Huey Ming Lo

MicroRNA-208a Increases Myocardial Endoglin Expression and Myocardial Fibrosis in Acute Myocardial Infarction

BACKGROUND MicroRNAs (miRs) play a role in cardiac remodelling, and acute myocardial infarction (AMI) can regulate miR expression. MiR-208a is essential for the expression of the genes involved in cardiac hypertrophy and fibrosis. MiR-208a activates endoglin expression and may result in cardiac fibrosis. The role of miR-208a and endoglin in AMI is not known. We sought to investigate the regulation of miR-208a and endoglin in AMI. METHODS Ligation of the proximal left anterior descending artery was performed in adult Sprague-Dawley rats to induce AMI. Echocardiography was used to measure heart size and left ventricular function. The TaqMan miR real-time quantitative assay was used to quantitate miR-208a. Myocardial fibrosis was detected by Masson trichrome staining. RESULTS AMI and overexpression of miR-208a in the sham group without infarction significantly increased myocardial miR-208a, endoglin, and β-myosin heavy chain (β-MHC) expression. Overexpression of antagomir-208a significantly inhibited the increase of myocardial endoglin and β-MHC protein expression induced by infarction. Overexpression of mutant miR-208a in the sham group did not induce myocardial endoglin and β-MHC expression. Pretreatment with atorvastatin and the angiotensin-receptor antagonist valsartan significantly attenuated the increase of endoglin and β-MHC induced by infarction. AMI and overexpression of miR-208a in the sham group significantly increased the area of myocardial fibrosis compared with the sham group. Overexpression of antagomir-208a and pretreatment with atorvastatin and valsartan in the AMI group significantly decreased the area of myocardial fibrosis induced by infarction. CONCLUSIONS MiR-208a increases endoglin expression to induce myocardial fibrosis in rats with AMI. Treatment with atorvastatin and valsartan can decrease myocardial fibrosis induced by AMI through attenuating miR-208a and endoglin expression.

Use of CHADS2 and CHA2DS2-VASc Scores to Predict Subsequent Myocardial Infarction, Stroke, and Death in Patients with Acute Coronary Syndrome: Data from Taiwan Acute Coronary Syndrome Full Spectrum Registry

Background Acute coronary syndrome (ACS) patients have a wide spectrum of risks for subsequent cardiovascular events and death. However, there is no simple, convenience scoring system to identify risk of adverse outcomes. We investigated whether CHADS2 and CHA2DS2-VASc scores were useful tools to assess the risk for adverse events among ACS patients. Methods This observational prospective study was conducted at 39 hospitals. Totally 3,183 patients with ACS were enrolled, and CHADS2 and CHA2DS2-VASc scores were calculated. The primary endpoint was occurrence of adverse event, including subsequent myocardial infarction, stroke, or death, within 1 year of discharge. Results CHADS2 and CHA2DS2-VASc scores were significant predictors of adverse events in separate multivariate regression analyses. A Kaplan-Meier analysis of CHADS2 and CHA2DS2-VASc scores of ≥2 showed a higher rate of adverse events as compared with scores of <2 (P<0.001;log-rank test). CHA2DS2-VASc score was better than CHADS2 score in predicting subsequent adverse events; the area under the receiver operating characteristic curve increased from 0.66 to 0.70 (p<0.001). Patients with CHADS2 scores of 0 or 1 were further classified according to CHA2DS2-VASc score, using a cutoff value of 2. The rate of adverse events significantly differed between those with a score of <2 and those with a score of ≥2 (4.1% vs.10.7%, P<0.001). Conclusions CHADS2 and CHA2DS2-VASc scores were useful predictors of subsequent adverse events in ACS patients.

Mechanical Stretch Induces Apoptosis Regulator TRB3 in Cultured Cardiomyocytes and Volume-Overloaded Heart.

The expression of TRB3 (tribbles 3), an apoptosis regulated gene, increases during endoplasmic reticulum (ER) stress. How mechanical stress affects the regulation of TRB3 in cardiomyocytes during apoptosis is not fully understood. An in vivo model of aorta-caval shunt in adult rats demonstrated the increased TRB3 protein expression in the myocardium. The tumor necrosis factor-alpha (TNF-α) antagonist etanercept reversed the TRB3 protein expression and cardiomyocyte apoptosis induced by AV shunt. An in vitro model of cyclic stretch in neonatal rats was also used to investigate TRB3 expression. We hypothesized that cardiomyocyte apoptosis induced by cyclic stretch is TRB3 dependent. Neonatal rat cardiomyocytes grown on a flexible membrane base were stretched by vacuum to 20% of maximum elongation, at 60 cycles/min. Cyclic stretch significantly increased TRB3 protein and mRNA expression. Addition of c-jun N-terminal kinase (JNK) inhibitor SP600125, TNF-α antibody and etanercept 30 min before stretch reversed the induction of TRB3 protein induced by stretch. Cyclic stretch induced the DNA-binding activity of growth arrest and DNA damaged inducible gene-153 (GADD153) by electrophoretic mobility shift assay. SP600125, JNK siRNA, TNF-α antibody and etanercept abolished the binding activity induced by stretch. TRB3 promoter activity was enhanced by stretch and TRB3-mut plasmid, SP600125, TNF-α antibody and etanercept attenuated TRB3 promoter activity induced by stretch. Exogenous administration of TNF-α recombinant protein to the non-stretched cardiomyocytes increased TRB3 protein expression similar to that seen after stretch. Cyclic stretch induced cardiomyocyte apoptosis is inhibited by TRB3 siRNA and etanercept. The stretch-induced TRB3 is mediated by TNF-α、JNK and GADD153 pathway. These results indicate that TRB3 plays an important role in stretch-induced cardiomyocyte apoptosis.

