Recent progress in the roles of microRNAs in pulmonary arterial hypertension associated with congenital heart disease.

Research on noncoding RNA, particularly microRNAs (miRNAs), is growing rapidly. Advances in genomic technologies have revealed the complex roles of miRNAs in pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD). It has been demonstrated that the progression of PAH associated with CHD is characterized by particular dysregulation of miRNAs and is related to cardiovascular remodeling, cell death, and right ventricle dysfunction. This review provides a comprehensive overview of the current state of knowledge regarding the involvement of miRNAs in the pathogenesis and progression of PAH associated with CHD. We commence by explaining the process of miRNA synthesis and its mode of action, as well as the role of miRNA in PAH associated with CHD. Moreover, the article delves into current breakthroughs in research, potential clinical implications, and prospects for future investigations. The review provides the insight into novel approaches for diagnosis, prognosis, and therapy of PAH associated with CHD.

Increased serum activin A level in congenital heart disease-associated pulmonary artery hypertension: A comparative study from the COHARD-PH registry.

Activin A, a member of TGF-ß superfamily, has been implicated in the pathogenesis of pulmonary artery hypertension (PAH). PAH due to congenital heart disease (CHD-PAH) is a major problem in developing countries. Activin A may have a role in PAH development and progression among uncorrected CHD. In this comparative study, serum activin A level was significantly increased in subjects with uncorrected CHD without the presence of PH and were more significantly risen in CHD-PAH, as compared to control. The utilization of serum activin A measurement seems promising to identify uncorrected CHD patients with PAH development and progression.

QT interval and repolarization dispersion changes during the administration of hydroxychloroquine/chloroquine with/without azithromycin in early COVID 19 pandemic: A prospective observational study from two academic hospitals in Indonesia.

BACKGROUND: Hydroxychloroquine/chloroquine (HCQ/CQ) treatment for COVID-19 was associated with QT interval prolongation and arrhythmia risks. This study aimed to investigate QTc interval and ventricular repolarization dispersion changes, as markers of arrhythmia risks, after HCQ/CQ administration with/without azithromycin (AZT) during COVID-19 pandemic. METHODS: A prospective observational study was performed in two academic hospitals in Indonesia. Adult patients who received HCQ/CQ alone and HCQ/CQ + AZT concomitant treatments for COVID-19 infection were enrolled. Baseline and post HCQ/CQ treatment electrocardiograms were obtained. Baseline and post HCQ/CQ treatment QT interval by Bazett (B-QTc) and Fridericia (F-QTc) formulas and ventricular repolarization dispersion indices by Tpeak-Tend (Tp-e) interval and Tpeak-Tend/QT (Tp-e/QT) ratio were calculated and analyzed. RESULTS: The study enrolled 55 (HCQ/CQ alone) and 77 subjects (HCQ/CQ + AZT concomitant). F-QTc interval significantly lengthened in subjects with HCQ/CQ + AZT (mean difference 11.89 ms [P = .028]). The incidences of severe B-QTc and F-QTc lengthening were 13.1% and 12.3%, B-QTc and F-QTc prolongation were 25.4% and 12.3%, and severe B-QTc and F-QTc prolongation were 6.2% and 3.2%. Tp-e interval lengthened significantly from baseline to posttreatment in HCQ/CQ alone and HCQ/CQ + AZT (mean difference 10.83 ms [P = .006] and 18.73 ms [P < .001], respectively). Tp-e/QT ratio increased significantly from baseline to posttreatment in HCQ/CQ + AZT concomitant (mean difference 0.035 [P < .001]). No fatal arrhytmia occurred. CONCLUSIONS: During COVID-19 pandemic, HCQ/CQ + AZT concomitant treatment caused significant F-QTc lengthening, significantly increased Tp-e interval and increased Tp-e/QT ratio. HCQ/CQ alone only caused significant increase of Tp-e interval. Incidences of severe QTc lengthening and prolongation were low in both HCQ/CQ alone and HCQ/CQ + AZT concomitant.

The screening of congenital heart disease by cardiac auscultation and 12-lead electrocardiogram among Indonesian elementary school students.

BACKGROUND: Screening for congenital heart disease (CHD) in school students is well-established in high-income countries; however, data from low-to-middle-income countries including Indonesia are limited. AIM: This study aimed to evaluate CHD screening methods by cardiac auscultation and 12-lead electrocardiogram to obtain the prevalence of CHD, confirmed by transthoracic echocardiography, among Indonesian school students. METHODS: We conducted a screening programme in elementary school students in the Province of Special Region of Yogyakarta, Indonesia. The CHD screening was integrated into the annual health screening. The trained general practitioners and nurses participated in the screening. The primary screening was by cardiac auscultation and 12-lead electrocardiogram. The secondary screening was by transthoracic echocardiography performed on school students with abnormal findings in the primary screening. RESULTS: A total of 6116 school students were screened within a 2-year period. As many as 329 (5.38%) school students were detected with abnormalities. Of those, 278 students (84.49%) had an abnormal electrocardiogram, 45 students (13.68%) had heart murmurs, and 6 students (1.82%) had both abnormalities. The primary screening programme was successfully implemented. The secondary screening was accomplished for 260 school students, and 18 students (6.9%) had heart abnormalities with 7 (2.7%) who were confirmed with septal defects and 11 (4.2%) had valve abnormalities. The overall prevalence was 0.29% (18 out of 6116). CONCLUSIONS: The primary screening by cardiac auscultation and 12-lead electrocardiogram was feasible and yielded 5.38% of elementary school students who were suspected with CHD. The secondary screening resulted in 6.9% confirmed cardiac abnormalities. The cardiac abnormality prevalence was 0.29%.

Serum soluble suppression of tumorigenicity-2 level associates with severity of pulmonary hypertension associated with uncorrected atrial septal defect.

Uncorrected atrial septal defect undergoes right ventricle chronic volume overload which may lead to pulmonary hypertension and Eisenmenger Syndrome. The soluble suppression of tumorigenicity-2 is a left ventricle strain biomarker; however, its role in right ventricle strain is unclear. This study aimed to investigate the implication of serum soluble suppression of tumorigenicity-2 in adult uncorrected atrial septal defect. This was a cross-sectional study. We enrolled 81 adult uncorrected secundum atrial septal defect patients. Clinical and hemodynamic data were collected. Serum samples were withdrawn from the pulmonary artery during right heart catheterization. Serum soluble suppression of tumorigenicity-2 and NT-proBNP levels were measured. Subjects were divided into three groups based on clinical and hemodynamic severity. The correlation of soluble suppression of tumorigenicity-2 with patients' data and comparison among groups were analyzed. A p value <0.05 was considered statistically significant. Results showed that, there were significant correlations between serum soluble suppression of tumorigenicity-2 and mean pulmonary artery pressure (r = 0.203, p = 0.035) and right ventricle end-diastolic diameter (r = 0.203, p <0.05). Median serum soluble suppression of tumorigenicity-2 level was incrementally increased from group I (atrial septal defect and no-pulmonary hypertension), group II (left-to-right atrial septal defect and pulmonary hypertension), to group III (Eisenmenger Syndrome): (17.4 ng/mL, 21.8 ng/mL, and 29.4 ng/mL, respectively). A post-hoc analysis showed that serum soluble suppression of tumorigenicity-2 level was significantly different between groups I and III (p = 0.01). Serum N terminal pro brain natriuretic peptide (NT-proBNP) level was consistently associated with worse clinical and hemodynamic parameters. No correlation was found between serum soluble suppression of tumorigenicity-2 and NT-proBNP level. In conclusion, serum soluble suppression of tumorigenicity-2 level had significant positive correlation with mean pulmonary artery pressure and right ventricle end-diastolic diameter in uncorrected secundum atrial septal defect patients. Higher serum soluble suppression of tumorigenicity-2 level was associated with the presence of pulmonary hypertension and Eisenmenger Syndrome in uncorrected secundum atrial septal defect patients.

Severe pulmonary hypertension and reduced right ventricle systolic function associated with maternal mortality in pregnant uncorrected congenital heart diseases.

BACKGROUND: Pregnant uncorrected congenital heart disease patients, especially those who already developed pulmonary hypertension, have increased risk for maternal mortality. The pulmonary hypertension severity and right ventricle function may be associated with higher maternal mortality. The study aimed to investigate the mortality rate of pregnant uncorrected congenital heart disease and the impact of pulmonary hypertension severity on mortality. METHODS: This is the sub study of COngenital HeARt Disease in adult and Pulmonary Hypertension Registry. The data of pregnant uncorrected congenital heart disease patients were analyzed from registry database. The maternal mortality was recorded. The data of demography, clinics, obstetrics, and transthoracic echocardiography were collected. The factors that influenced maternal mortality were analyzed. A statistical significance was determined when p value < 0.05. RESULTS: From 2012 until 2017, there were 78 pregnant congenital heart disease patients. Of them, 56 patients were eligible for analyses. The majority of congenital heart disease was atrial septal defect (91.1%). The maternal mortality rate was 10.7% (6 of 56). Pulmonary hypertension occurred in 48 patients, therefore the maternal mortality rate among congenital heart disease-pulmonary hypertension with majority of atrial septal defect was 12.5% (6 of 48). Among nonsurvivors, 100% suffered from severe pulmonary hypertension as compared to survivors (56.0%), p = 0.041. Most nonsurvivors were Eisenmenger syndrome (83.3%), significantly higher compared to survivors (22.0%), p = 0.006. Nonsurvivors had significantly worsened WHO functional class, reduced right ventricle systolic function, and right heart failure. The modes of maternal death were severe oxygen desaturation (66.7%) and respiratory failure and sepsis (33.3%). Most of the maternal deaths occurred within 24 h postpartum period. CONCLUSION: Maternal mortality rate among pregnant uncorrected congenital heart disease with majority of atrial septal defect was 10.7% and among congenital heart disease-pulmonary hypertension with majority of atrial septal defect was 12.5%. Factors related with maternal mortality were severe pulmonary hypertension, Eisenmenger syndrome, and reduced right ventricle systolic function.

Low Plasma Atherogenic Index Associated with Poor Prognosis in Hospitalized Patients with Acute Myocardial Infarction.

AIM: the impact of atherogenic index of plasma (AIP), calculated as logarithmic of triglyceride:HDL ratio (log10.[TG:HDL]), on major adverse cardiovascular events (MACE) during acute myocardial infarction (AMI) has not been fully accepted. This study aims to investigate the role of AIP in predicting major adverse cardiovascular events following AMI during intensive care in the hospital. METHODS: this was a prospective cohort study. We enrolled subjects with AMI hospitalized in intensive coronary care unit at Dr. Sardjito General Hospital, Yogyakarta. The AIP was measured in fasting blood within 24 hours of hospital admission. The total cholesterol, LDL, HDL, and triglyceride (TG), were measured and AIP value was determined as log10.[TG:HDL]). Based on AIP value, subjects were allocated into low AIP (<0.24) and high AIP (0.24). The outcome of the study was major adverse cardiovascular events during hospitalization, i.e. multipart of all cause mortality, acute heart failure, cardiogenic shock, reinfarction, and rescucitated VT/VF. RESULTS: among 277 subjects, the high AIP group comprised 213 subjects (77%) and low AIP group comprised 64 subjects (33%). During intensive hospitalisation, 66 subjects (24%) developed MACE and 20 subjects (7%) developed fatal outcome (all cause mortality). The incidence of MACE tended to be higher in low AIP group, however its difference was not significant. The incidence of all cause mortality was significantly higher in low AIP group (14%) than in high AIP group (5%). Multivariable analysis showed that low AIP predicted all cause mortality independently with a risk ratio 3.71 (95% CI 1.26-10.97, p=0.02). CONCLUSION: low AIP value (<0.24) is an independent predictor for all cause mortality in patients with acute myocardial infarction undergoing intensive hospitalisation.

On-admission High Neutrophil to Lymphocyte Ratio as Predictor of In-hospital Adverse Cardiac Event in ST-elevation Myocardial Infarction.

AIM: to investigate the role of neutrophil-to-lymphocyte ratio (NLratio) in predicting in-hospital adverse cardiac events in patients with STEMI. METHODS: this was a cohort study on patients with STEMI onset 24 hour hospitalised in ICCU. NLratio was calculated as absolute neutrophil count divided with lymphocyte count measured by automated blood cell counter on admission.The outcome was in-hospital adverse cardiac events, which were recorded during follow-up. The cut-off value of NLratio to predict outcome was determined by ROC curve analysis. Univariate and multivariable analysis to assess whether high NLratio was independent predictor for in-hospital adverse events were performed. RESULTS: among 165 subjects, in-hospital adverse cardiac events occurred in 49 subjects (29%). The cut-off value of NLratio was 6.2. The univariate analysis showed that NLratio >6.2 had an odd ratio of 3.19 (95% CI 1.55-6.55, p=0.002) to develop in-hospital adverse cardiac events. The multivariate analysis showed that NLratio was an independent predictor of in-hospital adverse cardiac events with an odd ratio of 4.10 (95% CI 1.59-10.54, p=0.003). CONCLUSION: high on-admission NLratio is an independent predictor for in-hospital adverse cardiac events in patients hospitalised for STEMI.

In-hospital major cardiovascular events between STEMI receiving thrombolysis therapy and primary PCI.

AIM: to compare the in-hospital major cardiovascular events between thrombolysis therapy and primary percutaneous coronary intervention (PCI) in patients with ST-elevation acute myocardial infarction (STEMI. METHODS: the study design is retrospective cohort. Medical record of patients with STEMI onset<12 hour receiving thrombolysis treatment or primary PCI in Dr. Sardjito Hospital Yogyakarta between January 2008 and March 2010 are evaluated. The primary outcome is major cardiovascular events which comprise cardiovascular death, reinfarction and stroke during hospitalisation. The secondary outcomes are post infarction angina pectoris, heart failure, cardiogenic shock and bleeding. RESULTS: among 78 patients with thrombolysis and 53 patients with primary PCI, in-hospital major cardiovascular events do not differ significantly (10.3% versus 9.4%; RR 1.09, 95%CI 0.33-3.55; p=0.87). Post infarction angina pectoris is 7% versus 3.8% (RR 2.51, 95%CI 0.50-12.60; p=0.24). The incidence of heart failure is significantly higher in thrombolysis (17.9% versus 5.7%; RR 3.64, 95%CI 0.99-13.38; p=0.04), primary PCI reduces 68.1% relative risk to develop acute heart failure in STEMI. The incidence of cardiogenic shock is not different. Major and minor bleeding do not differ significantly either. CONCLUSION: the in-hospital major cardiovascular events between STEMI receiving thrombolysis therapy and primary PCI is not significantly different. Heart failure is significantly higher in thrombolysis therapy and the primary PCI reduces the risk.

Predictive value of different estimated glomerular filtration rates on hospital adverse events following acute myocardial infarction.

AIM: to assess whether different glomerular filtration rate (GFR) equations render different predictive value on hospital adverse events in patients hospitalised due to acute myocardial infarction. METHODS: the study design is cross-sectional. Data from consecutive patients with acute myocardial infarction were analyzed. Three different estimated GFR equations, i.e. Cockroft-Gault (eGFRC-G), MDRD (eGFRMDRD) and CKD-EPI (eGFRCKD-EPI) were calculated. Hospital adverse events in these study patients were recorded. The predictive values of these eGFRs on hospital adverse events were compared with ROC curve. Univariate and multivariable analysis to assess which GFR equation as independent predictor for hospital adverse events were performed. RESULTS: among 103 study patients, 49 patients (47.6%) experienced hospital adverse events. Proportion of hospital adverse events were significantly associated with eGFRMDRD (p<0.01) and eGFRCKD-EPI (p=0.02), but not with eGFRC-G (p=0.10). Hospital adverse events were better predicted by eGFRMDRD than by eGFRCKD-EPI (AUC, 0.698; 95%CI: 0.596-0.800, p<0.01 versus AUC, 0.693; 95%CI: 0.591-0.796, p<0.01). Multivariable analysis showed moderate (adjusted OR 3.50; 95%CI: 1.38-8.85, p<0.01) and severe (adjusted OR 8.13, 95%CI: 1.38-47.91, p=0.02) kidney dysfunctions based on eGFRMDRD were independent predictors for hospital adverse events. CONCLUSION: an eGFR based on MDRD gave better predictive value than eGFR based on CKD-EPI on hospital adverse events among acute myocardial infarction. Moderate and severe kidney dysfunctions based on eGFRMDRD were independent predictors for hospital adverse events following acute myocardial infarction.

Coronary artery sequel of Kawasaki disease in adulthood, a concern for internists and cardiologists.

Young adults suffered from acute cardiac event, such as acute coronary syndrome, ischemic-associated arrhythmia and sudden death, are frequently encountered without known etiology and significant risk factors. Coronary vasculitis due to Kawasaki disease contributes to be a risk factor in young adult population to develop acute coronary event. Afflicted predominantly during childhood, Kawasaki disease gives rise to vasculitis of coronary artery which becomes major concern since it leads to coronary aneurysm and stenosis. Self-limited nature of Kawasaki disease make those suffered in childhood survive into adult life. Accelerated coronary atherosclerosis in the Kawasaki disease-related lesion occurring in young adult and subsequent acute coronary syndrome and sudden death in this population are devastating impacts of the sequel of Kawasaki disease. It is expected that internists and adult cardiologists become familiar with this sequel and provide better care for the patients.

Association between levels of circulating soluble CD40 ligand on admission and in-hospital events among acute coronary syndrome patients.

