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Variants in the KCNQ1 gene, encoding the α-subunit of the slow component of delayed rectifier K+ channel Kv7.1, cause long QT syndrome (LQTS) type 1. The location of variants may be one of the factors in determining prognosis. However, detailed genotype-phenotype relationships associated with C-terminus variants remain unelucidated. We investigated the clinical characteristics and variant-specific arrhythmic risks in patients with LQTS carrying Kv7.1 C-terminus variants. The study comprises 202 consecutive patients with LQTS (98 probands and 104 family members) who carry a rare heterozygous variant in the Kv7.1 C-terminus. Their clinical characteristics and arrhythmic events were investigated. We identified 36 unique C-terminus variants (25 missense and 11 non-missense). The p.R366W variant was identified in 8 families, and p.T587M was identified in 21 families in large numbers from northwestern Japan. As for the location of the variant, we found that the variants in highly conserved regions and nonhelical domains were associated with longer QTc intervals compared with the variants in other regions. Both p.R366W and p.T587M variants are located in the highly conserved and functionally pivotal regions close to helices A and D, which are associated with calmodulin binding and channel assembly (tetramerization), respectively. The probands carrying p.T587M and p.R366W variants had worse arrhythmia outcomes compared with those with other C-terminus variants. The haplotype analysis of p.T587M families was suggestive of a founder effect. The arrhythmic risk of C-terminus variants in Kv7.1 in LQTS is not homogeneous, and locations of variants can be a determining factor for prognosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Aims Lethal arrhythmias in hypertrophic cardiomyopathy (HCM) are widely attributed to myocardial ischaemia and fibrosis. How these factors modulate arrhythmic risk remains largely unknown, especially as invasive mapping protocols are not routinely used in these patients. By leveraging multiscale digital twin technologies, we aim to investigate ischaemic mechanisms of increased arrhythmic risk in HCM. Methods and results Computational models of human HCM cardiomyocytes, tissue, and ventricles were used to simulate outcomes of Phase 1A acute myocardial ischaemia. Cellular response predictions were validated with patch-clamp studies of human HCM cardiomyocytes (n = 12 cells, N = 5 patients). Ventricular simulations were informed by typical distributions of subendocardial/transmural ischaemia as analysed in perfusion scans (N = 28 patients). S1-S2 pacing protocols were used to quantify arrhythmic risk for scenarios in which regions of septal obstructive hypertrophy were affected by (i) ischaemia, (ii) ischaemia and impaired repolarization, and (iii) ischaemia, impaired repolarization, and diffuse fibrosis. HCM cardiomyocytes exhibited enhanced action potential and abnormal effective refractory period shortening to ischaemic insults. Analysis of ∼75 000 re-entry induction cases revealed that the abnormal HCM cellular response enabled establishment of arrhythmia at milder ischaemia than otherwise possible in healthy myocardium, due to larger refractoriness gradients that promoted conduction block. Arrhythmias were more easily sustained in transmural than subendocardial ischaemia. Mechanisms of ischaemia–fibrosis interaction were strongly electrophysiology dependent. Fibrosis enabled asymmetric re-entry patterns and break-up into sustained ventricular tachycardia. Conclusion HCM ventricles exhibited an increased risk to non-sustained and sustained re-entry, largely dominated by an impaired cellular response and deleterious interactions with the diffuse fibrotic substrate. [ABSTRACT FROM AUTHOR]

Introduction: Hypertrophic cardiomyopathy (HCM) is a leading cause of lethal arrhythmias in the young. Although the arrhythmic substrate has been hypothesised to be amenable to late Na+ block with ranolazine, the specific mechanisms are not fully understood. Therefore, this study aimed to investigate the substrate mechanisms of safety and antiarrhythmic efficacy of ranolazine in HCM. Methods: Computational models of human tissue and ventricles were used to simulate the electrophysiological behaviour of diseased HCM myocardium for variable degrees of repolarisation impairment, validated against in vitro and clinical recordings. S1-S2 pacing protocols were used to quantify arrhythmic risk in scenarios of (i) untreated HCM-remodelled myocardium and (ii) myocardium treated with 3μM, 6μM and 10μM ranolazine, for variable repolarisation heterogeneity sizes and pacing rates. ECGs were derived from biventricular simulations to identify ECG biomarkers linked to antiarrhythmic effects. Results: 10μM ranolazine given to models manifesting ventricular tachycardia (VT) at baseline led to a 40% reduction in number of VT episodes on pooled analysis of >40,000 re-entry inducibility simulations. Antiarrhythmic efficacy and safety were dependent on the degree of repolarisation impairment, with optimal benefit in models with maximum JTc interval <370 ms. Ranolazine increased risk of VT only in models with severe-extreme repolarisation impairment. Conclusion: Ranolazine efficacy and safety may be critically dependent upon the degree of repolarisation impairment in HCM. For moderate repolarisation impairment, reductions in refractoriness heterogeneity by ranolazine may prevent conduction blocks and re-entry. With severe-extreme disease substrates, reductions of the refractory period can increase re-entry sustainability. [ABSTRACT FROM AUTHOR]

