Serum uric acid and atrial fibrillation

Abstract

Background: Atrial fibrillation (AF) represents a significant health concern, due to the increased prevalence, morbidity, and mortality.

Methods and Results: There is a growing body of evidence correlating serum uric acid (SUA) with cardiovascular diseases such as arterial hypertension and AF.

Conclusion: Thus, a question arises as to whether SUA levels have a role in the pathophysiology of AF development.

Keywords:

• Atrial fibrillation
• cardiovascular disease
• arterial hypertension
• inflammatory indices

Introduction

Atrial fibrillation (AF) is the most common arrhythmia, and is associated with increased morbidity (especially stroke and heart failure), and mortality¹. The prevalence and incidence of AF is increased, and will further increase over the next decades. It is estimated that, in the US, by the year 2050, the number of adults with AF will have more than doubled². The increase of life expectancy, as well as the expected increase in the incidence and prevalence of all the risk factors and conditions that predispose for the development of atrial fibrillation, such as obesity diabetes mellitus and arterial hypertension, justifies these results. According to Heeringa et al.³, the prevalence of AF in a European population raised from 0.7% in the age group 55–59 years to 17.8% in those aged 85 years and above. In addition, the increased incidence of AF over two decades (between 1990–2010) also significantly increased mortality (Figure 1)^1,4.

Figure 1. Prevalence of AF: 1990–2010. Estimated age-adjusted global prevalence of AF (per 100,000 population) for males and females from 1990–2010 (AF, Atrial

Fibrillation). Reproduced with permission from Circulation 2014¹.

Risk factors, markers, and conditions pre-disposing for the development of atrial fibrillation

Many risk factors for the development of AF have been identified. These include: advanced age; male sex; diabetes mellitus; hypertension; obesity; elevated inflammatory marker concentrations; increased pulse pressure; aortic stiffness and PR-interval prolongation^5,6. Moreover, there are also several comorbidities associated with AF, such as: ischemic; hypertensive and valvular heart disease; congestive heart failure; chronic obstructive pulmonary disease; and diabetes mellitus⁷. Hypertension may be considered as the most important risk factor for the development of AF⁸. The prevalence of arterial hypertension in the AF populations from several clinical trials is very high, ranging from 80–90%⁸. The presence of arterial hypertension will increase further the risk of stroke in a patient with AF. Moreover, the use of anti-hypertensive therapy in patients with AF reduces the risk of stroke by ∼40%, while, for every 2-mmHg reduction of blood pressure, stroke rates will be reduced by 10%⁸. Arterial hypertension and AF frequently co-exists, since they share common pathophysiologic mechanisms and risk factors⁹. There is a growing body of evidence correlating serum uric acid with cardiovascular diseases such as arterial hypertension and AF. Thus, a question arises whether serum uric acid (SUA) levels have a role in the pathophysiology of AF development.

Is there a role for uric acid in atrial fibrillation?

