BACKGROUND AND AIMS:Patients with LMNA gene variants are at high risk for dilated cardiomyopathy and heart failure (HF), but no prediction model for severe HF events exists. This study aimed to describe the incidence of severe HF events and develop a prediction model in a large cohort of patients with adult-onset laminopathies. METHODS:From a population of 660 patients enrolled in the French LMNA nationwide registry, 470 adults were included in the derivation cohort. An independent international validation cohort included 245 additional patients. Baseline characteristics at genetic testing were assessed and the cumulative incidence of the primary endpoint HF-major adverse cardiac events (HF-MACE) was calculated, defined as HF hospitalization, HF-related death, mechanical circulatory support, or heart transplantation. Predictors of HF-MACE were studied after excluding patients with left ventricular ejection fraction (LVEF) <30% at baseline using a Fine-Gray competing risk model, adjusted hazard ratio (aHR) with 95% confidence interval (CI), and Harrell's concordance (C-) index. A secondary composite endpoint, without hospitalization, was also studied. RESULTS:Among 470 patients of the derivation cohort, HF-MACE occurred in 65 over a median follow-up of 7.1 years (interquartile range: 3.4-12.1). Four independent predictors of HF-MACE were identified: male sex (aHR 1.86; 95% CI 1.060-3.290), LVEF <50% (aHR 2.18; 95% CI 1.080-4.400), missense variants in head and rod domains (aHR 2.91; 95% CI 1.110-7.630), and complete left bundle branch block (aHR 2.99; 95% CI 1.400-6.400). The C-index of the model was 0.750 (95% CI 0.720-0.780) in the derivation cohort and 0.758 (95% CI 0.720-0.800) in the validation cohort. The 5-year cumulative incidence of HF-MACE was 1.5% (95% CI 0.6-3.6), 5.0% (95% CI 1.8-8.2), and 22.0% (95% CI 15.6-28.4) among patients with 0, 1, and ≥2 risk factors, respectively. In patients with LVEF <30% at baseline, the 1-year incidence of HF-MACE was 50%, and those patients were excluded from the risk score. CONCLUSIONS:The first prediction model for severe HF events in adult laminopathies was developed, which may facilitate early and optimal preventive management. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov Unique identifier: NCT03058185.

BACKGROUND:Hypertrophic cardiomyopathy (HCM) is a myocardial disorder characterized by left ventricular hypertrophy and progression to heart failure (HF). Approximately 40% of cases are caused by variants in genes encoding sarcomere proteins. OBJECTIVES:This study sought to determine the relationship between genotype and other clinical predictors of HF outcomes in HCM patients. METHODS:This observational, single-center cohort comprised 505 genotyped HCM patients (52 years of age [Q1-Q3: 41-62 years], 33% women). Patients were stratified into gene-positive (G+) and gene-elusive (G-) groups. The primary endpoint was HF-related death or cardiac transplantation. Secondary endpoints included cardiac death, arrhythmic events, and all-cause mortality. Proportional hazards models were used to evaluate predictors of outcomes, including genetic status, log-transformed N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, peak VO2, and left ventricular ejection fraction (LVEF). RESULTS:During a median follow-up of 10.6 years (Q1-Q3: 4.6-15.0 years), 34 patients (6.7%) experienced the primary outcome (HF-related death: 22 [4.4%] and heart transplantation: 12 [2.4%]). The HF endpoint occurred in 12.8% (28 of 219) of the G+ group compared with 2.1% (6 of 286) of the G- group. In multivariable Cox analysis, G+ status (HR: 5.86; 95% CI: 2.26-15.25; P < 0.001), log NT-proBNP (HR: 2.46; 95% CI: 1.59-3.80; P < 0.001), peak VO2 (HR: 0.90; 95% CI: 0.82-0.98; P < 0.001), and LVEF (HR: 0.74 per 5% increment; 95% CI: 0.63-0.86; P < 0.001) were independently associated with HF outcomes. For secondary endpoints, 60 patients (11.9%) died of cardiac causes, 34 (6.7%) experienced arrhythmic events, and 115 (22.8%) died of any cause. CONCLUSIONS:Genetic status, peak VO2, log NT-proBNP, and LVEF independently predict HF outcomes in HCM. Combining genotype with HF biomarkers and functional capacity measures identifies patients at increased risk of HF-related death or transplant and may support targeted monitoring and selection for disease-modifying trials.

