A Novel SCN5A Missense Variant Associated With Familial Non-Dilated Left Ventricular Cardiomyopathy.

IntroductionMyocardial fibrosis on cardiac magnetic resonance (CMR) has increasingly been detected in lifelong endurance athletes, particularly those who are male. In non-ischaemic cardiomyopathy, the presence of myocardial fibrosis on CMR...

Myocardial fibrosis is a common postmortem finding among young individuals with sudden cardiac death. Because there is no known single cause, we tested the hypothesis that some cases of myocardial fibrosis in the absence of identifiable causes (primary myocardial fibrosis [PMF]) are associated with genetic variants. Tissue was obtained at autopsy from 4031 consecutive individuals with sudden cardiac death in Northern Finland, among whom PMF was the only structural finding in 145 subjects with sudden cardiac death. We performed targeted next-generation sequencing using a panel of 174 genes associated with myocardial structure and ion channel function when autopsies did not identify a secondary basis for myocardial fibrosis. All variants with an effect on protein and with a minor allele frequency <0.01 were classified as pathogenic or variants of uncertain significance on the basis of American College of Medical Genetics consensus guidelines. Among the 96 specimens with DNA passing quality control (66%), postmortem genetic tests identified 24 variants of known or uncertain significance in 26 subjects (27%). Ten were pathogenic/likely pathogenic variants in 10 subjects (10%), and 14 were variants of uncertain significance in 11 genes among 16 subjects (17%). Five variants were in genes associated with arrhythmogenic right ventricular cardiomyopathy, 6 in hypertrophic cardiomyopathy-associated genes, and 11 in dilated cardiomyopathy-associated genes; 2 were not associated with these disorders. Four unique variants of uncertain significance cosegregated among multiple unrelated subjects with PMF. No pathogenic/likely pathogenic variants were detected in ion channel-encoding genes. A large proportion of subjects with PMF at autopsy had variants in genes associated with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy without autopsy findings of those diseases, suggesting that PMF can be an alternative phenotypic expression of structural disease-associated genetic variants or that risk-associated fibrosis was expressing before the primary disease. These findings have clinical implications for postmortem genetic testing and family risk profiling.

Background: The spectrum of genetic variants and their clinical significance of Hypertrophic cardiomyopathy (HCM) have been poorly studied in Asian patients. The objectives of this study were to assess the spectrum of genetic variants and genotype–phenotype relationships within a Korean HCM population. Methods: Eighty-nine consecutive unrelated HCM patients were included. All patients underwent genotypic analysis for 23 HCM-associated genes. Clinical parameters including echocardiographic and cardiac magnetic resonance (CMR) parameters were evaluated. A composite of major adverse cardiac and cerebrovascular events was assessed. Results: Genetic variants were detected in 55 of 89 subjects. Pathogenic variants or likely pathogenic variants were identified in 27 of HCM patients in MYBPC3, TNNI3, MYH7, and MYL7. Variants of uncertain significance were identified in 28 patients. There were significant differences in the presence of non-sustained ventricular tachycardia (p = 0.030) and myocardial fibrosis on CMR (p = 0.029) in the detected compared to the not-detected groups. Event-free survival was superior in the not-detected group (p = 0.006). Conclusion: Genetic variants in patients with HCM are relatively common and are associated with adverse clinical events and myocardial fibrosis on CMR. Genotypic analysis may add important information to clinical variables in the assessment of long-term risk for HCM patients.

Occurrence and Frequency of Arrhythmias in Hypertrophic Cardiomyopathy in Relation to Delayed Enhancement on Cardiovascular Magnetic Resonance

Role of myocardial inflammation and fibrosis in the development of ventricular arrythmias in patients with inflammatory cardiomyopathy (results of 1-year follow-up)

Chronic Chagas disease can progress to myocardial involvement with intense fibrosis, which may predispose patients to sudden cardiac death through ventricular arrhythmia. The associations of myocardial fibrosis detected by cardiac magnetic resonance (CMR) parameters with non-sustained ventricular tachycardia (NSVT) were evaluated. This cross-sectional study included patients in early stages of Chagas disease (n = 47) and a control group (n = 15). Patients underwent cardiac evaluation, including CMR examination. Myocardial fibrosis assessment by CMR with measurement of late gadolinium enhancement (LGE), native T1, and extracellular volume (ECV) was performed. There was an increase in myocardial fibrosis CMR parameters and ventricular arrhythmias among different stages of Chagas disease, combined with a decrease in the left ventricular ejection fraction (LVEF) by CMR and also in the right ventricular systolic function by S' wave on tissue Doppler. Fibrosis mass and ECV were associated with the Rassi score, ventricular extrasystole, and E/e' ratio in a logistic regression model adjusted for age and gender. The ECV maintained an association with the presence of NSVT, even after adjustments for fibrosis mass and LVEF assessed by CMR. The receiver-operating characteristic area under the curve for global ECV (0.85; 95% CI: 0.71-0.99) and NSVT was greater than that for fibrosis mass (0.75; 95% CI: 0.54-0.96), although this difference was not statistically significant. Extracellular volume could be an early marker of increased risk of ventricular arrhythmia in Chagas disease, presenting an independent association with NSVT in the initial stages of chronic Chagas cardiomyopathy, even after adjustment for fibrosis mass and LVEF.

