Introduction Current family screening approaches in dilated cardiomyopathy (DCM) depend on the presence or absence of a familial genetic variant, in which variant pathogenicity (i.e. benign or pathogenic) classification drives screening recommendations. However, this approach has never been systematically evaluated. Methods To describe the yield of DCM family screening stratified by variant classification in the Netherlands, we included 358 relatives (mean age +/- standard deviation: 44.4 +/- 15.9 years at baseline; 52% female; 41% (likely) pathogenic (LP/P) variant carriers from 210 families). Demographics, symptoms and genetic/cardiac test results were obtained. Endpoints were the development of DCM (left ventricular ejection fraction < 50% of non-ischaemic aetiology) or occurrence of major adverse cardiovascular events (MACE) (i.e. heart failure hospitalisation, ventricular arrhythmia or death). Probability of DCM or MACE was assessed with the Kaplan-Meier method. Results DCM was present in 32 relatives (9%) (25/32 (78%) with LP/P variant) at baseline and in an additional 10/97 relatives (10%) (9/10 (90%) with LP/P variant) who were re-evaluated during a median follow-up time of 5.0 years (interquartile range: 3.2-7.4). Of the 128 relatives without the familial LP/P variant, none developed DCM. MACE was experienced by 5 relatives (1%) (4/5 (80%) with LP/P variant), all of whom had DCM at the time of the event. Conclusion The yield of DCM family screening was similar to 10% at baseline and another similar to 10% during 5-year follow-up. Relatives without the familial LP/P variant could be safely discharged. These results reinforce the use of a genetics-first screening approach in relatives from families with an LP/P variant. This will lower the burden on resources in Dutch hospitals and help allocate resources to those who are most likely to benefit.

Introduction Desmoplakin cardiomyopathy (DSP-CMP) is a genetic cardiomyopathy characterized by high risk of ventricular arrhythmias (VAs), heart failure (HF), and recurrent myocarditis. Data regarding the use and impact of immunosuppression on those myocarditis episodes is scarce. Hypothesis Immunosuppression treatment in DSP-CMP associated myocarditis may improve clinical outcomes. Methods Patients (pts) with DSP-CMP and 1+ episode of myocarditis in the worldwide DSP-ERADOS Network (26 institutions across 9 countries in 3 continents) were enrolled. For each treated episode, immunosuppressive medication regimen and duration (acute vs chronic immunosuppression) were collected. The primary combined outcome was sustained VA and/or HF episodes during follow up. Outcomes of DSP-CMP patients receiving immunosuppression at the time of first myocarditis episode were compared with DSP-CMP patients with untreated myocarditis using a log-rank test. Results Of 815 patients in the DSP registry, 153 patients (age at first presentation 31.1±8.7 yo, 72.5% female, 71.2% proband, LVEF 46.7±8.6%) experiencing a total of 260 myocarditis episodes (age at first episode 32.5±7.4 yo; n=60/153 had myocarditis as initial DSP-CMP presentation; 1.7 episodes/pt; n=54 pts with 2+ episodes,) were enrolled in the current study (Table 1). Of these episodes, 79 (30.4%) were treated with immunosuppression, with 23 treated with multiple agents. Seven (4.6%) patients received chronic immunosuppression. Over a median follow up of 4.6 [1.6-8.2] years, 96 primary outcome events (HF: n=31, VA: n=65) where observed in 73 (47.7%) patients. Patients whose first episode was treated with immunosuppression were less likely to meet the combined endpoint of HF/VA than those whose first episode was not treated (6/31 (19.4%) vs 67/122 (54.9%) p<0.001). Conclusions In a large, multicenter DSP-CMP registry, we demonstrate that approximately one-third of all myocarditis episodes were treated with immunosuppression, most commonly corticosteroid-based strategies. Patients whose first episode of myocarditis was treated with immunosuppression had a lower rate of subsequent VA and HF events. These findings provide preliminary data to support a prospective trial to confirm the role of immunosuppression in DSP-CMP presenting with myocarditis.

