Isosorbide Dinitrate, With or Without Hydralazine, Does Not Reduce Wave Reflections, Left Ventricular Hypertrophy, or Myocardial Fibrosis in Patients With Heart Failure With Preserved Ejection Fraction

Abstract

BackgroundWave reflections, which are increased in patients with heart failure with preserved ejection fraction, impair diastolic function and promote pathologic myocardial remodeling. Organic nitrates reduce wave reflections acutely, but whether this is sustained chronically or affected by hydralazine coadministration is unknown.Methods and ResultsWe randomized 44 patients with heart failure with preserved ejection fraction in a double‐blinded fashion to isosorbide dinitrate (ISDN; n=13), ISDN+hydralazine (ISDN+hydral; n=15), or placebo (n=16) for 6 months. The primary end point was the change in reflection magnitude (RM; assessed with arterial tonometry and Doppler echocardiography). Secondary end points included change in left ventricular mass and fibrosis, measured with cardiac magnetic resonance imaging, and the 6‐minute walk distance. ISDN reduced aortic characteristic impedance (mean baseline=0.15 [95% CI, 0.14–0.17], 3 months=0.11 [95% CI, 0.10–0.13], 6 months=0.10 [95% CI, 0.08–0.12] mm Hg/mL per second; P=0.003) and forward wave amplitude (Pf, mean baseline=54.8 [95% CI, 47.6–62.0], 3 months=42.2 [95% CI, 33.2–51.3]; 6 months=37.0 [95% CI, 27.2–46.8] mm Hg, P=0.04), but had no effect on RM (P=0.64), left ventricular mass (P=0.33), or fibrosis (P=0.63). ISDN+hydral increased RM (mean baseline=0.39 [95% CI, 0.35–0.43]; 3 months=0.31 [95% CI, 0.25–0.36]; 6 months=0.44 [95% CI, 0.37–0.51], P=0.03), reduced 6‐minute walk distance (mean baseline=343.3 [95% CI, 319.2–367.4]; 6 months=277.0 [95% CI, 242.7–311.4] meters, P=0.022), and increased native myocardial T1 (mean baseline=1016.2 [95% CI, 1002.7–1029.7]; 6 months=1054.5 [95% CI, 1036.5–1072.3], P=0.021). A high proportion of patients experienced adverse events with active therapy (ISDN=61.5%, ISDN+hydral=60.0%; placebo=12.5%; P=0.007).Conclusions ISDN, with or without hydralazine, does not exert beneficial effects on RM, left ventricular remodeling, or submaximal exercise and is poorly tolerated. ISDN+hydral appears to have deleterious effects on RM, myocardial remodeling, and submaximal exercise. Our findings do not support the routine use of these vasodilators in patients with heart failure with preserved ejection fraction.Clinical Trial Registration URL: www.clinicaltrials.gov. Unique identifier: NCT01516346.

Accelerometer-Measured Daily Activity in Heart Failure With Preserved Ejection Fraction

“…In the current analysis, relative to baseline, changes in activity (ADAU or HAPD) with ISMN showed neither a significant nor directional relationship to changes in 6MWD, again suggesting that changes in activity were related to changes in functional capacity utilization rather than changes in functional capacity. More recently, Zamani et al tested a higher dose of organic nitrates (in the form of isosorbide dinitrate) in HFpEF and showed no change in 6MWD but a very high incidence of adverse side effects (60% with ISDN) and study drug discontinuation (10). While this study did not include assessment of daily activity, the findings support our interpretation of the mechanism of decreases in functional performance (daily activity) in the absence of decreases in functional capacity (6MWD).…”

Effects of organic and inorganic nitrate on aortic and carotid haemodynamics in heart failure with preserved ejection fraction

“…Key exclusion criteria were: (1) Clinically significant valve disease (more than mild aortic/mitral stenosis or more than moderate aortic/mitral regurgitation); (2) Atrial fibrillation/flutter; (3) Current nitrate therapy; (4) significant ischemia on stress testing within the past year that was not revascularized; (5) Other clinically important causes of dyspnea; (6) Hypertrophic, infiltrative or inflammatory cardiomyopathy; (7) Pericardial disease; (8) Primary pulmonary arteriopathy; (9) Blood pressure <110/40 mmHg or >180/100 mmHg; (10) Resting heart rate>100 bpm; (11) LV ejection fraction<50% in the past; (12) Adverse reactions to organic nitrates or phosphodiesterase inhibitor use; (13) Severe renal dysfunction (glomerular filtration rate<30 ml/min/1.73m 2 ) or liver disease. In sub-study 2, we utilized very similar inclusion/exclusion criteria, as previously described.…”

“…(7-11) The effects of organic nitrates on pulsatile arterial hemodynamics have not been well characterized in HFpEF. In recent trials in patients with HFpEF, (12, 13) organic nitrates have been poorly tolerated; important side effects of organic nitrate therapy included hypotension and headaches, suggesting adverse effects on the cerebrovascular territory.…”

Deep Phenotyping of Systemic Arterial Hemodynamics in HFpEF (Part 2): Clinical and Therapeutic Considerations

“…In a recent multi-center trial, isosorbide mononitrate reduced outpatient activity in a dose-dependent manner in this population [108]. In another recent trial [109], isosorbide dinitrate, with or without hydralazine, failed to improve wave reflections, LV remodeling, or the 6-min walk distance in HFpEF. Furthermore, in the isosorbide dinitrate-hydralazine arm, an increase in wave reflections at 24 weeks was seen, which was associated with worsened 6-min walk distance and an increased myocardial T1 (assessed by MRI T1 mapping), indicating adverse interstitial remodeling/ fibrosis.…”

“…In particular, the effects of common drugs based on studies in non-HFpEF populations should not be freely extrapolated to HFpEF, since this population (or subsets of it) may demonstrate unexpected responses. For example, whereas organic nitrates have been shown to reduce wave reflection in hypertension, as mentioned above, chronic administration of isosorbide dinitrate in HFpEF did not impact reflection magnitude, whereas the combination of isosorbide dinitrate with hydralazine was associated with increased wave reflections, reduced 6-min distance, and adverse myocardial remodeling in a recent trial [109]. …”