The Effect of Omega-3 Supplementation on Heart Failure Outcome: A Meta-Analysis of Randomized Clinical Trial.

The effect of omega-3 supplementation on cardiovascular (CV) disease has been widely studied in several large clinical trials. However, the evidence of the effect of omega-3 supplementation in patients with heart failure (HF) remains controversial. This meta-analysis investigated the effects of omega-3 supplementation on patients with HF. We conducted a literature search on MEDLINE, Embase, and Cochrane databases for clinical trials and preprints of relevant articles. Following a literature search and critical appraisal, 5 studies were included in the meta-analysis. The pooling of the result of the studies shows that there were no significant association between omega-3 supplementation and CV mortality (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.84-1.05, p=0.16) nor hospitalization due to HF (OR, 0.94; 95% CI, 0.88-1.02; p=0.13). Our systematic review and meta-analysis showed that omega-3 supplementation has no beneficial effect in patients with HF.

Adherence to penicillin treatment is essential for effective secondary prevention of rheumatic heart disease: a systematic review and meta-analysis.

Background: Penicillin is essential for secondary prevention of acute rheumatic fever (ARF) and rheumatic heart disease (RHD). However, the incidences of ARF recurrence and RHD progression remain high, particularly in endemic countries. This meta-analysis evaluated the effectiveness of penicillin adherence in secondary prevention of ARF recurrence and RHD progression. Methods: The authors included original articles employing an observational study design in which the study population included patients with ARF or RHD and documented adherence to secondary prophylaxis with penicillin for secondary prevention. Systematic searches of the PubMed, Scopus, and Cochrane databases were performed. Moreover, the authors also conducted a snowballing literature search from Europe PMC to expand the included studies. The quality of each study was assessed using the National Institute of Health Quality Assessment Tool. The statistical analyses were conducted using Review Manager 5.4.1 software developed by Cochrane. In addition, the authors utilized pooled odds ratios (ORs) to compare the adherence techniques. Results: A total of 310 studies were identified, of which 57 full-text articles were assessed for eligibility. The authors included six studies with 1364 patients for the qualitative synthesis and meta-analysis. Good adherence to penicillin for the secondary prophylaxis of ARF and RHD, significantly reduced the odds of ARF recurrence or RHD progression by up to 71% compared to that associated with poor adherence [pooled OR 0.29 (0.21-0.40); I²=0% (p=0.56); Z=7.64 (p <0.00001)]. Conclusion: Good adherence to penicillin for secondary prophylaxis in patients with ARF or RHD is essential for reducing the risk of ARF recurrence or RHD progression.

Current Evidence and Future Directions of Omega-3 Supplementation and Cardiovascular Disease Risk.

Omega-3 supplementation has a controversial role in the secondary prevention of cardiovascular diseases. Despite large clinical trials published over the years, the evidence of omega-3 in preventing cardiovascular diseases, especially coronary heart disease, is still inconclusive. However, recent clinical trials using higher dose of omega-3 or highly purified esters of omega-3 shows promising result, with reduction in cardiovascular death and incidence of cardiovascular disease. This review aims to summarize the possible mechanism of omega-3 in preventing cardiovascular disease and future directions of research regarding the benefit of omega-3 in cardiovascular disease.

The effect of resistance training on PCSK9 levels in patients undergoing cardiac rehabilitation after coronary artery bypass grafting: a randomized study.

BACKGROUND: Resistance training is commonly recommended as part of secondary prevention for post-coronary artery bypass graft (CABG) patients in conjunction with aerobic exercise. Despite its potential benefits, there is currently a lack of studies investigating the impact of resistance training on proprotein convertase subtilisin kexin 9 (PCSK9). AIM: To evaluate the effect of intensive resistance training on proprotein convertase subtilisin kexin 9 (PCSK9) levels among post-CABG patients undergoing cardiac rehabilitation (CR). METHODS: In this prospective, open-label, randomized trial, 87 post-coronary artery bypass graft (CABG) patients were randomly assigned into two groups: moderate to high intensity resistance training and aerobic training (n = 44) or aerobic training alone (n = 43) for a total of 12 sessions. Changes in PCSK9 levels was determined as a primary endpoint, while secondary endpoints included changes in the six-minute walk test (6-MWT) results, aerobic capacity, WHO-5 well-being index, fasting blood glucose, and lipid profile. Both groups underwent intention-to-treat analysis. RESULTS: Following completion of cardiac rehabilitation program, the intervention group demonstrated a significant decrease in mean PCSK9 levels when compared to the control group (ß = -55 ng/ml, 95% CI -6.7 to -103.3, p = 0.026), as well as significant improvements in the 6-MWT result (ß = 28.2 m, 95% CI 2.4-53.9, p = 0.033), aerobic capacity (ß = 0.9 Mets, 95% CI 0.1-1.7, p = 0.021), and WHO-5 well-being index (ß = 8.1, 95% CI 2.0-14.4, p = 0.011) in patients who received resistance and aerobic training. No statistically significant changes were observed in fasting blood glucose, cholesterol, LDL-C, HDL-C, and triglyceride levels. CONCLUSION: Resistance training in CR significantly reduced PCSK-9 levels and increases patient's functional capacity and quality of life. (NCT02674659 04/02/2016).

