RESPONDER-HF Trial

Multicenter, Prospective, Randomized, Sham Controlled, Double Blinded Clinical Trial, with; 1:1 randomization

Following supine bicycle exercise hemodynamic assessment to verify eligibility, patients are sedated then randomized to the treatment or control group. Patients in both arms will undergo placement of femoral venous access sheath.

Patients randomized to the treatment arm will undergo a fluoroscopically and intra-cardiac echocardiography (ICE), or transesophageal echocardiography (TEE) guided trans-septal puncture and Corvia Atrial Shunt implant procedure. Patients randomized to the control arm will undergo ICE from the femoral vein or TEE for examination of the atrial septum and left atrium.

Patients will be evaluated at pre-specified time intervals and followed for 5 years.

All patients will be unblinded after the 24 month follow up visit.

Eligibility Criteria:
Inclusion Criteria:

1. Chronic symptomatic heart failure (HF) documented by the following:

   1. Symptoms of HF requiring current treatment with diuretics if tolerated for ≥ 30 days AND
   2. New York Heart Association (NYHA) class II; OR NYHA class III, or ambulatory NYHA class IV symptoms; AND
   3. ≥ 1 HF hospital admission (with HF as the primary, or secondary diagnosis); or treatment with intravenous (IV) diuretics; or intensification of oral diuresis within the 12 months prior to study entry; OR an NT-proB-type Natriuretic Peptide (NT-pro BNP) value \> 150 pg/ml in normal sinus rhythm, \> 450 pg/ml in atrial fibrillation, or a brain natriuretic peptide (BNP) value \> 50 pg/ml in normal sinus rhythm, \> 150 pg/ml in atrial fibrillation within the past 6 months
2. Ongoing stable guideline-directed medical therapy (GDMT) HF management and management of comorbidities according to the 2022 American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines for the Management of Heart Failure. Stable management includes a minimum period of 4 weeks post-hospitalization for any cause, including treatment with IV diuretics
3. Site determined echocardiographic LV ejection fraction ≥ 40% within the past 6 months, without documented ejection fraction \< 30% in the 5 years prior.
4. Site determined echocardiographic evidence of diastolic dysfunction documented by one or more of the following:

   1. Left Atrial (LA) diameter \> 4 cm; or
   2. Diastolic LA volume \> 50 or LA volume index \> 28 ml/m2 or
   3. Lateral e' \< 10 cm/s; or
   4. e' \< 8 cm/s; or
5. Site determined elevated pulmonary capillary wedge pressure (PCWP) with a gradient compared to right atrial pressure (RAP) documented by end-expiratory PCWP during supine ergometer exercise ≥ 25 millimeters of mercury (mm Hg), and greater than RAP by ≥ 5 mm Hg.
6. Resting RAP ≤ 14 mmHg
7. Site determined hemodynamic evidence of peak exercise pulmonary vascular resistance (PVR) \< 1.75 Wood units
8. Age ≥ 40 years old
9. Participant has been informed of the nature of the study, agrees to its provisions and has provided written informed consent, approved by the Institutional Review Board (IRB) or Ethics Committee (EC)
10. Participant is willing to comply with clinical investigation procedures and agrees to return for all required follow-up visits, tests, and exams
11. Transseptal catheterization and femoral vein access to the right atrium is determined to be feasible by site interventional cardiology investigator.

Exclusion Criteria:

1. Advanced heart failure defined as one or more of the below:

   1. ACC/AHA/European Society of Cardiology (ESC) Stage D heart failure, non-ambulatory NYHA Class IV HF
   2. Cardiac index \< 2.0 L/min/m2
   3. Inotropic infusion (continuous or intermittent) for EF \< 40% within the past 6 months
   4. Patient is on the cardiac transplant waiting list.
2. Inability to perform 6-minute walk test (distance \< 50 meters), OR 6-minute walk test \> 600m
3. The patient has verified that the ability to walk 6 minutes is limited primarily by joint, foot, leg, hip or back pain; unsteadiness or dizziness or lifestyle (and not by shortness of breath and/or fatigue and/or chest pain)
4. Right ventricular dysfunction, assessed by the site cardiologist and defined as one or more of the following:

   1. More than mild right ventricular (RV) dysfunction as estimated by transthoracic echocardiogram (TTE); OR
   2. TAPSE \< 1.4 cm; OR
   3. Right ventricular (RV) size ≥ left ventricular (LV) size as estimated by TTE; OR
   4. Ultrasound or clinical evidence of congestive hepatopathy; OR
   5. Evidence of RV dysfunction defined by TTE as an RV fractional area change \< 35%.
5. Any implanted cardiac rhythm device
6. Structural heart repair aortic valve replacement (AVR) or mitral valve replacement (MVR) (surgical or percutaneous) within the past 12 months; planned valve intervention in the next 3 months, or presence of hemodynamically significant valve disease as assessed by the site cardiologist and defined as:

   1. Mitral valve disease grade ≥ 3+ mitral regurgitation (MR) or \> mild Mitral Stenosis (MS); OR
   2. Tricuspid valve (TR) regurgitation grade ≥ 2+ TR; OR
   3. Aortic valve disease ≥ 2+ aortic regurgitation (AR) or \> moderate aortic stenosis (AS)
7. Echocardiographic evidence of intra-cardiac mass, thrombus or vegetation
8. Participants with existing or surgically closed (with a patch) atrial septal defects. Participants with a patent foramen ovale (PFO), who meet PCWP criteria despite the PFO, are not excluded
9. Myocardial Infarction (MI) and/or percutaneous cardiac intervention within past 3 months; Coronary Artery Bypass Graft (CABG) surgery in past 3 months or any planned cardiac interventions in the 3 months following enrollment.
10. Known clinically significant un-revascularized coronary artery disease, defined as: coronary artery stenosis with angina or other evidence of ongoing active coronary ischemia
11. Known clinically significant untreated carotid artery stenosis likely to require intervention
12. Atrial fibrillation with resting heart rate (HR) \> 100 beats-per-minute (BPM)
13. Hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy, constrictive pericarditis, cardiac amyloidosis or infiltrative cardiomyopathy (e.g. hemochromatosis, sarcoidosis)
14. History of stroke, transient ischemic attack (TIA), deep vein thrombosis (DVT), or pulmonary emboli within the past 6 months
15. Participant is contraindicated to receive either dual antiplatelet therapy, or an oral anticoagulant; or has a documented coagulopathy
16. Anemia with Hemoglobin \< 10 g/dl
17. Chronic pulmonary disease requiring continuous home oxygen, OR significant chronic pulmonary disease defined as forced expiratory volume (FEV)1 \<1Liter
18. Resting arterial oxygen saturation \< 95% on room air, \<93% when residing at high altitude
19. Currently requiring dialysis; or estimated glomerular filtration rate eGFR \< 25ml/min/1.73 m2 by chronic kidney disease (CKD) CKD-Epi equation
20. Systolic blood pressure \> 170 mm Hg at screening
21. Significant hepatic impairment defined as 3 times upper limit of normal of transaminases, total bilirubin, or alkaline phosphatase
22. Participants on significant immunosuppressive treatment or on systemic steroid treatment
23. Life expectancy less than 12 months for known non-cardiovascular reasons
24. Known hypersensitivity to nickel or titanium
25. Women of childbearing potential
26. Severe obstructive sleep apnea not treated with continuous positive airway pressure (CPAP) or other measures
27. Body Mass Index (BMI) \> 45; BMI 40 - 45 is also excluded unless in the opinion of the investigator, vascular access can be obtained safely
28. Severe depression and/or anxiety
29. Currently participating in an investigational drug or device study that would interfere with the conduct or results of this study. Note: trials requiring extended follow-up for products that were investigational but have since become commercially available are not considered investigational
30. In the opinion of the investigator, the Participant is not an appropriate candidate for the study.