Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts — Role of late sodium current and intracellular ion accumulation

Sossalla, Samuel; Wagner, Stefan; Rasenack, Eva C.L.; Ruff, Hanna M.; Weber, S.; Schöndube, Friedrich A.; Tirilomis, Theodor; Tenderich, Gero; Hasenfuß, Gerd; Belardinelli, Luiz; Maier, Lars S.

doi:10.1016/j.yjmcc.2008.03.006

Cited by 241 publications

(246 citation statements)

References 47 publications

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“…In the clinic, ranolazine is used to attenuate the Na-dependent Ca overload through inhibiting the I Na-Late and promoting diastolic tension and oxygen handling during myocardial ischemia, which can act as an anti-anginal agent (17). Ranolazine was reported to have anti-arrhythmic effects in studies on ischemia and HF (28,29). However, the electropharmacological effects of ranolazine on SANs from patients with HF have remained elusive.…”

Section: Discussionmentioning

confidence: 99%

Heart failure modulates electropharmacological characteristics of sinoatrial nodes

Chang

Chuang

Chen

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The impact of heart failure (HF) on sinoatrial node (SAN) channel regulation and electropharmacological responses has remained elusive. The present study aimed to investigate the effects of HF on the electrical activity of SANs with and without pharmacological interventions. Action potentials (APs) were recorded in isolated SANs from normal rabbits (control) and those with HF (rapid ventricular pacing for 4 weeks) prior to and after administration of a funny current blocker (ivabradine; 0.1, 0.3, 3 or 10 µM), a calmodulin kinase II inhibitor (KN-93; 0.3 or 3 µM), a sarcoplasmic reticulum Ca 2+ release inhibitor (ryanodine; 0.3 or 3 µM), a sodium current inhibitor (tetrodotoxin; 1, 3 or 10 µM) and a late sodium current inhibitor (ranolazine; 10 µM). Western blot analysis was used to investigate the protein expression in SANs from normal rabbits and those with HF. Control SANs had a higher beating rate than SANs from rabbits with HF (2.3±0.1 vs. 1.5±0.1 Hz; P<0.001). Similarly, ivabradine (10 µM), KN-93 (3 µM), ranolazine (10 µM) and ryanodine (3 µM) decreased the beating rates of SANs in the control (n=6) and HF (n=6) groups. Ivabradine treatment resulted in a higher incidence of AP block in HF vs. control SANs (66.7 vs. 0%; P<0.05). Tetrodotoxin (1, 3 or 10 µM) decreased the beating rate to a higher extent in SANs from rabbits with HF than in those from control rabbits and induced a higher incidence of AP block (66.7 vs. 0%; P<0.05). Furthermore, SANs from rabbits with HF had higher protein levels of phospholamban (PLB) and lower levels of hyperpolarization-activated cyclic nucleotide-gated potassium channel 4, ryanodine receptor and phosphorylated PLB than control SANs. In conclusion, HF modulates electropharmacological responses in the SAN by channel regulation, which may result in SAN dysfunction.

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Section: Discussionmentioning

confidence: 99%

Heart failure modulates electropharmacological characteristics of sinoatrial nodes

Chang

Chuang

Chen

et al. 2016

Experimental and Therapeutic Medicine

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“…19 Data from in vitro and animal studies indicate that ranolazine improves diastolic function of the myocardium. We published results of a study that confirms the improvement of diastolic function by ranolazine in ex vivo (isolated) human myocardium from patients suffering from HF and diastolic dysfunction, 17 and more recently in another study using right atrial trabeculae from patients with chronic atrial fibrillation. 18 Ranolazine significantly reduced the increased diastolic tension in isolated myocardial muscle strips by ∼30%.…”

Section: Introductionmentioning

confidence: 89%

“…18 Ranolazine significantly reduced the increased diastolic tension in isolated myocardial muscle strips by ∼30%. 17 This effect was more pronounced at higher stimulation rates of the muscle strips, and especially in the myocardium with severe diastolic dysfunction. 17 This is important because patients with HFpEF typically decompensate at high heart rates (eg, during new onset of atrial fibrillation).…”

Section: Introductionmentioning

confidence: 97%

“…17 This effect was more pronounced at higher stimulation rates of the muscle strips, and especially in the myocardium with severe diastolic dysfunction. 17 This is important because patients with HFpEF typically decompensate at high heart rates (eg, during new onset of atrial fibrillation). Mechanistically, we could show that ranolazine inhibits the I Na,late and thereby reduces intracellular diastolic sodium and calcium concentrations.…”

Section: Introductionmentioning

confidence: 97%

“…Neither the sarcoplasmic reticulum calcium content nor the systolic function of the myocardium was significantly affected. 17 In a canine model of chronic HF, ranolazine significantly decreased the LV end-diastolic pressure (LVEDP) as a parameter for diastolic dysfunction. 22 Furthermore, ranolazine has been shown to improve diastolic function in patients with ischemic heart disease.…”

Section: Introductionmentioning

confidence: 99%

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

Jacobshagen

Belardinelli

Hasenfuß

et al. 2011

Clinical Cardiology

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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.

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The late sodium current in heart failure: pathophysiology and clinical relevance

Horváth

Bers

2014

ESC Heart Failure

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Large and growing body of data suggest that an increased late sodium current (I Na,late ) can have a significant pathophysiological role in heart failure and other heart diseases. The first goal of this article is to describe how I Na,late functions under physiological circumstances. The second goal is to show the wide range of cellular mechanisms that can increase I Na,late in cardiac disease, and also to describe how the up-regulated I Na,late contributes to the pathophysiology of heart failure. The final section of the article discusses the possible use of I Na,late -modifying drugs in heart failure, on the basis of experimental and preclinical data.

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Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts — Role of late sodium current and intracellular ion accumulation

Cited by 241 publications

References 47 publications

Heart failure modulates electropharmacological characteristics of sinoatrial nodes

Heart failure modulates electropharmacological characteristics of sinoatrial nodes

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

The late sodium current in heart failure: pathophysiology and clinical relevance

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