Combination of Arrhythmogenic Right Ventricular Dysplasia with Left Ventricular Non-Compaction as a Special Form of Cardiomyopathy: Clinic, Diagnostics, Genetic, Natural Course

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Abstract

Background. A few cases of combination of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) with left ventricular noncompaction (LVNC) have been described. Aims — to study the genetics, diagnostical features and clinical course of the combination of ARVC with LVNC. Methods. 58 patients with ARVC diagnosis (26 men; mean age 39.1 ± 14.2 years; mean follow-up period — 21.5 [6; 60] months) and 125 patients with LVNC (74 men; mean age 46.4 ± 15.1 years; mean follow-up period — 14 [3; 40] months). All patients underwent electrocardiogram (ECG), echocardiography, 24-h ECG monitoring. Heart MRI was performed in 53 (91.4%) patients with ARVC and 60 (48%) with LVNC, heart CT — in 18 (31%) patients with ARVC and 89 (71.2%) with LVNC. For all patients with combination of ARVC and LVNC DNA-diagnostic was performed using both ARVC (PKP2, DSG2, DSP, DSC2, JUP, TMEM43, TGFB3, PLN, LMNA, DES, CTTNA3, EMD, SCN5A, LDB3, CRYAB, FLNC) and LVNC (MYH7, MYBPC3, TAZ, TPM1, LDB3, MYL2, MYL3, ACTC1, TNNT2, TNI3) gene panels. Results. Combination of ARVC and LVNC was found in 9 patients (15.5% of patients form ARVC cohort and 7.2% from LVNC cohort). These patients were distinguished from patients with isolated ARVC or LVNC by aggressive ventricular arrhythmias (frequent premature ventricular beats, sustained ventricular tachycardia, significantly worse antiarrhythmic therapy effect, appropriate shocks of implanted cardioverter-defibrillators (ICD) in all patients with ICD). Patients with combination of ARVC + LVNC were also distinguished from patients with isolated LVNC by the dilatation of RV, low QRS voltage on ECG, presence of AV block, absence of signs of LV hypertrophy on ECG. LV dilatation with reduction of its ejection fraction distinguished patients with mixed cardiomyopathy from patients with isolated ARVC. Potentially pathogenic variants (IV–V classes of pathogenicity) and variants of unclear clinical significance (III class of pathogenicity) were found in both desmosomal and non-desmosomal genes in 78% of patients, including 3 (33%) — in DSP gene. Conclusions. The combination of ARVC and LVNC can be caused by mutations in both desmosomal and non-desmosomal genes and has typical features: aggressive, resistant ventricular rhythm abnormalities leading to appropriate ICD shocks and a high risk of sudden cardiac death.

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About the authors

Yu. A. Lutokhina

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Author for correspondence.
Email: lebedeva12@gmail.com
ORCID iD: 0000-0002-7154-6794
SPIN-code: 7061-5028

MD, PhD

Russian Federation, Moscow

O. V. Blagova

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: blagovao@mail.ru
ORCID iD: 0000-0002-5253-793X
SPIN-code: 7672-5142

MD, PhD

Russian Federation, Moscow

A. G. Shestak

B.V.Petrovsky Russian Research Center of Surgery

Email: anna.shestak87@gmail.com
ORCID iD: 0000-0002-4596-8950
SPIN-code: 2301-9841
Russian Federation, Moscow

M. Е. Polyak

B.V.Petrovsky Russian Research Center of Surgery

Email: AmetaNe@yandex.ru
ORCID iD: 0000-0003-4923-1945
SPIN-code: 8278-4758
Russian Federation, Moscow

A. A. Bukaeva

B.V.Petrovsky Russian Research Center of Surgery

Email: 16_anna_02@mail.ru
ORCID iD: 0000-0002-5932-1744
SPIN-code: 9225-7084
Russian Federation, Moscow

E. V. Zaklyazminskaya

B.V.Petrovsky Russian Research Center of Surgery;
Pirogov Russian National Research Medical University

Email: helenezak@gmail.com
ORCID iD: 0000-0002-6244-9546
SPIN-code: 9080-7523

MD, PhD, Professor

Russian Federation, Moscow

N. V. Varionchik

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: vanadya@gmail.com
ORCID iD: 0000-0002-8868-0623
SPIN-code: 3114-5637
Russian Federation, Moscow

V. P. Sedov

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: vps52@mail.ru
ORCID iD: 0000-0003-2326-9347
SPIN-code: 8713-6849

MD, PhD, Professor

Russian Federation, Moscow

E. A. Kogan

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: koganevg@gmail.com
ORCID iD: 0000-0002-1107-3753
SPIN-code: 2709-2449

MD, PhD, Professor

Russian Federation, Moscow

S. А. Alexandrova

A.N. Bakoulev Center for Cardiovascular Surgery

Email: svaleksandrova@yandex.ru
ORCID iD: 0000-0002-7795-9709
SPIN-code: 3480-0720

MD, PhD

Russian Federation, Moscow

A. V. Nedostup

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: avnedostup@mail.ru
ORCID iD: 0000-0002-5426-3151
SPIN-code: 9175-5816

MD, PhD, Professor 

Russian Federation, Moscow

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Supplementary files

Supplementary Files
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1. Рис. 1. ЭКГ пациентов с сочетанием аритмогенной дисплазии правого желудочка и некомпактного миокарда левого желудочка.

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2. Рис. 2. МРТ сердца пациентки с сочетанием аритмогенной дисплазии правого желудочка и некомпактного миокарда левого желудочка и мутацией c.1141-2A>G в гене DSP (пробанд № 4).

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3. Рис. 3. ЭхоКГ пациента с сочетанием аритмогенной дисплазии правого желудочка и некомпактного миокарда левого желудочка (пробанд № 2).

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4. Рис. 4. Результаты секвенирования пробанда № 6 с сочетанием аритмогенной дисплазии правого желудочка и некомпактного миокарда левого желудочка и выявленной мутацией c.728G>A (p.R243H) в гене MYH7.

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5. Рис. 5. Препараты миокарда умершего пациента с сочетанием аритмогенной дисплазии правого желудочка и некомпактного миокарда левого желудочка (пробанд № 9).

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