A Comprehensive Analysis of Non-Desmosomal Rare Genetic Variants in Arrhythmogenic Cardiomyopathy: Integrating in Padua Cohort Literature-Derived Data.

Arrhythmogenic cardiomyopathy (ACM) is an inherited myocardial disease at risk of sudden death. Genetic testing impacts greatly in ACM diagnosis, but gene-disease associations have yet to be determined for the increasing number of genes included in clinical panels. Genetic variants evaluation was undertaken for the most relevant non-desmosomal disease genes. We retrospectively studied 320 unrelated Italian ACM patients, including 243 cases with predominant right-ventricular (ARVC) and 77 cases with predominant left-ventricular (ALVC) involvement, who did not carry pathogenic/likely pathogenic (P/LP) variants in desmosome-coding genes. The aim was to assess rare genetic variants in transmembrane protein 43 (TMEM43), desmin (DES), phospholamban (PLN), filamin c (FLNC), cadherin 2 (CDH2), and tight junction protein 1 (TJP1), based on current adjudication guidelines and reappraisal on reported literature data. Thirty-five rare genetic variants, including 23 (64%) P/LP, were identified in 39 patients (16/243 ARVC; 23/77 ALVC): 22 FLNC, 9 DES, 2 TMEM43, and 2 CDH2. No P/LP variants were found in PLN and TJP1 genes. Gene-based burden analysis, including P/LP variants reported in literature, showed significant enrichment for TMEM43 (3.79-fold), DES (10.31-fold), PLN (117.8-fold) and FLNC (107-fold). A non-desmosomal rare genetic variant is found in a minority of ARVC patients but in about one third of ALVC patients; as such, clinical decision-making should be driven by genes with robust evidence. More than two thirds of non-desmosomal P/LP variants occur in FLNC.

Prevalence and determinants of low QRS voltages and QRS fragmentation in children and adolescents undergoing sports preparticipation screening.

AIMS: Low QRS Voltages (LQRSV) in limb leads and QRS fragmentation (FQRS) are possible electrocardiographic signs of myocardial fibrosis and cardiomyopathy, but they are not listed in current criteria for interpretating athlete's ECG. We investigated the prevalence and determinants of LQRSV and FQRS in a cohort of young apparently healthy athletes undergoing preparticipation screening (PPS). METHODS: We analysed a consecutive series of 2140 ECG obtained during PPS of young athletes (mean age 12.5±2.6 years, 7-18 year-old, 49% males). The peak-to-peak QRS voltage was measured in all limb leads and LQRSV were defined when maximum value was <0.5 mV. Fragmented QRS morphologies were grouped into five patterns. Lead aVR was not considered. RESULTS: Maximum peak-to-peak QRS voltage in limb leads was 1.4±0.4 mV, similar between younger and older athletes, but significantly lower in females than males (1.35±0.38mV vs 1.45±0.42mV; p<0.001). There was a weak correlation between maximal QRS voltages and body mass index (BMI), but not with type of sport or training load. Only 5 (0.2%) individuals showed LQRSV. At least one fragmented QRS complex was identified in 831 (39%) individuals but excluding the rSr' pattern in V1-V2, only 10 (0.5%) showed FQRS in ≥2 contiguous leads. They were older than those without FQRS, but did not differ in terms of gender, BMI, type of sport or training load. CONCLUSIONS: LQRSV in limb leads and FQRSV in ≥2 contiguous leads excluding V1-V2 are rare in young apparently healthy athletes and are not related to the type and intensity of sport activity. Therefore, they may require additional testing to rule out an underlying disease particularly when other abnormalities are present.

Low QRS Voltages (LQRSV) in limb leads and QRS fragmentation (FQRS) are possible electrocardiographic signs of myocardial fibrosis and cardiomyopathy. In our study, we analyzed the occurrence and characteristics of FQRS and LQRSV in young athletes undergoing preparticipation screening. We found a low prevalence of these abnormalities, with only 0.2% showing LQRSV and 0.5% displaying FQRS. These abnormalities were not associated with factors such as gender, age, type of sport, or training load.

Phenotype and Clinical Outcomes in Desmin-Related Arrhythmogenic Cardiomyopathy.