AIMS:Genetic testing in patients with dilated cardiomyopathy (DCM) is increasingly used to guide clinical management, but international guidance does not endorse genetic testing for older patients. This study sought to explore the yield and impact of genetic testing in older patients with DCM. METHODS AND RESULTS:Consecutive and unrelated genotyped patients with DCM were retrospectively recruited in a single referral centre. The yield of genetic testing was examined by age group. Genotype positive patients above and below 55 years of age were compared for a primary composite endpoint of end-stage heart failure (ESHF) or malignant ventricular arrhythmia (MVA).Six hundred and eighty-six patients (62.1% male, median [IQR] age 50 [37, 59] years) were recruited; 166 (24.2%) were genotype-positive. Sixty of 308 (19.5%) patients over 55 years of age were genotype-positive with 18 (30%) harbouring variants in genes associated with a higher risk of MVA.During a median follow-up of 50 months, twenty-one of 148 (14.2%) genotype-positive patients without baseline MVA had the primary composite endpoint with no significant difference between age groups (11/94 (11.7%) of those aged <55 years and 10/54 (18.5%) ≥55 years, log rank p value = 0.4). CONCLUSIONS:One fifth of older patients with DCM carry disease causing genetic variants, including those associated with a higher risk of MVA. Adverse event rates in older genotype-positive patients with DCM are comparable to their younger counterparts. These data highlight the value of extending genetic testing to older patients with DCM.

Pharmacological tools to selectively modulate extracellular vesicle (EV) secretion are scarce. Here, we identify the ALK5 (TGF-β receptor I) inhibitor SD-208 as a potent suppressor of small EV (sEV) secretion that acts independently of its canonical anti-fibrotic activity. SD-208 not only reversed myofibroblast activation but also markedly inhibited sEV secretion. Strikingly, this inhibitory effect persisted in non-activated cardiac fibroblasts and non-fibrotic HEK293 cells, demonstrating that SD-208 regulates EV secretion through mechanisms uncoupled from TGF-β/Smad signalling. Mechanistic analyses revealed that SD-208 disrupts vesicle trafficking rather than EV biogenesis. Reduced secretion of CD63+ EVs was accompanied by intracellular accumulation of CD63+ structures and their selective diversion into LAMP1+ lysosomes. Proteomic profiling of SD-208-treated and control HEK293 cells and cardiac fibroblasts revealed dysregulation of vesicle trafficking pathways, enrichment of ubiquitin ligase complexes, and enhanced endosome-to-lysosome transport. Together, these findings demonstrate that SD-208 diverts CD63+ multivesicular bodies (MVBs) from a secretory fate toward lysosomal degradation. This work identifies SD-208 as a small-molecule tool to interrogate the secretory-versus-degradative fate of MVBs and uncovers a new regulatory link between lysosomal pathways and EV trafficking. Beyond its established role as an anti-fibrotic agent, SD-208 provides mechanistic and therapeutic opportunities for the control of EV secretion in diseases such as fibrosis, cardiac remodelling, hypertrophic cardiomyopathy, and cancer.