A Multimodality Approach to Assessing Factor I Genetic Variants in Atypical Hemolytic Uremic Syndrome

An asymptomatic athletic 42-year-old man has an abnormal 12-lead ECG obtained during his initial employment examination at a new job (Figure 1). He had no family history of hypertrophic cardiomyopathy (HCM) or unexplained sudden deaths. Echocardiogram demonstrated a 13-mm ventricular septal thickness without systolic anterior motion of the mitral valve. The patient exercised on a standard Bruce protocol stress (exercise) echocardiogram for 12 minutes, without symptoms or arrhythmias, and with appropriate blood pressure augmentation. In the immediate recovery period, systolic anterior motion was absent and outflow tract velocities were normal. A 24-hour ambulatory (Holter) ECG demonstrated normal sinus rhythm without ventricular ectopy. This clinical evaluation left a number of unanswered questions for the patient regarding the diagnosis of HCM, prognosis, and whether a genetic heart disease was present in his family. Figure 1. Abnormal 12-lead ECG in a 42-year-old man demonstrating normal sinus rhythm with left anterior fascicular block, RSR′ in leads V1 and V2, and left ventricular hypertrophy. Since the early 1970s, cardiovascular imaging has played a critical role in describing the structure and function of the heart in HCM.1–5 Indeed, HCM is a disorder uniquely suited to noninvasive imaging, given HCM’s characteristic heterogeneous morphology and hemodynamics, including dynamic left ventricular (LV) outflow obstruction.2,3 For much of 40 years, echocardiography has been the dominant imaging technique, first with rudimentary M-mode and then ultimately 2-dimentional imaging and Doppler,2 now widely available and accessible. The past decade has witnessed the introduction of cardiac magnetic resonance (CMR) into clinical HCM practice.1,3–10 This contemporary technique provides images with high spatial and temporal resolution and sharp contrast between the myocardial border and blood pool, allowing precise measurements of LV wall thickness and complete tomographic reconstruction of the entire cardiac chamber (without …

Funding Acknowledgements Type of funding sources: None. Background Current guidelines suggest the presence of non-sustained ventricular tachycardia (NSVT) as a risk factor of sudden cardiac death in patients with hypertrophic cardiomyopathy (HCM). However, high burden of premature ventricular contraction (PVC) may reflect myocardial fibrosis although the absence of NSVT. Purpose We investigated the association between PVC burden and myocardial extracellular space expansion in HCM patients without NSVT. Methods Of the 212 patients prospectively enrolled to the HCM registry of genetics, 84 patients were evaluated with both cardiac magnetic resonance and 24hr holter. Among them, 71 patients (58 males, mean age: 71 ± 13 years) have not been diagnosed with NSVT. Results Patients with NSVT (n = 13) showed more impaired LA functional indices and higher myocardial fibrosis burden compared with patients without NSVT (n = 71). Among patients who have not been diagnosed with NSVT, patients with late gadolinium enhancement (LGE, n = 46) had a higher total beats (109 ± 332 vs. 7 ± 13 beats per a day, p = 0.003) and burden (0.114 ± 0.225 vs. 0.008 ± 0.014 %, p = 0.003) of PVC during 24-hour compared with patients without LGE (n = 25). %LGE was correlated with total beats of PVC (r = 0.358, p = 0.002) and PVC burden (r = 0.377, p = 0.001). ECV also correlated with total beats of PVC (r = 0.387, p = 0.001) and PVC burden (r = 0.401, p = 0.001). The optimal cutoff value for PVC number was 45 (37.0% of sensitivity and 100% of specificity) with 0.733 of the area under the ROC curve (p &amp;lt; 0.001). Pathogenic or likely pathogenic sarcomere mutation was higher in NSVT group than no NSVT group (p &amp;lt; 0.05), and had a higher tendency in higher PVC burden group (0.05 &amp;lt; p &amp;lt; 0.1) than lower PVC burden group. Conclusions Total beats and burden of PVC are significantly related to increase in myocardial fibrosis in HCM patients without NSVT. Abstract Figure. Mechanism of ventricular arrhythmia