BACKGROUND: Desmin (DES) pathogenic variants cause a small proportion of arrhythmogenic cardiomyopathy (ACM). Outcomes data on DES-related ACM are scarce. OBJECTIVES: This study sought to provide information on the clinical phenotype and outcomes of patients with ACM caused by pathogenic variants of the DES gene in a multicenter cohort. METHODS: We collected phenotypic and outcomes data from 16 families with DES-related ACM from 10 European centers. We assessed in vitro DES aggregates. Major cardiac events were compared to historical controls with lamin A/C truncating variant (LMNA-tv) and filament C truncating variant (FLNC-tv) ACM. RESULTS: Of 82 patients (54% males, median age: 36 years), 11 experienced sudden cardiac death (SCD) (n = 7) or heart failure death (HFd)/heart transplantation (HTx) (n = 4) before clinical evaluation. Among 68 survivors, 59 (86%) presented signs of cardiomyopathy, with left ventricular (LV) dominant (50%) or biventricular (34%) disease. Mean LV ejection fraction was 51% ± 13%; 36 of 53 had late gadolinium enhancement (ring-like pattern in 49%). During a median of 6.73 years (Q1-Q3: 3.55-9.52 years), the composite endpoint (sustained ventricular tachycardia, aborted SCD, implantable cardioverter-defibrillator therapy, SCD, HFd, and HTx) was achieved in 15 additional patients with HFd/HTx (n = 5) and SCD/aborted SCD/implantable cardioverter-defibrillator therapy/sustained ventricular tachycardia (n = 10). Male sex (P = 0.004), nonsustained ventricular tachycardia (P = 0.017) and LV ejection fraction ≤50% (P = 0.012) were associated with the composite endpoint. Males with DES variants had similar outcomes to historical FLNC-tv and LMNA-tv controls. However, females showed better outcomes than those with LMNA-tv. In vitro experiments showed the characteristic finding of DES aggregates in 7 of 12 variants. CONCLUSIONS: DES ACM is associated with poor outcomes which can be predicted with potentially successful treatments, underscoring the importance of familial evaluation and genetic studies to identify at risk individuals.

International Criteria for Reporting Study Quality for Sudden Cardiac Arrest/Death Tool.

BACKGROUND: Studies reporting on the incidence of sudden cardiac arrest and/or death (SCA/D) in athletes commonly lack methodological and reporting rigor, which has implications for screening and preventative policy in sport. To date, there are no tools designed for assessing study quality in studies investigating the incidence of SCA/D in athletes. METHODS AND RESULTS: The International Criteria for Reporting Study Quality for Sudden Cardiac Arrest/Death tool (IQ-SCA/D) was developed following a Delphi process. Sixteen international experts in sports cardiology were identified and invited. Experts voted on each domain with subsequent moderated discussion for successive rounds until consensus was reached for a final tool. Interobserver agreement between a novice, intermediate, and expert observer was then assessed from the scoring of 22 relevant studies using weighted and unweighted κ analyses. The final IQ-SCA/D tool comprises 8 domains with a summated score of a possible 22. Studies are categorized as low, intermediate, and high quality with summated IQ-SCA/D scores of ≤11, 12 to 16, and ≥17, respectively. Interrater agreement was "substantial" between all 3 observers for summated IQ-SCA/D scores and study categorization. CONCLUSIONS: The IQ-SCA/D is an expert consensus tool for assessing the study quality of research reporting the incidence of SCA/D in athletes. This tool may be used to assist researchers, reviewers, journal editors, and readers in contextualizing the methodological quality of different studies with varying athlete SCA/D incidence estimates. Importantly, the IQ-SCA/D also provides an expert-informed framework to support and guide appropriate design and reporting practices in future SCA/D incidence trials.

Phenotypic Expression and Clinical Outcomes in Patients With Arrhythmogenic Cardiomyopathies.

