Risk factors and consequences of atrial fibrillation: genetics, blood pressure, working hours, and cognitive decline

Although atrial fibrillation typically occurs in elderly subjects and particularly in those with longstanding hypertension or heart failure, younger individuals may be affected as well.1 In the latter population, a genetic basis has long been suspected.2 Hui-Nam Pak and colleagues from the Yonsei University Health System in Seoul, South Korea remind us that genetic susceptibility loci for atrial fibrillation identified by genome-wide association studies in a European database showed ethnic differences in the Asian population. They therefore explored novel atrial fibrillation susceptibility variants in Korean patients with early-onset atrial fibrillation, i.e. at age 60 or younger, who underwent catheter ablation. They report the results of their genome-wide association study performed in 672 cases and 3700 controls in their article ‘Koreanatrial fibrillationnetwork genome-wide association study for early-onset atrial fibrillation identifies novel susceptibility loci’.3 Five known genetic loci, i.e. 1q24/PRRX1, 4q25/PITX2, 10q24/NEURL 12q24/TBX5, and 16q22/ZFHX3, were validated and two novel loci were found on chromosomes 1q32.1/PPFIA4 and 4q34.1/HAND2 (and replicated in an additional independent sample. The identified loci implicate candidate genes that encode proteins related to cell to cell connection, hypoxic status, or long non-coding RNA. These novel findings are further discussed in a timely Editorial by Dawood Darbar from the University of Illinois at Chicago.4 Besides genetic factors, as outlined above, pre-hypertension and an impaired fasting glucose are associated with new-onset atrial fibrillation, as further investigated in another manuscript from Korea entitled ‘Clinical implication of an impaired fasting glucose and pre-hypertension related tonew-onset atrial fibrillation in a healthy Asian population without underlying disease:anationwide cohort study in Korea’, by Junbeom Park and colleagues from the Ewha Womans University in Seoul.5 Park et al. included 366 507 patients of which 139 306 with atrial fibrillation related to co-morbidities were excluded. They were compared with 227 102 healthy subjects. Subjects with impaired fasting glucose had a higher risk for atrial fibrillation (Figure 1). Surprisingly, diastolic blood pressure was a stronger indicator for atrial fibrillation than systolic blood pressure. The incidence of atrial fibrillation was dramatically increased by the combination of pre-hypertension and impaired fasting glucose in subjects with a body mass index (BMI) <25 kg/m2, but not in those with one ≥25 kg/m2. Thus, in healthy Asians without co-morbidities, pre-hypertension and an impaired fasting glucose represent important risk factors for atrial fibrillation, particularly if occurring together and in those with a BMI <25 kg/m2. These intruiging results are discussed in an interesting Editorial by Paulus Kirchhof from the University of Birmingham in the UK.6 AF incidence and risk based on the combination of risk factors. AF, atrial fibrillation; HTN, hypertension; IFG, impaired fasting glucose; BMI, body mass index; LCL, lower confidence limit; UCL, upper confidence limit (from Lee SS, Ae Kong K, Kim D, Lim Y-M, Yang P-S, Yi J-E, Kim M, Kwon K, Bum Pyun W, Joung B, Park J. Clinical implication of an impaired fasting glucose and prehypertension related to new onset atrial fibrillation in a healthy Asian population without underlying disease: a nationwide cohort study in Korea. See pages 2599–2607). Atrial fibrillation is a major risk factor for stroke.7,8 This is thought to be related to the formation of clots in the left atrium of the heart and in particular the left atrial appendix,9 a hypothesis supported by the fact that anticoagulants markedly reduce the incidence of strokes.10 Whether repetitive smaller emboli that are not associated with neurological deficits may lead to a decline in neurocognitive function is uncertain, but is convincingly addressed in the article entitled ‘Atrial fibrillation as a risk factor for cognitive decline and dementia’ by Archana Singh-Manoux and colleagues from the INSERM in Villejuif Cedex, France.11 They analysed the association of atrial fibrillation and cognitive dysfunction in 10 308 subjects recruited into the Whitehall II study. A battery of cognitive tests was administered to 7428 participants of which 414 had atrial fibrillation. Compared with atrial fibrillation-free participants, those with longer exposure to atrial fibrillation experienced faster cognitive decline after adjustment for socio-demographic factors, behavioural factors, and chronic diseases. Incident stroke or coronary heart disease individually did not explain the excess cognitive decline; however, this relationship was relevant when considering them together. An analysis of incident dementia further confirmed that atrial fibrillation was associated with a higher risk of dementia, with a hazard ratio of 1.87. Multistate models showed atrial fibrillation to increase the risk of dementia in those free of stroke, but not in those free of stroke and coronary heart disease. Thus, in adults, atrial fibrillation is associated with accelerated cognitive decline and higher risk of dementia even at ages when atrial fibrillation incidence is low. These clinically important findings are put into context in an Editorial by Hans-Christoph Diener from the Universität Essen in Germany.12 Previous studies have suggested that people who work long hours and particularly those who do not cope well with it13 might be at increased risk of stroke, but the association of long working hours with atrial fibrillation is unknown. Thus, Mika Kivimaki and collegues from University College London addressed this issue in their article ‘Long workinghoursas a risk factor for atrial fibrillation:amulti-cohort study’.14 They examined the risk of atrial fibrillation in 85 494 individuals working >55 h per week and those working 35–40 h per week over a 10-year follow-up. The authors identified 1061 new cases of atrial fibrillation corresponding to a 10-year cumulative incidence of 12.4 per 1000. After adjustment for age, sex, and socio-economic status, individuals working long hours had a 1.4-fold increased risk of atrial fibrillation compared with those working standard hours (Figure 2). There was no significant heterogeneity between the cohort-specific effect estimates, and the finding remained after excluding participants with coronary heart disease or stroke at baseline or during the follow-up. Adjustment for potential confounding factors, such as obesity, risky alcohol use, and high blood pressure, had little impact on this association. Thus, individuals who work long hours are more likely to develop atrial fibrillation than those working standard hours, a finding that has implications beyond medicine and that is critically discussed further an Editorial by Lucas V.A. Boersma from the Heart Lung Center Utrecht in The Netherlands.15 Association between working hours and risk of atrial fibrillation (AF) in 85 494 men and women free of AF at baseline. During the mean follow-up of 10.0 years, 1061 developed AF. The figure shows that persons who worked 55 h or more per week had a 1.4-fold increased risk of AF compared with those working standard 35–40 weekly hours (A). This estimate did not vary according to the method of AF ascertainment (B) (from Kivimäki M, Nyberg ST, Batty GD, Kawachi I, Jokela M, Alfredsson L, Bjorner JB, Borritz M, Burr H, Dragano N, Fransson EI, Heikkilä K, Knutsson A, Koskenvuo M, Kumari M, Madsen IEH, Nielsen ML, Nordin M, Oksanen T, Pejtersen JH, Pentti J, Rugulies R, Salo P, Shipley MJ, Suominen S, Theorell T, Vahtera J, Westerholm P, Westerlund H, Steptoe A, Singh-Manoux A, Hamer M, Ferrie JE, Virtanen M, Tabak AG, for the IPD-Work consortium. Long working hours as a risk factor for atrial fibrillation: a multi-cohort study. See pages 2621–2628). The editors hope that readers of this issue of the European Heart Journal will find it of interest.