BACKGROUND:Massive left ventricular hypertrophy (LVH) is a risk factor for sudden cardiac death in children with hypertrophic cardiomyopathy (HCM), but little is understood about its natural history. METHODS:Patients with pediatric-onset HCM identified from 2 registries (SHaRe [Sarcomeric Human Cardiomyopathy Registry] and IPHCC [International Paediatric Hypertrophic Cardiomyopathy Consortium]) with or without massive LVH were compared. Massive LVH was defined as absolute maximal left ventricular wall thickness (MLVWT) ≥30 mm or MLVWT z score ≥+20 at <18 years of age. Data from SHaRe and IPHCC include encounters from January 1960 through March 2024 and January 1970 through March 2024, respectively. Demographic, clinical, and serial MLVWT data were collected. Composite outcomes included major ventricular arrhythmia event (sudden cardiac death, aborted sudden cardiac death, or appropriate implantable cardioverter defibrillator therapy); heart failure (HF) event (left ventricular ejection fraction <50%, New York Heart Association class III or IV, transplant, or HF-related death); major adverse cardiac event (stroke or any major ventricular arrhythmia or HF outcome aside from left ventricular ejection fraction <50%); and HCM-related mortality (sudden cardiac death or HF-related death). Time-to-event analyses were performed using Cox proportional hazards models. RESULTS:We identified 587 patients (54 female [30%]). In 186 children with massive LVH, age at diagnosis was younger (median, 9.2 years [interquartile range, 2.1-13.1 years]) versus 13.6 years (9.7-15.5 years; P<0.001) and sarcomeric genetic variants more prevalent (72% versus 61%; P=0.034), as was HCM-related mortality (unadjusted hazard ratio, 3.3 [95% CI,1.2-9.7]; P=0.026), major adverse cardiac events (hazard ratio, 2.6 [1.7-3.9]; P<0.001), major ventricular arrhythmia (hazard ratio, 3.1 [1.8-5.2]; P<0.001), and HF (hazard ratio, 1.9 [1.1-3.1]; P=0.013). These associations remained significant when adjusted for sex and age at HCM diagnosis. In 115 patients with massive LVH with serial MLVWT data (62%), MLVWT increased significantly from first to last measurements (median, 26 mm [interquartile range, 18-32 mm] versus 31 mm [26-35 mm]; P<0.001), but there was no difference between z scores (median, +22 [interquartile range, +18 to +26] versus +23 [+20 to +28]; P=0.25). The last absolute MLVWT recorded was >5 mm less than the largest recorded MLVWT in 25 patients (22%). CONCLUSIONS:In pediatric HCM, massive LVH disproportionately affects those diagnosed in early childhood with sarcomeric disease, with increased risk for adverse events. Significant MLVWT regression is seen in nearly a quarter of patients.

BACKGROUND:Periodic reinterpretation of variants associated with hypertrophic cardiomyopathy (HCM) is recommended in the light of evolving knowledge, but it requires considerable resources, and its clinical impact is unresolved. OBJECTIVES:We here report the results of a systematic variant reclassification of HCM-associated variants identified at a national referral center, and the impact on clinical profiling. METHODS:A total of 805 consecutive probands with a definite HCM diagnosis genotyped in 1998-2023 (overall 276 variants: 162 pathogenic/likely pathogenic -P/LP-, 109 variants of uncertain significance -VUS-, and 5 benign/likely benign - B/LB) underwent variant reclassification. All were analyzed for all-cause death, ventricular arrhythmia composite (sudden death, cardiac arrest, appropriate implantable cardioverter-defibrillator therapy), atrial fibrillation or cerebrovascular events, heart failure composite (NYHA class III/IV, left ventricular ejection fraction <35%, cardiac transplantation). RESULTS:After a median follow-up of 8.8 [6.1-11.8] years, among the 276 variants, 61 (22.1%) were reclassified: 29 variants from P/LP to VUS or B/LB, 21 from VUS to P/LP, and 11 from VUS to B/LB, affecting 69 patients overall. The overall yield of genetic testing (% with P/LP) changed from 58.7 to 55.4%. At survival analysis, HRs associated with P/LP status improved after reclassification for both all-cause death and ventricular arrhythmia. No changes were observed for the other outcomes. CONCLUSION:Systematic reclassification of genetic variants led to a refinement of variant classification accuracy due to downgrading of 5.5% of P/LP variants, although 18.3%VUS/B/LB were upgraded to P/LP. Reclassification more accurately identified risks associated with P/LP status, compared to the initial adjudication.

