Cardiac Shock Wave Research Articles

Cardiac Shock Wave Therapy Improves Ventricular Function by Relieving Fibrosis Through PI3K/Akt Signaling Pathway: Evidence From a Rat Model of Post-infarction Heart Failure.

Objection: Cumulative studies have identified the effectiveness of cardiac shock wave therapy (CSWT) in treating heart failure after acute myocardial infarction (AMI), but little have been discussed with regard to the beneficial effects of CSWT on anti-fibrosis along with the underlying mechanism. In this study, we investigated whether CSWT could reduce post-AMI fibrosis and further explored the molecular mechanism.Methods: Rat heart failure (HF) models induced by ligating the left anterior descending coronary artery were established and validated by echocardiography. Eligible animals were randomly categorized into five groups: the sham group, the HF group, the HF + CSWT group, the HF + LY294002 group, and the HF + CSWT + LY294002 group. The cardiac weight, serum level of BNP, NT-pro BNP and echocardiography parameters were measured to assess cardiac function in different groups. Masson's trichrome staining was used to assess the proportions of the fibrotic area. The expression level of CD34, αSMA was measured by RT-PCR, Immunohistochemistry and Immunofluorescent analyses and the level of PI3K/Akt was quantified by Immunohistochemistry and Western blotting.Results: The application of CSWT significantly improved cardiac function and reduced myocardial fibrosis and level of CD34 and αSMA, compared to the HF group. CSWT led to significant elevations of p-PI3K and p-Akt expression levels compared to that of the HF group and the inhibition of the PI3K/Akt pathway abolished the observed beneficial effects of CSWT.Conclusion: CSWT can facilitate the alleviation of cardiac fibrosis induced by AMI through the activation of PI3K/Akt signaling pathway.

Cardiac Shock Wave Therapy Alleviates Hypoxia/Reoxygenation-Induced Myocardial Necroptosis by Modulating Autophagy.

Regulated necrosis (necroptosis) is crucially involved in cardiac ischaemia-reperfusion injury (MIRI). The aim of our study is to investigate whether shock wave therapy (SWT) is capable of exerting protective effects by inhibiting necroptosis during myocardial ischaemia-reperfusion (I/R) injury and the possible role of autophagy in this process. We established a hypoxia/reoxygenation (H/R) model in vitro using HL-1 cells to simulate MIRI. MTS assays and LDH cytotoxicity assay were performed to measure cell viability and cell damage. Annexin V/PI staining was used to determine apoptosis and necrosis. Western blotting was performed to assess the changes in cell signaling pathways associated with autophagy, necroptosis, and apoptosis. Reactive oxygen species (ROS) production was detected using DHE staining. Autophagosome generation and degradation (autophagic flux) were analysed using GFP and RFP tandemly tagged LC3 (tfLC3). HL-1 cells were then transfected with p62/SQSTM1 siRNA in order to analyse its role in cardioprotection. Our results revealed that SWT increased cell viability in the H/R model and decreased receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 expression. ROS production was also inhibited by SWT. Moreover, SWT decreased Beclin1 expression and the ratio of LC3-II/LC3-I following H/R. Simultaneously, in the tfLC3 assay, the SWT provoked a decrease in the cumulative autophagosome abundance. siRNA-mediated knockdown of p62 attenuated H/R-induced necroptosis, and SWT did not exert additive effects. Taken together, SWT ameliorated H/R injury by inhibiting necroptosis. SWT also relieved the blockade of autophagic flux in response to H/R injury. The restoration of autophagic flux by SWT might contribute to its cardioprotective effect on necroptosis following H/R injury.

