Vasodilator Therapy for Heart Failure and Preserved Ejection Fraction

The main objective is to test the effect of prolonged therapy (24 weeks) with isosorbide dinitrate ± hydralazine on arterial wave reflections (primary endpoint). Secondary endpoints include left ventricular (LV) mass, fibrosis and diastolic function) and exercise capacity (assessed via the 6-minute walk test) in patients with Heart Failure and Preserved Ejection Fraction (HFPEF). We will also test the hypothesis that the reduction in arterial wave reflections induced by vasoactive therapy will correlate with the improvement in exercise capacity, LV mass, fibrosis and diastolic function. Finally, we will assess whether the hemodynamic response to an acute dose of sublingual nitroglycerin (NTG) can predict the sustained changes in the reflected wave and other hemodynamic parameters in response to chronic vasodilator therapy.


Eligibility Criteria:
Inclusion Criteria:

1. Previous clinical diagnosis of heart failure with current New York Heart Association Class II-IV symptoms.
2. LV ejection fraction \>50% on a clinically indicated echocardiogram or ventriculogram within 12 months prior to consent, in the absence of a change in cardiovascular status, as assessed by the principal investigators.
3. Must have had at least one of the following within the 12 months prior to consent

   1. Hospitalization for decompensated HF
   2. Acute treatment for HF with intravenous loop diuretic or hemofiltration.
   3. Chronic treatment with a loop diuretic for control of HF symptoms.
   4. Chronic diastolic dysfunction on echocardiography as evidenced by left atrial enlargement or at least stage II diastolic dysfunction.
   5. Documentation of elevated NT-pro BNP levels or other natriuretic peptide marker (BNP, ANP) according to the laboratory and assay upper limit of normal in the previous year.
4. Stable medical therapy as defined by:

   1. No addition or removal of ACE, ARB, beta-blockers, or calcium channel blockers (CCBs) for 30 days.
   2. No change in dosage of ACE, ARBs, beta-blockers or CCBs of more than 100% for 30 days.
   3. No change in diuretic dose for 10 days.

Exclusion Criteria:

1. Rhythm other than sinus rhythm (i.e., atrial fibrillation).
2. Neuromuscular, orthopedic or other non-cardiac condition that prevents patient from walking in a hallway.
3. Non-cardiac condition limiting life expectancy to less than one year, per physician judgment.
4. Current or anticipated future need for nitrate therapy.
5. Valve disease (\> mild aortic or mitral stenosis; \> moderate aortic or mitral regurgitation).
6. Hypertrophic cardiomyopathy.
7. Known infiltrative or inflammatory myocardial disease (amyloid, sarcoid).
8. Pericardial disease.
9. Primary pulmonary arteriopathy.
10. Have experienced a myocardial infarction or unstable angina, or have undergone percutaneous transluminal coronary angiography (PTCA) or coronary artery bypass grafting (CABG) within 60 days prior to consent, or requires either PTCA or CABG at the time of consent.
11. Other clinically important causes of dyspnea such as morbid obesity or significant lung disease defined by clinical judgment or use of steroids or oxygen for lung disease.
12. Systolic blood pressure \< 110 mmHg or \> 180 mm Hg.
13. Diastolic blood pressure \< 40 mmHg or \> 100 mmHg.
14. Resting heart rate (HR) \> 100 bpm.
15. A history of reduced ejection fraction (EF\<50%).
16. Severe renal dysfunction (estimated GFR \<30 ml/min/1.73m2 by modified MDRD equation) GFR (mL/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if African American) (conventional units), which would impede the safe administration of gadolinium for MRI studies contrast.
17. Hemoglobin \<10 g/dL.
18. Patients with known severe liver disease (AST \> 3x normal, alkaline phosphatase or bilirubin \> 2x normal).
19. Patients with a clinically indicated stress test demonstrating significant ischemia within a year of enrollment which was not followed by percutaneous or surgical revascularization.
20. Listed for cardiac transplantation.
21. Allergy to isosorbide dinitrate or hydralazine.
22. Current therapy with phosphodiesterase inhibitors, such as sildenafil, vardenafil or tadalafil, since the combination of nitrates and phosphodiesterase inhibitors can result in severe hypotension.
23. We will also exclude patients who are not suitable candidates for a cardiac MRI by virtue of having the following absolute or relative contraindications: (i) Central nervous system aneurysm clips; (ii) Implanted neural stimulators; (iii) Implanted cardiac pacemaker or defibrillator; (iv) Cochlear implant; (v) Ocular foreign body (e.g. metal shavings); (vi) Other implanted medical devices: (e.g. drug infusion ports); (vii) Insulin pump; (viii) Metal shrapnel or bullet; (ix) Claustrophobia; (x) Extreme obesity rendering the patient unable to fit into narrow-bore scanners; (xi) Unwillingness of the patient to undergo a cardiac MRI. All patients with metallic implants will be individually evaluated prior to MRI.