BACKGROUND:Pathogenic/likely pathogenic (LP) desmin (DES) variants cause heterogeneous cardiomyopathy and skeletal myopathy phenotypes. Limited data suggest a high incidence of major adverse cardiac events (MACEs), including cardiac conduction disease, sustained ventricular arrhythmias (VA), and heart failure (HF) events (HF hospitalization, left ventricular assist device/cardiac transplant, HF-related death) in patients with pathogenic/LP DES variants. However, pleiotropic presentation and small cohort sizes have limited clinical phenotype and outcome characterization. We aimed to describe the natural history, phenotype spectrum, familial penetrance and outcomes in patients with pathogenic/LP DES variants through a systematic review and individual patient data meta-analysis using published reports. METHODS:We searched Medline (PubMed) and Embase for studies that evaluated cardiac phenotypes in patients with pathogenic/LP DES variants. Cardiomyopathy diagnosis or occurrence of MACE was considered evidence of cardiac involvement/penetrance. Lifetime event-free survival from cardiac conduction disease, sustained VA, HF events, and composite MACE was assessed. RESULTS:Of the 4212 screened publications, 71 met the inclusion criteria. A total of 230 patients were included (52.6% men, 52.2% probands, median age: 31 years [22.0-42.8] at first evaluation, median follow-up: 3 years [0-11.0]). Overall, 124 (53.9%) patients were diagnosed with cardiomyopathy, predominantly dilated cardiomyopathy (14.8%), followed by restrictive cardiomyopathy (13.5%), whereas other forms were less common: arrhythmogenic cardiomyopathy (7.0%), hypertrophic cardiomyopathy (6.1%), arrhythmogenic right ventricular cardiomyopathy (5.2%), and other forms (7.4%). Overall, 132 (57.4%) patients developed MACE, with 96 (41.7%) having cardiac conduction disease, 36 (15.7%) sustained VA, and 43 (18.7%) HF events. Familial penetrance of cardiac disease was 63.6% among relatives with pathogenic/LP DES variants. Male sex was associated with an increased risk of sustained VA (hazard ratio, 2.28; P=0.02) and HF events (hazard ratio, 2.45; P=0.008). CONCLUSIONS:DES cardiomyopathy exhibits heterogeneous phenotypes and a distinct natural history, characterized by high familial penetrance and a substantial MACE burden. Male patients face a higher risk of sustained VA events.

To summarize the available data on the use of immunosuppression therapies for the management of hot phases of disease and recurrent myocarditis in patients with desmoplakin cardiomyopathy (DSP-CMP). Occurrence of myocarditis episodes has been associated with worsening of outcomes in DSP-CMP. Multiple case reports and small case series have described potential benefit in using anti-inflammatory and immunosuppressive medications for the treatment of those episodes. Recently published translational data has shown a clear link between DSP variants and a propensity to inflammation. The presence of acute myocarditis episodes have been clearly demonstrated as a manifestation of DSP-CMP. These episodes are marked by myocardial inflammation and subsequent fibrosis, and, moreover, contribute to a heightened future risk of subsequent arrhythmias and heart failure. Identifying optimal strategies to prevent and/or interrupt myocardial inflammation is therefore a critical priority of patients with DSP-CMP.