BACKGROUND: In recent years, it has become evident that arrhythmogenic cardiomyopathy (ACM) displays a wide spectrum of ventricular involvement. Furthermore, the influence of various clinical phenotypes on the prognosis of the disease is currently being assessed. OBJECTIVES: The purpose of this study was to evaluate the impact of phenotypic expression in ACM on patient outcomes. METHODS: We conducted an analysis of 446 patients diagnosed with ACM. These patients were categorized into 3 groups based on their phenotype: arrhythmogenic right ventricular cardiomyopathy (ARVC) (right-dominant ACM), arrhythmogenic left ventricular cardiomyopathy (ALVC) (left-dominant ACM), and biventricular arrhythmogenic cardiomyopathy (BIV). We compared clinical, instrumental, and genetic findings among these groups and also evaluated their outcomes RESULTS: Overall, 44% of patients were diagnosed with ARVC, 23% with ALVC, and 33% with BIV forms. Subjects showing with ARVC and BIV phenotype had a significantly higher incidence of life-threatening ventricular arrhythmias compared with ALVC (P < 0.001). On the other hand, heart failure, heart transplantation, and death caused by cardiac causes were more frequent in individuals with BIV forms compared to those with ALVC and ARVC (P < 0.001). Finally, patients with an ALVC phenotype had a higher incidence of hot phases compared with those with ARVC and BIV forms (P = 0.013). CONCLUSIONS: The comparison of ACM phenotypes demonstrated that patients with right ventricular involvement, such as ARVC and BIV forms, exhibit a higher incidence of life-threatening ventricular arrhythmias. Conversely, ACM forms characterized by left ventricular involvement, such as ALVC and BIV, show a higher incidence of heart failure, heart transplantation, and hot phases.

Interpolated junctional extrasystoles mimicking complex polymorphic ventricular arrhythmias in a healthy young athlete: a case report.

Background: In young competitive athletes, ventricular arrhythmias could be a reason for concern as they may represent the sign of a serious underlying cardiac condition. On the other hand, atrial or conduction system premature beats are usually benign. However, when the properties of the His-Purkinje system lead to conduction aberrancies, there is a risk of misinterpreting benign arrhythmias as potentially at risk ventricular ectopic beats. Case summary: We described the case of a healthy young athlete with asymptomatic interpolated junctional ectopic beats interpreted as polymorphic ventricular tachycardia during pre-participation screening. Discussion: Strange and rare electrocardiogram pictures may be observed during sport pre-participation screening. The small atrioventricular (AV) junction is made up of many specialized fibres with different conduction properties. Junctional arrhythmias can have a normal anterograde conduction or can be conducted with aberrancy. Rarely, they can be interpolated and cause PR prolongation or bundle branch block by increasing the refractory period of the AV node and/or the conduction system. When aberrancy occurs, they can be mistaken for 'atypical' ventricular arrhythmias. Prognosis of these events remains uncertain.

Atrial electrofunctional predictors of incident atrial fibrillation in cardiac amyloidosis.

BACKGROUND: Atrial fibrillation (AF) is common in patients with cardiac amyloidosis (CA) and is a significant risk factor for heart failure hospitalization and thromboembolic events. OBJECTIVE: This study was designed to investigate the atrial electrofunctional predictors of incident AF in CA. METHODS: A multicenter, observational study was conducted in 4 CA referral centers including sinus rhythm patients with light-chain (AL) and transthyretin (ATTR) CA undergoing electrocardiography and cardiac magnetic resonance imaging. The primary end point was new-onset AF occurrence. RESULTS: Overall, 96 patients (AL-CA, n = 40; ATTR-CA, n = 56) were enrolled. During an 18-month median follow-up (Q1-Q3, 7-29 months), 30 patients (29%) had incident AF. Compared with those without AF, patients with AF were older (79 vs 73 years; P = .001). They more frequently had ATTR (87% vs 45%; P < .001); electrocardiographic interatrial block (IAB), either partial (47% vs 21%; P = .011) or advanced (17% vs 3%; P = .017); and lower left atrial ejection fraction (LAEF; 29% vs 41%; P = .004). Age (hazard ratio [HR], 1.059; 95% CI, 1.002-1.118; P = .042), any type of IAB (HR, 2.211; 95% CI, 1.03-4.75; P = .041), and LAEF (HR, 0.967; 95% CI, 0.936-0.998; P = .044) emerged as independent predictors of incident AF. Patients exhibiting any type of IAB, LAEF <40%, and age >78 years showed a cumulative incidence for AF of 40% at 12 months. This risk was significantly higher than that carried by 1 (8.5%) or none (7.6%) of these 3 risk factors. CONCLUSION: In patients with CA, older age, IAB on 12-lead electrocardiography, and reduced LAEF on cardiac magnetic resonance imaging are significant and independent predictors of incident AF. A closer screening for AF is advisable in CA patients carrying these features.

