Diane Fatkin

Circulation. Genomic and precision medicine • March 25, 2025

Susan Clasper, Gunjan Trivedi, Kate Thomson, Claire L Turner, Smrithi Devaiah, Catherine Mercer, Amnah Bdeir, Jumana Al Aama, Khalid Dagriri, Alex Hobson, Shankar Sadagopan, Julian Ormerod, Eszter Szepesvary, Justin Phan, Diane Fatkin, Jamie Vandenberg, Zahurul Bhuiyan, Chai-ann Ng

MedRxiv : The Preprint Server For Health Sciences • August 08, 2025

Brendan Floyd, Joyce Njoroge, Vikki Krysov, Bruna Gomes, Ryan Murtha, Chiaka Aribeana, Douglas Cannie, Eric Smith, Alessia Paldino, Emily Brown, Andreas Barth, Erkan Ilhan, Renee Johnson, Julianne Wojciak, Mohamad Alkhayat, Sharon Graw, Kristen Medo, Jan Haas, C Anwar Chahal, Kai Fenzl, Lars Steinmetz, Michael Gollob, Euan Ashley, Sharlene Day, Daniel Judge, Jason Roberts, Vasanth Vedantham, Chad Mao, Diane Fatkin, Neal Lakdawala, Matthew R Taylor, Luisa Mestroni, Ardan Saguner, Upasana Tayal, Julia Cadrin Tourigny, Andrew Krahn, Cynthia James, Matteo Dal Ferro, Gianfranco Sinagra, Marco Merlo, Anjali Owens, Nosheen Reza, Sara Saberi, Adam Helms, Perry Elliott, Benjamin Meder, Victoria Parikh

Genetic diagnosis has become increasingly important to guide clinical decision making for patients with dilated cardiomyopathy (DCM). Disease-causing (P/LP) missense variants in the gene RBM20 cause a highly penetrant arrhythmogenic dilated cardiomyopathy (DCM), but the role of truncating RBM20 variants ( RBM20tvs ) is unclear. Assess the contribution of RBM20tvs to DCM. We assembled an international cohort of DCM patients with RBM20 variants and used data from the genome-first UK Biobank (UKB) to assess the etiologic fraction, natural history and penetrance of RBM20tvs . The etiologic fraction of RBM20tvs in arrhythmogenic DCM was modest (0.53[0.32,0.67], p=7.5×10 -5 ). RBM20tv DCM patients presented to referral centers later in life than RBM20 P/LP DCM patients (53±10 vs. 34±18 years, p=4×10 -3 ), and were less likely to have a family history of sudden cardiac arrest (20% vs. 65%, p= 0.046) or cardiomyopathy (20% vs. 78% p=5.4×10 -3 ). There was no significant difference in age- and sex-adjusted incident major heart failure or arrhythmia events between RBM20tv and RBM20 P/LP DCM patients, though sex-adjusted lifetime hazard was reduced in RBM20tv DCM (HR 0.15[0.03,0.66],p=0.009). In UKB, lifetime incidence of cardiomyopathy, heart failure, or major ventricular arrhythmia diagnosis was lower in participants with RBM20tvs than in those with TTNtvs (HR 0.55 [0.36,0.84], p=5.9×10 -3 ). RBM20tvs contribute to arrhythmogenic DCM phenotypes, but confer milder disease severity alone than RBM20 P/LP variants, and reduced lifetime disease penetrance compared to TTNtvs . Their potential for additive interactions with other damaging variants should be considered in DCM patients and families.

Circulation Research • July 03, 2025

Eleanor Rye, Amy Mitchell, Celine Santiago, Andre La Gerche, Diane Fatkin

Exercise is generally considered beneficial for cardiovascular health, but for patients with inherited cardiomyopathies, exercise can be a source of anxiety due to concerns about arrhythmia risk and disease progression. In the general population, exercise avoidance can impact cardiometabolic health and diminished fitness is a risk factor for heart failure. At the other extreme, sustained high levels of exercise in competitive endurance athletes have been associated with an increased risk of some arrhythmias. Defining optimal threshold levels for exercise participation is not straightforward and one-size-fits-all recommendations are unlikely to be successful. In the context of inherited cardiomyopathies, the impact of exercise on myocardial function and arrhythmias depends on factors such as exercise frequency, intensity, and duration, as well as the type of cardiomyopathy, underlying genotype, and other unique intrinsic traits in each individual. This review outlines current knowledge with respect to the impact of exercise in hypertrophic, arrhythmogenic, and dilated cardiomyopathies based on studies in human cohorts and animal models. Several disease-specific and genotype-specific risk factors are highlighted, although our understanding of these factors remains incomplete. Importantly, although exercise activities remain restricted for those with high-risk features, emerging evidence suggests that moderate-to-high levels of exercise may be safe and beneficial for many patients. Harnessing the cardioprotective power of exercise holds enormous promise for expanding personalized strategies for cardiomyopathy treatment and prevention.

