Sudden cardiac arrest remains a major cause of death among young people. Babken Asatryan outlines his research into the genetic basis of the disease, and discusses the clinical usefulness that his findings on genetic mutations could have for the diagnosis of unexplained cardiac arrest
Since the early days of genomic medicine, medical researchers have invested tremendous effort in dissecting the genetic architecture of sudden cardiac arrest and sudden death. Many familial traits and conditions have been revealed, but sudden cardiac arrest continues to be an enormous public health problem worldwide, particularly because it is a major cause of death in apparently healthy young subjects. Nowadays, genetic testing of patients with potentially heritable arrhythmic heart disease helps in decision-making, and allows identification of genetically affected pre-symptomatic family members who might benefit from early diagnosis and therapy. A small proportion of cardiac arrest survivors have no history or signs of heart disease and first come to medical attention at the time of a cardiac arrest. Could genetically-mediated heart disease cause life-threatening arrhythmias at the stage when they are still “confined to the genome”—that is, before the manifestation of diagnostic signs of the disease?
To answer this question, I and my colleagues studied a cohort of 60 sudden cardiac arrest survivors, consisting of 24 patients with a clinical suspicion or diagnosis of cardiomyopathy or inherited arrhythmia, and 36 patients with uncertain cause of cardiac arrest after thorough evaluation. Our findings were published online in March 2019 in the American Journal of Cardiology.1 We performed comprehensive clinical examination of all enrolled survivors of cardiac arrest, following international guidelines. Patients with signs of a genetic arrhythmia or cardiomyopathy, and those whose clinical examination failed to reveal a cause, were then screened for disease-causing mutations in 185 genes with known association to heritable cardiovascular diseases.
We detected 32 disease-associated mutations in 27 patients—45% of the entire cohort. Mutation carriers included 17 out of 24 (71%) patients with a cardiomyopathy or primary arrhythmia syndrome, and 10 out of 36 (28%) survivors with no signs of heart disease. Among those with cardiomyopathy or arrhythmia the detected mutations confirmed the clinical diagnosis; in subjects with no signs of heart disease the mutations revealed clinically silent disease in a significant proportion of cases. It is noteworthy that the mutations detected in patients with no signs of heart disease were localised not only to cardiac ion channel genes, but also to genes encoding myocardial structural proteins involved in cardiomyopathies. Cardiac arrest in mutation carriers with otherwise normal heart function is likely to represent the first manifestation of a “concealed” inherited arrhythmia or a cardiomyopathy, and we have called for further investigations to assess this concept in follow-up studies.
The guidelines for evaluation of patients with primary arrhythmia syndromes, written in 2013, recommended against genetic testing in survivors of clinically unexplained cardiac arrest. But over the past five years, experimental evidence has been accumulating that suggests that some gene mutations may have pro-arrhythmic potential at an early disease phase. Our data establish the clinical usefulness of genetic testing in cardiac arrest survivors, and further expand the knowledge on genetics of clinically unexplained cardiac arrest. The main message of our study is that diagnostic cardiovascular genetic testing should be considered not only in survivors with robust phenotype, but also in unexplained cardiac arrest survivors, to allow for better identification of the arrhythmic substrate. However, investigators need to be careful when interpreting genetic data to avoid variant misclassification and subsequent unnecessary interventions.
And, what about the cases that remain unexplained after cardiac genetic testing? A number of factors can be involved in the pathogenesis of cardiac arrest. Potential explanations might include currently unknown monogenic causes, or a complex genetic susceptibility composed of the cumulative effect of genetic modifiers, intoxications with unknown cardiotoxic substances, autonomic imbalance, and perhaps other factors that we are currently not aware of. Further research needs to focus primarily on these aspects.
Babken Asatryan is a postdoctoral researcher in arrhythmias and cardiogenetics at the Department of Cardiology in Bern University Hospital, Bern, Switzerland.