Research and development of new drugs requires both long time and high costs, whereas safety and tolerability profiles make the success rate of approval very low. Drug repurposing, applying known drugs and compounds to new indications, has been noted recently as a cost-effective and time-unconsuming way in developing new drugs, because they have already been proven safe in humans. In this review, we discuss drug repurposing of approved cardiovascular drugs, such as aspirin, beta-blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, cardiac glycosides and statins. Regarding anti-tumor activities of these agents, a number of experimental studies have demonstrated promising pleiotropic properties, whereas all clinical trials have not shown expected results. In pathological conditions other than cancer, repurposing of cardiovascular drugs is also expanding. Numerous experimental studies have reported possibilities of drug repurposing in this field and some of them have been tried for new indications (‘bench to bedside’), while unexpected results of clinical studies have given hints for drug repurposing and some unknown mechanisms of action have been demonstrated by experimental studies (‘bedside to bench’). The future perspective of experimental and clinical studies using cardiovascular drugs are also discussed.

Although clonal hematopoiesis of indeterminate potential (CHIP) is an adverse prognostic factor for atherosclerotic disease, its impact on nonischemic dilated cardiomyopathy (DCM) is elusive. The authors performed whole-exome sequencing and deep target sequencing among 198 patients with DCM and detected germline mutations in cardiomyopathy-related genes and somatic mutations in CHIP driver genes. Twenty-five CHIP driver mutations were detected in 22 patients with DCM. Ninety-two patients had cardiomyopathy-related pathogenic mutations. Multivariable analysis revealed that CHIP was an independent risk factor of left ventricular reverse remodeling, irrespective of known prognostic factors. CHIP exacerbated cardiac systolic dysfunction and fibrosis in a DCM murine model. The identification of germline and somatic mutations in patients with DCM predicts clinical prognosis.

Approximately 10% of hypertrophic cardiomyopathy (HCM) patients have left ventricular systolic dysfunction (end-stage HCM) leading to severe heart-failure; however, risk stratification to identify patients at risk of progressing to end-stage HCM remains insufficient. In this study, the authors sought to elucidate whether the coexistence of other cardiovascular disease (CVD)-related variants is associated with progression to end-stage HCM in patients with HCM harboring pathogenic or likely pathogenic (P/LP) sarcomeric variants. The authors performed genetic analysis of 83 CVD-related genes in HCM patients from a Japanese multicenter cohort. P/LP variants in 8 major sarcomeric genes (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, and ACTC1) definitive for HCM were defined as "sarcomeric variants." In addition, P/LP variants associated with other CVDs, such as dilated cardiomyopathy and arrhythmogenic cardiomyopathy, were referred to as "other CVD-related variants." Among 394 HCM patients, 139 carried P/LP sarcomeric variants: 11 (7.9%) carried other CVD-related variants, 6 (4.3%) multiple sarcomeric variants, and 122 (87.8%) single sarcomeric variants. In a multivariable Cox regression analysis, presence of multiple sarcomeric variants (adjusted HR [aHR]: 3.35 [95% CI: 1.25-8.95]; P = 0.016) and coexistence of other CVD-related variants (aHR: 2.80 [95% CI: 1.16-6.78]; P = 0.022) were independently associated with progression to end-stage HCM. Coexisting other CVD-related variants were also associated with heart failure events (aHR: 2.75 [95% CI: 1.27-5.94]; P = 0.010). Approximately 8% of sarcomeric HCM patients carried other CVD-related variants, which were associated with progression to end-stage HCM and heart failure events. Comprehensive surveillance of CVD-related variants within sarcomeric HCM patients contributes to risk stratification and understanding of mechanisms underlying end-stage HCM.

Heart failure is a major public issue, and dilated cardiomyopathy (DCM) is one of the common etiologies of heart failure. DCM is generally progressive, and some patients with DCM need heart transplant despite optimal medical and mechanical therapy. Current guidelines recommend inhibitors of renin–angiotensin–aldosterone system, namely angiotensin-converting-enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), and mineralocorticoid receptor antagonist as well as beta-blockers for the medical treatment of heart failure with reduced ejection fraction, including DCM. Furthermore, because they have beneficial effects on the outcome of heart failure in a dose-related fashion, they should be titrated to the target dose. In clinical practice, the underuse and under-dose of these agents matter; however, the efficacy and safety of supramaximal dose of ACE inhibitor or ARB have never been investigated in the patients with DCM. In this issue of ESC Heart Failure, it is demonstrated that benazepril or valsartan at supramaximal dose improved left ventricular function and reduced cardiovascular events compared with each drug at low dose, respectively. In this editorial, the current evidence concerning the use of ACE inhibitor or ARB in patients with HF and future prospective will be discussed.

Background: Fulminant myocarditis is life‐threatening and often requires mechanical circulatory support. Predicting its clinical course is crucial, yet data on early recovery predictors, particularly with veno‐arterial extracorporeal membrane oxygenation, remain lacking. Methods and Results: We aimed to identify prognostic factors of early recovery in fulminant myocarditis requiring veno‐arterial extracorporeal membrane oxygenation by retrospective analysis of a nationwide registry in Japan. Early recovery was defined as successful weaning from mechanical circulatory support within 7 days and discharge without heart transplantation or long‐term mechanical circulatory support. A total of 343 patients were analyzed; 71 were classified as early recovery and 272 as nonearly recovery. The early recovery group was significantly younger, had higher white blood cell counts, and lower creatine kinase‐myocardial band level than the nonearly recovery group. To enhance clinical interpretability, we dichotomized continuous variables using optimal cutoff values derived from the Youden index. Multivariable logistic regression analysis showed the independent factors of early recovery were age ≤40 years (odds ratio [OR], 3.25), white blood cell count ≥11 000/μL (OR, 3.10), and creatine kinase‐myocardial band ≤61 U/L (OR, 2.46), and if all conditions were fulfilled, the early recovery rate increased to 61.5%. Additionally, although not statistically significant, the number of rehospitalization with cardiovascular causes, death, or heart transplantation at 1‐year follow‐up was higher in the nonearly recovery group. Conclusions: Our study suggested younger patients who have a strong inflammatory response but less myocardial damage on admission could recover earlier. Conversely, in cases where mechanical circulatory support duration is prolonged, careful monitoring is required for prolonged left ventricular dysfunction and subsequent prognosis. Registration: URL: https://www.umin.ac.jp/ ; Unique identifier: UMIN000039763.