Cardiomyopathies are important causes of arrhythmias, sudden cardiac death, and heart failure. With accumulating knowledge in clinical, genetic, and molecular phenotyping, the number of distinct disease entities is growing. There is a need for broad, inclusive, high-quality prospective multi-center registries to better analyze these phenotypes, provide accurate risk stratification, and tailor therapies. The Dutch Cardiomyopathy Registry (DCR) will serve as a longitudinal registry for all cardiomyopathy patients, exploiting previously built local databases, allowing adequately powered research studies. The DCR is a multi-center observational registry that unites all Dutch University Medical centers. The registry will have local and central shared databases, which will be hosted and coordinated by the Netherlands Heart Institute. Patients with an established cardiomyopathy diagnosis and carriers of pathogenic or likely-pathogenic cardiomyopathy gene variants will be included. Furthermore, selected family members and individuals who are referred for screening for potential cardiomyopathy are eligible for inclusion. The subjects will receive, per best clinical practice, guideline-recommended diagnostics and treatment. Clinical data will be collected from clinical care at baseline and follow-up, including clinical visits, imaging studies, laboratory assessments, ECG, and additional functional tests. Outcome data consists of clinical performance status, cardiovascular complications and major adverse events, recorded through regular electronic health record files. The DCR will function as a national database, providing relevant information on epidemiology, demographics, natural history, diagnosis, and treatment. This will aid risk prediction and monitoring of new therapies. The DCR can identify patients who are eligible for future studies, including registry-based research.

BACKGROUND AND AIMS:Hypertrophic cardiomyopathy (HCM) is characterized by increased risk of malignant ventricular arrhythmias (MVA) and heart failure (HF). There is increasing awareness that epicardial adipose tissue (EAT) is associated with an adverse prognosis in cardiovascular disease, but its role in genotype-positive HCM patients is unknown. METHODS:EAT volume was quantified by cardiovascular magnetic resonance in a retrospective genotype-positive HCM cohort. Patients were split into high and low EAT groups by the median. Multivariable Cox regression was used to examine the association between EAT volume and (1) MVA (sustained ventricular tachycardia, ventricular fibrillation, appropriate implantable cardioverter defibrillator shock, sudden cardiac death (SCD), or death of unknown cause), and (2) HF events (HF hospitalization, heart transplantation, or HF-related mortality). RESULTS:We included 282 patients (48±14 years, 64.5% male). The high EAT group had greater maximal wall thickness (25.0±6.4 vs 20.8±4.9mm, p<0.001), more extensive late gadolinium enhancement (6.1% [0.0-14.0] vs 1.0% [0.0-6.2], p<0.001), and more frequent left ventricular outflow tract obstruction (42.6% vs 15.6%, p<0.001) compared with the low EAT group. During 62 [32-96] months of follow-up, EAT volume was independently associated with the incidence of MVA (HR 1.04 [95%CI 1.02-1.06], p<0.001) and HF events (HR 1.05 [95%CI 1.03-1.08], p<0.001). EAT volume showed good discriminative ability for both MVA (C-statistic 0.79, p<0.001) and HF events (C-statistic 0.79, p<0.001), and appeared to perform better than the HCM SCD risk score for MVA (C-statistic comparison p=0.011). CONCLUSION:EAT accumulation is associated with phenotype severity and independently associated with the incidence of MVA and HF events in genotype-positive HCM patients.These findings suggest that EAT should be considered a novel factor in HCM risk assessment.