Background: While late gadolinium enhancement (LGE) is proposed as a diagnostic criterion for arrhythmogenic right ventricular cardiomyopathy (ARVC), the potential of LGE to distinguish ARVC from differentials remains unknown. We aimed to assess the diagnostic value of LGE for ARVC diagnosis. Methods: We included 132 subjects (60% male, 47 +/- 11 years) who had undergone cardiac magnetic resonance imaging with LGE assessment for ARVC or ARVC differentials. ARVC was diagnosed as per 2010 Task Force Criteria (n = 55). ARVC differentials consisted of familial/genetic dilated cardiomyopathy (n = 25), myocarditis (n = 13), sarcoidosis (n = 20), and amyloidosis (n = 19). The diagnosis of all differentials was based on the most current standard of reference. The presence of LGE was evaluated using a 7-segment right ventricle (RV) and 17-segment left ventricle (LV) model. Subsequently, we assessed LGE patterns for every patient individually for fulfilling LV- and/or RV-LGE per Padua criteria, independent of their clinical diagnosis (i.e. phenotype). Diagnostic values were analyzed using sensitivity and specificity for any RV-LGE, any LV-LGE, RV-LGE per Padua criteria, and prevalence graphs for LV-LGE per Padua criteria. The optimal integration of LGE for ARVC diagnosis was determined using classification and regression tree analysis. Results: One-third (38%) of ARVC patients had RV-LGE, while half (51%) had LV-LGE. RV-LGE was less frequently observed in ARVC vs non-ARVC patients (38% vs 58%, p = 0.034) leading to a poor discriminatory potential (any RV-LGE: sensitivity 38%, specificity 42%; RV-LGE per Padua criteria: sensitivity 36%, specificity 44%). Compared to ARVC patients, non-ARVC patients more often had LV-LGE (91% vs 51%, p < 0.001) which was also more globally distributed (median 9 [interquartile range (IQR): 3-13] vs 0 [IQR: 0-3] segments, p < 0.001). The absence of anteroseptal and absence of extensive (>= 5 segments) mid-myocardial LV-LGE, and absence of moderate (>= 2 segments) mid-myocardial LV-LGE predicted ARVC with good diagnostic performance (sensitivity 93%, specificity 78%). Conclusion: LGE is often present in ARVC differentials and may lead to false positive diagnoses when used without knowledge of LGE patterns. Moderate RV-LGE without anteroseptal and mid-myocardial LV-LGE is typically observed in ARVC.

Cardiac amyloidosis (CA) is a progressive and life-threatening cardiomyopathy characterized by deposition of misfolded proteins in the myocardium, leading to heart failure (HF), conduction disorders, and (supra)ventricular arrhythmias. Disease prognosis is mainly determined by (a) the presence of HF at time of diagnosis and (b) etiology of the misfolded proteins (i.e. light chain (AL) or transthyretin [TTR] amyloidosis [ATTR]), with a median survival of ˜3.5 years, if left untreated [1]. Due to a lack of treatment options in the past, CA was considered untreatable resulting often in underdiagnosis of the disease [2].

Arrhythmogenic cardiomyopathy (ACM) is a genetically heterogeneous inherited cardiomyopathy with an estimated prevalence of 1:5000-10 000 that predisposes patients to life-threatening ventricular arrhythmias (VA) and sudden cardiac death (SCD). ACM diagnostic criteria and risk prediction models, particularly for arrhythmogenic right ventricular cardiomyopathy (ARVC), the most common form of ACM, are typically genotype-agnostic, but numerous studies have established clinically meaningful genotype-phenotype associations. Early signs of ACM onset differ by genotype indicating the need for genotype-specific diagnostic criteria and family screening paradigms. Likewise, risk factors for SCD vary by genetic subtype, indicating that genotype-specific guidelines for management are also warranted. Of particular importance, genotype-specific therapeutic approaches are being developed. Results from a randomized controlled trial for flecainide use in ARVC patients are currently pending. Research in a plakophilin-2-deficient mouse model suggests this antiarrhythmic drug may be particularly useful for patients with likely pathogenic or pathogenic (LP/P) PKP2 variants. Additionally, the first gene therapy clinical trials in ARVC patients harboring LP/P PKP2 variants are currently underway. This review aims to provide clinicians caring for ACM patients with an up-to-date overview of the current literature in genotype-specific natural history of disease and management of ACM patients and describe scientific advances that have led to upcoming clinical trials.

