult First-time Aortic valve surgery for aortic stenosis +/ coronary artery bypass Diabetes Mellitus Renal impairment with Creatinine greater than or equal to 200micromol/L Atrial fibrillation Amiodarone therapy, recent (in last month) or current Hepatic impairment, significant preoperative Peripheral neuropathy Pregnancy or breast-feeding Emergency surgery or required on clinical grounds within 5 days of referral

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): 18.0-55.0, Musculoskeletal Pain Signed and dated informed consent prior to participation Subjects in good health as determined by the Investigator Age 18-55 Willing to abstain from any physical therapy, hard physical work, exercise or sauna during the study observation period (Screening to Final Visit) For females, subjects of childbearing potential (including peri-menopausal women who have had a menstrual period within 1 year) must be using appropriate birth control (defined as a method which results in a low failure rate, i.e., less than 1% per year when used consistently and correctly, such as implants, injectables, some intrauterine contraceptive devices (IUDs), sexual abstinence, or a vasectomized partner). Oral contraceptive medications are allowed in this study. Female subjects, who are surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy) are also allowed for participation Participation in another clinical study within the last 30 days and during the study Subjects who are inmates of psychiatric wards, prisons, or other state institutions Investigator or any other team member involved directly or indirectly in the conduct of the clinical study Pregnancy or lactation Alcohol or drug abuse Malignancy within the past 2 years with the exception of in situ removal of basal cell carcinoma Skin lesions, dermatological diseases or tattoo in the treatment areas Known hypersensitivity or allergy (including photoallergy) to NSAID´s including celecoxib, sulfonamides and ingredients used in pharmaceutical products and cosmetics including galactose Varicosis, thrombophlebitis and other vascular disorders of the lower extremities Major traumatic lesions (e.g. fracture, tendon or muscle ruptures) of the musculo-skeletal system of the lower limbs

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, HIV Infection Liver Failure Evidence of Liver Transplantation Age ≥ 18 Documented HIV-1 infection, hepatitis B or C co-infection is allowed Plasma viral load at screening visit below 50 copies per mL for at least 6 months Patient with severe liver failure (Meld Score ≥ 15 and/or refractory ascites and/or haemorrhage of digestive tract and/or hepatic encephalopathy) for taking part into period 1 Patient eligible for the liver transplant waiting list or immediate post transplantation for taking part into period 2 Abstinence from alcohol intake for at least 6 months (WHO norm) Withdrawal from intravenous drug use for at least 6 months (methadone substitution is permitted) No ongoing class C opportunistic infection (1993 CDC classification) Patient whose clinical and immunovirological condition allows triple therapy with raltegravir + 2 NRTI or raltegravir + NRTI + enfuvirtide Patient whose HIV population, according to cumulative genotypes carried out on viral RNA together with treatment history (if available and interpreted as per the ANRS-AC11 algorithm version no.19) does not present a profile of mutations associated with resistance to raltegravir and is sensitive to at least two fully active* agents selected among nucleoside/nucleotide reverse transcriptase analogs NRTI (abacavir, lamivudine, emtricitabine, tenofovir) or enfuvirtide *An ARV agent is considered to be fully active if the cumulative genotypes do not show any mutation associated with resistance or any mutation associated with "possible resistance" More than two virological failures during antiretroviral treatment Currently receiving treatment with an agent in development (apart from an authorization for temporary use) Plasma viral load at screening visit ≥ 50 copies per mL during at least the last 6 months Pregnant women, or women liable to become pregnant, breast-feeding women, no contraception, or refusal to use contraception All conditions (including but not limited to alcohol intake and drug use) liable to compromise, in the investigator's opinion, the safety of treatment and/or the patient's compliance with the protocol Patient not having any effective options for NRTI +/ enfuvirtide (defined in the criteria) Ongoing treatment with interferon-alpha or ribavirin for hepatitis C Concomitant medication including one or more agents liable to induce UGT1A1 and reduce raltegravir concentrations anti-infective agents: rifampicin/rifampin

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): 0.5-999.0, HIV Infection Rheumatic Disease Cancer Transplant Pediatrics medically recommended influenza A(H1N1) immunization signed informed consent failure or refusal to provide sufficient blood for antibody determination

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): 14.0-80.0, Bicuspid Aortic Valve Any adult patient ≥ 14 years of age may be recruited regardless of gender, ethnicity or racial group Patients with a diagnosis of bicuspid aortic valve will be enrolled Patients who have had their bicuspid aortic valve previously replaced will also be enrolled Relatives of patients with a diagnosis of bicuspid aortic valve are also welcomed to be enrolled regardless if they have BAV or not, as it is helpful to examine the DNA of first degree relatives Non-English speaking

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): 18.0-59.0, First Episode Psychosis Aged 18-59 years and meet DSM-IV diagnostic for first episode of schizophrenia, schizophreniform disorder, schizoaffective disorder or psychotic disorder NOS as assessed by using the Structured Clinical Interview for DSM-IV, research version Meeting DSM-IV for another axis I diagnosis, including substance abuse or dependence Needing another nonantipsychotic psychotropic medication at enrollment Having a serious or unstable medical illness Pregnant or lactating women or women without adequate contraception will be also excluded

