Clinical trial NCT06642168: Sudden Cardiac Arrest Related to Sport in Young and Value of the Genetic Assessment: a French Prospective Register
Official title: Registre Prospectif Français Des Morts Subites Chez Des Sportifs Jeunes
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Sudden Cardiac Arrest
Sudden Cardiac Death
Keywords: Sport related sudden cardiac arrest
Sport related sudden cardiac death
Young athlete
Etiological Diagnosis
Autopsy
Genetic
Toxicology
Hereditary Cardiac disease
Prevention
Lead sponsor: Rennes University Hospital
Sponsor class: OTHER
First posted: 2024-10-15
Enrollment: 80
Sex: ALL
Minimum age (years): 12
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study will include French victims of sports-related SCA/SCD between the ages of 12 and 35, as well as their first-degree relatives over 12 years of age, when applicable.

Brief summary: The increased risk of sudden cardiac arrest (SCA) or sudden cardiac death (SCD) related to vigorous physical activity is well-documented. Currently, for young victims (under 35 years) of SCA/SCD, no etiology is found in 40 to 50% of cases after a standard medical assessment, leading to two important consequences. For the victim's family, it is difficult to understand and accept this tragic event, and the risk of it occurring in another family member is a source of concern. Medically, the absence of a known cause limits the ability to effectively prevent such events.

The RESOUDRE study will be a national, prospective, observational registry of young victims (12-35 years) of sports-related SCA/SCD. All cases will undergo the recommended etiological assessment, including autopsy for SCA cases, along with whole exome genetic analysis and toxicological testing. In the event a genetic pathology is identified, a genetic evaluation will be offered to other family members, and appropriate medical care will be provided if necessary. The results of this study could significantly reduce the number of unexplained sport-related SCA/SCD cases and aid in preventing these incidents among affected families.

Detailed description: Background:

The beneficial effects of moderate physical activity on health are well-established. However, it is also well-proven that intense sports participation increases the risk of cardiovascular events by 2.4 to 4.5 times before the age of 35 in individuals with known or unknown heart conditions. Sudden cardiac arrest (SCA), sometimes leading to sudden cardiac death (SCD), is the most dramatic event linked to sports.

Before the age of 35, sports-related SCA/SCD is rare, occurring in 0.7 to 2.7 per 100,000 athletes, which amounts to approximately 80 cases per year according to two French prospective studies. Despite its rarity, these events are often traumatic and highly publicized, presenting a significant public health and safety concern. Non-traumatic sports-related SCA/SCD is primarily of cardiovascular origin, irrespective of the level of sports participation. In most cases, SCA results from ventricular arrhythmia caused by known or undiagnosed arrhythmogenic cardiovascular disease, which varies by the victim's age. After the age of 35, atheromatous coronary artery disease accounts for 80-85% of cases. However, before the age of 35, a wider range of etiologies are observed. Arrhythmogenic genetic heart diseases-structural (e.g., arrhythmogenic right ventricular cardiomyopathy and hypertrophic cardiomyopathy) or non-structural (e.g., channelopathies)-are the most frequent causes. Congenital abnormalities, particularly anomalous connection of coronary artery, represent the second most common cause. Acquired heart diseases, such as fibrous scars (mainly post-myocarditis) and atheromatous coronary lesions, are less frequently involved. In this younger population, classical autopsy often fails to determine the cause in more than 40% of cases, leading to the term "sudden arrhythmic syndrome".

Few prospective studies have combined classical autopsy with systematic genetic analysis to identify the cause of SCA/SCD in the general young population, with no specific link to sports. One Australian study demonstrated the value of genetic testing, identifying a "clinically relevant" cardiac genetic variant for sudden death in 27% of cases. Moreover, the same pathology was identified in 13% of relatives of the victims who underwent clinical and genetic screening. Another small Swedish study (n=15), focusing specifically on channelopathies in cases of negative autopsies, revealed the disease in 40% of victims' families through genetic analysis.

Additionally, the role of acute or chronic toxic substance intake has been suggested, albeit without formal proof, as a factor promoting sports-related SCA/SCD. Toxicological screening is thus recommended as part of the etiological assessment. Including toxicological analysis alongside other etiological evaluations could help clarify the impact of illicit substances on sports-related SCA/SCD.

Justifications for the Study:

No prospective study has systematically combined the recommended hospital assessment in cases of successful resuscitation or the recommended medical autopsy in the event of death with global genetic and toxicological analyses in victims of sports-related SCA/SCD.

This combined approach is justified for several reasons. First, it would enhance our understanding of the etiologies of these events. Notably, so-called idiopathic left ventricular hypertrophy is found in more than 10% of sports-related SCD cases following classical autopsies. Further genetic exploration could help determine whether these anatomical forms are pathological. Additionally, many arrhythmic cardiac diseases are associated with an elevated risk of sports-related SCA/SCD. While arrhythmogenic right ventricular cardiomyopathy is well-documented, other forms of disease are characterized by areas of fibrosis or fatty infiltration in the myocardium, often due to genetic mutations affecting intercellular desmosomes. Comprehensive genetic testing, including whole exome sequencing, could clarify the contribution of various arrhythmogenic heart diseases to unexplained sports-related SCA/SCD.