Primary ciliary dyskinesia (PCD), a disorder of the motile cilia, is now recognised as an underdiagnosed cause of bronchiectasis. Accurate PCD diagnosis comprises clinical assessment, analysis of cilia and the identification of biallelic variants in one of 50 known PCD-related genes, including HYDIN. HYDIN-related PCD is underdiagnosed due to the presence of a pseudogene, HYDIN2, with 98% sequence homology to HYDIN. This presents a significant challenge for Short-Read Next Generation Sequencing (SR-NGS) and analysis, and many diagnostic PCD gene panels do not include HYDIN. We have used a combined approach of SR-NGS with bioinformatic masking of HYDIN2, and state-of-the-art long-read Nanopore sequencing (LR_NGS), together with analysis of respiratory cilia including transmission electron microscopy and immunofluorescence to address the underdiagnosis of HYDIN as a cause of PCD. Bioinformatic masking of HYDIN2 after SR-NGS facilitated the detection of biallelic HYDIN variants in 15 of 437 families, but compromised the detection of copy number variants. Supplementing testing with LR-NGS detected HYDIN deletions in 2 families, where SR-NGS had detected a single heterozygous HYDIN variant. LR-NGS was also able to confirm true homozygosity in 2 families when parental testing was not possible. Utilising a combined genomic diagnostic approach, biallelic HYDIN variants were detected in 17 families from 242 genetically confirmed PCD cases, comprising 7% of our PCD cohort. This represents the largest reported HYDIN cohort to date and highlights previous underdiagnosis of HYDIN-associated PCD. Moreover this provides further evidence for the utility of LR-NGS in diagnostic testing, particularly for regions of high genomic complexity.

INTRODUCTION:Current guidelines recommend suspecting transthyretin amyloid cardiomyopathy (ATTR-CM) in patients over 65 years of age with unexplained left ventricular (LV) hypertrophy in a non-dilated LV, heart failure (HF) and preserved ejection fraction (HFpEF), hypertrophic cardiomyopathy or severe aortic stenosis. However, there is evidence indicating a high prevalence of ATTR-CM in other HF phenotypes. As such, this study aimed to characterize the diversity of HF phenotypes of ATTR-CM by examining the LV ejection fraction and LV dilatation using echocardiography. METHODS:This multicentre, retrospective observational study included patients diagnosed with ATTR-CM between 2015-2023. The diagnosis was based on a positive cardiac biopsy or positive bone scintigraphy without monoclonal gammopathy. Echocardiographic measurements were categorized according to LV ejection fraction (LVEF) into HFpEF (LVEF ≥50%), HF with mildly reduced EF (HFmrEF, LVEF 40-49%), and HF with reduced EF (HFrEF, LVEF <40%). LV cavity size was categorized by LV end-diastolic diameter (LVEDD) and volume index (LVEDVi) as normal, moderately increased and severe dilatation. RESULTS:The study included 135 patients with ATTR-CM (mean age, 78 years; 89% male; 89% wild-type ATTR-CM). Most patients were screened for ATTR-CM because of unexplained HF and increased LV wall thickness (57%). Echocardiography showed LVEF <50% in 60% of the patients, with a significant portion presenting with HFrEF. Patients with LVEF <50% had higher NYHA class and elevated N-terminal pro-B-type natriuretic peptide levels than HFpEF patients. LV dilatation was observed in 43% of the patients, with 10% presenting with both LVEF <50% and severe LV dilatation. CONCLUSION:This study revealed significant variability in HF phenotypes among patients with ATTR-CM, from HFpEF without LV dilatation to HFrEF with severe LV dilatation. Relying solely on HFpEF for screening may lead to under-diagnosis. These findings suggest the need for more comprehensive diagnostic criteria beyond echocardiographic measures to improve ATTR-CM detection and management.

Hypertrophic cardiomyopathy (HCM) is a common genetically heterogeneous inherited heart condition most frequently associated with pathogenic variants in genes encoding the cardiac sarcomere. Identifying at-risk relatives through cardiovascular screening and cascade genetic testing promotes early diagnosis and enables personalised management. Multispecialty expertise is required to efficiently and effectively engage HCM families in this process. Initial assessments include clinical evaluation, cardiac imaging, family history analysis, and genetic testing/ counselling. These elements are optimally combined in a multidisciplinary family-based clinic that facilitates coordinated management and family support. Here we describe the rationale for, and components of, a multidisciplinary family-based HCM screening clinic.

