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. 2026 May 4;29:101351. doi: 10.1016/j.resplu.2026.101351

Evaluation of genetic-molecular causes of out-of-hospital cardiac arrest – from patients to families: the GenetiCA study

Arianna Morena a,b,c, Sara Bendotti a,b, Annapaola D’Ambrosio d, Gianluca Marconi d, Giuseppe Stirparo d, Catherine Klersy e, Alessia Currao a,b,f, Roberto Primi a,b,g, Leila UImanova a,b, Mario Urtis h, Enrico Contri i, Alessandra Palo i, Alessandro Vicentini a, Simone Savastano a,b, Maurizia Grasso h, Eloisa Arbustini h, Leonardo De Luca a,†, Enrico Baldi a,b,⁎,†
PMCID: PMC13199836  PMID: 42199521

Abstract

Background

Out-of-hospital cardiac arrest (OHCA) is a public health priority. In patients aged ≤50 years, inherited arrhythmogenic and structural heart diseases represent a leading etiology, yet existing evidence is largely derived from small, selected cohorts, and population-based estimates of genetic contribution to OHCA in young are still lacking.

Methods

A multicenter, prospective observational study enrolling all patients aged ≤50 years who experience a medically-caused OHCA in Lombardy Region (Italy). (ClinicalTrials.gov NCT06844851). Blood samples will be collected in the pre-hospital by Emergency Medical System during Advanced Life Support. Genetic analysis will be performed using Next-Generation Sequencing with a comprehensive multigene panel targeting inherited arrhythmogenic syndromes and cardiomyopathies. Pre-hospital clinical data, environmental air pollution data and clinical outcomes will be collected. Family members of probands carrying pathogenic (P), likely-pathogenic (LP), or uncertain variants will be offered genetic counseling and clinical evaluation. The primary outcome will be to determine the prevalence of inherited arrhythmogenic and structural cardiomyopathies among young OHCA cases in this geographic area. Secondary outcomes will assess regional variability, associations with initial rhythm, sex, environmental pollution, and survival according to genetic findings.

Expected results

Based on the regional OHCA registry (LombardiaCaRe), approximately 575 resuscitated young OHCA cases are expected annually. P/LP variants are anticipated in 15–25% of cases, corresponding to 86–144 individuals/year.

Discussion

GenetiCA study will provide the first population-based assessment of inherited cardiac diseases among young OHCA patients within an entire geographic region. It aims to clarify the genetic burden of OHCA, support targeted family screening with potential implications for public health policies.

Keywords: Out-of-hospital cardiac arrest, Sudden cardiac death, Inherited cardiac diseases, Molecular autopsy, Next-generation sequencing, Cardiomyopathies, Channelopathies, Genetic screening, Public health, Epidemiology

Introduction

Out-of-hospital cardiac arrest (OHCA) represents one of the leading causes of death, at least in high-income countries, and is mainly caused by cardiovascular diseases.1 The estimated annual incidence of OHCAs is 55 per 100,000 inhabitants in Europe, with a range from 17 per 100,000 to 104 per 100,0002; Among these, a non-negligible proportion of OHCA victims are young people, with an estimated incidence ranging from 1 to 20 cases per 100,000 inhabitants per year.3

In this population, unlike individuals older than 40–50 years, acute coronary artery disease accounts for only a minority of cases, whereas most deaths are related to structurally abnormal or arrhythmogenic cardiomyopathies with a genetic basis.4 Therefore, in addition to macroscopic autopsy evaluation, genetic testing is currently recommended by major European and American scientific societies in cases of unexplained cardiac death.2, 5, 6, 7 Post-mortem genetic testing can explain up to 15–25% of sudden cardiac deaths in young individuals, and for this reason a joint consensus document from the European Society of Human Genetics, the European Council of Legal Medicine, the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases, the European Reference Network for rare, low-prevalence and complex cardiac diseases (ERN GUARD-Heart), and the Association for European Cardiovascular Pathology emphasizes that sudden death in the young should be considered a public health priority. This position reflects both the high prevalence of inherited cardiac diseases and the profound impact on affected families, while encouraging public investment in research in this field.8, 9

