Cardiac contractility modulation in heart failure management: unraveling molecular mechanisms to improve patient selection in heart failure management

Managing patients with heart failure remains continues to be a global health challenge despite advances in medical therapy. For patients with heart failure and reduced ejection fraction (HFrEF) who are ineligible for cardiac resynchronization therapy, cardiac contractility modulation (CCM) represents a promising device-based therapeutic alternative. CCM delivers non-excitatory, high-voltage electrical impulses during the absolute refractory period of the cardiac cycle, thereby enhancing myocardial contractility without increasing myocardial oxygen demand. Clinical studies have shown that CCM can improve exercise tolerance, quality of life, and left ventricular function. However, its long-term effects on mortality and heart failure hospitalizations in the diverse patient populations ranging from end-stage HFrEF to heart failure with preserved ejection fraction, remain inconclusive. This review explores the underlying molecular mechanisms of CCM contributing to reverse cardiac remodeling, including improved intracellular calcium handling, phosphorylation of key proteins related to contractility, and reversal of maladaptive gene expression. We also highlight the results of clinical trials using CCM and emphasize the need for improved patient selection criteria. Early identification of potential responders may be based on left ventricular ejection fraction and fibrosis burden. Furthermore, the expanding role of CCM in patients with heart failure with preserved ejection fraction and specific cardiomyopathies underscores its evolving therapeutic potential. Future research should focus on large-scale randomized controlled trials to establish efficacy on hard clinical endpoints and evaluate long-term benefits, alongside targeted studies aimed at refining patient selection.