Objectives: Sudden cardiac death (SCD) is a leading cause of mortality, accounting for approximately 50% of all cardiovascular deaths and 20% of all-natural deaths in Western countries. In individuals over 50 years of age, coronary artery disease (CAD) is responsible for more than 80% of cases, whereas in younger subjects SCD is more frequently associated with non-ischemic myocardial diseases, including hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (ACM), dilated cardiomyopathy (DCM), and myocarditis. Additional causes in young adults include coronary artery anomalies and primary arrhythmic disorders related to channelopathies. This study evaluated the diagnostic performance of post-mortem cardiac magnetic resonance imaging (PM-CMR) in identifying morphological substrates underlying SCD in formalin-fixed explanted hearts, with particular attention to the concordance between PM-CMR findings and autopsy results in cases of sudden coronary death. Material and Methods: We retrospectively reviewed 110 PM-CMR examinations from the Regional Register of Sudden Cardiac Death of Friuli-Venezia Giulia, of which 101 were included in the final analysis. Results: PM-CMR detected pathological findings in 60 hearts (59%), including acute ischemic lesions in 39 cases and other conditions, such as hypertrophic cardiomyopathy, chronic fibrotic ischemic changes, and adipose metaplasia in 21 cases. A good agreement between PM-CMR and autopsy findings was observed (Cohen’s kappa = 0.8). Conclusions: Overall, PM-CMR proved effective in identifying relevant morphological and signal alterations, supporting conventional autopsy. Despite some limitations, particularly in hyperacute ischemic lesions, PM-CMR appears to play a promising role in the diagnostic work-up of SCD and in supporting family screening programs for primary prevention.

Concomitant transthyretin cardiac amyloidosis (ATTR-CA) is increasingly recognized among elderly patients with severe aortic stenosis (AS) referred to transcatheter aortic valve implantation (TAVI), yet its impact on early and late outcomes remains incompletely defined. We conducted a systematic review of studies comparing TAVI outcomes in patients with isolated AS and those with AS+ATTR-CA. Eleven observational studies were included, comprising 644,107 patients with isolated AS and 1,637 with AS+ATTR-CA. AS+ATTR-CA patients were older, more frequently male, and showed more atrial fibrillation, mildly reduced left ventricular ejection fraction, and markedly elevated cardiac biomarkers. Thirty-day mortality was low and similar between groups, with no consistent differences in stroke or major bleeding, whereas acute kidney injury and permanent pacemaker implantation were more frequent in AS+ATTR-CA. During follow-up, AS+ATTR-CA patients experienced higher heart failure readmissions and late all-cause mortality. ATTR-CA should not preclude TAVI but should inform risk stratification, peri-procedural management, and post-TAVI follow-up.

Human genomic studies link reduced CUB domain-containing protein 1 (CDCP1) expression with myocardial recovery in heart failure. While CDCP1 regulates cardiac fibroblast proliferation in vitro, it's in vivo role in cardiac fibrosis remains unclear. Using a Cdcp1-knockout (KO) angiotensin II/phenylephrine mouse model, we show that Cdcp1 deletion reduces echocardiographic left ventricular mass, histologic cardiac fibrosis, and pro-fibrotic gene expression, along with decreased fibroblast activation and inflammatory markers. Spatial transcriptomics identified a pressure overload-expanded fibroblast subpopulation enriched for growth factor and TGF-β signaling (FB5), which was markedly attenuated in Cdcp1-KO hearts, alongside reduction of a pro-inflammatory cardiomyocyte subtype (CM4). Complementary studies in human ventricular fibroblasts demonstrate that CDCP1 knockdown reduced extracellular matrix gene expression and collagen I deposition. These findings establish CDCP1 as a regulator of cardiac fibrotic remodeling in vivo and open avenues for its further investigation as a potential therapeutic target.