Abstract Background and Aims The risk of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF) in dilated cardiomyopathy (DCM) may vary by genotype. Comparative analyses remain limited. The aim of this study was to compare clinical outcomes and risk predictors across genotypes. Methods and results Carriers of pathogenic variants in DCM-associated genes were identified from a dedicated database. Clinically affected variant-carriers from the five most prevalent genotypes were compared with genotype-negative patients. A composite primary endpoint consisted of MVA or ESHF. Secondary endpoints were MVA and ESHF individually. Incidence rates and baseline variables associated with outcomes were evaluated. Among 484 patients, 57 (11.8%) met the primary endpoint after 5 years. Genotype-negative patients had the lowest primary endpoint incidence rates [1.4 (0.7–2.1) per 100 person-years], whereas LMNA had the highest [6.2 (3.0–9.5)]. With a genotype-negative reference, incidence rate ratios were 1.3 for TTN, 1.7 for FLNC, 2.0 for DSP, 2.7 for RBM20 and 4.4 for LMNA. Rates were higher in LMNA and RBM20 than genotype-negative patients (P < .001 and P = .003, respectively) and higher in LMNA than TTN (P = .001). Results were similar for MVA. LMNA had higher ESHF rates than genotype-negative, TTN and DSP. Left ventricular diastolic diameter, LMNA variants and late gadolinium enhancement were independently associated with the primary endpoint. Baseline predictors varied by genotype. Conclusion Genotype stratification in DCM reveals a risk hierarchy with risk lowest in genotype-negative and TTN patients, two-fold higher in DSP and FLNC, and three- and four-fold higher in RBM20 and LMNA, respectively. Accounting for genotype improves risk prediction.

Abstract Background and Aims Genetic testing in dilated cardiomyopathy (DCM) guides risk stratification and family screening. Likely pathogenic or pathogenic (LP/P) variants are identified in approximately one-third of patients, leaving many without a genetic diagnosis. Cohort studies suggest that ‘gene-elusive’ patients have a lower risk of adverse events. This study aims to better characterise this group and identify factors associated with adverse outcomes. Methods Consecutive and unrelated DCM patients undergoing genetic testing and returning no LP/P variants were retrospectively recruited and compared to two control cohorts of DCM patients carrying LP/P variants in LMNA and TTN for a primary composite endpoint of end-stage heart failure (ESHF) or malignant ventricular arrhythmia (MVA). Results Among patients without prior MVA, the composite endpoint occurred in 36/423 (8.5%) gene-elusive, 14/39 (35.9%) LMNA and 11/100 (11%) TTN cardiomyopathy patients (log-rank p < 0.001 for LMNA vs gene-elusive and LMNA vs TTN ; p = 0.96 for TTN vs gene-elusive). For gene-elusive patients, lower left ventricular ejection fraction, larger left ventricular internal diameter in diastole, absence of LBBB and ventricular ectopy on ECG were independent predictors of the primary endpoint. Gene-elusive patients with LBBB had less atrial arrhythmia and a lower burden of ventricular ectopy at baseline and a low risk of the primary composite endpoint (HR 0.3 [0.1-0.8], p-value 0.01). Conclusions Gene-elusive DCM patients have a risk of adverse events similar to TTN cardiomyopathy. Gene-elusive patients with LBBB form a particularly low-risk subgroup, likely reflecting a distinct aetiology of left ventricular systolic dysfunction.

Isolated RVOT dilatation occurred in more than 20% of ARVC patients. All RVOT diameters showed good diagnostic power, were strongly associated with time to adverse events, were associated with adverse events in primary and secondary prevention, and exhibited superior feasibility, reproducibility, and outcome association compared with RV free-wall strain.

Mitochondrial myopathies are heritable conditions caused by genetic variations in mitochondrial DNA or nuclear DNA. These result in dysfunctional cellular oxidative phosphorylation and ATP production, affecting organs with high-energy requirements such as the heart, brain and skeletal muscle. Cardiac involvement is common affecting one third of patients and includes left ventricular hypertrophy, conduction disease, Wolff-Parkinson-White syndrome, and dilated cardiomyopathy. Due to the variability in the clinical presentation, a multiparametric approach incorporating clinical, biochemical, histological/histochemical and genetic criteria is required to make the diagnosis. Cardiologists should be aware of the clinical red flags and imaging findings and how to differentiate mitochondrial cardiomyopathy from other causes of left ventricular hypertrophy. Cardiovascular magnetic resonance imaging is a highly sensitive tool for depicting myocardial abnormalities to aid in both the diagnosis of patients presenting with left ventricular hypertrophy, and in the assessment of cardiac involvement in patients with a known diagnosis of mitochondrial myopathy, as this is an independent predictor of morbidity and early mortality. The most common CMRI findings include increased maximal LV wall thickness and mass and non-ischaemic subepicardial and midwall LGE, most commonly affecting the basal inferolateral or lateral wall. Future studies should consider integrating late gadolinium enhancement imaging into risk prediction models to enhance stratification of major adverse cardiac events such as heart failure and arrhythmia. As our understanding of mitochondrial disease evolves, integrating advanced imaging with molecular diagnostics will be essential for early detection of disease, improved risk prediction and outcomes.

