Cardiac Shockwave Therapy: Commentary

Jargin SV

Published on: 2025-12-24

Abstract

The evidence supporting efficacy of cardiac shockwave therapy (CST) comes mostly from small, observational studies. Clinical benefits from CST are attributed to enhanced myocardial perfusion and angiogenesis explained among others by the up-regulation of vascular endothelial growth factors of the VEGF family. The role of VEGF in coronary artery disease and atherosclerosis is ambiguous; details are discussed here. A shockwave induces tissue cavitation leading to shear stress on cell membranes. The vulnerability of cardiomy ischemia is increased. Additional impact might contribute to the cell loss. Reported effects of CST may transient and reactive. Clinical improvements in humans are caused, at least in part, by the placebo effect. Placebo treatments are beneficial for some patients; however, placebo by definition must be harmless. Animal experiments with a longer follow-up are needed. However, some potential late consequences e.g. angiogenesis within plaques and their instability are hardly reproducible in experiments. The most reliable way to evaluate the net harm or benefit could be lifelong animal experiments with comparisons of average life duration between test and control groups.

Keywords

Cardiac shockwave therapy; Coronary artery disease; Angina; Myocardial perfusion

Commentary

The cardiac shockwave therapy (CST) is a non-invasive treatment that is supposed to promote angiogenesis through the use of low-intensity shockwaves aimed at the area of ischemia of myocardium [1]. The therapeutic potential of CST was first demonstrated in a porcine model of chronic myocardial ischemia, where the treatment heightened the left ventricular ejection fraction, regional myocardial blood flow and capillary density in the ischemic region [2]. Similar results were obtained in porcine models of acute myocardial infarction and ischemia-reperfusion injury [2-4]. Experimental studies have been relatively short-term [2-6], thus being not informative in regard to potential late consequences in humans. Indeed, it is doubtful “whether a chronic myocardial ischemia model of 4 weeks in an otherwise healthy pig can be compared with chronic ischemia of several months to years in our patients” [7]. The evidence supporting efficacy of CST in humans comes mostly from small, uncontrolled, low to moderate quality observational studies, while there is heterogeneity across reports [8-11]. Under these circumstances, theoretic considerations gain in importance. Concerns about the CST safety have been published [12-14].

CST with the following characteristics was applied to patients in the recent study: “300 impulses per coronary supply territory were applied at an energy flux density (EFD) of 0.38 mJ/mm2 and a frequency of 3 Hz” and “A high peak positive pressure amplitude (up to 120 MPa) is followed by a wave of negative pressure (up to 10 MPa)” [15]. Similar figures (300 impulses with EFD 0.38 mJ/mm²) are given in a newer article [16] and other papers referenced in [12]. It should be commented that shockwaves induce alternating positive/negative pressure and shear stress in targeted tissue [17,18]; if powerful enough, it can damage cell membranes, cytoskeleton and microvessels. Vulnerability of heart muscle cells in conditions of hypoxia is increased; the cells may undergo necrosis or apoptosis spontaneously, under influence of physical factors or myotoxicity [19]. Physical characteristics of CST partly overlap with those associated with injury. For example, shockwaves with the peak pressure 10 MPa caused lung bleeding in dogs [20]. Tissue damage was observed histologically in renal medulla of mice following the shockwave impact starting with peak pressures 3-5 MPa [21]. Of note, ultrastructural damage can be histologically invisible. Abnormalities were seen by electron microscopy in rats after shockwaves with EFD = 0.1 mJ/mm2 [18]. In vitro, cell necrosis was observed at EFD = 0.15 mJ/mm2 under certain conditions [17].

Biophysical mechanisms of supposed curative effect of CST in ischemic heart disease (IHD) are not well understood [17]. Vasodilatation has been ascribed to nitric oxide (NO), the half-life of which in living tissues is a few seconds only. Accordingly, the effects of NO in tissues must be transitory. The stimulation of angiogenesis is supposed to result from activation of the vascular endothelial growth factor (VEGF) and possibly of other growth factors [15]. VEGF plays an ambivalent role in IHD as it can induce proliferation of fibroblasts and myofibroblasts, thus contributing to fibrosis. In coronary arteries, the smooth muscle proliferation stimulated by VEGF may facilitate the growth of atherosclerotic plaques. Presumably, VEGF attracts inflammatory cells at different stages of atherogenesis [22,23], which may contribute to plaque instability. In conditions of atherosclerosis, elevated serum VEGF was associated with adverse cardiac events [23]. More references are in the preceding article [12].