Introduction: Hypertrophic cardiomyopathy (HCM) is a leading cause of lethal arrhythmias in the young. Although the arrhythmic substrate has been hypothesised to be amenable to late Na+ block with ranolazine, the specific mechanisms are not fully understood. Therefore, this study aimed to investigate the substrate mechanisms of safety and antiarrhythmic efficacy of ranolazine in HCM.Methods: Computational models of human tissue and ventricles were used to simulate the electrophysiological behaviour of diseased HCM myocardium for variable degrees of repolarisation impairment, validated against in vitro and clinical recordings. S1-S2 pacing protocols were used to quantify arrhythmic risk in scenarios of (i) untreated HCM-remodelled myocardium and (ii) myocardium treated with 3µM, 6µM and 10µM ranolazine, for variable repolarisation heterogeneity sizes and pacing rates. ECGs were derived from biventricular simulations to identify ECG biomarkers linked to antiarrhythmic effects.Results: 10µM ranolazine given to models manifesting ventricular tachycardia (VT) at baseline led to a 40% reduction in number of VT episodes on pooled analysis of >40,000 re-entry inducibility simulations. Antiarrhythmic efficacy and safety were dependent on the degree of repolarisation impairment, with optimal benefit in models with maximum JTc interval

Introduction: Mitral valve prolapse (MVP) is a common clinical condition in the general population. A subgroup of patients with MVP may experience ventricular arrhythmias and sudden cardiac death ("arrhythmic mitral valve prolapse" [AMVP]) but how to stratify arrhythmic risk is still unclear. Our meta‐analysis aims to identify predictive factors for arrhythmic risk in patients with MVP. Methods: We systematically searched Medline, Cochrane, Journals@Ovid, Scopus electronic databases for studies published up to December 28, 2022 and comparing AMVP and nonarrhythmic mitral valve prolapse (NAMVP) for what concerns history, electrocardiographic, echocardiographic and cardiac magnetic resonance features. The effect size was estimated using a random‐effect model as odds ratio (OR) and mean difference (MD). Results: A total of 10 studies enrolling 1715 patients were included. Late gadolinium enhancement (LGE) (OR: 16.67; p =.005), T‐wave inversion (TWI) (OR: 2.63; p <.0001), bileaflet MVP (OR: 1.92; p <.0001) and mitral anulus disjunction (MAD) (OR: 2.60; p <.0001) were more represented among patients with AMVP than in NAMVP. Patients with AMVP were shown to have longer anterior mitral leaflet (AML) (MD: 2.63 mm; p <.0001), posterior mitral leaflet (MD: 2.96 mm; p <.0001), thicker AML (MD: 0.49 mm; p <.0001), longer MAD length (MD: 1.24 mm; p <.0001) and higher amount of LGE (MD: 1.41%; p <.0001) than NAMVP. AMVP showed increased mechanical dispersion (MD: 8.04 ms; 95% confidence interval: 5.13–10.96; p <.0001) compared with NAMVP. Conclusions: Our meta‐analysis proved that LGE, TWI, bileaflet MVP, and MAD are predictive factors for arrhythmic risk in MVP patients. [ABSTRACT FROM AUTHOR]

Arrhythmogenic cardiomyopathy (ACM) is a heart disease characterized by a fibrotic replacement of myocardial tissue and a consequent predisposition to ventricular arrhythmic events, especially in the young. Post-mortem studies and the subsequent diffusion of cardiac MRI have shown that left ventricular involvement in arrhythmogenic cardiomyopathy is common and often develops early. Regarding the arrhythmic risk stratification, the current scores underestimate the arrhythmic risk of patients with arrhythmogenic cardiomyopathy with left involvement. Indeed, the data on arrhythmic risk stratification in this group of patients are contradictory and not exhaustive, with the consequence of not correctly identifying patients at a high arrhythmic risk who deserve protection from arrhythmic death. We propose a literature review on arrhythmic risk stratification in patients with ACM and left involvement to identify the main features associated with an increased arrhythmic risk in this group of patients. [ABSTRACT FROM AUTHOR]

Development of life-threatening ventricular arrhythmias is often associated with an increase in the dispersion of ventricular repolarization (DOR), which can be detected by electrocardiographic (ECG) methods. For several decades, there was an active search for ECG markers reflecting the magnitude of DOR and the associated arrhythmic risk. The interval from the peak to the end of the T-wave (Tpe) was found to be the most accurate measure of DOR and a reliable marker of arrhythmic risk in various cardiac disorders. In addition to Tpe interval itself, its derivatives-Tpe dispersion and Tpe/QT ratiowere proposed as arrhythmic risk markers. In this review, several aspects regarding Tpe and its derivatives are discussed: (1) physiological rationale for relationship to DOR and arrhythmic risk, (2) clinical significance for predicting ventricular arrhythmias, and (3) clinical limitations. Based on the experimental, clinical and simulation studies, the review demonstrates that Tpe, dTpe and Tpe/QT ratio are informative concerning both the global and the local DOR. They are significant predictors of arrhythmias associated with increased DOR, and the overall mortality. Besides, Tpe magnitude showed itself as a simple, non-invasive, inexpensive and quick indirect assessment of hemodynamic and volumetric ventricular parameters, the extent and severity of coronary artery stenosis, therapy response and the expected hospital stay. However, the lack of consensus in measurements led to large variations of cut-off values reported by different researchers. The inclusion of Tpe in routine ECG analysis requires further research based on the more unified measurements, including machine learning and artificial intelligence tools. [ABSTRACT FROM AUTHOR]

