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Atrial fibrillation (AFib) is characterized by a complex genetic component. We aimed to investigate the association between variations in genes related to cardiac ion handling and AFib in a cohort of Romanian patients with hypertrophic cardiomyopathy (HCM). Forty-five unrelated probands with HCM were genotyped by targeted next-generation sequencing (NGS) for 24 genes associated with cardiac ion homeostasis. Subsequently, the study cohort was divided into two groups based on the presence (AFib+) or absence (AFiB−) of AFib detected during ECG monitoring. We identified two polymorphisms (rs1805127 located in KCNE1 and rs55742440 located in SCN1B) linked to AFib susceptibility. In AFib+, rs1805127 was associated with increased indexed left atrial (LA) maximal volume (LAVmax) (58.42 ± 21 mL/m2 vs. 32.54 ± 6.47 mL/m2, p < 0.001) and impaired LA strain reservoir (LASr) (13.3 ± 7.5% vs. 24.4 ± 6.8%, p < 0.05) compared to those without respective variants. The rs55742440 allele was less frequent in patients with AFib+ (12 out of 25, 48%) compared to those without arrhythmia (15 out of 20, 75%, p = 0.05). Also, AFib+ rs55742440 carriers had significantly lower LAVmax compared to those who were genotype negative. Among patients with HCM and AFib+, the rs1805127 variant was accompanied by pronounced LA remodeling, whereas rs55742440's presence was related to a milder LA enlargement. [ABSTRACT FROM AUTHOR]

• Arrhythmia stratification risk is essential in hypertrophic cardiomyopathy (HCM). • Non-sustained ventricular tachycardia correlates to mechanical dispersion (MD). • Left and right ventricular MD improve arrhythmia risk stratification in HCM. Ventricular arrhythmias are the most frequent cause of sudden cardiac death in individuals with hypertrophic cardiomyopathy (HCM). In the present study we investigated if combined left ventricular (LV) and right ventricular (RV) mechanical dispersion (MD) are correlated with ventricular arrhythmias. We aimed also to analyze if MD enhances the arrhythmic risk stratification in HCM. The cohort included 47 subjects with HCM and 36 healthy individuals. All the studied population underwent clinical, 24-h electrocardiographic (ECG) monitoring for detection and description of non-sustained ventricular tachycardia (NSVT) in terms of number of events, maximal rate and length and comprehensive transthoracic echocardiography, including strain rate imaging. MD was calculated as standard deviation of time from the peak of R wave on ECG to maximum LV or RV shortening in 17 LV and 3 RV segments. HCM subjects with NSVT on ECG monitoring had increased LVMD (81 ± 18 ms vs 42 ± 8 ms) and RVMD (52 ± 26 vs 25 ± 23 ms) compared with the HCM group without NSVT or compared with the healthy controls. On receiver operating characteristic curves the cut-off values associated with optimal specificity and sensitivity were 62 ms for LVMD and 39 ms for RVMD. LVMD (OR = 1.86, 95% CI 1–1.06, p = 0.01) and RVMD (OR = 1.04, 95% CI 1.01–1.07, p = 0.003) were the only independent variables that correlated with longer and faster NSVT and furthermore improved the risk stratification of NSVTs. In a cohort of subjects with HCM, LVMD and RVMD correlates with the presence of NSVT on ECG monitoring. Combined LVMD and RVMD may improve the risk stratification of HCM with NSVT. [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy (HCM) and arterial hypertension (HTN) are conditions with different pathophysiology, but both can result in left-ventricular hypertrophy (LVH). The role of left-atrial (LA) functional changes detected by two-dimensional speckle-tracking echocardiography (STE) in indicating LVH etiology is unknown. Methods: We aimed to characterize LA mechanics using STE in LVH patients with HCM and HTN. LA 2D volumetric and STE parameters were analyzed in 86 LVH patients (43 HCM and 43 isolated HTN subjects) and 33 age- and sex-matched controls. Results: The volumetric study showed that LA reservoir and conduit function were impaired in the HCM group compared to controls, while, in the HTN group, only LA conduit function was deteriorated. The HCM group had all three STE-derived LA functions impaired compared to controls. The HTN group, consistently with volumetric analysis, had solely LA conduit function reduced compared to controls. Ratios of LA booster-pump strain (S) and strain rate (SR) to interventricular septum (IVS) thickness were the most accurate parameters to discriminate between HCM and HTN. The subgroup harboring sarcomeric pathogenic (P)/likely pathogenic (LP) variants had reduced LA booster-pump S and SR compared with the genotype-negative subgroup. Conclusions: LA reservoir, conduit, and pump functions are decreased in HCM compared to HTN patients with similar LVH. We report the ratios between LA contraction S/SR and IVS thickness as novel parameters with high accuracy in discriminating LVH due to HCM. The presence of P/LP variants in sarcomeric or sarcomeric-associated genes could be associated with more severe LA dysfunction. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to explore the rare variants in a cohort of Romanian index cases with hypertrophic cardiomyopathy (HCM). Methods: Forty-five unrelated probands with HCM were screened by targeted next generation sequencing (NGS) of 47 core and emerging genes connected with HCM. Results: We identified 95 variants with allele frequency < 0.1% in population databases. MYBPC3 and TTN had the largest number of rare variants (17 variants each). A definite genetic etiology was found in 6 probands (13.3%), while inconclusive results due to either known or novel variants were established in 31 cases (68.9%). All disease-causing variants were detected in sarcomeric genes (MYBPC3 and MYH7 with two cases each, and one case in TNNI3 and TPM1 respectively). Multiple variants were detected in 27 subjects (60%), but no proband carried more than one causal variant. Of note, almost half of the rare variants were novel. Conclusions: Herein we reported for the first time the rare variants identified in core and putative genes associated with HCM in a cohort of Romanian unrelated adult patients. The clinical significance of most detected variants is yet to be established, additional studies based on segregation analysis being required for definite classification. [ABSTRACT FROM AUTHOR]

Background and aim: Most of detected variants in cardiogenetic panels are still classified as variants of unknown significance, requiring supplementary analyses for a definite classification. Performing further in-depth studies on such vast number of candidates is unfeasible. We sought to prioritise the novel nonsynonymous missense variants identified in titin gene (TTN) in a cohort of Romanian index cases with hypertrophic cardiomyopathy (HCM). Methods: 45 unrelated probands with HCM were screened by targeted next generation sequencing (NGS) covering all TTN exons. A stepwise strategy was used to select and prioritize the candidate variants for subsequent investigation. Results: Using rigorous bioinformatic filtering, 7 novel TTN nonsynonymous missense variants were identified and were the subject of in silico sequential analysis. 4 of the 7 variants were predicted to be possibly pathogenic by the Mendelian Clinically Applicable Pathogenicity (M-CAP) algorithm. Of these, three sequence variants (c.30392G>T, c.2518G>T, and c.49G>T) were also predicted to be destabilizing according to the second computational tool (TITINdb) and were designated as likely function-impacting. Conclusions: Herein we presented our strategy to hand-pick the novel TTN missense variants to be considered for further experimental studies. By applying various in silico tools, we restricted the list of sequence variants to be investigated to those most likely to be disease-associated, and thus reducing the need to perform expensive and time-consuming additional studies. [ABSTRACT FROM AUTHOR]