Journal Of The American Heart Association • May 02, 2025

Stacey Peters, Leah Wright, Jess Yao, Lauren Mccall, Tina Thompson, Bryony Thompson, Renee Johnson, Quan Huynh, Celine Santiago, Alison Trainer, Mark Perrin, Paul James, Dominica Zentner, Jon Kalman, Thomas Marwick, Diane Fatkin

Background: Familial dilated cardiomyopathy (DCM) is characterized by marked variability in phenotypic penetrance. The extent to which this is determined by patient-specific environmental factors is unknown. Results: A retrospective longitudinal cohort study was performed in families with DCM-causing genetic variants. Environmental factors were classified into 2 subsets based on evidence for a causal link to depressed myocardial contractility, termed (1) DCM-promoting factors and (2) heart failure comorbidities. These factors were correlated with DCM diagnosis and disease trajectory after accounting for relevant confounders and familial relatedness. A total of 105 probands and family members were recruited: 51 genotype positive, phenotype positive, 24 genotype positive, phenotype negative, and 30 genotype negative, phenotype negative. Demographic characteristics were similar between the 3 genotype groups. DCM-promoting environmental factors (eg, alcohol excess) were enriched in genotype-positive, phenotype-positive individuals compared with genotype-positive, phenotype-negative (P<0.001) and genotype-negative, phenotype-negative (P=0.003) individuals and were significantly associated with age at DCM onset (hazard ratio, 2.01; P=0.014). Heart failure comorbidities (eg, diabetes) had a similar prevalence in genotype-positive, phenotype-positive and genotype-negative, phenotype-negative individuals but were significantly reduced in the genotype-positive, phenotype-negative group. Fluctuations in left ventricular ejection fraction during follow-up were linked to changes in environmental factors in 35 of 45 (78%) of instances: 32 (91%) of these were DCM-promoting factors. Conclusions: We identified distinct subsets of environmental factors that affect DCM penetrance and trajectory. Our data highlight DCM-promoting environmental factors as key determinants of penetrance and natural history. Collectively, these findings provide a new framework for risk factor assessment in familial DCM and have important implications for clinical management.

JAMA Cardiology • February 12, 2025

Davide Stolfo, Giulia Barbati, Sharon Graw, Suet Chen, Marco Merlo, Kristen Medo, Caterina Gregorio, Matteo Dal Ferro, Alessia Paldino, Maria Perotto, J Peter Van Tintelen, Anneline S J Te Riele, Annette Baas, Arthur Wilde, Ahmad Amin, Arjan Houweling, Perry Elliott, Douglas Cannie, Michelle Michels, Stephan A Schoonvelde, Sanjay Prasad, Paz Tayal, Momina Yazdani, Deborah Morris Rosendahl, Pablo Garcia Pavia, Eva Cabrera Romero, Barbara Bauce, Kalliopi Pilichou, Diane Fatkin, Renee Johnson, Daniel Judge, Kimberly Foil, Stephane Heymans, Job A Verdonschot, Sophie L Stroeks, Neal Lakdawala, Purohit Anisha, Matthew O'neill, M Shoemaker, Dan Roden, Hugh Calkins, Cynthia James, Brittney Murray, Victoria Parikh, Euan Ashley, Chloe Reuter, Massimo Imazio, Marco Canepa, Pietro Ameri, Jiangping Song, Gianfranco Sinagra, Matthew R Taylor, Luisa Mestroni

Filamin C truncating variants (FLNCtv) are a rare cause of cardiomyopathy with heterogeneous phenotypic presentations. Despite a high incidence of life-threatening ventricular arrhythmias and sudden cardiac death (SCD), reliable risk predictors to stratify carriers of FLNCtv are lacking. To determine factors predictive of SCD/major ventricular arrhythmias (MVA) in carriers of FLNCtv. This was an international, multicenter, retrospective cohort study conducted from February 2023 to June 2024. The Filamin C Registry Consortium included 19 referral centers for genetic cardiomyopathies worldwide. Participants included carriers of pathogenic or likely pathogenic FLNCtv. Phenotype negative was defined as the absence of any pathological findings detected by 12-lead electrocardiogram (ECG), Holter ECG monitoring, echocardiography, or cardiac magnetic resonance. Composite of SCD and MVA in carriers of FLNCtv. The primary outcome was a composite of SCD and MVA, the last including aborted SCD, sustained ventricular tachycardia, and appropriate implantable cardioverter-defibrillator (ICD) interventions. Among 308 individuals (median [IQR] age, 45 [33-56] years; 160 male [52%]) with FLNCtv, 112 (36%) were probands, and 72 (23%) were phenotype negative. Median (IQR) left ventricular ejection fraction (LVEF) was 51% (38%-59%); 89 participants (34%) had LVEF less than 45%, and 50 (20%) had right ventricular dysfunction. During a median (IQR) follow-up of 34 (8-63) months, 57 individuals (19%) experienced SCD/MVA, with an annual incidence rate of 4 cases per 100 person-years (95% CI, 3-6). Incidence rates were higher in probands vs nonprobands and in phenotype-positive vs phenotype-negative individuals. A predictive model estimating SCD/MVA risk was derived from multivariable analysis, which included older age, male sex, previous syncope, nonsustained ventricular tachycardia, and LVEF with a time-dependent area under the curve (AUC) ranging between 0.76 (95% CI, 0.67-0.86) at 12 months and 0.78 (95% CI, 0.70-0.86) at 72 months. Notably, the association of LVEF with the SCD/MVA risk was not linear, showing significant lower risk for values of LVEF greater than 58%, and no increase for values less than 58%. Internal validation with bootstrapping confirmed good accuracy and calibration of the model. Results were consistent in subgroups analysis (ie, phenotype-positive carriers and phenotype-positive carriers without MVA at onset). Results suggest that the risk of SCD/MVA in phenotype-positive carriers of FLNCtv was high. A 5-variable predictive model derived from this cohort allows risk estimation and could support clinicians in the shared decision for prophylactic ICD implantation. External cohort validation is warranted.