BACKGROUND:N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a cornerstone biomarker for the diagnosis and management of heart failure, but its use may be limited by the need for blood testing and laboratory infrastructure. Artificial intelligence (AI) applied to electrocardiograms (ECGs) may offer a widely accessible, non-invasive approach to estimate NT-proBNP levels. METHODS:We developed a convolutional neural network incorporating residual and attention-based layers to estimate NT-proBNP levels from standard 12-lead ECGs. The model was trained using 84,895 ECG-NT-proBNP pairs from 40,762 adult patients; 8,545 patients were held out for internal validation. The model generated a nine-level ECG-BNP score. External validation was conducted in 679 patients at two tertiary cardiovascular centers. Discrimination for prespecified thresholds (>250, >500, >1,000 pg/mL) was assessed by AUROC with 95% CIs; calibration and threshold-specific sensitivity, specificity, PPV/NPV were evaluated. RESULTS:In internal validation, the AI-ECG score showed a strong correlation with measured NT-proBNP levels (Spearman ρ=0.85, p<0.001) and high discrimination across thresholds (AUROC >0.92). In external validation, the model achieved AUROCs of 0.866 (95% CI 0.838-0.894) for >250 pg/mL, 0.882 (95% CI 0.857-0.907) for >500 pg/mL, and 0.885 (95% CI 0.859-0.914) for >1,000 pg/mL. Performance was consistent across key clinical subgroups. CONCLUSIONS:An AI-enabled ECG model can identify patients with elevated NT-proBNP levels with good accuracy in both internal and external validation cohorts. This approach may help identify patients who should undergo confirmatory NT-proBNP testing, particularly when biomarker testing is delayed, unavailable, or not routinely performed. Prospective studies are warranted to define whether this strategy provides incremental clinical value and can be integrated into clinical pathways.

Importance:In transthyretin amyloid cardiomyopathy (ATTR-CM), tricuspid regurgitation (TR) severity may be underestimated by conventional (semi-)quantitative echocardiographic criteria derived from nonamyloid populations, given the restrictive, low-flow hemodynamics characteristic of the disease. Objectives:To derive and validate disease-specific prognostic, quantitative TR risk thresholds in ATTR-CM and to compare their prognostic performance with current guideline definitions and the Tricuspid Valve Academic Research Consortium (TVARC) 5-grade extension. Design, Setting, and Participants:This international, multicenter cohort study was conducted from January 2016 to February 2026 at 8 high-volume tertiary referral centers across Austria, Italy, Germany, and the Netherlands, with data analysis February to May 2026. Patients with newly diagnosed ATTR-CM were enrolled and underwent standardized transthoracic echocardiography with blinded core laboratory quantitative analysis of echocardiography TR severity parameters (vena contracta width [VCW], effective regurgitant orifice area [EROA], and regurgitant volume [RegVol]). Exposures:TR severity defined by VCW, EROA, and RegVol from blinded core laboratory quantitative analysis and TR severity according to 2025 European Society of Cardiology/European Association for Cardio-Thoracic Surgery, 2020 American Heart Association/American College of Cardiology, 2017 American Society of Echocardiography, and 2023 TVARC grading schemes. Main Outcomes and Measures:Outcomes were all-cause mortality (primary end point) and time to first heart failure hospitalization (HFH; secondary end point). Results:A total of 1124 patients with newly diagnosed ATTR-CM were enrolled (derivation cohort: n = 745; validation cohort: n = 379). Median (IQR) patient age was 80 (75-84) years, and 260 patients (23.1%) were female. Over a median (IQR) follow-up of 25.2 (12.2-43.2) months, 324 patients (28.8%) died and 251 (22.3%) experienced HFH. All TR metrics independently predicted both end points. Spline-derived thresholds delineated intermediate (VCW ≥3 mm; EROA ≥0.15 cm2; RegVol ≥10 mL), high (≥5 mm; ≥0.25 cm2; ≥20 mL), and extreme risk (≥8 mm; ≥0.50 cm2; ≥40 mL), with stepwise Kaplan-Meier separation in both cohorts. Whereas the guideline-based and TVARC schemes each classified 130 patients (11.6%) as having severe TR, the proposed framework classified 334 patients (29.7%) as having at least high or extreme risk (P < .001 for comparison to all other definitions). The framework was independently associated with both end points, with the highest point estimate among the schemes (mortality: hazard ratio [HR], 1.41; 95% CI, 1.23-1.62; HFH: HR, 1.31; 95% CI, 1.12-1.54), and showed superior discrimination over guideline definitions, particularly at later time points. Conclusions and Relevance:In this multicenter cohort study among patients with ATTR-CM, a validated, risk-based conceptual framework of echocardiographic parameters to quantify TR improved prediction of mortality and HFH over standard classification of TR severity, better reflecting restrictive low-flow pathophysiology and supporting disease-specific TR grading in ATTR-CM.

