Genetic landscape in Russian patients with familial left ventricular noncompaction.

Background: Left ventricular noncompaction (LVNC) cardiomyopathy is a disorder that can be complicated by heart failure, arrhythmias, thromboembolism, and sudden cardiac death. The aim of this study is to clarify the genetic landscape of LVNC in a large cohort of well-phenotyped Russian patients with LVNC, including 48 families (n=214). Methods: All index patients underwent clinical examination and genetic analysis, as well as family members who agreed to participate in the clinical study and/or in the genetic testing. The genetic testing included next generation sequencing and genetic classification according to ACMG guidelines. Results: A total of 55 alleles of 54 pathogenic and likely pathogenic variants in 24 genes were identified, with the largest number in the MYH7 and TTN genes. A significant proportion of variants -8 of 54 (14.8%) -have not been described earlier in other populations and may be specific to LVNC patients in Russia. In LVNC patients, the presence of each subsequent variant is associated with increased odds of having more severe LVNC subtypes than isolated LVNC with preserved ejection fraction. The corresponding odds ratio is 2.77 (1.37 -7.37; p <0.001) per variant after adjustment for sex, age, and family. Conclusion: Overall, the genetic analysis of LVNC patients, accompanied by cardiomyopathy-related family history analysis, resulted in a high diagnostic yield of 89.6%. These results suggest that genetic screening should be applied to the diagnosis and prognosis of LVNC patients.

The predictive role of early recurrences of atrial arrhythmias after pulmonary vein cryoballoon ablation. Is blanking period an outdated concept? Insights from 12-month continuous cardiac monitoring.

BACKGROUND: Early recurrences of atrial arrhythmias (ERAA) after atrial fibrillation (AF) catheter ablation do not predict procedural failure. A well-demarcated homogeneous lesion delivered by cryoballoon is less arrhythmogenic, and the recommended three-months blanking period may not refer to cryoballoon ablation (CBA). OBJECTIVE: We aimed to evaluate the predictive role of ERAA after second-generation CBA using an implantable loop recorder. METHODS: This prospective observational study enrolled 100 patients (58 males, median age 58) with paroxysmal/persistent AF undergoing pulmonary vein (PV) CBA using second-generation cryoballoon with simultaneous ECG loop recorder implantation. The duration of follow-up was 12 months, with scheduled visits at 3, 6 and 12 months. RESULTS: 99 patients from 100 completed the 12-month follow-up period. ERAA occurred in 31.3 % of patients. 83.9 % of patients with ERAA also developed late recurrences. The 12-month freedom from AF in patients with ERAA was significantly lower than in those without ERAA (p < 0.0001). Non-paroxysmal AF and longer arrhythmia history were associated with increased risk of both early (HR 3.27; 95 % CI 1.32-8.08; p = 0.010 and HR 1.0147; 95 % CI 1.008-1.086; p = 0.015, respectively) and late recurrences (HR 3.89; 95 % CI 1.67-9.04; p = 0.002 and HR 1.0142; 95 % CI 1.007-1.078; p = 0.019, respectively) of AF. ERAA were another predictor for procedural failure (HR 15.2; 95 % CI (6.42-35.99; p = 0.019). CONCLUSIONS: ERAA occurred in the third of the patients after PV second-generation CBA and are strongly associated with procedural failure. Longer duration of AF history and persistent AF are independent predictors of AF's early and late recurrence.

Noncompaction cardiomyopathy is caused by a novel in-frame desmin (DES) deletion mutation within the 1A coiled-coil rod segment leading to a severe filament assembly defect.

Mutations in DES, encoding desmin protein, are associated with different kinds of skeletal and/or cardiac myopathies. However, it is unknown, whether DES mutations are associated with left ventricular hypertrabeculation (LVHT). Here, we performed a clinical examination and subsequent genetic analysis in a family, with two individuals presenting LVHT with conduction disease and skeletal myopathy. The genetic analysis revealed a novel small in-frame deletion within the DES gene, p.Q113_L115del, affecting the α-helical rod domain. Immunohistochemistry analysis of explanted myocardial tissue from the index patient revealed an abnormal cytoplasmic accumulation of desmin and a degraded sarcomeric structure. Cell transfection experiments with wild-type and mutant desmin verified the cytoplasmic aggregation and accumulation of mutant desmin. Cotransfection experiments were performed to model the heterozygous state of the patients and revealed a dominant negative effect of the mutant desmin on filament assembly. DES:p.Q113_L115del is classified as a pathogenic mutation associated with dilated cardiomyopathy with prominent LVHT.

Atrial appendage transcriptional profile in patients with atrial fibrillation with structural heart diseases.

During the last few years DNA microarray studies of gene expression changes in human atrial tissues from patients with and without atrial fibrillation (AF) have been performed. For this purpose, tissue samples are usually collected from AF patients undergoing open heart surgery. These investigations have limitations associated with the unavoidable heterogeneity of compared groups which is due to the presence of various structural changes accompanying different sets of underlying heart diseases in both groups. It is thus reasonable to compare the atrial tissue samples from AF patients with those from individuals without signs of cardiovascular disease. To address this, we selected the atrial tissue samples from 12 AF patients (who underwent open heart surgery) and compared them with control atrial tissue samples from 10 individuals with no signs of cardiovascular diseases (those who died due to street accident). cDNA microarray method and reverse transcription-polymerase chain reaction (RT-PCR) analysis were used to identify genes which can discriminate between control and pathologically altered atrial tissues. Thirty-nine genes were found to be differentially expressed in pathologically altered tissues samples independently of the type of the underlying structural heart disease. These genes are involved in signal transduction, gene transcription regulation, cell proliferation, and apoptosis. The greatest alterations were observed for NOR1, DEC1, MSF, and Bcl2A1 genes (5 to 28-fold decrease, P < 0.05). Additional studies are needed to determine the specific role of each selected gene in pathophysiological changes leading to AF.