No abstract

Background-Small RNA molecules, called microRNAs, freely circulate in human plasma and correlate with varying pathologies. In this study, we explored their diagnostic potential in a selection of prevalent cardiovascular disorders. Methods and Results-MicroRNAs were isolated from plasmas from well-characterized patients with varying degrees of cardiac damage: (1) acute myocardial infarction, (2) viral myocarditis, (3) diastolic dysfunction, and (4) acute heart failure. Plasma levels of selected microRNAs, including heart-associated (miR-1, -133a, -208b, and -499), fibrosisassociated (miR-21 and miR-29b), and leukocyte-associated (miR-146, -155, and -223) candidates, were subsequently assessed using real-time polymerase chain reaction. Strikingly, in plasma from acute myocardial infarction patients, cardiac myocyte-associated miR-208b and -499 were highly elevated, 1600-fold (PϽ0.005) and 100-fold (PϽ0.0005), respectively, as compared with control subjects. Receiver operating characteristic curve analysis revealed an area under the curve of 0.94 (PϽ10 Ϫ10 ) for miR-208b and 0.92 (PϽ10 Ϫ9 ) for miR-499. Both microRNAs correlated with plasma troponin T, indicating release of microRNAs from injured cardiomyocytes. In viral myocarditis, we observed a milder but significant elevation of these microRNAs, 30-fold and 6-fold, respectively. Plasma levels of leukocyte-expressed microRNAs were not significantly increased in acute myocardial infarction or viral myocarditis patients, despite elevated white blood cell counts. In patients with acute heart failure, only miR-499 was significantly elevated (2-fold), whereas no significant changes in microRNAs studied could be observed in diastolic dysfunction. Remarkably, plasma microRNA levels were not affected by a wide range of clinical confounders, including age, sex, body mass index, kidney function, systolic blood pressure, and white blood cell count. Conclusions-Cardiac damage initiates the detectable release of cardiomyocyte-specific microRNAs-208b and -499 into the circulation. (Circ Cardiovasc Genet. 2010;3:499-506.)

Rationale: Long noncoding RNAs (lncRNAs) constitute a novel class of noncoding RNAs that regulate gene expression. Although recent data suggest that lncRNAs may be associated with cardiac disease, little is known about lncRNAs in the setting of myocardial ischemia. Objective: To measure lncRNAs in patients with myocardial infarction (MI). Methods and Results: We enrolled 414 patients with acute MI treated by primary percutaneous coronary intervention. Blood samples were harvested at the time of reperfusion. Expression levels of 5 lncRNAs were measured in peripheral blood cells by quantitative polymerase chain reaction: hypoxia inducible factor 1A antisense RNA 2, cyclin-dependent kinase inhibitor 2B antisense RNA 1 (ANRIL), potassium voltage-gated channel, KQT-like subfamily, member 1 opposite strand/antisense transcript 1 (KCNQ1OT1), myocardial infarction–associated transcript, and metastasis-associated lung adenocarcinoma transcript 1. Levels of hypoxia inducible factor 1A antisense RNA 2, KCNQ1OT1, and metastasis-associated lung adenocarcinoma transcript 1 were higher in patients with MI than in healthy volunteers ( P <0.01), and levels of ANRIL were lower in patients with MI ( P =0.003). Patients with ST-segment–elevation MI had lower levels of ANRIL ( P <0.001), KCNQ1OT1 ( P <0.001), myocardial infarction–associated transcript ( P <0.001), and metastasis-associated lung adenocarcinoma transcript 1 ( P =0.005) when compared with patients with non–ST-segment–elevation MI. Levels of ANRIL were associated with age, diabetes mellitus, and hypertension. Patients presenting within 3 hours of chest pain onset had elevated levels of hypoxia inducible factor 1A antisense RNA 2 when compared with patients presenting later on. ANRIL, KCNQ1OT1, myocardial infarction–associated transcript, and metastasis-associated lung adenocarcinoma transcript 1 were significant univariable predictors of left ventricular dysfunction as assessed by an ejection fraction ≤40% at 4-month follow-up. In multivariable and reclassification analyses, ANRIL and KCNQ1OT1 improved the prediction of left ventricular dysfunction by a model, including demographic features, clinical parameters, and cardiac biomarkers. Conclusions: Levels of lncRNAs in blood cells are regulated after MI and may help in prediction of outcome. This motivates further investigation of the role of lncRNAs after MI.

Recent studies have focused their attention on the role of the proinflammatory cytokine tumor necrosis factor (TNF) in the development of heart failure. First recognized as an endotoxin-induced serum factor that caused necrosis of tumors and cachexia, it is now recognized that TNF participates in the pathophysiology of a group of inflammatory diseases including rheumatoid arthritis and Crohn's disease. The normal heart does not express TNF; however, the failing heart produces robust quantities. Furthermore, there is a direct relationship between the level of TNF expression and the severity of disease. In addition, both in vivo and in vitro studies demonstrate that TNF effects cellular and biochemical changes that mirror those seen in patients with congestive heart failure. Furthermore, in animal models, the development of the heart failure phenotype can be abrogated at least in part by anticytokine therapy. Based on information from experimental studies, investigators are now evaluating the clinical efficacy of novel anticytokine and anti-TNF strategies in patients with heart failure; one such strategy is the use of a recombinantly produced chimeric TNF alpha soluble receptor. Thus, in view of the emerging importance of proinflammatory cytokines in the pathogenesis of heart disease, we review the biology of TNF, its role in inflammatory diseases, the effects of TNF on the physiology of the heart and the development of clinical strategies that target the cytokine pathways.

BACKGROUND Rapid and correct diagnosis of acute myocardial infarction (MI) has an important impact on patient treatment and prognosis. We compared the diagnostic performance of high-sensitivity cardiac troponin T (hs-cTnT) and cardiac enriched microRNAs (miRNAs) in patients with MI. METHODS Circulating concentrations of cardiac-enriched miR-208b and miR-499 were measured by quantitative PCR in a case-control study of 510 MI patients referred for primary mechanical reperfusion and 87 healthy controls. RESULTS miRNA-208b and miR-499 were highly increased in MI patients (&gt;105-fold, P &lt; 0.001) and nearly undetectable in healthy controls. Patients with ST-elevation MI (n= 397) had higher miRNA concentrations than patients with non–ST-elevation MI (n = 113) (P &lt; 0.001). Both miRNAs correlated with peak concentrations of creatine kinase and cTnT (P &lt; 10−9). miRNAs and hs-cTnT were already detectable in the plasma 1 h after onset of chest pain. In patients who presented &lt;3 h after onset of pain, miR-499 was positive in 93% of patients and hs-cTnT in 88% of patients (P= 0.78). Overall, miR-499 and hs-cTnT provided comparable diagnostic value with areas under the ROC curves of 0.97. The reclassification index of miR-499 to a clinical model including several risk factors and hs-cTnT was not significant (P = 0.15). CONCLUSION Circulating miRNAs are powerful markers of acute MI. Their usefulness in the establishment of a rapid and accurate diagnosis of acute MI remains to be determined in unselected populations of patients with acute chest pain.