Efficacy and safety of cardiac shock wave therapy for patients with severe coronary artery disease: A randomized, double-blind control study.

BACKGROUND: Previous studies proved the efficacy of cardiac shock wave therapy (CSWT) for coronary artery disease (CAD) patients who are not candidate for reperfusion therapy. Randomized control trials are limited. We try to explore the efficacy and safety of CSWT for patients with severe CAD. METHODS: Thirty patients with severe CAD who had obvious ischemia on myocardial perfusion imaging (MPI) were enrolled and randomly assigned to the CSWT group or the control group. They had received optimal medication treatment for at least three months. Nine sessions of shock wave therapy were conducted over 3 months. CSWT group received the real treatment, while the control group received the pseudo-treatment. Clinical symptom, imaging outcomes and safety parameters were compared between two groups. RESULTS: After treatment, regional stress score (P = .023), improvement rate (IR) of ischemic area (IA) stress (P < .001) and IR of IA difference (P < .001) were significantly favor CSWT group. The interaction of summed rest score (P < .001), summed stress score (P = .004), summed difference score (P = .036) were significantly improved in the CSWT group compared to the control group. Seattle angina questionnaire, quality of life (QOL) and the distance of six-minute walking test (6MWT) were improved in both groups without significant difference between them. Hemodynamic parameters were stable during procedure. Myocardial injury markers showed no changes in two groups. CONCLUSIONS: Our study demonstrated CSWT could effectively and safely improve myocardial perfusion in patients with severe CAD. Clinical symptom, QOL and 6MWT were all improved after treatment, but no significant difference between two groups.

Attenuation of Myocardial Dysfunction in Hypertensive Cardiomyopathy Using Non-R-Wave-Synchronized Cardiac Shock Wave Therapy.

Cardiac shock wave therapy (CSWT) is a novel therapeutic procedure for patients with angina that is refractory to conventional therapy. We investigated the potential mechanism and therapeutic efficacy of non-R-wave-triggered CSWT to attenuate myocardial dysfunction in a large animal model of hypertensive cardiomyopathy. Sustained elevated blood pressure (BP) was induced in adult pigs using a combination of angiotensin-II and deoxycorticosterone acetate (DOCA). Two sessions of non-R-wave-triggered CSWT were performed at 11 and 16 weeks. At 10 weeks, systolic and diastolic blood pressure, LV posterior wall thickness and intraventricular septum thickness significantly increased in both the hypertension and CSWT groups. At 20 weeks, +dP/dt and end-systolic pressure-volume relationship (ESPVR) decreased significantly in the hypertension group but not the CSWT group, as compared with week 10. A significant improvement in end-diastolic pressure-volume relationship (EDPVR) was observed in the CSWT group. The CSWT group exhibited significantly increased microvascular density and vascular endothelial growth factor (VEGF) expression in the myocardium. Cytokine array demonstrated that the CSWT group had significantly reduced inflammation compared with the hypertension group. Our results demonstrate that non-R-wave-triggered CSWT is safe and can attenuate LV systolic and diastolic dysfunction via enhancement of myocardial neovascularization and anti-inflammatory effect in a large animal model of hypertensive cardiomyopathy.

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 0.09 mJ/mm2) were applied to 40-60 spots in the ischemic myocardium 3 times in the first week. The patients were followed up for 3 months thereafter. Forty-one patients underwent CSWT and completed the follow-up at 3 months. 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 ± 122 m, 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 ± 15.7 mL, 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.

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

BACKGROUND: Recent 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). METHODS: Prospective, 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. RESULTS: OMT + 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). CONCLUSIONS: Cardiac 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 REGISTRATION: Clinicaltrials.gov ( NCT02339454 ). The trial was registered retrospectively on 12 January 2015.

[Role of PI3K/Akt signaling pathway in ischemic rats underwent cardiac shock waves therapy].