Effectiveness and Safety of Extracorporeal Shockwave Myocardial Revascularization in Patients With Refractory Angina Pectoris and Heart Failure

Extracorporeal shockwave myocardial revascularization (ESMR) is a therapy for refractory angina pectoris. Our aim was to assess the efficacy and safety of ESMR in the management of patients with stable coronary artery disease (CAD) and heart failure as well as its effects on inflammation and angiogenesis. In this single-arm prospective trial, we included 48 patients with CAD, myocardial ischemia assessed by radionuclide imaging, echocardiographic evidence of left ventricular systolic dysfunction and without revascularization options. Changes in angina grading score, myocardial perfusion, left ventricular ejection fraction, and six-minute walk test after ESMR therapy were used for efficacy assessment. Changes of inflammation and angiogenesis biomarkers were also evaluated. ESMR therapy was performed using a commercially available cardiac shockwave generator system (Cardiospec; Medispec). After 9 weeks of ESMR therapy, a significant improvement was found regarding the initial angina class, severity of ischemia, left ventricular ejection fraction, and six-minute walk test in most patients. No deleterious side effects after treatment were detected. Regarding biomarkers, endothelial progenitor cells and angiopoietin-3 were significantly increased whereas IL-18 and TGF-β were significantly decreased after ESMR in the total group. Notably, VEGF, IL-1ß, and lipoxin A4 levels were significantly increased only in patients with myocardial ischemia improvement. In conclusion, ESMR therapy is safe and effective in most but not all patients with CAD and heart failure. ESMR is associated with increased markers of angiogenesis and decreased markers of inflammation. Myocardial ischemia improvement after ESMR is associated with increased markers of angiogenesis and pro-resolving mediators.

Reduced effects of cardiac extracorporeal shock wave therapy on angiogenesis and myocardial function recovery in patients with end-stage coronary artery and renal diseases

BackgroundGrowing evidence have shown cardiac extracorporeal shock wave therapy (ESWT) improve clinical symptoms and left ventricular ejection fraction (LVEF) for patients with end-stage diffuse coronary artery disease (EnD-CAD) unsuitable for coronary interventions. However, little is known whether cardiac ESWT remains effective on symptomatic relief and improvement of LVEF for the EnD-CAD patients with end-stage renal disease (ESRD). MethodsThis was a small-scale prospective study. Between August 2016 and January 2019, a total of 16 subjects received cardiac ESWT for their EnD-CAD. They were divided into two groups according to ESRD or not, i.e., EnD-CAD group (n = 8) and EnD-CAD/ESRD group (n = 8). Clinical symptoms including angina and dyspnea, levels of circulating endothelial progenitor cells (EPC), LVEF, and adverse events were regularly followed up for one year to compare safety and efficacy of cardiac ESWT between the EnD-CAD patients with or without ESRD. ResultsAll participants tolerated cardiac ESWT without any relevant side effects such as skin allergic reaction, local redness/tenderness or cardiac arrhythmia. There were similar baseline comorbidities and clinical features between two groups, but the EnD-CAD/ESRD group had significantly higher serum potassium level as well as lower renal function and lipid profile (all p-values <0.03). After cardiac ESWT, the patients in both groups had significant improvement in angina and dyspnea at 1 year (all p-values <0.03). However, the EnD-CAD/ESRD group did not have increase in either circulating EPC levels or LVEF at 6 months (mean change in LVEF: −4.00% ± 8.32%, p = 1.000). In contrast, the EnD-CAD group had gradually improving levels of circulating EPC surface markers and increased LV systolic function (mean change in LVEF: +4.87% ± 8.76%, p = 0.092). Notably, patients in the EnD-CAD/ESRD group suffered from high incidental clinical adverse events before and after enrollment into the ESWT study (75% vs. 25%, p = 0.132). ConclusionAlthough cardiac ESWT provided improvement of clinical symptoms in the EnD-CAD patients, its long-term effects on the angiogenesis and LVEF were reduced for those high-risk patients with concomitant EnD-CAD and ESRD. Trial registrationnone.

Therapeutic Angiogenesis with Sound Waves.