BACKGROUND AND AIMS:The prediction of the first major arrhythmic event (MAE) is still an unmet need in the recently defined scenario of non-dilated left ventricular cardiomyopathy (NDLVC). METHODS:A cohort of 337 patients with NDLVC and no history of MAE was retrospectively identified at two large centres. Patient-tailored diagnostic workup included cardiac magnetic resonance (CMR), endomyocardial biopsy, and genetic testing. The primary endpoint was the occurrence of the first MAE, including sustained ventricular tachycardia (VT), ventricular fibrillation, or appropriate implantable cardioverter-defibrillator therapy, by 60-month follow-up. A pool of 216 NDLVC patients from 11 European centres served as a validation cohort. RESULTS:In the study cohort (mean age 37 ± 15 years, 62% male), the mean left ventricular ejection fraction (LVEF) was 52 ± 8%, and 79% of patients had late gadolinium enhancement (LGE) at baseline CMR. By 60-month follow-up, 51 patients (15%) experienced a MAE. The primary endpoint was predicted by male sex [hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.3-4.4, P = .007], baseline non-sustained VT (HR 3.1, 95% CI 1.7-5.6, P < .001), LVEF < 45% (HR 5.5, 95% CI 2.7-11.0, P < .001), septal (HR 2.0, 95% CI 1.0-4.0, P = .046) and ring-like pattern of LGE (HR 1.3, 95% CI .6-2.6, P = .54), pathogenic/likely pathogenic variants in guideline-defined high-risk genes (HR 4.6, 95% CI 2.3-9.1, P < .001), and biopsy/CMR-proven myocardial inflammation (HR 15.7, 95% CI 6.1-40.3, P < .001). The results were confirmed in the validation cohort (Uno's C-index 0.81, 95% CI .75-.88). A novel risk score was subsequently derived. CONCLUSIONS:In NDLVC, male sex, non-sustained VT, LVEF < 45%, septal and ring-like LGE, high-risk genotypes, and myocardial inflammation predicted the first episode of MAE by 60 months.

BACKGROUND:Patients with hypertrophic cardiomyopathy able to maintain regular exercise over time may represent a selected subgroup with a more favourable clinical phenotype. However, the clinical, morphological, and arrhythmic profile of low-risk HCM patients engaged in regular exercise programs over follow-up remains incompletely characterized. This study aimed to compare the phenotype and follow-up outcomes of low-risk HCM patients according to reliably documented and stable exercise habits during follow-up. METHODS:253 low-risk HCM were classified by their reported habitual physical activity into three groups: sedentary (n = 93), mild exercise (<30 METs/week, n = 117), and vigorous exercise (>30 METs/week, n = 43). Clinical data, ECGs, echocardiography, CMR, and Holter monitoring were compared. Mean follow-up from initial diagnosis was 3.5 ± 2.7 years. RESULTS:Physically active patients showed significantly lower BMI (24.2 ± 3.8 and 24.8 ± 3.2 kg/m2 in vigorous and mild exercise, respectively, vs. 26.6 ± 4.3 kg/m2 in sedentary p = 0.004); lower max LV wall thickness (15.9 ± 2.9 and 17.5 ± 3.9 mm vs. 18.9 ± 3.9 mm; p < 0.0001) and better diastolic function (p < 0.0001). On CMR, late gadolinium enhancement was less prevalent in physically active patients (p < 0.0002). Active patients also showed fewer symptoms (p < 0.0001). Finally, no differences in arrhythmic burden or adverse events were observed among groups in the follow-up. CONCLUSIONS:In a low-risk HCM patients with stable exercise habits during follow-up, those participating in vigorous exercise programs showed a milder phenotype and did not experience excess arrhythmic burden or adverse cardiovascular events over time compared to sedentary HCM patients.

