Sleep Disordered Breathing, Obesity and Atrial Fibrillation: A Mendelian Randomisation Study

Abstract

It remains unclear whether the association between obstructive sleep apnoea (OSA), a form of sleep-disordered breathing (SDB), and atrial fibrillation (AF) is causal or mediated by shared co-morbidities such as obesity. Existing observational studies are conflicting and limited by confounding and reverse causality. We performed Mendelian randomisation (MR) to investigate the causal relationships between SDB, body mass index (BMI) and AF. Single-nucleotide polymorphisms associated with SDB (n = 29) and BMI (n = 453) were selected as instrumental variables to investigate the effects of SDB and BMI on AF, using genetic association data on 55,114 AF cases and 482,295 controls. Primary analysis was conducted using inverse-variance weighted MR. Higher genetically predicted SDB and BMI were associated with increased risk of AF (OR per log OR increase in snoring liability 2.09 (95% CI 1.10–3.98), p = 0.03; OR per 1-SD increase in BMI 1.33 (95% CI 1.24–1.42), p < 0.001). The association between SDB and AF was not observed in sensitivity analyses, whilst associations between BMI and AF remained consistent. Similarly, in multivariable MR, SDB was not associated with AF after adjusting for BMI (OR 0.68 (95% CI 0.42–1.10), p = 0.12). Higher BMI remained associated with increased risk of AF after adjusting for OSA (OR 1.40 (95% CI 1.30–1.51), p < 0.001). Elevated BMI appears causal for AF, independent of SDB. Our data suggest that the association between SDB, in general, and AF is attributable to mediation or confounding from obesity, though we cannot exclude that more severe SDB phenotypes (i.e., OSA) are causal for AF.

Obesity as a risk factor for cardiac arrhythmias

“…Nevertheless, a Mendelian randomisation study of data from 55 114 patients with AF and 482 295 controls, published in 2022, showed that sleep disordered breathing was not associated with AF after adjusting for body mass index. 30 Importantly, however, body mass index remained associated with AF after adjusting for obstructive sleep apnoea. This finding suggests that the link between obstructive sleep apnoea and AF might be mediated or confounded by concurrent obesity in patients with mild-to-moderate obstructive sleep apnoea 30 and supports aggressive strategies for weight reduction to mitigate AF risk in these patients.…”

“…30 Importantly, however, body mass index remained associated with AF after adjusting for obstructive sleep apnoea. This finding suggests that the link between obstructive sleep apnoea and AF might be mediated or confounded by concurrent obesity in patients with mild-to-moderate obstructive sleep apnoea 30 and supports aggressive strategies for weight reduction to mitigate AF risk in these patients.…”

“…Mendelian randomisation studies use genetic variation to investigate causal relations between modifiable risk factors and health outcomes in observational data; the results of which have supported a causal association between higher body mass index and AF risk. 30 Mendelian randomisation studies also show that obesity often co-exists with hypertension, 20 insulin resistance, 31 and obstructive sleep apnoea, 32 which each independently confer increased arrhythmic risk (figure 1). In the following sections we explore the extent to which increases in arrhythmic risk in obesity is explained by increases in adipose volume, particularly epicardial fat, or by obesity related comorbidity.…”

“…Indeed, another Mendelian randomisation study including almost sixfold single nucleotide polymorphisms showed that although obstructive sleep apnoea was associated with AF in univariable analysis (odds ratio 2.09 (95% confidence interval 1.10 to 3.98)), this finding became non-significant after adjustment for body mass index (0.68 (0.42 to 1.10)). 30 In brief, available data suggest that proarrhythmic risks associated with obstructive sleep apnoea are partly mediated by obesity.…”

Peripheral sympathectomy alters neuroinflammatory responses and microglial activity in response to sleep fragmentation in female mice

“…There is accumulating evidence that sleep dysfunction promotes in ammatory responses in brain and peripheral tissues, which can contribute to the development of chronic pathologies, such as metabolic and cardiovascular diseases and neurological disorders [1][2][3]. The global increase in obesity rates has led to a pronounced rise in the incidence of obstructive sleep apnea [4]. Chronic sleep fragmentation (SF) simulates the interrupted sleep experienced by patients with obstructive sleep apnea and other sleep disorders [5][6][7].…”