Along with the progress of global aging, the prognosis of severe ischemic heart disease (IHD) remains poor, and thus the development of effective angiogenic therapy remains an important clinical unmet need. We have developed low-energy extracorporeal cardiac shock wave therapy as an innovative minimally invasive angiogenic therapy and confirmed its efficacy in a porcine chronic myocardial ischemia model in animal experiments as well as in patients with refractory angina. Since ultrasound is more advantageous for clinical application than shock waves, we then aimed to develop ultrasound therapy for IHD. We demonstrated that specific conditions of low-intensity pulsed ultrasound (LIPUS) therapy improve myocardial ischemia in animal models through the enhancement of angiogenesis mediated by endothelial mechanotransduction. To examine the effectiveness of our LIPUS therapy in patients with severe angina pectoris, we are now conducting a prospective multicenter clinical trial in Japan. Furthermore, to overcome the current serious situation of dementia pandemic but with no effective treatments worldwide, we have recently demonstrated that our LIPUS therapy also improves cognitive impairment in mouse models of Alzheimer’s disease and vascular dementia. Here, we summarize the progress in our studies to develop angiogenic therapies with sound waves.

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

BackgroundCoronary artery diseases (CAD) remains a severe socio-economic burden in the Western world. Coronary obstruction and subsequent myocardial ischemia result in progressive replacement of contractile myocardium with dysfunctional, fibrotic scar tissue. Post-infarctional remodeling is causal for the concomitant decline of left-ventricular function and the fatal syndrome of heart failure. Available neurohumoral treatment strategies aim at the improvement of symptoms. Despite extensive research, therapeutic options for myocardial regeneration, including (stem)-cell therapy, gene therapy, cellular reprogramming or tissue engineering, remain purely experimental. Thus, there is an urgent clinical need for novel treatment options for inducing myocardial regeneration and improving left-ventricular function in ischemic cardiomyopathy.Shockwave Therapy (SWT) is a well-established regenerative tool that is effective for the treatment of chronic tendonitis, long-bone non-union and wound-healing disorders. In preclinical trials, SWT regenerated ischemic myocardium via the induction of angiogenesis and the reduction of fibrotic scar tissue, resulting in improved left-ventricular function.Methods/designIn this prospective, randomized controlled, single-blind, monocentric study, 80 patients with reduced left-ventricular ejection fraction (LVEF≤ 40%) are subjected to coronary-artery bypass-graft surgery (CABG) surgery and randomized in a 1:1 ratio to receive additional cardiac SWT (intervention group; 40 patients) or CABG surgery with sham treatment (control group; 40 patients). This study aims to evaluate (1) the safety and (2) the efficacy of cardiac SWT as adjunctive treatment during CABG surgery for the regeneration of ischemic myocardium. The primary endpoints of the study represent (1) major cardiac events and (2) changes in left-ventricular function 12 months after treatment. Secondary endpoints include 6-min Walk Test distance, improvement of symptoms and assessment of quality of life.DiscussionThis study aims to investigate the safety and efficacy of cardiac SWT during CABG surgery for myocardial regeneration. The induction of angiogenesis, decrease of fibrotic scar tissue formation and, thus, improvement of left-ventricular function could lead to improved quality of life and prognosis for patients with ischemic heart failure. Thus, it could become the first clinically available treatment strategy for the regeneration of ischemic myocardium alleviating the socio-economic burden of heart failure.Trial registrationClinicalTrials.gov, ID: NCT03859466. Registered on 1 March 2019.

Cardiac Shock Wave Therapy for Coronary Heart Disease: an Updated Meta-analysis.

IntroductionThe aim of this article is to study the efficacy and safety of cardiac shock wave therapy (CSWT) in the treatment of coronary heart disease (CAD).MethodsA comprehensive search of electronic databases and a manual search of conference papers and abstracts were performed until September 30, 2018. The studies using RevMan 5.3 and STATA 14.0 softwares were reviewed, and meta-analyses were performed on 13 indicators, such as a six-min walking distance test (6MWT), New York Heart Association (NYHA) functional class, Seattle Angina Questionnaire (SAQ) score, angina class (Canadian Cardiology Society [CCS]), etc.ResultsA total of 26 articles were included. The total patient population was 855, of which 781 patients were treated with CSWT. Meta-analyses indicated that 6MWT (mean difference [MD] 75.64, 95% confidence interval [CI] 49.03, 102.25, P<0.00001) and NYHA (MD -0.70, 95% CI -0.92) in the CSWT group were comparable to those in the conventional revascularization group (MD -0.70, 95% CI -0.92, -0.49, P<0.00001). SAQ (MD 10.75, 95% CI 6.66, 14.83, P<0.00001), CCS (MD -0.99, 95% CI -1.13, -0.84, P<0.00001), nitrate dosage (MD -1.84, 95% CI -2.77, -1.12, P<0.00001), LVEF (MD 3.77, 95% CI 2.17, 5.37, P<0.00001), and SSS (MD -4.29, 95% CI -5.61, -2.96, P<0.00001), SRS (MD -2.90, 95% CI -4.85, -0.95, P=0.004), and the exercise test (standard mean difference 0.57, 95% CI 0.12, 1.02, P=0.01) all showed significant differences.ConclusionCSWT may offer beneficial effects to patients with CAD, but more large-scale clinical studies are needed to further verify its therapeutic effect.