BACKGROUND:Marfan syndrome (MFS) patients with a history of aortic root surgery (ARS) are at increased risk of type B aortic dissection, possibly because the noncompliant graft fails to absorb systolic forces, leading to undampened flow in the proximal descending aorta (pDAo). In this study, we investigated the magnitude and location of abnormal aortic displacement and wall shear stress (WSS) using cardiac magnetic resonance (CMR) imaging. METHODS:We examined 82 MFS patients (32 with ARS, 34 ± 8 years, 36 women) and 45 age- and sex-matched controls, all undergoing four-dimensional high-resolution balanced steady-state free precession and flow CMR. Peak displacement and WSS were calculated using automated aortic segmentations. Heatmaps were created to identify and quantify regions with abnormal displacement and WSS. The surface areas of abnormal displacement and WSS were quantified in four aortic regions. The Wilcoxon signed-rank test was used for comparison of abnormal CMR parameter quantification, and Pearson correlation was used to assess correlations between displacement and WSS. RESULTS:WSS was higher in the proximal (p < 0.001) and distal ascending aorta (Aao) (p = 0.031) of ARS MFS patients compared to native MFS patients. ARS MFS patients had significantly larger surface areas of decreased displacement (p < 0.001; present in 97% (31/32) of ARS MFS patients) and increased WSS (p < 0.001; present in 100% (32/32) of patients) in the proximal Aao. There was a trend toward a larger surface area of increased displacement in the pDAo of ARS MFS patients (p = 0.062; present in 72% (23/32) of patients), mainly located in the outer pDAo. pDAo displacement was positively correlated with pDAo WSS (Pearson r = 0.46 [95% confidence interval: 0.13, 0.70], p = 0.008). CONCLUSION:Aortic displacement and flow characteristics are abnormal in MFS patients, both with and without a history of ARS. ARS MFS patients exhibit distinct features in both the AAo and descending aorta (DAo), particularly in the proximal DAo, which is the region susceptible to type B aortic dissections.

Abstract Background Hypertrophic cardiomyopathy (HCM) is a clinically variable disease in terms of onset and progression. Pathogenic MYBPC3 variants account for a substantial proportion of HCM diagnoses. This study sought to identify protein biomarkers associated with HCM severity. Methods Olink-assayed plasma proteins of 144 MYBPC3 pathogenic variant carriers were tested for associations with HCM severity based on HCM diagnostic criteria (unaffected, mildly, or severely affected). The UK Biobank was used to replicate the identified proteins through considering time to onset of HCM (67 cases), cardiomyopathy (156 cases),and associations with cardiac MRI derived left ventricular maximum wall thickness (6,492 participants). Replicated proteins were further prioritised based on cardiac tissue expression and druggability, and annotated using pathway enrichment and association with onset of: heart failure (HF), dilated cardiomyopathy (DCM), sudden cardiac arrest (SCA), and ventricular arrhythmias (VA). Results Among pathogenic MYBPC3 variant carriers, we identified 27 proteins associated with HCM severity. We independently replicated 21 proteins in the UK Biobank. Of the five prioritised proteins (NT-proBNP, GDF-15, FGF-23, ADM, and NCAM1), all but NT-proBNP were targeted by drugs with repurposing potential. The replicated proteins additionally associated with the incidence of HF (n=5), DCM (n=4), SCA (n=4), and VA (n=4). Conclusion This study replicated 21 and prioritised five proteins associated with HCM severity in pathogenic MYBPC3 variant carriers. Replication in unselected HCM suggests the prioritised proteins are associated with HCM independent of genotype, providing important leads for plasma-based markers for diagnoses, disease monitoring, and drug targets.

This article contextualises the 2023 European Society of Cardiology (ESC) guidelines for the management of cardiomyopathies for clinical practice in the Netherlands. The guideline addendum provides additional recommendations for situations where the ESC guidelines may not fully align with Dutch clinical practice. By endorsing the ESC guidelines through this addendum, the Netherlands Society of Cardiology (Nederlandse Vereniging Voor Cardiologie) supports its members in adhering to evidence-based management strategies for cardiomyopathies. As Dutch cardiologists generally adopt the ESC guidelines quickly, this contextualisation is essential for effective application thereof within the Dutch healthcare setting.