Objective: To investigate the role of PI3K/Akt signaling pathway in ischemic rats underwent cardiac shock therapy. Methods: Adult male Sprague Dawley (SD) rats weighing 220-250 g were used to establish a heart failure model by ligation of the left anterior descending coronary artery. Rat models were defined by echocardiographic assessment at 4 weeks post operation and heart failure rats were randomly divided into 4 groups,namely heart failure group (HF group, 9 cases),heart failure+cardiac shock waves therapy group (HF+CSWT group, 9 cases),heart failure+inhibitor(HF+LY294002 group, 9 cases),heart failure+cardiac shock waves therapy group+inhibitor (HF+CSWT+LY294002 group, 9 cases),and another 9 sham-operated SD rats served as control group (sham group, 9 cases). At 8 weeks postoperation, echocardiography was used to evaluate cardiac function in each group,myocardial infarct size was measured by TTC staining,the apoptotic index of rats cardiomyocytes were detected by TUNEL method,the myocardial mRNA expression of apoptosis-related factor was detected by real-time quantitative PCR, the protein expression levels of PI3K/Akt signaling pathway and apoptosis-related pathways were detected by Western blot. Results: (1) Eight weeks after operation, left ventricular end diastolic diameter (LVEDD) and left ventricular end systolic diameter (LVESD) were significantly lower in HF+CSWT group than in HF group (all P<0.05), left ventricular ejection fraction (LVEF) and left ventricular shortening rate (LVFS) were significantly higher in HF+CSWT group than in HF group (all P<0.05),LVEF was significantly lower in the HF+ CSWT+ LY294002 group than in HF+ CSWT group (P<0.05). (2) Myocardial infarct size was significantly lower in the HF+ CSWT group than in HF group ((5.57 ± 0.51)% vs. (25.56 ± 0.56)%, P<0.05), which was significantly higher in the HF+CSWT+LY294002 group than in HF+CSWT group ((12.90±2.34)% vs. (5.57±0.51)%,P<0.05). (3) The cardiomyocyte apoptotic index was significantly lower in the HF+CSWT group than in the HF group ((30.25±6.12)% vs. (53.85±9.89)%,P<0.05), which was significantly higher in the HF+CSWT+LY294002 group than in the HF+CSWT group ((46.12±3.42)% vs.(30.25±6.12)%,P<0.05). (4) The myocardial mRNA expression of Bcl-2 was significantly higher, while myocardial mRNA Bax and Caspase-3 expression were significantly lower in HF+CSWT group than in HF group and HF+CSWT+LY294002 group (all P<0.05). (5) The expression levels of p-Akt, Bcl-2 and pro-Caspase-3 in myocardial tissue were significantly higher in the HF+CSWT group than in the HF group and HF+CSWT+LY294002 group (all P<0.05), which were significantly lower in the HF+LY294002 group than in the HF and HF+CSWT+LY294002 groups (all P<0.05). Myocardial Bax protein expression was significantly lower in the HF+CSWT group than in the HF group and the HF+CSWT+LY294002 group (all P<0.05), which was significantly higher in the HF+LY294002 group than in the HF group (P<0.05). Conclusion: CSWT improves cardiac function and inhibits cardiomyocyte apoptosis through PI3K/Akt signaling pathways in this rat HF model.

Cardiac shock-wave therapy in the treatment of coronary artery disease: systematic review and meta-analysis.

AIM: To systematically review currently available cardiac shock-wave therapy (CSWT) studies in humans and perform meta-analysis regarding anti-anginal efficacy of CSWT. METHODS: The Cochrane Controlled Trials Register, Medline, Medscape, Research Gate, Science Direct, and Web of Science databases were explored. In total 39 studies evaluating the efficacy of CSWT in patients with stable angina were identified including single arm, non- and randomized trials. Information on study design, subject's characteristics, clinical data and endpoints were obtained. Assessment of publication risk of bias was performed and heterogeneity across the studies was calculated by using random effects model. RESULTS: Totally, 1189 patients were included in 39 reviewed studies, with 1006 patients treated with CSWT. The largest patient sample of single arm study consisted of 111 patients. All selected studies demonstrated significant improvement in subjective measures of angina symptoms and/or quality of life, in the majority of studies left ventricular function and myocardial perfusion improved. In 12 controlled studies with 483 patients included (183 controls) angina class, Seattle Angina Questionnaire (SAQ) score, nitrates consumption were significantly improved after the treatment. In 593 participants across 22 studies the exercise capacity was significantly improved after CSWT, as compared with the baseline values (in meta-analysis standardized mean difference SMD = -0.74; 95% CI, -0.97 to -0.5; p < 0.001). CONCLUSIONS: Systematic review of CSWT studies in stable coronary artery disease (CAD) demonstrated consistent improvement of clinical variables. Meta-analysis showed a moderate improvement of exercise capacity. Overall, CSWT is a promising non-invasive option for patients with end-stage CAD, but evidence is limited to small sample single-center studies. Multi-center adequately powered randomised double blind studies are warranted.

