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 six-minute walk test (6MWT), peak oxygen consumption (Peak VO 2 ), 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 1,658 patients were included. CCM therapy resulted in a significant improvement in 6MWT distance (mean increase: 44.96 meters, 95% CI: 2.73 to 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 VO 2 (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 to 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. backend=biber, style=alphabetic, sorting=ynt ]biblatex CARDIAC CONTRACTILITY MODULATION IN SYMPTOMATIC HEART FAILURE WITH REDUCED EJECTION FRACTION: A SYSTEMATIC REVIEW AND SINGLE-ARM META-ANALYSIS Ricardo Fonseca Oliveira Suruagy Motta* 1, Christian Ken Fukunaga 2, Everton Victor Belmiro da Silva 3, Gabriel Rezende Neves 4, Karlos Daniell Araújo dos Santos 5, Laila Leite Pacheco Vieira 1, Maria Helena Nobrega Nunes Sampaio 1, Beatriz Calaça de Pádua Carvalho 1, Edvaldo Ferreira Xavier Júnior M.D 6, Alexandra Régia Dantas Brígido M.D. 7, Alfredo Aurélio Marinho Rosa Filho M.D. 8, Guilherme Dagostin de Carvalho M.D., MSc 8 1 Department of Medicine, Cesmac University Center, Maceió/AL, Brazil 2 Department of Medicine, FMABC University Center, São Paulo/SP, Brazil 3 Department of Medicine, Federal University of Pernambuco, Recife/PE, Brazil 4 Department of Medicine, State University of Pará - Belém/PA, Brazil 5 Department of Medicine, Federal University of Roraima - Boa Vista/RR 6 Department of Electrophysiology, Santa Casa de Misericórdia de Maceió/AL, Brazil 7 Department of Electrophysiology, Heart Institute of the Hospital das Clínicas of FMUSP - São Paulo/SP, Brazil 8 Department of Electrophysiology, Dante Pazzanese Institute of Cardiology, São Paulo/SP, Brazil Short title: Cardiac Contractility Modulation in Symptomatic HFrEF: A Systematic Review and Meta-Analysis *Corresponding Author: Ricardo FO Suruagy-Motta M.S. Disclosures: All authors report no relationships that could be construed as a conflict of interest. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Article summary This article is one of the first to comprehensively evaluate the comparative effectiveness and safety of Cardiac Contractility Modulation (CCM) devices in the management and treatment of reduced ejection fraction heart failure (HFrEF). It analyzes functional and structural outcomes and other safety profiles. Additionally, it explores potential factors contributing to variability in outcomes, including differences in pathology complexity, patient populations, and procedural techniques across studies.

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).

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 six-minute 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).

Fifteen studies encompassing 1,658 patients were included. CCM therapy resulted in a significant improvement in 6MWT distance (mean increase: 44.96 meters, 95% CI: 2.73 to 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 to 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.

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.

Cardiac contractility modulation (CCM); Heart failure with reduced ejection fraction (HFrEF); Cardiac Remodeling, Ventricular; Quality of Life; Exercise Tolerance.

Heart failure with reduced ejection fraction (HFrEF) remains a leading cause of morbidity, mortality, and hospitalizations globally, despite substantial advances in pharmacologic and device-based therapies (1,2). A significant proportion of patients continue to experience debilitating symptoms and reduced functional capacity, even with optimal guideline-directed medical therapy (GDMT) (3). To address this persistent clinical gap, novel device-based strategies have been developed, among which cardiac contractility modulation (CCM) has emerged as a promising therapeutic option. CCM therapy delivers non-excitatory electrical impulses during the absolute refractory period of the cardiac cycle, enhancing myocardial contractility without increasing myocardial oxygen demand (4,5). In contrast to cardiac resynchronization therapy (CRT), which is primarily indicated for patients with electrical dyssynchrony and prolonged QRS duration, CCM is specifically designed for individuals with symptomatic HFrEF, a left ventricular ejection fraction (LVEF) between 25% and 45%, New York Heart Association (NYHA) class III symptoms despite optimal medical therapy, and a QRS duration of less than 130 milliseconds (4). Beyond symptomatic relief, cardiac contractility modulation therapy has been associated with favorable molecular and cellular adaptations. Preclinical studies have improved calcium handling, including increased phospholamban phosphorylation and upregulation of SERCA2a expression, contributing to enhanced cardiomyocyte efficiency (6). Moreover, CCM has been linked to improved myocardial energetics, as evidenced by increases in global longitudinal strain (GLS) and myocardial mechano-energetic efficiency following six months of therapy (7). Emerging evidence suggests that CCM may improve exercise capacity, quality of life, left ventricular function, and heart failure-related biomarkers in this patient population (8–10). However, most current data are derived from single-arm studies and observational cohorts, contributing to ongoing uncertainty regarding the magnitude and consistency of clinical benefit. To address this gap, we conducted a systematic review and single-arm meta-analysis to synthesize the available evidence on the effects of CCM therapy on clinical, functional, structural, and biomarker outcomes in patients with symptomatic HFrEF.