Cardiac shock wave therapy protects cardiomyocytes from hypoxia‑induced injury by modulating miR‑210.

Cardiac shock wave therapy (SWT) has been described as a novel therapeutic strategy that is able to alleviate myocardial ischemic injury. microRNA (miRNA/miR)-210 plays a cytoprotective role in cardiomyocytes in response to hypoxia by regulating cell apoptosis. The aim of the present study was to investigate whether cardiac SWT could protect cardiomyocytes from hypoxia-induced injury by regulating miR-210 expression. The murine adult cardiomyocyte cell line HL-1 was incubated for 5 h in hypoxic conditions, followed by reoxygenation for 12 h and treatment with SWT immediately following hypoxia in the present study. The cell viability was determined using an MTS assay. Western blot analyses were performed in order to detect cell signaling changes. Reactive oxygen species production was detected using dihydroethidium staining, and malondialdehyde levels were measured using the thiobarbituric acid method. miRNA and mRNA expression levels were confirmed via reverse transcription-quantitative PCR. Apoptosis was evaluated by means of flow cytometry. HL-1 cells were then transfected with miR-210 mimics or inhibitors in order to alter miR-210 expression levels, and the effects on HL-1 cells were determined. Hypoxia led to elevated oxidative stress, enhanced cell apoptosis and upregulated miR-210 expression levels in HL-1 cells, while SWT could alleviate hypoxia-induced cell injury and further promote miR-210 expression. miR-210 overexpression decreased apoptosis and oxidative stress during hypoxic stress in HL-1 cells, whereas inhibition of miR-210 increased cell apoptosis and promoted oxidative stress. Furthermore, miR-210 inhibition could reverse the effects of SWT on HL-1 cells. Finally, the mRNA analysis revealed that SWT significantly attenuated apoptosis-inducing factor mitochondrion-associated 3 and caspase 8 associated protein 2 mRNA expression levels in cardiomyocytes exposed to hypoxia, which were two targets of miR-210. SWT could exert cardioprotective effects against hypoxia-induced cardiac injury by modulating miR-210.

Various protocols of extracorporeal shock wave therapy in the treatment of stable angina

Aim. To evaluate effects of various protocols of cardiac shock wave therapy (CSWT) on quality of life and exercise tolerance in patients with stable angina against the background of optimal medication therapy (OMT). Material and methods . Overall 53 patients (37 men, 16 women) were included in the study. The mean age of examined patients was 67,3 ±8,1 years. Inclusion criteria: CCS class I-IV angina pectoris, stable therapy for at least 1 month before inclusion in the study and a stable course of coronary artery disease for more than 3 months (no cardiovascular events) before inclusion in the study. Patients were divided into 2 groups. The Group 1 (n=37) received OMT+CSWT standard-modified protocol, Group 2 (n=16) received OMT+CSWT rapid-modified protocol. Electrocardiography, echocardiography, treadmill test, and Seattle quality of life questionnaire (SAQ) were performed at inclusion and 6 months follow up. Results. Both CSWT with rapid-modified protocol and standard-modified protocol significantly reduced the number of short-acting nitrates from 2 (2; 7) to 1 (0; 2) (p=0,04) and from 2 (0; 6) to 0 (0; 2) (p ≤0,001) at 6 months, respectively, as well as the number of angina attacks per week (from 4 (2; 7) to 1 (1; 1) (p=0,007) and 6 (2; 20) to 1 (0; 5) (p ≤0,001). Treadmill test total exercise duration was significantly increased from 393 (326; 574) to 561 (411; 650) seconds (p=0,007) and 365+140,4 to 411,5±156,1 seconds (p=0,01), respectively. Time to 1 mm ST segment depression was also significantly increased from 399,8+169 to 460+182 seconds (p ≤0,05) and from 303,1+179 to 389,9+203 seconds (p=0,001), respectively. Conclusion. In our study, CSWT with rapid-modified protocol improved quality of life and exercise tolerance in patients with stable angina similar to the standard-modified protocol. Rapid-modified protocol of CSWT reduced total duration of the treatment.