BACKGROUND:Titin truncating variants (TTNtv) represent the most common genotype underlying dilated cardiomyopathy but are also detected in the general population, exhibiting incomplete penetrance and marked phenotypic variability. This heterogeneity complicates clinical interpretation and risk stratification. Emerging molecular evidence suggests that truncating location within the gene may influence disease mechanisms. We aimed to investigate whether TTNtv location also affects clinical phenotype and prognosis. METHODS:We established an international multicenter registry of phenotypically affected carriers of pathogenic or likely pathogenic TTNtv. Patients were classified into 3 groups: A-band, Z/I-band, and M-band. A case-control study assessed the enrichment of TTNtv across regions. The primary outcome was a composite of all-cause mortality and heart transplantation. Secondary outcomes included: (1) sudden cardiac death or major ventricular arrhythmias and (2) heart failure-related death/heart transplantation/left ventricular assist device implantation. RESULTS:The study included 467 patients (81% probands, 73% male, median age 47 years, 81% dilated cardiomyopathy phenotype). Most carried TTNtv in the A-band (80% versus 15% Z/I-band and 5% M-band). All groups showed enrichment compared with GnomAD, with greater Bayesian-estimated penetrance for A-band variants. Over a median follow-up of 83 months, the primary end point was similar across groups. However, the risk of sudden cardiac death/major ventricular arrhythmias was significantly higher in M-band carriers (45% M-band versus 23% Z/I-band versus 12% A-band; P=0.001), especially as the first disease manifestation. Band location independently predicted sudden cardiac death/major ventricular arrhythmias risk, whereas left ventricular ejection fraction was predictive only in A- and Z/I-band groups. CONCLUSIONS:TTNtv are differently enriched across the gene in patients with dilated cardiomyopathy/nondilated left ventricular cardiomyopathy. Penetrance and risk of sudden cardiac death/major ventricular arrhythmias differ according to variant location, supporting the TTN truncation site as a parameter that should be considered for personalized risk stratification in TTN cardiomyopathy.

BACKGROUND:Patients harboring pathogenic/likely pathogenic (P/LP) variants in the desmoplakin (DSP) gene are at risk of ventricular arrhythmias (VAs). In this population, a risk prediction model estimating the 5-year risk of VAs has been recently developed. OBJECTIVE:This study aimed to provide external validation of this prediction model in a new large, international, multicenter cohort and to test its reliability in patients with and without a history of myocarditis-like episodes. METHODS:All patients with a P/LP pathogenic DSP variant enrolled in the Desmoplakin Specific Effort for a Rare Disease Outcome Study Network with no sustained VA before or at first assessment and who were not used for the development of the DSP-risk score (www.DSP-risk.com) were used to test its performance. Model performance was assessed using the c-statistic in both the overall cohort and stratifying by history of myocarditis-like episodes. RESULTS:450 DSP patients from 30 centers were enrolled (mean age 42.2 ± 17.6; 40.4% female; 18.4% with previous myocarditis-like episode). Over a median of 4.3 years (1.6-10.0), 60 sustained VAs were observed. The DSP-risk score yielded good discrimination both overall (c-statistic, 0.719; 95% confidence interval [CI], 0.706-0.733) and for patients with (c-statistic, 0.719; 95% CI, 0.702-0.737) and without previous myocarditis-like episodes (c-statistic, 0.749; 95% CI, 0.740-0.759). CONCLUSION:In a large independent cohort of DSP patients, this study showed external validity of the DSP-risk score. These findings support the use of the DSP-risk score to facilitate shared decision making regarding implantable cardioverter-defibrillator implantation in the primary prevention of VAs in patients harboring DSP P/LP variants.