Significance of left circumflex artery-related acute myocardial infarction without ST-T changes

INTRODUCTION Left circumflex (LC)-related acute myocardial infarction (AMI) presenting without ST-T changes has been underdiagnosed in the emergency department. There is little information on its clinical features and significance. AIMS The aims of the study were to investigate the clinical characteristics and outcomes of LC-related AMI without ST-T changes. POPULATION AND METHODS Ninety-six patients were admitted for LC-related AMI. Comparisons between those with and without ST-T changes were analyzed. RESULTS Twenty-two patients (23%) did not have ST-T changes, whereas 74 patients (77%) had them. Patients without ST-T changes had younger age (55.6 + or - 16.8 vs 62.6 + or - 12.0 years, P = .03), fewer presented as Killip III/IV (4.5% vs 27.4%, P = .02) and with lower creatine kinase (1647.3 + or - 1602.2 vs 2778.2 + or - 2343.3 IU/L, P = .037) and creatine kinase-MB (136.8 + or - 130.3 vs 247.7 + or - 200.0 IU/L, P = .017), and more were with concurrent culprit lesion in the middle or distal LC and right- or balanced-dominant coronary circulation (86.4% vs 44.6%, P < .001). During follow-up, the need for repeat percutaneous coronary intervention (48.6% vs 45.5%, P = .40) and recurrent infarction (13.5% vs 13.6%, P = .62) were similar between the 2 groups. The 30-day mortality (0% vs 5.4%, P = .35) and overall mortality rate (4.5% vs 12.2%, P = .28) between them were not different statistically. CONCLUSION The relatively lower prevalence of LC-related AMI without ST-T changes in the study might be underestimated. These patients have smaller infarct size than patients with ST-T changes without differences in the short- and long-term outcomes between them.

Gastrointestinal Bleeding and Outcomes After Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction

BACKGROUND Gastrointestinal bleeding is a hemorrhagic complication after primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction (STEMI). OBJECTIVES To determine predictors of gastrointestinal bleeding and the impact of gastrointestinal bleeding on outcomes in STEMI patients undergoing primary percutaneous coronary intervention. METHODS AND RESULTS Gastrointestinal bleeding occurred in 18 (3.5%) of 519 consecutive patients with STEMI undergoing primary percutaneous coronary intervention. Univariate predictors of gastrointestinal bleeding were previous gastrointestinal bleeding (33% vs 4%, P < .001), impaired renal function (89% vs 37%, P<.001), Killip class IV at presentation (61% vs 18%, P<.001), higher peak creatinine kinase level (mean [SD], 3801.6 [3280.2] vs 2721.3 [2286.6] IU/L, P=.05), and mechanical ventilator support (44% vs 12%, P<.001). Coprescription of proton-pump inhibitors did not reduce the risk of gastrointestinal bleeding (22.2% vs 13.4%, P=.22). Multivariate analysis showed an odds ratio (95% confidence interval) for gastrointestinal bleeding of 22.1 (5.6-86.89, P<.001) for previous gastrointestinal bleeding, 6.74 (1.30-34.89, P=.02) for impaired renal function, and 4.68 (1.35-16.2, P=.01) for Killip class IV at presentation. Gastrointestinal bleeding was associated with longer intensive care unit stay (mean [SD], 5.4 [6.7] vs 3.6 [3.6] days, P=.04), and higher in-hospital (44% vs 9%, P<.001) and overall (44% vs 13%, P<.001) mortality rate. CONCLUSIONS Although rare, gastrointestinal bleeding in patients with STEMI significantly prolongs intensive care unit stay and increases mortality. Previous gastrointestinal bleeding, impaired renal function, and Killip class IV at presentation are associated with higher incidence of gastrointestinal bleeding.

