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.

Soluble CD146 in the detection and grading of intravascular and tissue congestion in patients with acute dyspnoea: analysis of the prospective observational Lithuanian Echocardiography Study of Dyspnoea in Acute Settings (LEDA) cohort.

OBJECTIVES: To evaluate the potential of soluble cluster of differentiation 146 (sCD146) in the detection and grading of congestion in patients with acute dyspnoea. DESIGN: Subanalysis of the prospective observational Lithuanian Echocardiography Study of Dyspnoea in Acute Settings (LEDA) cohort. SETTING: Two Lithuanian university centres. PARTICIPANTS: Adult patients with acute dyspnoea admitted to the emergency department. METHODS: Congestion was assessed using clinical and sonographic parameters. All patients underwent sCD146 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing. RESULTS: The median value of sCD146 concentration in the study cohort (n=437) was 405 (IQR 315-509) ng/mL. sCD146 was higher in patients with peripheral oedema than in those without (median (IQR) 472 (373-535) vs 400 (304-501) ng/mL, p=0.009) and with pulmonary rales than in those without (439 (335-528) vs 394 (296-484) ng/mL, p=0.001). We found a parallel increase of estimated right atrial pressure (eRAP) and sCD146 concentration: sCD146 was 337 (300-425), 404 (290-489) and 477 (363-572) ng/mL in patients with normal, moderately elevated and high eRAP, respectively (p=0.001). In patients with low NT-proBNP, high sCD146 distinguished a subgroup with a higher prevalence of oedema as compared with patients with low levels of both biomarkers (76.0% vs 41.0%, p=0.010). Moreover, high sCD146 indicated a higher prevalence of elevated eRAP, irrespective of NT-proBNP concentration (p<0.05). CONCLUSION: sCD146 concentration reflects the degree of intravascular and tissue congestion assessed by clinical and echocardiographic indices, with this association maintained in patients with low NT-proBNP. Our data support the notion that NT-proBNP might represent heart stretch while sCD146 rather represents peripheral venous congestion.

Technical Recommendations for Real-Time Echocardiography and Fluoroscopy Imaging Fusion in Catheter-Based Mitral Valve Paravalvular Leak and Other Procedures.

Widespread catheter-based interventions for structural heart disease have overtaken the treatment of paravalvular leaks (PVL). Multimodality imaging techniques play a crucial role in accurate diagnosis, procedure planning and performance. However, PVL closure is often technically challenging due to the complex anatomy of the defects and their relation to surrounding anatomical structures. The application of echocardiography and fluoroscopy imaging fusion (EFF) may simplify challenging imaginative three-dimensional reconstruction of the intracardiac anatomy and facilitate the procedure. To master new technology, personnel must make cognitive changes, overcome a learning curve, and obtain adequate theoretical knowledge. Main aim of this manuscript is to present basic recommendations for EFF application in practice, alongside, each scenario is supported by technically challenging clinical examples. We may conclude that our manuscript may provide useful information for physicians on EEF application in clinical practice.

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.

A randomized, triple-blind trial of cardiac shock-wave therapy on exercise tolerance and symptoms in patients with stable angina pectoris.

BACKGROUND: Despite major advances in managing coronary artery disease and continuous research on alternative techniques to enhance myocardial perfusion and reduce symptoms, coronary artery disease is still one of the leading causes of adult disability worldwide. Cardiac shock-wave therapy (CSWT) has shown promising results in the amelioration of myocardial ischemia in experimental studies; however, clinical results are limited to single-center, mostly uncontrolled and underpowered trials. The current study aimed to evaluate whether CSWT can improve exercise tolerance and relieve angina symptoms in addition to optimal medical treatment in patients with stable angina. PARTICIPANTS AND METHODS: A prospective, randomized, triple blind, sham-procedure-controlled study was carried out. The primary endpoint was total exercise duration in the modified Bruce treadmill test at the 6-month follow-up. The secondary endpoints were changes in ST-segment depression during the treadmill test, angina symptoms during the treadmill test, number of angina attacks per week, number of sublingual nitroglycerin consumption per week, Canadian Cardiovascular Society angina functional class, and the Seattle Angina Questionnaire score at the 6-month follow-up. Patients were randomized at a 1 : 1 ratio to optimal medical plus cardiac shock-wave therapy (OMT+CSWT) and optimal medical therapy with sham procedure (OMT+placebo) groups. RESULTS: The mean exercise time improved in both study arms - CSWT and placebo treatment - at the 3- and 6-month follow-up, without a significant difference between groups. The magnitude and frequency of peak exercise ST-segment depression reduced significantly in the CSWT+OMT group compared with the OMT+placebo group at the 6-month follow-up (51.4 vs. 90.6%, P=0.001). Percentage of angina-free patients increased progressively in both groups throughout the study. The Seattle Angina Questionnaire scores improved significantly in both arms for four of five domains at the 3- and the 6-month follow-up. Numerically, although insignificant, the decrease in the number of angina episodes was more prominent in the OMT+CSWT group compared with the OMT+placebo group. CONCLUSION: The total exercise duration in the modified Bruce treadmill test at the 6-month follow-up did not differ significantly in patients treated with CSWT compared with optimal medical therapy alone. In addition, CSWT exerted a neutral effect on the quality of life and level of angina.