Post-mortem genetic testing has also been shown to be a cost-effective strategy, reducing both economic burden and the need for potentially distressing investigations in the victim’s relatives, by allowing targeted clinical evaluation at specialized Genetic Arrhythmia Centers once a genetic result is available.9 The informative data coming from such type of testing, combined with the phenotype and the familial analysis, increase the diagnostic yield in the OHCA context.10

Over the past two decades, several studies have investigated variants in patients who survived or died following cardiac arrest. The studies conducted in the early 2000s focused primarily on genes associated with Long QT Syndrome (LQTS) and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), identifying pathogenic variants (PVs) in 11–40% of cases.11, 12, 13 More recently, the advent of next-generation sequencing (NGS) has enabled broader analyses at reduced cost and with lower DNA requirements, allowing the use of multigene panels encompassing genes associated with LQTS, CPVT, Short QT Syndrome (SQTS), Brugada Syndrome (BrS), arrhythmogenic cardiomyopathy (ACM), hypertrophic (HCM), restrictive (RCM), dilated (DCM), and left ventricular non-compaction cardiomyopathy (LVNC).10, 14

However, all studies published to date have included relatively small cohorts, typically selected either among survivors of OHCA or among OHCA victims for whom an autopsy was requested. To the best of our knowledge, no studies have systematically and comprehensively evaluated all OHCA cases occurring within an entire geographical area independently of the patients’ outcome.

Methods

Study design

This is a multicenter, prospective, longitudinal observational clinical study with an epidemiological focus (Fig. 1). The planned study duration is three years, with the possibility of extension to additional years depending on the availability of funding. This study has been prospectively registered on ClinicalTrials.gov with the ID NCT06844851 and has been approved by the competent Ethical Committee (CET Lombardia 6 – protocol number 0021809/25 – version 3.1 03/10/2024). The study is Sponsored by IRCCS Policlinico San Matteo di Pavia. Patients aged ≤50 years who experience an OHCA occurring in the Lombardy Region and for whom the Emergency Medical Services (EMS) are be included in the study. The study is currently actively recruiting participants. The first patient was enrolled on 7 January 2026.

Fig. 1.

Fig. 1

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Central figure summarizing the GenetiCA study.

Inclusion criteria

The study will include all patients aged ≤50 years who experience an OHCA occurring in the Lombardy Region and for whom the Emergency Medical Services (EMS) were activated and resuscitation maneuvers were initiated. Prior to initiating genetic analyses, the Coordinating Center will contact the patients’ relatives by telephone to assess the presence of known genetically determined cardiac diseases within the family.

Exclusion criteria

Patients with a non-medical etiology of cardiac arrest will be excluded.

Primary outcome

The primary objective of this study is to systematically assess the prevalence of inherited arrhythmogenic or structural cardiac diseases among all patients aged ≤50 years who experience an out-of-hospital cardiac arrest (OHCA) of medical etiology in the Lombardy Region.

Secondary outcomes

The secondary outcomes are (1) to evaluate whether the prevalence of inherited arrhythmogenic or structural cardiac diseases differs across the provinces of the Lombardy Region among patients aged ≤50 years with medically caused OHCA; (2) to assess whether the prevalence of inherited arrhythmogenic or structural cardiac diseases differs according to the first documented cardiac rhythm (shockable vs. non-shockable); (3) to investigate differences in the prevalence of inherited arrhythmogenic or structural cardiac diseases according to Utstein-recommended patient subgroups (witnessed shockable rhythm, shockable rhythm with bystander-initiated cardiopulmonary resuscitation, and witnessed non-shockable rhythm), as well as according to patient sex and levels of ambient air pollution in the area where the cardiac arrest occurred; (4) to compare treatment characteristics and survival to hospital arrival between patients in whom a pathogenic or likely pathogenic variant associated with inherited arrhythmogenic or structural cardiac disease is identified and those in whom no such variant is detected.

Collection and storage of genetic material

A 3 ml tube with EDTA (ethylenediaminetetraacetic acid) will be used to collect blood during advanced cardiovascular life support (ACLS), through vascular access routes (venous and/or intraosseous) established for the administration of life-saving medications in all the patients who respect the inclusion criteria. No additional procedures beyond standard-of-care management for cardiac arrest will be performed on the patient. Blood samples will be collected within 3 days by the Coordinating Center (Fondazione IRCCS Policlinico San Matteo) for genetic analysis at the Laboratory of Genetics of the Center for Inherited Cardiovascular Diseases of the same institution. Samples will be stored for a period of 25 years.

