Direct epicardial shock wave therapy improves ventricular function in a porcine model of ischemic heart disease: evidence for induction of angiogenesis and stimulation of VEGF receptors

Abstract

Purpose: Shock waves were shown to induce angiogenesis in ischemic myocardium in rodent models. In the present experiments we aimed to address safety and efficacy of direct epicardial shock wave therapy in a preclinical large animal model and to further evaluate mechanism of action of this novel therapy. Methods: Four weeks after left anterior descending (LAD) artery ligation in pigs, animals underwent re-thoracotomy with (SW group, n=6) or without (CTR, n=5) direct epicardial shock waves (300 impulses at 0.38mJ/mm2) applied to the infarcted anterior wall. Efficacy endpoints were improvement of LVEF and induction of angiogenesis 6 weeks after shock wave therapy. Safety endpoints were hemodynamic stability during treatment and myocardial damage. A receptor tyrosine kinase profiler was performed in human coronary artery endothelial cells to proof receptor activation. Results: Four weeks after LAD ligation, LVEF decreased in both shock wave (43±3%, p<0.001) and control (41±4%, p=0.012) group. LVEF markedly improved in shock wave animals 6 weeks after treatment (62±9%, p=0.006), no improvement was observed in controls (41±4%, p=0.36). Quantitative histology revealed significant angiogenesis six weeks after treatment as shown by number of arterioles (CTR 2±0.4 arterioles/high power field vs. SW 9±3, p=0.004), number of capillaries (CTR 9±4 vs. SWT 53±12, p<0.001) and number of vital cells (CTR 212±32 vs. SWT 310±48, p=0.003). No acute or chronic adverse effects were observed. In-vitro experiments revealed a two- and four-fold increase in VEGF receptor 1 and 2 phosphorylation in human coronary artery endothelial cells. Conclusions: Direct epicardial shock wave treatment in a large animal model of ischemic heart failure exerted positive effect on LVEF improvement and did not show any adverse effects. Angiogenesis was induced by stimulation of VEGF receptors. It may serve in future as an adjunct to CABG surgery.