Background/Objectives: Early detection of familial dilated cardiomyopathy (DCM) is crucial for initiating timely interventions. Myocardial work (MW) analysis, which integrates strain imaging and blood pressure, shows promise in identifying subclinical disease. To assess the utility of MW in detecting early myocardial changes in relatives of DCM patients with a positive genotype (G+) compared to genotype-negative (G−) controls. Methods: This study involved asymptomatic relatives of DCM patients who underwent comprehensive echocardiographic evaluation, including MW analysis. Subjects (N = 77) were classified into G+ (n = 39) and (n = 38) groups based on genetic testing. Myocardial work parameters—myocardial global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE)—were measured. Statistical analyses compared these parameters between groups and assessed their predictive value for genotype status. Follow-up data were collected and analysed accordingly. Results: Among 77 participants (mean age 36 ± 14 years; 49% women), there were no significant differences in baseline characteristics between G+ and G− groups. S’ septal, s′ average, e′ lateral, E max and E/A were found to be significantly different between the two groups. G+ individuals had significantly reduced GWE (94% vs. 96%, p < 0.001) and increased GWW (113 mmHg% vs. 80 mmHg%, p = 0.001). After adjustment for significant echocardiographic parameters, GWE (OR = 0.746, 95% CI: 0.560–0.994, p = 0.045) and GWW (OR = 1.012, 95% CI: 1.002–1.024, p = 0.047) remained significant predictors of gene carrier status in multivariable analysis. The addition of GWE and GWW significantly increased the area under the curve of a model identifying G+ individuals (p < 0.05). During a median period of follow-up of 53 months, 16 (21%) individuals expressed a cardiomyopathy phenotype. There was a significant correlation between increased baseline GWW, reduced GWE, and the expression of cardiomyopathy phenotype. Conclusions: Myocardial work analysis, specifically GWE and GWW, identifies early myocardial dysfunction in asymptomatic carriers of genetic variants for DCM. These findings suggest that MW could complement traditional imaging in the early detection and management of familial DCM.

Abstract Introduction Advancements in cancer treatments are resulting in improved prognosis for patients. However, these therapies may cause cardiotoxicity, including left ventricular systolic dysfunction which may manifest years later. Echocardiographic monitoring frequency for cancer survivors, timing and role of initiation of cardioprotective medication to manage asymptomatic mild systolic dysfunction in this cohort is poorly understood. Aims To assess role of combined cardiopulmonary exercise test stress echo (CPET-SE) in providing additional benefit in monitoring patients at risk of cardiotoxicity. Methods Retrospective analysis of patients in the late effects clinic who were at higher risk of cardiotoxicity due to treatment received. Patients were referred for CPET-SE due to borderline reduced LVEF (<55%) with absence of heart failure symptoms. Results A total of 57 patients (mean age 32 years, 82% male, 70% receiving anthracycline treatment) were assessed between January 2019 and September 2022. Forty-nine (86%) patients performed a maximal exercise test, with all patients reporting fatigue as the reason to stop. 86% of patients showed appropriate contractile reserve with mean increase in LVEF of 9±6%. Mean resting and peak LVEF was 50 and 59% respectively (mean difference 9±5%). Only four patients saw no improvement in peak LVEF (3 of whom experienced a decrease with mean drop of -2%). There was improvement of longitudinal function: average resting and peak GLS were -14 and -17% respectively, with mean improvement of -3±2.1%. Average lateral S’ was 7.4 cm/s at rest and 12.5cm/s at peak exercise, mean increase was 5.1± 2.5cm/s. Despite improvement in cardiac function, all patients had reduced peak VO2 on CPET: average VO2 peak 26.8 ml/kg/min (69% target or moderately reduced). Mean peak O2 pulse was 11.5 ml/beat. VE/VCO2 was 25.5 suggesting there was no respiratory limitation, supported by normal spirometry, breathing reserve and oxygen saturations in all patients. Markers of contractile reserve and peak VO2/O2 pulse were significantly correlated (Figure 1): peak O2 pulse and peak EF r = 0.4 (P=0.004); between delta S’ and VO2 peak r = 0.3 (P=0.047), albeit relatively weak, indicating likely influence of non-cardiac causes on reduced peak VO2 / O2 pulse. Limitation in most patients was thought to be secondary to deconditioning. Conclusion Our data indicate that cancer survivors may demonstrate significant exercise limitation which remains underdiagnosed, and that non-cardiac factors likely contribute. CPET-SE differentiates cardiac dysfunction from other causes of exercise limitation and guide management focusing on rehabilitation programmes or early initiation of cardioprotective medication in patients with impaired contractile reserve.

