*Article* **Can Circulating Cardiac Biomarkers Be Helpful in the Assessment of** *LMNA* **Mutation Carriers?**

**Przemyslaw Chmielewski 1, Ewa Michalak 1, Ilona Kowalik 2, Maria Franaszczyk 3, Malgorzata Sobieszczanska-Malek 4, Grazyna Truszkowska 3, Malgorzata Stepien-Wojno 1, Elzbieta Katarzyna Biernacka 5, Bogna Foss-Nieradko 1, Michal Lewandowski 6, Artur Oreziak 7, Maria Bilinska 7, Mariusz Kusmierczyk 8, Frédérique Tesson 9, Jacek Grzybowski 10, Tomasz Zielinski 4, Rafal Ploski <sup>11</sup> and Zofia T. Bilinska 1,\***


Received: 1 April 2020; Accepted: 8 May 2020; Published: 12 May 2020

**Abstract:** Mutations in the lamin A/C gene are variably phenotypically expressed; however, it is unclear whether circulating cardiac biomarkers are helpful in the detection and risk assessment of cardiolaminopathies. We sought to assess (1) clinical characteristics including serum biomarkers: high sensitivity troponin T (hsTnT) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) in clinically stable cardiolaminopathy patients, and (2) outcome among pathogenic/likely pathogenic lamin A/C gene (*LMNA)* mutation carriers. Our single-centre cohort included 53 patients from 21 families. Clinical, laboratory, follow-up data were analysed. Median follow-up was 1522 days. The earliest abnormality, emerging in the second and third decades of life, was elevated hsTnT (in 12% and in 27% of patients, respectively), followed by the presence of atrioventricular block, heart failure, and malignant ventricular arrhythmia (MVA). In patients with missense vs. other mutations, we found no difference in MVA occurrence and, surprisingly, worse transplant-free survival. Increased levels of both hsTnT and NT-proBNP were strongly associated with MVA occurrence (HR > 13, *p* ≤ 0.02 in both) in univariable analysis. In multivariable analysis, NT-proBNP level > 150 pg/mL was the only independent indicator of MVA. We conclude that assessment of circulating cardiac biomarkers may help in the detection and risk assessment of cardiolaminopathies.

**Keywords:** laminopathy; *LMNA*; biomarkers; troponin T; NT-proBNP; malignant ventricular arrhythmia; arrhythmic risk stratification

#### **1. Introduction**

Dilated cardiomyopathy (DCM) is a major cause of heart failure (HF) and has a genetic basis in 40–50% of cases [1]. There is growing evidence of distinct arrhythmogenic phenotype in DCM related to *LMNA*, *SCN5A*, *PLN*, *RBM20*, *FLNC*, and *DSP* mutations [2–6]. Of these, cardiolaminopathies have been studied most extensively and are phenotypically quite well characterized [7–13]. Nevertheless, none of the studies involved baseline characteristics including circulating cardiac biomarkers. In 2005, a Canadian–Irish–Polish joint study showed the presence of *LMNA* mutations in 4.4% of consecutive DCM cases [14]. In a further study, we found that 7.6% of 66 heart transplant (HTX) recipients and 9.1% of consecutive DCM patients referred for familial evaluation carry *LMNA* mutations [15]. Since then, we have identified subsequent 28 *LMNA* mutation carriers in the National Institute of Cardiology, Warsaw.

In this study, we sought to assess the clinical characteristics including serum biomarkers, penetrance of abnormal clinical findings, and prognostic risk factors in all identified *LMNA* mutation carriers.

#### **2. Materials and Methods**

All carriers signed a written informed consent form for the genotyping and consented to the publishing of all data generated. This study was funded by external grant 0010/P05B/98/14 from the Polish Committee for Scientific Research, statutory grants from the National Institute of Cardiology (Warsaw, Poland) no 2.57/VII/03, 2.18/II/08, 2.10/II/10, and 2.56/II/14; external grant from National Science Centre Poland 2011/01/B/NZ4/03455 RP; and the recent NCBiR ERA-CVD DETECTIN-HF/2/2017 IB.4/II/17 grant. The study received the approval of the Bioethics Committee of the National Institute of Cardiology.

Data from all persons (probands and relatives) with *LMNA* mutations and cardiac involvement in the care of the National Institute of Cardiology, Warsaw, were retrospectively collected. All mutations were identified between 2000 and 2018 and were considered to be pathogenic/likely pathogenic according to The American College of Medical Genetics and Genomics (ACMG) criteria [16]. On a prospective basis, genetic testing was offered to all probands and all agreed to participate in the study. Cascade screening was offered to all probands' families. Baseline clinical information from the first documented visit to the Institute and follow-up data were recorded. In particular, data were obtained for all major cardiovascular events. The probands as well as their informed and consenting relatives underwent a clinical examination, 12-lead electrocardiography, two-dimensional Doppler echocardiography, 24-h Holter ECG monitoring, and blood sampling for genetic testing. In all probands, coronary angiography or, more recently, coronary computed tomography angiography was performed. In addition, whenever available, we quantified the serum biomarkers—high sensitivity troponin T (hsTnT) and N-terminal prohormone brain natriuretic peptide (NT-proBNP)—at baseline and during ambulatory visits in patients without worsening of HF for 3 months.

In patients with no history of sudden cardiac arrest (SCA) or sustained ventricular tachycardia (sVT), we evaluated the prognostic value of circulating cardiac biomarker concentrations, assessed during initial visit or in the time window ± 6 months with regard to occurrence of malignant ventricular arrhythmia (MVA) during the follow-up, and compared it with other established risk factors. We also sought to examine the influence of such factors as proband status, sex, and type of mutation on life-time prognosis with regard to occurrence of end-stage HF and MVA.