This systematic review and meta-analysis were conducted following the Cochrane Handbook for Systematic Reviews of Interventions and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (11,12). The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (registration number: CRD420251001549). 2.1 Search strategy: A comprehensive search of PubMed, Embase, SCOPUS, and the Cochrane Library was performed by two independent reviewers, covering all records from database inception to March 2025. The search strategy combined the following terms using Boolean operators (”AND”, ”OR”): (“Cardiac Contractility Modulation” OR “CCM Therapy”) AND (“Heart Failure” OR “Chronic Heart Failure” OR “Reduced Ejection Fraction” OR “HFrEF”) AND (“Ejection Fraction” OR “Left Ventricular Function” OR “Cardiac Function”). The same strategy was applied consistently across all databases. No language or publication date restrictions were imposed. Additionally, reference lists of included studies and relevant review articles were manually screened to identify further eligible studies. backend=biber, style=alphabetic, sorting=ynt ]biblatex 2.2 Study selection: Titles and abstracts were independently screened by two reviewers (L.V and E.S). Full texts of potentially relevant articles were subsequently assessed for eligibility. Disagreements were resolved by discussion or adjudication by a third reviewer (R.S-M). 2.3. Inclusion criteria: • Adult patients (≥18 years) with symptomatic heart failure with reduced ejection fraction; • Intervention with cardiac contractility modulation therapy; • Availability of baseline and follow-up outcome data. 2.4 Exclusion criteria: • Studies exclusively enrolling patients with preserved ejection fraction (HFpEF); • Comparative studies evaluating CCM against other therapies; • Studies evaluating CCM in combination with other device therapies (e.g., CRT); • Studies focused exclusively on procedural or anesthetic techniques; • Case reports, conference abstracts, narrative reviews, or other non-original research formats. Reviewer disagreements were resolved through discussion or consultation with a third reviewer (R.S-M). backend=biber, style=alphabetic, sorting=ynt ]biblatex 2.5 Outcomes: The outcomes assessed were categorized into functional and structural endpoints. • Functional outcomes related to patient quality of life included: • Six-minute walk test (6MWT) distance (meters); • Peak oxygen consumption (Peak VO₂, mL/kg/min); • New York Heart Association functional class; • Minnesota Living with Heart Failure Questionnaire (MLHFQ) score. • Structural cardiac outcomes included : • Left ventricular ejection fraction (LVEF, %); • Left ventricular end-systolic volume (LVESV, mL); • Left ventricular end-diastolic volume (LVEDV, mL). As this was a single-arm meta-analysis, outcomes were assessed by comparing baseline and follow-up measurements within the same patient cohort. 2.6 Data extraction: The following data were extracted from the selected articles according to the study criteria: authors, year of publication, study location, type of study (RCTs or studies observational retrospective/prospective), sample size and age, patient characteristics, duration of intervention, follow-up time, primary outcomes, (6-Minute Walk Test (6MWT), Peak VO 2 Left ventricle ejection fraction (LVEF), Left ventricle end systolic volume (LVESV), Left ventricle end diastolic volume (LVEDV), Minnesota Living with Heart Failure Questionnaire (MLHFQ) and New York Heart Association (NYHA) of Heart Failure). Two reviewers (R.S-M and G.N) independently extracted and managed the data recorded in an EXCEL® spreadsheet. Any doubts were resolved with the assistance of a third researcher (L.L). 2.7 Quality assessment: Risk of bias was independently evaluated by two reviewers (C.F and L.V) using the Risk of Bias 2 (RoB 2) tool for randomized controlled trials (13) and the Risk Of Bias In Non-Randomized Studies of Interventions (ROBINS-I) tool for observational studies (14). All assessments were performed manually. Discrepancies were resolved through discussion or consultation with a third reviewer (R.S-M). 2.8 Statistical Analysis: Continuous outcomes were pooled using mean differences (MD) and 95% confidence intervals (CI) under a random-effects model, accounting for inter-study variability. Heterogeneity was assessed using Cochran’s Q and Higgins and Thompson’s I² statistics, with I² categorized as: Low (≤25%), Moderate (26–50%), or High (>50%). A p-value ≤ 0.10 for Cochran’s Q indicated significant heterogeneity. Sensitivity analyses were conducted using the leave-one-out method for outcomes with moderate to high heterogeneity (I² > 50%) to evaluate the influence of individual studies. Publication bias was assessed via funnel plot inspection for outcomes reported in fewer than 10 studies. Egger’s regression test was employed to detect funnel plot asymmetry for outcomes reported in ≥10 studies (e.g., LVEF). All statistical analyses were performed using R software (version 4.4.1) and the ”meta” package.

