Swapna Varakantam

Pharmacokinetics and Pharmacodynamics of Inorganic Nitrate in Heart Failure With Preserved Ejection Fraction

Rationale: Nitrate-rich beetroot juice has been shown to improve exercise capacity in heart failure with preserved ejection fraction, but studies using pharmacological preparations of inorganic nitrate are lacking. Objectives: To determine (1) the dose–response effect of potassium nitrate (KNO3) on exercise capacity; (2) the population-specific pharmacokinetic and safety profile of KNO3 in heart failure with preserved ejection fraction. Methods and Results: We randomized 12 subjects with heart failure with preserved ejection fraction to oral KNO3 (n=9) or potassium chloride (n=3). Subjects received 6 mmol twice daily during week 1, followed by 6 mmol thrice daily during week 2. Supine cycle ergometry was performed at baseline (visit 1) and after each week (visits 2 and 3). Quality of life was assessed with the Kansas City Cardiomyopathy Questionnaire. The primary efficacy outcome, peak O2-uptake, did not significantly improve (P=0.13). Exploratory outcomes included exercise duration and quality of life. Exercise duration increased significantly with KNO3 (visit 1: 9.87, 95% confidence interval [CI] 9.31–10.43 minutes; visit 2: 10.73, 95% CI 10.13–11.33 minute; visit 3: 11.61, 95% CI 11.05–12.17 minutes; P=0.002). Improvements in the Kansas City Cardiomyopathy Questionnaire total symptom (visit 1: 58.0, 95% CI 52.5–63.5; visit 2: 66.8, 95% CI 61.3–72.3; visit 3: 70.8, 95% CI 65.3–76.3; P=0.016) and functional status scores (visit 1: 62.2, 95% CI 58.5–66.0; visit 2: 68.6, 95% CI 64.9–72.3; visit 3: 71.1, 95% CI 67.3–74.8; P=0.01) were seen after KNO3. Pronounced elevations in trough levels of nitric oxide metabolites occurred with KNO3 (visit 2: 199.5, 95% CI 98.7–300.2 &mgr;mol/L; visit 3: 471.8, 95% CI 377.8–565.8 &mgr;mol/L) versus baseline (visit 1: 38.0, 95% CI 0.00–132.0 &mgr;mol/L; P<0.001). KNO3 did not lead to clinically significant hypotension or methemoglobinemia. After 6 mmol of KNO3, systolic blood pressure was reduced by a maximum of 17.9 (95% CI −28.3 to −7.6) mm Hg 3.75 hours later. Peak nitric oxide metabolites concentrations were 259.3 (95% CI 176.2–342.4) &mgr;mol/L 3.5 hours after ingestion, and the median half-life was 73.0 (interquartile range 33.4–232.0) minutes. Conclusions: KNO3 is potentially well tolerated and improves exercise duration and quality of life in heart failure with preserved ejection fraction. This study reinforces the efficacy of KNO3 and suggests that larger randomized trials are warranted. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02256345

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.

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

To assess the haemodynamic effects of organic vs. inorganic nitrate administration among patients with heart failure with preserved ejection fraction (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.

Inactive Matrix Gla-Protein and Arterial Stiffness in Type 2 Diabetes Mellitus

BACKGROUND Large artery stiffness is increased in diabetes mellitus and causes an excessive pulsatile load to the heart and to the microvasculature. The identification of pathways related to arterial stiffness may provide novel therapeutic targets to ameliorate arterial stiffness in diabetes. Matrix Gla-Protein (MGP) is an inhibitor of vascular calcification. Activation of MGP is vitamin K dependent. We hypothesized that levels of inactive MGP (dephospho-uncarboxylated MGP; dp-ucMGP) are related to arterial stiffness in type 2 diabetes. METHODS We enrolled a multiethnic cohort of 66 participants with type 2 diabetes. Carotid-femoral pulse wave velocity (CF-PWV) was measured with high-fidelity arterial tonometry (Sphygmocor Device). Dp-ucMGP was measured with ELISA (VitaK; The Netherlands). RESULTS The majority of the participants were middle-aged (62 ± 12 years), male (91%), and had a history of hypertension (82%). Average hemoglobin A1C was 7.2% (55 mmol/mol). Mean dp-ucMGP was 624 ± 638 pmol/l and mean CF-PWV was 11 ± 4 m/sec. In multivariable analyses, dp-ucMGP was independently related to African American ethnicity (&bgr; = −0.24, P = 0.005), warfarin use (&bgr; = 0.56, P < 0.001), and estimated glomerular filtration rate (eGFR, &bgr; = −0.32, P < 0.001). Dp-ucMGP predicted CF-PWV (&bgr; = 0.40, P = 0.011), even after adjustment for age, gender, ethnicity, mean arterial pressure, eGFR, and warfarin use. CONCLUSIONS In our cross-sectional analysis, circulating dp-ucMGP was independently associated with CF-PWV in type 2 diabetes. This suggests that deficient vitamin K-dependent activation of MGP may lead to large artery stiffening and could be targeted with vitamin K supplementation in the patients with diabetes.

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.

CARDIO-FEMORAL VASCULAR INDEX: A NEW MARKER OF ARTERIAL AGING

Background: Aortic stiffness (AS) is an important mediator of CVD risk with aging. Operator-independent methods to assess AS are needed. Cardio-ankle vascular index (CAVI) is a noninvasive estimate of AS that can be automatically measured with cuff-based systems. Its specificity to AS as a marker of