Clinical effect of cardiac shock wave therapy on patients with ischaemic heart disease: a systematic review and meta-analysis.

BACKGROUND: After several years of study, CSWT has been initially applied to IHD treatment, but the actual effectiveness has never been well evaluated with a meta-analysis. METHODS: MEDLINE, EMBASE, Science Direct, Cochrane Controlled Trials Register database and Chinese database were searched. The randomized controlled trials, and single-arm and cohort study related to in patients with IHD undergoing CSWT were included and 14 articles were finally analysed. The data related to the study design, patient characteristics and outcomes were extracted. All the selected data were calculated with random-effects models in weighted mean differences, and heterogeneity was carefully evaluated as well. RESULTS: (i) Cardiac shock wave therapy improves the angina pectoris symptom (including the decrease of Canadian Cardiovascular Society class [-0·86 (-1·12, -0·65), P < 0·00001], nitroglycerin dosage (times/weeks) [-0·71 (-1·08, -0·33), P = 0·0002] and a increase of Seattle Angina Questionnaire score [5·64 (3·12, 8·15), P < 0·0001)]); (ii) CSWT leads to a reduce in heart failure (including a reduction of New York Heart Association functional class [-0·49 (-0·62, -0·37), P < 0·00001], a stable rise in 6-min walking distance [68·38 (39·70, 97·05), P < 0·00001] and a growth in left ventricular ejection fraction with echocardiography screening [6·73 (4·67,8·80), P < 0·00001]); (iii) CSWT improves myocardial viability within improving in total score of perfusion imaging [-5·19 (-8·08, -2·30), P = 0·0004] and total score of metabolism imaging [-5·33 (-7·77, -2·90), P < 0·0001]. CONCLUSIONS: The meta-analysis suggests that CSWT may offer beneficial effects to patients with IHD, although there was significant heterogeneity across the studies.

Observation of the effectiveness of clinical indicators of cardiac shock wave therapy in patients with ischemic heart disease: A systematic review and meta-analysis.

Objective: Ischemic heart disease (IHD) has a high prevalence and mortality rate, imposing a heavy burden on patients and society, and there is still a need to optimize treatment options for IHD patients. Cardiac shock wave therapy (CSWT) is gaining popularity as a new treatment for IHD patients. The objective of this meta-analysis is to reassess the effects of CSWT on IHD patients in light of the limited number of clinical studies included in previously published reviews, inconsistent methodological quality, and unclear outcomes. Methods: From database creation until September 1, 2022, 4 English databases and 3 Chinese databases were rigorously searched for any current controlled trials of CSWT for IHD. The Cochrane Risk of Bias Assessment Tool was used for methodological quality assessment. Review Manager v.5.4 software was used for meta-analysis. Results: Nineteen published controlled trials totaling 1,254 subjects were included. Results showed that CSWT could enhance left ventricular function and myocardial viability, improve cardiac function and alleviate angina pectoris symptoms. The effects of CSWT and control groups on SAQ scores and exercise time were not statistically significant. Conclusion: According to this systematic review and meta-analysis, CSWT may be beneficial for a number of IHD clinical indications. To verify these findings, more RCT studies with bigger sample numbers and higher methodological standards are required in the future.

The association of catestatin and endocan with the effects of cardiac shock wave therapy: Biomarker sub-study of the randomized, sham procedure-controlled trial.