Screening of heart failure (HF) remains suboptimal. However, vocal biomarkers are an emerging tool to screen for HF and predict adverse outcomes. This article is a literature review of the current evidence, exploring the use of vocal biomarkers to screen for HF and predict hospitalisation and mortality. Voice may be utilised as a time-efficient method for the screening of HF, risk stratification, and monitoring of disease progression. Vocal biomarkers such as pause ratio and artificial neural networks can screen for HF accurately in a case-control setting. Other vocal markers like maximum phonation time, creak percent are useful to monitor disease progression. Vocal biomarkers appear to match current predictors of one-year mortality, HF related decompensation and hospitalisation. The integration of vocal biomarkers assessment in HF healthcare is promising across primary and secondary care settings. Key challenges including health data protection, regulatory compliance, and user acceptance must be addressed before these tools can be fully integrated into HF clinical care pathway.

BACKGROUND:Peak oxygen uptake (pVO2) is a predictor of adverse cardiovascular outcomes, supporting cardiopulmonary exercise testing as a primary end point for assessing drug therapies in obstructive hypertrophic cardiomyopathy (oHCM). Characterizing changes in pVO2 that patients perceive as meaningful has not been determined. METHODS:Data from patients with symptomatic oHCM enrolled in SEQUOIA-HCM and MAPLE-HCM were pooled. Patients were randomized 1:1 to daily aficamten (5-20 mg) or placebo (SEQUOIA-HCM, n = 282), and 1:1 to aficamten (5-20mg) or metoprolol (50-200 mg) (MAPLE-HCM, n = 175). PRIMARY OUTCOME:change from baseline to week 24 (Δ) in pVO2 using Patient Global Impression of Change with anchor-based analysis to define minimal important difference. RESULTS:At week 24, ΔpVO2 (95% CI) corresponding to no change, 1-category improvement, and 1-category worsening were -0.05 (-0.58, 0.48), +0.35 (-0.22, 0.91), and -0.61 (-1.36, 0.13) mL/kg/min, respectively. Minute ventilation to carbon dioxide production ratio (VE/VCO2) slope (95% CI) corresponding to no change, 1-category improvement, and 1-category worsening were 0.16 (-0.59, 0.90), -1.15 (-1.89, -0.42), and 0.88 (-0.42, 2.19), respectively. In a responder analysis using the new threshold, 60% of aficamten-treated vs 31% of placebo- or metoprolol-treated patients achieved ΔpVO2 ≥0.35 (odds ratio [OR], 3.4 [95% CI: 2.3, 4.9]; P < .001). Consistent findings were seen with VE/VCO2 responder analysis. CONCLUSIONS:Changes in pVO2 of +0.35 and -0.61 mL/kg/min were associated with small improvement and worsening, respectively. Applying this new threshold resulted in excellent differentiation of treatment effect. These data provide a measure of clarity for interpreting changes in pVO2 following interventions. CLINICAL TRIAL REGISTRATION:SEQUOIA-HCM (NCT05186818); MAPLE-HCM (NCT05767346).

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.