Improving this knowledge will benefit ongoing discussions about enhancing the content and effectiveness of pre-participation screening for athletes. Moreover, identifying the cause of SCA/SCD is critical for the victims and their families. Understanding the cause may help families come to terms with the event and assist in preventing recurrence for successfully resuscitated individuals. Furthermore, since most hereditary heart diseases follow an autosomal dominant inheritance pattern, each first-degree relative has a 50% chance of carrying the same genetic mutation. Predictive testing, clinical assessment, and, if necessary, preventive treatment can be offered to these family members to reduce the risk of arrhythmic events.

Statistical Analysis:

Data analyses will be performed using specialized software, with a significance threshold set at 5%. Hypotheses will be formulated bilaterally.

A descriptive analysis of the collected population data will be conducted. Qualitative variables will be presented as numbers and percentages, while quantitative variables will be described using the mean, standard deviation, median, interquartile range, minimum, and maximum values.

For the primary analysis of the main outcome, the cause of sports-related SCA/SCD will be described in terms of numbers and percentages, along with the corresponding 95% confidence intervals.

For the secondary analyses, the judgment criteria, both overall and by vital status (survived or deceased), will be described in numbers and percentages, with 95% confidence intervals.

Eligibility criteria: Inclusion Criteria:

* Victims of SCA:

  * Aged between 12 and 35 years
  * No known cardiovascular pathology
  * Experienced a sudden and non-traumatic SCA during or within one hour of participating in sports activities (leisure, training, or competition)
  * For resuscitated victims (SCA group): A person or legal representative who does not oppose participation in the research after being informed about the study (including individuals, organs, or authorities responsible for assisting or representing them if they are unable to express their wishes).
  * For non-resuscitated victims (SCD group): A person who has not formally objected to the reuse of their medical data during their lifetime.
* First-Degree Relatives:

  * A person or legal representative who does not oppose participation in the research after being informed about the study (including individuals, bodies, or authorities responsible for assisting or representing them if they are unable to express their wishes).

Non-Inclusion Criteria:

* For resuscitated SCA cases, individuals weighing less than 20 kg
* Victims or legal representatives who are subject to legal protection or deprived of their liberty

Primary outcomes:
measure: Identification of the Cause of Sports-Related Cardiorespiratory Arrest in a Young, Healthy Population
timeFrame: Through study completion, approximately 39 months
Secondary outcomes:
measure: Evaluation of the Contribution of Medical Autopsy in Identifying the Etiology of Sports-Related SCA
timeFrame: 3 to 6 months after the event
measure: Evaluation of the Contribution of Classical Genetic Analysis in Identifying the Etiology of Sports-Related Cardiorespiratory Arrest
timeFrame: 3 to 6 months after the event
measure: Evaluation of the Contribution of Whole Exome Sequencing in Identifying the Etiology of Sports-Related Cardiorespiratory Arrest
timeFrame: 24 to 30 months after the event
measure: Evaluation of the Contribution of Toxicological Analysis in Identifying the Etiology of Sports-Related Cardiorespiratory Arrest
timeFrame: 3 to 6 months after the event
measure: Evaluation of the Familial Transmission of Hereditary Cardiovascular Pathologies Detected
timeFrame: 3 to 12 months after the event.
Other outcomes:
Locations:
city: Besançon
country: France
facility: CHRU Besançon
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Brest
country: France
facility: CHU Brest
city: Caen
country: France
facility: CHU Caen
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand
city: Créteil
country: France
facility: APHP Hôpital Henri-Mondor
city: Dijon
country: France
facility: CHU Dijon Bourgogne
city: Grenoble
country: France
facility: CHU de Grenoble Alpes
city: Lille
country: France
facility: CHRU Lille
city: Lyon
country: France
facility: Hospices Civils de Lyon
city: Marseille
country: France
facility: APHM Hôpitaux universitaires de Marseille
city: Montpellier
country: France
facility: CHRU Montpellier
city: Nancy
country: France
facility: CHRU Nancy
city: Nantes
country: France
facility: CHU Nantes
city: Nice
country: France
facility: CHU de Nice
city: Paris
country: France
facility: APHP Hôpital Pitié-Salpêtrière
city: Paris
country: France
facility: APHP Hôpital Bichat
city: Paris
country: France
facility: APHP Hôpital Européen Georges Pompidou
city: Poitiers
country: France
facility: CHU Poitiers
city: Reims
country: France
facility: CHU Reims
city: Rennes
country: France
facility: CHU Rennes
city: Rouen
country: France
facility: CHU Rouen
city: Saint-Étienne
country: France
facility: CHU Saint-Etienne
city: Strasbourg
country: France
facility: CHRU Strasbourg
city: Toulouse
country: France
facility: CHU Toulouse
city: Tours
country: France
facility: CHRU Tours
Study officials:
affiliation: Study Principal Investigator
name: Frédéric SCHNELL
role: PRINCIPAL_INVESTIGATOR
References: