Nicotinamide for the treatment of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD+). Elevating NAD+ by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats), or cardiometabolic syndrome (in ZSF1 obese rats). This effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium adenosine triphosphatase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD+ precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD+ precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans.

A Controlled Trial of Rivaroxaban after Transcatheter Aortic-Valve Replacement.

BACKGROUND: Whether the direct factor Xa inhibitor rivaroxaban can prevent thromboembolic events after transcatheter aortic-valve replacement (TAVR) is unclear. METHODS: We randomly assigned 1644 patients without an established indication for oral anticoagulation after successful TAVR to receive rivaroxaban at a dose of 10 mg daily (with aspirin at a dose of 75 to 100 mg daily for the first 3 months) (rivaroxaban group) or aspirin at a dose of 75 to 100 mg daily (with clopidogrel at a dose of 75 mg daily for the first 3 months) (antiplatelet group). The primary efficacy outcome was the composite of death or thromboembolic events. The primary safety outcome was major, disabling, or life-threatening bleeding. The trial was terminated prematurely by the data and safety monitoring board because of safety concerns. RESULTS: After a median of 17 months, death or a first thromboembolic event (intention-to-treat analysis) had occurred in 105 patients in the rivaroxaban group and in 78 patients in the antiplatelet group (incidence rates, 9.8 and 7.2 per 100 person-years, respectively; hazard ratio with rivaroxaban, 1.35; 95% confidence interval [CI], 1.01 to 1.81; P = 0.04). Major, disabling, or life-threatening bleeding (intention-to-treat analysis) had occurred in 46 and 31 patients, respectively (4.3 and 2.8 per 100 person-years; hazard ratio, 1.50; 95% CI, 0.95 to 2.37; P = 0.08). A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (5.8 and 3.4 per 100 person-years, respectively; hazard ratio, 1.69; 95% CI, 1.13 to 2.53). CONCLUSIONS: In patients without an established indication for oral anticoagulation after successful TAVR, a treatment strategy including rivaroxaban at a dose of 10 mg daily was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding than an antiplatelet-based strategy. (Funded by Bayer and Janssen Pharmaceuticals; GALILEO ClinicalTrials.gov number, NCT02556203.).