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, Metastatic Melanoma ENTRY Locally advanced or metastatic melanoma Measurable Histologically or cytologically confirmed Surgically incurable HLA-A2 positive and tumors that present HLA-A2.1/p53aa264-272 complexes PRIOR/CONCURRENT If prior Proleukin treatment, must have had clinical benefit No prior systemic cytotoxic chemotherapy for melanoma No concurrent radiotherapy, chemotherapy, or other immunotherapy More than 4 weeks since prior major radiotherapy

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): 19.0-100.0, Cardiovascular Risk Factors Age ≥ 65 years 2. Hypertension (HTN) 3. Diabetes 4. Obesity (body mass index [BMI] >35) 5. Renal insufficiency 6. Tobacco usage 7. Hypercholesterolemia 8. Sleep apnea/heavy snoring at night 9. Clinical diagnosis of CHF as defined by: 1. Dyspnea on exertion 2. Paroxysmal nocturnal dyspnea 3. Orthopnea 4. Elevated jugular venous pressure 5. Pulmonary rales 6. Third heart sound 7. Cardiomegaly or pulmonary edema on chest x-ray 8. Peripheral edema 9. Hepatomegaly 10. Pleural effusion 10. Palpitations/irregular heart beats 11. Chest pain at rest and or exercise 12. Murmur on examination 13. Known coronary artery disease (CAD)/stents/coronary artery bypass graft (CABG) 14. Known valvular disease 15. Known stroke or transient ischemic attacks (TIA) Patients expected to say in the hospital for less than 24 hours. 2. Inability of undergo TEE and TTE 3. Clinical evidence or suspicion of elevated intracranial pressure. 4. Preoperative shock or systemic sepsis 5. Emergency Operation 6. ASA Class V 7. Inability of give informed consent 8. Participation in another clinical trial 9. Prisoner

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): 19.0-70.0, Mitral Regurgitation Criteria:Patients who have Moderate MR documented by color flow doppler: 1. LV ejection fraction > 55%; LV end-systolic dimension < 4.0 cm. 2. Quantifiable by Doppler-Echo equal or more than moderate in severity. 3. Organic disease of the mitral valve demonstrated by echocardiography (not normal valve as in functional or ischemic MR). 4. Isolated MR (no valve disease other than mild tricuspid or pulmonic regurgitation by Doppler-Echocardiography that is often associated with mitral valve prolapse). 5. Asymptomatic (or mildly symptomatic but not considered as candidates for immediate surgery by their attending physician) Significant obstructive coronary artery disease and/or myocardial ischemia on graded exercise test with myocardial perfusion. 2. Previous myocardial infarction or percutaneous coronary intervention. 3. Hypertrophic cardiomyopathy, congenital or pericardial disease. 4. Aortic valve disease (> trace aortic regurgitation or mean gradient > 10 mmHg). 5. Mitral stenosis (mean gradient >5 mmHg, valve area < 1.5 cm2). 6. Intolerance or contraindication to Beta1-AR blockade. 7. Renal failure with creatinine > 2.5 mg/dl. 8. Hypertension requiring medical treatment or renal artery stenosis. 9. Severe comorbidity: liver disease, malignancy, collagen vascular, steroid requirement. 10. Pregnancy (negative pregnancy test and effective contraceptive methods are required prior to enrollment of females of childbearing potential). 11. Uncontrolled (rate > 120/min) or recent (<4 weeks) atrial fibrillation. 12. Routine, regular use of anti-inflammatory medications Related to MRI 1. Severe claustrophobia. 2. Presence of a pacemaker or non-removable hearing aid. 3. Presence of metal clips in the body

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, Mitral Regurgitation 21 years old or older. 2. Severe MR by echo or catheterization without evidence of ischemia requiring surgery documented by cardiac catheterization and/or maximal stress test with myocardial perfusion imaging Significant obstructive coronary artery disease and/or myocardial ischemia on graded exercise test with myocardial perfusion. 2. Previous myocardial infarction. 3. Hypertrophic cardiomyopathy, congenital or pericardial disease. 4. Aortic valve disease (> trace aortic regurgitation or mean gradient > 10 mmHg) 5. Mitral stenosis (mean gradient > 5 mmHg, valve area < 1.5 cm2). 6. Renal failure with creatinine > 2.5 mg/dl. 7. Renal artery stenosis. 8. Severe comorbidity such as liver disease, malignancy, collagen vascular disease, or chronic steroid requirement. 9. Pregnancy (negative pregnancy test and effective contraceptive methods are required prior to enrollment of females of childbearing potential (not post-menopausal or surgically sterilized) Related to MRI 1. Severe claustrophobia. 2. Presence of a pacemaker or non-removable hearing aid. 3. Presence of metal clips in the body

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, Hypertension, Pulmonary Ventricular Dysfunction, Left Male and female patients with symptomatic pulmonary hypertension due to left ventricular systolic dysfunction despite optimized heart failure therapy Types of pulmonary hypertension other than group 2.1 of Dana Point Classification