Background In hypertrophic cardiomyopathy (HCM) patients, quantification of left ventricular (LV) mass carries important prognostic implications. Two-dimensional echocardiography (2DE) has limited accuracy for LV mass calculation, due to plane position errors, geometric assumptions and asymmetric distribution of LV hypertrophy in HCM. Purpose We aimed to explore: (1) the accuracy of three-dimensional echocardiography (3DE) vs 2DE to quantify LV mass in HCM compared to cardiac magnetic resonance (CMR); (2) the relationship of 3DE LV mass with non-sustained ventricular tachycardia (NSVT) and late gadolinium enhancement (LGE)≥15% by CMR. Methods In consecutive HCM patients referred to our Cardiomyopathy Clinic between 2020 and 2023, 2DE and 3DE were used to assess LV mass. LV systolic function was assessed by 3DE ejection fraction (LVEF) and peak global 2D longitudinal strain (2DGLS). Clinical, 24h ECG Holter and CMR data were collected. Results A total of 180 HCM patients (pts, age 58±18 years, 55% men) were enrolled. Apical HCM was present in 56 pts (31%) and obstructive HCM in 69 pts (38%). Maximal LV wall thickness (MWT) by 2DE was 19.5±4.6 mm. LV mass was 150±51 g/m2 by 2DE, 80±25 g/m2 by 3DE, and 79±26 g/m2 by CMR. Fifty-seven pts (32%) had evidence of NSVT at ECG Holter monitoring. LGE≥15% was present in 32% pts. Aim #1: In a subset of 63 pts who underwent CMR, 3DE LV mass was strongly correlated with CMR LV mass (r=0.85, p&amp;lt;0.001), while 2DE LV mass was not (p=0.38). LV mass by 3DE showed a better agreement with LV mass (bias 3.8 g/m2, LOA -25 to 32 g/m2) by CMR than 2DE (bias 68 g/m2, LOA -35 to 172 g/m2). Aim #2: In the entire cohort, 3DE LV mass had a stronger association compared to 2DE LV mass with the presence of LGE≥15% (AUC 0.68 for 3DE versus 0.56 for 2DE, p=0.08) and NSVT (AUC 0.65 for 3DE versus 0.54 for 2DE, p=0.06). By multivariable analysis, LV mass by 3DE was an independent predictor of LGE≥15% (HR 1.03) and of NSVT (HR 1.03), outperforming 2DGLS and MWT in the latter regression. Using the Youden Index from ROC curve, the optimal cutoff for predicting LGE≥15% using 3DE mass was 87 g/m² (sensitivity 47%, specificity 91%). The addition of 3DE LV mass to a model including 2DE MWT, 2DE LV mass and 2DGLS had a significant incremental value for the prediction of LGE≥15% (Figure 1). Conclusions In HCM patients, LV mass by 3DE was strongly correlated to LV mass by CMR and was an independent predictor of significant LV myocardial fibrosis and ventricular arrhythmias. In centers with low access to CMR, implementation of 3DE to measure LV mass in HCM patients may improve arrhythmic risk stratification compared to 2DE.

