Cardiac Contractility Modulation In Symptomatic Heart Failure With Reduced Ejection Fraction: A Systematic Review and Single-Arm Meta-Analysis.

Background: Heart failure with reduced ejection fraction (HFrEF) is a leading cause of morbidity and mortality, with many patients remaining symptomatic despite optimal medical therapy. Cardiac contractility modulation (CCM), which delivers non-excitatory electrical impulses during the refractory period, enhances myocardial contractility without increasing oxygen demand. This therapy targets symptomatic HFrEF patients with narrow QRS complexes who are ineligible for cardiac resynchronization therapy (CRT).

Methods: We performed a systematic review and single-arm meta-analysis, following PRISMA guidelines, to evaluate the functional, structural, and quality-of-life effects of CCM in symptomatic HFrEF patients. Primary outcomes were 6-min walk test (6MWT), peak oxygen consumption (peak VO₂), New York Heart Association (NYHA) functional class, and Minnesota Living with Heart Failure Questionnaire (MLHFQ) scores. Secondary outcomes included left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and left ventricular end-diastolic volume (LVEDV).

Results: Fifteen studies encompassing 1658 patients were included. CCM therapy resulted in a significant improvement in 6MWT distance (mean increase: 44.96 m, 95% CI: 2.73-87.20; p = 0.037) and a reduction in NYHA functional class (mean change: -0.89, 95% CI: -1.18 to -0.60; p < 0.001). Quality of life, as measured by MLHFQ, improved significantly (mean decrease: 11.83 points, 95% CI: -15.65 to -8.02; p < 0.001). Although there was a nominal increase in Peak VO₂ (mean increase: 0.13 mL/kg/min, 95% CI: -0.73 to 0.98; p = 0.770), it was not statistically significant. Structural improvements included a 5.96% increase in LVEF (95% CI: 4.65-7.26; p < 0.001), a reduction in LVESV of 24.17 mL (95% CI: -40.12 to -8.22; p = 0.003), and a reduction in LVEDV of 18.44 mL (95% CI: -29.97 to -6.91; p = 0.002). Sensitivity analyses confirmed the robustness of these findings.

Conclusion: CCM therapy provides significant improvements in functional capacity, symptom relief, quality of life, and cardiac remodeling in symptomatic HFrEF patients who are ineligible for CRT. These findings support the role of CCM in addressing an important therapeutic gap. Further large-scale randomized trials are needed to validate long-term clinical outcomes.