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 Aortic Stenosis Patients with severe aortic valve stenosis requiring treatment Patient is an acceptable candidate for elective treatment with the Medtronic CoreValve System and in conformity with the local regulatory and medico economical context Patient is above the minimum age as required by local regulations to be participating in a clinical study The patient or legal representative 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") Currently participating in another trial High probability of non-adherence to the follow-up requirements (due to social, psychological or medical reasons) 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): 2.0-21.0, Focal Segmental Glomerulosclerosis Steroid Resistant Nephrotic Syndrome 2-21 years old 2. Biopsy proven FSGS or minimal change with steroid resistance 3. Presence of FSPF (defined as permeability activity >0.5) 4. Presence of nephrotic range proteinuria (urine protein: creatinine ratio >2) at the time of enrollment. 5. Persistent nephrotic range proteinuria despite being on stable immunosuppressive medications (cyclosporine, tacrolimus or mycophenolate mofetil) for at least 12 weeks and/or persistent nephrotic range proteinuria despite being on stable dose of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for 12 weeks. 6. Stable serum creatinine (change of less than 0.3 mg/dl) in the prior 3 months. 7. Schwartz estimated (e) glomerular filtration rate (GFR) >60ml/min/1.73m2 Secondary FSGS 2. Onset of nephrotic syndrome in infancy. 3. Presence of acute renal failure (as defined by acute kidney injury criteria) at the time of enrollment. These children can be enrolled 1 month after resolution of acute renal failure (ARF). 4. Decreasing renal function (persistent increase in serum creatinine of greater than 0.3 mg/dl over baseline in the prior 3 months). 5. Use of another investigational drug 6. Pregnant or unable to comply with contraceptive measures in females of child bearing age 7. eGFR < 60 ml/min per 1.73 m2 8. Children with Galactosemia 9. Children with type 1 or 2 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): 0.0-999.0, Pulmonary Hypertension Diastolic Heart Failure LVEF >50% sinus rhythm and stable clinical condition defined as no changes in therapeutic regimen, or hospitalization in the 6 months preceding recruitment pulmonary artery systolic pressure > 40 mm Hg Patients receiving nitrates A history of pulmonary disease Alternative causes of PH other than cardiac-related Renal failure (creatinine > 2mg/dL) Anemia Pericardial disease Cardiac amyloidosis

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): 18.0-70.0, Aortic Valve Insufficiency Moderate to severe aortic valve insufficiency Asymptomatic Arrhythmia Other severe valve 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): 0.0-999.0, Aortic Valve Insufficiency Aortic Valve Stenosis All consecutive patients from participating hospitals with aortic valve defects who have received one of the following therapies: 1. surgical aortic valve replacement, 2. aortic valve surgery (Ross procedure, David procedure) 3. percutaneous transvascular (retrograde) aortic valve implantation 4. percutaneous transapical aortic valve implantation 5. aortic valve valvuloplasty as principal indication. If the aortic valve insufficiency is concurrent with combination procedures (e.g. coronary artery bypass graft, mitral valve surgery) the aortic valve stenosis must fulfil only the for indication according to the German guidelines (Hamm et al. 2008) No consent from the patient to collection and analysis of data

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 Patients scheduled to undergo a clinically indicated left heart cardiac catheterization will be recruited for the study Suspected acute ST elevation myocardial infarction Acute coronary syndrome with active ongoing chest pain Known or suspected acute aortic dissection Known or suspected cardiac tamponade Known history of unoperated constrictive pericarditis Known or suspected severe aortic stenosis or severe mitral regurgitation Heart rhythm other than sinus rhythm on pre-cath EKG Age < 18 years old Unable to provide 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): 18.0-999.0, Aortic Valve Disease Patients > or = to 18 years of age Presenting with aortic stenosis and to undergo elective aortic valve replacement or repair with or without aortic aneurysm dilation repair Able to sign informed consent document Patients unable to provide informed consent for any reason Patients with predominant aortic regurgitation valve disease Patients with other known connective tissue disorders (such as Marfan's Syndrome, Ehlers-Danlos Syndrome)

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, Cardiac Disease Age => 18 years Men and women with BAV and ascending aorta measuring > 37mm Written informed consent General Study History of cardiac diseases, such as Symptomatic aortic stenosis or aortic regurgitation referred for surgical intervention or asymptomatic severe aortic stenosis or regurgitation based on current guidelines Uncontrolled heart failure, right ventricular failure due to pulmonary hypertension Cardiogenic shock 2. Systolic blood pressure < 100 mmHg 3. History of drug sensitivity, contraindication or adverse reaction to both BB and ARB. Participants who are able to tolerate only a BB will be allocated to the BB vs. placebo arm, and participants who are able to tolerate only an ARB will be allocated to the ARB vs. placebo arm, assuming no other are met. 4. Ascending aorta measuring ≥ 50mm, requiring prophylactic ascending aorta surgery 5. Unable to provide informed consent 6. Need for both BB and ARB for treatment of concomitant medical conditions for which there are no other alternatives. Participants who are taking an ARB which cannot be discontinued will be allocated to the BB arm, and participants who are taking a BB which cannot be discontinued will be allocated to the ARB arm, if no other are met. 7. Prior surgery on ascending aorta or aortic root (balloon valvuloplasty, aortic valvotomy or post coarctation surgery are acceptable) 8. Women who are pregnant at screening visit 9. Contraindication to MRI (claustrophobia, pacemaker, metallic clip in eye or brain) 10. History of any illness which limits the participants' ability to complete the study Additional for BB arm only 1. Heart rate <60 bpm 2. Heart block (1st, 2nd and 3rd degree AV block on ECG), or sick sinus syndrome 3. Asthma of sufficient severity to represent a contraindication to BB use in the judgment of the patient's physician 4. History of severe peripheral artery disorders 5. History of pheochromocytoma without the use of alpha-adrenergic blockers 6. History of metabolic acidosis Additional for ARB arm only 1. Women who are pregnant, lactating or who intend to become pregnant during the course of the study 2. Women who are of childbearing age and are not on reliable, accepted form of birth control 3. Hyperkalemia [serum potassium > 5.5 mmol/L] or renal dysfunction [GFR<45% measured by MDRD) 4. Patients being treated with an ACE Inhibitor that cannot be discontinued. (These patients may be randomized in the BB arm if no are met.) 5. History of bilateral renal artery stenosis or unilateral renal artery stenosis to a solitary kidney 6. History of hepatic insufficiency and hepato-biliary obstruction 7. History of fructose intolerance