(1) Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease of autoimmune etiology. Increased scientific evidence suggests that immune-mediated inflammatory dis-eases are associated with autonomic nervous system (ANS) dysfunction. Studies proved that autonomic imbalance is correlated with RA evolution and may explain augmented cardiovascular pathology and mortality not attributable to classical risk factors. (2) Methods: 75 patients (25 males, 50 females) with RA were submitted to standard ECG recording and 24 h Holter monitoring. Twenty-five healthy patients were used as controls. Both time (SDNN, SDANN, SDANN Index, RRmed, rMSSD, and pNN50) and frequency domain (TP, VLF, HF, LF and LF/HF) heart rate variability (HRV) parameters were obtained. Parameters were compared to controls, and correlations with the QTc-interval and inflammatory status expressed through the C-reactive protein (CRP) were evaluated. (3) Results: In patients with a CRP > 5 mg/L, HRV parameters were lower compared to controls and to patients with a CRP ≤ 5 mg/L. All HRV parameters generated by Holter monitoring are negatively correlated with CRP levels and QTc values. The number of premature ventricular contractions (PVC) recorded is correlated with SDNN, SDANN, and LF/HF values. (4) Conclusions: Our study supports recent data suggesting that in RA there is an autonomic system dysfunction strongly connected with the inflammatory status of the patient. The autonomic dysfunction can contribute to the increased risk of cardiovascular death observed in patients with RA. [ABSTRACT FROM AUTHOR]

Background Interatrial block (IAB) is a conduction delay in Bachmann's bundle with a well-described association with structural heart disease, supraventricular arrhythmias, and cardiovascular events. Case summary We report the case of an asymptomatic 35-year-old man in whom the presence of IAB at electrocardiogram led to a comprehensive evaluation including speckle-tracking echocardiography, 24 h Holter monitoring, and genetic testing. Speckle-tracking echocardiography demonstrated a decrease in the longitudinal strain of interventricular septum, a typical feature of LMNA-related cardiomyopathy, and decreased indices of left atrial deformation. A diagnosis of cardiac laminopathy related to the frame shift variant c.1367 (p.Asn456Thrfs*24) of the LMNA gene was made. A dual-chamber implantable cardioverter defibrillator implantation was performed for the high risk of life-threatening ventricular tachyarrhythmias. Discussion This case demonstrates that IAB could be a rare presentation of a life-threatening laminopathy. Strain echocardiography is an essential tool to evaluate the deposition of fibrosis tissue in subclinical cardiomyopathies. Our report describes a novel variant of LMNA gene associated with a high risk of sudden cardiac death. [ABSTRACT FROM AUTHOR]

Background Although accumulating data indicate that IL‐6 (interleukin‐6) can promote heart rate‐corrected QT interval (QTc) prolongation via direct and indirect effects on cardiac electrophysiology, current evidence comes from basic investigations and small clinical studies only. Therefore, IL‐6 is still largely ignored in the clinical management of long‐QT syndrome and related arrhythmias. The aim of this study was to estimate the risk of QTc prolongation associated with elevated IL‐6 levels in a large population of unselected subjects. Methods and Results An observational study using the Veterans Affairs Informatics and Computing Infrastructure was performed. Participants were US veterans who had an ECG and were tested for IL‐6. Descriptive statistics and univariate and multivariate regression analyses were performed to study the relationship between IL‐6 and QTc prolongation risk. Study population comprised 1085 individuals, 306 showing normal (25 pg/mL) IL‐6 levels. Subjects with elevated IL‐6 showed a concentration‐dependent increase in the prevalence of QTc prolongation, and those presenting with QTc prolongation exhibited higher circulating IL‐6 levels. Stepwise multivariate regression analyses demonstrated that increased IL‐6 level was significantly associated with a risk of QTc prolongation up to 2 times the odds of the reference category of QTc (e.g. QTc >470 ms men/480 ms women ms: odds ratio, 2.28 [95% CI, 1.12–4.50] for IL‐6 >25 pg/mL) regardless of the underlying cause. Specifically, the mean QTc increase observed in the presence of elevated IL‐6 was quantitatively comparable (IL‐6 >25 pg/mL:+6.7 ms) to that of major recognized QT‐prolonging risk factors, such as hypokalemia and history of myocardial infarction. Conclusions Our data provide evidence that a high circulating IL‐6 level is a robust risk factor for QTc prolongation in a large cohort of US veterans, supporting a potentially important arrhythmogenic role for this cytokine in the general population.

