Shock Wave Therapy Improves Cardiac Function in a Model of Chronic Ischemic Heart Failure: Evidence for a Mechanism Involving VEGF Signaling and the Extracellular Matrix

Abstract

Background Mechanical stimulation of acute ischemic myocardium by shock wave therapy ( SWT ) is known to improve cardiac function by induction of angiogenesis. However, SWT in chronic heart failure is poorly understood. We aimed to study whether mechanical stimulation upon SWT improves heart function in chronic ischemic heart failure by induction of angiogenesis and postnatal vasculogenesis and to dissect underlying mechanisms. Methods and Results SWT was applied in a mouse model of chronic myocardial ischemia. To study effects of SWT on postnatal vasculogenesis, wild‐type mice received bone marrow transplantation from green fluorescence protein donor mice. Underlying mechanisms were elucidated in vitro in endothelial cells and murine aortic rings. Echocardiography and pressure/volume measurements revealed improved left ventricular ejection fraction, myocardial contractility, and diastolic function and decreased myocardial fibrosis after treatment. Concomitantly, numbers of capillaries and arterioles were increased. SWT resulted in enhanced expression of the chemoattractant stromal cell–derived factor 1 in ischemic myocardium and serum. Treatment induced recruitment of bone marrow–derived endothelial cells to the site of injury. In vitro, SWT resulted in endothelial cell proliferation, enhanced survival, and capillary sprouting. The effects were vascular endothelial growth factor receptor 2 and heparan sulfate proteoglycan dependent. Conclusions SWT positively affects heart function in chronic ischemic heart failure by induction of angiogenesis and postnatal vasculogenesis. SWT upregulated pivotal angiogenic and vasculogenic factors in the myocardium in vivo and induced proliferative and anti‐apoptotic effects on endothelial cells in vitro. Mechanistically, these effects depend on vascular endothelial growth factor signaling and heparan sulfate proteoglycans. SWT is a promising treatment option for regeneration of ischemic myocardium.

Shock waves promote spinal cord repair via TLR3

“…Most of these effects could not be mimicked by poly(I:C) exposure but were strictly dependent on TLR3. Both TLR3 stimulation as well as SWT have been described to induce release of growth factors, including VEGF, FGF, and NGF (10,21). Consistently, we observed upregulation of VEGF and its receptor VEGFR2 (Supplemental Figure 2).…”

“…Previously, our group showed that SWT reduces scarring after myocardial infarction (10). To analyze whether SWT may decrease lesion size after SCI, we performed MRI of the spinal cord ( Figure 1D).…”

“…SWT has been described to induce tissue regeneration through stimulation of the innate immune receptor TLR3 in skin, bone, tendons, and cardiac tissue (8)(9)(10). Here, we aimed to substantiate (a) the physiological role of TLR3 in spinal cord repair after injury and (b) the efficacy of TLR3 stimulation via SWT in traumatic SCI.…”

Mechanical Stimulation of Fibroblasts by Extracorporeal Shock Waves: Modulation of Cell Activation and Proliferation Through a Transient Proinflammatory Milieu

“…ESWTs have been applied as a successful therapy in heart failure and cardiovascular diseases in humans 43 – 45 . Moreover, in vivo experiments carried out in rats in the presence of LPS or ESWTs resulted in post-infarct cardiac tissue regeneration 46 , 47 .…”

Large Animal Models of Cell-Free Cardiac Regeneration

“…Since then, multiple groups have replicated these results, although mostly with an invasive methodology that applies the SWT directly to the affected myocardial area. This invasive protocol has been tested in mice [ 81 ], rats [ 82 ], and finally in pigs [ 83 ], with very similar outcomes in the treatment group as observed by Nishida et al The therapeutic effect seems to be driven mainly by increased angiogenesis via the upregulation of VEGF and chemoattraction of endothelial cells via stromal cell-derived factor 1 [ 81 ].…”