3.1 Study selection: A total of 737 records were identified from PubMed (n = 135), Embase (n = 382), SCOPUS (n = 197), and Cochrane (n = 23). After removing 369 duplicates, 368 records remained for title and abstract screening. Among these, 32 articles were selected for full-text evaluation. Ultimately, 15 studies met our inclusion criteria and were included in the final analysis, including 1658 patients (15–29) (Figure 1) . backend=biber, style=alphabetic, sorting=ynt ]biblatex Figure 1: PRISMA Flow Chart 3.2 Baseline characteristics of the included studies and patients: All 15 included studies were observational in design, encompassing both retrospective and prospective cohorts. Sample sizes ranged from 10 to 503 participants, with mean ages spanning 54.3 to 69.0 years. Reported follow-up durations varied between 3 and 50 months. A summary of study and patient characteristics is provided in Table 1 . Table 1. Baseline Characteristics of the Studies and Patients. backend=biber, style=alphabetic, sorting=ynt ]biblatex | Study | Country | Design | Sample Size | Follow-Up | Age | Mens | Patients with ICD | Diabetes Mellitus | LVEF (%) | Atrial Fibrillation | | Abraham, 2018 | GERMANY & USA | Randomized Controlled Trial | 191 | 6 months | 60 ± 12 | 137 (71.3%) | 158 (82.72%) | 95 (49.74%) | 32 ± 5.0 | N/A | | Amiraslanov, 2022 | RUSSIA | Retrospective Study | 61 | 25 months | 60.39 ± 12.81 | 47 (77%) | 23 (37.7%) | 17 (27.9%) | 31.3 ± 7.8 | 8 (13.1%) | | Anker, 2019 | GERMANY | Prospective Study | 140 | 24 months | 66.0 ± 11.0 | 111 (79%) | 97 (69%) | 64 (46%) | 32.7 ± 5.1 | 39 (28%) | | Kasish, 2011 | USA | Randomized Controlled Trial | 215 | 3-6 months | 58.09 ± 12.79 | 158 (73.5%) | N/A | 102 (47.89%) | 26.09 ± 6.54 | N/A | | Kuschyk, 2019 | GERMANY & USA | Prospective Study | 17 | 6 months | 69.0 ± 9.6 | 14 (82%) | N/A | N/A | 22.8 ± 6.5 | N/A | | Kuschyk, 2021 | GERMANY & USA | Prospective Study | 503 | 6-24 months | 66.2 ± 10.6 | 401 (79.7%) | 378 (75.1%) | 222 (44.1%) | 29.7 ± 8.0 | 154 (30.6%) | | Masarone, 2022 | ITALY | Prospective Study | 25 | 6 months | 62.8 ± 9.7 | 22 (88%) | 16 (64%) | 9 (36%) | 32.8 ± 7.1 | 9 (36%) | | Muller, 2017 | GERMANY | Retrospective Study | 114 | 24 months | 63 ± 12 | 87 (76%) | 91 (80%) | N/A | 26.1 ± 5.0 | N/A | | Roger, 2018 | GERMANY | Prospective Study | 20 | 3-4 months | 54.3 ± 11.5 | 18 (90%) | 6 (30%) | 4 (20%) | 24.4 ± 8.1 | N/A | | Tint, 2023 | ROMANIA | Prospective Study | 20 | 12 months | 66.5 ± 6.9 | 19 (95%) | N/A | 6 (30%) | 24.7 ± 4.5 | 9 (45%) | | Vartanian, 2022 | USA | Prospective Study | 10 | 6 months | 63.4 ± 9.85 | 8 (80%) | N/A | N/A | N/A | N/A | | Yu, 2009 | CHINA & USA | Prospective Study | 30 | 3 months | 60 ± 11 | 24 (80%) | N/A | N/A | 29.0 ± 6.5 | N/A | | Yücel, 2022 | GERMANY | Retrospective Study | 174 | 36-50 months | 69 ± 12 | 127 (83%) | N/A | 62 (41%) | 21.98 ± 5.4 | 37 (24%) | | Yücel, 2025 | GERMANY & USA | Retrospective Study | 105 | 12 months | 62.7 ± 12.5 | 84 (80%) | N/A | 48 (45.7%) | 23.6 ± 6.2 | 27 (25.7%) | | Zhang, 2013 | CHINA & HONG KONG | Prospective Study | 33 | 3 