The effect of cardiac shock wave therapy on myocardial function and perfusion in the randomized, triple-blind, sham-procedure controlled study

BackgroundRecent triple-blind sham procedure-controlled study revealed neutral effects of the cardiac shock wave therapy (CSWT) on exercise tolerance and symptoms in patients with stable angina. Current data about the effects of CSWT on global and regional myocardial contractility and perfusion is limited. Hereby we report the results of an imaging sub-study that evaluated the capacity of CSWT to ameliorate myocardial ischemia induced during dobutamine stress echocardiography (DSE) and cardiac single photon emission computed tomography (SPECT).MethodsProspective, randomized, triple-blind, sham procedure-controlled study enrolled 72 adult subjects who complied with defined inclusion criteria. The subjects were assigned to the OMT + CSWT and the OMT + sham procedure study groups with 1:1 ratio. Application of the CSWT covered all segments of the left ventricle. Imaging ischemia tests were performed in 59 study patients: DSE and SPECT before the CSWT treatment and after 6 months, with DSE carried out additionally at 3 months after randomization. Co-primary endpoints of the study were: change in wall motion score index (WMSI), representing the stress-induced impairment of regional myocardial function, and change in summed difference score (SDS), representing the amount of perfusion defect.ResultsOMT + CSWT and OMT + sham procedure study groups included 30 and 29 patients, respectively. Regional myocardial contractility during DSE significantly improved at 3 months follow-up in OMT + CSWT group compared to baseline as shown by WMSI at stress (1.4 ± 0.4 vs 1.6 ± 0.4, p = 0.001), but not in OMT + sham procedure group (1.5 ± 0.3 vs 1.6 ± 0.4, p = 0.136). The difference in stress DSE results between both study groups disappeared after 6 months. SPECT results demonstrated a significant reduction of inducible ischemia in OMT + CSWT group compared to OMT + sham procedure group at 6 months follow-up (SDS dropped from 5.4 ± 3.7 to 3.6 ± 3.8 vs 6.4 ± 5.9 to 6.2 ± 5 respectively, p = 0.034).ConclusionsCardiac shock wave treatment showed the ability to reduce stress-induced myocardial ischemia, as assessed by wall motion abnormalities and perfusion defects, compared to sham procedure.Trial registrationClinicaltrials.gov (NCT02339454). The trial was registered retrospectively on 12 January 2015.

Safety and Efficacy of Cardiac Shockwave Therapy in Patients Undergoing Coronary Artery Bypass Grafting

Safety and Efficacy of Cardiac Shockwave Therapy in Patients Undergoing Coronary Artery Bypass Grafting

Влияние кардиальной ударно-волновой терапии на клинико-функциональное состояние пациентов с ишемической болезнью сердца после операции реваскуляризации миокарда

Влияние кардиальной ударно-волновой терапии на клинико-функциональное состояние пациентов с ишемической болезнью сердца после операции реваскуляризации миокарда

Cardiac shock wave therapy: an alternative non-invasive therapy for refractory angina.