The consequences of CST (hyperemia, up-regulation of growth factors, angiogenesis) may be manifestations of an unspecific injury-and-repair process, being transient and reactive in their nature. Besides, the placebo effect can explain some subjective improvements. Additional impact upon heart muscle cells, pre-damaged or atrophic due to hypoxia, may cause further injury. Given the limited regeneration capacity of myocardium, this can contribute to interstitial fibrosis and, in the long term, to functional decline.

According to a recent experimental study, shockwaves enhance DNA accessibility via Toll-like receptor 3 (TLR3) activation and facilitate the transdifferentiation of fibroblasts towards endothelial cells in ischemic myocardium. This was supposed to be a molecular mechanism underlying beneficial effects of CST [16]. However, TLR3 activation is not a priori beneficial. It is generally regarded to be a pro-inflammatory event, triggered by pathogen- and damage-associated factors. Conversely, inhibition of TLR3 alleviated inflammation and protected from tissue injury in ischemia-reperfusion murine models [24]. Presumably, activation of TLR3 by itself may cause damage [24,25]. In addition, TLR3 can lower the function of endothelial progenitor cells i.e. exert an anti-angiogenic effect [26]. At the same time, TLR3 is supposed to participate in VEGF-mediated mechanisms of vascularization of atherosclerotic plaques [24]. Certainly, the topic is controversial and understudied. It can be reasonably assumed that TLR3 activation is just another component of the non-specific reaction to the physical injury by CST.

Evaluation of interstitial fibrosis by morphometry in animal experiments with a longer follow-up is technically feasible. Other potential late outcomes such as accelerated arteriosclerosis, angiogenesis within plaques and their instability, would be difficult or impossible to assess in experiments. In clinical studies, both the CST and certain research methods may be associated with adverse effects. For example, in the study [8] and a substudy of [10], single-photon emission computed tomography (SPECT) was applied twice to all patients, both the CST-treated ones and controls. The average effective dose from a single clinical SPECT procedure across different protocols is ~7 mSv [27], which is 2-3 times more than annual global average from the natural radiation background. Individual effective doses of ionizing radiation were not given in the papers [8-10]. A net harm or benefit can be evaluated in animal studies with comparison of average life duration in the test and control groups. In the author’s opinion, experiments with a longer follow-up should be performed prior to large-scale clinical trials.

Conclusion

Reported CST effects such as increased ventricular function and myocardial perfusion may be transient and reactive in their nature. An issue of interest is the duration of improvements [28], and long-term outcomes. In the author’s opinion, experiments with longer follow-up are needed prior to the initiation of clinical studies in larger cohorts of patients. The most reliable way to evaluate the net harm or benefit would be lifelong animal experiments with comparisons of average life duration between the test and control groups. Clinical improvements after CST are probably caused, at least in part, by the placebo effect [29]. However, CST cannot be called placebo-therapy because of insufficiently known adverse events, especially those developing after repeated procedures in the long run. Treatments with unknown adverse effects are called pseudo-placebo [30]. Placebo therapy can be beneficial for some patients; but in the professional literature a topic should be elucidated objectively. Furthermore, the publication bias with a preferable publication of positive results is a well-known phenomenon. Another tendency is that substances and treatments with unproven effects are advertized under the guise of evidence-based medicine [31]. Under such circumstances, theoretic considerations gain in importance. Some questions are not completely clarified so that the arguments provided here may give rise to a constructive discussion and further research.

Declaration

No conflict of interest.

Journal of Cardiology and Cardiovascular Research

Cardiac Shockwave Therapy: Commentary

Abstract

Keywords

Commentary

Conclusion

References