Aims As many current approaches for heart regeneration exert unfavourable side effects, the induction of endogenous repair mechanisms in ischaemic heart disease is of particular interest. Recently, exosomes carrying angiogenic miRNAs have been described to improve heart function. However, it remains challenging to stimulate specific release of reparative exosomes in ischaemic myocardium. In the present study, we sought to test the hypothesis that the physical stimulus of shock wave therapy (SWT) causes the release of exosomes. We aimed to substantiate the pro-angiogenic impact of the released factors, to identify the nature of their cargo, and to test their efficacy in vivo supporting regeneration and recovery after myocardial ischaemia. Methods and results Mechanical stimulation of ischaemic muscle via SWT caused extracellular vesicle (EV) release from endothelial cells both in vitro and in vivo. Characterization of EVs via electron microscopy, nanoparticle tracking analysis and flow cytometry revealed specific exosome morphology and size with the presence of exosome markers CD9, CD81, and CD63. Exosomes exhibited angiogenic properties activating protein kinase b (Akt) and extracellular-signal regulated kinase (ERK) resulting in enhanced endothelial tube formation and proliferation. A miRNA array and transcriptome analysis via next-generation sequencing were performed to specify exosome content. miR-19a-3p was identified as responsible cargo, antimir-19a-3p antagonized angiogenic exosome effects. Exosomes and target miRNA were injected intramyocardially in mice after left anterior descending artery ligation. Exosomes resulted in improved vascularization, decreased myocardial fibrosis, and increased left ventricular ejection fraction as shown by transthoracic echocardiography. Conclusion The mechanical stimulus of SWT causes release of angiogenic exosomes. miR-19a-3p is the vesicular cargo responsible for the observed effects. Released exosomes induce angiogenesis, decrease myocardial fibrosis, and improve left ventricular function after myocardial ischaemia. Exosome release via SWT could develop an innovative approach for the regeneration of ischaemic myocardium.
Aims The most appropriate definition of perioperative myocardial infarction (pMI) after coronary artery bypass grafting (CABG) and its impact on clinically relevant long-term events is controversial. We aimed to (i) analyse the incidence of pMI depending on various current definitions in a ‘real-life’ setting of CABG surgery and (ii) determine the long-term prognosis of patients with pMI depending on current definitions. Methods and results A consecutive cohort of 2829 coronary artery disease patients undergoing CABG from two tertiary university centres with the presence of serial perioperative cardiac biomarker measurements (cardiac troponin and creatine kinase-myocardial band) were retrospectively analysed. The incidence and prognostic impact of pMI were assessed according to (i) the 4th Universal Definition of Myocardial Infarction (4UD), (ii) the definition of the Society for Cardiovascular Angiography and Interventions (SCAI), and (iii) the Academic Research Consortium (ARC). The primary endpoint of this study was a composite of myocardial infarction, all-cause death, and repeat revascularization; secondary endpoints were mortality at 30 days and during 5-year follow-up. There was a significant difference in the occurrence of pMI (49.5% SCAI vs. 2.9% 4UD vs. 2.6% ARC). The 4th Universal Definition of Myocardial Infarction and ARC criteria remained strong independent predictors of all-cause mortality at 30 days [4UD: odds ratio (OR) 12.18; 95% confidence interval (CI) 5.00–29.67; P < 0.001; ARC: OR 13.16; 95% CI 5.41–32.00; P < 0.001] and 5 years [4UD: hazard ratio (HR) 2.13; 95% CI 1.19–3.81; P = 0.011; ARC: HR 2.23; 95% CI 1.21–4.09; P = 0.010]. Moreover, the occurrence of new perioperative electrocardiographic changes was prognostic of both primary and secondary endpoints. Conclusion Incidence and prognosis of pMI differ markedly depending on the underlying definition of myocardial infarction for patients undergoing CABG. Isolated biomarker release-based definitions (such as troponin) were not associated with pMI relevant to prognosis. Additional signs of ischaemia detected by new electrocardiographic abnormalities, regional wall motion abnormalities, or coronary angiography should result in rapid action in everyday clinical practice. Key question We aimed to (i) analyse the incidence of perioperative myocardial infarction (pMI) depending on different current definitions in a ‘real-life’ setting of coronary artery bypass graft surgery and (ii) determine the long-term prognosis of patients with pMI according to current definitions. Key finding There was a significant difference in the occurrence of pMI. The 4th Universal Definition of Myocardial Infarction and Academic Research Consortium criteria remained strong independent predictors for all-cause mortality at 30 days and during 5-year follow-up. Take-home message Isolated biomarker release-based definitions were not associated with pMI relevant to prognosis. Additional signs of ischaemia detected by new electrocardiogram abnormalities, regional wall motion abnormalities, or coronary angiography should result in rapid action in clinical practice.
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