A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design.

BACKGROUND: Leakage of Ca2+ from the sarcoplasmic reticulum (SR) is a critical contributing factor to heart failure pathophysiology. Therefore, reducing SR Ca2+ leaks may provide significant additive benefits when used in combination with conventional therapies. Dantrolene, a drug routinely used to treat malignant hyperthermia, also stabilizes the cardiac isoform of the release channel (RyR2), thus decreasing SR Ca2+ leaks. The purpose of this study is to evaluate the effect of chronic administration of dantrolene on heart failure and lethal arrhythmia in patients with chronic heart failure and reduced ejection fraction in a multicenter, randomized, double-blind, controlled study. METHODS: Patients with chronic heart failure who had functional status of New York Heart Association class II and III and a left ventricular ejection fraction <40% were treated according to the Japanese Circulation Society, the European Society of Cardiology, and the American Heart Association/the American College of Cardiology guidelines for diagnosis and treatment of acute and chronic heart failure. Patients were randomized and divided into two groups in a double-blind fashion: dantrolene group and placebo group (target sample size: 300 cases). These drugs were administered for 96 weeks. The primary endpoint is cardiovascular death, first hospitalization for exacerbation of heart failure, or lethal arrhythmia [ventricular tachycardia (VT) storm, sustained VT, ventricular fibrillation] for 2 years after starting administration of dantrolene 1 cap (25mg) three times daily (if not tolerable, two times daily) or matching placebo. RESULTS: This paper presents the rationale and trial design of the study. Recruitment for the study started on 8 December 2017. CONCLUSIONS: The results of this trial will clarify the efficacy and safety of dantrolene for ventricular arrhythmia, as well as mortality and morbidity in patients with chronic heart failure and reduced ejection fraction during guideline-directed medical treatment.

Norepinephrine spillover during exercise as a novel parameter to evaluate the severity of heart failure.

BACKGROUND: The washout rate (WR) of (123)I-metaiodobenzylguanidine (MIBG) is now widely used for assessing the severity of heart failure. Although the WR of MIBG is usually measured at rest, the assessment of WR of MIBG during exercise might have a different clinical relevance. In this study, we measured the WR rate of MIBG during low-grade exercise and studied the clinical importance of this novel index. METHODS: Twenty-four patients with dilated cardiomyopathy (DCM) were enrolled in this study. Planar images were obtained 20 minutes after MIBG injection (first image) and after 270 minutes (second image); the third image was obtained after 15 minutes of low-grade (10 W) bicycle ergometer exercise (300 minutes after MIBG injection). The decay of the specific counts was calculated from the first two images. The estimated third counts were calculated from the resting decay and were compared with the actual third counts. RESULTS: In the receiver operating characteristic (ROC) curve analysis, we set a 10% decrease from the estimated counts as a cut-off value for severe heart failure (New York Heart Association [NYHA] Class IIm or worse). In 15 patients, the actual third count value was within 10% of the estimated count (N-group). In nine patients, the WR during exercise was high, and the actual third count values showed more than a 10% decrease from the estimated count value (H-group). In the H-group, 78% of the patients were in NYHA class IIm or III. In contrast, in the N-group, no patient had NYHA class III, and only 20% of the patients were in class IIm. The brain natriuretic peptide (BNP) level was significantly higher in the H-group than in the N-group (525 ± 263 pg/mL vs 176 ± 144 pg/mL; P < .01). No significant differences were observed in heart/mediastinal (H/M) activity ratio, the regular WR, and left ventricular ejection fraction values between the two groups. CONCLUSIONS: The WR of MIBG during exercise may be an independent prediction variable, with a clinical relevance different from that of the WR at rest. This measurement could be used as a new index for assessing the severity of heart failure.