Despite the progress made in risk stratification, sudden cardiac death and heart failure remain dreaded complications for hypertrophic cardiomyopathy (HCM) patients. Myocardial ischaemia is widely acknowledged as a contributor to cardiovascular events, but the assessment of ischaemia is not yet included in HCM clinical guidelines. This review aims to evaluate the HCM-specific pro-ischaemic mechanisms and the potential prognostic value of imaging for myocardial ischaemia in HCM. A literature review was performed using PubMed to identify studies with non-invasive imaging of ischaemia (cardiovascular magnetic resonance, echocardiography, and nuclear imaging) in HCM, prioritising studies published after the last major review in 2009. Other studies, including invasive ischaemia assessment and post-mortem histology, were also considered for mechanistic or prognostic relevance. Pro-ischaemic mechanisms in HCM reviewed included the effects of sarcomeric mutations, microvascular remodelling, hypertrophy, extravascular compressive forces and left ventricular outflow tract obstruction. The relationship between ischaemia and fibrosis was re-appraised by considering segment-wise analyses in multimodal imaging studies. The prognostic significance of myocardial ischaemia in HCM was evaluated using longitudinal studies with composite endpoints, and reports of ischaemia-arrhythmia associations were further considered. The high prevalence of ischaemia in HCM is explained by several micro- and macrostructural pathological features, alongside mutation-associated energetic impairment. Ischaemia on imaging identifies a subgroup of HCM patients at higher risk of adverse cardiovascular outcomes. Ischaemic HCM phenotypes are a high-risk subgroup associated with more advanced left ventricular remodelling, but further studies are required to evaluate the independent prognostic value of non-invasive imaging for ischaemia. [ABSTRACT FROM AUTHOR]

Purpose. To study the diagnostic value of cascade family screening and the spectrum of genetic variants in patients with familial and sporadic DCM, assess clinical outcomes and comparative analysis of 5-year event-free survival.Materials and methods. The study included 156 unrelated patients with verified DCM. All patients (aged 46 [34; 57] years; 125 (80%) male; LVEF 31 [24; 38]%; LV EDD 68 [61; 74] mm; follow-up period - 77 [59; 108] months) a complex of clinical and instrumental studies (ECG, ECHO, HM, MRI), cascade family screening with genetic testing (NGS+Sanger) and segregation analysis were performed.Results. Criteria for familial DCM were identified in 73 (46.8%) probands. The genetic cause of DCM was identified in 47 (64,4%) familial cases, while for sporadic form DCM pathogenic variants were detected in 19 (22,9%) patients. The dominant mutations were truncating variants in the titin gene (10,9%) and variants in the lamin A/C (LMNA) gene - 8,33%. As a result of the evaluation of cumulative event-free survival (Kaplan-Meier curves), LMNA carriers showed the poor 5-year prognosis for ventricular tachyarrhythmic events (x2=39.9; p=0,0001) and composite adverse outcomes (x2=12.1; p=0.001). Probands who had a familial DCM (log rang x2=38.5; p=0,0001) showed the worst prognosis and low cumulative survival when compared with patients of the sporadic DCM.Conclusion. Cascade clinical family screening and genetic testing in the DCM cohort increased the level of diagnosis of familial DCM from 4.5% to 46.8%. Associations of LMNA mutations with life-threatening tachyarrhythmias are defined as prognostically significant, that confirms the important role of genetic stratification of arrhythmic risk.

BackgroundSome patients with cardiac resynchronisation therapy (CRT) experience super-response (LVEF improvements to ≥50%). At generator exchange (GE), downgrading (DG) from CRT-defibrillator (CRT-D) to CRT-pacemaker (CRT-P) could be an option for these patients on primary prevention ICD indication and no required ICD therapies. Long-term data on arrhythmic events in super-responders is scarce.MethodsCRT-D patients with LVEF improvement to ≥50% at GE were identified in four large centres for retrospective analysis. Mortality, significant ventricular tachyarrhythmia and appropriate ICD-therapy were determined, and patient analysis was split into two groups (downgraded to CRT-P or not).ResultsSixty-six patients (53% male, 26% coronary artery disease) on primary prevention were followed for a median of 129 months [IQR: 101–155] after implantation. 27 (41%) patients were downgraded to CRT-P at GE after a median of 68 [IQR: 58–98] months (LVEF 54% ± 4%). The other 39 (59%) continued with CRT-D therapy (LVEF 52% ± 6%). No cardiac death or significant arrhythmia occurred in the CRT-P group (median follow-up (FU) 38 months [IQR: 29–53]). Three appropriate ICD-therapies occurred in the CRT-D group [median FU 70 months (IQR: 39–97)]. Annualized event-rates after DG/GE were 1.5%/year and 1.0%/year in the CRT-D group and the whole cohort, respectively.ConclusionsNo significant tachyarrhythmia were detected in the patients downgraded to CRT-P during follow-up. However, three events were observed in the CRT-D group. Whilst downgrading CRT-D patients is an option, a small residual risk for arrhythmic events remains and decisions regarding downgrade should be made on a case-by-case basis.

Purpose of Review: Hot phases are a challenging clinical presentation in arrhythmogenic cardiomyopathy (ACM), marked by acute chest pain and elevated cardiac troponins in the absence of obstructive coronary disease. These episodes manifest as myocarditis and primarily affect young patients, contributing to a heightened risk of life-threatening arrhythmias and potential disease progression. This review aims to synthesize recent research on the pathophysiology, diagnostic challenges, and therapeutic management of hot phases in ACM., Recent Findings: Hot phases have been linked to genetic mutations, particularly in desmosomal proteins such as Desmoplakin (DSP). Diagnostic challenges include differentiating hot phases from isolated acute myocarditis, through identification of red flags and a multimodal approach, including CMR, FDG-PET, endomyocardial biopsy and genetic testing. Emerging therapies, such as immunosuppressive and anti-inflammatory treatments, show promise in managing hot-phase episodes. Hot phases in ACM present a significant risk for arrhythmias and disease progression, necessitating a comprehensive diagnostic and therapeutic management. A multimodal diagnostic approach is essential for accurate diagnosis, but further research is needed to refine these strategies and improve prognosis for affected patients., Competing Interests: Declarations. Human and Animal Rights and Informed Consent: No animal or human subjects by the authors were used in this study. Conflict of Interest: The authors declare no competing interests., (© 2025. The Author(s).)

