Myocardial ultrastructure can augment genetic testing for sporadic dilated cardiomyopathy with initial heart failure.

Autor: Saito T; Smidt Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.; Department of Cardiovascular Medicine, Nippon Medical School Graduate School, Tokyo, Japan., Sato NS; Department of Neurology, Japanese Red Cross Medical Center, Tokyo, Japan., Mozawa K; Department of Cardiovascular Medicine, Nippon Medical School Graduate School, Tokyo, Japan., Adachi A; Division of Morphological and Biomolecular Research, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan., Sasaki Y; Division of Morphological and Biomolecular Research, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan., Nakamura K; Smidt Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA., Oka E; Department of Cardiovascular Medicine, Nippon Medical School Graduate School, Tokyo, Japan., Otsuka T; Department of Hygiene and Public Health, Nippon Medical School Graduate School, Tokyo, Japan., Kodani E; Department of Internal Medicine and Cardiology, Nippon Medical School Tama Nagayama Hospital, Tokyo, Japan., Asai K; Intensive Care Unit, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan., Mizuno K; Department of Cardiovascular Medicine, Nippon Medical School Graduate School, Tokyo, Japan., Shimizu W; Department of Cardiovascular Medicine, Nippon Medical School Graduate School, Tokyo, Japan., Gottlieb RA; Smidt Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.
Jazyk: angličtina
Zdroj: ESC heart failure [ESC Heart Fail] 2021 Dec; Vol. 8 (6), pp. 5178-5191. Date of Electronic Publication: 2021 Sep 06.
DOI: 10.1002/ehf2.13596
Abstrakt: Aims: The aim of the present study was to consider whether the ultrastructural features of cardiomyocytes in dilated cardiomyopathy can be used to guide genetic testing.
Methods and Results: Endomyocardial biopsy and whole-exome sequencing were performed in 32 consecutive sporadic dilated cardiomyopathy patients [51.0 (40.0-64.0) years, 75% men] in initial phases of decompensated heart failure. The predicted pathogenicity of ultrarare (minor allele frequency ≤0.0005), non-synonymous variants was determined using the American College of Medical Genetics guidelines. Focusing on 75 cardiomyopathy-susceptibility and 41 arrhythmia-susceptibility genes, we identified 404 gene variants, of which 15 were considered pathogenic or likely pathogenic in 14 patients (44% of 32). There were five sarcomeric gene variants (29% of 17 variants) found in five patients (16% of 32), involving a variant of MYBPC3 and four variants of TTN. A patient with an MYBPC3 variant showed disorganized sarcomeres, three patients with TTN variants located in the region encoding the A-band domain showed sparse sarcomeres, and a patient with a TTN variant in encoding the I-band domain showed disrupted sarcomeres. The distribution of diffuse myofilament lysis depended on the causal genes; three patients with the same TMEM43 variant had diffuse myofilament lysis near nuclei (P = 0.011), while two patients with different DSP variants had lysis in the peripheral areas of cardiomyocytes (P = 0.033).
Conclusions: Derangement patterns of myofilament and subcellular distribution of myofilament lysis might implicate causal genes. Large-scale studies are required to confirm whether these ultrastructural findings are related to the causative genes.
(© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)
Databáze: MEDLINE
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