Titin-Related Dilated Cardiomyopathy: The Clinical Trajectory and the Role of Circulating Biomarkers in the Clinical Assessment

Przemysław Chmielewski,Małgorzata Stępień-Wojno,Artur Oręziak,Małgorzata Rydzanicz,Tomasz Zieliński,Michał Lewandowski,Ewa Michalak,Maria Bilińska,Rafał Płoski,Przemysław Leszek,Małgorzata Sobieszczańska-Małek,Zofia T Bilińska,Piotr Stawiński,Ilona Kowalik,Maria Franaszczyk,Grażyna Truszkowska

doi:10.3390/diagnostics12010013

Przemysław Chmielewski, Małgorzata Stępień-Wojno + Show 14 more

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https://doi.org/10.3390/diagnostics12010013

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Abstract

Titin truncating variants (TTNtv) are known as the leading cause of inherited dilated cardiomyopathy (DCM). Nevertheless, it is unclear whether circulating cardiac biomarkers are helpful in detection and risk assessment. We sought to assess 1) early indicators of cardiotitinopathy including the serum biomarkers high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in clinically stable patients, and 2) predictors of outcome among TTNtv carriers. Our single-center cohort consisted of 108 TTNtv carriers (including 70 DCM patients) from 43 families. Clinical, laboratory and follow-up data were analyzed. The earliest abnormality was left ventricular dysfunction, present in 8, 26 and 47% of patients in the second, third and fourth decade of life, respectively. It was followed by symptoms of heart failure, linked to NT-proBNP elevation and severe left ventricular systolic dysfunction, and later by arrhythmias. Hs-cTnT serum levels were increased in the late stage of the disease only. During the median follow-up of 5.2 years, both malignant ventricular arrhythmia (MVA) and end-stage heart failure (esHF) occurred in 12% of TTNtv carriers. In multivariable analysis, NT-proBNP level ≥650 pg/mL was the best predictor of both composite endpoints (MVA and esHF) and of MVA alone. In conclusion, echocardiographic abnormalities are the first detectable anomalies in the course of cardiotitinopathies. The assessment of circulating cardiac biomarkers is not useful in the detection of the disease onset but may be helpful in risk assessment.

Highlights

Dilated cardiomyopathy (DCM) is a major cause of heart failure (HF) and has a genetic basis in 40 to 50% of cases [1]
We identified 41 different Titin truncating variants (TTNtv) in 46 unrelated probands: Two variants were shared by two probands each and one was identified in four probands
We analyzed the penetrance of cardiac abnormalities in the group of 49 TTNtv carriers who came to our Unit for screening

Summary

Introduction

Dilated cardiomyopathy (DCM) is a major cause of heart failure (HF) and has a genetic basis in 40 to 50% of cases [1]. Titin truncating variants (TTNtv) account for as many as 20–25% of the genetic background in DCM [2,3,4,5,6,7] of European but not African ancestry [8]. Earlier studies showed good response to optimal medical therapy [7,12,13], the impact of mutation location on the course of disease [2,6] and similar prognosis as in other forms of DCM [2,3]. The presence of TTNtv was shown to be an important risk factor for clinically significant arrhythmia in DCM patients [14,15]

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