Introduction: Cardiac shock-wave therapy (CSWT) is a non-invasive regenerative treatment method based on low-frequency ultrasound waves, which stimulate angiogenesis. Current data about the effects of revascularization procedures on angiogenesis biomarkers is limited. Recently, an association of catestatin and endocan with coronary collateral development was shown in several trials. In this study, we aimed to evaluate the impact of CSWT on the dynamics of catestatin and endocan levels and to assess their correlation with parameters of myocardial perfusion and function. Methods: Prospective, randomized, triple-blind, sham procedure-controlled study enrolled 72 adult subjects who complied with defined inclusion criteria (NCT02339454). We measured biomarkers in 48 patients with stable angina (24 patients of CSWT group, 24 patients of sham-procedure group). Additionally, patients were divided into responders and non-responders according to improvement in myocardial perfusion and/or contractility assessed by myocardial scintigraphy and dobutamine echocardiography (30 and 13 patients, respectively). The blood samples were collected at baseline, after the last treatment procedure (9th treatment week) and at 6-month follow-up to evaluate biomarkers concentration and stored at -80° until analysis. Serum catestatin and endocan levels were determined by commercially available ELISA kits. Results: Serum catestatin concentration significantly increased in all patients. While endocan levels significantly decreased in the responders sub-group. The increase in catestatin levels at 9th week and 6 months was positively associated with improvement in summed difference score (rho = 0.356, p = 0.028) and wall motion score, WMS (rho = 0.397, p = 0.009) at 6 months in the whole study population. Meanwhile, the decrease in endocan levels over 6 months was positively correlated with improvement in WMS at 3- and 6- months (r = 0.378, p = 0.015 and r = 0.311, p = 0.045, respectively). ROC analysis revealed that a change at 6 months in catestatin and endocan levels significantly predicted improvement in myocardial perfusion and contractile function with 68.9% sensitivity and 75.0% specificity (p = 0.039) and 51.7% sensitivity, and 91.7% specificity (p = 0.017), respectively. Baseline endocan concentration and its change at 6 months predicted response to CSWT with 68.8% sensitivity and 83.3% specificity (p = 0.039) and 81.3% sensitivity and 100% specificity (p < 0.0001), respectively. Conclusion: This study demonstrates the association of increase in catestatin and decrease in endocan levels with the improvement of myocardial perfusion and contractile function. The potential predictive value of catestatin and endocan dynamics for the response to regenerative therapy is shown.

Cardiac Shock Wave Therapy in Coronary Artery Disease: A Systematic Review and Meta-Analysis.

Objective: Coronary artery disease (CAD) has been one of the leading causes of morbidity and mortality worldwide. Cardiac shock wave therapy (CSWT) is a novel and non-invasive therapy for CAD. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy of CSWT on CAD. Methods and results: We performed a comprehensive search of electronic databases such as PubMed, Embase, the Cochrane Library, and Wanfang Data in October 2021. The results were reported as weighted mean difference (WMD) with a 95% confidence interval (CI). Statistical heterogeneity scores were assessed with the standard Cochran's Q test and the I 2 statistic. A total of 8 randomized trials and 2 prospective cohort studies, together involving 643 patients (n = 336 CSWT and n = 307 control), were included in our study. Eight studies with 371 patients showed significantly improved rest left ventricular ejection fraction (LVEF) with CSWT as compared to that of the control group (WMD 3.88, 95% CI 1.53-6.23, p = 0.001, I 2 = 51.2%). Seven studies with 312 patients reported left ventricular internal diameter in diastole (LVIDd) were markedly decreased in the CSWT group compared to the control group (WMD -1.81, 95% CI -3.23 to -0.39, p = 0.012, I 2 = 20.3%). The summed stress score significantly favored the CSWT group (WMD -3.76, 95% CI -6.15 to -1.37, p = 0.002, I 2 = 56.8%), but there was no significant difference for the summed rest score. Our data were acquired from studies without a perceived high risk of bias, so plausible bias is unlikely to seriously affect the main findings of the current study. Conclusion: Based on data from our present meta-analysis, CSWT was shown to moderately improve myocardial perfusion and cardiac function among patients with CAD, which would provide the clinicians with a meaningful and valuable option. Systematic Review Registration: The meta-analysis was registered on the Open Science Framework (OSF) (https://osf.io/r2xf9).

