Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction.

BACKGROUND: Inorganic nitrate (NO3(-)), abundant in certain vegetables, is converted to nitrite by bacteria in the oral cavity. Nitrite can be converted to nitric oxide in the setting of hypoxia. We tested the hypothesis that NO3(-) supplementation improves exercise capacity in heart failure with preserved ejection fraction via specific adaptations to exercise. METHODS AND RESULTS: Seventeen subjects participated in this randomized, double-blind, crossover study comparing a single dose of NO3-rich beetroot juice (NO3(-), 12.9 mmol) with an identical nitrate-depleted placebo. Subjects performed supine-cycle maximal-effort cardiopulmonary exercise tests, with measurements of cardiac output and skeletal muscle oxygenation. We also assessed skeletal muscle oxidative function. Study end points included exercise efficiency (total work/total oxygen consumed), peak VO2, total work performed, vasodilatory reserve, forearm mitochondrial oxidative function, and augmentation index (a marker of arterial wave reflections, measured via radial arterial tonometry). Supplementation increased plasma nitric oxide metabolites (median, 326 versus 10 µmol/L; P=0.0003), peak VO2 (12.6±3.7 versus 11.6±3.1 mL O2·min(-1)·kg(-1); P=0.005), and total work performed (55.6±35.3 versus 49.2±28.9 kJ; P=0.04). However, efficiency was unchanged. NO3(-) led to greater reductions in systemic vascular resistance (-42.4±16.6% versus -31.8±20.3%; P=0.03) and increases in cardiac output (121.2±59.9% versus 88.7±53.3%; P=0.006) with exercise. NO3(-) reduced aortic augmentation index (132.2±16.7% versus 141.4±21.9%; P=0.03) and tended to improve mitochondrial oxidative function. CONCLUSIONS: NO3(-) increased exercise capacity in heart failure with preserved ejection fraction by targeting peripheral abnormalities. Efficiency did not change as a result of parallel increases in total work and VO2. NO3(-) increased exercise vasodilatory and cardiac output reserves. NO3(-) also reduced arterial wave reflections, which are linked to left ventricular diastolic dysfunction and remodeling. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov. Unique identifier: NCT01919177.

Predictive Ability of Pressure-Corrected Arterial Stiffness Indices: Comparison of Pulse Wave Velocity, Cardio-Ankle Vascular Index (CAVI), and CAVI0.

BACKGROUND: Pulse wave velocity (PWV) is blood pressure (BP) dependent, leading to the development of the BP-corrected metrics cardio-ankle vascular index (CAVI) and CAVI0. We aimed to assess risk prediction by heart-to-ankle PWV (haPWV), CAVI, and CAVI0 in a US population. METHODS: We included 154 subjects (94.8% male; 47.7% African American) with and without heart failure (HF). Left and right haPWV, CAVI, and CAVI0 were measured with the VaSera 1500N device. We prospectively followed participants for a mean of 2.56 years for the composite endpoint death or HF-related hospital admission (DHFA). RESULTS: Left and right haPWV, CAVI, and CAVI0 values did not differ significantly. In unadjusted analyses, haPWV (left standardized hazard ratio [HR] = 1.51, P = 0.007; right HR = 1.66, P = 0.003), CAVI (left HR = 1.45, P = 0.012; right HR = 1.58, P = 0.006), and CAVI0 (left HR = 1.39, P = 0.022; right HR = 1.44, P = 0.014) significantly predicted DHFA. Predictive ability showed a decreasing trend from haPWV to CAVI to CAVI0; in line with the increasing amount of BP correction in these metrics. In Cox models, right-sided metrics showed a trend toward stronger predictive ability than left-sided metrics. After adjustment for baseline HF status, the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score, and systolic BP, right haPWV (HR = 1.58, P = 0.025) and CAVI (HR = 1.44, P = 0.044), but no other stiffness metrics, remained predictive. CONCLUSIONS: Although conceptually attractive, BP-corrected arterial stiffness metrics do not offer better prediction of DHFA than conventional arterial stiffness metrics, nor do they predict DHFA independently of systolic BP. Our findings support PWV as the primary arterial stiffness metric for outcome prediction.