Cardiac contractility modulation: from molecular patterns to tailored treatment in heart failure subgroups

Cardiac contractility modulation (CCM) signals are non-excitatory signals that are applied during the myocyte's absolute refractory period. These signals have been demonstrated to have an inotropic effect without increasing myocardial oxygen consumption. This has been observed in both preclinical animal studies and randomized clinical trials. CCM influences the expression of various genes that are abnormally expressed in heart failure: it reverses fetal myocyte gene programming associated with heart failure and regulates the expression of genes associated with calcium cycling and myocardial contractile machinery. Clinical investigations have primarily focused on patients with heart failure and normal QRS duration where CCM has demonstrated its safety and effectiveness in reducing heart failure-related hospitalizations, as well as improving symptoms, functional capacity, and overall quality of life. Currently, for individuals experiencing symptomatic heart failure with an ejection fraction ranging from 25% to 45% and a QRS duration of less than 130 ms, who are not suitable candidates for cardiac resynchronization therapy, CCM offers a viable treatment option. Even though promising results in specific HF subgroups have been published, further studies are needed to understand the role of CCM in tailored treatment for heart failure. Moreover, the role of multimodality imaging in lead placement and prognostic stratification in CCM patients should be further investigated. This review aims to summarize the main pathophysiological evidence related to the use of CCM and to highlight its role as a possible additional weapon in tailored treatment for specific subgroups of patients with heart failure.