Background Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. Methods In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1•5 mL/kg per min or greater increase in peak oxygen consumption (pVO 2) and at least one NYHA class reduction or a 3•0 mL/kg per min or greater pVO 2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO 2 , NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545.

Randomized clinical trials initially used heart failure (HF) patients with low left ventricular ejection fraction (LVEF) to select study populations with high risk to enhance statistical power. However, this use of LVEF in clinical trials has led to oversimplification of the scientific view of a complex syndrome. Descriptive terms such as ‘HFrEF’ (HF with reduced LVEF), ‘HFpEF’ (HF with preserved LVEF), and more recently ‘HFmrEF’ (HF with mid-range LVEF), assigned on arbitrary LVEF cut-off points, have gradually arisen as separate diseases, implying distinct pathophysiologies. In this article, based on pathophysiological reasoning, we challenge the paradigm of classifying HF according to LVEF. Instead, we propose that HF is a heterogeneous syndrome in which disease progression is associated with a dynamic evolution of functional and structural changes leading to unique disease trajectories creating a spectrum of phenotypes with overlapping and distinct characteristics. Moreover, we argue that by recognizing the spectral nature of the disease a novel stratification will arise from new technologies and scientific insights that will shape the design of future trials based on deeper understanding beyond the LVEF construct alone.

Background— To assess the prevalence, determinants, and prognosis value of right ventricular (RV) ejection fraction (EF) impairment in organic mitral regurgitation. Methods and Results— Two hundred eight patients (62±12 years, 138 males) with chronic organic mitral regurgitation referred to surgery underwent an echocardiography and biventricular radionuclide angiography with regional function assessment. Mean RV EF was 40.4±10.2%, ranging from 10% to 65%. RV EF was severely impaired (≤35%) in 63 patients (30%), and biventricular impairment (left ventricular EF<60% and RV EF≤35%) was found in 34 patients (16%). Pathophysiologic correlates of RV EF were left ventricular septal function (β=0.42, P <0.0001), left ventricular end-diastolic diameter index (β=−0.22, P =0.002), and pulmonary artery systolic pressure (β=−0.14, P =0.047). Mitral effective regurgitant orifice size (n=84) influenced RV EF (β=−0.28, P =0.012). In 68 patients examined after surgery, RV EF increased strongly (27.5±4.3–37.9±7.3, P <0.0001) in patients with depressed RV EF, whereas it did not change in others ( P =0.91). RV EF ≤35% impaired 10-year cardiovascular survival (71.6±8.4% versus 89.8±3.7%, P =0.037). Biventricular impairment dramatically reduced 10-year cardiovascular survival (51.9±15.3% versus 90.3±3.2%, P <0.0001; hazard ratio, 5.2; P <0.0001) even after adjustment for known predictors (hazard ratio, 4.6; P =0.004). Biventricular impairment reduced also 10-year overall survival (34.8±13.0% versus 72.6±4.5%, P =0.003; hazard ratio, 2.5; P =0.005) even after adjustment for known predictors ( P =0.048). Conclusions— In patients with organic mitral regurgitation referred to surgery, RV function impairment is frequent (30%) and depends weakly on pulmonary artery systolic pressure but mainly on left ventricular remodeling and septal function. RV function is a predictor of postoperative cardiovascular survival, whereas biventricular impairment is a powerful predictor of both cardiovascular and overall survival.