Heart failure (HF) represents a growing global health burden, affecting over 64 million individuals worldwide and accounting for significant morbidity, hospitalizations, and healthcare costs (1). Despite advances in pharmacological and device-based therapies, a substantial subset of patients remains symptomatic and unresponsive to standard treatment protocols, commonly referred to as refractory heart failure (RHF) (2,3). These patients are particularly vulnerable to recurrent decompensation, progressive ventricular dysfunction, and poor quality of life.

In this context, non-pharmacological interventions have gained attention as adjunctive strategies to improve hemodynamics and myocardial function. Enhanced External Counterpulsation (EECP) is a non-invasive circulatory support therapy that augments diastolic coronary perfusion and reduces cardiac workload by applying cyclic external pressure to the lower extremities in synchrony with the cardiac cycle (4). Clinical trials have shown EECP to improve angina, exercise tolerance, and endothelial function in both ischemic and non-ischemic cardiomyopathies (5,6).

Similarly, External Myocardial Synchronous Reconditioning (EMSR) is an emerging modality that delivers timed mechanical impulses to the thoracic wall, aimed at promoting myocardial entrainment and functional remodeling (7). While EMSR has shown promise in enhancing ventricular synchrony and contractility, comparative studies with EECP in RHF populations remain sparse.

The integration of biomarkers and imaging modalities provides a multidimensional approach to evaluating therapeutic efficacy in heart failure. Biomarkers such as NT-proBNP, galectin-3, and high-sensitivity troponin are well-established indicators of myocardial stress, fibrosis, and injury, offering dynamic insight into disease progression and recovery (8). Concurrently, advanced imaging techniques, including echocardiographic strain analysis and cardiac magnetic resonance imaging (MRI), allow for precise assessment of structural and functional myocardial changes (9,10).

Patient Selection

Patients aged 40–75 years diagnosed with refractory heart failure (NYHA Class III or IV) despite optimal medical management for at least 6 months were screened. Inclusion criteria included left ventricular ejection fraction (LVEF) ≤ 35%, elevated NT-proBNP levels (>500 pg/mL), and the ability to comply with outpatient intervention protocols. Exclusion criteria were recent myocardial infarction (<3 months), decompensated arrhythmias, severe valvular disease requiring surgery, active infection, malignancy, and contraindications to EECP or EMSR therapy.

Randomization and Group Allocation

Eligible participants (n=120) were randomized using a computer-generated block randomization technique into two equal groups:

• Group A (EECP group) received standard Enhanced External Counterpulsation therapy.
• Group B (EMSR group) received External Myocardial Synchronous Reconditioning therapy.

Intervention Protocols

• EECP Protocol: Patients underwent 35 one-hour EECP sessions over 7 consecutive weeks using standard pneumatic cuffs applied to the calves, thighs, and buttocks. Inflation and deflation cycles were synchronized with the cardiac cycle via ECG monitoring.
• EMSR Protocol: Participants in the EMSR group received 35 sessions of thoracic synchronized reconditioning over the same duration. EMSR was delivered using a device programmed to deliver low-amplitude mechanical impulses during diastole, synchronized with ECG rhythm.

Biomarker Assessment

Blood samples were collected at three time points: baseline (pre-intervention), immediately after the last session, and at 3-month follow-up. Serum levels of NT-proBNP, high-sensitivity cardiac troponin I (hs-cTnI), and galectin-3 were analyzed using standardized ELISA-based methods in certified laboratories.

Imaging Evaluation

All participants underwent transthoracic echocardiography using a standardized protocol to assess left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), and end-systolic diameter (LVESD). Global longitudinal strain (GLS) was measured using speckle-tracking echocardiography. In a subset of 40 patients (20 from each group), cardiac MRI was performed to evaluate myocardial perfusion, fibrosis (via late gadolinium enhancement), and ventricular remodeling.

Safety Monitoring

Adverse events during the intervention period were monitored and recorded. All sessions were supervised by trained cardiology personnel.

Statistical Analysis

Statistical analysis was performed using SPSS version 26.0. Continuous variables were expressed as mean ± standard deviation, and categorical variables as frequencies and percentages. Inter-group comparisons were analyzed using the independent t-test or Mann–Whitney U test, and intra-group comparisons using paired t-tests. A p-value of <0.05 was considered statistically significant.

A total of 120 patients were enrolled, with 60 in the EECP group and 60 in the EMSR group. Baseline demographic and clinical characteristics were comparable between the groups (Table 1). The mean age of participants was 64.2 ± 7.8 years in the EECP group and 63.5 ± 8.1 years in the EMSR group. Both groups had similar baseline LVEF (EECP: 28.4 ± 3.1%, EMSR: 27.9 ± 3.4%; p = 0.32).