BACKGROUND:Phospholamban (PLN) p.(Arg14del)-positive individuals are at high risk of developing PLN p.(Arg14del)-related cardiomyopathy, which can lead to progressive heart failure that is poorly amenable to standard heart failure treatment. Genetic therapies for patients with hereditary cardiomyopathy are rapidly advancing, but identifying patients who will benefit from and rely on these therapies is challenging because of reduced penetrance and highly variable expression. OBJECTIVES:The aim of this study is to identify clinical predictors of heart failure outcomes in PLN p.(Arg14del)-positive individuals. METHODS:Data were collected of 904 PLN p.(Arg14del)-positive individuals from the PLN/ACM Registry. The primary endpoint of the study was a composite endpoint of heart failure outcomes, defined as heart failure hospitalization, left ventricular or biventricular assist device implantation, heart transplantation, or heart failure-related death. Predictors of heart failure outcomes were identified using Least Absolute Shrinkage and Selection Operator Cox regression analyses with different penalization parameters. RESULTS:During a median follow-up of 5.4 years (Q1-Q3: 2.3-9.7 years), 116 study participants (13%) reached the primary endpoint (heart failure hospitalization [75%], heart transplantation [10.3%], left ventricular or biventricular assist device implantation [9.5%], and heart failure-related death [5.2%]). The predictors that remained significant across all analyses were left ventricular ejection fraction, low-voltage electrocardiogram, and NYHA functional class ≥II, measured at first evaluation. CONCLUSIONS:This study identified predictors for heart failure outcomes in PLN p.(Arg14del)-positive individuals that can improve risk prediction. Identifying those at risk for heart failure outcomes is of great importance given the rapid advancements in genetic therapies that may offer potential treatments for hereditary cardiomyopathy.

This article contextualises the 2023 European Society of Cardiology (ESC) guidelines for the management of cardiomyopathies for clinical practice in the Netherlands. The guideline addendum provides additional recommendations for situations where the ESC guidelines may not fully align with Dutch clinical practice. By endorsing the ESC guidelines through this addendum, the Netherlands Society of Cardiology (Nederlandse Vereniging Voor Cardiologie) supports its members in adhering to evidence-based management strategies for cardiomyopathies. As Dutch cardiologists generally adopt the ESC guidelines quickly, this contextualisation is essential for effective application thereof within the Dutch healthcare setting.

BACKGROUND:Penetrance and risk of ventricular arrhythmias (VAs) in arrhythmogenic right ventricular cardiomyopathy (ARVC) are increasingly recognized as being genotype specific. Therefore, genotype-informed family screening protocols may lead to safer and more personalized recommendations than the current one-size-fits-all screening recommendations. We aimed to develop a safe, evidence-based plakophilin-2 (PKP2)-specific longitudinal screening algorithm. METHODS:We included 295 relatives (41% male; age 30.9 years [18.0-47.7 years]) with a pathogenic or likely pathogenic PKP2 variant from 145 families. Phenotype was ascertained with ECG, Holter monitoring, and cardiac imaging and classified by the 2010 Task Force Criteria. VA was defined as a composite of sudden cardiac arrest or death, spontaneous sustained ventricular tachycardia, ventricular fibrillation, or appropriate implantable cardioverter defibrillator intervention. We performed Cox regression to determine predictors of ARVC development and multistate modeling to assess the probability of ARVC development and occurrence of VA. RESULTS:At baseline, 110 relatives (37%) had definite ARVC. During 8.5 years (4.2-12.9 years) of follow-up, 62 of 185 relatives (34%) without definite ARVC at baseline progressed to definite ARVC diagnosis, and 35 of 295 of all relatives (12%) had VA. VAs occurred only in relatives who previously fulfilled definite ARVC diagnosis. Relatives with borderline ARVC (fulfillment of one minor criterion plus the major family history criterion) progressed 5 times faster in the multistate model to definite ARVC diagnosis and compared with genotype-positive/phenotype-negative (G+/P-) relatives (ie, major family history criterion alone). Relatives 20 to 40 years of age had increased risk for developing definite ARVC (hazard ratio, 2.23; P=0.012) compared with those ≥40 years of age. New Task Force Criteria fulfillment most commonly occurred first on ECGs, followed by Holter monitoring and cardiac imaging. Consequently, 3 risk profiles were identified, and appropriate screening protocols were derived: relatives with borderline ARVC (annual ECG and Holter monitoring; complete evaluation [ie, ECGs, Holter monitoring, and imaging] every 2 years), younger (<40 years of age) or symptomatic G+/P- relatives (every 2 years an ECG and Holter monitoring; complete evaluation every 4 years), and older (≥40 years of age) and asymptomatic G+/P- relatives (complete evaluation every 5 years). CONCLUSIONS:An evidence-based longitudinal screening algorithm that integrates age, symptoms, and baseline clinical phenotype may improve patient care and improve efficiency of clinical resource allocation.