The heart rarely develops cancer, and, at the same time, it lacks regenerative capacity, as cardiomyocytes stop proliferating after birth. This suggests that mechanisms limiting cardiac regeneration may also protect against cancer. In this work, we investigated the role of mechanical load and used in vivo cancer models and ex vivo engineered heart tissues to show that mechanical load reduces cancer cell proliferation in the myocardium. Spatial transcriptomics of human cardiac metastases revealed decreased histone methylation and chromatin compaction. These changes affect chromatin accessibility at proliferation-related loci, with Nesprin-2 identified as a key mechanosensor. Our results uncover how mechanical forces protect the heart from cancer and suggest potential strategies for cancer therapy based on mechanical stimulation.

BACKGROUND:In approximately 5-10% of cases, hypertrophic cardiomyopathy (HCM) presents left ventricular remodeling with hypokinesia and dilatation, defined "end-stage" phase (ES) of the disease, typically associated with development of advanced heart failure (HF). Prescription of conventional medical treatments for HF with a reduced ejection fraction (HFrEF) have never been investigated in ES-HCM. METHODS:ES-HCM patients from 11 Italian referral centres were retrospectively evaluated. We included only patients with a last clinical evaluation after 2019, to ensure all patients were potentially evaluated in the era of the "4 HFrEF pillars" (beta blockers [BB], renin-angiotensin system inhibitors [RASi], mineralocorticoid receptor antagonists [MRA], and sodium-glucose cotransporter-2 inhibitors [SGLT2i]). For all patients we collected clinical information, with a focus on medical therapy at last clinical evaluation. RESULTS:The study population included 274 ES-HCM patients (59% males, mean age 60 ± 15 years). All 4 HFrEF pillars were prescribed in 26%. Specifically, 90% were treated with BB, 75% with RASi, 66% with MRA, 46% with SGLT2i. Few differences emerged when comparing patients taking versus not taking BB or RASi. Patients taking versus not taking MRA and SGLT2i more commonly had atrial fibrillation and showed worse echocardiographic features. SGLT2i use was significantly higher among ES-HCM patients with LVEF <40%. CONCLUSIONS:While BB and RASi are commonly used in ES-HCM, MRA and SGLT2i are prescribed less frequently and in patients with a worse clinical profile. Combination of all classes is not common, suggesting both clinical inertia and limitations inherent to the disease pathophysiology.

Antiarrhythmic drug therapy in cardiomyopathies remains challenging because arrhythmic risk, drug efficacy, and pro-arrhythmic vulnerability vary substantially across phenotypes. This review summarizes contemporary guideline and consensus recommendations on antiarrhythmic drug use in hypertrophic, dilated, non-dilated left ventricular, and arrhythmogenic cardiomyopathies. Recent guidelines increasingly emphasize phenotype-oriented arrhythmia management, but specific recommendations for antiarrhythmic drug therapy remain fragmented. Beta-blockers and amiodarone are the most consistently recommended agents in structural heart disease, whereas class I drugs are generally restricted. Evidence is strongest for hypertrophic and arrhythmogenic cardiomyopathies, while recommendations for dilated and non-dilated left ventricular cardiomyopathies are largely extrapolated from broader heart failure populations. Antiarrhythmic drugs are mainly used to reduce arrhythmic burden, symptoms, and implantable cardioverter-defibrillator therapies rather than to improve survival. Future studies should define phenotype-specific strategies based on ventricular function, myocardial scar, genotype, and clinical context.

Light chain (AL) amyloidosis is a rare systemic disease caused by monoclonal immunoglobulin light chains with abnormal folding that aggregate into fibrils, which deposit in extracellular tissues. This process leads to cytotoxicity and organ dysfunction. Cardiac involvement is the main prognostic determinant and requires a multidisciplinary management approach. In recent years, the treatment of AL amyloidosis has significantly evolved with the introduction of innovative agents such as proteasome inhibitors, immunomodulators, and monoclonal antibodies like daratumumab, which has shown a favorable impact on hematological outcomes and organ function. The daratumumab-CyBorD regimen is currently the standard first-line therapeutic option. The therapy is tailored based on the stage of cardiac and renal damage, aim ing for a complete hematological and organ response. The management of cardiac involvement, including aortic stenosis, atrial fibrillation, thromboembolic risk, conduction disorders, arrhythmias, and heart failure, plays a crucial role in prognosis. An integrated multidisciplinary approach in specialized centers experienced in the disease is essential to optimize clinical outcomes.