Background: The early repolarization pattern (ERp) is an electrocardiographic finding previously associated with arrhythmic risk in adults. The purpose of this study is to evaluate the prevalence and characteristics of ERp in a group of adolescent athletes according to gender. Furthermore, potential associations with clinical, electrocardiographic, and echocardiographic parameters are explored. Methods: In this cross‐sectional study young athletes (age < 18 years) were consecutively enrolled during the annual pre‐participation evaluation, undergoing also transthoracic echocardiography assessment from January 2015 to March 2020. Results: The prevalence of ERp was 27% in the whole population. Athletes with ERp were more frequently men practicing endurance sports. Women with ERp showed lower heart rate at rest, greater posterior, and relative ventricular wall thickness than those without ERp. Men with ERp presented higher systolic blood pressure at peak exercise, greater septal wall thickness, and indexed left ventricular mass than those without ERp. Both genders with ERp showed increased QRS voltage and narrower QRS duration. The ERp phenotype in men was more frequently notched with higher amplitude and ascending ST segment. Women's ERp presented more frequently a slurred morphology, especially in the inferior leads, and horizontal ST slope. No differences emerged in the occurrence of arrhythmias at rest and during maximal exercise test between groups, even considering higher risk phenotypes. Conclusions: ERp is an ECG finding compatible with normal cardiac adaptations to training in young athletes. ERp demonstrated gender differences regarding phenotypes previously associated with increased cardiovascular risk, not showing any differences in arrhythmias during maximal exercise test. [ABSTRACT FROM AUTHOR]

ObjectiveTo assess the arrhythmic safety profile of the adipose graft transposition procedure (AGTP) and its electrophysiological effects on post-myocardial infarction (MI) scar.BackgroundMyocardial repair is a promising treatment for patients with MI. The AGTP is a cardiac reparative therapy that reduces infarct size and improves cardiac function. The impact of AGTP on arrhythmogenesis has not been addressed.MethodsMI was induced in 20 swine. Contrast-enhanced magnetic resonance (ce-MRI), electrophysiological study (EPS), and left-ventricular endocardial high-density mapping were performed 15 days post-MI. Animals were randomized 1:1 to AGTP or sham-surgery group and monitored with ECG-Holter. Repeat EPS, endocardial mapping, and ce-MRI were performed 30 days post-intervention. Myocardial SERCA2, Connexin-43 (Cx43), Ryanodine receptor-2 (RyR2), and cardiac troponin-I (cTnI) gene and protein expression were evaluated.ResultsThe AGTP group showed a significant reduction of the total infarct scar, border zone and dense scar mass by ce-MRI (p = 0.04), and a decreased total scar and border zone area in bipolar voltage mapping (p < 0.001). AGTP treatment significantly reduced the area of very-slow conduction velocity (

In a 37-year-old cardiac arrest survivor with autosomal dominant Carvajal syndrome and arrhythmogenic cardiomyopathy, a desmoplakin mutation was identified. Cascade screening identified 2 affected family members and 2 healthy children carrying the mutation. Strategies for primary and secondary risk prevention emphasize the role of genetic testing in rare cardiomyopathies. (Level of Difficulty: Advanced.)

Dilated cardiomyopathy (DCM) represents one of the primary cardiomyopathies and may lead to heart failure and sudden death. Until recently, ventricular arrhythmias were considered to be a direct consequence of the systolic dysfunction of the left ventricle (LV) and guidelines for implantable cardioverter defibrillator implantation were established on this basis. However, the identification of heritable dilated cardiomyopathy phenotypes that presented with mildly impaired or moderate LV dysfunction, with or without chamber dilatation, and ventricular arrhythmias exceeding the degree of the underlying morphological abnormalities lead to the identification of the arrhythmogenic phenotypes and genotypes of DCM. This subset of DCM patients presents phenotypic and in many cases genotypic overlaps with left dominant arrhythmogenic cardiomyopathy (LDAC). LMNA, SCN5A, FLNC, TTN, and RBM20 are the main genes responsible for arrhythmogenic DCM. Moreover, desmosomal genes such as DSP and other non-desmosomal such as DES and PLN have been associated with both LDAC and arrhythmogenic DCM. The aim of this review is to highlight the importance of genetic profiling among DCM patients with disproportionate arrhythmic burden and the significance of the electrocardiogram, cardiac magnetic resonance, Holter monitoring, detailed family history, and other assays in order to identify red flags for arrhythmogenic DCM and proceed to an early preventive approach for sudden cardiac death. A special consideration was given to the phenotypic and genotypic overlap with LDAC. The role of myocarditis as a common disease expression of LDAC and arrhythmogenic DCM is also analyzed supporting the premise of their phenotypic overlap. [ABSTRACT FROM AUTHOR]