Refractory angina (RFA), known as "no option angina" before, is increasing worldwide. The prognosis for RFA patients still remains poor due to the lack of effective treatments. The potential of cardiac shock wave therapy (CSWT) to treat RFA by promoting angiogenesis was first shown by Nishida et al in a porcine model of chronic ischemic cardiomyopathy. The main objective of this paper is to review the mechanisms of its action, influence on the cardiac tissue, and also clinical studies demonstrating its efficacy. This is a literature review of recent articles published on MEDLINE and SciELO databases in English. Researchers found that CSWT leads to multiple biochemical effects, such as angiogenesis, inflammatory response modulation, ameliorate myocardial fibrosis, and so on. Based on the promising results above, a series of clinical studies have been performed. And the studies demonstrated that CSWT is associated with the improvement of angina symptoms, heart function, and myocardial perfusion for patients with refractory angina. No procedural complications or adverse effects were noted in these studies. CSWT appears to be an effective, safe, and non-invasive approach to treat RFA.

Cardiac shock wave therapy improves myocardial perfusion and preserves left ventricular mechanics in patients with refractory angina: A study with speckle tracking echocardiography.

Cardiac shockwave therapy (CSWT) is a new potential option for the treatment of patients with chronic coronary disease and refractory angina (RA). We aimed to study the effects of CSWT on left ventricular myocardial perfusion and mechanics in patients with RA. We prospectively studied 19 patients who underwent CSWT. Left ventricular mechanics were evaluated by speckle tracking echocardiography (STE), and myocardial perfusion by single-photon emission computed tomography, using stress/rest-Technetium-99m Sestamibi, for determination of summed stress score (SSS). Canadian Cardiac Society (CCS), New York Heart Association (NYHA), and quality of life by Seattle Angina Questionnaire (SAQ) were assessed at baseline and 6months after therapy. CSWT therapy was applied without major side effects. At baseline, 18 patients (94.7%) had CCS class III or IV, and after CSWT there was reduction to 3 (15.8%), P=.0001, associated with improvement in SAQ (38.5%; P<.001). Thirteen (68.4%) had class NYHA III or IV before treatment, with significant reduction to 7 (36.8%); P=.014. No change was observed in the global SSS from baseline to 6-month follow-up (15.33±8.60 vs 16.60±8.06; P=.157). However, there was a significant reduction in the average SSS of the treated ischemic segments (2.1±0.87 pre vs 1.6±1.19 post CSWT; P=.024). Global longitudinal strain by STE remained unaltered (-13.03±8.96 pre vs -15.88±3.43 6-month post CSWT; P=.256). CSWT is a safe procedure for the treatment of patients with RA that results in better quality of life, improvement in myocardial perfusion of the treated segments with preservation of left ventricular mechanics.

A multicenter trial of extracorporeal cardiac shock wave therapy for refractory angina pectoris: report of the highly advanced medical treatment in Japan.

We have previously demonstrated that cardiac shock wave therapy (CSWT) effectively improves myocardial ischemia through coronary neovascularization both in a porcine model of chronic myocardial ischemia and in patients with refractory angina pectoris (AP). In this study, we further addressed the efficacy and safety of CSWT in a single-arm multicenter study approved as a highly advanced medical treatment by the Japanese Ministry of Health, Labour and Welfare. Fifty patients with refractory AP [mean age 70.9 ± 12.6 (SD) years, M/F 38/12] without the indications of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) were enrolled in 4 institutes in Japan. Ischemic myocardial regions in the left ventricle (LV) were identified by drug-induced stress myocardial perfusion imaging (MPI). Shock waves (200 shots/spot at 0.09mJ/mm2) were applied to 40-60 spots in the ischemic myocardium 3 times in the first week. The patients were followed up for 3months thereafter. Forty-one patients underwent CSWT and completed the follow-up at 3months. CSWT markedly improved weekly nitroglycerin use [from 3.5 (IQR 2 to 6) to 0 (IQR 0 to 1)] and the symptoms [Canadian Cardiovascular Society functional class score, from 2 (IQR 2 to 3) to 1 (IQR 1 to 2)] (both P < 0.001). CSWT also significantly improved 6-min walking distance (from 384 ± 91 to 435 ± 122m, P < 0.05). There were no significant changes in LV ejection fraction evaluated by echocardiography and LV stroke volume evaluated by cardiac magnetic resonance imaging (from 56.3 ± 14.7 to 58.8 ± 12.8%, P = 0.10, and from 52.3 ± 17.4 to 55.6 ± 15.7mL, P = 0.15, respectively). Percent myocardium ischemia assessed by drug-induced stress MPI tended to be improved only in the treated segments (from 16.0 ± 11.1 to 12.1 ± 16.2%, P = 0.06), although no change was noted in the whole LV. No procedural complications or adverse effects related to the CSWT were noted. These results of the multicenter trial further indicate that CSWT is a useful and safe non-invasive strategy for patients with refractory AP with no options of PCI or CABG.

