Xiao‐Lei Moore

BACKGROUND: Circulating microRNAs may represent novel markers for cardiovascular diseases. We evaluated whether circulating miRNAs served as potential biomarkers for diffuse myocardial fibrosis in patients with hypertrophic cardiomyopathy (HCM). METHODS: Cardiac magnetic resonance imaging with postcontrast T1 mapping was performed to non-invasively quantify diffuse myocardial fibrosis in HCM patients who were classified into two groups (T1 < 470 ms or T1 ≥ 470 ms, as likely or unlikely to have diffuse fibrosis, respectively). First, we screened 84 miRNAs using human serum/plasma miRNA array on plasma of 8 HCM patients (4/group based on T1 time) and 4 healthy controls. From the results of this initial array, 16 miRNAs were selected based on their fold changes and relevance to myocardial fibrosis for further validation by Taqman real-time PCR in 55 HCM patients. RESULTS: Among the 16 miRNAs, the expression of miR-96-5p and miR-373-3p was low. The remaining 14 (miR-18a-5p, miR-146a-5p, miR-30d-5p, miR-17-5p, miR-200a-3p, miR-19b-3p, miR-21-5p, miR-193-5p, miR-10b-5p, miR-15a-5p, miR-192-5p, miR-296-5p, miR-29a-3p, and miR-133a-3p) were upregulated in HCM patients with T1 < 470 ms compared with those with T1 ≥ 470 ms, and 11 (except miR-192-5p, miR-296-5p and miR-133a-3p) were significantly inversely correlated with postcontrast T1 values. Individual miRNA had moderate diagnostic value for diffuse myocardial fibrosis (AUC: 0.663-0.742), but the diagnostic value was greatly improved (AUC: 0.87) for a combination of 8 miRNAs. In comparison, circulating markers of collagen turnover did not have predictive values for diffuse myocardial fibrosis. CONCLUSIONS: These findings suggest that circulating miRNAs provide attractive candidates as putative biomarkers for diffuse myocardial fibrosis in HCM.

BACKGROUND AND OBJECTIVE: Inhibition of established left ventricular hypertrophy (LVH) and fibrosis may bring clinical benefits by reducing cardiac morbidity and mortality. The mammalian target of rapamycin, mTOR, is known to play a critical role in determining cell and organ size. We investigated whether mTOR inhibition can inhibit the chronic pressure-overload-induced LVH and fibrosis. METHODS: Male FVB/N mice underwent transverse aortic constriction (TAC) for 5 weeks to allow for establishment of LVH, followed by treatment with the mTOR inhibitor, Rapamune (2 mg/kg per day, gavage), for 4 weeks. Echocardiography was used to monitor changes in LVH and function. Haemodynamic, morphometric, histological and molecular analyses were conducted. RESULTS: Inhibition of mTOR by Rapamune was confirmed by a suppression of activated phosphorylation of ribosomal S6 protein and eukaryotic translation initiation factor-4E due to pressure overload. Despite a comparable degree of pressure overload between the vehicle- or Rapamune-treated TAC groups, Rapamune treatment for 4 weeks attenuated TAC-induced LVH by 46%, estimated by LV weight or myocyte size, and LV fractional shortening was also preserved versus vehicle-treated control (39 +/- 1 versus 32 +/- 2%, P < 0.05). Inhibition of established LVH by Rapamune was associated with a 38% reduction in collagen content. Moreover, altered gene expression due to pressure overload was largely restored. CONCLUSION: Despite sustained pressure overload, inhibition of mTOR by a 4-week period of Rapamune treatment attenuates chronically established LVH and cardiac fibrosis with preserved contractile function.