AIM: to investigate the association between on admission circulating sCD40L level and in-hospital events among patients admitted with acute coronary syndrome. METHODS: a short prognostic study which recruited consecutively patients with acute coronary syndrome (ACS) admitted in Intensive Coronary Care Unit (ICCU). INCLUSION CRITERIA: between 35-70 years old, onset of chest pain 24 hours and approved informed consent. Patients with acute infection, renal failure, heart failure, liver cirrhosis, chronic inflammation, venous thromboemboli, malignancies and pregnancy were excluded. Blood samples of sCD40L was withdrawn on admission and measured with ELISA. Follow-up was conducted during intensive hospitalization. In-hospital events were re-infarction, acute heart failure, cardiogenic shock and mortality. RESULTS: of 77 study patients, 64 (83%) were male with mean age 55 years old. In-hospital events occurred in 33 (43%) patients, namely mortality 6 (18%), acute heart failure 25 (75%) and cardiogenic shock 2 (6%). The level of circulating sCD40L was significantly higher in patients with in-hospital events compared with those without in-hospital events (8559.6 pg/ml vs. 7393.8 pg/ml respectively, p value <0.05). Using ROC curve, we determined cut-off point 7107.0 pg/ml. On multivariate analysis, high sCD40L (7107.0 pg/ml) had a trend to increase the risk of in-hospital events, although statistically not significant (adjusted OR 1.66, 95% CI : 0.56-4.87; p value 0.36). CONCLUSION: on admission circulating sCD40L level was higher in patients with in-hospital events. Nonetheless, high sCD40L level did not significantly associate with increasing risk to develop in-hospital events among ACS.

On Arrival High Blood Glucose Level is Associated With Detrimental and Fatal Hospitalization Outcomes for Acute Coronary Syndrome.

BACKGROUND: High blood glucose level is frequently encountered in acute coronary syndrome. We investigated the effects of high blood glucose measured on arrival on hospitalization adverse events in acute coronary syndrome. Our study patients were Javanese in ethnicity, which constitute half of population in Indonesia. We hypothesized that elevated blood glucose has detrimental effects on hospitalization for acute coronary syndrome. METHODS: We designed an observasional cohort study and recruited 148 consecutive patients with acute coronary syndrome. Venous blood was collected on hospital arrival. High blood glucose level was determined as plasma glucose > 140 mg/dL. Adverse hospitalization events were recorded, i.e. mortality, acute heart failure, cardiogenic shock and heart rhythm disorders. Echocardiography examination was performed to determine left ventricular function. RESULTS: The prevalence of on arrival high blood glucose among Javanese patients with acute coronary syndrome was considerably high (36%). On arrival high blood glucose was associated with acute heart failure (P < 0.001) and shock cardiogenic (P = 0.02). Heart rhythm disorders were higher in high blood glucose patients (P = 0.004). Left ventricular dysfunction was more prevalent in high blood glucose patients (P = 0.001) and ejection fraction was lower (P = 0.001). On arrival high blood glucose was independently associated with hospitalization adverse events (adjusted odds ratio = 2.3, 95% confidence interval: 1.1-4.9, P = 0.03) and hospital mortality (adjusted odds ratio = 6.9, 95% confidence interval: 1.2-38.6, P = 0.03). CONCLUSIONS: Our study suggests that on arrival high blood glucose among Javanese patients with acute coronary syndrome is considerably high and is associated with detrimental and fatal hospitalization outcomes.

Circulating soluble CD40 ligand mediates the interaction between neutrophils and platelets in acute coronary syndrome.

Following plaque rupture, activated platelet will induce subsequent inflammatory process including neutrophil recruitment. In vitro study demonstrated an interaction between neutrophils and platelets via a mechanism involving CD40-CD40 ligand. However, whether this mechanism exists in the clinical setting remains unknown. Fifty-four patients with acute myocardial infarction (AMI) and 25 with unstable angina of pain onset of < or = 24 h were enrolled consecutively. Acute myocardial infarction was diagnosed from three diagnostic criteria, i.e., anginal pain, electrocardiogram ST-T changes, and cardiac enzyme elevation. Unstable angina was diagnosed in patients without elevated cardiac enzymes. Peripheral venous blood was drawn at admission for routine blood count and soluble CD40 ligand (sCD40L) measurement. Neutrophil count was determined by an automated blood cell counter. Circulating sCD40L was measured using a standard enzyme-linked immunosorbent assay. Neutrophil count was significantly higher in AMI as compared with unstable angina (P < 0.001), whereas circulating sCD40L did not significantly differ. Despite marked elevation, no correlation was observed between neutrophil count and circulating sCD40L in AMI. Interestingly, we observed a strong and positive significant correlation between neutrophil count and circulating sCD40L level (r = 0.607, P = 0.002) in unstable angina. Circulating sCD40L is associated with neutrophil count and may mediate interaction between neutrophils and platelets in acute coronary syndrome, particularly in unstable angina.