Genetic analysis

Genomic DNA will be extracted from blood samples using the Maxwell® RSC 48 automated extractor with the Maxwell® RSC Blood DNA Kit. Extracted DNA samples will be sequenced using next-generation sequencing (NGS) technology on the Illumina MiSeq platform, employing the Illumina TruSight Cardio multigene panel. This panel includes genes most associated with LQTS, CPVT, SQTS, BrS, ACM, HCM, RCM, DCM, LVNC, Noonan syndromes, lipid metabolic disorders, rare congenital heart diseases, and rare forms of autosomal recessive myopathies. For survived patients physical evaluation will be performed during hospital admission and includes electrocardiography and color Doppler echocardiography and further tests, as needed (e.g. cardiac magnetic resonance). For deceased patients, the results of the autopsy (if available) will be assessed on the recommendation of the patient’s physician. This evaluation together with genetic testing will guide the diagnosis. The complete list of analyzed genes is provided in the Appendix to this study protocol.

Data management

Data regarding pre-hospital cardiac arrest characteristics and resuscitation interventions will be collected according to the Utstein recommendations. Data on environmental pollution levels across the provinces of the Lombardy Region will be obtained from the Regional Environmental Protection Agency (ARPA Lombardia). All procedures related to data handling and security will comply with Directive 95/46/EC on the protection of personal data. Data will be collected using the REDCap platform (REDCap), hosted on secure servers at the Fondazione IRCCS Policlinico San Matteo in Pavia. The results of genetic testing will be communicated to the family members identified in the informed consent form. In cases of pathogenic variants (P), likely pathogenic variant (LP) or variant of uncertain significance (VUS) identified in the analyzed genes, genetic counseling and a comprehensive clinical evaluation of first and second degree family members will be offered. This evaluation will include electrocardiography and color Doppler echocardiography and further tests at the physician discretion and will be conducted at the Division of Cardiology and/or at the Center for Inherited Cardiovascular Diseases of the Fondazione IRCCS Policlinico San Matteo. The flow chart on the management of counseling based on genetic result is presented in Fig. 2.

Fig. 2.

Fig. 2

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Flow chart on the management of counseling based on genetic result.

Informed consent acquisition

For patients, who are hospitalized after the event and regain full decision-making capacity, written informed consent will be obtained directly from the patient. For patients who die before hospital admission or who do not regain decision-making capacity, informed consent will be obtained from a third party belonging to the same genetic lineage, in accordance with Regulation (EU) 2016/679 (GDPR, Recital 27) and Authorization No. 8/2016 of the Italian Data Protection Authority. Indeed, identification of P or LP variants may allow preventive and/or therapeutic interventions and informed reproductive choices for relatives. All procedures will comply with Good Clinical Practice, the Declaration of Helsinki, and applicable local regulations. Patients and relatives will be informed about study objectives, methods, risks, benefits, and their right to refuse or withdraw consent at any time without affecting medical care. Written informed consent will be documented and archived according to regulatory requirements.

Given the public health relevance of this study and its potential implications for population-based screening and preventive strategies, if informed consent cannot be obtained despite all reasonable efforts, data will be fully anonymized and genetic analyses will be performed exclusively for scientific research purposes, in accordance with Regulation (EU) 2016/679 (Article 9), Authorization No. 8/2016, and Measure No. 146/2019 of the Italian Data Protection Authority.

Statistical methods

Continuous variables will be summarized as mean and standard deviation (SD) and compared with the t-test or described as median and interquartile range (IQR, 25th–75th percentile) and compared with the Mann–Whitney, according to their normal distribution tested with the Shapiro–Wilk test. Categorical variables will be reported as counts and percentages and compared with the chi-squared test or Fisher’s exact test depending on the expected frequencies.

For the primary objective, the prevalence of genetic variants will be calculated as the proportion of patients in whom a pathogenic or likely pathogenic is identified over the total number of patients with out-of-hospital cardiac arrest. Exact binomial 95% confidence intervals (95% CI) will be provided.

For secondary objectives 1–3, differences in prevalence across subgroups will be assessed using generalized binomial models. Results will be reported as prevalence differences with corresponding 95% CI.

