Abstract
Reflex syncope is the major cause of transient loss of consciousness, which affects one-third of the population, but effective treatment for individuals with severe syncope is lacking. Better understanding of reflex syncope predisposition may offer new therapeutic solutions. To determine the familial risk of syncope in first-, second-, and third-degree relatives of affected individuals and to explore the role of genes and family environment in reflex syncope. In this national population-based family cohort study, the Swedish multigeneration register was linked to 3 Swedish nationwide registers: hospital discharge, outpatient care, and primary care registers for the period from 1997 to 2015. Sibling pairs born to Swedish parents between 1948 and 2005 were included. Linkage was also made to half-siblings and cousins. Data analysis was performed from June to October 2020. Register-based syncope diagnosis among relatives: pairs of twins, siblings, half-siblings, and cousins. Odds ratios for syncope were calculated for relatives (twins, siblings, half-siblings, and cousins) of individuals who had syncope compared with relatives of individuals without syncope for reference. Sensitivity analysis excluding families with definite nonreflex syncope diagnosis was performed. Among the study population of 2 694 442 participants, 1 381 453 (51.3%) were male, and the median (interquartile range) age was 32 (22-43) years. The study population consisted of 24 020 twins, 1 546 108 siblings, 264 244 half-siblings, and 1 044 546 cousins. In total, 61 861 (2.30%) unique individuals were diagnosed with syncope. Sixty-two percent (38 226) of the syncope-positive individuals were female. The odds ratio (OR) for syncope was 2.39 (95% CI, 1.61-3.53) for twins, 1.81 (95% CI, 1.71-1.91) for siblings, 1.28 (95% CI, 1.20-1.37) for half-siblings, and 1.13 (95% CI, 1.10-1.17) for cousins of individuals with syncope. The OR was highest among male twins at 5.03 (95% CI, 2.57-9.85). The proportion of syncope-positive individuals was consistently higher in women vs men, regardless of degree of relationship (twins: 346 [2.88%] vs 193 [1.61%]; siblings: 22 111 [2.92%] vs 13 419 [1.70%], half-siblings: 4148 [3.44%] vs 2425 [1.93%], cousins: 14 498 [2.87%] vs 9246 [1.72%]). Exclusion of nonreflex syncope diagnoses did not change syncope risk in affected families. In this Swedish national population-based study, the risk of syncope among relatives of affected individuals was associated with the relationship degree and was strongest in twins and siblings, which suggests that there are genetic components of reflex syncope. Women were more likely to experience syncope independently of family relationship. A better understanding of genetic predisposition to reflex syncope may offer new therapeutic options in severely affected individuals.
Highlights
The odds ratio (OR) was highest among male twins at 5.03
Exclusion of nonreflex syncope diagnoses did not change syncope risk in affected families. In this Swedish national population-based study, the risk of syncope among relatives of affected individuals was associated with the relationship degree and was strongest in twins and siblings, which suggests that there are genetic components of reflex syncope
Syncope is associated with trauma risk in affected individuals,6 whereas reflex syncope at a young age may be correlated with family history of cardiovascular disease7 and coronary events many years later
Summary
Reflex syncope is the most common form of transient loss of consciousness (TLOC), defined as sudden-onset bradycardia and vasodilation leading to an abrupt decrease in cardiac output, cerebral hypoperfusion, and temporary loss of consciousness, typically triggered by orthostatic or emotional stress, pain, and gastrointestinal symptoms. According to self-reported epidemiological data, approximately one-third of the human population may be affected by reflex syncope during their lifetime. prognosis of reflex syncope is usually benign, especially in younger individuals, recent observations have indicated that admission for syncope in middle and advanced age heralds an increased risk of future cardiovascular events and higher mortality. syncope is associated with trauma risk in affected individuals, whereas reflex syncope at a young age may be correlated with family history of cardiovascular disease and coronary events many years later.8Why some individuals are susceptible to the reflex syncope, often referred to as vasovagal, is not well understood. Syncope is associated with trauma risk in affected individuals, whereas reflex syncope at a young age may be correlated with family history of cardiovascular disease and coronary events many years later.. Sheldon et al have reported gender-specific association of single-nucleotide variation in genes involved in serotonin signaling with reflex syncope likelihood, and a genome-wide association study has identified single-nucleotide variation in proximity to the gene zinc finger protein 804a that is associated with vasovagal syncope.. Sheldon et al have reported gender-specific association of single-nucleotide variation in genes involved in serotonin signaling with reflex syncope likelihood, and a genome-wide association study has identified single-nucleotide variation in proximity to the gene zinc finger protein 804a that is associated with vasovagal syncope.16 Even if these reports suggest heredity, large population-based studies on familial aggregation of reflex syncope are lacking Studies on familial predisposition to reflex syncope have suggested higher incidence in affected families, especially among twins and for episodes before age 20 years. candidate gene association studies on reflex syncope have been inconclusive, difficult to replicate, and generally based on small patient series, which precludes generalizability. Recently, Sheldon et al have reported gender-specific association of single-nucleotide variation in genes involved in serotonin signaling with reflex syncope likelihood, and a genome-wide association study has identified single-nucleotide variation in proximity to the gene zinc finger protein 804a that is associated with vasovagal syncope. Even if these reports suggest heredity, large population-based studies on familial aggregation of reflex syncope are lacking
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