Effect of cardiac shock wave therapy plus optimal medical therapy on rehospitalization in patients with severe coronary artery disease: A meta-analysis and trial sequential analysis.

Objective: Several small sample-sized clinical studies have demonstrated that cardiac shock wave therapy (CSWT) might reduce the risk of rehospitalization in patients with severe coronary artery disease (CAD). However, other observational studies did not reported that clinical benefit of CSWT. Therefore, the effect of CSWT plus optimal medical therapy (OMT) on rehospitalization is still controversial. Methods: We performed an updated meta-analysis and systematic review of randomized clinical trials (RCTs) and prospective cohort studies identified in systematic searches of Pubmed, Embase, the Cochrane library, the ClinicalTrials.gov website and Chinese SinoMed Database (up to December 2021). Primary endpoint was the rate of major adverse cardiac events (MACEs, the composite outcome of mortality, coronary artery revascularization, and rehospitalization). Meta-regression and subgroup analyses were used to identify possible contributors to between-study variances in the HDRS. Required information size (RIS) was calculated with trial sequential analysis (TSA). Results: A total of 11 RCTs and 5 prospective cohort studies involving 1,149 patients with a mean follow-up of 10.3 months (range 3-72) months were included. Overall, CSWT plus OMT significantly decreased the rate of MACEs compared with the OMT group (RR, 0.39; 95% CI, 0.29-0.53), which was mainly attributed to markedly lower risk of rehospitalization (RR, 0.37; 95% CI, 0.27-0.51). Subgroup analysis showed that the pooled RRs for MACEs was significantly lower in studies enrolling patients with higher baseline Canadian Cardiovascular Society angina class (≥2.2) (RR, 0.36; 95% CI, 0.26-0.50) or studies with short follow-up period (followed ≤ 6 months, RR, 0.39; 95% CI, 0.24-0.64; followed 7-12 months, RR, 0.38; 95% CI, 0.26-0.54) or studies with HF with reduced ejection fraction (RR, 0.31; 95% CI, 0.13-0.72) or with preserved ejection fraction (RR, 0.40; 95% CI, 0.29-0.56). TSA showed that The RIS for MACE was 935, and the accrued information size was 577. Conclusion: Cardiac shock wave therapy plus OMT could decrease the rate of rehospitalization among patients with severe CAD. However, this result must be interpreted with caution, for the evidence supporting the use of CSWT for severe CAD is limited by the small sample size and short follow-up period of previous studies. Larger RCTs with longer follow-up are warranted to confirm these findings. Systematic review registration: [https://inplasy.com/], identifier [INPLASY202210103].

Case Series: Extracorporeal Shockwave Myocardial Revascularization Therapy Improves Ischemic Response, Functional Capacity, and Quality of Life in Indicated CABG-Stable Angina Pectoris Patients.

INTRODUCTION: Extracorporeal shockwave myocardial revascularization (ESMR) is included in the guidelines only for patients with refractory angina pectoris having no option for invasive revascularization. We intend to report a case series with ESMR therapy is indicated patients with coronary artery bypass grafting-stable angina pectoris (CABG-SAP) who refuse the surgery, irrespective of angina symptoms. METHODS: We review medical records of patients with SAP admitted to ESMR therapy in Dr. Hasan Sadikin General Hospital, Bandung, Indonesia from January 2018 to December 2019. Recorded variables at baseline and after therapy extracted, namely, (1) ischemic response, double product, and (2) functional capacity measured as metabolic equivalent (MET) using treadmill test; (3) six-minute walking test distance achieved; and (4) quality of life using SF-36 Questionnaire. RESULTS: A total of four indicated patients with CABG-SAP from 50 to 75 years old were included in this study. At baseline, one patient is CCS class I and two patients are CCS class II with SDS ranging from 3 to 17. Ischemic response improved in all the patients. The double product improved in patient 1 9,600-14,872 mm Hg × bpm, patient 2 9,460-10,640 mm Hg × bpm, and patient 4 17,220-20,480 mm Hg × bpm. The functional capacity improved in Patient 1 8.07-8.91 METs, patient 2 1.91-4.01 METs, patient 3 3.45-6.39 METs, and patient 4 3.9-4.43 METs. The 6-min walking distance improved in patient 1 540-570 m and patient 2 345-405 m. The CCS class, bodily pain, and general health domain scores improved in all patients. CONCLUSION: ESMR therapy might be beneficial for indicated patients with CABG-SAP to improve ischemic response, functional capacity, and physical component of quality of life.

Cardiac Shock Wave Therapy Ameliorates Myocardial Ischemia in Patients With Chronic Refractory Angina Pectoris: A Randomized Trial.

Background: Cardiac shock wave therapy (CSWT) is a non-invasive new option for the treatment of chronic refractory angina pectoris (CRAP). This study aimed to evaluate the safety and efficiency of CSWT in the treatment of CRAP. Methods: Eighty-seven patients with CRAP were randomly allocated into CWST group (n = 46) and Control group (n = 41). Canadian Cardiovascular Society (CCS) grade of angina pectoris, Seattle Angina Questionnaire (SAQ) score, 6-min walk test (6MWT), weekly dosage of nitroglycerin, and myocardial perfusion on D-SPECT were determined at baseline and during the follow-up period. Adverse events were also evaluated. Results: CSWT was well-tolerated in the CSWT patients. CSWT significantly improved the CCS grade, SAQ score, and 6MWT (p < 0.05). Imaging examinations showed that the ischemic area was reduced after CSWT. However, no significant changes were observed in the Control group. Conclusions: CSWT may improve the myocardial perfusion and reduce clinical symptoms without increasing adverse effects in CRAP patients. It provides a non-invasive and safe clinical therapy for CRAP patients. Clinical Trial registration: www.ClinicalTrials.gov, identifier: NCT03398096.

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.

Protective effect of extracorporeal cardiac shock wave combined with ultrasound microbubble post-conditioning on myocardial ischemia-reperfusion injury in rats / 中华超声影像学杂志

Objective:To investigate the myocardial protective effect of extracorporeal cardiac shock wave therapy (CSWT) combined with sulfur hexafluoride microbubble post-conditioning on myocardial ischemia-reperfusion injury (MI/RI) in rats, and to provide theoretical support for clinical treatment of MI/RI.Methods:A total of 32 male SD rats were randomly divided into 4 groups: sham operation group (Sham group), MI/RI group (IR group), CSWT group (IR+ SW group), and CSWT combined with sulfur hexafluoride microbubble treatment group (IR+ SW+ MB group), with 8 rats in each group. Therapeutic intervention was performed in IR+ SW group and IR+ SW+ MB group on the 1st, 3rd and 5th day after modeling. The left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) of the rats were measured by echocardiography before and after treatment. On the 7th day, myocardial fibrosis was assessed by Masson staining, and cardiomyocyte apoptosis was observed by TUNEL staining. The myocardial apoptotic proteins Bcl-2, BAX, Cleaved-Caspase-3 and Cleaved-Caspase-9 in the infarct boundary area were detected by Western blot. The differences of the above indexes among different groups were compared.Results:①There was no significant change in heart rhythm and heart rate among the groups before and after treatment, and there was no significant difference in heart rate ( P>0.05). ②The echocardiographic results after treatment showed that, compared with IR group, LVEDD and LVESD in IR+ SW group and IR+ SW+ MB group decreased in turn, while LVEF and LVFS increased in turn with significant differences between each two groups (all P<0.05). ③Compared with IR group, the degrees of myocardial fibrosis and apoptosis in IR+ SW group and IR+ SW+ MB group were alleviated in turn, and the relief in IR+ SW+ MB group was the most obvious. Quantitative analysis showed that compared with IR group, the proportions of cardiomyocyte apoptosis in IR+ SW group and IR+ SW+ MB group decreased in turn, and there were significant differences between each two groups (all P<0.05). ④The results of Western blot detection showed that compared with IR group, the levels of Bcl-2 in IR+ SW group and IR+ SW+ MB group increased in turn, while the levels of BAX and the activation level of Caspase-3 and Caspase-9 protein decreased in turn. These differences were all statistically significant between each two groups (all P<0.05) except for the activation level of Caspase-3 protein between IR+ SW group and IR+ SW+ MB group ( P>0.05). Conclusions:CSWT combined with sulfur hexafluoride microbubble therapy can improve left ventricular remodeling and left ventricular systolic function by inhibiting cardiomyocyte apoptosis.