Smartphone-Based Cardiac Rehabilitation Program Improves Functional Capacity in Coronary Heart Disease Patients: A Systematic Review and Meta-Analysis.

Cardiac rehabilitation (CR) reduces mortality and morbidity in coronary heart disease (CHD); however, patients show a lack of adherence to CR. Alternatively, telehealth interventions have shown promising results for improving target outcomes in CR. This study aimed to review the effect of smartphone-based CR on the functional capacity of CHD patients. A literature search was performed using PubMed, MEDLINE, Embase, and Cochrane Library on 21 March, 2022 to find randomised controlled trials on smartphone usage in CR to improve functional capacity. Outcomes included maximal oxygen consumption (VO2 max), a 6-min walk test (6-MWT), quality of life, smoking cessation, and modifiable risk factors. Eleven trials recruiting CHD patients were reviewed. Wearable devices connected to smartphone- or chat-based applications were commonly used for CR delivery. Most trials managed to provide exercise prescriptions, education on medication adherence and controlling risk factors, and psychosocial counselling through the intervention. Functional capacity improved significantly following smartphone-based CR in CHD patients compared to control groups, as measured by VO2 max and 6-MWT; patients were more likely to quit smoking. Compared to traditional care, smartphones that delivered CR to CHD patients demonstrate superior outcomes regarding increasing functional capacity. There is no significant improvement on lipid profile, blood pressure, HbA1C, body mass index, and quality of life. It can be used either alone or as an adjunct. Ultimately, the patients' preferences and circumstances should be considered.

Highlighting Exosomes' Function in Cardiovascular Diseases.

Exosomes, as one of the extracellular vesicles' subgroups, played an important role in the cell to cell communication. The cargos and surface protein of exosomes have been known to affect the cardiovascular system both positively and negatively in chronic heart failure, ischemic heart disease, and atherosclerosis. There have been several exosomes that emerged as potential diagnostic and prognostic markers in cardiovascular patients. However, the conditions affecting the patients and the method of isolation should be considered to create a standardized normal value of the exosomes and the components. CPC-derived exosomes, ADSCs-derived exosomes, and telocyte- derived exosomes have been proven to be capable of acting as a therapeutic agent in myocardial infarction models. Exosomes have the potential to become a diagnostic marker, prognostic marker, and therapeutic agent in cardiovascular diseases.

External Counterpulsation Improves Angiogenesis by Preserving Vascular Endothelial Growth Factor-A and Vascular Endothelial Growth Factor Receptor-2 but Not Regulating MicroRNA-92a Expression in Patients With Refractory Angina.

Objective: External counterpulsation (ECP) provides long-term benefits of improved anginal frequency and exercise tolerance in patients with refractory angina (RA). This is postulated as a result of improved angiogenesis and endothelial function through an increase in shear stress. Angiogenesis is mainly represented by vascular endothelial growth factor-A (VEGF-A) and its receptor, vascular endothelial growth factor receptor-2 (VEGFR-2). The microRNA-92a (miR-92a) is a flow-sensitive miRNA that regulates atherosclerosis and angiogenesis in response to shear stress. Thus, ECP beneficial effect might be achieved through interaction between VEGF-A, VEGFR-2, and miR-92a. This study aims to evaluate the ECP effect on VEGF-A, VEGFR-2, and miR-92a in patients with RA in a sham-controlled manner. Methods: This was a randomized sham-controlled trial, enrolling 50 patients with RA who have coronary artery disease (CAD). Participants were randomized (1:1 ratio) to 35 sessions of either ECP (n = 25) or sham (n = 25), each session lasting for 1 h. Plasma levels of VEGF-A and VEGFR-2 were assayed by the ELISA technique. The quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to measure miR-92a circulating levels in plasma. Result: External counterpulsation significantly preserved VEGF-A and VEGFR-2 level compared to sham [ΔVEGF-A: 1 (-139 to 160) vs.-136 (-237 to 67) pg/ml, p = 0.026; ΔVEGFR-2: -171(-844 to +1,166) vs. -517(-1,549 to +1,407) pg/ml, p = 0.021, respectively]. Circulating miR-92a increased significantly in ECP [5.1 (4.2-6.4) to 5.9 (4.8-6.4), p < 0.001] and sham [5.2 (4.1-9.4) to 5.6 (4.8-6.3), p = 0.008] post-intervention. The fold changes tended to be higher in ECP group, although was not statistically different from sham [fold changes ECP = 4.6 (0.3-36.5) vs. sham 2.8 (0-15), p = 0.33)]. Conclusion: External counterpulsation improved angiogenesis by preserving VEGF-A and VEGFR-2 levels. Both ECP and sham increased miR-92a significantly, yet the changes were not different between the two groups. (Study registered on www.clinicaltrials.gov, no: NCT03991871, August 8, 2019, and received a grant from the National Health Research and Development of Ministry of Health of Indonesia, No: HK.02.02/I/27/2020).