Introduction Non-ischaemic myocardial fibrosis can be detected by cardiovascular magnetic resonance (CMR) imaging in a significant proportion of lifelong endurance athletes. 1 Similar focal fibrosis is known to be arrhythmogenic in non-ischaemic cardiomyopathy but its significance in asymptomatic athletes is unknown. Purpose To determine whether focal myocardial fibrosis in asymptomatic veteran endurance athletes is associated with incident ventricular arrhythmia by comparing incidence of ventricular arrhythmia detected on implantable loop recorder (ILR) in those with and without fibrosis. Methods 106 healthy amateur competitive cyclists and triathletes aged over 50 years old were prospectively recruited. They underwent resting 12 lead ECG, comprehensive stress-perfusion CMR to detect myocardial fibrosis and maximal effort exercise testing. Each athlete had an ILR implanted to detect the presence of arrhythmia. Athletes were followed up for 2 years for the presence of ventricular arrhythmia (ventricular tachycardia (VT)/ non-sustained VT (NSVT)). VT was defined as at least 30 consecutive beats of broad complex tachycardia (BCT) whilst NSVT was defined as at least 3 consecutive beats of BCT. Participants were contacted after every arrhythmic event to establish any associated symptoms. Statistical analysis included logistic regression to investigate which clinical parameters were associated with fibrosis and univariable Cox regression to identify variables associated with VT/NSVT. Log rank testing was also used to compare incidence of ventricular arrhythmia in those with and without myocardial fibrosis. Results 47.2% (50/106) athletes had focal myocardial fibrosis, all of which was a non-ischaemic distribution and predominantly affected the basal inferolateral myocardial segment. Although athletes with myocardial fibrosis were slightly older than those without fibrosis (61.2 ± 5.7 vs 57.3 ± 4.9, p&amp;lt;0.001), there was no detectable difference in any other demographic characteristic, CMR parameter or training variable including both training history and maximal effort exercise testing (Figure 1). 18 participants had at least one ventricular arrhythmic event (2 VT, 16 NSVT) during median follow up 542 days (interquartile range 485-576 days). No participants were aware of any episodes of VT/NSVT and all were detected asymptomatically on ILR. By Cox regression analysis, the presence of myocardial fibrosis was associated with an increased risk of VT/NSVT (hazard ratio (HR) 3.19, 95% confidence interval (CI) 1.14-8.94, P=0.028). This remained significant even after correcting for age (HR 3.20, CI 1.05 – 9.78, P=0.042). Conclusion In asymptomatic lifelong endurance athletes, focal myocardial fibrosis was highly prevalent and associated with the incidence of ventricular arrhythmia. However, despite nearly 100 patient years of follow up in athletes with myocardial fibrosis, there was not a single episode of symptomatic ventricular arrhythmia. Figure 1 Figure 2

Genomics in hypertrophic cardiomyopathy (HCM) are now 25 years old.1,2 The article of Li et al3 in this issue of the journal provides an opportunity to revisit and place into perspective several important principles related to the clinical application of genetic testing to the HCM patient population, thereby assessing progress in understanding this heterogeneous condition, the most common of the inherited heart diseases.4,5 Article see p 416 ### Genetic Testing Perhaps, most important is recognizing the current role achieved by genetic testing in contemporary HCM patient management and family screening. This technology has been available commercially in the United States since 2003, now with 4 fee-for-service companies that have brought advances in genomics for HCM and other genetic diseases out of the research laboratory, and widely available to clinicians.1,2 As a result, the landscape of HCM has changed in several ways. Notable in this regard is the emergence of a new patient subgroup known as gene positive-phenotype negative (ie, genetically affected family members without left ventricular hypertrophy).6 Recognition of relatives who are gene carriers and, therefore, at risk for developing clinical disease demonstrates the power of HCM mutational analysis not otherwise possible. However, the precise likelihood of incurring clinical disease, or the age at which phenotype conversion could occur, remain uncertain with the possibility that some patients will achieve advanced age without developing left ventricular hypertrophy. The most clinically impactful outcome of predictive family screening is the possibility of excluding those relatives without the family mutation from the risk of developing HCM and further clinical consideration.2 However, for such an initiative to be actionable, a pathogenic (disease-causing) mutation must be identified in a family member with clinically expressed HCM (ie, with left ventricular hypertrophy).2 Figure 1. Top , Distribution of genetic test …

Rhetorical Strategies Used in the Reporting of Implantable Defibrillator Primary Prevention Trials

Background and purposeOver the last decade, the implementation of multigene panels for hereditary tumor syndrome has increased at our institution (Inselspital, University Hospital Berne, Switzerland). The aim of this study was to determine the prevalence of variants of unknown significance (VUS) in patients with suspected Lynch syndrome and suspected hereditary breast and ovarian cancer syndrome, the latter in connection with the trend toward ordering larger gene panels.ResultsRetrospectively collected data from 1057 patients at our institution showed at least one VUS in 126 different cases (11.9%). In patients undergoing genetic testing for BRCA1/2, the prevalence of VUS was 6%. When < 10 additional genes were tested in addition to BRCA1/2, the prevalence increased to 13.8%, and 31.8% for > 10 additional genes, respectively. The gene most frequently affected with a VUS was ATM. 6% of our patients who were tested for Lynch syndrome had a VUS result in either MLH1, MSH2 or MSH6.ConclusionsOur data demonstrate that panel testing statistically significantly increases VUS rates due to variants in non-BRCA genes. Good genetic counseling before and after obtaining results is therefore particularly important when conducting multigene panels to minimize patient uncertainty due to VUS results.

31P Survival outcomes in BRCA pathogenetic mutated, variant of unknown significance, and wild type ovarian cancer patients treated with PARP inhibitors