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, Multiple Myeloma Each patient must meet all of the following to be enrolled in the study Male or female patients 18 years or older Previously untreated multiple myeloma diagnosed according to standard requiring systemic treatment Patients must have measurable disease Nonsecretory multiple myeloma based upon standard M-component (i.e., measurable serum/urine M-component) is not allowed unless the baseline serum free light chain level (Freelite™) is evaluated Patients must meet clinical laboratory as specified in study protocol Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 Female and male patients MUST adhere to the guidelines of the lenalidomide pregnancy prevention program Must be able to take concurrent aspirin 325 mg daily Voluntary written consent Patients meeting any of the following are not to be enrolled in the study Peripheral neuropathy that is greater or equal to Grade 2 Female patients who are lactating or pregnant Major surgery or radiotherapy within 14 days before the first dose of study drug Serious infection requiring systemic antibiotic therapy within 14 days before the first dose of study drug Diarrhea greater than Grade 1 based on the National Cancer Institute Common Terminology for Adverse Events Central nervous system involvement Evidence of current uncontrolled cardiovascular conditions within the past 6 months Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection

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, Adults With Congenitally Malformed Hearts adults with uncomplicated congenitally malformed hearts (ventricular septal defect, atrial septal defect, coarctation of the aortae, aortic valve stenosis) and complicated congenitally malformed hearts (tetralogy of Fallot, complete transposition of the great arteries, congenitally corrected transposition of the great arteries, Ebstein anomaly and Eisenmenger syndrome) complicating serious co-morbidity such as hereditary heart diseases (age-related coronary heart diseases, valve diseases), other diseases or life-threatening diseases, psychiatric illness or inability to read or understand Swedish

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 EuroSCORE of ≥ 15 % 2. Severe senile degenerative aortic valve stenosis 3. Symptomatic aortic valve stenosis 4. Informed consent 5. Compliance 1. Logistic Euroscore > 40 % 2. Evidence of an acute myocardial infarction 3. Congenital unicuspid or congenital bicuspid valve/ non-calcified 4. Mixed aortic valve 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): 0.0-999.0, Severe Aortic Stenosis Extreme Risk Only: Subject must have comorbidities 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 High Risk Surgical Only: Subject must have comorbidities such that one cardiologist and two cardiac surgeons agree that predicted risk of operative mortality is ≥15% (and predicted operative mortality or serious, irreversible morbidity risk of < 50%) at 30 days Subject has senile degenerative aortic valve stenosis with: mean gradient > 40 mmHg, or jet velocity greater than 4.0 m/sec 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 or simultaneous pressure recordings at cardiac catheterization 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 trial, 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 intended treatment Any percutaneous coronary or peripheral interventional procedure performed within 30 days prior to the intended treatment. (High Risk Surgical Only: Including bare metal stents. Additionally, any drug eluting stents placed within 6 months prior to the index 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) End stage renal disease requiring chronic dialysis or creatinine clearance < 20 cc/min

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 Patients with severe aortic stenosis (AVA < 1.0 cm2) Left ventricular hypertrophy EF ≥ 45% NYHA functional class ≥ 2 Ambulatory (able to perform a 6 minute walk test) Normal sinus rhythm Able and willing to comply with all the requirements for the study Need for ongoing nitrate medications SBP < 110mmHg or MAP < 75mmHg Moderately severe or severe mitral regurgitation Moderately severe or severe aortic regurgitation Creatinine clearance < 30 mL/min Increased risk of priapism Retinal or optic nerve problems or unexplained visual disturbance If a subject requires ongoing use of an alpha antagonist typically used for benign prostatic hyperplasia (BPH) (prazosin, terazosin, doxazosin, or tamsulosin), SBP < 120 mmHg or MAP < 80 mmHg is excluded Need for ongoing use of a potent CYP3A inhibitor or inducer (ritonavir, ketoconazole, itraconazole, rifampin) Cirrhosis

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 Stenosis LV Remodeling, Hypertrophy Patients with moderate to severe aortic stenosis (AVA < 1.5 cm2) Left ventricular hypertrophy Diastolic dysfunction as evidenced by tissue Doppler e' (average of septal and lateral) ≤ 7 cm/s EF ≥ 50% None or minimal symptoms related to aortic stenosis (NYHA ≤ 2) The subject and treating physician are not planning on a valve replacement procedure to occur during the next 6 months Ambulatory Normal sinus rhythm Able and willing to comply with all the requirements for the study Need for ongoing nitrate medications SBP < 110mmHg or MAP < 75mmHg Moderately severe or severe mitral regurgitation Moderately severe or severe aortic regurgitation Contraindication to MRI Creatinine clearance < 30 mL/min Cirrhosis Pulmonary fibrosis Increased risk of priapism Retinal or optic nerve problems or unexplained visual disturbance