months | 60 ± 11 | 26 (78.8%) | N/A | N/A | 27.7 ± 6.9 | N/A | Data are presented as mean ± standard deviation, number (no.), or median (interquartile range). Abbreviations: N/A = Not Available; ICD = Implantable cardioverter-defibrillator; LVEF = Left-Ventricular Ejection Fraction backend=biber, style=alphabetic, sorting=ynt ]biblatex 3.3 Functional outcomes: Across the included studies, CCM therapy was associated with a mean increase of 44.96 meters in 6MWT distance (95% CI: 2.73 to 87.20; Z = 2.09; P = 0.037; I² = 86.3%) (Figure 2A) . Peak oxygen consumption demonstrated a small, non-significant mean change of 0.13 mL O₂/kg/min (95% CI: –0.73 to 0.98; Z = 0.29; P = 0.770; I² = 79.1%) (Figure 2B) . New York Heart Association functional class showed a mean decrease of 0.89 (95% CI: −1.18 to −0.60; Z = −6.06; P < 0.001; I² = 85.7%) (Figure 2C) . Minnesota Living with Heart Failure Questionnaire scores showed a mean reduction of 11.83 points (95% CI: −15.65 to −8.02; Z = −6.07; P < 0.001; I² = 63.0%) (Figure 2D) . backend=biber, style=alphabetic, sorting=ynt ]biblatex Figure 2A: Forest plot for the outcome of the 6-Minute Walk Test. The analysis shows the 6MWT rates, analyzing the efficiency of cardiac contractility modulation across all included studies. The blue diamonds at the bottom represent the pooled MD derived from the meta-analysis, under both common-effect and random-effects models, along with their corresponding CI. CI: Confidence Interval; MD: Mean Difference Figure 2B: Forest plot for the outcome of Peak VO 2 . The analysis shows the Peak VO 2 rates, analyzing the efficiency of cardiac contractility modulation across all included studies. The blue diamonds at the bottom represent the pooled MD derived from the meta-analysis under both common-effect and random-effects models and their corresponding CI. CI: Confidence Interval; MD: Mean Difference Figure 2C: Forest plot for the outcome of New York Heart Association (NYHA) classification of heart failure. The analysis shows the NYHA rates, analyzing the efficiency of cardiac contractility modulation across all included studies. The blue diamonds at the bottom represent the pooled MD derived from the meta-analysis, under both common-effect and random-effects models, and their corresponding CI. CI: Confidence Interval; MD: Mean Difference Figure 2D: Forest plot for the outcome of the Minnesota Living with Heart Failure Questionnaire (MLHFQ). The analysis shows the MLHFQ rates, analyzing the efficiency of cardiac contractility modulation across all included studies. The blue diamonds at the bottom represent the pooled MD derived from the meta-analysis, under both common-effect and random-effects models, and their corresponding CI. CI: Confidence Interval; MD: Mean Difference backend=biber, style=alphabetic, sorting=ynt ]biblatex 3.4 Structural Outcomes: Structural cardiac parameters demonstrated favorable remodeling after CCM therapy. Left ventricular ejection fraction increased by a mean of 5.96% (95% CI: 4.65 to 7.26; Z = 8.96; P < 0.001; I² = 68.0%) (Figure 3A) . Reductions were observed in