Determinants of Ventricular Arrhythmias in Mitral Valve Prolapse.

BACKGROUND: Mitral valve prolapse (MVP) may be associated with ventricular arrhythmias (VA) even in the absence of significant valvular regurgitation. Curling, mitral annulus disjunction (MAD) and myocardial fibrosis (late gadolinium enhancement [LGE]) may account for arrhythmogenesis. OBJECTIVES: This study investigated the determinants of VA in patients with MVP without significant regurgitation. METHODS: This study included 108 patients with MVP (66 female; median age: 48 years) without valve regurgitation. All patients underwent 12-lead electrocardiography, 12-lead 24-hour electrocardiographic Holter monitoring, exercise stress test, and cardiac magnetic resonance. Patients were divided into 2 groups (arrhythmic and no-arrhythmic MVP), according to the presence of VA with a right bundle branch block pattern. RESULTS: The 62 patients (57%) with arrhythmic MVP showed: 1) higher MAD (median length: 6.0 vs 3.2 mm; P = 0.017); 2) higher prevalence of curling (79% vs 52%; P = 0.012); and 3) higher prevalence of left ventricular LGE (79% vs 52%; P = 0.012). Mediation analysis showed that curling had both a direct (P = 0.03) and indirect effect mediated by LGE (P = 0.04) on VA, whereas the association between MAD and VA was completely mediated by LGE. Patients with severe VA showed more pronounced morphofunctional alterations, in terms of MAD (7.0 vs 4.6 mm; P = 0.004) and presence and severity of curling (respectively, 91% vs 64%; P = 0.010; and 4 vs 3 mm; P = 0.004), compared to those without severe VA. CONCLUSIONS: In patients with MVP the occurrence of VA with right bundle branch block morphology is the expression of more severe morphologic, mechanical, and tissue alterations. Curling has both a direct and an indirect effect on VA.

Prevalence and clinical significance of low QRS voltages in healthy individuals, athletes and patients with cardiomyopathy: implications for sports preparticipation cardiovascular screening.

Low QRS voltages (LQRSV), defined as a QRS amplitude from peak to nadir <0.5 mV in all limb leads, are an emerging diagnostic finding on the electrocardiogram (ECG). In healthy individuals and athletes, LQRSV are rare (2.2-4% of elite athletes, 0.5% of recreational athletes and 0.3% of sedentary individuals). LQRSV athletes commonly show ventricular arrhythmias (VAs) on exercise, and up to 40% of those with LQRSV and VAs have late gadolinium (LGE) on cardiac magnetic resonance (CMR). The prevalence of LQRSV in arrhythmogenic cardiomyopathy (ACM) ranges 17-40%, predicts left ventricular (LV) involvement, and is correlated with more extensive LGE replacement on CMR. In hypertrophic cardiomyopathy (HCM), LQRSV ranges 0.7% to 11%. LQRSV-HCM patients have more segments with LGE, despite relatively smaller LV mass, suggesting a more advanced clinical stage and a worse prognosis. In dilated cardiomyopathy (DCM), LQRSV range 6%-7%, but may be higher (36%) in certain genetic forms of DCM. On a follow-up, LQRSV are independently associated with incident cardiac events, such as sudden death, sustained ventricular arrhythmia, or appropriate internal cardioverter defibrillator discharge. In cardiac amyloid (CA), LQRSV range from 34% to 66% and demonstrate a negative prognostic value, with worse clinical outcomes regardless of underlying biologic, genetic, and clinical variables. In conclusion, LQRSV deserve careful consideration for exclusion of arrhythmogenic substrates in healthy individuals, athletes, and patients. While additional research is needed, it is reasonable that LQRSV should trigger clinical investigation to exclude underlying diseases at risk of life-threatening arrhythmias.

Thinning of compact layer and systolic dysfunction in isolated left ventricular non-compaction: A cardiac magnetic resonance study.

BACKGROUND: The Petersen' index reflects an excess of myocardial trabeculation which is not a specific morpho-functional feature of left ventricular non-compaction (LVNC) cardiomyopathy, but a "phenotypic trait" even observed in association with other myocardial diseases and over-loading conditions. The present study was designed to evaluate the relation between a critical thinning of compact layer and the development of systolic dysfunction and LVNC cardiomyopathy. METHODS: We compared CMR morpho-functional features and measurements of LV wall thickness using a 17 segment model of a cohort of patients fulfilling the Petersen criterion for LVNC with LV systolic dysfunction versus those of a cohort of age- and sex-matched controls with LVNC and preserved LV systolic function. All the study patients had an "isolated" LVNC defined as positive Petersen criterion in the absence of other diseases such as hypertrophic and dilated cardiomyopathy, valvular heart disease, or congenital heart disease and over-loading conditions. RESULTS: he study population included 33 patients with "isolated" LVNC: 11 consecutive index patients with a reduced LV ejection fraction (LVNCrEF) and 22 controls with a preserved LVEF (LVNCpEF). The compact myocardial layer was thinner in patients with LVNCrEF than in those with LVNCpEF patients, both in mid-ventricular and apical LV segments. On linear regression analysis, there was a linear correlation between median thickness of mid-ventricular free wall segments and left ventricular ejection fraction (r = 0.51, p = 0.005). On the ROC curves analysis, ≥2 segments with a compact myocardial layer <5 mm in the free wall mid-ventricular segments showed the best accuracy for reduced LVEF (100% sensitivity and 60% specificity; AUC 0.81, p < 0.01). The negative predictive value for LV systolic dysfunction of <2 free wall mid ventricular segments <5 mm was 100%. On quantitative analysis, the mass of papillary muscles was lower in patients with LVNCrEF [1.2 (0.8-1.4) versus 1.6 (1.1-1.8) g/mq; p = 0.08]. CONCLUSIONS: A thinned compact layer of mid-ventricular segments of the LV free wall was associated with a reduced systolic function and "isolated" LVNC cardiomyopathy.

Proposed diagnostic criteria for arrhythmogenic cardiomyopathy: European Task Force consensus report.

Arrhythmogenic cardiomyopathy (ACM) is a heart muscle disease characterized by prominent "non-ischemic" myocardial scarring predisposing to ventricular electrical instability. Diagnostic criteria for the original phenotype, arrhythmogenic right ventricular cardiomyopathy (ARVC), were first proposed in 1994 and revised in 2010 by an international Task Force (TF). A 2019 International Expert report appraised these previous criteria, finding good accuracy for diagnosis of ARVC but a lack of sensitivity for identification of the expanding phenotypic disease spectrum, which includes left-sided variants, i.e., biventricular (ABVC) and arrhythmogenic left ventricular cardiomyopathy (ALVC). The ARVC phenotype together with these left-sided variants are now more appropriately named ACM. The lack of diagnostic criteria for the left ventricular (LV) phenotype has resulted in clinical under-recognition of ACM patients over the 4 decades since the disease discovery. In 2020, the "Padua criteria" were proposed for both right- and left-sided ACM phenotypes. The presently proposed criteria represent a refinement of the 2020 Padua criteria and have been developed by an expert European TF to improve the diagnosis of ACM with upgraded and internationally recognized criteria. The growing recognition of the diagnostic role of CMR has led to the incorporation of myocardial tissue characterization findings for detection of myocardial scar using the late­gadolinium enhancement (LGE) technique to more fully characterize right, biventricular and left disease variants, whether genetic or acquired (phenocopies), and to exclude other "non-scarring" myocardial disease. The "ring-like' pattern of myocardial LGE/scar is now a recognized diagnostic hallmark of ALVC. Additional diagnostic criteria regarding LV depolarization and repolarization ECG abnormalities and ventricular arrhythmias of LV origin are also provided. These proposed upgrading of diagnostic criteria represents a working framework to improve management of ACM patients.