The association of heart failure-related microRNAs with neurohormonal signaling.

Heart failure (HF) is a widely prevalent syndrome imposing a significant burden of morbidity and mortality world-wide. Differential circulating microRNA profiles observed in HF cohorts suggest the diagnostic utility of microRNAs as biomarkers. Given their function in fine tuning gene expression, alternations in microRNA landscape could reflecting the underlying mechanisms of disease and present potential therapeutic targets. Using multiple computational target predicting algorithms together with the luciferase-based reporting platform, the interactions between HF-related microRNAs and the 3' untranslated regions (3'UTRs) of neurohormone associated genes were examined and compared. Our results indicate that although in silico prediction provides an overview of possible microRNA-mRNA target pairs, less than half of the predicted interactions were experimentally confirmed by reporter assays in HeLa cells. Thus, the establishment of microRNA/3'UTR reporters is essential to systemically evaluate the roles of microRNAs for signaling cascades of interest, including cardiovascular neurohormonal signaling. The physiological relevance of HF-related microRNAs on the expression of putative gene targets was further established by using gain-of-function assays in two human cardiac-derived cells. Our findings, for the first time, provide direct evidence of the regulatory effects of HF-related microRNAs on the neurohormonal signaling in cardiac cells. More importantly, our study presents a rational approach to further exploring microRNA profiling data in deciphering the role of microRNA in complex syndromes such as HF. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren & Megan Yingmei Zhang.

MicroRNA-143 modulates the expression of Natriuretic Peptide Receptor 3 in cardiac cells.

Natriuretic Peptide Receptor 3 (NPR3), the clearance receptor for extracellular bio-active natriuretic peptides (NPs), plays important roles in the homeostasis of body fluid volume and vascular tone. Using luciferase reporter and antagomir-based silencing assays, we demonstrated that the expression of NPR3 could be modulated by microRNA-143 (miR-143-3p), a microRNA species with up-regulated circulating concentrations in clinical heart failure. The regulatory effect of miR-143 on NPR3 expression was further evidenced by the reciprocal relationship between miR-143 and NPR3 levels observed in hypoxia-treated human cardiac cells and in left ventricular tissue from rats undergoing experimental myocardial infarction. Further analysis indicated elevation of miR-143 in response to hypoxic challenge reflects transcriptional activation of the miR-143 host gene (MIR143HG). This was corroborated by demonstration of the induction of host gene promoter activity upon hypoxic challenge. Moreover, miR-143 was shown to enhance its own expression by increasing MIR143HG promoter activity, as well as targeting the expressions of NPPA, NPPC, NR3C2, and CRHR2 in cardiac cells. Taken together, these findings suggest that the elevation of miR-143 upon hypoxic insult may be part of a microRNA-based feed forward loop that results in fine tuning the levels of NPs and neurohormonal receptors in cardiac cell lineages.

[Long-term outcome and cardiac arrhythmias in infants with right atrial isomerism].

OBJECTIVE: The investigators compared the outcome of infants and children having right atrial isomerism with normal pulmonary venous drainage to those with anomalous drainage and determined factors associated with poor outcome. They further determined the prevalence of symptomatic cardiac arrhythmia in these patients and its relation to long-term morbidity and mortality. METHODS: The authors made a retrospective review of management and outcome of 116 infants and children diagnosed to have right atrial isomerism between January 1980 and December 2000. The type, timing and precipitating factors of symptomatic cardiac arrhythmia that occurred in patients, among a cohort of 85 who had or are awaiting surgical interventions, were noted. RESULTS: The 116 patients presented at a median of 1 day (range 1 day to 3.7 years) with cyanosis in the majority (96%). No interventions were planned in 31 (27%) patients who all died. The early surgical mortality for pulmonary venous repair was 25% (2/8), Fontan procedure 26% (5/19), cavopulmonary shunting 8% (1/13) and systemic-pulmonary arterial shunt insertion 2% (1/53). Late mortality was related to infection (n = 10), sudden death of unknown aetiology (n = 7) and documented arrhythmia (n = 1). Patients with obstructed anomalous pulmonary venous drainage had poor survival (P < 0.001). The mean (SEM) survival estimates for those with normal pulmonary venous drainage at 1, 5, 10 and 15 years were 81 (5)%, 67 (7)%, 60 (8)% and 43 (12)%, respectively, similar to those of patients with non-obstructed anomalous drainage (P = 0.06). Independent risk factors for mortality included pulmonary venous obstruction (relative risk RR 3.8, P = 0.001) and a single ventricle (RR 2.9, P = 0.016). Symptomatic cardiac arrhythmia occurred in 15/85 (18%) patients; 11 of whom had supraventricular tachycardia, and 1 atrial tachycardia, 1 atrial flutter, 1 ventricular tachycardia and 1 congenital complete heart block. The arrhythmias occurred before surgery in 4, early after surgery in 5, and late after surgery in 6 patients. Freedom from arrhythmia at 1, 5, 10, 15 and 20 years was (93 +/- 3)%, (86 +/- 4)%, (80 +/- 6)%, (73 +/- 9)% and (48 +/- 15)%, respectively. Logistic regression failed to identify any risk factors for symptomatic arrhythmia. CONCLUSION: The long-term outcome of infants and children with right atrial isomerism, whether associated with normal or anomalous pulmonary venous drainage, remains unfavourable. Sepsis and sudden death are major causes of late mortality. While symptomatic cardiac arrhythmias are not uncommon. They do not seem to relate to the overall high mortality and occurrence of sudden death in this patient group. Nonetheless, detailed assessment and aggressive management of cardiac arrhythmias once they occur are warranted in light of the precarious single ventricular haemodynamics.