BACKGROUND Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetic heart disease associated with life-threatening ventricular arrhythmias. Diagnosis of ARVC is based on the 2010 Task Force Criteria (TFC), application of which often requires clinical expertise at specialized centers. OBJECTIVE The purpose of this study was to develop and validate an electrocardiogram (ECG) deep learning (DL) tool for ARVC diagnosis. METHODS ECGs of patients referred for ARVC evaluation were used to develop (n = 551 [80.1%]) and test (n = 137 [19.9%]) an ECG-DL model for prediction of TFC-defined ARVC diagnosis. The ARVC ECG-DL model was externally validated in a cohort of patients with pathogenic or likely pathogenic (P/LP) ARVC gene variants identified through the Geisinger MyCode Community Health Initiative (N = 167). RESULTS Of 688 patients evaluated at Johns Hopkins Hospital (JHH) (57.3% male, mean age 40.2 years), 329 (47.8%) were diagnosed with ARVC. Although ARVC diagnosis made by referring cardiologist ECG interpretation was unreliable (c-statistic 0.53; confidence interval [CI] 0.52-0.53), ECG-DL discrimination in the hold-out testing cohort was excellent (0.87; 0.86-0.89) and compared favorably to that of ECG interpretation by an ARVC expert (0.85; 0.84-0.86). In the Geisinger cohort, prevalence of ARVC was lower (n = 17 [10.2%]), but ECG-DL-based identification of ARVC phenotype remained reliable (0.80; 0.77-0.83). Discrimination was further increased when ECG-DL predictions were combined with non-ECG-derived TFC in the JHH testing (c-statistic 0.940; 95% CI 0.933-0.948) and Geisinger validation (0.897; 95% CI 0.883-0.912) cohorts. CONCLUSION ECG-DL augments diagnosis of ARVC to the level of an ARVC expert and can differentiate true ARVC diagnosis from phenotype-mimics and at-risk family members/genotype-positive individuals.

Background: Pathogenic/likely pathogenic variants (P/LP) in the desmin ( DES ) gene cause heterogeneous cardiomyopathy and skeletal myopathy phenotypes. Research Questions: Limited data suggest that patients with P/LP DES variants have a high incidence of major adverse cardiac events (MACEs), including cardiac conduction disease requiring pacemaker implantation (CCD-PM), sustained ventricular arrhythmias (VA), and heart failure (HF) events (HF hospitalization, heart transplant, HF-related death). However, small cohort sizes have limited full clinical characterization. Aims: We aimed to describe the natural history, phenotype spectrum, familial penetrance and MACE in patients with P/LP DES variants identified via clinical genetic testing. Methods: We conducted a systematic review and individual patient data meta-analysis of cardiac and skeletal myopathy phenotypes and MACE (CCD-PM, VA and HF events) in patients with P/LP DES variants by retrieving publications from Medline (PubMed) and Embase. Diagnosis of cardiomyopathy or MACE were both considered evidence of cardiac involvement. Results: Out of 4,212 screened records, 72 met inclusion criteria. In total, 230 patients were included (52.6% male, 52.2% probands, median age: 31 years at first evaluation [22.0; 42.8]). Eighty-five (37.0%) patients showed isolated cardiac involvement, 89 (38.7%) cardiac and skeletal muscle involvement, 39 (17.0%) only skeletal muscle involvement, and 17 (7.4%) had neither phenotype. Overall, 130 (56.5%) patients were diagnosed with a cardiomyopathy and 134 (57.4%) patients developed MACE (96 [41.7%] had CCD-PM, 36 [15.7%] sustained VA, and 43 [18.7%] HF events). Familial cardiac disease penetrance was 69.1% (76/110) in relatives with P/LP DES variants. Out of 40 patients who presented with isolated CCD-PM phenotype, 18 (45.0%) were diagnosed with a cardiomyopathy after 6 [2.0; 16.0] years of follow-up. In multivariable analysis, male sex and non-missense variants were associated with higher risk of sustained VA (HR 2.71, p=0.008, and HR 4.62, p<0.001, respectively) and HF events (HR 2.63, p=0.005, and HR 2.79, p=0.015). Conclusions: DES cardiomyopathy demonstrates a distinct natural history, characterized by high familial penetrance and a high MACE burden. Male patients and those carrying non-missense variants are at higher risk for sustained VA events and may benefit from primary preventive ICD implantation even in the absence of severe LV systolic dysfunction.