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): 19.0-999.0, Symptomatic Severe Aortic Stenosis Patient has senile degenerative aortic valve stenosis with echocardiographically derived mean gradient >40 mmHg or jet velocity greater than 4.0 m/s and an initial aortic valve area (AVA) of ≤0.8 cm2 or indexed EOA < 0.5 cm2/m2 Qualifying echo must be within 60 days of the date of the procedure. 2. Patient is symptomatic from his/her aortic valve stenosis, as demonstrated by NYHA Functional Class II or greater. 3. The heart team agrees (and verified in the case review process) that valve implantation will likely benefit the patient. 4. The study patient or the study 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) of the respective clinical site. 5. The study patient agrees to comply with all required post-procedure follow-up visits including annual visits through 5 years and analysis close date visits, which will be conducted as a phone follow-up. 6. Study patient agrees to undergo surgical aortic valve replacement (SAVR) if randomized to control treatment Evidence of an acute myocardial infarction ≤ 1 month (30 days) before the intended treatment [defined as: Q wave MI, or non-Q wave MI with total CK elevation of CK-MB ≥ twice normal in the presence of MB elevation and/or troponin level elevation (WHO definition)]. 2. Aortic valve is a congenital unicuspid or congenital bicuspid valve, or is non-calcified. 3. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation >3+). 4. Preexisting mechanical or bioprosthetic valve in any position (except NR3). 5. 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). Implantation of a permanent pacemaker or ICD (S3 Cohort only) is not excluded. 6. Heart team assessment of inoperability (including examining cardiac surgeon)

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 Stenosis Disorder of Prosthetic Cardiac Valve Aortic Valve Insufficiency Mitral Valve Insufficiency Hypertrophic Cardiomyopathy Tricuspid Valve Insufficiency patients with mild, moderate, or severe aortic stenosis or aortic or mitral prosthesis. Patients with aortic or mitral regurgitation. patients with hypertrophic cardiomyopathy. Patients with dysfunctional heart valve replacement or repair. Patients with severe tricuspid regurgitation associated with pacemaker or defibrillator lead. Ten normal control patients who will not be required to have echocardiography referred for a clinically indicated echocardiogram; the echo must be of good quality and specifically have patient height, weight, left ventricular outflow tract diameter, subaortic velocity profile by Doppler, and aortic transvalvular continuous wave Doppler velocity profile. For mitral regurgitation and aortic regurgitation the data must be adequate to allow calculation of regurgitant volume. For hypertrophic cardiomyopathy, a recording of left ventricular outflow tract peak velocity must be recorded years or older patients with aortic stenosis, defined as peak aortic velocity greater than 2.5 m/sec with evidence of aortic valve thickening, or an aortic or mitral valve prosthesis able to provide written informed consent Missing or inadequate echocardiographic data inability to give informed consent inability to provide a research blood sample hemoglobin less than 8 severe valvular regurgitation stenosis of the mitral valve

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, Myocardial Infarction Both gender Age > 18 First episode of acute ST-elevation MI An echocardiographic left ventricular ejection fraction less than 50 % Patients who provide written informed consent Contraindications for use of angiotensin receptor blockers (ARBs)(hypersensitivity, pregnancy, bilateral renal artery stenosis) Urgent need for revascularization procedure Severe heart failure (need for intravenous inotropic support) Persistent (> 1 hour) severe hypotension (systolic blood pressure < 90 mmHg) Refractory or potentially lethal arrhythmias Hemodynamically significant right ventricular infarction Primary valvular diseases Congenital heart disease Idiopathic hypertrophic cardiomyopathy Concomitant inflammatory cardiopathy

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 With Preserved Ejection Fraction Pulmonary Disease Left Ventricular Hypertrophy/Hypertension Male or female; Age 18 or older Left ventricular ejection fraction ≥ 50% Symptomatic heart failure or appropriate comparator group Informed consent signed by the subject Symptoms of active ischemia Moderate or severe mitral or aortic stenosis, or severe aortic insufficiency Serum creatinine > 3.0 or chronic hemodialysis Known chronic hepatic disease; defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels > 3.0 times the upper limit of normal as read at the local lab Severe renal dysfunction, i.e. glomerular filtration rate (GFR) <30 ml/min Atrial fibrillation Myocardial infarction within the last year Coronary bypass surgery within the last 6 months Stroke within the last 6 months Known aortic aneurysm

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, Bicuspid Aortic Valve Thoracic Aortic Aneurysm Adults >age 18 years and < 65 years old Able to give informed consent Presence of a bicuspid aortic valve (functional or true bicommisural)and ascending aorta or sinus of Valsalva >4.0cm No contraindications to treatment with Losartan, an Angiotensin II receptor blocker Able to safely participate in a 4 week drug washout period if currently taking an angiotensin II receptor blocker or ACE inhibitor Unable to safely take losartan due to one or more of the following Hypersensitivity to losartan or other angiotensin receptor blockers Pregnancy Nursing mothers History of angioedema Hypotension chronically volume depleted patients Hepatic or renal impairment (Cr>1.5mg/dL) Hyperkalemia (K+>4.8) Renal artery 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): 18.0-999.0, Hypertension Adults aged 18 or older who are receiving ongoing medical care at the clinic (one or more routine visits in the year prior to the visit during the study enrollment period at which their blood pressure is found to be abnormal), are capable of giving consent, and live at a fixed address Must state that they intend to continue to receive care in the clinic Measured BP is greater than 140mm systolic or 90mm diastolic (or 130/80 respectively for "high risk" subjects with: diabetes, established coronary artery disease, prior cardiovascular event, left ventricular hypertrophy by ECG, chronic kidney disease, or diagnosed heart failure) Those whose BP's have returned to normal 1-2 weeks after the original obtained average reading Children, prisoners, institutionalized individuals, or pregnant women

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, Internal Carotid Stenosis Patients (male-female) over 18 y.o Presenting an internal carotid stenosis requiring surgery Mini Mental State Examination >24 during preoperative examination Informed written consent Severe renal failure or requiring dialysis Liver failure or cirrhosis (Child class ≥ B) or prothrombin activity<50% Heart failure (NYHA ≥ III), left ventricular ejection fraction < 40%, acute coronary syndrome Associated surgery Pregnancy Contraindication to MRI History of allergy to modified gelatine or starch History of allergy to adhesive part of electrode

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, Aortic Valve Stenosis Patients who were judged difficult to safely undergo AVR Severe senile degenerative aortic valve stenosis NYHA Functional Class II or greater Signed Informed Consent Aortic valve is congenital unicuspid or bicuspid Annulus size between < 16 mm or > 19 mm 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 Subject must have co-morbidities such that one cardiologist and one 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. 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. Subject has been informed of the nature of the trial and has signed an Informed Consent Form. 5. Subject 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 < 20 mm or > 27 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 > 43 mm (in case of the aortic annulus is 23-27 mm) unless the aortic annulus is 20-23 mm in which case the ascending aorta diameter > 40 mm. 28. Congenital bicuspid or unicuspid valve verified by echocardiography. 29. For patients with native coronary artery dependent circulation

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 With Insufficiency Aortic Valve Stenosis years or older Aortic stenosis or stenosis-insufficiency of aortic valve requiring a planned replacement as indicated in the preoperative evaluation Scheduled to undergo planned aortic valve replacement with or without concomitant coronary bypass surgery, MAZE procedure, septal myectomy, pacemaker/ICD implant and or atrial appendage occlusion/removal Signed and dated the informed consent form prior to investigation procedures Geographically stable and agrees to attend Follow up assessments at the hospital of surgical services for a maximum of 5 years Pure aortic insufficiency Requires emergency surgery Aneurysm of the aortic root and/or ascending aorta requiring surgical intervention Left ventricular ejection fraction of ≤ 25% Active endocarditis within 3 months prior to the scheduled aortic valve replacement surgery Concomitant valve (mitral, tricuspid, or pulmonic) disease requiring repair with an annuloplasty ring or replacement with prosthesis Prior mitral, tricuspid or pulmonic valve surgery, which included implantation of a bioprosthetic valve, mechanical valve, or annuloplasty ring Myocardial infarction (MI) within 1 month prior to the scheduled aortic valve replacement surgery Previously implanted with Aortic valve; alcohol or drug abuser Disease limiting life expectancy to less than 12 months

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, Carotid Artery Stenosis Aortic Calcification Group A patients, age 40-99 years, that had a CT scan for any indication Group B - patients with severe carotid artery stenosis, that indicated for treatment Group A age <40 years Group B carotid artery stenosis, without intention-to-treat

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, Symptomatic Aortic Stenosis Subject has given written study Informed Consent for participation prior to procedure. 2. Subject is ≥ 18 years of age or legal age in host country. 3. Subject's aortic annulus diameter meets the range indicated in the Instructions for use as measured by echocardiogram (echo) or CT conducted within the past 90 days. 4. Subject has senile degenerative aortic stenosis with echocardiography (echo) derived mean gradient >40mmHg or jet velocity greater than 4.0 m/s or an initial valve area of <1.0 cm2 (or aortic valve area index ≤ 0.6 cm2/m2). (Baseline measurement taken by echo within 30 days of procedure). 5. Subject has symptomatic aortic stenosis as demonstrated by NYHA Functional Classification of II or greater. 6. Subject is deemed high operable risk and suitable for TAVI per the medical opinion of the Subject Selection Committee (See Section 3.1 for the definition of the Subject Selection Committee) 7. Subject's predicted operative mortality or serious, irreversible morbidity risk is <50% at 30 days. 8. In the opinion of the Subject Selection Committee and based upon angiographic measurements, the subject has suitable peripheral vessels and aorta to allow for access of the 18 French delivery system. 9. Subject has structurally normal cardiac anatomy. 10. Subject is willing and able to comply with all required follow-up evaluations Subject has a history of a cerebral vascular accident (CVA) or transient ischemic attack (TIA) within the past 6 months (≤180 days) of the index procedure. 2. Subject has carotid artery disease requiring intervention. 3. Subject has evidence of a myocardial infarction (MI) within the past 6 months (≤180 days) of the index procedure. 4. Subject has hypertrophic cardiomyopathy. 5. Subject has a native aortic valve that is congenitally unicuspid, bicuspid, quadricuspid or non-calcified as seen by echocardiography. 6. Subject has mitral or tricuspid valvular regurgitation (>grade III) or moderate to severe mitral stenosis. 7. Subject has aortic root angulation >70 degrees (horizontal aorta). 8. Subject has a pre-existing prosthetic valve or prosthetic ring in any position. 9. Subject refuses blood transfusion or surgical valve replacement. 10. Subject has left ventricular ejection fraction (LVEF) < 20%. 11. The subject has documented, untreated coronary artery disease (CAD) requiring revascularization. 12. Subject has severe basal septal hypertrophy. 13. Subject has had a percutaneous interventional or other invasive cardiac or peripheral procedure ≤ 14 days of the index procedure. 14. Subject has a history of or has active endocarditis. 15. Subject has echocardiographic evidence of intracardiac mass, thrombus, or vegetation. 16. Subject has hemodynamic instability (requiring inotropic support or mechanical heart assistance). 17. Subject is in acute pulmonary edema or requiring intravenous diuretic therapy to stabilize heart failure. 18. Subject with significant pulmonary disease. 19. Subject has significant chronic steroid use. 20. Subject has a known hypersensitivity or contraindication to anticoagulant or antiplatelet medication. 21. Subject has renal insufficiency as evidenced by a serum creatinine > 3.0 mg/dL (265µmol/L) or end-stage renal disease requiring chronic dialysis. 22. Subject has morbid obesity defined as BMI ≥ 40. 23. Subject's iliac arteries have severe calcification, tortuosity (>two 90 degree bends), diameter <6mm, or subject has had an aorto-femoral bypass. 24. Subject has ongoing infection or sepsis. 25. Subject has blood dyscrasias (leukopenia, acute anemia, thrombocytopenia, history of bleeding diathesis, or coagulopathy). 26. Subject has a current autoimmune disease that, in the opinion of the Principal Investigator precludes the subject from study participation. 27. Subject has significant aortic disease, including aortic abdominal aneurysm (AAA) ≥ 4cm thoracic aneurysm (defined as a maximal luminal diameter of 5 cm or greater) marked tortuosity significant aortic arch atheroma or narrowing of the abdominal or thoracic aorta severe tortuosity of the thoracic aorta. 28. Subject has a pre-existing endovascular stent graft in the supra or infrarenal aorta or pre-existing stent grafts in the ileo-femoral arteries. 29. Subject has an active peptic ulcer or has had gastrointestinal (GI) bleeding within the past 90 days prior to the index procedure. 30. Subject is currently participating in another investigational drug or device study. 31. Subject requires emergency surgery for any reason. 32. Subject has a life expectancy < 12 months. 33. Subject has other medical, social or psychological conditions that, in the opinion of the Subject Selection Committee, preclude the subject from study participation. 34. Subject is suffering from dementia or admitted to a chronic care facility which would fundamentally complicate rehabilitation from the procedure or compliance with follow-up visits. 35. Subject has a known allergy to contrast media, nitinol alloys, porcine tissue, or bovine tissue

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, Ischemic Congestive Heart Failure Willing and able to sign informed consent 2. Age >18 years and < 80 years 3. New York Heart Association (NYHA) Class II-IV 4. Ischemic cardiomyopathy without an acute coronary syndrome during the prior 6 months 5. Left Ventricular Ejection Fraction (LVEF) less than or equal to 40% measured by echocardiography at both local and investigative sites, AND Well-demarcated region of LV systolic dysfunction Left ventricular wall without mural thrombus and of thickness greater than 0.5 cm No significant valvular disease including: Moderate-to-severe mitral regurgitation (3-4+), aorticstenosis (valve area <1.5 cm2), aortic insufficiency (3-4+) 6. Up to date on all age and gender appropriate cancer screening per American Cancer Society Limiting symptoms due to non-CHF causes, such as lung disease, peripheral vascular disease, arthritis or other musculoskeletal disorders 2. Inability to complete a 6-minute walk test for any reason 3. Need for intravenous CHF medications, chronic continuous oxygen therapyor oral steroids, 4. Coronary Artery Bypass Graft (CABG) surgery within 60 days prior to screening 5. Planned revascularization within 4 months following enrollment 6. Aortic aneurysm or dilatation (>3.8 cm by echocardiography or other imaging modality) 7. Peripheral vascular disease at or below the distal aorta that may interfere with catheter use 8. Hemodynamically significant pericardial disease 9. Prior aortic or mitral valve replacement 10. Biventricular pacing device implant within the last 3 months OR whose device is scheduled to be revised following enrollment in this trial 11. Scheduled to receive or history of cardiac transplant, surgical remodeling procedure, left ventricular assist device 12. Stroke within 180 days of screening 13. Positive pregnancy test in women of child bearing potential or who are unwilling to use an acceptable method of contraception. 14. Drug or alcohol dependence 15. Life expectancy of less than 1 year 16. History of cancer (other than non-melanoma skin cancer or in situ cervical cancer) in the last five years 17. Exposure to angiogenic therapy (including myocardial laser) or another investigational drug within 60 days of screening, or enrollment in any concurrent study that may confound the results of this study 18. Any factors in the opinion of the Investigator which render the patient unsuitable for participation that will interfere with conduct of the study or interpretation of the results