According to several studies, SUA levels were associated with some cardiovascular conditions that are considered important risk factors for AF. A correlation between uric acid level and the incident hypertension was found by Krishnan et al.¹⁰ in middle-aged men without diabetes/glucose intolerance or metabolic syndrome. In a prospective study, normotensive men with baseline hyperuricemia had an 80% excess risk for the development of arterial hypertension (hazard ratio (HR) = 1.81; 95% confidence interval (CI) = 1.59–2.07) in comparison with those who did not, after adjustment for: baseline values of age; systolic and diastolic blood pressure; serum creatinine; proteinuria; serum triglycerides; total cholesterol; alcohol use; smoking; and body mass index¹¹. Each unit increase in SUA was associated with a 9% increase in the risk for the development of arterial hypertension (hazard ratio = 1.09; 95% CI = 1.02–1.17). High SUA levels are a strong and independent marker of impaired prognosis in patients with moderate-to-severe chronic heart failure¹¹. In addition, a recent meta-analysis found that hyperuricemia might increase the risk of coronary heart disease and all-cause mortality¹². Moreover, in a study based on a single-center database (n = 3,043), the left atrium diameter was significantly correlated with SUA (r = 0.341, p-value <.001)¹³. The same authors found in the nationwide longitudinal cohort in Taiwan (n = 122,524) that the AF occurrence rate was higher in patients with hyperuricemia that those without it (2.1% vs 1.7%; p-value <.001). Hyperuricemia was a significant risk factor of new-onset AF with a hazard ratio of 1.191 (95% CI = 1.098–1.292, p-value <.001) in the multivariate Cox regression analysis¹³. In another study that had the purpose to investigate the relationship of SUA with arterial hypertension and AF, 678 hypertensive patients (mean age = 61.9) and 143 controls (mean age = 68.3) were prospectively enrolled¹⁴. The group of hypertensives was divided into two sub-groups: sub-group A (n = 47), hypertensives with atrial fibrillation; and sub-group B (n = 631), hypertensives in sinus rhythm. SUA levels were significantly higher in the group with both hypertension and atrial fibrillation (group A: 7.3 ± 8.1 mg/dl) in comparison with those with hypertension without AF (group B: 5.2 ± 0.9 mg/dl), and the control group (4.8 ± 1 mg/dl, p < .001)¹⁴. Furthermore, SUA levels were significantly associated with left ventricular mass (p < .001) and left atrial diameter (p < .001). These data suggested that hyperuricemia might have a role in the left atrium and left ventricular remodeling, and, finally, for the development of AF¹⁴. In another study, Letsas et al.¹⁵ evaluated 45 patients with paroxysmal AF, 41 patients with permanent AF, and 48 control subjects. Overall, a significant variance in uric acid levels was evident between patients with paroxysmal AF (5.7 mg/dl), permanent AF (6.7 mg/dl), and control subjects (5.1 mg/dl) (p < .001). In the sub-group analysis, C reactive protein (CRP) (odds ratio (OR) = 1.434) and left ventricular ejection fraction (LVEF) (OR = 0.361) were independent predictors of paroxysmal AF, while CRP (OR = 3.048), SUA (OR = 2.172), and LVEF (OR = 0.34) were predictors of permanent AF. In a single hospital-based cohort (n = 11,123), SUA level was recorded in 7,155 patients. SUA level significantly increased the crude AF prevalence in both men and women (both, p < .001) (Table 1). Nevertheless, after adjustment for various cardiovascular risk factors for AF, the effect of SUA on AF was independent in women (OR = 1.888; 95% CI = 1.278–2.790), but not in men¹⁶. A positive correlation between SUA and AF, independent of sex and other cardiovascular risk factors, was found in a Japanese general population study¹⁷. A meta-analysis of six cohort studies showed that hyperuricemia was significantly associated with increased risk of AF (relative risk (RR) = 1.49, 95% CI = 1.24−1.79, p < .001)¹⁸ (Figure 2). This study confirmed the results of previous meta-analyses by Xu et al.¹⁹ and by Tamariz et al.²⁰. In a large population-based cohort study, gout was associated with a modestly increased risk of AF incident compared with osteoarthritis and non-gout after adjusting for other risk factors²¹. Over a mean 2-year follow-up, the incidence rate of AF per 1,000 person-years was 7.19 in gout and 5.87 in osteoarthritis. In a multivariable Cox regression, adjusting for age, sex, comorbidities, medications, and healthcare usage, the hazard ratio (HR) of AF in gout was 1.13 (95% CI = 1.04–1.23). When compared with non-gout, the multivariable HR of AF in gout was also increased (HR = 1.21, 95% CI = 1.11–1.33). Several studies reported that, in populations with different risk factors for AF, there is a significant increase in the risk of AF new onset, if hyperuricemia is present. In 450 consecutive patients with hypertension, independent predictors of AF were SUA level (OR = 1.008; 95% CI = 1.003–1.013, p = .002) and left atrial diameter (OR = 1.160; 95% CI = 1.068–1.260; p < .001)²². Hyperuricemia was found to increase the risk for incident AF also in patients with chronic heart failure²³, type 2 diabetes mellitus (p < .0001 for each 1 mg/dl increase in SUA level)²⁴, and obstructive sleep apnoea²⁵, even after adjustment for multiple clinical risk factors for AF. In addition, baseline SUA was a strong risk factor for developing AF after artery bypass graft. Using a cut-off point of 6.55, the pre-operative SUA level correlated with the appearance of AF with a sensitivity of 91.4% and specificity of 84.2%. So, SUA level can increase the sensitivity and specificity in predicting AF in patients after artery bypass graft operation²⁶. Hyperuricemia was associated with an increased prevalence of AF (20.6 vs 7.1%; p < .001) in hospitalized patients with type 2 diabetes, independently of multiple risk factors and potential confounders²⁷. Increased SUA levels are not an independent risk factor for AF development; evidence suggests that increases also AF morbidity²⁸. In a retrospective study, 1,359 consecutive patients undergoing transoesophageal echocardiography before catheter ablation of AF were enrolled. Sixty-one of the 1,359 patients (4.5%) had left atrial thrombus. SUA levels in patients with thrombus were significantly greater (413.5 ± 98.8 μmol/L vs 366.7 ± 94.3 μmol/L; p < .001). The incidence of left atrial thrombus was significantly greater in patients with hyperuricemia than in those with a normal SUA level in women (12.1% vs 1.9%; p < .001) and in men (8.5% vs 2.8%; p < .001)²⁸. Data regarding the prognostic significance of serum UA in AF ablation outcomes are indeed conflicting. A recent meta-analysis could not solve the problem, as the findings included suggested that elevated SUA was not associated with increased risk of AF recurrence after catheter ablation. However, the small number of studies included the heterogeneity of AF type, the follow-up duration, and ablation technique²⁹ limited the meta-analysis relevance.

