Biomedical subjects

Gianfranco Sinagra

Publications and source records attributed to Gianfranco Sinagra.

5 recordsLinked to original sources

PubMed2026

RBM20 Truncating Variants and Human Cardiomyopathy.

IMPORTANCE: Genetic diagnosis has become increasingly important to guide clinical decision-making for patients with dilated cardiomyopathy (DCM). Pathogenic or likely pathogenic (P/LP) missense variants in the gene RBM20 cause a highly penetrant arrhythmogenic DCM, but the role of RBM20 truncating variants (RBM20tvs) is unclear. OBJECTIVE: To assess the contribution of RBM20 variants to arrhythmogenic DCM. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, participants in the genome-first UK Biobank (UKB) and All of Us populations were evaluated to assess the etiologic fraction, natural history and penetrance of RBM20 variants. Retrospective data were collected from an international cohort of patients with DCM and RBM20 variants identified at centers of excellence for genetic heart disease and compared based on time to event. Study dates are not disclosed because the institutional review board did not authorize the sharing of this information. EXPOSURES: RBM20 variants were compared to known P/LP variants and variants of uncertain significance in RBM20 as well as titin truncating variants (TTNtvs). MAIN OUTCOMES AND MEASURES: Major ventricular arrhythmias, end-stage heart failure, and heart failure hospitalization as measured by medical record review (retrospective cohort) and diagnostic codes (UKB). RESULTS: Two main cohorts were studied for this project. In UK Biobank, a cohort of participants with RBM20tvs, RBM20 synonymous variants, and TTNtvs was studied. Of these 4249 participants, 1869 (44%) were male. The mean (SD) age at enrollment was 56 (8.2) years. In the RBM20 registry, of 179 patients, 105 (58.6%) were male, and the mean (SD) age at enrollment was 43.8 (19.1) years. A validation cohort from the All of Us biobank was also used. This consisted of 7002 participants, 4342 of whom (62.0%) were male, and the mean (SD) age was 52.7 (16.7) years. The etiologic fraction of RBM20 variants in arrhythmogenic DCM was 0.53 (95% CI, 0.32-0.67; P < .001). In genome-first biobanks, lifetime incidence of cardiomyopathy, heart failure, or major ventricular arrhythmia diagnosis was lower in participants with RBM20 variants than in those with TTNtvs (hazard ratio, 0.55; 95% CI, 0.36-0.84; P < .001). Patients with RBM20tvs and DCM presented to referral centers later in life than those with P/LP RBM20 and DCM (mean [SD], 53 [10] vs 34 [18] years; P < .001) and were less likely to have a family history of sudden cardiac arrest (2 of 10 [20%] vs 11 of 17 [65%]; P = .046) or cardiomyopathy (2 of 10 [20%] vs 14 of 18 [78%]; P < .001). There was no significant difference in age- and sex-adjusted incident major heart failure or arrhythmia events between patients with RBM20tv and DCM or those with P/LP RBM20 and DCM, though sex-adjusted lifetime hazard was reduced in those with RBM20tv and DCM (hazard ratio, 0.13; 95% CI, 0.03-0.56; P = .01). CONCLUSIONS AND RELEVANCE: This study found that RBM20 variants contributed to arrhythmogenic DCM phenotypes but conferred reduced lifetime disease penetrance compared to TTNtvs and milder disease severity alone than P/LP RBM20 variants. Their potential for additive interactions with other damaging variants should be considered in patients with DCM and their families.

Humans↗

PubMed2026

Red Flags for Differentiating Desmosomal "Hot-Phase" Cardiomyopathy From Acute Myocarditis.

BACKGROUND: Desmosomal "hot-phase" cardiomyopathy (HPC), characterized by bursts of myocardial inflammation mimicking acute myocarditis (AM), carries relevant risks of adverse outcomes. This study aimed to identify diagnostic "red flags" favoring HPC over AM. METHODS: Patients (n=134) receiving a first diagnosis of AM, proven by endomyocardial biopsy or cardiac magnetic resonance plus troponin elevation, were retrospectively identified at a referral center. HPC was defined by presence of pathogenic desmosomal gene variants (DGVs). Clinical, imaging, and electrical features were compared between HPC cases and controls with gene-negative AM to identify red flags. Diagnostic algorithms were derived and tested in an external multicenter cohort of DGV carriers (n=30). RESULTS: Patients with HPC (n=22; 91% DSP+) were more frequently female (73% versus 24%, P<0.001) and younger than unmatched controls with AM (32±14 versus 41±14 years, P=0.007). When matched 1:1 by age, sex, and presentation, DGV carriers showed distinctive red flags: family history of cardiomyopathy/AM/sudden death; recurrent troponin peaks; persistent left ventricular systolic dysfunction; right ventricular involvement; ring-like late gadolinium enhancement; late gadolinium enhancement persistence or extension; low QRS voltages; life-threatening ventricular arrhythmias at <45 years; persistent >1000/24 hours ventricular ectopy; and recurrent nonsustained ventricular tachycardia. A "first-contact" algorithm based on female sex and age <30 years achieved 77% accuracy, identifying 63% of DGV carriers in the external cohort. An alternative algorithm incorporating ring-like late gadolinium enhancement, right ventricular involvement, and family history showed higher accuracy (93%) and yield (93%). CONCLUSIONS: Myocarditis in DGV carriers predominantly affects young women. A red flag-based approach improves recognition of desmosomal HPC over classic AM.

Humans↗

PubMed2026

Cardiovascular prognostic impact of missense vs nonmissense lamin A/C variants: A systematic review and meta-analysis.