Introduction: The clinical utility of inferolateral early repolarisation (ER) and late potentials (LP) in children with Brugada Syndrome (BrS) has not been previously evaluated. The aim of this study was to determine the prevalence of electrocardiographic (ECG) abnormalities in children with BrS, and to investigate their relationship with clinical outcomes.Methods: 43 patients with BrS and 47 controls aged ≤18 undergoing systematic clinical and ECG evaluation, including signal-averaged ECG (SAECG) and pharmacological provocation testing, between 2003 and 2019 were included.Results: Four patients with BrS (9%) presented with a spontaneous type 1 Brugada pattern; the remaining 39 (91%) were diagnosed following ajmaline provocation testing. Twelve BrS patients (28%) had late potentials (LP) on SAECG compared to 1 (2%) in controls (p = 0.001). LP were more common in 5 patients with a high-risk phenotype (60% vs 24%) but this was not statistically significant. Twelve patients with BrS (28%) had inferolateral early repolarisation (ER) and 2 (5%) had fractionated QRS (f-QRS), but there were no statistically-significant differences with controls in these parameters. A significant arrhythmia (non-sustained ventricular tachycardia or atrial fibrillation) was seen in 4 patients (9%).Conclusions: This study shows a high prevalence of SAECG abnormalities in children with BrS compared with controls, but this was not significantly associated with a high-risk phenotype. [ABSTRACT FROM AUTHOR]

Aims We aimed to assess structural progression in arrhythmogenic cardiomyopathy (AC) patients and mutation-positive family members and its impact on arrhythmic outcome in a longitudinal cohort study. Methods and results Structural progression was defined as the development of new Task Force imaging criteria from inclusion to follow-up and progression rates as annual changes in imaging parameters. We included 144 AC patients and family members (48% female, 47% probands, 40 ± 16 years old). At genetic diagnosis and inclusion, 58% of family members had penetrant AC disease. During 7.0 [inter-quartile range (IQR) 4.5–9.4] years of follow-up, 47% of family members without AC at inclusion developed AC criteria, resulting in a yearly new AC penetrance of 8%. Probands and family members had a similar progression rate of right ventricular outflow tract diameter (0.5 mm/year vs. 0.6 mm/year, P  = 0.28) by mixed model analysis of 598 echocardiographic examinations. Right ventricular fractional area change progression rate was even higher in family members (−0.6%/year vs. −0.8%/year, P  < 0.01). Among 86 patients without overt structural disease or arrhythmic history at inclusion, a first severe ventricular arrhythmic event occurred in 8 (9%), of which 7 (88%) had concomitant structural progression. Structural progression was associated with higher incidence of severe ventricular arrhythmic events adjusted for age, sex, and proband status (HR 21.24, 95% CI 2.47–182.81, P  < 0.01). Conclusion More than half of family members had AC criteria at genetic diagnosis and yearly AC penetrance was 8%. Structural progression was similar in probands and family members and was associated with higher incidence of severe ventricular arrhythmic events. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

Some forms of early ECG repolarization QRS pattern (ERp) with J‐point elevation of 0.1 mV in two contiguous inferior and/or lateral leads with or without ST‐elevation are potentially associated with a higher arrhythmic risk in adults. We assessed the prevalence of ERp among non‐professional adolescent athletes and correlated it with age, sex, ethnicity, and structural and electric cardiac parameters. We retrospectively analyzed 414 ECGs obtained from young athletes referred to our center from 2006 to 2017. We found ERp in 22% of cases. In the ERp group, we found a greater percentage of black athletes, a higher systolic blood pressure, and lower heart rate (HR) compared with the group without ERp. This pattern was less frequent in female athletes. In athletes with ERp, the occurrence of ventricular ectopic beats was less frequent and QRS‐duration was shorter. They also exhibited greater (a) ECG‐based left ventricular hypertrophy (LVH), (b) left ventricular mass, and (c) relative wall thickness (RWT), suggesting a tendency to concentric geometry. At logistic regression analysis, we found that HR (OR 0.98 [0.96‐0.99] P = .013), QRS‐duration (OR 0.96 [0.94‐0.99], P = .003), LVH (OR 1.09 [1.05‐1.12], P < .001), and RWT (OR 1.08 [1.01‐1.16] P = .032) were significant predictors of ERp incidence. ERp is quite common in adolescent athletes and correlates with concentric LV remodeling. Specific clinical and ECG‐findings related to training such as lower HR, LVH, and QRS‐duration are also predictors of ERp. In adolescent non‐professional athletes, ERp is a benign finding associated with some structural and electric cardiac modifications induced by training. [ABSTRACT FROM AUTHOR]

