Intervention: ISOSORBIDE MONONITRATE
Trial phase: Phase 2
ATC code: C01DA14
SMILES: [H][C@]12OC[C@@H](O[N+](=O)[O-])[C@@]1([H])OC[C@@H]2O
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 51
Group description: Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN
Eligibility criteria:
Inclusion Criteria:

Age ≥ 50 years
Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea
Ejection fraction (EF) ≥ 50% as determined on imaging study within 12 months of enrollment with no change in clinical status suggesting potential for deterioration in systolic function

Stable medical therapy for 30 days as defined by:

No addition or removal of ACE, Angiotensin receptor blockers (ARBs), beta-blockers, calcium channel blockers (CCBs) or aldosterone antagonists
No change in dosage of ACE, ARBs, beta-blockers,CCBs or aldosterone antagonists of more than 100%

One of the following within the last 12 months

Previous hospitalization for heart failure (HF) with radiographic evidence of pulmonary congestion (pulmonary venous hypertension, vascular congestion, interstitial edema, pleural effusion) or
Catheterization documented elevated filling pressures at rest (LVEDP≥15 or PCWP≥20) or with exercise (PCWP≥25) or
Elevated NT-proBNP (> 400 pg/ml) or BNP (> 200 pg/ml) or
Echo evidence of diastolic dysfunction / elevated filling pressures (at least two) E/A > 1.5 + decrease in E/A of > 0.5 with valsalva Deceleration time ≤ 140 ms Pulmonary vein velocity in systole < diastole (PVs<PVd)sinus rhythm) E/e'≥15 Left atrial enlargement (≥ moderate) Pulmonary artery systolic pressure > 40 mmHg Evidence of left ventricular hypertrophy
LV mass/BSA ≥ 96 (♀) or ≥ 116 (♂) g/m2
Relative wall thickness ≥ 0.43 (♂ or ♀) [(IVS+PW)/LVEDD]
Posterior wall thickness ≥ 0.9 (♀) or 1.0 (♂) cm
No chronic nitrate therapy or infrequent (≤ 1x week) use of intermittent sublingual nitroglycerin within last 3 months
Ambulatory (not wheelchair / scooter / walker / cane dependent)
HF is the primary factor limiting activity as indicated by answering # 2 to the following question:

My ability to be active is most limited by:

Joint, foot, leg, hip or back pain
Shortness of breath and/or fatigue and/or chest pain
Unsteadiness or dizziness
Lifestyle, weather, or I just don't like to be active

9. Body size allows wearing of the accelerometer belt as confirmed by ability to comfortably fasten the test belt provided for the screening process (belt designed to fit persons with BMI 20-40 Kg/m2 but belt may fit some persons outside this range)

10. Willingness to wear the accelerometer belt for the duration of the trial 11. Willingness to provide informed consent

Exclusion Criteria:

Recent (< 3 months) hospitalization for HF
Hemoglobin < 8.0 g/dl
Glomerular filtration rate < 20 ml/min/1.73 m2 on most recent clinical laboratories
SBP < 110 mmHg or > 180 mmHg at consent
Diastolic blood pressure < 40 mmHg or > 100 mmHg at consent
Resting HR > 110 bpm at consent
Previous adverse reaction to nitrates necessitating withdrawal of therapy
Chronic therapy with phosphodiesterase type-5 inhibitors (intermittent use of phosphodiesterase type-5 inhibitors for erectile dysfunction is allowable if the patient is willing to hold for the duration of the trial)
Regularly (> 1x per week) swims or does water aerobics
Significant COPD thought to contribute to dyspnea
Ischemia thought to contribute to dyspnea
Documentation of previous EF < 50%
Acute coronary syndrome within 3 months defined by electrocardiographic changes and biomarkers of myocardial necrosis (e.g. troponin) in an appropriate clinical setting (chest discomfort or anginal equivalent)
Percutaneous coronary intervention, coronary artery bypass grafting or new biventricular pacing within past 3 months
Primary hypertrophic cardiomyopathy
Infiltrative cardiomyopathy (amyloid)
Constrictive pericarditis or tamponade
Active myocarditis
Complex congenital heart disease
Active collagen vascular disease
More than mild aortic or mitral stenosis
Intrinsic (prolapse, rheumatic) valve disease with moderate to severe or severe mitral, tricuspid or aortic regurgitation
Acute or chronic severe liver disease as evidenced by any of the following: encephalopathy, variceal bleeding, INR > 1.7 in the absence of anticoagulation treatment
Terminal illness (other than HF) with expected survival of less than 1 year
Enrollment or planned enrollment in another therapeutic clinical trial in the next 3 months
Inability to comply with planned study procedures
Pregnant women