Mechanical Stretch Inhibits MicroRNA499 via p53 to Regulate Calcineurin-A Expression in Rat Cardiomyocytes

Background MicroRNAs play an important role in cardiac remodeling. MicroRNA 499 (miR499) is highly enriched in cardiomyocytes and targets the gene for Calcineurin A (CnA), which is associated with mitochondrial fission and apoptosis. The mechanism regulating miR499 in stretched cardiomyocytes and in volume overloaded heart is unclear. We sought to investigate the mechanism regulating miR499 and CnA in stretched cardiomyocytes and in volume overload-induced heart failure. Methods & Results Rat cardiomyocytes grown on a flexible membrane base were stretched via vacuum to 20% of maximum elongation at 60 cycles/min. An in vivo model of volume overload with aorta-caval shunt in adult rats was used to study miR499 expression. Mechanical stretch downregulated miR499 expression, and enhanced the expression of CnA protein and mRNA after 12 hours of stretch. Expression of CnA and calcineurin activity was suppressed with miR499 overexpression; whereas, expression of dephosphorylated dynamin-related protein 1 (Drp1) was suppressed with miR499 overexpression and CnA siRNA. Adding p53 siRNA reversed the downregulation of miR499 when stretched. A gel shift assay and promoter-activity assay demonstrated that stretch increased p53 DNA binding activity but decreased miR499 promoter activity. When the miR499 promoter p53-binding site was mutated, the inhibition of miR499 promoter activity with stretch was reversed. The in vivo aorta-caval shunt also showed downregulated myocardial miR499 and overexpression of miR499 suppressed CnA and cellular apoptosis. Conclusion The miR499-controlled apoptotic pathway involving CnA and Drp1 in stretched cardiomyocytes may be regulated by p53 through the transcriptional regulation of miR499.

Renal dysfunction and the risk of postoperative atrial fibrillation after cardiac surgery: role beyond the CHA2DS2-VASc score.

AIMS To investigate whether renal dysfunction is a useful predictor of postoperative atrial fibrillation (POAF) after cardiac surgery. We also aimed to determine whether the addition of renal dysfunction into the scoring system could improve diagnostic accuracy of the CHA2DS2-VASc score to predict POAF. METHODS AND RESULTS The study prospectively enrolled 350 consecutive patients who underwent cardiac surgery. Echocardiography was performed before cardiac surgery. Renal dysfunction was defined as estimated glomerular filtration rate < 60 mL min(-1) 1.73 m(-2). All patients were monitored with continuous electrocardiographic telemetry for the occurrence of POAF until the day of hospital dismissal. Postoperative atrial fibrillation occurred in 103 of 350 patients (29%). Patients with POAF was associated with longer intensive care unit stay compared with those without POAF (3.7 ± 2.2 vs. 3.1 ± 1.4 days, P = 0.002). Both the CHA2DS2-VASc score and renal dysfunction were independent predictors of POAF in multivariate analysis. Renal dysfunction can further stratify patients with a CHA2DS2-VASc score of 0 or 1 into two groups with different POAF rates (3.1% vs. 68.8%, P < 0.001). A new scoring system (R-CHA2DS2-VASc score) derived by assigning an additional point representing renal dysfunction to the CHA2DS2-VASc score could improve its predictive accuracy. The area under the receiver operating characteristic curve increased from 0.68 to 0.71 (P < 0.001). Furthermore, the rate of left ventricular diastolic dysfunction also increased with increasing renal dysfunction. CONCLUSION Renal dysfunction, associated with left ventricular diastolic dysfunction, was a significant risk factor for POAF after cardiac surgery and may improve the diagnostic accuracy of the CHA2DS2-VASc score.

Incidence, Predictors and Outcomes of Subacute Stent Thrombosis following Primary Stenting for ST-elevation Myocardial Infarction

BACKGROUND/PURPOSE Knowledge concerning subacute stent thrombosis (SST) following primary stenting for ST-elevation myocardial infarction (STEMI) is not widely available. We studied the incidence, predictors, and clinical outcomes of SST following STEMI. METHODS We analyzed data from 455 consecutive patients who underwent primary stenting for STEMI. Baseline clinical characteristics, coronary angiographic features, medication and outcome were compared in patients with and without SST. RESULTS SST occurred in 17 patients, and the incidence was 3.7%. Univariate predictors of SST were being a current smoker (53.0%vs. 82.4%, p = 0.01), Killip class >or= II (38.4%vs. 58.8%, p = 0.05), no coronary re-flow after stenting (6.2%vs. 17.6%, p = 0.05) and lack of coprescription with a statin (39.5%vs. 5.9%, p<0.01). After multivariate analysis, being a current smoker (odds ratio = 4.76; 95% confidence interval 1.20-18.95) and using statin therapy (odds ratio = 0.09; 95% confidence interval = 0.01-0.75) were independent correlates of SST. Patients with SST were associated with higher 30-day mortality (37.5%vs. 3.1%, p<0.01) and all-cause mortality (23.5%vs. 5.3%, p = 0.01) at long-term follow-up. CONCLUSION Although SST is rare in patients with STEMI treated by primary stenting, it imparts a significantly higher mortality at short-term and long-term follow-up. Being a current smoker and the lack of co-prescription with a statin were associated with higher incidence of SST. Our results suggest initiation of statin therapy in patients with STEMI should be considered before discharge.

Prognostic impact of renal dysfunction in patients with acute coronary syndrome—role beyond the CHA2DS2-VASc score: Data from Taiwan acute coronary syndrome full spectrum registry

CHA2DS2‐VASc score has been proven to have great prognostic value in patients with acute coronary syndrome (ACS). We aimed to determine whether the addition of renal dysfunction in the CHA2DS2‐VASc score would improve the prognostic impact of the scoring system to predict prognosis among ACS patients.