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

Payman Zamani, Scott Akers, Haideliza Soto-Calderon, Melissa Beraun, Maheswara R Koppula, Swapna Varakantam, Deepa Rawat, Prithvi Shiva-Kumar, Philip G Haines, Jesse Chittams, Raymond R Townsend, Walter R Witschey, Patrick Segers, Julio A Chirinos, Payman Zamani, Scott Akers, Haideliza Soto-Calderon, Melissa Beraun, Maheswara R Koppula, Swapna Varakantam, Deepa Rawat, Prithvi Shiva-Kumar, Philip G Haines, Jesse Chittams, Raymond R Townsend, Walter R Witschey, Patrick Segers, Julio A Chirinos

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 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.

Keywords: heart failure; hemodynamics; magnetic resonance imaging; remodeling heart failure; vascular biology; vascular stiffness; vasodilators.

© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1
Figure 1
Arterial tonometry and flow methods for input impedance and wave separation analysis. Carotid tonometry (top left) and pulsed wave Doppler (top right) are used to obtain signal‐averaged pressure and flow waveforms (middle panel). Aortic root characteristic impedance (Zc) is computed in the frequency domain as the mean value of the modulus of higher harmonics (bottom left panel, dashed line). In the middle panel, the flow waveform is displayed in the pressure axis as the flow×Zc. This can be seen as the minimum pulse pressure required to eject the observed flow across the local aortic root impedance, in the complete absence of wave reflections. Additional pressure is related to wave reflections arising from more distal segments. The bottom right panel displays separation of the measured pressure wave into forward (Pf, blue) and backward components (Pb, green) components; the reflection magnitude is computed as the ratio of Pb/Pf. LVOT indicates left ventricular outfow tract.
Figure 2
Figure 2
CONSORT diagram and flow of patients through each study visit. eGFR indicates estimated glomerular filtration rate; HF, heart failure; HTN, hypertension; hydral, hydralazine; ISDN, isosorbide dinitrate; LVEF, left ventricular ejection fraction; PDE5‐I, phosphodiesterase type 5 inhibitor.
Figure 3
Figure 3
Changes in end points as compared with baseline (marginal mean differences with standard error presented). A, Reflection magnitude (RM). B, Characteristic impedance (Zc). C, Forward wave magnitude (Pf). D, Total arterial compliance (TAC). E, Six‐minute walk (6MW) distance. F, Native T1 myocardial relaxation time. Hydral indicates hydralazine; ISDN, isosorbide dinitrate.

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