Study of the Safety of Extracorporeal Cardiac Shock Wave Therapy: Observation of the Ultrastructures in Myocardial Cells by Transmission Electron Microscopy.

Extracorporeal cardiac shock wave therapy (CSWT) has been used to treat patients with severe coronary heart disease and cardiac failure with good results; however, the safety of this treatment is still controversial. Its safety in clinical setting and on microstructures has been confirmed, but the influence of shock wave on the ultrastructures of myocardial cells is not clear. In this study, 12 Sprague-Dawley rats were randomly divided into control (NC) and CSWT therapy (NC+SW) groups. The heart rate, blood pressure, serum troponin I (TNI), and cardiac ultrasound were evaluated, and the myocardial inflammatory responses and fibrosis changes were compared. The samples were observed by transmission electron microscopy to evaluate the changes in myocardial tissue ultrastructure. The CSWT had no significant influence on rat hemodynamics indices and serum TNI, did not affect left ventricular function, and did not cause myocardial inflammatory response and fibrosis changes. The scores of myocardial ultrastructure damage in the NC and NC+SW groups were 1.39 ± 0.982 and 2.42 ± 1.009, respectively ( P = .103). The CSWT did not cause significant additional damage to myocardial ultrastructures. The safety of CWST has been preliminarily proved at the clinical, microstructure, and ultrastructure levels, but its long-term safety needs further exploration.

Case report: improvement of cardiac remodeling with shock wave therapy of a patient with ischemic cardiomyopathy.

Percutaneous coronary intervention (PCI) and coronary-artery bypass grafting (CABG) are two major preferred reperfusion strategies to restore the ischemic-related artery patency, but PCI and CABG do not necessarily guarantee the recovery of post-procedure left ventricular (LV) dysfunction and release of symptoms. Moreover, there is no definitive effective way to enhance microcirculations. Theoretically, shock wave therapy (SWT) is an option. We report here a case of patient who received SWT. The patient's medical history was characterized by chest pain for 20 years, having received CABG 13 years ago. The follow-up angiography showed all blood vessels are stiff and rigid therefore no chance for a second CABG. After cardiac SWT treatment for 1 year, the patient's symptoms of chest pain and chronic heart failure significantly improved, the odds of cardiac muscle survival increased, the cardiac remodeling was also improved. What's more, left ventricular ejection fraction (LVEF) was improved from 34% to 51% and 43% in half year and 1 year after SWT which is indicated by single-photon emission computed tomography (SPECT), respectively. To our knowledge, this is the first report of 2-cycle cardiac SWT treatments over 1 year with a complete follow-up, indicating that SWT can not only improve the symptoms of chronic heart failure, but also improve LVEF and cardiac remodeling caused by ischemic cardiomyopathy.

Clinical Effect of Cardiac Shock Wave Therapy on Myocardial Ischemia in Patients With Ischemic Heart Failure.

BACKGROUND: Cardiac shock wave therapy (CSWT) can improve myocardial ischemia and cardiac function in patients with coronary artery disease and refractory angina. The aim of the study was to test its potential role to relieve symptoms in patients with ischemic heart failure (HF) and to identify CSWT-affected genes. METHODS: Cardiac shock wave therapy was performed on 23 patients (mean age: 67 ± 6 years) with ischemic HF 3 times per week for 3 weeks. Clinical assessment parameters were measured for all patients, and peripheral blood mononuclear cells (PBMCs) were isolated from whole blood of all patients 3 days before CSWT and 1 week after the 3-week CSWT schedule. RNA sequencing of PBMCs collected from 3 patients before and after CSWT was performed on the Illumina Genome Analyzer. Gene expression was determined by quantitative reverse transcription-polymerase chain reaction. RESULTS: Cardiac shock wave therapy significantly attenuated myocardial ischemia and severity of angina, health-related quality of life, and myocardial blood flow as estimated by New York Heart Association class, Canadian Cardiovascular Society classification, Seattle Angina Questionnaire, and single photon emission computed tomography images, respectively. We then tried to investigate how CSWT improved myocardial ischemia by RNA sequencing on PBMCs. Gene set enrichment analysis on the sequencing data revealed that CSWT treatment was positively correlated with cytokine and cytokine receptor interaction and chemokine signaling pathway. Furthermore, we demonstrated that CSWT resulted in a significant increase in the expression of promoters of neovascularization (vascular endothelial growth factor A [VEGF-A], VEGF-B, chemokine (C-X-C motif) ligand 1 [CXCL1], CXCL2, CXCL3 and TNFRSF12A) and a notable decrease in the expression of a mediator of cell apoptosis (mitogen-activated protein kinase 9). CONCLUSIONS: Cardiac shock wave therapy can improve myocardial ischemia and represents as a treatment option for patients with ischemic HF through promoting neovascularization and inhibiting cell apoptosis.