OBJECTIVES:To characterize prevalence, patterns, and clinical correlates of cardiac involvement in a cohort of patients with Behçet's syndrome (BS) undergoing clinically driven cardiological assessment. METHODS:This retrospective study included adult patients with BS, followed at a tertiary referral centre (Florence, Italy), who underwent clinically driven cardiological evaluation. Clinical, demographic and therapeutic characteristics were compared in patients with and without evidence of cardiac involvement. Timing, type of cardiac involvement, disease activity, cardiovascular risk factors and treatments were analysed. RESULTS:Among 312 patients with BS, 90 underwent cardiological assessment and 49 had confirmed cardiac involvement. Arrhythmias were the most frequent manifestation (n = 15), followed by pericarditis (n = 12) and ischaemic heart disease (n = 8). Cardiac involvement occurred a median of 6.1 (2.5-8.7) years after BS diagnosis, although in a proportion of patients it preceded or coincided with diagnosis. Most patients had active systemic disease at the time of the cardiac involvement (93.9%) and were receiving immunosuppressant treatment (84%). Over 80% had at least one traditional cardiovascular risk factor, yet <40% were receiving cardiovascular primary prevention therapy before the first event. Male patients more frequently experienced ischaemic manifestations, while arrhythmias were more common in females. No cardiac-related deaths were observed. CONCLUSION:Cardiac involvement in BS is more common than traditionally reported when actively investigated. Cardiac involvement frequently occurs during active disease and in patients with a high burden of cardiovascular risk factors but suboptimal preventive therapy. These findings support the need for integrated cardio-rheumatologic management in BS.

Aims Left ventricular hypertrophy (LVH) is one of the main prognostic factors in Fabry disease (FD). Despite the known impact of sex on the phenotypic expression of the disease, a 'fixed' threshold of left ventricular maximal wall thickness (LVMWT) > 12 mm is conventionally used for defining overt cardiac involvement. We aimed to investigate sex-differences in the association between LVH degree and cardiovascular outcomes in FD. Methods and results In this multicenter retrospective study, 347 patients with FD (57% women) were enrolled and echocardiographic data collected. The study endpoint was defined as the composite of mortality, hospitalization for heart failure, atrial fibrillation, major brady- or tachy-arrhythmias and ischaemic stroke. Women had lower LV wall thickness and LV mass than men and these differences were confirmed also indexing for body surface area (BSA) (all P < 0.001). After a median follow-up of 53 (IQR: 26-90) months, 64 patients (18%) met the study endpoint. The composite-event rate at 8 years was significantly higher in men vs. women (33% vs. 11%; P = 0.015). Values of LVMWT > 10 mm (or indexed LVMWT > 6.1 mm/m2) were associated with an increased risk of the composite endpoint in women, while a LVMWT prognostic threshold of 13 mm (or 6.9 mm/m2) was identified in men (both P < 0.001). These cut-off values were independently associated with outcomes, after adjustment for age, exposure to specific therapy and renal function. Conclusion In FD patients, sex-specific prognostic thresholds of LVH were identified, with women experiencing cardiovascular events at significantly lower values of LVMWT than men, even after accounting for BSA.

BACKGROUND:Atrial fibrillation (AF) is the most common arrhythmia in dilated cardiomyopathy (DCM) and is associated with adverse outcomes. However, the genetic determinants of AF risk and its prognostic significance across genotyped DCM subtypes remain unknown. METHODS:In this observational cohort study, we analyzed 3117 genotyped patients with DCM from the SHaRe (Sarcomeric Human Cardiomyopathy Registry). AF prevalence, incidence, and clinical characteristics were assessed by genotype. Patients were classified as genotype-positive [G(+)] if they had a pathogenic or likely pathogenic variant in a DCM-associated gene, and genotype-negative [G(-)] if genetic testing was negative. Factors associated with incident AF were evaluated using Cox regression. AF was modeled as a time-dependent variable to evaluate associations with clinical outcomes. RESULTS:Among 3117 genotyped patients with DCM (mean age, 48±15 years; 39% were female; and 35% were G[+]), 12.3% (n=384) had prevalent AF. Of 2491 patients without prevalent AF and with follow-up, 312 (12.5%) developed AF during a median of 4.5 years (interquartile range, 1.6-9.0). Among 2851 patients with follow-up, cumulative AF prevalence was 23.6%. LMNA had the highest AF incidence (7.6/100 patient-years) and cumulative AF prevalence (56.7%) and was the only genotype independently associated with incident AF compared with that in G(-) patients (hazard ratio, 5.52 [95% CI, 3.84-7.95]; P<0.001). TTN had an AF incidence of 2.1 per 100 patient-years and cumulative AF prevalence of 24.4%, comparable to that in G(-) patients. Older age, male sex, and prior heart failure hospitalization were also independently associated with incident AF. AF was independently associated with a higher risk of the composite clinical outcome (hazard ratio, 1.58 [95% CI, 1.29-1.94]; P<0.001), including heart failure, ventricular arrhythmias, and all-cause mortality. CONCLUSIONS:In this large genotyped DCM cohort, AF burden and incident AF risk varied across genotypes. Only LMNA was associated with an increased risk of incident AF. AF onset was independently associated with adverse outcomes, supporting genotype-guided AF surveillance and management in DCM.