Abstract Background Hypertrophic cardiomyopathy (HCM) is defined by unexplained hypertrophy and often characterized by diastolic and systolic dysfunction. HCM patients are known to have impaired left ventricular (LV) myocardial work (MW), a more load-independent parameter compared to global longitudinal strain (GLS). We hypothesized that impaired MW might occur in sarcomere mutation carriers without LV hypertrophy. Methods and results A single centre study with a case-control design. Patients with overt nonobstructive HCM and a causal sarcomere gene variant (n = 44), carriers (n = 51) and age and sex matched (to the carriers) healthy controls (n = 32) underwent a transthoracic echocardiogram including myocardial deformation analysis to calculate GLS and MW. Global work index (GWI) (1695 ± 332mmHg% vs. 1881.50 ± 490mmHg%, p = 0.001) and global constructive work (GCW) (2017.78 ± 323.05mmHg% vs. 2329.31 ± 485.44 mmHg%, p = 0.002) were lower in sarcomere mutation carriers compared to controls. LV ejection fraction and GLS were similar between these two groups. GWI (1209 ± 735mmHg% vs. 1695 ± 332mmhg%, p < 0.001), GCW (1456 ± 703mmHg% vs. 1993 ± 389mmHg%, p < 0.001), global wasted work (GWW) (117 ± 148mmHg% vs. 96 ± 69mmHg%, p = 0.006) and global work efficiency (GWE) (89 ± 7% vs. 95 ± 3%, p < 0.001)] were worse in overt non-obstructive HCM patients. Conclusion We show for the first time that MW indexes were significantly worse in sarcomere mutation carriers compared to controls, suggesting that MW is more sensitive to early changes than GLS and could have a significant role in the evaluation and follow-up of carriers.

AIMS:In light of recent advances in imaging techniques, molecular understanding and therapeutic options in hypertrophic cardiomyopathy (HCM), we performed a systematic review of current guidelines for the diagnosis and management of HCM in order to identify consensus and discrepant areas in the clinical practice guidelines. METHODS AND RESULTS:We systematically reviewed the English language guidelines and recommendations for the management of HCM in adults. MEDLINE and EMBASE databases were searched for guidelines published in the last 10 years. Following a systematic search, three guidelines on the diagnosis and management of HCM were identified, all of which were robustly developed (AGREE rigour of development score ≥50%). These guidelines were authored by the major European (European Society of Cardiology; 2023), American (American Heart Association /American College of Cardiology/American Medical Society for Sports Medicine /Heart Rhythm Society/Pediatric and Congenital Electrophysiology Society/Society for Cardiovascular Magnetic Resonance; 2024), and Japanese [Japanese Circulation Society (JCS)/Japanese Heart Failure Society (JHFS); 2018] cardiovascular societies. There was broad consensus on echocardiographic recommendations, the medical and invasive management of HCM, the application of genetic testing and family screening, and exercise and reproductive recommendations in HCM. There were areas of variability in the definition and diagnostic criteria for HCM, cardiovascular magnetic resonance imaging recommendations, and assessment of sudden cardiac death (SCD) risk and prevention strategies. Due to the JCS/JHFS guidelines being older, there are no recommendations on the use of cardiac myosin ATPase inhibitors. CONCLUSION:Contemporary guidelines for HCM achieve consensus across a broad range of criteria and recommendations concerning diagnosis and management. However, variations in the approach towards risk assessment for SCD exist between the guidelines. There are also more subtle differences concerning diagnostic criteria and the utility of late gadolinium enhancement for risk stratification, which will likely evolve as the evidence-base broadens.