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart muscle disorder associated with an increased risk of life-threatening arrhythmias in some patients. Risk stratification remains challenging. Therefore, we sought a non-invasive, easily applicable risk score to predict sustained ventricular arrhythmias in these patients. Cohort of Patients who fulfilled the 2010 ARVC task force criteria were consecutively recruited. Detailed clinical data were collected at baseline and during follow up. The clinical endpoint was a composite of recurrent sustained ventricular arrhythmias and hospitalization due to ventricular arrhythmias. Multivariable logistic regression was used to develop models to predict the arrhythmic risk. A cohort including patients from other registries in UK, Canada and Switzerland was used as a validation population. One hundred and thirty-five patients were included of whom 35 patients (31.9%) reached the endpoint. A model consisting of filtered QRS duration on signal-averaged ECG, non-sustained VT (NSVT) on 24 h-ECG, and absence of negative T waves in lead aVR on 12‑lead surface ECG was able to predict arrhythmic events with a sensitivity of 81.8%, specificity of 84.0% and a negative predictive value of 95.5% at the first presentation of the disease. This risk score was validated in international ARVC registry patients. A risk score consisting of a filtered QRS duration ≥117 ms, presence of NSVT on 24 h-ECG and absence of negative T waves in lead aVR was able to predict arrhythmic events at first presentation of the disease. • A risk score for ARVC utilizing ECG, signal averaged ECG and 24 h-ECG was developed. • The risk score predicts the arrhythmic risk at the initial investigation. • A risk score of 0 points virtually excludes an arrhythmic risk. • A higher score indicates a higher arrhythmic risk. • The risk score has been validated in an international cohort. [ABSTRACT FROM AUTHOR]

The author discusses arrhythmic risk stratification in left ventricular noncompaction (LVNC), which is a cardiomyopathy linked with increased risk of ventricular arrhythmias (VA). Topics include a study of LVNC patients undergoing catheter ablation procedure for ventricular tachycardia (VT) and frequent premature ventricular complexes (PVC), and the clinical parameters, namely, programmed ventricular stimulation (PVS) and late gadolinium enhancement (LGE).

Rheumatoid arthritis (RA) is a chronic immuno-mediated disease primarily affecting the joints, characterized by persistent high-grade systemic inflammation. Cardiovascular morbidity and mortality are significantly increased in RA, with .50% of premature deaths attributable to cardiovascular disease. In particular, RA patients were twice as likely to experience sudden cardiac death compared with non-RA subjects, pointing to an increased propensity to develop malignant ventricular arrhythmias. Indeed, ventricular repolarization (QT interval) abnormalities and cardiovascular autonomic nervous system dysfunction, representing two well-recognized risk factors for life-threatening ventricular arrhythmias in the general population, are commonly observed in RA. Moreover, large population-based studies seem to indicate that also the prevalence of atrial fibrillation is significantly higher in RA subjects than in the general population, thus suggesting that these patients are characterized by an abnormal diffuse myocardial electrical instability. Although the underlying mechanisms accounting for the pro-arrhythmogenic substrate in RA are probably intricate, the leading role seems to be played by chronic systemic inflammatory activation, able to promote arrhythmias both indirectly, by accelerating the development of ischaemic heart disease and congestive heart failure, and directly, by affecting cardiac electrophysiology. In this integrated mechanistic view, lowering the inflammatory burden through an increasingly tight control of disease activity may represent the most effective intervention to reduce arrhythmic risk in these patients. Intriguingly, these considerations could be more generally applicable to all the diseases characterized by chronic systemic inflammation, and could help elucidate the link between low-grade chronic inflammation and arrhythmic risk in the general population. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to investigate early markers of arrhythmic events (AEs) and improve risk stratification in early arrhythmogenic right ventricular cardiomyopathy (ARVC). Background AEs are frequent in patients with ARVC, but risk stratification in subjects with early ARVC is challenging. Methods Early ARVC disease was defined as possible or borderline ARVC diagnosis according to the ARVC Task Force Criteria 2010. We performed resting and signal averaged electrocardiogram (ECG). Using echocardiography, we assessed right ventricular (RV) outflow tract diameter and right ventricular basal diameter (RV diameter). Global longitudinal strain and mechanical dispersion (MD) from strain echocardiography were assessed in both the right and left ventricle. AEs were defined as documented ventricular tachycardia, cardiac syncope, or aborted cardiac arrest. Results Of 162 included subjects with ARVC (41 ± 16 years of age, 47% female), 73 had early ARVC, including mutation positive family members not fulfilling definite ARVC diagnosis. AEs occurred in 15 (21%) subjects with early ARVC. Those with AEs in early disease had larger RV diameter (40 ± 4 mm vs. 37 ± 5 mm), more pronounced RVMD (39 ± 15 ms vs. 26 ± 11 ms), and more pathological signal averaged ECGs compared with those without AEs (all p ≤ 0.05). Adding measurements of RV diameter and RVMD to electrical parameters improved identification of subjects with AEs compared with electrical parameters alone (p = 0.05). Conclusions ECG parameters, RV diameter, and RVMD were markers of previous arrhythmic events in patients with early ARVC. A combination of electrical and echocardiographic parameters improved identification of subjects with AEs in early ARVC disease. [ABSTRACT FROM AUTHOR]

