Hypertrophic cardiomyopathy (HCM) is a complex disease caused by excessive cardiac myosin-actin cross-bridging. Patients with HCM have left ventricular hypertrophy, hypercontractility, as well as diastolic dysfunction and suffer from severe impaired functionality and quality of life. HCM symptoms include dyspnoea, fatigue, chest pain and syncope. Mavacamten is a small molecule, which selectively inhibits cardiac myosin. This treatment option could potentially improve cardiac function in patients with HCM. The EXPLORER-HCM trial (NCT03470545) was a randomised, double-blind, placebo-controlled, phase 3 study which randomised 251 patients at a 1:1 ratio to either mavacamten or placebo (1). The results, published in 2020, demonstrated that mavacamten did not only improve symptoms for patients with HCM but also a broad variety of cardiac parameters as well as cardiorespiratory fitness.
Recently, Wheeler et al. published a prespecified exploratory analysis of the EXPLORER-HCM data (2). The goal of their analysis was to assess the effect of Mavacamten on parameters measured during cardiopulmonary exercise testing beyond peak oxygen consumption. The authors included 123 patients who received mavacamten and 128 patients who received the placebo. The mean age in both groups was 58.5 years. The mavacamten group included 46% women while the control group had only 35% of female study participants. The cardiorespiratory fitness level was comparable in both groups (19/20 ml/min/kg). Since this was a multi-center trial, 45% of the patients participated in cardiopulmonary exercise testing on a bicycle ergometer while 55% took part on a treadmill. Mavacamten treatment improved the peak VE/VCO2 ratio, metabolic equivalent tasks, circulatory power, exercise time, and partial pressure of end-tidal carbon dioxide. With regards to non-peak exercise parameters, mavacamten improved the VE/VCO2 slope, ventilatory power, VO2/workload slope and partial pressure of end-tidal carbon dioxide at rest. Wheeler et al. also related parameters from cardiopulmonary exercise testing with other patient characteristics.
Interestingly, in patients who received mavacamten, the change in both, peak oxygen uptake and the VE/VCO2 were inversely associated with the change of NTproBNP. The patients in the control group did not show these associations. Wheeler et al. speculate that mavacamten induced increases in exercise capacity may be related to better diastolic function allowing for longer left ventricular filling times. Unfortunately, most patients with HCM are unable to regularly exercise at levels of maximal exercise intensity.
Hence, parameters based on submaximal exercise testing may be superior to CPET values derived from full exhaustion tests. The mavacamten-related improvements in submaximal parameters (i.e. VE/VCO2 slope, ventilatory power, VO2/workload slope, partial pressure of end-tidal carbon dioxide at rest) could be indicative for better symptomatic benefits which patients are experiencing after treatment with mavacamten.
The important finding of Wheeler et al. with regards to preventive cardiology is that one may speculate that the mavacamten induced improvements in submaximal exercise capacity allow these patients to increase their level of physical activity, which in turn may lead to even larger improvements in peak oxygen uptake.