Importance:Prior studies have suggested that patients with nonmissense (ie, truncating) variants causing LMNA cardiomyopathy have worse arrhythmic outcomes compared to those with missense variants. However, the effect of the spatial distribution of missense and truncating variants on clinical outcomes remains poorly understood. Objective:To determine the association of the spatial distribution of missense and truncating LMNA variants with cardiac outcomes. Design, Setting, and Participants:This multicenter, retrospective, observational cohort study used data from an international registry (from January 2013 on) and data derived from tertiary cardiomyopathy centers (January 2000 and June 2017). Patients with likely pathogenic/pathogenic LMNA variants and no prior malignant ventricular arrhythmia (VA) were eligible for inclusion. Data analysis was completed from March 2022 to March 2025. Main Outcomes and Measures:The primary outcome of time to VA was defined as sudden cardiac death, appropriate implantable cardioverter-defibrillator therapy, or other manifestations of hemodynamically unstable VA. The secondary composite outcome of advanced heart failure was defined as nonsudden cardiac death, implantation of a left ventricular assist device, or cardiac transplant. Outcomes were stratified by type of variant (missense or truncating), affected transcript position (head, rod, or tail), and location on the LMNA gene. Results:A total of 718 patients were included, among whom mean (SD) age was 41.1 (14.3) years, 381 patients (53.1%) were female, and mean (SD) baseline left ventricular ejection fraction was 55.8% (13.3%). Over a median follow-up of 4.2 years, 223 patients experienced the primary outcome of malignant VA and 109 experienced the secondary outcome of advanced heart failure. Patients with truncating variants had a higher risk of VA (hazard ratio [HR], 1.72; 95% CI, 1.19-2.48; P = .004) but no difference in advanced heart failure (HR, 0.94; 95% CI, 0.64-1.40; P = .77) compared with patients with missense variants. There were no significant differences in the primary and secondary outcomes when stratifying truncating variants by location on the LMNA gene or transcript position. In contrast, on multivariable analysis, missense variants affecting the tail domain of LMNA (HR, 0.35; 95% CI, 0.16-0.78; P = .02) and located in exons 7 through 12 (HR, 0.39; 95% CI, 0.17-0.89; P = .035) were associated with a significantly lower risk of the primary outcome of malignant VA. Conclusions and Relevance:In this retrospective cohort study, truncating LMNA variants were associated with worse arrhythmic outcomes independent of variant position, whereas missense variants affecting the tail domain and located in exons 7 through 12 had better arrhythmic and heart failure outcomes. Understanding the mechanisms underlying these differences may have future therapeutic implications.

