Ranolazine for the Treatment of Heart Failure With Preserved Ejection Fraction: Background, Aims, and Design of the RALI‐DHF Study

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF), formerly referred to as diastolic heart failure (DHF), accounts for >50% of all HF patients. So far, there has been no specific treatment for impaired left ventricular (LV) relaxation. Data from in vitro and animal studies indicate that ranolazine improves diastolic function by inhibiting the late sodium current. Hypothesis: RAnoLazIne for the Treatment of Diastolic Heart Failure (RALI-DHF) is a prospective, single-center, randomized, double-blind, placebo-controlled proof-of-concept study to determine if ranolazine compared with placebo will be more effective in improving diastolic function in patients with HFpEF. Methods: Twenty patients with HFpEF (EF ≥ 50% and ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity [E/E ] >15 or N-terminal pro-type brain natriuretic peptide >220 pg/mL) will be randomized to receive ranolazine or placebo in a 1.5:1 ratio during their catheterization if the LV end-diastolic pressure is ≥18 mm Hg and the time constant of relaxation (τ) is ≥50 ms. Treatment will consist of intravenous infusion of study drug (or placebo) for 24 hours, followed by oral treatment for a total of 14 days. Endpoints: The study will include the following exploratory endpoints: (1) change from baseline to 30 minutes from initiation of intravenous study drug administration during cardiac catheterization hemodynamic parameters at both resting and paced (120 beats per minute) conditions: τ, LV end-diastolic pressure, and dP/dt min .; and (2) change from baseline to day 14 in E/E , maximal oxygen consumption, and N-terminal pro-type brain natriuretic peptide. Conclusions: The RALI-DHF study is designed as a translational study to bridge the gap between basic science and therapeutics and to determine if ranolazine, compared with placebo, will be more effective in improving diastolic function in patients with HFpEF.

Heart failure with preserved ejection fraction: Refocusing on diastole

“…1). These criteria have not been endorsed by the American College of Cardiology/American Heart Association [6], but they have recently been used as inclusion criteria for clinical trials [11][12][13]48]. These criteria intend to identify one or more of many different processes reflecting diastolic dysfunction in HFpEF.…”

“…These uncertainties in defining HFpEF have likely impacted numerous observational and interventional clinical trials in which the patient population displayed a wide variability of clinical characteristics across the different studies [7,[9][10][11][12][13]. Following the attempt to standardize the diagnosis of HFpEF by the ESC [4], those criteria have been frequently cited and used for inclusion criteria in the more contemporary studies of HFpEF [11][12][13]. These criteria rely heavily on the concept of diastolic dysfunction of the LV, which is now considered the cornerstone of the diagnosis of HFpEF, at least in Europe [4,5].…”

Can Brain Natriuretic Peptide Be Used to Guide the Management of Patients With Heart Failure and a Preserved Ejection Fraction?

“…15 The requirement that eligible patients have unequivocally increased levels of BNP serves 3 potentially useful purposes: (1) markedly increased levels of BNP may reflect increased left ventricular filling pressures, even in women with advanced age and renal insufficiency; (2) increased levels of BNP may identify patients at increased risk of experiencing a major cardiac event, thus reducing the sample size needed to detect a clinically relevant treatment effect; and (3) increased levels of BNP may identify patients most likely to respond favorably to drugs that act by interfering with the renin-angiotensin system. Unfortunately, only a small proportion of elderly patients who have received a diagnosis of HFPEF have plasma levels of BNP high enough to qualify for entry into many current trials; the rarity of these patients has made recruitment for these studies very difficult.…”

18β-Glycyrrhetinic acid preferentially blocks late Na current generated by ΔKPQ Nav1.5 channels

“…The reduction of I Na,L would therefore be expected to have therapeutic potential [2][3][4] . For example, ranolazine, a relatively selective inhibitor of I Na,L , has been shown to be effective in reducing angina and the incidence of nonsustained VT in patients with ischemic heart disease [5][6][7] . Pronounced I Na,L was also observed in the congenital long QT syndrome (LQTS) caused by the mutation of Nav1.5.…”