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.

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.

Long-term results of minimally invasive stand-alone bi-atrial surgical ablation with a bipolar ablation device for persistent and longstanding persistent AF: a single-center case series of 91 patients.

BACKGROUND: Minimally invasive surgical treatment of lone atrial fibrillation (AF) is an alternative for AF that is refractory to medical treatment. We present long-term results of standalone surgical ablation of AF using a bipolar ablation device in 91 consecutive patients. METHODS: This was an observational, retrospective study of 91 patients (77 % males; mean age, 53 ± 10 years [range, 23-75 years]) who underwent minimally invasive standalone surgical ablation of persistent and longstanding persistent AF using a bipolar ablation device from 2008 to 2014. Mean follow-up was 60 ± 21 months. The absence of arrhythmia was confirmed at 3, 6, and 12 months, and annually thereafter, with 24-hour Holter monitoring. RESULTS: The mean duration of preoperative AF was 6.5 ± 5.4 years. Persistent AF was present in 86 % of patients and longstanding persistent AF in 14 %. Mean left atrial diameter was 4.3 ± 0.8 cm. There were two postoperative strokes (2 %) and three conversions to median sternotomy (3 %). Permanent pacemakers were implanted in six (7 %) patients. There were no intra- or postoperative deaths. At 1, 2, 3, 4, and 5 years postoperatively, freedom from AF was 59, 45, 41, 38, and 38 % of patients, respectively. The failure to achieve pulmonary vein isolation was the only independent predictor of long-term recurrence of AF (HR -3 [95 % CI 1,858 to 8,586], p = 0,001). There was a tendency towards higher rates of SR at long term follow up in patients with pulmonary vein isolation if division of ligament of Marshall was performed (HR - 2 [95 % CI 0.987 to 4,202], p = 0,067). CONCLUSIONS: In the present series, the efficacy of epicardial surgical ablation was similar to that reported previously. The rate of arrhythmia recurrence increased over time. Achieving pulmonary vein isolation is essential to AF elimination. The division of ligament of Marshall could contribute to improved rates of SR restoration in patients with persistent or long-standing persistent AF if PVI is achieved.

Extracorporeal shockwave myocardial revascularization improves clinical symptoms and left ventricular function in patients with refractory angina.

BACKGROUND: Medical therapy for refractory angina is limited and the prognosis is poor. Experimental data suggest that the use of extracorporeal shockwave myocardial revascularization (ESMR) can contribute to angiogenesis and improve symptoms of angina and left ventricular (LV) function. The objective of this study was to examine the effects of ESMR on clinical symptoms as well as LV function as assessed by cardiac MRI in patients with refractory angina. METHODS: Patients with Canadian Cardiovascular Society (CCS) class III-IV angina despite medical therapy and ischemia documented on thallium or echo-dobutamine were eligible for the study. ESMR therapy was applied with a commercially available cardiac shockwave generator system under echocardiographic guidance. LV function was assessed before and 6 months after therapy by cardiac MRI. RESULTS: Twenty patients (four women, 16 men; mean age 64 years, range 45-83) were included in the study. The CCS class after treatment improved in all patients (16 patients angina pectoris CCS from III to II and four patients from IV to III). The use of sublingual nitroglycerin was significantly reduced as well. There was a significant improvement in LV ejection fraction as assessed by blinded MRI following therapy in the overall population (51 vs. 59%, P<0.05). CONCLUSION: This study demonstrates the potential efficacy of ESMR for the treatment of refractory angina pectoris. The patients showed both a significant clinical response as well as improved LV ejection fraction on serial MRI imaging. Larger studies are needed to adequately define the clinical utility of this novel therapy.

Sensitisation and post-transplant course after the implantation of ventricular assist device.

The purpose of this study was to evaluate sensitisation, occurring because of bridging with VAD, and development of rejection episodes after transplantation in selected groups of patients using triple drug immunosuppression, without induction or desensitisation therapy. Sensitisation using standard complement dependent cytotoxicity was tested in 16 patients awaiting cardiac transplantation before VAD placement, one month post-implantation and on a six-monthly basis later on. Long-term (955+/-998 days) post-transplant course of six transplanted post-VAD patients was compared with 19 non-bridged recipients (follow-up time 1425+/-1273 days) of the same age. One-third of VAD recipients had developed anti-HLA antibodies one month post-implantation; 4/16 patients were sensitised six months after implantation. No de novo sensitisation development was revealed in VAD group post-transplantation. All sensitised patients independent of VAD placement underwent graft rejection episodes. Only 1 of 6 VAD recipient was treated because of grade 2R rejection, compared to 6/19 in the non-bridged group, P=0.63. None of the patients had failed because of early graft rejection. In conclusion, VAD devices used in our centre cause low level risk for anti-HLA antibodies development. There were no differences in survival due to immunologic reasons between VAD bridged and non-bridged patients.