Genetic susceptibility to atrial fibrillation: does heart failure change our perspective?

Abstract

This editorial refers to ‘Genetic polymorphisms confer risk of atrial fibrillation in patients with heart failure: a population-based study’, by J.G. Smith et al., published in this issue on pages 250–257. Both atrial fibrillation (AF) and heart failure (HF) are prevalent conditions associated with substantial morbidity and healthcare costs.1 The lifetime risk of AF is ∼25% after the age of 40,2 whereas that of HF is ∼20%.3 By virtue of their common prevalence, AF and HF often occur together. However, evidence also suggests that each is an independent risk factor for the other.4 Regardless of which occurs first, the concomitant presence of both AF and HF is associated with substantially elevated risks of mortality, although it appears that pre-existing HF may portend a particularly adverse prognosis among patients with AF.4,5 There has been longstanding recognition of familial clustering of AF; however, only recently has it become apparent that there is a widespread heritable component underlying the arrhythmia.6 In the community-based Framingham Heart Study, 27% of individuals with AF had a first-degree relative with AF.6 Furthermore, the risk of AF was increased by ∼40% among those with familial AF as compared with those without AF.6 Genome-wide association studies have now identified nine common genome-wide susceptibility loci for AF.7–11 The mechanisms by which these loci influence AF susceptibility are under active investigation; however, the closest genes implicate transcription factors involved in cardiopulmonary development, cardiac expressed ion channels, and signalling molecules. Although the genetic basis for AF is evident in the community, it remains unclear whether individuals with AF in the context of HF have the same genetic susceptibility to the arrhythmia. Indeed, there is substantial phenotypic heterogeneity and it is conceivable that AF in the setting of HF is due to genetic mechanisms different from those that influence AF risk in the community. In this issue of the journal, Smith et al.12 examined the associations between AF and the two most significantly associated susceptibility signals for the arrhythmia on chromosomes 4q25 and 16q22, in individuals with HF. They studied 28 454 participants in the population-based Swedish Malmö Diet and Cancer Study who contributed DNA. Participants with HF or AF were identified using Swedish national registries by way of diagnostic codes. The investigators genotyped two single nucleotide polymorphisms (SNPs) that tag the chromosome 4q25 (rs2200733) and 16q22 (rs2106261) AF susceptibility loci. They then tested associations between these SNPs and AF using logistic regression, with adjustment for several common risk factors for each of the two conditions that were all measured at baseline enrolment. In total, 2339 were diagnosed with either prevalent or incident AF. A total of 1040 were diagnosed with prevalent or incident HF requiring hospitalization in the sample. Of these participants, 500 had diagnoses of both AF and HF. The majority of participants diagnosed with both AF and HF were diagnosed with AF first (57%), whereas 23% were diagnosed with HF first and 21% were diagnosed with both conditions simultaneously. Interestingly, the magnitudes of risk associated with each of the non-genetic risk factors and AF were substantially attenuated among individuals with HF as compared with the entire Malmö study sample, to the extent that several risk factors were not significantly associated with AF at all (e.g. age, male sex, body mass index, hypertension, and diabetes). For example, among those with HF, the investigators observed only about a 20% increased odds of developing AF with each increasing decade of age, whereas the odds were increased more than two-fold in the general population. These observations suggest that either that HF itself might mediate some of the AF risk attributed to these clinical risk factors, or that the pathophysiology of AF in patients with HF differs from that in the general population. With respect to the genetic analyses, the investigators observed a 57% increased odds of AF per copy of each chromosome 4q25 risk allele in participants with HF, and a 75% increased odds with the chromosome 16q22 risk allele. The HF risk attributable to these SNPs was 12% for the 4q25 SNP and 19% for the 16q22 SNP. There was no observed difference in AF risk associated with the chromosome 4q25 SNP between participants with or without HF. In contrast, there was a significantly increased risk of AF associated with the chromosome 16q22 SNP in individuals with HF as compared with those without HF (Figure 1). In prospective analyses, only the risk variant at chromosome 16q22 was associated with incident AF after HF, but not the chromosome 4q25 risk variant. Whether this reflects a lack of power in this sample or a true absence of association remains unclear. As with any observational study, this one has several limitations. First, as the authors point out, individuals with HF were diagnosed on the basis of hospitalizations, and the HF phenotype is not detailed with information about LVEF, functional status, and cardiomyopathy aetiology, each of which may influence the prevalence of concomitant AF and HF. These factors may limit the generalizability of these findings to other patients with HF. Secondly, AF is a polygenic disease, as evidenced by the nine genome-wide susceptibility signals7−11 and multiple independent signals at the 4q25 locus that have been identified.13 However, only two signals were tested for association in this analysis. Thirdly, given the targeted genotyping performed, the authors were not able to control for population stratification, an important factor in genetic studies that may result in confounding by subtle differences in population ancestry. Fourthly, the study includes only European individuals, and may have no relevance to those of different ancestral backgrounds. Despite these limitations, the authors should be congratulated for their contribution to the literature. Their findings may implicate that (i) the same genetic susceptibility to AF that exists in the general population appears to be present in patients with HF (at least definitively for the chromosome 16q22 SNP); and (ii) the AF susceptibility signal at chromosome 16q22 may have an even greater effect in patients with HF than in the general population. An attempt to replicate this observation is warranted. What explains the risk of AF observed in HF patients carrying AF susceptibility signals on chromosome 4q25? The susceptibility variant on chromosome 4q25 lies ∼150 kb upstream of the transcription factor gene PITX2. One isoform of this transcription factor, Pitx2c, is responsible for the development of myocardial sleeves in the pulmonary veins of mice,14 where many of the ectopic triggers originate in human AF.15 This same isoform also suppresses the default formation of an additional sinoatrial node in the left atrium in mice,16,17 and expression appears to be down-regulated in patients with AF as compared with those with sinus rhythm.18,19 Pitx2c also may directly modulate sodium and potassium cell currents.18 Why is AF risk increased among carriers of the 16q22 signal with HF? Less is understood about the role of the chromosome 16q22 locus and AF. The signal lies within the transcription factor gene ZFHX3, which has been implicated in Kawasaki disease20 as well as in malignancies such as prostate21 and breast22 cancer. In their discussion,12 Smith et al. suggest that ZFHX3 might mediate atrial fibrosis, an important factor in AF pathogenesis, via regulation of interstitial matrix deposition pathways. However, this hypothesis remains to be tested. What are the next steps with this information? First, the observed interaction reported in this study must be replicated. Assuming the association is valid, then it would be reasonable to test the remaining seven AF susceptibility signals published to date for associations with AF in patients with HF. Furthermore, determining the causal mechanisms by which these AF susceptibility signals influence AF risk, in patients both with and without HF, is critical to identifying potential novel therapeutic targets for this morbid and costly arrhythmia. Ultimately, whether there is any utility in directly incorporating AF genetic risk into clinical practice has yet to be determined; such information could theoretically facilitate efforts to prevent AF in subsets of patients with HF, to avoid inappropriate implantable cardioverter defibrillator (ICD) shocks in ICD patients, or to ensure biventricular pacing in CRT patient by alternative programming algorithms in patients with a genetic risk of AF. Conflict of interest: none declared.