BACKGROUND:Although adeno-associated virus (AAV) gene-replacement therapy is a potentially transformative therapy for severe genetic diseases, its cardiac immunotoxicity may challenge broad clinical use. METHODS:Medical Literature Analysis and Retrieval System Online, Embase, and PubMed databases were searched from January 2005 to March 2025. Studies including patients treated with AAV-replacement therapy were deemed eligible. Prespecified items (type of vector, dose, timing, and clinical significance of the adverse event) were extracted by 2 independent observers. Random-effects models were fitted using restricted maximum likelihood estimation and the method of Hartung, Knapp, Sidik, and Jonkman (International Prospective Register of Systematic Reviews [PROSPERO]. VigiBase and the US Food and Drug Administration Adverse Event Reporting System were searched for the occurrence of myocarditis with commercially available AAV-replacement drugs. RESULTS:Eighty studies including 1939 human patients were analyzed. A total of 734 adverse events were reported over 2122 patient-years of pooled observation. Seventy-one cases of myocarditis were identified. The pooled incidence rate per 100 patient-years was 8.6 (95% CI, 5.8-10.7; I2=63.2%). Events occurred in patients with Duchenne muscular dystrophy, spinal muscular atrophy, and X-linked myotubular myopathy, with recombinant AAVs and adeno-associated virus serotype 8. All received an intravenous dose >1013 vector genomes per kilogram body weight. Myocardial injury peaked in week 1 after injection (90% [95% CI, 85.7%-96.2%]; I2=43.2%), whereas myocarditis occurred mostly after week 2 (55% [95% CI, 48.7%-65.2%]; I2=33.1%), with no cases after the first month. Most myocarditis/myocardial injury did not have a relevant clinical impact (62, 87%), with only 8 (12%) cases having transient left ventricular dysfunction. The latter recovered during the follow-up. The only death occurred in the setting of cytokine-mediated capillary leak syndrome with cardiac dysfunction. Myocarditis occurred in relation to delandistrogene moxeparvovec (1/16 [6%]) and onasemnogene abeparvovec (14/217 [6%]) in the Food and Drug Administration Adverse Event Reporting System and VigiBase. CONCLUSIONS:Immune-mediated myocarditis/myocardial injury after systemic AAV gene therapy occurred in <10 per 100 patient-years (peaking at weeks 1-3) and was usually clinically mild, with a minority showing transient dysfunction. All events followed intravenous doses >1×1013 vector genomes per kilogram body weight, clustered in neuromuscular programs, and were associated with certain recombinant capsids/serotypes. These data support intensive early cardiac monitoring, cautious dose selection, and delivery strategies to minimize systemic exposure. REGISTRATION:URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD420251046546).

