Background: Cardiogenic shock (CS) following myocardial infarction (MI) in patients undergoing primary coronary intervention is characterized by severe ischemia–reperfusion injury (IRI), which leads to a strong induction of cellular senescence in the myocardium. Senescent cells release pro-inflammatory and pro-fibrotic mediators, compiled as the senescence-associated secretory phenotype (SASP), which drive adverse cardiac remodeling, fibrosis, and pump dysfunction. Mechanical circulatory support (MCS) with temporary microaxial flow devices (ImpellaÒ) is often applied in CS after MI. Notably, several patients show sustained recovery after ImpellaÒ explantation, suggesting that left ventricular (LV) unloading may attenuate senescence induction and thereby enhance functional recovery.
Methods: Serum samples from 14 patients with CS after MI treated with ImpellaÒ support were analyzed at baseline, and on days 1, 3, and 7 after implantation. Patients were stratified according to their degree of cardiac functional improvement: moderate recovery was defined as an improvement of 10–20% in LV ejection fraction (LVEF) as assessed by echocardiography, and strong recovery as an LVEF-improvement of more than 20%. To assess senescence induction, a Human-Cytokine-Panel-A-48-Plex-Discovery-Assay® in addition to single ELISA was performed to quantify SASP factors. Moreover, we measured the expression of DPP4, a novel systemic, senescence biomarker expressed on extracellular vesicles (EVs) deriving from senescent cells thus also correlating with their abundancy in tissues. Therefore, EVs were isolated from serum samples using the exoEasy Maxi Kit, lysed with RIPA buffer and subsequently DPP4 expression was assessed using ELISA.
Results: ImpellaÒ therapy was associated with a significant reduction in circulating pro-inflammatory SASP factors, including MCP-1, IL-1β, IL-1α and TNF-α (p<0.001), with a more pronounced decrease in patients showing greater functional recovery (p<0.05). Consistently, the cardiomyocyte-specific SASP factor GDF15, which is implicated in fibrosis and heart failure following MI, declined more profoundly in patients exhibiting strong recovery (p<0.01). Pro-fibrotic SASP factors including VEGF, IL-17a and sCD40L followed a similar trend (p<0.05). Most importantly, the expression of DPP4 declined significantly more profoundly in the patient group showing strong recovery after 3 days of ImpellaÒ support (62±10 pg/ml vs. 42±7 pg/ml, p<0.01) indicating a diminished senescence induction in these patients.
Conclusion: Our data provide novel mechanistic insights suggesting that ImpellaÒ support in patients experiencing CS after MI promotes myocardial recovery through limiting the induction of cellular senescence associated with decreased pro-inflammatory and pro-fibrotic SASP factors. Evaluating senescence biomarkers during ImpellaÒ therapy may support the identification of patients with cardiac recovery. Moreover, targeting cellular senescence following MI could display a novel therapeutic target.
