Cardiac Contractility Modulation (CCM) Therapy in Contemporary Heart Failure Care: Mechanisms, Evidence, Patient Selection, and Emerging Directions

Abstract

Cardiac contractility modulation (CCM) is a bioelectronic therapy that delivers precisely timed electrical signals during ventricular refractoriness to modulate myocardial contractility without triggering depolarization. Unlike pacing-based therapies, CCM does not initiate a new depolarization but instead modulates intracellular signaling pathways to enhance myocardial contractility without increasing myocardial oxygen consumption. CCM therefore represents a myocardial conditioning strategy distinct from cardiac resynchronization therapy, conduction system pacing, or neuromodulation. Experimental and translational studies demonstrate that repeated CCM delivery induces sustained myocardial adaptations, including improvements in excitation–contraction coupling, molecular signaling pathways, and structural remodeling that extend beyond transient hemodynamic effects. Across clinical investigations, CCM has been associated with meaningful improvements in exercise tolerance, health-related quality of life, and functional status in carefully selected populations. Observational data further suggest a potential reduction in heart failure-related hospitalizations when therapy is applied within evidence-aligned indications. Recent technological developments—including simplified ventricular lead configurations, rechargeable compact generators, and integrated CCM–defibrillator platforms—have reduced procedural complexity and may broaden clinical applicability, particularly in patients with concomitant implantable cardioverter–defibrillator indications. This review synthesizes mechanistic insights, clinical evidence, patient selection principles, and practical considerations to define the evolving role of CCM within contemporary heart failure care pathways. © 2026 by the authors.