Maheswara R Koppula

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

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.

Heart Failure, Left Ventricular Remodeling, and Circulating Nitric Oxide Metabolites.

Background Stable plasma nitric oxide (NO) metabolites (NOM), composed predominantly of nitrate and nitrite, are attractive biomarkers of NO bioavailability. NOM levels integrate the influence of NO‐synthase‐derived NO production/metabolism, dietary intake of inorganic nitrate/nitrite, and clearance of NOM. Furthermore, nitrate and nitrite, the most abundant NOM, can be reduced to NO via the nitrate‐nitrite‐NO pathway. Methods and Results We compared serum NOM among subjects without heart failure (n=126), subjects with heart failure and preserved ejection fraction (HFpEF; n=43), and subjects with heart failure and reduced ejection fraction (HFrEF; n=32). LV mass and extracellular volume fraction were measured with cardiac MRI. Plasma NOM levels were measured after reduction to NO via reaction with vanadium (III)/hydrochloric acid. Subjects with HFpEF demonstrated significantly lower unadjusted levels of NOM (8.0 μmol/L; 95% CI 6.2–10.4 μmol/L; ANOVA P=0.013) than subjects without HF (12.0 μmol/L; 95% CI 10.4–13.9 μmol/L) or those with HFrEF (13.5 μmol/L; 95% CI 9.7–18.9 μmol/L). There were no significant differences in NOM between subjects with HFrEF and subjects without HF. In a multivariable model that adjusted for age, sex, race, diabetes mellitus, body mass index, current smoking, systolic blood pressure, and glomerular filtration rate, HFpEF remained a predictor of lower NOM (β=−0.43; P=0.013). NOM did not correlate with LV mass, or LV diffuse fibrosis. Conclusions HFpEF, but not HFrEF, is associated with reduced plasma NOM, suggesting greater endothelial dysfunction, enhanced clearance, or deficient dietary ingestion of inorganic nitrate. Our findings may underlie the salutary effects of inorganic nitrate supplementation demonstrated in recent clinical trials in HFpEF.

Late Systolic Myocardial Loading Is Associated With Left Atrial Dysfunction in HypertensionCLINICAL PERSPECTIVE

Background— Late systolic load has been shown to cause diastolic dysfunction in animal models. Although the systolic loading sequence of the ventricular myocardium likely affects its coupling with the left atrium (LA), this issue has not been investigated in humans. We aimed to assess the relationship between the myocardial loading sequence and LA function in human hypertension. Methods and Results— We studied 260 subjects with hypertension and 19 normotensive age- and sex-matched controls. Time-resolved central pressure and left ventricular geometry were measured with carotid tonometry and cardiac magnetic resonance imaging, respectively, for computation of time-resolved ejection-phase myocardial wall stress (MWS). The ratio of late/early ejection-phase MWS time integrals was computed as an index of late systolic myocardial load. Atrial mechanics were measured with cine-steady-state free-precession magnetic resonance imaging using feature-tracking algorithms. Compared with normotensive controls, hypertensive participants demonstrated increased late/early ejection-phase MWS and reduced LA function. Greater levels of late/early ejection-phase MWS were associated with reduced LA conduit, reservoir, and booster pump LA function. In models that included early and late ejection-phase MWS as independent correlates of LA function, late systolic MWS was associated with lower, whereas early systolic MWS was associated with greater LA function, indicating an effect of the relative loading sequence (late versus early MWS) on LA function. These relationships persisted after adjustment for multiple potential confounders. Conclusions— A myocardial loading sequence characterized by prominent late systolic MWS was independently associated with atrial dysfunction. In the context of available experimental data, our findings support the deleterious effects of late systolic loading on ventricular–atrial coupling.

Beta‐Blocker Use Is Associated With Impaired Left Atrial Function in Hypertension

Background Impaired left atrial (LA) mechanical function is present in hypertension and likely contributes to various complications, including atrial arrhythmias, stroke, and heart failure. Various antihypertensive drug classes exert differential effects on central hemodynamics and left ventricular function. However, little is known about their effects on LA function. Methods and Results We studied 212 subjects with hypertension and without heart failure or atrial fibrillation. LA strain was measured from cine steady‐state free‐precession cardiac MRI images using feature‐tracking algorithms. In multivariable models adjusted for age, sex, race, body mass index, blood pressure, diabetes mellitus, LA volume, left ventricular mass, and left ventricular ejection fraction, beta‐blocker use was associated with a lower total longitudinal strain (standardized β=−0.21; P=0.008), and lower LA expansion index (standardized β=−0.30; P<0.001), indicating impaired LA reservoir function. Beta‐blocker use was also associated with a lower positive strain (standardized β=−0.19; P=0.012) and early diastolic strain rate (standardized β=0.15; P=0.039), indicating impaired LA conduit function. Finally, beta‐blocker use was associated with a lower (less negative) late‐diastolic strain (standardized β=0.15; P=0.049), strain rate (standardized β=0.18; P=0.019), and a lower active LA emptying fraction (standardized β=−0.27; P<0.001), indicating impaired booster pump function. Use of other antihypertensive agents was not associated with LA function. Conclusions Beta‐blocker use is significantly associated with impaired LA function in hypertension. This association could underlie the increased risk of atrial fibrillation and stroke seen with the use of beta‐blockers (as opposed to other antihypertensive agents) demonstrated in recent trials.