both left ventricular end-systolic volume, with a mean decrease of 24.17 mL (95% CI: −40.12 to −8.22; Z = −2.97; P = 0.003; I² = 64.2%) (Figure 3B), and left ventricular end-diastolic volume, with a mean reduction of 18.44 mL (95% CI: −29.97 to −6.91; Z = −3.13; P = 0.002; I² = 29.0%) (Figure 3C) . backend=biber, style=alphabetic, sorting=ynt ]biblatex Figure 3A: Forest plot for the outcome of left ventricle ejection fraction. The analysis shows the LVEF rates, analyzing the efficiency of cardiac contractility modulation across all included studies. The blue diamonds at the bottom represent the pooled MD derived from the meta-analysis, under both common-effect and random-effects models, and their corresponding CI. CI: Confidence Interval; MD: Mean Difference Figure 3B: Forest plot for the outcome of left ventricle end-systolic volume. The analysis shows the LVESV rates, analyzing the efficiency of cardiac contractility modulation across all included studies. The blue diamonds at the bottom represent the pooled MD derived from the meta-analysis, under both common-effect and random-effects models, and their corresponding CI. CI: Confidence Interval; MD: Mean Difference Figure 3C: Forest plot for the outcome of left ventricle end-diastolic volume. The analysis shows the LVEDV rates, analyzing the efficiency of cardiac contractility modulation across all included studies. The blue diamonds at the bottom represent the pooled MD derived from the meta-analysis, under both common-effect and random-effects models, and their corresponding CI. CI: Confidence Interval; MD: Mean Difference 3.5 Sensitivity analysis: Sensitivity analyses using the leave-one-out method were performed to investigate sources of heterogeneity. Exclusion of the study by Tint (20) for the 6MWT outcome reduced heterogeneity to 18% and yielded a revised mean difference of +15.91 meters (Figure S2A) . In the analysis of Peak VO₂, excluding the Kadish (26) study resulted in a mean difference of +0.63 mL O₂/kg/min and a heterogeneity of 47.4% (Figure S2B) . For the MLHFQ outcome, the omission of Abraham’s study (29) reduced heterogeneity to 41.7% and resulted in a mean difference of −10.48 points (Figure S2D) . For LVESV, removal of Yuecel’s (16) study resulted in a mean difference of −15.21 mL with no residual heterogeneity (I² = 0%) (Figure S2F) . No single study was found to significantly influence the pooled estimates for NYHA functional class or LVEF. 3.6 Quality assessment: Egger’s regression test for the LVEF outcome indicated no evidence of significant publication bias (t = 0.38; df = 11; P = 0.7142), with a bias estimate of 0.4406 (SE = 1.1724) (Figure S3) . Among the observational studies assessed using the ROBINS-I tool, the majority were rated as having a serious risk of bias, primarily attributable to confounding factors. The remaining studies were classified as having either moderate or low risk of bias. For all other outcomes, publication bias was evaluated visually using funnel plot analysis, as the number of included studies was fewer than ten (Figure S4A-S4B and S5A-S5B) .

