Safety and efficacy of direct Cardiac Shockwave Therapy in patients with ischemic cardiomyopathy undergoing coronary artery bypass grafting (the CAST-HF trial): study protocol for a randomized controlled trial

The trial protocol has been approved by Ethics Committee of Medical University Innsbruck (reference number: EK 1118/2018) and by the Austrian Federal Office for Safety in Health Care (reference number: BASG 11262210). The study initiation was held in November 2018, the first patient was recruited in December 2018 and patient recruitment is scheduled to be finished within December 2020. Current study protocol version number 1.3 (effective date: 1st Dec 2019) is basis for this manuscript and written in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Statement.

Ischemic cardiomyopathy due to coronary artery disease remains a major burden for affected patients and, thus, represent a major challenge for Western health care systems. Post-infarctional remodeling and replacement of contractile myocardium with dysfunctional scar tissue leads to alteration of left-ventricular geometry and, hence, cardiac output for organ perfusion resulting in heart failure. Congestion, fatigue, dyspnea and angina severely impact on patients’ quality of life and can cause repeated episodes of cardiac decompensation concomitant with the need for hospital admission. Patients with heart failure due to ischemic cardiomyopathy have a decreased life-expectancy [3].

Current neurohumoral treatment strategies mainly aim at the improvement of symptoms. Complete revascularization of viable myocardium remains a cornerstone in the treatment of ischemic cardiomyopathy. The available scientific evidence currently favors CABG over PCI in patients with multivessel disease and impaired LV systolic function [23]. However, CABG surgery represents a somewhat palliative strategy, as it mainly aims at avoiding novel MI rather than regenerating myocardium and improving contractility.

SWT represents a promising therapeutic tool for the regeneration of dysfunctional tissue. It has proven effective in numerous pathologies, mainly by induction of neovascularization and modulation of inflammation. Extensive preclinical studies in small animals as well as large animals show a clear benefit of SWT for the functional restoration of ischemic myocardium. For this purpose, the CAST-HF trial was initiated in 2018, representing the first randomized controlled trial to evaluate the benefit of direct cardiac shockwave therapy. Based on well-described evidence from in-vitro as well as numerous small and large animal experiments, this trial marks the next milestone to develop direct cardiac SWT for broad clinical routine use in patients suffering from ischemic heart failure [15‐18, 21, 24, 25]. Thus, it could become the first available treatment option for the regeneration of ischemic myocardium. In contrast to other experimental treatment strategies, SWT has been used for many decades in medicine and to date there are no unfavorable long-term side-effects reported. In contrast, other promising experimental approaches for myocardial regeneration could not be translated into a clinical setting. Stem cells for myocardial regeneration have been investigated intensively. Despite promising preclinical results, the clinical translation has not been successful so far due to reports of arrhythmogenic events, lack of efficacy, failed incorporation into the site of injury or having malignant potential. In addition, severe allegations of scientific misconduct have caused the cancellation of large-scale trials further nourishing the doubts over the efficacy of stem-cell therapy for cardiac regeneration [26]. Another approach for myocardial regeneration remains the reprogramming of fibroblasts within the dysfunctional scar tissue towards functional cardiomyocytes using the Yamanaka factors. Again, apart from promising results in in-vitro and first-animal trials, the clinical translation remains far from close, as the method of delivery of the Yamanaka factors and the reprogramming efficacy remain questionable [27, 28].

Successful application of transthoracic SWT for the treatment of angina and left-ventricular dysfunction has been described. However, in contrast to direct epicardial SWT, the application window of transthoracic SWT remains limited due to the adjacent lung tissue. Due to the physical properties of shockwaves, they are absorbed by air simultaneously to ultrasound waves. In contrast, direct epicardial application enables treatment of the entire myocardium. In addition, direct coupling of the SWT applicator with the epicardium might ensure the more efficient delivery of SWT impulses [29, 30].

Although our group could elucidate the fundamental effects underlying the regenerative potential of SWT and found clear hints for the translation of the mechanical impulse to a biological response the exact underlying mechanism remains to be uncovered. The release of microvesicles (exosomes) containing angiogenic cargo and the subsequent stimulation of immune receptor Toll-like receptor 3 have been found. The origin of exosomes as well as the exact pathway from TLR3 induction to tissue regeneration will still be a major experimental research effort in parallel to CAST-HF. Exact knowledge of the underlying mechanism is of pivotal importance to establish further SWT options. This might possibly allow SWT not only during CABG, but also as an non-invasive standalone therapy via a minimally invasive cardiac applicator.

In conclusion, CAST-HF represents the first trial investigating the efficacy of direct cardiac SWT for the improvement of left-ventricular function in patients with ischemic cardiomyopathy. If positive, this trial could introduce SWT for broad clinical application, thus representing the first available therapeutic strategy for the regeneration of ischemic myocardium. Millions of affected patients could benefit from SWT effects and overcome ischemic heart failure. In addition, further knowledge of cardiac SWT could help develop new approaches and indications for SWT.