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.

Sex Differences in Ischemic and Bleeding Outcomes in Patients With Non-ST-Segment-Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: Insights From the TAO Trial.

BACKGROUND: Previous studies have observed poorer outcomes in females with myocardial infarction, but older age and lower use of percutaneous coronary intervention in females are factors that potentially explain the worse outcome. This study sought to determine if female sex is an independent factor of ischemic and bleeding outcomes in non-ST-segment-elevation acute coronary syndrome treated with a systematic invasive approach. METHODS: The TAO trial (Treatment of Acute Coronary Syndrome With Otamixaban) randomized patients with non-ST-segment-elevation acute coronary syndrome treated invasively to heparin plus eptifibatide versus otamixaban. In this post hoc analysis, the primary ischemic end point (all-cause death, myocardial infarction within 180 days) and the primary safety end point (Thrombolysis in Myocardial Infarction major or minor bleeding within 30 days) were analyzed according to sex. RESULTS: Of 13 229 randomized patients, 3980 (30.1%) were females and 9249 (69.9%) were males. Females were older (64.8±11.0 versus 60.7±11.1 years), had more comorbidities, received less peri-procedural antithrombotic therapy, and underwent less frequently revascularization. Overall, females experienced a higher risk of ischemic (10.2% versus 9.1%; odds ratio [OR], 1.15 [1.01-1.30]) and bleeding events (4.2% versus 3.4%; OR, 1.23 [1.02-1.49]) than males. After multivariate analysis, the risk of ischemic outcomes (OR, 1.04 [0.90-1.19]), death (OR, 1.00 [0.75-1.23]), or bleeding (OR, 1.05 [0.85-1.28]), were similar between females and males. Only, noncoronary artery bypass graft related Thrombolysis in Myocardial Infarction major bleeding were increased in females (OR, 1.69 [1.11-2.56]). CONCLUSIONS: In patients with non-ST-segment-elevation acute coronary syndrome with systematic invasive management, ischemic outcomes, bleeding events, and mortality were higher in females. After multivariate analyses, female sex was not an independent predictor of ischemic and bleeding events although noncoronary artery bypass graft related Thrombolysis in Myocardial Infarction major bleeding was higher in females. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01076764.

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 rare case of REM sleep-related bradyarrhythmia syndrome with concomitant severe hypertension: a case report and a review of literature.

INTRODUCTION: Rapid eye movement (REM) sleep-related bradyarrhythmia syndrome is characterized by pathological asystoles during the REM sleep phase. It is a rare rhythm disorder, being reported only few times in the literature. Due to non-specific symptoms, REM sleep-related bradyarrhythmia might be often underdiagnosed. Other cardiac diseases associated with pathological sinus arrests must be excluded to establish the correct diagnosis of and appropriate therapy for REM sleep-related bradyarrhythmia. We report a case of this syndrome followed by hypertension and diastolic heart failure. THE CASE: A 49-year-old male with severe hypertension presented for a cardiologist's consultation. His main complaints were palpitations, fatigue, dyspnoea, and snoring. Polysomnography test revealed a normal sleep structure with episodes of bradycardia and increased parasympathetic activity during phasic events of REM sleep. Heart rate variability Poincare plot analysis demonstrated similar results. REM sleep-related bradyarrhythmia syndrome was diagnosed and patient was treated with dual chamber heart pacemaker implantation. DISCUSSION: Various components of the autonomic nervous system influence the development of REM sleep-related bradyarrhythmia syndrome. The main factor is likely an increased vagal tone during the phasic REM sleep with the absence of normal compensatory sympathetic activity. Concomitant hypertension in REM sleep-related bradyarrhythmia syndrome is caused by a paradoxically abnormal control of the autonomic nervous system and can be explained through the acetylcholine metabolism pathway. Best suited diagnostic and treatment options for REM sleep-related bradyarrhythmia syndrome are discussed. CONCLUSIONS: Patients with REM sleep-related bradyarrhythmia syndrome often present with indistinct symptoms. Polysomnography is an essential diagnostic test for the differential diagnosis of various nocturnal arrhythmias and sleep disorders. Severe hypertension is a common complication of sleep disorders and requires appropriate treatment of the underlying condition. An implantation of a heart pacemaker is the first-choice treatment for patients with REM sleep-related bradyarrhythmia syndrome.

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.

Aerobic Training Effect on Arterial Stiffness in Metabolic Syndrome.

BACKGROUND: Metabolic syndrome, physical inactivity, and central obesity contribute to early vascular aging, which leads to increased risk of cardiovascular disease. This study aimed to assess the effect of heart rate (HR)-targeted aerobic exercise training on the indices of early vascular aging, in particular, arterial stiffness, and on anthropometric and clinical profile of metabolic syndrome subjects. METHODS: There were 126 metabolic syndrome subjects randomly selected. Anthropometric parameters, blood pressure (BP), blood sample, and arterial wall functional and structural parameters were obtained prior to and after the 8-week (84 patients) supervised training program. The age- and sex-matched control group (42 patients) followed the same protocol, except for the HR-targeted training program. RESULTS: In the study group, HR-targeted training was associated with decreased aortic pulse wave velocity (8.47 ± 1.40 vs 8.01 ± 1.06 m/s; P = .005), HR (P < .001), systolic (P < .015) and diastolic (P < .004) BP, waist circumference (P < .004), total and low-density-lipid cholesterol (respectively, 6.42 ± 1.41 vs 5.89 ± 1.32, P = .003 and 4.2 ± 1.18 vs 3.8 ± 1.21, P = .002), and an increase in aerobic capacity (P < .001). In the control group there were no statistically significant changes of arterial stiffness parameters. Multivariate analysis revealed that reduction of arterial stiffness was BP dependent. CONCLUSIONS: In subjects with metabolic syndrome, HR-targeted exercise training is associated with BP-dependent decrease in aortic stiffness and improvement of metabolic and fitness parameters.