The Validity and Reliability of the MacNew Heart Disease Health Related Quality of Life Questionnaire: The Indonesian Version.

BACKGROUND: The MacNew heart disease health related quality of life tool is used widely in the cardiac populations to evaluate the impact of disease and intervention including rehabilitation. In addition to the English version, it is also available for several other languages except the Indonesian language. Therefore, the purpose of this study were 1) to translate the MacNew questionnaire from the English version to the Indonesian language and 2) to estimate the preliminary validity and reliability of the Indonesian MacNew for patients with coronary artery disease. METHODS: Forward and backward translation procedure was used to develop the Indonesian MacNew. The Indonesian MacNew was administered to 24 patients after one week of revascularization surgery. Reliability was assessed by internal consistency and test-retest reliability. To evaluate concurrent validity, the correlation of the compatible domain of the Indonesian MacNew and SF-36 was assessed. RESULTS: Internal consistency reliability of the Indonesian MacNew was confirmed with Cronbach's α of the global scale and all three subscales exceeding 0.95. Test- retest reliability was acceptable with intraclass correlation coefficient of 0.66 for the global score. Furthermore, an acceptable concurrent validity was established with statistically significant correlation between Indonesian MacNew and SF-36 (pearson correlation ranging from 0.47 to 0.71). CONCLUSION: The first results of the Indonesian MacNew indicate acceptable validity and reliability as a measurement tool to assess health related quality of life of Indonesian patients with coronary artery disease.

Determinants and Prediction Equations of Six-Minute Walk Test Distance Immediately After Cardiac Surgery.

Background: To date, there is no reference for a 6-min walk test distance (6-MWD) immediately after cardiac surgery. Therefore, this study aimed to identify the determinants and to generate equations for prediction reference for 6-MWD in patients immediately after cardiac surgery. Methods: This is a cross-sectional study of the 6-min walk test (6-MWT) prior to participation in the cardiac rehabilitation (CR) program of patients after coronary artery bypass surgery (CABG) or valve surgery. The 6-MWT were carried out in a gymnasium prior to the CR program immediately after the cardiac surgery. Available demographic and clinical data of patients were analyzed to identify the clinical determinants of 6-MWD. Results: This study obtained and analyzed the data of 1,509 patients after CABG and 632 patients after valve surgery. The 6-MWD of all patients was 321.5 ± 73.2 m (60-577). The distance was longer in the valve surgery group than that of patients in the CABG group (327.75 ± 70.5 vs. 313.59 ± 75.8 m, p < 0.001). The determinants which significantly influence the 6-MWD in the CABG group were age, gender, diabetes, atrial fibrillation, and body height, whereas in the valve surgery group these were age, gender, and atrial fibrillation. The multivariable regression models generated two formulas using the identified clinical determinants for patients after CABG: 6-MWD (meter) = 212.57 + 30.47 (if male gender) - 1.62 (age in year) + 1.09 (body height in cm) - 12.68 (if with diabetes) - 28.36 (if with atrial fibrillation), and for patients after valve surgery with the formula: 6-MWD (meter) = 371.05 + 37.98 (if male gender) - 1.36 (age in years) - 10.61 (if atrial with fibrillation). Conclusion: This study identified several determinants for the 6-MWD and successively generated two reference equations for predicting 6-MWD in patients after CABG and valve surgery.

Randomised controlled trial into the role of ramipril in fibrosis reduction in rheumatic heart disease: the RamiRHeD trial protocol.

