Identification of cardiomyopathy associated circulating miRNA biomarkers in patients with muscular dystrophy using a complementary cardiovascular magnetic resonance and plasma profiling approach

Abstract

BackgroundDuchenne and Becker muscular dystrophy (DMD and BMD) are X-chromosomal recessive neuromuscular disorders that are caused by mutations in the dystrophin gene and characterized by cardiac involvement. Circulating microRNAs (miRNAs) have been proposed as diagnostic biomarkers for various cardiovascular diseases. However, circulating miRNAs reflecting the presence and/or disease severity of cardiac involvement in DMD/BMD patients have not been described so far.MethodsSixty-three male patients with known MD and 26 age-matched healthy male controls were prospectively enrolled. All MD patients and controls underwent comprehensive cardiovascular magnetic resonance (CMR) studies as well as venous blood sampling on the same day.ResultsAn impaired left ventricular (LV) systolic function (defined as LV-EF <55 %) was detected in 29 (46 %) and presence of late gadolinium enhancement (LGE) indicative of myocardial fibrosis in 48 (76 %) MD patients with an exclusively non-ischemic pattern. Whereas no significant differences were observed for the 27 selected circulating miRNAs in MD patients with abnormal CMR findings (comprising structural and/or functional impairments) compared to those with completely normal CMR studies, a significant up-regulation of three miRNAs was observed in LGE-positive MD patients compared to LGE-negative ones: miR-222 (1.8-fold, p = 0.035), miR-26a (2.1-fold, p = 0.03) and miR-378a-5p (2.4-fold, p = 0.026). A signature of these three miRNAs (miR-26a, miR-222 and miR-378a-5p) resulted in an area under the curve (AUC) value of 0.74 for the diagnosis of LGE-positive MD patients. In a multivariable model, three independent predictors for LGE presence were identified comprising not only clinical and laboratory markers (LV-EF: OR 0.47, 95 % CI 0.24-0.89, p = 0.021 and elevated hs-Trop: OR 2559, 95 % CI 2.97-22.04*105, p = 0.023) but also the circulating miR-222 (OR 938, 95 % CI 938.46, 3.56-24.73*104, p = 0.016).ConclusionsUp-regulation of circulating miRNAs miR-222, miR-26a and miR-378a-5p indicates the presence of myocardial scars in MD patients. Plasma miR-222 appears to be a promising novel biomarker reflecting structural – but not functional – cardiac alterations in MD patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12968-016-0244-3) contains supplementary material, which is available to authorized users.

Role of Cardiac Magnetic Resonance in the Diagnosis and Prognosis of Nonischemic Cardiomyopathy

“…In addition to abnormalities in circumferential strain, the presence of LGE (Figure 3) may also precede a decrease in LVEF (37). In one study (38), 36% of DMD patients had LGE, and the prevalence increased with age.…”

Role of microRNA in diabetic cardiomyopathy: From mechanism to intervention

“…In addition, plasma miR-503 has been associated with endothelial dysfunction and ischemia in diabetic patients [108]. Upregulation of plasma miR-222, miR-26a and miR-378a-5p have been reported in muscular dystrophic patients with cardiomyopathy, and plasma miR-222 has been suggested as a promising biomarker for monitoring cardiac structural changes [109]. Plasma miR-454, miR-500, miR-142-3p/5p and miR-1246 have been identified in patients with diastolic dysfunction [110].…”

Biomarker MicroRNAs for Diagnosis of Oral Squamous Cell Carcinoma Identified Based on Gene Expression Data and MicroRNA-mRNA Network Analysis

“…Since many key biological processes including the development, differentiation, and cell cycles are regulated by microRNAs, the abnormal expression of microRNAs is often associated with the initialization and progression of many diseases [ 6 , 7 ]. Thus miRNAs usually could serve as suitable biomarkers for many diseases, such as neurodevelopmental disorders [ 8 ], cancer, and cardiovascular disease [ 9 – 11 ].…”