BACKGROUND:Right ventricular outflow tract (RVOT) dilatation is a phenotypic feature of arrhythmogenic right ventricular cardiomyopathy (ARVC). The echocardiographic RVOT diameter is part of the 2010 Task Force Criteria and is widely measured in clinical practice. Nevertheless, few data exist on its prevalence, diagnostic value, and prognostic significance. OBJECTIVES:This study aimed to explore the association of RVOT diameter with adverse outcomes in ARVC patients without (primary prevention) or with (secondary prevention) previous ventricular arrhythmia (VA), identify the best RVOT diameter for diagnosing ARVC, and understand whether isolated RVOT dilatation occurs in ARVC. METHODS:Patients with definite ARVC and genetic testing results were included in a cross-sectional outcome study. Isolated RVOT dilatation was defined as an enlarged RVOT diameter without concurrent right ventricular (RV) end-diastolic area dilatation. The diagnostic power of RVOT diameter was assessed compared with 100 healthy control subjects. The time to first event after baseline echocardiography was analyzed by Cox regression. RESULTS:The cohort consisted of 370 patients (mean age: 47 years; 56% male; 65% primary prevention; median follow-up: 6.8 years [Q1-Q3: 3.8-10.5 years]; 136 events [100 VA; 35 deaths]). RVOT dilatation occurred in 69% and isolated dilatation in 24% of patients. All RVOT diameters had similar diagnostic power (RVOT3/body surface area, AUC: 0.71 [95% CI: 0.66-0.76]) and a similar association with VA (RVOT3/body surface area, HR: 1.08 [95% CI: 1.04-1.13]; P < 0.001) or death (HR: 1.26 [95% CI: 1.18-1.35]; P < 0.001). Dilated RVOT was associated with a shorter time to VA or death in primary prevention and death in secondary prevention, and its feasibility was higher, its reproducibility was better, and its outcome association was stronger than those of RV free-wall strain. CONCLUSIONS:Isolated RVOT dilatation occurred in >20% of ARVC patients. All RVOT diameters showed good diagnostic power, were strongly associated with time to adverse events, were associated with adverse events in primary and secondary prevention, and exhibited superior feasibility, reproducibility, and outcome association compared with RV free-wall strain.

Background Lamin (LMNA) heart disease is a lethal form of dilated cardiomyopathy (DCM). Objectives The authors explored its cardiovascular magnetic resonance (CMR) phenotype to discover prognostically useful and subclinical biomarkers. Methods This prospective multicenter study recruited 4 groups: LMNA carriers with left ventricular ejection fraction ≥55% (Lamin+EF), LMNA carriers with left ventricular ejection fraction <50% (Lamin–EF), individuals with DCM with wild-type LMNA (DCMwt), and healthy volunteers. Phantom-calibrated CMR comprising cines, late gadolinium enhancement, and multiparametric mapping was undertaken. Left ventricular shapes were reconstructed using generalized Procrustes analysis. Serum biomarkers were collected at the time of CMR. Using a major adverse cardiovascular events (MACE) outcome of cardiovascular death, life-threatening ventricular tachyarrhythmia, heart transplantation, or atrioventricular block requiring pacing, we explored the prognostic value of CMR metrics using Cox regression. Results A total of 187 individuals were recruited (50% male): 29 with Lamin+EF (38 ± 14 years), 38 with Lamin–EF (45 ± 17 years), 73 with DCMwt (45 ± 15 years), and 47 healthy volunteers (44 ± 20 years). Compared to HVs, Lamin+EF had longer phantom-normalized T2 by 10 (95% CI: 2-20), higher ECV by 3% (95% CI: 1%-6%), and worse myocardial dynamics. Compared with DCMwt participants, Lamin+EF participants had better myocardial dynamics, higher phantom-normalized T2 (20 vs 12; P = 0.010), higher serum troponin (27 ng/L vs 5 ng/L; P < 0.001), and higher C-reactive protein (8 mg/L vs 3 mg/L; P = 0.021). Lamin–EF participants had similar myocardial dynamics but higher serum troponin (13 ng/L vs 5 ng/L; P < 0.001), higher N-terminal pro–B-type natriuretic peptide (668 pg/mL vs 228 pg/mL; P = 0.025), longer phantom-normalized T2 by 16 (95% CI: 1-31), and higher extracellular volume by 5% (95% CI: 1%-9%) than DCMwt participants. Over 4 years, 21% of lamin and 6% of DCMwt participants experienced MACE (P < 0.001). In lamin participants, each 1% increase in global late gadolinium enhancement and each 1% decrease in Procrustes trajectory sizes associated with HRs for MACE of 1.15 (95% CI: 1.02-1.30) and 1.01 (95% CI: 1.01-1.02), respectively (both P ≤ 0.025). Conclusions The CMR phenotype of LMNA carriers with preserved left ventricular systolic function consists of longer T2, higher serum troponin levels, higher extracellular volume, and impaired strain. CMR-derived focal fibrosis and strain biomarkers are prognostic, and future studies should explore their added clinical utility beyond the currently available MACE risk prediction tools. (The Deep Phenotype of Lamin A/C Cardiomyopathy; NCT03860454)