Low-energy cardiac shockwave therapy to suppress left ventricular remodeling in patients with acute myocardial infarction: a first-in-human study.

Although primary percutaneous coronary intervention (PCI) substantially reduces the mortality of patients with acute myocardial infarction (AMI), left ventricular (LV) remodeling after AMI still remains an important issue in cardiovascular medicine. We have previously demonstrated that low-energy cardiac shockwave (SW) therapy ameliorates LV remodeling after AMI in pigs. In this first-in-human study, we examined the feasibility and the effects of the SW therapy on LV remodeling after AMI in humans. Seventeen patients with AMI who successfully underwent primary PCI (peak-creatine kinase<4000 U/l) were treated with the SW therapy. Low-energy shock waves were applied to the ischemic border zone around the infarcted area at 2, 4, and 6 days since AMI. Next, we compared these patients with historical AMI controls by propensity score matching (N=25). There were no procedure-related complications or adverse effects. At 6 and 12 months after AMI, LV function as assessed by MRI showed no signs of deleterious LV remodeling. When we compared the SW-treated group with the historical AMI controls at 6 months after AMI, LV ejection fraction was significantly higher in the SW-treated group (N=7) than in the historical control group (N=25) by echocardiography (66±7 vs. 58±12%, P<0.05). LV end-diastolic dimension also tended to be smaller in the SW than in the control group (47.5±4.6 vs. 50.0±5.9 mm, P=0.29). These results suggest that low-energy extracorporeal cardiac SW therapy is feasible and may ameliorate postmyocardial infarction LV remodeling in patients with AMI as an adjunctive therapy to primary PCI.

EFFICACY OF EXTRACORPOREAL SHOCKWAVE MYOCARDIAL REVASCULARIZATION THERAPY IN PATIENTS WITH STABLE ANGINA PECTORIS: MULTICENTRE RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED STUDY

recent studies showed that the application of low intensity shockwaves may induce angiogenesis and ameliorate myocardial ischemia in patients with refractory angina. The aim of the study was to investigate the efficacy of cardiac shock wave therapy (CSWT) in improvement of exercise tolerance in

Cardiac shock wave therapy promotes arteriogenesis of coronary micrangium, and ILK is involved in the biomechanical effects by proteomic analysis

Cardiac Shock Wave Therapy (CSWT) improves myocardial perfusion and ameliorates cardiac remodeling after acute myocardial infarction (AMI), but the precise mechanisms remain obscure. Herein, we have applied CSWT to a rat model of AMI to demonstrate the arteriogenesis of coronary micrangium and protein expression changes in ischemic myocardium after CSWT. Four weeks after CSWT, the fraction shortening of rats was improved greatly and the cardiomyocyte apoptosis index was significantly lower than the AMI group (P < 0.05). Besides, the fibrotic area was markedly decreased in the CSWT group. In the infarction border zone, the thickness of smooth muscle layer was expanded apparently after CSWT. Label-free quantitative proteomic analysis and bioinformatics analysis revealed that the differentially expressed proteins were largely enriched in the focal adhesion signaling pathway. And integrin linked kinase (ILK) may be a key factor contributed to arteriogenesis of coronary micrangium during CSWT. In conclusion, non-invasive cardiac shock wave could promote arteriogenesis of coronary micrangium and alleviate myocardial apoptosis and fibrosis after AMI. Furthermore, focal adhesion signaling pathway may have a central role in the related signal network and ILK was closely related to the arteriogenesis of coronary micrangium during CSWT.

