Differential Cardiac MicroRNA Expression Predicts the Clinical Course in Human Enterovirus Cardiomyopathy

Abstract

Background— Investigation of disease pathogenesis confined to protein-coding regions of the genome may be incomplete because many noncoding variants are associated with disease. We aimed to identify novel predictive markers for the course of enterovirus (CVB3) cardiomyopathy by screening for noncoding elements influencing the grossly different antiviral capacity of individual patients. Methods and Results— Transcriptome mapping of CVB3 cardiomyopathy patients revealed distinctive cardiac microRNA (miR) patterns associated with spontaneous virus clearance and recovery (CVB3-ELIM) versus virus persistence and progressive clinical deterioration (CVB3-PERS). Profiling of protein-coding genes and 754 miRs in endomyocardial biopsies of test cohorts was performed at their initial presentation, and those spontaneously eliminating the virus were compared with those with virus persistence on follow-up. miR profiling revealed highly significant differences in cardiac levels of 16 miRs, but not of protein-coding genes. Evaluation of this primary distinctive miR pattern in validation cohorts, and multivariate receiver operating characteristic curve analysis, confirmed this pattern as highly predictive for disease course (area under the curve, 0.897±0.071; 95% confidence interval, 0.758–1.000). Eight miRs were strongly induced in CVB3-PERS (miRs 135b, 155, 190, 422a, 489, 590, 601, 1290), but undetectable in CVB3-ELIM or controls. They are predicted to target multiple immune response genes, and 2 of these were confirmed by antisense-mediated ablation of miRs 135b, 190, and 422a in the monocytic THP-1 cell line. Conclusions— An immediate clinical application of the data is cardiac miR profiling to assess the risk of virus persistence and progressive clinical deterioration in CVB3 cardiomyopathy. Patients at risk are eligible for immediate antiviral therapy to minimize irreversible cardiac damage.

Viral heart disease — treatment

“…Symptomatic improvement was also observed in patients with PVB19 load reduction, probably due to PVB19 transcriptional activity silencing [6]. Transcriptionally active PVB19 is associ- HSV-DCM Aciclovir 500 mg intravenously every 8 h for the first 5 days and then 9 days orally 400 mg every 4 h except one dose at night [28] INF-b -interferon b; CK -creatinine kinase; CK-MB -creatinine kinase MB isoenzyme; TnI -cardiac troponin I; TnT -cardiac troponin T; TSH -thyroid stimulating hormone; T3 -triiodothyronine; T4 -thyroxine; PVB19 -parvovirus B19; HHV-6 -human herpes virus 6 ated with a higher rate of dyspnoea, fatigue, and angina. The number of circulating apoptotic endothelial cells is reduced, while the number of circulating progenitor cells is increased [14].…”

“…Based on the following information, specific treatments can be initiated earlier, and minimise tissue injury [28].…”

“…They affect all biological processes including cardiomyocyte proliferation, angiogenesis, fibrosis, and cell death. MiRNA profiling allows the identification of patients with CVB3 infection, who will benefit from INF-b administration, and those who will spontaneously eliminate the virus [28,29]. Latent and reactivated PVB19 infection are characterised by distinct miRNA expression profiles [30].…”

Absent MicroRNAs in Different Tissues of Patients with Acquired Cardiomyopathy

“…Differential miRNA patterns allow the identification of different heart disorders or disease situations [17], [21]. The role of these human miRNAs in pathogenesis [18] highlights their value as potential molecular biomarkers for complex diseases such as cardiomyopathies [16], [27], [28]. The discriminating power of single miRNAs for diagnosis of complex diseases can be increased by its integration in a larger panel presenting a specific miRNA signature.…”

“…The discriminating power of single miRNAs for diagnosis of complex diseases can be increased by its integration in a larger panel presenting a specific miRNA signature. The application of myocardial miRNA profiling allows the differentiation of distinct phases of viral infections and the prediction of the clinical course of virally-induced disease at the time point of primary diagnostic biopsy [16], [11], [28], [12]. In the same individual, miRNA signatures in tissue, serum, peripheral blood mononuclear cells (PBMCs), or other body fluids show specific features for the current condition.…”