BACKGROUND:On-site computed tomography (CT)-derived fractional flow reserve (FFR) solutions are increasingly needed to reduce delays, costs, and reliance on external platforms. OBJECTIVES:This single-center prospective study evaluated the diagnostic performance of an on-site deep learning and fluid dynamic-based CT-FFR algorithm (xFFR, GE HealthCare) against off-site HeartFlow CT-FFR (FFRct) and invasive FFR (iFFR) for coronary artery disease (CAD) assessment. METHODS:In this single-center prospective study, 250 symptomatic patients at intermediate-to-high CAD risk (mean age: 65 ± 9 years; 76% male) underwent coronary computed tomography angiography (CTA), xFFR, FFRct, and invasive coronary angiography with iFFR. Areas under the curve (AUCs) were calculated for xFFR and FFRct, with Spearman's correlations and Cohen's κ used to assess agreement with iFFR. RESULTS:Functionally significant CAD was detected in 56.6% (xFFR), 54% (FFRct), and 48% (iFFR) of cases; xFFR showed sensitivity, specificity, and accuracy of 95%, 81%, and 88%, respectively. The overall diagnostic accuracy was comparable to FFRct (AUC: 0.91 vs AUC: 0.89; P = 0.274), superior only for left anterior descending coronary artery assessment (AUC: 0.96 vs AUC: 0.84; P = 0.001). Correlation analysis showed good agreement with iFFR (ρ = 0.67) and FFRct (ρ = 0.53). The mean xFFR analysis time was 8 ± 3.4 minutes. CONCLUSIONS:This study establishes xFFR as a robust and efficient on-site tool for assessing CAD, demonstrating high diagnostic accuracy, reproducibility, and agreement with invasive methods. Its rapid processing and integration into clinical workflows position xFFR as a promising alternative to off-site FFRct solutions. Further studies are warranted to confirm its generalizability and optimize its implementation.

Peripartum cardiomyopathy (PPCM) can be a serious condition, presenting with heart failure with reduced ejection fraction towards the end of pregnancy or in the months following delivery. Less than half of the patients fully recover their cardiac function within 6 months of diagnosis, with substantial regional variation. This clinical consensus statement addresses the global and regional heterogeneity of epidemiological data on PPCM, substantial variation in access to medical care, and the contributing factors to poor adherence, as well as the impact of socioeconomic factors. The scope of this document encompasses contemporary challenges and approaches for the management of women diagnosed with PPCM. We provide a framework of practical aspects of starting disease-specific and guideline-recommended medical therapy, rapid up-titration, and improving adherence. Furthermore, the importance of involving women with a new diagnosis of PPCM in the decision-making processes regarding various therapeutic options is highlighted, as this also affects the mental health and quality of life for the patient, as well as for the extended family.

Abstract Transthyretin amyloid cardiomyopathy (ATTR-CM) has undergone a profound transformation over the past decade, evolving from an underrecognized and largely untreatable condition into a rapidly advancing field characterized by multiple disease-modifying therapies and an expanding therapeutic pipeline. This collection summarizes current knowledge on the biological basis of disease and its therapeutic implications, reflecting a key paradigm shift from late-stage management to early intervention. Earlier diagnosis requires a redefinition of treatment goals, from slowing progression to preserving function and preventing disease evolution. This transition highlights the need for more sensitive tools to monitor disease activity and therapeutic response. At the same time, management of comorbidities, including heart failure and atrial fibrillation, remains a critical component of care. ATTR-CM is entering a new era characterized by earlier detection, expanding therapeutic options, and increasing complexity, requiring an integrated and personalized approach.