Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Clinical Presentation of Left Ventricular Noncompaction Cardiomyopathy and Bradycardia in Three Families Carrying HCN4 Pathogenic Variants

Version 1 : Received: 17 February 2022 / Approved: 21 February 2022 / Online: 21 February 2022 (03:16:22 CET)

A peer-reviewed article of this Preprint also exists.

Paszkowska, A.; Piekutowska-Abramczuk, D.; Ciara, E.; Mirecka-Rola, A.; Brzezinska, M.; Wicher, D.; Kostrzewa, G.; Sarnecki, J.; Ziółkowska, L. Clinical Presentation of Left Ventricular Noncompaction Cardiomyopathy and Bradycardia in Three Families Carrying HCN4 Pathogenic Variants. Genes 2022, 13, 477. Paszkowska, A.; Piekutowska-Abramczuk, D.; Ciara, E.; Mirecka-Rola, A.; Brzezinska, M.; Wicher, D.; Kostrzewa, G.; Sarnecki, J.; Ziółkowska, L. Clinical Presentation of Left Ventricular Noncompaction Cardiomyopathy and Bradycardia in Three Families Carrying HCN4 Pathogenic Variants. Genes 2022, 13, 477.

Journal reference: Genes 2022, 13, 477
DOI: 10.3390/genes13030477

Abstract

Background: Left ventricular noncompaction (LVNC) is a genetically and phenotypically heterogeneous cardiomyopathy characterized by a two-layered myocardium consisting of compacted and noncompacted segments, prominent ventricular trabeculations, and intertrabecular recesses. Patients with LVNC are at increased risk to develop heart failure, atrial and ventricular arrhythmias, and/or systemic thromboembolic events. Familial forms of primary sinus bradycardia have been attributed to mutations in HCN4. There are very few reports about the association between HCN4 mutations and LVNC. The aim of our study was to characterize the clinical phenotype of families with LVNC and sinus bradycardia caused by mutation of the HCN4 gene. Methods: From March 2008 to July 2021 we prospectively enrolled 6 patients from 4 families with diagnosed isolated LVNC based on the clinical presentation, family history and echocardiographic and cardiovascular magnetic resonance (CMR) evidence of LVNC. Next generation sequencing (NGS) analysis was undertaken for evaluation of the molecular basis of the disease in each family. Results: A total of 6 children (median age 11 years) were enrolled and followed prospectively for the median of 12 years. All 6 patients were diagnosed with LVNC by echocardiography and 5 participants additionally by CMR. The presence of LGE was found in 3 children. Sinus bradycardia and dilation of the ascending aorta occurred in 5 studied patients. In 4 patients from 3 families the molecular studies demonstrated the presence of rare heterozygous HCN4 mutations. Conclusion: (1) The HCN4 mutation influences the presence of a complex LVNC phenotype, sinus bradycardia and dilation of the ascending aorta. (2) HCN4 mutation may be associated with the early presentation of clinical symptoms and the severe course of the disease. (3) It is particularly important to assess myocardial fibrosis not only within the ventricles, but also in the atria in patients with LVNC and sinus bradycardia.

Keywords

left ventricular noncompaction; cardiomyopathy; sinus bradycardia; HCN4 mutation; late gado-linium enhancement; children

Subject

MEDICINE & PHARMACOLOGY, Cardiology

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