Increasing evidence indicates that patients with chronic inflammatory arthritis (CIA), including rheumatoid arthritis and spondyloarthropathies, have an increased risk of arrhythmic events, significantly contributing to the higher cardiovascular disease (CVD) morbidity and mortality observed in these subjects compared to the general population. Although the mechanisms accounting for such an arrhythmogenic substrate are not fully understood, the main role is probably played by chronic systemic inflammation, able to accelerate the development of structural CVD, as well as to directly affect cardiac electrophysiology. In the past decade, biologic therapies have revolutionized the treatment of CIA by highly enhancing the probability to effectively control disease activity and its systemic consequences, including cardiovascular involvement. Accordingly, accumulating data demonstrated that by potently inhibiting systemic inflammation, biologic drugs can reduce CVD progression and ameliorate arrhythmic risk parameters, with a putative beneficial impact on arrhythmia incidence. Nevertheless, a significant number of reports from clinical trials and postmarketing experience suggest that some of these medications, particularly TNF inhibitor monoclonal antibodies and rituximab, may in some circumstances precipitate arrhythmia occurrence, probably by acutely amplifying myocardial electric instability intrinsically associated with these diseases. In this review, we analyze the intricate link between biologic drugs and arrhythmias in CIA in the effort to identify which factors are involved in the fine-tuning of antiarrhythmic/pro-arrhythmic balance, and understand how this knowledge should be translated in the clinical practice to obtain the most favorable benefit-to-risk profile when biologic drugs are used in these patients. [ABSTRACT FROM AUTHOR]

The use of cardiovascular magnetic resonance (CMR) has been implemented in the diagnostic work-up of patients with cardiomyopathies by providing an accurate assessment of biventricular volumes and function and a detailed myocardial tissue characterization in a one-stop-shop multi-parametric imaging technique. Its unique capability to perform an accurate tissue characterization of the myocardium, which is superior to other imaging modalities, has prompt its use in the analysis of myocardial arrhythmic substrates and in the prognostic risk stratification of patients. Although left ventricular ejection fraction (LVEF) has always been the best-known predictor of arrhythmic risk, the quantification of myocardial scar by CMR has been recognised as a powerful risk stratification tool, independent of LVEF. Moreover, due to its ability to identify myocardial arrhythmic substrate, both ventricular but more recently also atrial, CMR is increasingly offered as a guide to ablation procedures. [ABSTRACT FROM AUTHOR]

Background Left ventricular ejection fraction (LVEF) recovers during follow-up in a significant proportion of patients implanted with a cardioverter defibrillator (ICD) for primary prevention. Little is known about the midterm arrhythmic risk in this population, particularly in relation to the presence or absence of ischemic cardiomyopathy. Methods and Results We retrospectively analyzed 286 patients with an ICD implanted for primary prevention between 2002 and 2010. Patients were divided into two groups based on their last LVEF assessment: (1) Recovery, defined as an LVEF > 35%; and (2) No-Recovery, defined as an LVEF ≤ 35%. Kaplan-Meir curves and multivariate Cox regression analysis were performed separately for patients with ischemic (211 patients) and nonischemic (75 patients) cardiomyopathy. Forty-nine patients (17.1%) had LVEF recovery to >35% at last follow-up. Overall, 72 patients (25.2%) experienced ventricular arrhythmias requiring ICD therapy during a median follow-up of 4.4 years. With multivariate Cox regression, LVEF recovery was associated with a lower arrhythmic risk in the whole cohort (hazard ratio [HR]: 0.38 [0.13-0.85]; P = 0.02) and in the nonischemic cardiomyopathy cohort (HR: 0.10 [0.005-0.55]; P = 0.005), but not in the ischemic cardiomyopathy cohort (HR: 0.84 [0.25-2.10]; P = 0.74). Conclusion In conclusion, patients with nonischemic cardiomyopathy who improved their LVEF to >35% after primary prevention ICD implantation were at very low absolute arrhythmic risk. Our study raises the possibility that the LVEF cutoff to safely withhold ICD replacement might be higher in patients with ischemic compared to nonischemic cardiomyopathy. This will need to be confirmed in prospective studies. [ABSTRACT FROM AUTHOR]

We examined whether long QT syndrome status moderates the association between stressful life events and depressive symptoms. Participants were 562 (n = 246 symptomatic) long QT syndrome mutation carriers. Depressive symptoms were measured with a modified version of the Beck’s Depression Inventory. There was an interaction between long QT syndrome status and stressful life events on depressive symptoms. In the symptomatic long QT syndrome patients, stressful life events were associated with depressive symptoms (B = 0.24, p < 0.001). In the asymptomatic long QT syndrome mutation carriers, this association was 62.5 percent weaker (B = 0.09, p = 0.057). Compared to asymptomatic long QT syndrome mutation carriers, symptomatic long QT syndrome patients are more sensitive to the depressive effects of stressful life events. [ABSTRACT FROM AUTHOR]

The dependence on heart rate of the QT interval has been investigated for many years and several mathematical formulae have been proposed to describe the QT interval/heart rate (or QT interval/RR interval) relationship. While the most popular is Bazett’s formula, it overcorrects the QT interval at high heart rates and under-corrects it at slow heart rates. This formulae and many others similar ones, do not accurately describe the natural behaviour of the QT interval. The QT interval/RR interval relationship is generally described as QT dynamics. In recent years, several methods of its assessment have been proposed, the most popular of which is linear regression. An increased steepness of the linear QT/RR slope correlates with the risk of arrhythmic death following myocardial infarction. It has also been demonstrated that the QT interval adapts to heart rate changes with a delay (QT hysteresis) and that QT dynamics parameters vary over time. New methods of QT dynamics assessment that take into account these phenomena have been proposed. Using these methods, changes in QT dynamics have been observed in patients with advanced heart failure, and during morning hours in patients with ischemic heart disease and history of cardiac arrest. The assessment of QT dynamics is a new and promising tool for identifying patients at increased risk of arrhythmic events and for studying the effect of drugs on ventricular repolarisation.