Recurrent pericarditis: a case report and literature review.

BACKGROUND: Recurrence affects about 30% (20% to 50%) of patients within 18 months after the initial episode of acute pericarditis resulting in subsequent rehospitalizations. Bearing in mind high treatment costs of patients admitted to hospital with acute and recurrent pericarditis, there is a need to optimize the treatment of both of these conditions. MATERIALS AND METHODS: We present a case of recurrent pericarditis. The first episode of pericarditis was diagnosed in 2006. Three months later the patient was hospitalized due to clinical symptoms suggesting recurrence of a past condition. Ten years after the initial episode of acute pericarditis the patient was hospitalized for the treatment of recurrent pericarditis. The search for etiology of the disease was unsuccessful, the patient received treatment with nonsteroidal anti-inflammatory drugs; empiric antimicrobial therapy was also administered. RESULTS AND CONCLUSIONS: Acute pericarditis is the most common disease of the pericardium encountered in clinical practice. Colchicine has been demonstrated as a first-line drug to be added to conventional anti-inflammatory therapies in patients with a first episode of pericarditis or its recurrences in order to improve the response to therapy and reduce recurrences. Despite a large amount of new data, there are still several issues that require additional research and clarification, including the search for new individualized therapies, the best duration of treatment for patients with pericardial diseases, and optimization of patient follow-up in order to collect data on long-term outcomes that would allow shortening the duration of in-patient treatment and reduction of recurrences.

Use of troponin assay 99th percentile as the decision level for myocardial infarction diagnosis.

BACKGROUND: The Universal Definition of Myocardial Infarction recommends the 99th percentile concentration of cardiac troponin in a normal reference population as part of the decision threshold to diagnose type 1 spontaneous myocardial infarction. Adoption of this recommendation in contemporary worldwide practice is not well known. METHODS: We performed a cohort study of 276 hospital laboratories in 31 countries participating in the National Heart, Lung, and Blood Institute-sponsored International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial. Each hospital laboratory's troponin assay manufacturer and model, the recommended assay's 99th percentile upper reference limit (URL) from the manufacturer's package insert, and the troponin concentration used locally as the decision level to diagnose myocardial infarction were ascertained. RESULTS: Twenty-one unique troponin assays from 9 manufacturers were used by the surveyed hospital laboratories. The ratio of the troponin concentration used locally to diagnose myocardial infarction to the assay manufacturer-determined 99th percentile URL was <1 at 19 (6.6%) laboratories, equal to 1 at 91 (31.6%) laboratories, >1 to ≤5 at 101 (35.1%) laboratories, >5 to ≤10 at 34 (11.8%) laboratories, and >10 at 43 (14.9%) laboratories. The variability in troponin decision level for myocardial infarction relative to the assay 99th percentile URL was present for laboratories in and outside of the United States, as well as for high- and standard-sensitivity assays. CONCLUSIONS: There is substantial hospital-level variation in the troponin threshold used to diagnose myocardial infarction; only one-third of hospital laboratories currently follow the Universal Definition of Myocardial Infarction consensus recommendation for use of troponin concentration at the 99th percentile of a normal reference population as the decision level to diagnose myocardial infarction. This variability across laboratories has important implications for both the diagnosis of myocardial infarction in clinical practice as well as adjudication of myocardial infarction in clinical trials.

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.

Differentiation of acute myocarditis and acute myocardial infarction by the regional distribution of myocardial irreversible injury using cardiovascular magnetic resonance imaging.

BACKGROUND AND OBJECTIVE: In this study, we have sought for differences between cardiovascular magnetic resonance patterns of acute myocarditis and acute myocardial infarction. MATERIAL AND METHODS: A prospective analysis of 110 consecutive patients was performed. The presence, precise location, and pattern of late gadolinium enhancement (LGE) by cardiovascular magnetic resonance were investigated. RESULTS: The subendocardial LGE pattern was much more frequent in the myocardial infarction group (76.7%) than myocarditis group (10.0%) (P<0.001). Meanwhile, midmyocardial LGE was much more typical of myocarditis (65.0%) than acute myocardial infarction (1.1%) (P<0.001), and epicardial LGE was also much more typical of myocarditis (55.0%) than acute myocardial infarction (0.0%) (P<0.001). Midmyocardial and epicardial LGE patterns were defined as a nonischemic LGE pattern more typical of myocarditis. Logistic regression analysis revealed that the subendocardial and midmyocardial LGE locations played the greatest role in differentiation between acute myocarditis and acute myocardial infarction. A statistical model based on midmyocardial LGE distribution and age showed a sensitivity of 90% and a specificity of 93.3% in differentiating between acute myocarditis and acute myocardial infarction. CONCLUSION: Our findings suggest that in clinical practice, differentiation between acute myocardial infarction and acute myocarditis can be done based on the subendocardial and midmyocardial LGE location. The presence of subendocardial LGE was found to be strongly associated with acute myocardial infarction; meanwhile, the presence of midmyocardial LGE indicated acute myocarditis. However, other clinical factors should also be taken into account when making the final diagnosis.