For secondary objective 4, survival to hospital arrival will be compared using logistic regression models and reported as odds ratios (OR) with 95% CI. Depending on the final sample size, multivariable models may also be evaluated. Model goodness of fit will be assessed with Pearson’s test. The sensitivity and specificity of the model will be also computed. Differences in treatment strategies between patients with and without identified genetic variants will likewise be assessed using logistic regression models and reported as ORs with 95% CI.

All statistical analyses will be performed using STATA statistical software Stata version (StataCorp. 2025. Stata Statistical Software: Release 19 or later. College Station, TX, StataCorp LLC). A two-sided p-value of <0.05 will be considered statistically significant.

Expected results

Based on the analysis of 2019 data from the Lombardy Region Cardiac Arrest Registry (LombardiaCARe), 122 patients aged ≤50 years with a medical etiology of OHCA were identified in the provinces of Pavia, Lodi, Cremona, and Mantova, corresponding to a population of approximately 1.5 million inhabitants and fully covered by the registry as of December 31, 2019. Among these patients, resuscitation maneuvers were initiated by Emergency Medical Services (EMS) in 89 cases.

Extrapolating these data to the entire Lombardy Region, which has a population of about 10 million inhabitants, 787 individuals aged ≤50 years are expected to experience a medically caused OHCA each year, of whom approximately 575 are estimated to receive EMS-initiated resuscitation.

Based on these estimates and considering literature data11, 12, 13, 14, 15 reporting the identification of P/LP variants in 15–25% of OHCA victims, the expected prevalence and the annual number of patients with P/LP variants are summarized in Table 1 for different prevalence scenarios and varies from 86 to 144 expected cases per year.

Table 1.

Expected prevalence of OHCA cases with P/LP.

Sample size Prevalence 95%CI Precision Expected cases/year
575 15% 12.1–18.1% ±3 86
575 20% 16.8–23.5% ±3.4 115
575 25% 21.5–28.8% ±3.6 144
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The study will potentially have an important impact on the regional healthcare system and on patient well-being. The project, indeed, will disclose genetic variants associated with heritable cardiovascular diseases in about 258–432 patients, allowing to extend the screening to the family members of the victim. This will make it possible to perform diagnostic and therapeutic actions in these persons to stratify their arrhythmic risk and prevent further sudden cardiac deaths. Therefore, this will also prevent the social costs linked to the potential sudden death of a family member and the hospital cost in case of out-of-hospital cardiac arrest.

Moreover, considering that the study will define the exact prevalence of hereditary heart diseases in OHCA patients, this will allow also to estimate the prevalence in the general population, allowing possible important reasoning about any possible preventive diagnostic action in the general population by the regional healthcare system and decision-makers. Furthermore, the evaluation of the family members of patients in whom a variant of unknown significance will be found, will allow for refinement of the classifications of these variants: this will permit a significant improvement for all the patients with suspected heritable cardiovascular diseases as will enable the re- classification, in a pathogenic or non-pathogenic sense, of their variants, improving their personalized treatment.

Discussion

Sudden cardiac death (SCD) in the young is increasingly recognized as a major public health issue but very often, the cause of death remains unknown.9, 15

The GenetiCA project is designed to overcome this limitation by consecutively enrolling all OHCA cases with attempted resuscitation within a large regional population, thus minimizing referral and selection bias.

Moreover, by focusing on a single, well-defined region with uniform emergency care organization, this protocol will allow a homogeneous assessment of inter-provincial variation and potential environmental modifiers such as ambient air pollution, which have been only sparsely explored in previous work.16, 17

From a health economic perspective, post-mortem genetic testing and family screening appear to be cost-effective strategies. In a pilot study, a comparison between post-mortem genetic testing and extended clinical evaluation of relatives alone suggested that the non-genetic strategy involved higher cumulative costs (approximately $1 million more in that model) while identifying subjects at risk less efficiently.18 In addition, NGS technologies have also significantly reduced the cost per gene/panel, making molecular autopsy a relatively economical procedure in relation to the number of additional etiological diagnoses obtained, and cascade testing in family members is often more effective than periodic clinical follow-up of all at-risk relatives alone. This is because it allows non-carriers to be discharged from long-term monitoring, focusing resources on those who are really at risk and reducing unnecessary tests and visits.19, 20

