The Time Has Come to Explore Plasma Biomarkers in Genetic Cardiomyopathies

Abstract

For patients with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM), screening for pathogenic variants has become standard clinical practice. Genetic cascade screening also allows the identification of relatives that carry the same mutation as the proband, but disease onset and severity in mutation carriers often remains uncertain. Early detection of disease onset may allow timely treatment before irreversible changes are present. Although plasma biomarkers may aid in the prediction of disease onset, monitoring relies predominantly on identifying early clinical symptoms, on imaging techniques like echocardiography (Echo) and cardiac magnetic resonance imaging (CMR), and on (ambulatory) electrocardiography (electrocardiograms (ECGs)). In contrast to most other cardiac diseases, which are explained by a combination of risk factors and comorbidities, genetic cardiomyopathies have a clear primary genetically defined cardiac background. Cardiomyopathy cohorts could therefore have excellent value in biomarker studies and in distinguishing biomarkers related to the primary cardiac disease from those related to extracardiac, secondary organ dysfunction. Despite this advantage, biomarker investigations in cardiomyopathies are still limited, most likely due to the limited number of carriers in the past. Here, we discuss not only the potential use of established plasma biomarkers, including natriuretic peptides and troponins, but also the use of novel biomarkers, such as cardiac autoantibodies in genetic cardiomyopathy, and discuss how we can gauge biomarker studies in cardiomyopathy cohorts for heart failure at large.

Keywords: ACM; DCM; HCM; cardiac autoantibodies; early detection; genetic cardiomyopathy; noncoding RNA; plasma biomarkers.

Figure 1

The most common genetic cardiomyopathies and a selection of the most frequently implicated genes. The hearts used in this figure are adapted from McCauley and Wehrens (2009) [23], licensed under a Creative Commons Attribution Non-Commercial Share Alike 3.0 Unported License (https://creativecommons.org/licenses/by-nc-sa/3.0/legalcode, accessed on 14 March 2021). ACM = arrhythmogenic cardiomyopathy; DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy.

Figure 2

Suggested stages of disease development in genetic cardiomyopathy.

Figure 3

Moment of disease detection in relation to the level of cardiac impairment. ECG = electrocardiogram; Echo = echocardiography; BNPs = B-type natriuretic peptide and N-terminal pro BNP; LGE = late gadolinium enhancement, cTns= cardiac-specific Troponin I and T; cAAbs = cardiac autoantibodies; Gal-3 = galectin-3; Others include GDF15 and sST2.

Figure 4

Overview of the current spectrum of potential biomarkers in genetic cardiomyopathies, including examples of biomarker proteins, noncoding RNAs (ncRNAs) and antibodies. Red/orange ovals indicate proteins/ncRNAs from the heart. Blue/purple: ovals indicate proteins/ncRNAs from multiple tissues. Green ovals indicate antibodies. AAbs = autoantibodies, cAAbs = cardiac autoantibodies, BNP = B-type natriuretic peptide, ANP = atrial natriuretic peptide, BMP10 = bone morphogenetic protein 10, Gal-3 = galectin-3, GDF15 = growth differentiation factor 15, sST2 = soluble suppression of tumorigenesis-2, β1 = G-protein coupled β1 receptor, M2 = muscarin-2 receptor, DSG2 = desmoglein-2, cTnI = cardiac troponin I, cTnT = cardiac troponin T, MyBPC3 = cardiac myosin-binding protein C3, hFABP = heart-type fatty acid-binding protein. Components of the figure are derived from Servier Medical Art (https://smart.servier.com/, accessed on 14 March 2021), licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/, accessed on 14 March 2021).

Figure 5

Genetic cardiomyopathy as a cardiac disease-specific model to explore biomarkers. ECG = electrocardiography, echo = echocardiography, EF = ejection fraction, GFR = glomerular filtration rate (a measure of kidney function). Components of the figure are derived from Servier Medical Art (https://smart.servier.com/, accessed on 14 March 2021), licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/, accessed on 14 March 2021).