Effect of cardiac shock wave therapy on the microvolt T wave alternans of patients with coronary artery disease.

OBJECTIVE: The aim of this study was to evaluate the effect of cardiac shock wave therapy (CSWT) on microvolt T wave alternans (MTWA) in patients with coronary artery disease (CAD). METHODS: 87 patients with old myocardial infarction (OMI) were enrolled in this study. Sixty-two patients were randomized into the CSWT group, 32 patients into the regular treatment group (Group A) according to different shock wave procedure, and 30 into the expanding scope treatment group (Group B), and 25 patients were randomized into the control group (Group C). But the shock wave (SW) energy was only applied to the patients in the CSWT group and not to the patients in the control group. Three months was a treatment course, thus patients received a total of 9 CSWT treatment sessions. RESULTS: Technetium-99m sestamibi myocardial perfusion, fluorine-18 fluorodeoxyglucose myocardial metabolism single-photon emission computed tomography (SPECT) were performed to identify segments of myocardial ischemia, myocardial viability, and microvolt T wave alternans (MTWA) before and after CSWT. After CSWT, the rehospitalization rates of CSWT group were lower than control group (P<0.05). The myocardial ischemic segments, metabolism abnormal segments, total radioactive score of perfusion imaging and metabolism imaging, MTWA, and MTWA/HR in CSWT group were reduced significantly (P<0.05). And the heart rate of maximum MTWA, exercise time were increased significantly (P<0.05). All of the parameters in the control group did not change significantly even worsen after the treatment (P>0.05). CONCLUSIONS: CSWT can reduce the MTWA value, improve the heart chronotropic function and increase the threshold of frequency which causes MTWA.

Cardiac shock wave therapy and myocardial perfusion in severe coronary artery disease.

BACKGROUND: Ultrasound guided cardiac shock wave therapy (CSWT) is a noninvasive therapeutic option in the treatment of chronic-refractory angina. Clinical trials have shown that CSWT reduces angina symptoms, improves regional systolic function, LV ejection fraction, myocardial perfusion and quality of life parameters. Absolute measurements of myocardial perfusion before and after CSWT have not been performed so far. METHODS AND RESULTS: We studied a total of 21 CCS III patients with history of CAD and multiple interventions who suffered from disabling angina despite individually optimized medical therapy. An N-13 NH3 PET perfusion scan under adenosine was performed before and after CSWT treatment. CSWT was well tolerated in all patients. Absolute perfusion under adenosine of the global left-ventricular myocardium did not change under therapy or minimal coronary resistance. The treated segments, however, showed in terms of both perfusion and resistance a mild but significant improvement, by 11 and 15 %, respectively, whereas no change could be observed in the remote segments. Considering a threshold of increased perfusion of 5 %, 10 (77 %) out of 13 patients with a better target perfusion improved in their CCS class, whereas 3 (43 %) out of 7 patients without improved target perfusion improved in their CCS class too. CONCLUSION: Standard CSWT has the potential to improve myocardial perfusion of the therapy zone and clinical CAD symptomatology without affecting global myocardial perfusion. As a noninvasive and well tolerated therapeutic option, these data suggest the use of CSWT in patients with end-stage CAD.