Ventricular remodeling in ischemic heart failure stratifies responders to stem cell therapy

Abstract

Response to stem cell therapy in heart failure is heterogeneous, warranting a better understanding of outcome predictors. This study assessed left ventricular volume, a surrogate of disease severity, on cell therapy benefit. Small to large infarctions were induced in murine hearts to model moderate, advanced, and end-stage ischemic cardiomyopathy. At 1 month postinfarction, cardiomyopathic cohorts with comparable left ventricular enlargement and dysfunction were randomized 1:1 to those that either received sham treatment or epicardial delivery of cardiopoietic stem cells (CP). Progressive dilation and pump failure consistently developed in sham. In comparison, CP treatment produced significant benefit at 1 month post-therapy, albeit with an efficacy impacted by cardiomyopathic stage. Advanced ischemic cardiomyopathy was the most responsive to CP-mediated salvage, exhibiting both structural and functional restitution, with proteome deconvolution substantiating that cell therapy reversed infarction-induced remodeling of functional pathways. Moderate cardiomyopathy was less responsive to CP therapy, improving contractility but without reversing preexistent heart enlargement. In end-stage disease, CP therapy showed the least benefit. This proof-of-concept study thus demonstrates an optimal window, or "Goldilocks principle," of left ventricular enlargement for maximized stem cell-based cardiac repair. Disease severity grading, prior to cell therapy, should be considered to inform regenerative medicine interventions.

Keywords: cardiopoiesis; left ventricular volume; myocardial infarction; outcome; proteomics; regenerative medicine.

Figure 1

Range of stem cell therapy benefit in myocardial infarction. A, In age‐matched inbred mice devoid of heart failure risk factors, LV size demonstrated a narrow bell‐shaped distribution, underscoring homogeneity before disease initiation. B, Left anterior descending artery was ligated from a distal to a proximal site, inducing mild to severe ischemic cardiomyopathy. ST elevation on the electrocardiogram and wall motion abnormality on ultrasound confirmed anterior wall myocardial infarction. Within 1 month postinfarction, LV end‐diastolic volume increased from 43 ± 1 μl (n = 50; A) to 77 ± 4 μl (n = 50, p < .001). C, Along with structural alteration (B), LV pump function, measured by ejection fraction, decreased from 68% ± 1% preinfarction to 37% ± 1% 1 month postinfarction (n = 50, p < .0001). Cardiomyopathic animals were randomized into those treated with epicardial delivery of CP cells (CP(+), n = 25) and sham (CP(−), n = 25). In contrast to progressive decline in sham, ejection fraction significantly recovered with CP therapy (1 month post‐therapy, 30% ± 3% in CP(−), 45% ± 3% in CP(+), p < .0001). D, Similarly, pathological chamber dilatation was reversed in CP‐treated cardiomyopathy (LV end‐systolic volume post‐therapy, 69 ± 10 μl in CP(−), 42 ± 5 μl in CP(+), p < .001). E, F, Comparing pretherapy and post‐therapy unmasked individual variability in response. CP, cardiopoietic stem cells; LV, left ventricle

Figure 2

Effectiveness of stem cell therapy in ischemic cardiomyopathy depends on the extent of preexistent chamber dilatation. A, CP therapy‐mediated (CP(+), n = 25) recovery of LV contractility, observed during 1 month follow‐up, inversely correlated with LV size at time of intervention (pretherapy LVEDV). Disease severity was categorized based on pretherapy LVEDV into moderate (LVEDV <65 μl, 7 CP(+), low 28% of the CP(+) cohort), advanced (65 μl < LVEDV <100 μl, 13 CP(+), middle 52%), and end‐stage (100 μl < LVEDV, 5 CP(+), upper 20%). Adjusted by body weight, moderate‐, advanced‐, and end‐stage ischemic cardiomyopathy in mice corresponds to that of LVEDV <200, 200‐370, >370 ml, respectively in humans.17, 21, 22 Δ ejection fraction, change in ejection faction post‐therapy vs pretherapy; blue solid lines, predetermined criteria of improvement (>4%) and worsening (<−4%) in Δ ejection fraction. B, Reverse remodeling (>15% reduction in LV end‐systolic volume) occurred in the majority of advanced stage recipients, displaying a v‐shaped relationship between Δ end‐systolic volume and pretherapy LVEDV. CP, cardiopoietic stem cells; LV, left ventricle; LVEDV, LV end‐diastolic volume

Figure 3

Grading of cardiac dilatation identifies a window of optimal response to stem cell therapy. At time of randomization (pretherapy), echocardiographic parameters were equivalent between ischemic cardiomyopathy cohorts. Prospective 1 month follow‐up (post‐therapy) validated the superiority of the CP‐treated (CP(+)) over CP‐untreated (CP(−)) cohort across all stages of cardiomyopathy, yet the effectiveness depended on the pretherapy LV volume. Specifically, in moderate cardiomyopathy (pretherapy LVEDV <65 μl; A, B), CP therapy improved EF (−6% ± 3% in CP(−), 8 ± 3% in CP(+), p < .01; A bottom), but did not change the natural course of progressive LV dilatation (A top). Advanced ischemic cardiomyopathy (65 μl < pretherapy LVEDV <100 μl; C, D) was most responsive to CP‐mediated improvement with both structural (C top) and functional (C bottom) restitution. In end‐stage cardiomyopathy (100 μl < pretherapy LVEDV; E, F), cell therapy‐hampered disease progression into terminal heart failure which was unavoidable in the untreated cohort. However, CP intervention fell short in salvaging the underlying end‐stage conditions (F). CP, cardiopoietic stem cells; EF, ejection fraction; LV, left ventricle; LVEDV, LV end‐diastolic volume

Figure 4

CP‐dependent proteome underpins advanced‐disease rescue. A, None of the untreated cohorts (CP(−)) recovered from ischemic cardiomyopathy, indicating the malignant nature of heart failure following anterior wall myocardial infarction. CP therapy (CP(+)) achieved both EF improvement and reverse remodeling, defined by >4% absolute increase (ΔEF > 4%) and >15% reduction in LVESV (ΔLVESV <−15%), respectively. These endpoints were achieved in the majority (62%, 8/13) only for the advanced stage cohort, while rarely in moderate (14%, 1/7) and end‐stage (20%, 1/5) groups. B, To decode the molecular basis of benefit, differential proteomic analysis was conducted specifically within the advanced cohort, revealing 79 differentially expressed proteins between CP(+) and CP(−), organized here by agglomerative clustering of z‐score transformed relative expression data. C, Ingenuity Pathway Analysis of these proteins independently predicted the observed functional outcomes, with significant enrichment for improvement in contractility and reversal of cardiac dilatation. CP, cardiopoietic stem cells; EF, ejection fraction; LVESV, left ventricular end‐systolic volume