BACKGROUND: Variants in the LMNA gene, responsible for laminopathies, are associated with severe cardiovascular outcomes, including arrhythmias and heart failure (HF). However, the differential prognostic impact of missense vs nonmissense variants remains unclear. OBJECTIVE: The primary end point of this systematic review and meta-analysis was to compare the cardiovascular outcome defined as combined malignant ventricular arrhythmias (MVAs) and HF among patients with missense vs nonmissense variants in the LMNA gene. Secondary outcomes included a comparison of MVAs and HF-related events analyzed separately. METHODS: A systematic search of PubMed, Ovid MEDLINE, and Cochrane Library was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analyses were performed using fixed or random effects models, depending on heterogeneity. PROSPERO identifier: CRD42024584721. RESULTS: 12 studies comprising 1818 participants were included. Of these, 969 had missense variants, and 849 had nonmissense variants. The nonmissense group showed a significantly higher rate of cardiovascular events (30.5% vs 21.3%; odds ratio [OR] 2.22; P < .001). MVAs were more frequent in nonmissense carriers (25.5% vs 18.9%; OR 2.37; P < .001). Although limited by the small number of studies (n = 5) and single-study bias, the incidence of HF-related severe events seemed similar between the groups (18.2% vs 23.9%; OR 0.956; P = .801). CONCLUSION: Nonmissense LMNA variants are associated with worse cardiovascular outcomes, particularly arrhythmic events, whereas HF-related events seem comparable between nonmissense and missense variants.

Humans↗

PubMed2025

What Should a Clinical Cardiologist Know About Cardiogenetics?

Inherited cardiovascular diseases are becoming increasingly prominent in clinical practice, significantly impacting diagnosis, risk assessment, and family screening strategies. Progress in genetic testing has broadened access to cardiogenetic evaluations, while also presenting new challenges in interpreting variants and incorporating findings into clinical care. This narrative review explores 20 essential questions that clinical cardiologists may face when dealing with suspected or confirmed inherited cardiac conditions. Organized as a practical, question-driven guide, it outlines when to consider a genetic cause, how to choose and interpret genetic tests, and how to manage patients regardless of their genetic test results. The review emphasizes variant classification based on American College of Medical Genetics and Genomics criteria, the importance of clinical context in interpreting uncertain results, and the principles behind family cascade screening. Particular attention is given to the management of relatives who carry a genetic variant but show no symptoms, and to the current limitations of genetic testing technologies (eg, performance). Ethical considerations, including the appropriate timing of testing in children minors, are also discussed. By connecting genetic insights with clinical cardiology, this review aims to support practical, informed decision making and promote effective collaboration with cardiogenetic specialists.

Humans↗

PubMed2025

Clinical Phenotype and Prognosis of Asymptomatic Patients With Transthyretin Cardiac Amyloid Infiltration.

IMPORTANCE: Patients with transthyretin (ATTR) cardiac amyloid infiltration are increasingly diagnosed at earlier disease stages with no heart failure (HF) symptoms and a wide range of cardiac amyloid infiltration. OBJECTIVE: To characterize the clinical phenotype and natural history of asymptomatic patients with ATTR cardiac amyloid infiltration. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed data of all patients at 12 international centers for amyloidosis from January 1, 2008, through December 31, 2023. Inclusion criteria were asymptomatic ATTR cardiac amyloid infiltration, defined as an absence of HF history, HF signs and symptoms, diuretic therapy, and plasma cell dyscrasia with evidence of myocardial uptake on bone scintigraphy. If plasma cell dyscrasia was present, histologic confirmation of ATTR amyloid was required. EXPOSURE: Asymptomatic ATTR cardiac amyloid infiltration. MAIN OUTCOMES AND MEASURES: The primary outcomes were all-cause and cardiovascular (CV) mortality. The secondary outcomes were unplanned HF hospitalization, unplanned CV-related hospitalization, and a composite outcome of CV mortality and HF hospitalization. RESULTS: The study comprised 485 patients with asymptomatic ATTR cardiac amyloid infiltration (mean [SD] age, 74.9 [9.9] years, 85.8% male, 112 [23.1%] with hereditary ATTR amyloidosis), with 369 (76.1%) having grade 2 or 3 and 116 (23.9%) having grade 1 cardiac uptake at baseline. Patients with grade 2 or 3 uptake exhibited significantly more cardiac functional and structural abnormalities vs patients with grade 1 uptake. At 3 years, compared with grade 1 uptake, patients with grade 2 or 3 uptake had greater development of HF (54.3% [95% CI, 47.7%-61.3%] vs 23.1% [95% CI, 14.8%-35.1%]), greater outpatient diuretic initiation and N-terminal pro-B-type natriuretic peptide progression (35.0% [95% CI, 28.0%-43.2%] vs 12.4% [95% CI, 6.3%-23.7%]), and greater HF hospitalization (8.7% [95% CI, 5.9%-12.9%] vs 0%) and unplanned CV hospitalization (20.0% [95% CI, 15.7%-25.3%] vs 4.3% [95% CI, 1.6%-11.3%]). Over a median follow-up of 37 months (IQR, 20-64 months), the all-cause death rate was similar between patients with grade 1 vs 2 and 3 uptake; however, those with grade 2 or 3 compared with grade 1 uptake had a significantly higher risk of CV mortality (unadjusted hazard ratio, 5.30; 95% CI, 1.92-14.65). CONCLUSIONS AND RELEVANCE: This study shows that asymptomatic ATTR cardiac amyloid infiltration encompasses a wide spectrum of disease severity, with patients with grade 2 or 3 cardiac uptake experiencing an increased rate of CV events and CV mortality and patients with grade 1 uptake experiencing a lower CV event rate and predominantly non-CV mortality. These findings support the use of disease-modifying treatments in asymptomatic patients with grade 2 or 3 uptake and highlight the need of large-scale studies to assess their role in grade 1 uptake.

Humans↗