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

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.