Another strength of this study is the analysis of VUS. Although VUS do not currently assist physicians in therapeutic management, systematic clinical screening of family members may facilitate the reclassification of certain variants allowing a direct clinical impact on counseling and family management.21 Recent studies involving systematic reinterpretation of VUS in cardiomyopathies show that, thanks to new population data, updates to ACMG/ClinGen guidelines, and additional family information, a significant proportion of variants (≈15–30%) are reclassified over time, significantly reducing the “gray area” and improving the accuracy of genomic medicine.22, 23, 24 Furthermore, family assessments structured around a “hot” VUS—conducted in expert centers and in the context of adequate clinical surveillance—allow for better risk stratification for relatives and facilitate the early identification of individuals who develop subclinical signs of cardiomyopathy, thus helping to optimize the timing of preventive treatments and personalized follow-up.25, 26

The approach proposed by the GenetiCA study is perfectly in line with the latest guidelines of the European Resuscitation Council, published in 2025, which recommend to perform a post-mortem genetic testing in all OHCA victims under 50 years of age.2 Moreover, the guidelines stress the importance of managing of genetic results by multidisciplinary teams in specialized clinics to provide family counseling and eventual familial screening,2 which represents one of the cornerstones of the GenetiCA study.

The GenetiCA study will not include autopsy, which is currently underperformed in Europe, and which remains a fundamental examination, together with family screening, for understanding the cause of cardiac arrest.2

Conclusions

To our knowledge, the study will be the first in Italy and the most extensive all over the world aimed at identifying the prevalence of inherited arrhythmogenic or structural cardiac diseases in young OHCA patients, potentially causing the cardiac arrest. It will also be the first study on this topic covering an entire regional territory (Lombardy) in a homogenous and cross-sectional way. The potential impact on healthcare concerns both OHCA victims, who in some cases may be able to determine the cause of cardiac arrest, and their families, with the possibility of preventing similar events in relatives and identifying potential asymptomatic family members exposed to arrhythmogenic risk who are unaware of their genetic status. This could have significant positive effects as it could allow, depending on the results obtained, the implementation of screening and prevention measures in the general population.

Dissemination plans

The study will also include dissemination of the results, possibly involving also cardiac arrest survivors as facilitators. This will consist of abstracts for congresses and scientific publications. Periodic newsletters will be spread among all personnel involved in the study in order to update on study status and to share preliminary findings.

CRediT authorship contribution statement

Arianna Morena: Writing – original draft, Investigation, Data curation. Sara Bendotti: Writing – original draft, Investigation, Data curation. Annapaola D’Ambrosio: Investigation. Gianluca Marconi: Investigation. Giuseppe Stirparo: Investigation. Catherine Klersy: Formal analysis. Alessia Currao: Investigation, Data curation. Roberto Primi: Investigation, Data curation. Leila UImanova: Investigation, Data curation. Mario Urtis: Investigation. Enrico Contri: Investigation. Alessandra Palo: Investigation. Alessandro Vicentini: Writing – review & editing, Resources, Investigation, Conceptualization. Simone Savastano: Writing – review & editing, Resources, Investigation, Conceptualization. Maurizia Grasso: Resources, Investigation. Eloisa Arbustini: Writing – review & editing, Resources, Project administration, Investigation, Conceptualization. Leonardo De Luca: Supervision, Resources. Enrico Baldi: Writing – review & editing, Resources, Project administration, Methodology, Investigation, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

The GenetiCA study was funded by a grant received by the Fondazione Regionale per la Ricerca Biomedica (FRRB) within the call “Early Career Award – II edition” (project ID 4980634). The funder provided the financial support necessary for the conduct of the study, including personnel, travel costs, dissemination, materials and supplies. The funder had no role in the study conduct.

Footnotes

Appendix A

Supplementary material to this article can be found online at https://doi.org/10.1016/j.resplu.2026.101351.

Appendix A. Supplementary material

The following are the Supplementary material to this article:

Supplementary Data 1

Protocol of the study (Italian version – 3.1 of 03/10/2024) and list of genes analyzed.

mmc1.pdf (872.1KB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Data 1

Protocol of the study (Italian version – 3.1 of 03/10/2024) and list of genes analyzed.

mmc1.pdf (872.1KB, pdf)

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