Cardiac Shock Wave Therapy Attenuates Cardiomyocyte Apoptosis after Acute Myocardial Infarction in Rats

Background/Aims: Researches have showed that cardiac shock wave therapy (CSWT) could improve left ventricular function and attenuate LV remodeling of the ischemic heart. Apoptosis plays an important role in myocardial infarction and determines heart function and prognosis. However, it is still not clear whether CSWT is sufficient to attenuate acute myocardial infarction (AMI) induced cardiomyocyte apoptosis in vivo. In this study, we used a rat model to examine whether CSWT could attenuate cardiomyocyte apoptosis after AMI and to explore potential mechanisms. Methods: We generated an AMI rat model to investigate the function and possible regulatory mechanisms of CSWT. All rats were randomly divided into four groups: the sham-operated only group, sham-operated with SW treatment group, AMI only group, and AMI treated with SW treatment group.The rats were treated with a left anterior descending coronary artery ligation for 12h and then treated with or without CSWT (800 shots at 0.1 mJ/ mm²). Cytochrome c release was measured to analyze mitochondrial function and integrity. The apoptotic cell rate was determined by TUNEL assay. Western blot was used to analyze the cell apoptosis-, inflammation-, and survival-related signaling pathways. Results: First, the methodology of CSWT in the rat model of AMI was established. Second, CSWT attenuated the cardiomyocyte apoptosis rate in the infarct border zone. Third, CSWT suppressed the expression of apoptosis and inflammation molecules after AMI. Fourth, CSWT inhibited activation of the JNK pathway, which indicated inhibition of the cell inflammatory pathways and promotion of cardiomyocyte survival after AMI. Conclusion: These results indicate that CSWT exerts a protective effect against AMI-induced cardiomyocyte apoptosis, potentially by attenuating cytochrome c release from the mitochondria and inhibiting of the mitochondrial-dependent intrinsic apoptotic pathway. We also demonstrate that CSWT suppresses the JNK pathway and cardiomyocyte inflammation, which may also decrease cardiomyocyte apoptosis in vivo.

Efficacy of cardiac shock wave therapy in patients with stable angina: The design of randomized, triple blind, sham-procedure controlled study

Objective:Despite revascularization and optimal medical treatment (OMT), patients with angina often have a reduced quality of life due to inadequate relief from symptoms. Recent studies have shown that the application of shock waves may reduce angina symptoms and improve quality of life, exercise capacity, and myocardial perfusion due to the stimulation of angiogenesis. However, there is limited evidence due to small, single-arm, single-center studies of low to moderate quality. The purpose of this study is to evaluate the impact of cardiac shock wave therapy (CSWT) on exercise tolerance and angina symptoms in patients with coronary artery disease and objective evidence of myocardial ischemia who cannot undergo traditional revascularization and experience angina despite OMT in comparison to sham procedure.Methods:We designed a randomized, triple-blind, placebo-controlled, multicentre trial (NCT02339454) to assess the efficacy of CSWT in addition to OMT in patients with stable angina and myocardial ischemia documented by exercise treadmill test (ETT). All patients were treated with stable doses of standard medical treatment 4 weeks before screening. An increase in the total exercise duration on ETT by ≥90 s from the baseline at the end of the study was set as the primary endpoint. Secondary endpoints included angina class, Seattle angina questionnaire scores, symptoms, and ECG changes during stress test. Patients underwent nine sessions of CSWT or corresponding sham procedure applied to all segments of the left ventricle, within 9 weeks. Endpoint assessments were performed at 6-month follow-up. The imaging substudies assessed the potential of CSWT to reduce stress-induced myocardial ischemia detected by dobutamine stress echocardiography, cardiac single-photon emission computed tomography, and cardiac magnetic resonance imaging.Results:At two centers, 72 of the 323 screened patients were randomized in two groups (ratio 1:1): active treatment and placebo control. Study patients were predominantly males (70.8%); the mean age of the patients was 68.4±8.3 years. Of these, 44 patients had angina Canadian Cardiovascular Society class III, and 66.7% of the patients had a history of myocardial infarction.Conclusion:Using sham applicators, blinding study participants, investigators, and endpoints assessors to the study data as well as centralized randomization ensures rigorous methodology and low risk of bias in this large randomized controlled CSWT study.