Pacing Beyond Rhythm – Improving Myocardial Function by Tickling the Heart Electrically?

This article refers to ‘Cardio-microcurrent device treatment for heart failure with reduced ejection fraction: Results from the C-MIC II open-label randomized controlled trial’ by J.E. Rame et al., published in this issue on pages 1837–1849. Guideline-directed medical therapy decreases morbidity and mortality in patients with heart failure.1 Beyond pharmacological options, device-based therapy such as cardiac resynchronization therapy (CRT) has demonstrated improvements in symptoms and survival in selected heart failure populations.2, 3 Other device-based approaches, like cardiac contractility modulation (CCM), which delivers non-excitatory electrical impulses during the refractory period aiming at reverse remodelling of impaired intracellular calcium handling, did not achieve widespread clinical adoption.4 A novel concept involves the application of non-stimulatory microcurrent directly to the myocardium through a surgical implant (C-MIC). Experimental data suggest that this approach may reverse the myofibroblast phenotype, possibly reducing cardiac fibrosis and oedema, two key contributors to adverse remodelling in heart failure. In chronic heart failure, alterations in local electrical fields and impaired lymphatic drainage may promote myocardial oedema and cardiac dysfunction.5 Initial human data demonstrated that C-MIC may improve left ventricular ejection fraction (LVEF) and functional capacity as measured by 6-min walk distance (6MWD) in a small cohort of patients with heart failure.6 In this issue of the Journal, Rame and colleagues now present the first randomized controlled trial of C-MIC in patients with New York Heart Association (NYHA) class III or ambulatory NYHA class IV heart failure due to non-ischaemic cardiomyopathy and LVEF between 25% and 35%.7 Of the 70 randomized patients, 65 were included in a modified intention-to-treat analysis. The primary endpoint was change in LVEF after 6 months. Secondary endpoints included 6MWD, the Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS), and improvement by at least one NYHA class. The study showed a significant improvement in LVEF in the device group (+6.6%) compared to controls (+1.5%), resulting in an estimated treatment difference of 5.1% (Figure 1). Likewise, all three secondary clinical endpoints improved in the intervention group. Of note, separation of effect curves was observed as early as the 4-week follow-up. The improvement in quality of life measured by KCCQ-OSS was quite pronounced, raising the possibility of a placebo component. More objective measures, such as N-terminal pro-B-type natriuretic peptide levels or left ventricular end-diastolic diameter on echocardiography did not significantly differ between groups, arguing against reduced wall stress as the mechanism of benefit. The implantation of C-MIC devices requires both positioning of a left ventricular pericardial patch in addition to a right ventricular lead. Although more invasive than standard defibrillator or CRT implantation, the average skin-to-skin time was reasonable with approximately 2 h, with no perioperative mortality observed in the trial. When interpreting the findings, several aspects warrant consideration. The trial initially planned to enrol 92 patients. However, the Data Safety Monitoring Board recommended early termination after an interim analysis of the first 40 patients showed a significantly greater improvement in LVEF in the device group as compared to controls. Although the trial was not powered to assess mortality differences and the protocol discouraged early termination based on interim analysis, the trial was halted after enrolment of only 64 patients. This is unfortunate, as early termination in a small trial is known to introduce confounding and risk overestimating treatment effects. The primary analysis followed a modified intention-to-treat approach, which included only patients with successful device implantation in the intervention group. This means that potential implantation failures or intra-procedural complications are not reflected in the primary endpoint. While all implantations were technically successful and dropouts occurred prior to surgery, the latter comes at a cost. The rate of serious adverse events was higher in the device group, including two cases of haemothorax and one pericardial effusion. Moreover, the procedure was not sham-controlled. A more rigorous design would have included C-MIC implantation in all participants, with activation limited to the intervention group. Device-based therapies are particularly susceptible to placebo effects, and the lack of a sham procedure may have led to an overestimation of the treatment effect.8 Notably, only patients in the treatment group remained hospitalized for an average of 5 days, raising the question of whether additional in-hospital treatment optimization or behavioural changes may have influenced outcomes. Although echocardiography assessments were performed by a blinded core laboratory, the visibility of the right ventricular lead and the left ventricular epicardial patch in the device group may have compromised blinding and introduced bias. Finally, it should be noted that the devices were activated for only 6 months; whether alternative durations of therapy are equally safe and effective remains to be shown. The authors should be commended for conducting this randomized controlled trial early in the clinical investigation of this novel modality, thereby paving the way for future trials on this promising non-pharmacological treatment approach for heart failure. However, several important questions must be addressed before C-MIC can be considered for broader clinical use. Can similar benefits be replicated in patients with ischaemic cardiomyopathy? Would the amount and distribution of late gadolinium enhancement on cardiac magnetic resonance imaging correlate with treatment response? Does earlier initiation of C-MIC therapy in the disease course yield different outcomes? Can the device be safely applied in the many patients with heart failure requiring concomitant pacemaker, CRT, or implantable cardioverter-defibrillator therapy? And finally, what are the long-term implications for the pericardial left ventricular patch once cardiac microcurrent therapy is discontinued? This study opens a compelling and exciting avenue for future research into this novel device-based heart failure therapy. We remain optimistic but ever cautious. Conflict of interest: none declared.