Peripheral microRNA panels to guide the diagnosis of familial cardiomyopathy

Abstract

We would like to thank the Reviewers for their thorough review of our manuscript which greatly improved its quality. In the following pages are our point-bypoint responses to each of the comments of the Reviewers. Reviewer's comments: Reviewer #1: The study by Belmonte and colleagues assessed the utility of peripheral miRNAs as biomarkers for DCM management. The authors profiled the expression of 179 miRNAs in the plasma of 254 subjects, including healthy subjects idiopathic DCM patients, ischemic DCM patients, and patients carrying DCM pathogenic variants in LMNA or BAG3 genes. The authors identified a 6-miRNA panel that can distinguish between familial and non-familial DCM, and specific DCM etiologies. Additionally, a separate 5-miRNA panel could discriminate between phenotypically negative carriers and healthy controls. The authors concluded that panels combining miRNAs into panels could serve as a robust biomarker to rule out the presence of pathogenic variants associated with familial DCM in both patients phenotypically positive and negative for the disease Overall, the study is straightforward and well designed. In this manuscript, the authors expanded the scope and findings of one of their recently published studies (J Mol Med (Berl) 2018; 96:845-856). There are several limitations that the authors have discussed.

MicroRNAs in Hypertrophic, Arrhythmogenic and Dilated Cardiomyopathy

“…Due to the difficulty of tissue sampling in children, circulating miRNAs could be promising biomarkers for DCM in young patients, together with their possible use as biomarkers for risk stratification in prognosis related to young people affected by DCM. miR-124-5p upregulated miR-548 downregulated DCM with stable chronic heart failure [66] miR-423-5p upregulated DCM-related heart failure [67] miR-185 upregulated upregulation linked to a favourable prognosis in DCM patients [68] miR-3135b, miR-3908, miR-5571-5p upregulated [69] miR-26, miR-30 similar levels chronic and new-onset DCM with and without fibrosis [70] miR-92b-5p upregulated acute heart failure due to DCM [71] miR-24-3p, miR-28-5p, miR-100-5p, miR-103-3p, miR-125b5p, miR-214-3p, let-7b-5p, let-7c-5p upregulated ischemic and idiopathic DCM [72] let-7a-5p, miR-142-3p, miR-145-5p, miR-454-3p upregulated DCM with pathogenic LMNA mutations compared to idiopathic DCM or controls [73] let-7a-5p, let-7g-5p, miR-16-2-3p, miR-210-3p, miR-215-5p, miR-629-5p upregulated in familiar DCM compared to no familiar [74] miR-154-5p, miR-182-5p, miR-1249-ep, miR-3191-3p, miR-6769b-3p, miR-6855-5p upregulated in DCM patients BAG3+ mutation carriers compared to BAG3 wt [75] miR-133a upregulated increased expression in LVRR compared to non-LVRR [76] miR-130b-3p, miR-150-5p, miR-210-3p upregulated distinguish DCM with severe reduced systolic ejection fraction from moderately reduced ejection fraction…”

“…The same group, two years later, proposed a six-miRNA panel (let-7a-5p, let-7g-5p, miR-16-2-3p, miR-210-3p, miR-215-5p, and miR-629-5p) to differentiate DCM subjects with pathogenic BAG3 or LMNA variants from wild-type variant carriers. A second group of five miRNAs (miR-19b-3p, miR-29a-3p, miR-130b-3p, miR-215-5p, miR-629-5p) was proposed instead to distinguish phenotypically negative variant carriers from healthy subjects [ 74 ].…”

Well-Known and Novel Serum Biomarkers for Risk Stratification of Patients with Non-ischemic Dilated Cardiomyopathy

“…Their evaluation could help with the differentiation of the etiology behind heart failure (ischemic vs. nonischemic) and possibly with the prediction of the future course of the disease [ 87 , 88 ]. Although current evidence is lacking, there are some small studies that discovered high plasma levels of miRNA-16 in patients with ischemic and familial dilated cardiomyopathy, confirming its relationship with these etiologies [ 89 , 90 , 91 ].…”

Circulating circRNA as Biomarkers For Dilated Cardiomyopathy Etiology

“…DCM was de ned as either LVEF levels below 50% and/or LV end-diastolic diameter larger than 56 mm [10]. BAG3 and LMNA participants were con rmed genetically and ful lled the diagnostic clinical criteria for familial DCM [11]. The LMNA cohort was subclassi ed as a carrier of the pathogenic variant, phenotypically negative (LMNA Ph− ) and genetically and phenotypically positive (LMNA Ph+ ) as previously described [11].…”

“…BAG3 and LMNA participants were con rmed genetically and ful lled the diagnostic clinical criteria for familial DCM [11]. The LMNA cohort was subclassi ed as a carrier of the pathogenic variant, phenotypically negative (LMNA Ph− ) and genetically and phenotypically positive (LMNA Ph+ ) as previously described [11]. Genetic etiology was ruled out in all idiopathic DCM patients.…”