Cardiac Contractility Modulation in 2018
Authors: Martin Borggrefe, Douglas L. Mann
Journal: Circulation (2018)

ardiac contractility modulation (CCM) is a device-based therapy for heart failure (HF) that involves applying relatively high-voltage (≈7.5 V), long-duration (≈20 milliseconds), biphasic electric signals to the right ventricular septal wall during the absolute myocardial refractory period.Accordingly, CCM signals do not elicit a new contraction; rather, they influence the biology of the failing myocardium.CCM signals have been shown to induce an acute, mild augmentation of left ventricular (LV) contractile strength without an increase in myocardial oxygen consumption in both animal HF models 1 and patients with reduced ejection fraction (EF).Three-dimensional echocardiographic studies showed that CCM induces reverse LV remodeling and improves LVEF over time.The myocardial effects of CCM are multifactorial: Studies show effects on molecular, cellular, and extracellular properties that express themselves over different time frames.Acute effects appear to involve alterations of myocardial calcium handling, whereas over intermediate and longer time frames, CCM exerts a multitude of biochemical and molecular effects locally and remotely from the site of stimulation, including shifts of a large number of abnormally expressed genes toward normal, many of which involve pathways that regulate calcium cycling and myocardial contraction.Although the major clinical trials (reviewed below) have focused on patients with normal conduction, CCM effects appear to be additive to those of cardiac resynchronization therapy (CRT) when applied to patients with prolonged QRS duration.Three randomized prospective studies have compared patients treated with guideline-directed optimal medical therapy (including an implanted cardiac defibrillator, when indicated) with those treated with optimal medical therapy plus CCM.The earliest of these, the FIX-HF-4 study, which was conducted in European Union, showed that 3 months of CCM treatment improved exercise tolerance and quality of life. 2 Although the FIX-HF-5 study, which randomized 428 patients who were followed up for 1 year, missed its US Food and Drug Administrationmandated primary end point (an analysis of anaerobic threshold measured on cardiopulmonary stress test), it showed significant improvements in the secondary end points of peak Vo 2 and Minnesota Living With Heart Failure Questionnaire score with treatment effects of 1.4 mL O 2 •kg -1 •min -1 and 11.8 points, respectively. 3This study was also the first to show that patients with an LVEF between 35% and 45% benefited the most, whereas those with EF <25% derived inadequate benefit.Most recently, the FIX-HF-5C study (n=160), conducted in sites in the United States and European Union, was designed to confirm findings that CCM improves peak Vo 2 and Minnesota Living With Heart Failure Questionnaire score in patients with LVEF between 25% and 45% and, secondarily, to confirm even larger effects in patients with LVEF of 35% to 45%. 4 The study used a bayesian statistical design, meaning that there was statistically appropriate pooling of data from the prior FIX-HF-5 study conducted in the United States. 3Data from