Exploring the Correlation Between Fibrosis Biomarkers and Clinical Disease Severity in PLN p.Arg14del Patients

Stephanie M van der Voorn; Mimount Bourfiss; Anneline S J M Te Riele; Karim Taha; Marc A Vos; Remco de Brouwer; Tom E Verstraelen; Rudolf A de Boer; Carol Ann Remme; Toon A B van Veen

doi:10.3389/fcvm.2021.802998

Exploring the Correlation Between Fibrosis Biomarkers and Clinical Disease Severity in PLN p.Arg14del Patients

Front Cardiovasc Med. 2022 Jan 13:8:802998. doi: 10.3389/fcvm.2021.802998. eCollection 2021.

Affiliations

¹ Division Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, Utrecht, Netherlands.
² Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, Netherlands.
³ Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
⁴ Heart Center, Department of Cardiology, Amsterdam University Medical Center, Location Academic Medical Center, Amsterdam, Netherlands.
⁵ Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Univeristy Medical Center, Location Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.

Abstract

Background: Pathogenic variants in phospholamban (PLN, like p. Arg14del), are found in patients diagnosed with arrhythmogenic (ACM) and dilated cardiomyopathy (DCM). Fibrosis formation in the heart is one of the hallmarks in PLN p.Arg14del carriers. During collagen synthesis and breakdown, propeptides are released into the circulation, such as procollagen type I carboxy-terminal propeptide (PICP) and C-terminal telopeptide collagen type I (ICTP). Aim: To investigate if PICP/ICTP levels in blood are correlative biomarkers for clinical disease severity and outcome in PLN p.Arg14del variant carriers. Methods: Serum and EDTA blood samples were collected from 72 PLN p.Arg14del carriers (age 50.5 years, 63% female) diagnosed with ACM (n = 12), DCM (n = 14), and preclinical variant carriers (n = 46). PICP levels were measured with an enzyme-linked immune sorbent assay and ICTP with a radio immuno-assay. Increased PICP/ICTP ratios suggest a higher collagen deposition. Clinical data including electrocardiographic, and imaging results were adjudicated from medical records. Results: No correlation between PICP/ICTP ratios and late gadolinium enhancement (LGE) was found. Moderate correlations were found between the PICP/ICTP ratio and end-diastolic/systolic volume (both r _s = 0.40, n = 23, p = 0.06). PICP/ICTP ratio was significantly higher in patients with T wave inversion (TWI), especially in leads V4-V6, II, III, and aVF (p < 0.022) and in patients with premature ventricular contractions (PVCs) during an exercise tolerance test (p = 0.007). Conclusion: High PICP/ICTP ratios correlated with clinical parameters, such as TWI and PVCs. Given the limited size and heterogeneity of the patient group, additional studies are required to substantiate the incremental prognostic value of these fibrosis biomarkers in PLN p.Arg14del patients.

Keywords: biomarkers; cardiomyopathy; collagen; fibrosis; phospholamban (PLN).