This systematic review and meta-analysis demonstrate that cardiac contractility modulation therapy significantly improves clinical, functional, and structural outcomes in patients with symptomatic HFrEF. CCM therapy led to a mean increase of 5.96% in LVEF and reductions in LVESV (−24.17 mL) and LVEDV (−18.44 mL), indicating favorable reverse remodeling. Functional status and quality of life also improved, as evidenced by a decrease in NYHA functional class (−0.89), an increase in 6MWT distance (+44.96 meters), and a reduction in Minnesota Living with Heart Failure Questionnaire scores (−11.83 points). Although peak VO₂ did not initially reach statistical significance, sensitivity analyses excluding outlier studies revealed a positive trend. Importantly, no publication bias was detected for the LVEF outcome. These findings reinforce the therapeutic potential of CCM for HFrEF patients who remain symptomatic despite optimal medical therapy and are ineligible for cardiac resynchronization therapy. CRT remains the cornerstone non-pharmacological intervention for patients with HFrEF who are in sinus rhythm, have left bundle branch block (LBBB), a QRS duration of >130 milliseconds, and NYHA class II–IV symptoms despite optimized therapy (30). However, only approximately 30% of HFrEF patients meet CRT eligibility criteria (31), and among those who undergo CRT, up to one-third are classified as non-responders (32,33). This highlights a substantial therapeutic gap in HFrEF management, especially given the limited availability and contraindications associated with advanced therapies such as heart transplantation and mechanical circulatory support. CCM has thus emerged as a promising strategy to address this unmet clinical need. Randomized controlled trials, including FIX-HF-5 and FIX-HF-5C, have shown that CCM therapy is safe and improves functional capacity (as measured by peak VO₂), NYHA class, and quality of life, with a trend toward reduced heart failure hospitalizations (26,29). Long-term follow-up data and real-world registries have confirmed the device’s favorable safety profile and suggested potential prognostic benefits, particularly in patients with an LVEF between 25% and 45% (27). These data have led to regulatory approvals, including from the U.S. Food and Drug Administration (FDA), and incorporation of CCM into international heart failure guidelines (1,2). The magnitude of improvements observed in this analysis aligns with findings from prior randomized trials and meta-analyses (26,27,34,35). The observed reverse remodeling, reflected by increased LVEF and reduced ventricular volumes, along with consistent improvements in functional status and quality of life, supports the biological plausibility and clinical efficacy of CCM therapy in this population. Although peak VO₂ did not initially achieve statistical significance, sensitivity analyses confirmed a positive trend, consistent with results from pivotal trials. The clinical and structural benefits of CCM align with its established molecular mechanisms. Preclinical studies have shown that CCM enhances myocardial calcium handling and energetics through increased phosphorylation of phospholamban, upregulation of SERCA2a, and improvements in GLS and myocardial mechano-energetic efficiency (1,6,7,34). These adaptations likely underlie the observed improvements in myocardial performance and functional capacity. However, several limitations should be acknowledged. First, significant heterogeneity was observed across several outcomes, likely reflecting differences in study design, patient populations, intervention protocols, and follow-up durations. While sensitivity analyses mitigated some of this heterogeneity, residual variability remains a limitation. Second, most included studies were observational and of small sample size, introducing potential selection bias and limiting generalizability. Third, the limited number of studies reporting specific outcomes, such as peak VO₂ and ventricular volumes, hindered robust assessments of publication bias. Fourth, variability in imaging modalities and outcome definitions may have contributed to measurement inconsistencies. Finally, the range of follow-up durations limited time-dependent analyses and subgroup comparisons.

In conclusion, this meta-analysis supports using CCM as an effective, device-based therapy that provides meaningful structural and functional benefits in patients with symptomatic HFrEF who are not candidates for CRT. These findings highlight the potential of CCM to address a critical therapeutic gap in advanced heart failure management. Future large-scale, randomized trials with standardized protocols and long-term follow-up are warranted to confirm these benefits and to clarify further the role of CCM in improving survival and reducing hospitalizations in this high-risk population.

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Information & Authors Information Version history Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Authors Metrics & Citations Metrics Article Usage 208views 152downloads Citations Download citation Ricardo Fonseca Oliveira Suruagy Motta, Christian K. Fukunaga, Everton Victor Belmiro da Silva, et al. CARDIAC CONTRACTILITY MODULATION IN SYMPTOMATIC HEART FAILURE WITH REDUCED EJECTION FRACTION: A SYSTEMATIC REVIEW AND SINGLE-ARM META-ANALYSIS. Authorea. 03 September 2025. DOI: https://doi.org/10.22541/au.175692110.03294929/v1 DOI: https://doi.org/10.22541/au.175692110.03294929/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.