Risk Factors for Syncope Associated With Multigenerational Relatives With a History of Syncope

Abstract

IMPORTANCE 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.OBJECTIVES 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. DESIGN, SETTING, AND PARTICIPANTSIn 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. EXPOSURES Register-based syncope diagnosis among relatives: pairs of twins, siblings, halfsiblings, and cousins. MAIN OUTCOMES AND MEASURESOdds 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. RESULTSAmong 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. CONCLUSIONS AND RELEVANCEIn 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 (continued) Key Points Question Is there a familial risk of syncope in first-, second-, and thirddegree relatives of individuals who have had syncope? Findings In this population-based cohort study among adults in Sweden, family ...

Underlying hemodynamic differences are associated with responses to tilt testing

“…As SBP mainly increases with greater stroke volume, reduced arterial elastance, and, to a lesser degree, with elevated peripheral vascular resistance 24 , higher SBP may suggest that those who are capable of tolerating TT have greater intravascular volume, better cardiac filling, and higher systemic vascular resistance compared with those who developed vasovagal syncope during TT. Interestingly, the association of combined heart rate and systolic blood pressure with TT positivity was markedly attenuated in younger women, who are genetically most predisposed to reflex syncope 25 , a fact that deserves more studies. Hypertension, on the other hand, implies chronic sympathetic activation with increased total peripheral resistance and elevated arterial tone in the precapillary vascular bed 26 .…”

Risk stratification of syncope: Current syncope guidelines and beyond

“…The genetic basis of vasovagal syncope is discussed in detail in another article in the current collection. Briefly, family pedigree studies, twin studies, genome-wide association studies, and gene duplicate studies indicate loci in the genome that associate with reflex syncope, although precise genes and proteins remain undetermined (Sheldon et al, 2019b;Fedorowski et al, 2021). Our understanding of the genetics underpinning hypotensive susceptibility, reflex syncope (Sheldon and Sandhu, 2019) and orthostatic intolerance syndromes (Fedorowski et al, 2012) is in an early phase, with much yet to be explored and, thus, cannot be applied in risk stratification.…”

Sex-Related Differences in Patients With Unexplained Syncope and Bundle Branch Block: Lower Risk of AV Block and Lesser Need for Cardiac Pacing in Women

“…In the general population, syncope seems to be more frequent in women (1,2,14,21,23). In a recent national population-based cohort study that included more than 2.5 million participants, Fedorowsky et al (21) found that 62% of the patients with syncope were women.…”

“…In the general population, syncope seems to be more frequent in women (1,2,14,21,23). In a recent national population-based cohort study that included more than 2.5 million participants, Fedorowsky et al (21) found that 62% of the patients with syncope were women. However, this proportion is reversed when a cohort of patients with structural heart disease (6,24,25) or abnormal ECG (3,5,7,26) is selected, probably because men have a higher prevalence of cardiovascular risk factors and other comorbidities.…”