Circulating miRNAs in Pediatric Pulmonary Hypertension Show Promise as Biomarkers of Vascular Function

Background/Objectives. The objective of this study was to evaluate the utility of circulating miRNAs as biomarkers of vascular function in pediatric pulmonary hypertension. Method. Fourteen pediatric pulmonary arterial hypertension patients underwent simultaneous right heart catheterization (RHC) and blood biochemical analysis. Univariate and stepwise multivariate linear regression was used to identify and correlate measures of reactive and resistive afterload with circulating miRNA levels. Furthermore, circulating miRNA candidates that classified patients according to a 20% decrease in resistive afterload in response to oxygen (O2) or inhaled nitric oxide (iNO) were identified using receiver-operating curves. Results. Thirty-two circulating miRNAs correlated with the pulmonary vascular resistance index (PVRi), pulmonary arterial distensibility, and PVRi decrease in response to O2 and/or iNO. Multivariate models, combining the predictive capability of multiple promising miRNA candidates, revealed a good correlation with resistive (r=0.97, P2−tailed<0.0001) and reactive (r=0.86, P2−tailed<0.005) afterloads. Bland-Altman plots showed that 95% of the differences between multivariate models and RHC would fall within 0.13 (mmHg−min/L)m2 and 0.0085/mmHg for resistive and reactive afterloads, respectively. Circulating miR-663 proved to be a good classifier for vascular responsiveness to acute O2 and iNO challenges. Conclusion. This study suggests that circulating miRNAs may be biomarkers to phenotype vascular function in pediatric PAH

Expression profile of microRNAs in young stroke patients

10.1371/journal.pone.0007689PLoS ONE41

Interaction between PPARA genotype and β-blocker treatment influences clinical outcomes following acute coronary syndromes

β-blockers (BB) are strongly recommended after an acute coronary syndrome (ACS), although all patients may not benefit. Causes for variable patient responses to BB are unknown. Given that myocardial ischemia and BB influence metabolic processes regulated by peroxisome proliferator-activated receptor α (PPARα), we hypothesized that interactions between polymorphisms of the PPARα gene (PPARA) and BB treatment would influence clinical outcome following ACS

Common MicroRNA Signatures in Cardiac Hypertrophic and Atrophic Remodeling Induced by Changes in Hemodynamic Load

BACKGROUND: Mechanical overload leads to cardiac hypertrophy and mechanical unloading to cardiac atrophy. Both conditions produce similar transcriptional changes including a re-expression of fetal genes, despite obvious differences in phenotype. MicroRNAs (miRNAs) are discussed as superordinate regulators of global gene networks acting mainly at the translational level. Here, we hypothesized that defined sets of miRNAs may determine the direction of cardiomyocyte plasticity responses. METHODOLOGY/PRINCIPAL FINDINGS: We employed ascending aortic stenosis (AS) and heterotopic heart transplantation (HTX) in syngenic Lewis rats to induce mechanical overloading and unloading, respectively. Heart weight was 26±3% higher in AS (n = 7) and 33±2% lower in HTX (n = 7) as compared to sham-operated (n = 6) and healthy controls (n = 7). Small RNAs were enriched from the left ventricles and subjected to quantitative stem-loop specific RT-PCR targeting a panel of 351 miRNAs. In total, 153 miRNAs could be unambiguously detected. Out of 72 miRNAs previously implicated in the cardiovascular system, 40 miRNAs were regulated in AS and/or HTX. Overall, HTX displayed a slightly broader activation pattern for moderately regulated miRNAs. Surprisingly, however, the regulation of individual miRNA expression was strikingly similar in direction and amplitude in AS and HTX with no miRNA being regulated in opposite direction. In contrast, fetal hearts from Lewis rats at embryonic day 18 exhibited an entirely different miRNA expression pattern. CONCLUSIONS: Taken together, our findings demonstrate that opposite changes in cardiac workload induce a common miRNA expression pattern which is markedly different from the fetal miRNA expression pattern. The direction of postnatal adaptive cardiac growth does, therefore, not appear to be determined at the level of single miRNAs or a specific set of miRNAs. Moreover, miRNAs themselves are not reprogrammed to a fetal program in response to changes in hemodynamic load

Midkine’s Role in Cardiac Pathology

Midkine (MDK) is a heparin-binding growth factor that is normally expressed in mid-gestational development mediating mesenchymal and epithelial interactions. As organisms age, expression of MDK diminishes; however, in adults, MDK expression is associated with acute and chronic pathologic conditions such as myocardial infarction and heart failure (HF). The role of MDK is not clear in cardiovascular disease and currently there is no consensus if it plays a beneficial or detrimental role in HF. The lack of clarity in the literature is exacerbated by differing roles that circulating and myocardial MDK play in signaling pathways in cardiomyocytes (some of which have yet to be elucidated). Of particular interest, serum MDK is elevated in adults with chronic heart failure and higher circulating MDK is associated with worse cardiac function. In addition, pediatric HF patients have higher levels of myocardial MDK. This review focuses on what is known about the effect of exogenous versus myocardial MDK in various cardiac disease models in an effort to better clarify the role of midkine in HF