Since the development of heart failure in PLN-associated cardiomyopathy is highly variable, accurate risk prediction in phospholamban (PLN) p.(Arg14del)-positive individuals is essential to identify patients who may benefit from and rely on future (gene) therapies. Vectorcardiographic data may improve heart failure predictions as it holds information on ventricular depolarization and repolarization patterns which are likely altered in this genetic variant due to fibrosis and fibrofatty replacement. To assess the prognostic value of vectorcardiograic data using repeated measurements for predicting heart failure in PLN p.(Arg14del)-positive individuals. Data were collected of 417 PLN p.(Arg14del)-positive individuals (mean age 44.3 ± 16 years, 45.6% male) with no history of heart failure. During a median follow-up of 6 years (Interquartile range 3.1-10.7 years) after first cardiological investigation, 61 (14.6%) carriers experienced a heart failure composite endpoint, consisting of heart failure hospitalization, left ventricular assist device implantation, heart transplantation and heart failure related death. Vectorcardiographic data was derived from 12-lead ECG and four vector parameters over time were included in a multivariable Cox regression model: spatial QRS amplitude, spatial T wave amplitude, QRS-T angle, and vector gradient. After backward selection two parameters remained significantly associated with heart failure events: spatial T wave amplitude (p-value = 0.002) and QRS-T angle (p-value < 0.001). These variables were then used in a joint model with repeated vector measurements to provide individualized risk predictions (Figure 1). The model yielded a C-statistic of 0.86 (95% confidence interval [CI], 0.85 – 0.87) after 10-fold cross validation in the training set and 0.86 (95% CI, 0.83-0.89) in the test set. Vectorcardiographic data over time holds important prognostic information that can predict heart failure in phospholamban p.(Arg14del)-positive individuals. These results may identify individuals at highest risk for heart failure.Figure 1.Example individual trajectory

BACKGROUND:Acute aortic syndromes in Marfan syndrome (MFS) often occur before reaching the surgical diameter threshold, highlighting the need for new imaging biomarkers. OBJECTIVES:Aim was to compare cardiovascular magnetic resonance (CMR)-derived aortic three-dimensional (3D) distensibility and displacement in MFS patients with or without a history of aortic root surgery (RR or native) and healthy volunteers. METHODS:The participants underwent 3T CMR of the thoracic aorta using an accelerated non-contrast-enhanced, free breathing, 3D cine balanced steady state free precession sequence, with spatiotemporal resolution: (1.0 mm)3/∼33ms. A deep learning-based algorithm was used to obtain aorta segmentations. Non-rigid registration of these segmentations was subsequently used to calculate 3D distensibility and its separate components: 2-dimensional distensibility, longitudinal strain, and displacement in the ascending (AAo) and descending aorta (DAo). RESULTS:Forty-seven volunteers, 51 native, and 33 RR MFS patients were included. AAo and DAo distensibility (10-3*mmHg-1) were different for healthy volunteers vs native vs RR patients (AAo: 5.1±1.4 vs 3.6±1.4 vs. 1.4±0.7, p<0.001, DAo: 3.2±1.1 vs. 2.5±0.9 vs 2.4±1.0, p=0.001). Sinotubular junction displacement (mm) was significantly higher for healthy volunteers vs native MFS vs RR MFS patients (10.3±1.3 vs 8.7±2.1 vs 5.7±1.6, p<0.001). In native patients, age (β=-0.06 (95% CI:-0.10 to -0.01), p=0.014) and root diameter (β=-0.1 (95% CI: -0.19 to -0.02), p=0.018) were negatively associated with AAo 3D distensibility, independent of male sex, body surface area, and aortic tortuosity index. CONCLUSION:Aortic 3D distensibility and displacement, derived from 4-dimensional CMR, were significantly diminished in MFS compared to volunteers and should be investigated longitudinally to assess their potential value in predicting aortic events and guiding therapy.

