Enhancing the Natriuretic Peptide System in HFpEF

Prior treatment

• Received an investigational drug within 1 month prior to dosing.

Other illness

• Diabetes.
• Myocardial infarction within 6 months of screening.
• Unstable angina within 6 months of screening, or any evidence of myocardial ischemia.
• Significant valvular heart diseases.
• Primary pulmonary hypertension.
• Severe congenital heart diseases.
• Cardiac amyloidosis.
• Fabry disease.
• Second or third degree heart block without a permanent cardiac pacemaker.
• Stroke within 3 months of screening, or other evidence of significantly compromised CNS perfusion.
• Patients with an allergy to iodine;

Lab values

• Hemoglobin \< 9 g/dl
• ALT \> 2 times the upper limit of normal;
• Serum sodium of \< 135 mEq/dL or \> 150 mEq/dL
• Serum potassium of \< 3.5 mEq/dL or \> 5.7 mEq/dL.
• Other acute or chronic medical conditions or laboratory abnormality which may increase the risks associated with study participation or may interfere with interpretation of the data.

Other

• Body mass index \> 35.
• Blood pressure \< 100/60 or \> 180/100 mmHg.
• Hypertrophic, restrictive or obstructive cardiomyopathy.
• Constrictive pericarditis.
• Biopsy proven active myocarditis.
• Sarcoidosis.
• Sustained ventricular tachycardia or ventricular fibrillation within 14 days of screening.
• female subject who is pregnant or breastfeeding.
• In the opinion of the investigator, is unlikely to comply with the study protocol or is unsuitable for any reasons.

• Group 1: HFpEF-CKD-will consist of 30 subjects with:
• Ejection fraction of equal or greater than 55%; and
• Evidence of increased LV filling pressures, including at least 2 of the following: average septal-lateral E/e' ratio ≥ 15; tricuspid regurgitation (TR) peak velocity \> 2:8 m/s;
• Left atrial volume index \>34mL/m\^2 assessed by echocardiography; and
• Previous diagnosis of HF with New York Heart Association (NYHA) functional class II-III symptoms on chronic diuretic therapy; and
• CKD defined as glomerular filtration rate (eGFR) of 15-80 mL/min/1.73 m\^2 as estimated by the Modification of Diet in Renal Disease equation. Subject needs to be on stable dose of chronic diuretic for at least 4 weeks prior to study and maintained on the same dose for the duration of the study. In addition to the exclusion criteria listed below, to ensure a more homogenous group of subjects, we will exclude subjects with Diabetes or BMI \> 35 (because endogenous natriuretic peptide levels are low in obese subjects).
  • Group 2: HFpEF-EI-will consist of 30 subjects with:
• Ejection fraction of equal or greater than 55%; and
• Previous invasive determination of normal pulmonary capillary wedge pressure ≤ 15 mmHg) at rest and ≥ 25 mmHg during exercise; and
• New York Heart Association (NYHA) functional class II-III symptoms; and
• Glomerular filtration rate (eGFR) of \> 50 mL/min/1.73 m\^2 as estimated by the Modification of Diet in Renal Disease equation. In addition to the exclusion criteria listed below, to ensure a more homogenous group of subjects, we will exclude subjects with Diabetes or BMI\>35 (because endogenous natriuretic peptide levels are low in obese subjects).