Historically, individuals with hypertrophic cardiomyopathy (HCM) have been systematically excluded from vigorous exercise and competitive sports due to concerns about increased sudden cardiac death (SCD) risk. However, emerging evidence has challenged this paradigm. Observational studies and randomized trials demonstrate improvements in functional capacity, quality of life, and overall cardiovascular and psychological health with tailored exercise in HCM populations -including competitive sports in low-risk individuals-in the absence of safety signals. Low-risk individuals are defined by the lack of well-established adverse features such as a high European Society of Cardiology HCM SCD risk score, exercise-induced syncope, severe left ventricular outflow tract obstruction and ventricular arrhythmias. The concept that this low-risk subset can safely engage in competitive sports is becoming widely accepted internationally, although local differences exist in terms of regulations and clinical approaches. For individuals who do not meet low-risk criteria, evidence is more limited. Nevertheless, participation in competitive sports may still be considered on an individual basis, after appropriate risk mitigation strategies (including treatment of obstruction and ICD implantation when indicated). A contemporary approach to HCM should be based on individualized, goal-oriented exercise prescription, supported by multidisciplinary counselling and shared decision-making, recognizing the importance of aligning medical recommendations with individual safety, values, goals, and quality of life. In this review, we critically appraise the emerging evidence surrounding vigorous exercise and competitive sports in HCM and explore how novel data are reshaping clinical practice and international guidelines, setting the stage for a paradigm in the field.

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.

The heart relies on finely tuned spatial heterogeneity in wall structure, fibre orientation, blood distribution and excitation-contraction coupling to maintain mechanical homeostasis. Even minor deviations may interact with anisotropy to promote maladaptation and disease. While cardiomyopathies have classically been attributed to primary cellular defects, emerging evidence suggests that abnormal regional stress may act as a primary driver of pathology even in the absence of intrinsic sarcomeric dysfunction. This review proposes the concept of 'cardiac mechanopathies', conditions in which misdirected or disproportionate mechanical forces are hypothesised to act as primary determinants of maladaptive remodelling, culminating in a cardiomyopathic phenotype. Clinical paradigms include arrhythmogenic mitral valve prolapse and apical hypertrophic cardiomyopathy with papillary muscle displacement. While a direct causality link still needs to be established, this concept is conceived as a working hypothesis for future studies. Advanced imaging may help identify subtle structural abnormalities early, while insights into the molecular basis of maladaptation may reveal new therapeutic targets. Clinically, studies are needed to understand whether reducing mechanical stress through interventions and lifestyle modifications can mitigate disease expression and progression.

AIMS:Juvenile sudden cardiac death (SCD) is predominantly caused by inherited or congenital heart conditions. While structured screening programmes for competitive athletes are well established, current international guidelines emphasize a gap of evidence regarding the value of mass screening in the general youth population. This systematic review aimed to assess the effectiveness of large-scale screening programmes in detecting conditions associated with SCD among young individuals. METHODS AND RESULTS:We conducted a systematic review following PRISMA guidelines, with the protocol registered in PROSPERO (CRD42024540606). Original studies evaluating cardiovascular screening in young individuals were included, while studies exclusively involving competitive athletes were excluded. Nineteen studies encompassing 1 079 781 participants from multiple countries were finally analysed. Most studies (68%) were published recently and primarily targeted children and adolescents aged 6-19 years; 63% were assessed as having a low risk of bias. Screening modalities included electrocardiography (ECG) alone (26.3%), questionnaires alone (5.3%), and a combination of both (68.4%). Following second- or third-line investigations, the overall diagnostic yield for SCD-risk conditions was 1.4‰ (1.9‰ in the meta-analysis). The pooled prevalence, estimated using a random-effects model, was 2.23‰ (95% CI: 0.94-5.29‰), with extremely high heterogeneity among studies (I2 = 100%, P < 0.0001). CONCLUSION:Systematic cardiovascular screening may help identify young individuals at increased risk for SCD, providing a potentially meaningful diagnostic yield. However, the absence of long-term data on outcome and cost-effectiveness underscores the need for further research to refine screening protocols, assess sustainability, and inform evidence-based public health policies.