BACKGROUND:New treatment strategies are required to reduce aortic events in Marfan syndrome (MFS). Resveratrol is a dietary supplement that intervenes in aortic wall cellular metabolism and may benefit MFS patients. PURPOSE:To evaluate whether treatment with Resveratrol affects aorta hemodynamics derived from 4D flow MRI in MFS. STUDY TYPE:Prospective single-arm open-label multicenter trial. POPULATION:46 MFS patients (mean age 36 ± 9 years, 23 female), 20 with and 26 without a history of aortic root surgery (RR and native MFS), and 25 age- and sex-matched healthy controls. FIELD STRENGTH/SEQUENCE:3T, temporally resolved 3D phase contrast (4D flow MRI) and 3D mDixon sequences. ASSESSMENT:MFS patients underwent 4D flow MRI before (baseline) and after 1 year of 500 mg daily Resveratrol treatment (follow-up). Velocity magnitude and wall shear stress (WSS) in six regions in the thoracic aorta were evaluated. Incidence maps showing abnormal hemodynamics compared to healthy controls were generated. Pulse wave velocity (PWV) was assessed in 45 subjects. The relationships between MRI parameters and annual aortic growth from the 3D mDixon scans and age were investigated. STATISTICAL TESTS:Student's paired and unpaired t-tests, Fisher's exact tests, McNemar's exact test, and Pearson correlation coefficients (r). Statistical significance was defined as p < 0.05. RESULTS:No significant changes in any of the hemodynamic parameters were observed: inner descending aorta WSS (Pa), native: from 1.08 ± 0.21 to 1.08 ± 0.17, p = 0.818, RR: from 1.02 ± 0.29 to 0.98 ± 0.21, p = 0.270; velocity (m/s), native: from 0.64 ± 0.10 to 0.65 ± 0.10, p = 0.359, RR: 0.68 ± 0.15, to 0.67 ± 0.12, p = 0.629; abnormally directed WSS incidence: native: from 17 (65%) to 14 (54%), p = 0.453, RR: 13 (65%) to 13 (65%), p = 1.000; PWV (m/s) native: from 7.7 ± 1.9 to 7.9 ± 1.8, p = 0.582, RR: 9.2 ± 1.6 to 8.2 ± 3.2, p = 0.184. PWV correlated with age in RR MFS patients (r = 0.59, n = 19). DATA CONCLUSION:No significant changes in aortic hemodynamics derived from 4D flow MRI were observed after 1 year of Resveratrol treatment. EVIDENCE LEVEL:1. TECHNICAL EFFICACY:Stage 4.