INTRODUCTION: Rheumatic heart disease (RHD) is a major burden in developing countries and accounts for 80% of all people living with the disease, where it causes most cardiovascular morbidity and mortality in children and young adults. Chronic inflammation and fibrosis of heart valve tissue due to chronic inflammation in RHD will cause calcification and thickening of the impacted heart valves, especially the mitral valve. This fibrogenesis is enhanced by the production of angiotensin II by increased transforming growth factor ß expression and later by the binding of interleukin-33, which is known to have antihypertrophic and antifibrotic effects, to soluble sST2. sST2 binding to this non-natural ligand worsens fibrosis. Therefore, we hypothesise that ACE inhibitors (ACEIs) would improve rheumatic mitral valve stenosis. METHODS AND ANALYSIS: This is a single-centre, double-blind, placebo-controlled, randomised clinical trial with a pre-post test design. Patients with rheumatic mitral stenosis and valve dysfunction will be planned for cardiac valve replacement operation and will be given ramipril 5 mg or placebo for a minimum of 12 weeks before the surgery. The expression of ST2 in the mitral valve is considered to be representative of cardiac fibrosis. Mitral valve tissue will be stained by immunohistochemistry to ST2. Plasma ST2 will be measured by ELISA. This study is conducted in the Department of Cardiology and Vascular Medicine, Universitas Indonesia, National Cardiac Center Harapan Kita Hospital, Jakarta, Indonesia, starting on 27 June 2019. ETHICS AND DISSEMINATION: The performance and dissemination of this study were approved by the ethics committee of National Cardiovascular Center Harapan Kita with ethical code LB.02.01/VII/286/KEP.009/2018. TRIAL REGISTRATION NUMBER: NCT03991910.

The effect of external counterpulsation on intrinsic myocardial function evaluated by speckle tracking echocardiography in refractory angina patients: a randomized controlled trial.

External Counterpulsation (ECP) is one of the therapeutic options in patients with refractory angina inadequately controlled by medical, interventional, or surgical therapy. The 2D Speckle Tracking Echocardiography (2D-STE) method is considered superior in assessing clinical improvement. We would like to evaluate any improvement of myocardial intrinsic function using 2D-STE in patients underwent standard ECP protocol (35 sessions). We conducted a double-blind randomized controlled trial. Patients with refractory angina who could not be revascularized conventionally were randomized into two groups: (1) the ECP group (300 mmHg) and (2) the Sham/control group (75 mmHg). ECP standard therapy was given for 35 sessions (1 h/day/session). The 2D-STE data, including longitudinal strain and post systolic index (PSI) were obtained before and after therapy. 43 subjects were analyzed, with 22 subjects in ECP group and 21 control subjects (Sham group). A homogenous baseline strain was found either globally (12.42 ± 4.55 vs 12.00 ± 4.92 [- %]; P = 0.774) or segmentally/regionally (12.63 (0.01-25.16) vs 12.43 (0.01-27.20) [- %]; P = 0.570). There was no statistically significant improvement between groups in the left ventricle longitudinal strain globally (P = 0.535) and segmentally/regionally (P = 0.434). PSI parameters showed improvement in the ECP group (P = 0.049), and segments with PSI ≥ 20% seemed to improve longitudinal strains in the ECP group after therapy (P = 0.042). In conclusion, 35 ECP therapy sessions did not improve either global or segmental/regional left ventricular mechanical function in patients with refractory angina. However, the mechanical function of myocardial segments with PSS tends to improve after ECP therapy.

Angiotensin Converting Enzyme Inhibitors (ACEIs) Decrease the Progression of Cardiac Fibrosis in Rheumatic Heart Disease Through the Inhibition of IL-33/sST2.

Rheumatic heart disease (RHD) is common in developing countries and poses a big medical challenge and burden. The pathogenesis of RHD is influenced by the triad of host, agent, and environment. Autoantigens generated from Group A Streptococcus (GAS) infection are captured by the resident dendritic cells (DCs) in the heart's valvular endothelium. DCs differentiate into antigen presenting cells (APC) in the valve interstices. APC induces activation of autoreactive T cells, which triggers inflammation and tissue fibrosis. Cardiac fibrosis is promoted through the activation of Mitogen activated protein kinases (MAPKs) and its downstream signaling, including its interaction with transforming growth factor-ß (TGF-ß) and Smad proteins. TGF-ß-induced phosphorylation of Smad2 complexes with Smad3 and Smad4, and translocates into the nucleus. Angiotensin II enhances the migration, maturation, and presentation of DC. In RHD, Angiotensin II induces fibrosis via the stimulation of TGF-ß, which further increases the binding of IL-33 to sST2 but not ST2L, resulting in the upregulation of Angiotensin II and progression of cardiac fibrosis. This cascade of inflammation and valvular fibrosis causes calcification and stiffening of the heart valves in RHD. Angiotensin converting enzyme inhibitors (ACEIs) inhibit Angiotensin II production, which in turn decreases TGF-ß expression and the onset of overt inflammatory response. This condition leads to a reduction in the sST2 as the decoy receptor to "steal" IL-33, and IL-33 binds to ST2L and results in cardioprotection against cardiac fibrosis in the pathogenesis of RHD.