A Quest for Non-Invasive Biomarkers in Arrhythmogenic and Phospholamban Cardiomyopathy: New Tools to Facilitate Diagnosis, Prognosis and Prediction

Coordination of the electrical signal to induce orchestrated contraction is vital for a proper functioning of the heart. If the signal gets disturbed, the heart becomes vulnerable for the onset of fatal ventricular arrhythmias. Disruption of the electrical signal due to a pathological condition can promote changes to the heart, which initially might cause a short-term relieve, but gradually results in progressive worsening of cardiac function. For coupling of the electrical signal to contraction of the heart, calcium is important. An important protein that facilitates an adequate calcium handling is phospholamban (PLN). This protein regulates the calcium ATPase pump (SERCA) which is located at the sarcoplasmic reticulum, being the calcium storage compartment within cardiomyocytes. The function of PLN is tightly regulated through phosphorylation. A Dutch founder mutation in PLN exists, the p.Arg14del pathogenic variant, which is proposed to result in super inhibition of SERCA. Consequently, calcium handling gets dysregulated and therefore ventricular arrhythmias can arise.
Another important component of cardiomyocytes is the intercalated disc. This protein complex is located at specific areas of the cell membrane and includes multiple structures. One of these structures are desmosomes, which consist of multiple proteins, such as plakophilin-2 and plakoglobin. When a pathogenic variant is found in genes that code for one of these desmosomal proteins, arrhythmogenic cardiomyopathy (ACM) can develop.
Both ACM and PLN cardiomyopathy are inherited familial cardiac diseases, however prevalence is rather rare. The prevalence for ACM is estimated between 1:1000–1:5000. Patients with ACM or PLN cardiomyopathy suffer from ventricular arrhythmias, palpitations, and eventually the disease can progress into heart failure. Furthermore, fibrosis in the heart is found in both cardiomyopathies, which likely contributes to the arrhythmogenic phenotype. Because of its heterogenic nature, fibrosis formation not only disturbs the coordinated fashion of impulse propagation, but also interferes with contraction and relaxation.
Until now, no curative treatment exists for these patients. Therefore, current treatment is focused on reducing ventricular arrhythmias, and attenuation of symptoms by medication and lifestyle advice. In addition, patients at high risk for severe rhythm disorders might be treated with an ICD, or upon heart failure with a heart transplantation. A complicating factor is that if and how severe family members will become affected by the disease, when carrying a pathogenic variant associated with ACM or PLN cardiomyopathy, is hard to predict. Thus, a better prediction of disease onset and development is necessary to stratify patients at risk. Therefore, the overall aim of this thesis is to identify new early diagnostic and/or predictive biomarkers for ACM and PLN cardiomyopathy. These new biomarkers might be able to identify patients at risk for development of the disease, development of life-threatening arrhythmias, or can be used to simplify diagnosis and prediction of disease in patients. Recent work pinpoint to a potential relationship between certain biomarkers that can be measured in blood from patients and fibrosis formation in the heart. In addition, other data propose alternative modes to acquire information about the degree of intercellular coupling of cardiomyocytes and their calcium homeostasis.