Serum circular RNAs act as blood-based biomarkers for hypertrophic obstructive cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is one of the most common hereditary heart diseases and is associated with a high risk of sudden cardiac death. HCM is characterized by pronounced hypertrophy of cardiomyocytes, fiber disarray and development of fibrosis and can be divided into a non-obstructive (HNCM) and obstructive form (HOCM) therefore requiring personalized therapeutic therapies. In the present study, we investigated the expression patterns of several circulating circular RNAs (circRNAs) as potential biomarkers in patients with HCM. We included 64 patients with HCM and 53 healthy controls to the study and quantitatively measured the expression of a set of circRNAs already known to be associated with cardiac diseases (circDNAJC6) and/or being highly abundant in blood (circTMEM56 and circMBOAT2). Abundancy of circRNAs was then correlated to relevant clinical parameters. Serum expression levels of circRNAs DNAJC6, TMEM56 and MBOAT2 were downregulated in patients with HCM. The inverse association between circRNA levels and HCM remained unchanged even after adjusting for confounding factors. All circRNAs, evaluated separately or in combination, showed a robust discrimination capacity when comparing control subjects with HCM, HNCM or HOCM patients (AUC from 0.722 to 0.949). Two circRNAs, circTMEM56 and circDNAJC6, significantly negatively correlated with echocardiographic parameters for HOCM. Collectively, circulating circRNAs DNAJC6, TMEM56 and MBOAT2 can distinguish between healthy and HCM patients. In addition, circTMEM56 and circDNAJC6 could serve as indicators of disease severity in patients with HOCM. Thus, circRNAs emerge as novel biomarkers for HCM facilitating the clinical decision making in a personalized manner.

Circular RNAs: Functions and Clinical Significance in Cardiovascular Disease

“…A study using whole blood revealed that the hsa_circ_0037911 level was significantly increased in hypertensive patients in contrast to the control group ( Bao et al, 2018 ). Another study revealed reduced expression levels of circRNAs (DNAJC6, TMEM56 and MBOAT2) in the serum of patients with HCM ( Sonnenschein et al, 2019 ). All three circRNAs had high discrimination power between HCM patients and the control cohort.…”

“…With the use of advanced technologies in sequencing and data analysis, a lot of circRNAs have been detected in human hearts and been reported to be associated with CVD ( Jakobi et al, 2016 ; Werfel et al, 2016 ; Fan et al, 2017 ; Tan et al, 2017 ) ( Table 2 and Figure 2 ). Moreover, circRNAs have been observed to have great potential as biomarkers for the diagnosis and prognosis of CVD ( Vausort et al, 2016 ; Sonnenschein et al, 2019 ; Wu et al, 2019 ; Vilades et al, 2020 ) ( Table 3 and Figure 2 ).…”

“…All three circRNAs had high discrimination power between HCM patients and the control cohort. Moreover, circTMEM56 and circDNAJC6 could be indicators of disease severity in patients with HCM ( Sonnenschein et al, 2019 ). Wu et al (2019) reported three notably downregulated circRNAs (hsa_circRNA_004183, hsa_circRNA_079265 and hsa_circRNA_105039) in the plasma of children with congenital heart diseases (CHD) and employed ROC analyses to determine their potential to be biomarkers.…”

Circular RNAs in Cardiac Regeneration: Cardiac Cell Proliferation, Differentiation, Survival, and Reprogramming

“…Three of the investigated circRNAs, DNAJC6, TMEM56, and MBOAT2 were found in serum and can help distinguish healthy from HCM patients. Furthermore, DNAJC6 and TMEM56 could serve as indicators for disease severity in patients with obstructive HCM (Sonnenschein et al, 2019). Identifying differentially regulated circRNAs through newly available sequencing technologies is the first step in planning further research with circRNAs.…”

Circular RNAs Are Regulators of Diverse Animal Transcriptomes: One Health Perspective

“…Notably, Sry circRNA, previously reported to be predominant over linear Sry transcript in mouse testis (Capel et al, 1993), was not found. Significant new findings were the identification of several porcine heart-specific circRNAs related to hypertrophic cardiomyopathy, recapitulating circRNAs in human heart development and pathogenesis of cardiac diseases (Sonnenschein et al, 2019). Results identified MREs in 30% of the porcine circRNAs, implicating functionalities beyond miR sponging for porcine circRNAs.…”