Biomarker Outcomes

At the end of the 7-week intervention period, significant reductions were observed in NT-proBNP, hs-cTnI, and galectin-3 levels in both groups, with greater improvement in the EECP group. NT-proBNP levels decreased by 420 ± 75 pg/mL in EECP vs. 310 ± 65 pg/mL in EMSR (p = 0.01). Similarly, galectin-3 levels reduced more significantly in the EECP group (4.2 ± 0.6 ng/mL) than in the EMSR group (2.9 ± 0.5 ng/mL; p = 0.02) (Table 2).

Imaging Outcomes

Echocardiographic assessment showed notable improvement in LVEF in both groups. The EECP group demonstrated an increase in LVEF from 28.4% to 36.9% (p < 0.001), while the EMSR group showed improvement from 27.9% to 34.2% (p < 0.001). Global longitudinal strain (GLS) values also improved more substantially in the EECP group (-14.1% vs. -12.7%; p = 0.04). MRI findings in the sub-cohort indicated improved myocardial perfusion in 65% of EECP patients compared to 48% in the EMSR group (p = 0.03).

No major adverse events were reported in either group during the study period.

Table 1. Baseline Characteristics of the Study Population

Table 2. Post-Intervention Changes in Biomarkers and Imaging Parameters

These tables clearly demonstrate the superior biomarker and imaging outcomes in the EECP group as compared to the EMSR group (Table 1 and Table 2).

This multi-center comparative study evaluated the effects of Enhanced External Counterpulsation (EECP) and External Myocardial Synchronous Reconditioning (EMSR) in patients with refractory heart failure (RHF), using both biomarker and imaging modalities as outcome measures. The findings suggest that while both interventions lead to significant improvements in myocardial function, EECP provides a more pronounced benefit in terms of biomarker reduction and echocardiographic and MRI-based recovery.

The significant reduction in NT-proBNP levels following EECP therapy aligns with prior studies suggesting its ability to unload the left ventricle and enhance diastolic perfusion (1,2). NT-proBNP is a reliable indicator of myocardial wall stress and is strongly correlated with adverse cardiac outcomes (3). The greater decline in NT-proBNP in the EECP group supports the hypothesis that mechanical counterpulsation may lead to meaningful hemodynamic improvements in RHF (4).

Galectin-3, a biomarker of myocardial fibrosis and remodeling, also decreased significantly post-EECP compared to EMSR. Elevated galectin-3 levels are associated with progressive myocardial dysfunction and poor survival in HF patients (5). The superior reduction in galectin-3 with EECP may suggest that its therapeutic effects extend beyond hemodynamics, potentially influencing myocardial extracellular matrix dynamics (6).

Moreover, EECP led to a greater improvement in high-sensitivity cardiac troponin I (hs-cTnI), which reflects ongoing subclinical myocardial injury. Persistent elevation of hs-cTnI is associated with worse outcomes even in clinically stable HF patients (7). Our findings are consistent with those of previous investigations reporting reduced myocardial injury markers following counterpulsation therapy (8,9).

Imaging parameters also favored EECP over EMSR. The improvement in left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) was more significant in the EECP group. GLS is recognized as a sensitive indicator of early myocardial functional improvement and provides prognostic information beyond traditional LVEF measures (10). Furthermore, cardiac MRI in a subset of patients revealed more frequent perfusion improvement in the EECP group, further corroborating its impact on myocardial recovery (11).

While EMSR also demonstrated improvements across all parameters, the magnitude of change was relatively modest. EMSR, although still under clinical investigation, appears to enhance myocardial synchrony through external entrainment of myocardial motion (12). However, its clinical utility and long-term effects in RHF remain under-evaluated. Previous small-scale trials have reported improvements in cardiac performance with EMSR, but direct comparisons with established interventions like EECP are scarce (13).

Both therapies were well tolerated, with no major adverse events reported. This is consistent with the existing safety profiles of EECP and EMSR, which are considered non-invasive and suitable for outpatient application (14,15). The absence of complications supports their feasibility for adjunctive use in patients unsuitable for invasive interventions.

Limitations of the current study include the relatively short follow-up period and the lack of long-term outcome data such as hospitalization rates and survival. Additionally, the cardiac MRI sub-cohort size was limited, which may restrict the generalizability of those findings.

In conclusion, while both EECP and EMSR offer clinical benefits in patients with refractory heart failure, EECP appears to provide superior improvements in biomarkers and cardiac imaging indices. These results underscore the potential of EECP as a preferred non-invasive strategy for myocardial recovery in RHF management.

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