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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

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Abstract
Background-Wave 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 Results-We 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 6months. 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] mmHg/mL per second; P=0.003) and forward wave amplitude (P-f, 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] mmHg, 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.
Keywords
SYMPATHETIC-NERVOUS-SYSTEM, ARTERIAL STIFFNESS, BLOOD-PRESSURE, OLDER, PATIENTS, PULSE-WAVE, DIASTOLIC FUNCTION, SYSTOLIC FUNCTION, NITROGLYCERIN, HYPERTENSION, EXERCISE, heart failure, hemodynamics, magnetic resonance imaging, remodeling, heart failure, vascular biology, vascular stiffness, vasodilators

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Chicago
Zamani, Payman, Scott Akers, Haideliza Soto-Calderon, Melissa Beraun, Maheswara R. Koppula, Swapna Varakantam, Deepa Rawat, et al. 2017. “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.” Journal of the American Heart Association 6 (2).
APA
Zamani, P., Akers, S., Soto-Calderon, H., Beraun, M., Koppula, M. R., Varakantam, S., Rawat, D., et al. (2017). 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. JOURNAL OF THE AMERICAN HEART ASSOCIATION, 6(2).
Vancouver
1.
Zamani P, Akers S, Soto-Calderon H, Beraun M, Koppula MR, Varakantam S, et al. 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. JOURNAL OF THE AMERICAN HEART ASSOCIATION. Hoboken: Wiley; 2017;6(2).
MLA
Zamani, Payman, Scott Akers, Haideliza Soto-Calderon, et al. “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.” JOURNAL OF THE AMERICAN HEART ASSOCIATION 6.2 (2017): n. pag. Print.
@article{8547103,
  abstract     = {Background-Wave 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 Results-We 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 6months. 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] mmHg/mL per second; P=0.003) and forward wave amplitude (P-f, 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] mmHg, 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.},
  articleno    = {e004262},
  author       = {Zamani, Payman and Akers, Scott and Soto-Calderon, Haideliza and Beraun, Melissa and Koppula, Maheswara R. and Varakantam, Swapna and Rawat, Deepa and Shiva-Kumar, Prithvi and Haines, Philip G. and Chittams, Jesse and Townsend, Raymond R. and Witschey, Walter R. and Segers, Patrick and Chirinos, Julio A.},
  issn         = {2047-9980},
  journal      = {JOURNAL OF THE AMERICAN HEART ASSOCIATION},
  language     = {eng},
  number       = {2},
  pages        = {16},
  publisher    = {Wiley},
  title        = {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},
  url          = {http://dx.doi.org/10.1161/JAHA.116.004262},
  volume       = {6},
  year         = {2017},
}

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