Background and Aims Pathogenic variants in the desmoplakin (DSP) gene are associated with the development of a distinct arrhythmogenic cardiomyopathy phenotype not fully captured by either dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), or arrhythmogenic right ventricular cardiomyopathy (ARVC). Prior studies have described baseline DSP cardiomyopathy genetic, inflammatory, and structural characteristics. However, cohort sizes have limited full clinical characterization and identification of clinical and demographic predictors of sustained ventricular arrhythmias (VAs), heart failure (HF) hospitalizations, and transplant/death. In particular, the relevance of acute myocarditis-like episodes for subsequent disease course is largely unknown. Methods All patients with pathogenic/likely pathogenic (P/LP) DSP variants in the worldwide DSP-ERADOS Network (26 academic institutions across nine countries) were included. The primary outcomes were the development of sustained VA and HF hospitalizations during follow-up. Fine-Gray regressions were used to test association between clinical and instrumental parameters and the development of outcomes. Results Eight hundred patients [40.3 +/- 17.5 years, 47.5% probands, left ventricular ejection fraction (LVEF) 49.5 +/- 13.9%] were included. Over 3.7 [1.4-7.1] years, 139 (17.4%, 3.9%/year) and 72 (9.0%, 1.8%/year) patients experienced sustained VA and HF episodes, respectively. A total of 32.5% of individuals did not fulfil diagnostic criteria for ARVC, DCM, or NDLVC; their VA incidence was 0.5%/year. In multivariable regression, risk features associated with the development of VA were female sex [adjusted hazard ratio (aHR) 1.547; P = .025], prior non-sustained ventricular tachycardia (aHR 1.721; P = .009), prior sustained VA (aHR 1.923; P = .006), and LVEF <= 50% (aHR: 1.645; P = .032), while for HF, they were the presence of T-wave inversion in 3+ electrocardiogram leads (aHR 2.036, P = .007) and LVEF <= 50% (aHR 3.879; P < .001). Additionally, 70 (8.8%) patients experienced a myocardial injury episode at presentation or during follow-up. These episodes were associated with an increased risk of VA and HF thereafter (HR 2.394; P < .001, and HR 5.064, P < .001, respectively). Conclusions Patients with P/LP DSP variants experience high rates of sustained VA and HF hospitalizations. These patients demonstrate a distinct clinical phenotype (DSP cardiomyopathy), whose most prominent risk features associated with adverse clinical outcomes are the presence of prior non-sustained ventricular tachycardia or sustained VA, T-wave inversion in 3+ leads on electrocardiogram, LVEF <= 50%, and myocardial injury events.

BACKGROUND:Phospholamban (PLN) p.(Arg14del) variant carriers are at risk for development of malignant ventricular arrhythmia (MVA). Accurate risk stratification allows timely implantation of intracardiac defibrillators and is currently performed with a multimodality prediction model. OBJECTIVE:This study aimed to investigate whether an explainable deep learning-based approach allows risk prediction with only electrocardiogram (ECG) data. METHODS:A total of 679 PLN p.(Arg14del) carriers without MVA at baseline were identified. A deep learning-based variational auto-encoder, trained on 1.1 million ECGs, was used to convert the 12-lead baseline ECG into its FactorECG, a compressed version of the ECG that summarizes it into 32 explainable factors. Prediction models were developed by Cox regression. RESULTS:The deep learning-based ECG-only approach was able to predict MVA with a C statistic of 0.79 (95% CI, 0.76-0.83), comparable to the current prediction model (C statistic, 0.83 [95% CI, 0.79-0.88]; P = .054) and outperforming a model based on conventional ECG parameters (low-voltage ECG and negative T waves; C statistic, 0.65 [95% CI, 0.58-0.73]; P < .001). Clinical simulations showed that a 2-step approach, with ECG-only screening followed by a full workup, resulted in 60% less additional diagnostics while outperforming the multimodal prediction model in all patients. A visualization tool was created to provide interactive visualizations (https://pln.ecgx.ai). CONCLUSION:Our deep learning-based algorithm based on ECG data only accurately predicts the occurrence of MVA in PLN p.(Arg14del) carriers, enabling more efficient stratification of patients who need additional diagnostic testing and follow-up.