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 High Risk: Subject must have co-morbidities such that one cardiologist and two cardiac surgeons agree that predicted risk of operative mortality is ≥15% (and predicted operative mortality or serious, irreversible morbidity risk of < 50%) at 30 days. OR Extreme Risk: 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. 2. Subject has senile degenerative aortic valve stenosis with Mean gradient > 40 mmHg, or jet velocity greater than 4.0 m/sec 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 or simultaneous pressure recordings at cardiac catheterization 3. Subject is symptomatic from his/her aortic valve stenosis, as demonstrated by New York Heart Association (NYHA) Functional Class II or greater. 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. 5. The subject and the treating physician agree that the subject will return for all required post-procedure follow-up visits Clinical 1. Evidence of an acute myocardial infarction ≤ 30 days before the intended treatment. 2. Any percutaneous coronary or peripheral interventional procedure performed within 30 days prior to the MCS TAVI procedure including bare metal and drug eluting stents. 3. Blood dyscrasias as defined: leukopenia (WBC < 1000mm3), thrombocytopenia (platelet count <50,000 cells/mm3), history of bleeding diathesis or coagulopathy. 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 or creatinine clearance < 20 cc/min. 10. Active GI bleeding that would preclude anticoagulation. 11. A known hypersensitivity or contraindication to any of the following which cannot be adequately pre-medicated Aspirin Heparin (HIT/HITTS) and bivalirudin Nitinol (titanium or nickel) Ticlopidine and clopidogrel Contrast media 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. 18. Symptomatic carotid or vertebral artery disease. Anatomical 19. High Risk:Native aortic annulus size < 20 mm or > 29 mm per the baseline diagnostic imaging (until 23mm valve enrollment completion/closure in the CoreValve® US Pivotal Trial-High Risk Cohort) OR Extreme Risk: Native aortic annulus size < 18 mm or > 29 mm per the baseline diagnostic imaging. (High risk and extreme risk upon 23mm valve enrollment completion/closure in the CoreValve® US Pivotal Trial-High Risk Cohort) 20. Pre-existing prosthetic heart valve any position. 21. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation (3-4+)). 22. Moderate to severe (3-4+) or severe (4+) mitral or severe (4+) tricuspid regurgitation. 23. Moderate to severe mitral stenosis. 24. Hypertrophic obstructive cardiomyopathy. 25. Echocardiographic evidence of new or untreated intracardiac mass, thrombus or vegetation. 26. Severe basal septal hypertrophy with an outflow gradient. 27. Aortic root angulation (angle between plane of aortic valve annulus and horizontal plane/vertebrae) > 70° (for femoral and left subclavian/axillary access) and > 30° (for right subclavian/axillary access). 28. Ascending aorta diameter >43 mm if the aortic annulus diameter is 23-29 mm; ascending aortic diameter > 40 mm if the aortic annulus diameter is 20-23 mm; or an ascending aorta diameter > 34 mm if the aortic annulus diameter is 18-20 mm (Extreme Risk only until 23 mm valve enrollment completion/closure in the CoreValve® US Pivotal Trial-High Risk Cohort). 29. Congenital bicuspid or unicuspid valve verified by echocardiography. 30. Sinus of valsalva anatomy that would prevent adequate coronary perfusion. Vascular 31. Transarterial access not able to accommodate an 18Fr sheath

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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): 50.0-90.0, Aortic Stenosis age 21 years native aortic valve leaflet thickening with reduced systolic opening on two-dimensional echocardiography and an aortic jet velocity at rest between 2.8 and 3.1 m/s or a valve area calculated by the continuity equation of 1.7 to 1.5 cm2, evaluated at a heart rate between 60 and 90/ minute and at a systolic arterial pressure of 120-140mmHg at baseline LVEF > 55% (calculated by modified Simpson formula) positive stress test (symptoms including dyspnoea, angina, syncope, ECG pathological changes, WMA) positive pulmonary disease (spirometry) heart failure LVEF < 55% moderate/severe aortic or mitral regurgitation or mitral stenosis, subvalvular or supravalvular AS, dynamic subaortic obstruction CAD (history of MI or coronary artery stenosis on coronary angiography) active endocarditis rhythm other than sinus rhythm severe uncontrolled risk factors for CAD uncontrolled DM

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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): 20.0-70.0, Aortic Stenosis Mild to moderate aortic stenosis defined by peak velocity of aortic jet between 2.0 and 3.5 m/sec Untreated hypertension: systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg Treated hypertension using dihydropiridine calcium channel blockers, ACE inhibitors, ARB or diuretics Patients received no beta-blocker therapy for more than 12 months Symtomatic aortic stenosis: presence of exertional dyspnea, angina or syncope Planned cardiac surgery (e.g., CABG, valve repair or replacement, or aneurysmectomy) or planned major non-cardiac surgery within the study period Stroke or resuscitated sudden death in the past 6 months Evidence of congestive heart failure, or left ventricular ejection fraction < 50% Significant renal disease manifested by serum creatinine > 2.0mg/dL History of intolerance to beta-blocker History of adult asthma manifested by bronchospasm in the past 6 months, or currently taking regular anti-asthmatic medication(s) Moderate or severe aortic regurgitation Atrial fibrillation Female of child-bearing potential who do not use adequate contraception and women who are pregnant or breast-feeding

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