Figure 2. Hyperuricemia was significantly associated with atrial fibrillation risk. Reproduced with permission from Karger Publishers, Basel, Switzerland, 2012¹⁸.

Table 1. Serum uric acid and prevalence rate of AF.

Uric acid tertile	No. subjects	AF	Prevalence rate (%)	Non-adjusted model		Adjusted model
				OR	95% CI	OR	95% CI
Total	7,155	1,131	15.8
Men	4,412	611	18.4
Low (<5.5 mg/dl)	1,459	239	16.4	Reference		Reference
Middle (5.5–6.5 mg/dl)	1,464	250	17.1	1.051	0.865–1.276	1.114	0.890–1.394
High (6.6 mg/dl)	1,489	322	21.6	1.408	1.169–1.695	1.176	0.935–1.478
Women	2,743	320	11.7
Low (<4.2 mg/dl)	954	62	6.5	Reference		Reference
Middle (4.2–5.0 mg/dl)	893	88	9.9	1.572	1.120–2.206	1.162	0.778–1.737
High (5.1 mg/dl)	896	170	19.0	3.368	2.478–4.578	1.888	1.278–2.790

OR in adjusted model was adjusted for age, eGFR, body mass index, hypertension, diabetes mellitus, low HDL cholesterolemia, use of diuretics and RAS, heart failure, organic cardiac disease and history of cerebral infarction/TIA.

AF, atrial fibrillation; OR, odds ratio; CI, confidence interval.

Reproduced with permission¹⁶.

Therapeutic implications

From a mechanistic point of view, inflammatory indices such as CRP, and also IL6 and TNF, have been related with AF and left atrial enlargement. In the long-term, AF induces tissue remodeling of the myocardium, which is responsible for increased conduction deficit, reduced contractility, and histopathologic changes³⁰. At the same time, CRP, IL6 and TNF are also related with higher uric acid levels. Hyperuricemia and gout exert pro-oxidant effects and decrease nitric oxide bioavailability in the vessel wall, inducing inflammation and endothelial dysfunction³¹. These effects may directly promote conduction changes, and increase the incidence of cardiovascular risk factors for AF such as hypertension, metabolic syndrome, and diabetes. Therefore, inflammation and tissue remodeling seem to be the linking pathophysiological issues between AF and SUA¹⁸.

The therapy of AF focuses also on risk factors treatment, taking into consideration the known pathophysiological mechanisms, for the prevention of new onset AF, and/or reduction of AF morbidity. In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, new-onset AF and associated stroke were significantly reduced by losartan- compared to atenolol-based anti-hypertensive treatment, although similar blood pressure reduction was attained³². New-onset AF occurred in 150 patients randomized to losartan vs 221 randomized to atenolol (6.8 vs 10.1 per 1,000 person-years; RR = 67, 95% CI = 0.55–0.83, p < .001), despite similar blood pressure reduction. There were fewer composite end-points (n = 31 vs 51, hazard ratio = 0.60, 95% CI = 0.38–0.94, p < .03) and strokes (n = 19 vs 38, HR = 0.49, 95% CI = 0.29–0.86, p < .01) in patients who developed new-onset AF in the losartan compared to the atenolol treatment arm of the study³². The ability of losartan to lower SUA levels could explain the significantly lower risk of stroke vs atenolol, in hypertensive patients with left ventricular hypertrophy, despite similar reductions in blood pressure³³. In addition, it is possible that uric acid lowering partly mediates the beneficial effect of losartan on atrial remodeling³⁴.

Similar anti-hypertensive efficacy, coupled with different lowering effect rate, has been observed also in a trial comparing losartan 50 mg/100 mg, candesartan 8 mg/16 mg, and losartan 50 mg/50 mg plus hydrochlorothiazide (HCTZ) 12.5 mg. After 12 weeks of treatment, both monotherapies attained equivalent reduction of systolic blood pressure. Nevertheless, candesartan increased SUA levels (0.13 mg/dL; 95% CI = 0.04–0.23), whereas losartan decreased them (–0.14 mg/dL; 95% CI = –0.24 to –0.04), and losartan plus HCTZ left them unchanged (0.06 mg/dL; 95% CI = –0.07 to 0.20)³⁵.

Conclusions

Atrial fibrillation represents a significant health concern, due to the increased prevalence and morbidity. Inflammation and oxidative stress play a major role in the pro-thrombotic state associated with AF. A better understanding of the pathogenesis of AF can help to develop new and effective treatments or preventive methods. Both inflammation and oxidative stress are strongly associated with uric acid metabolism and activity of xanthine dehydrogenase. There is growing evidence showing that SUA may be considered an emerging risk factor for AF, and suggesting that urate lowering therapy may have a role in prevention and treatment of AF.

Transparency

Declaration of funding

This review was funded by Fondazione Menarini.

Declaration of financial/other relationships

AJM declares consultancy/advisory fees and speakers bureau from Menarini. Peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no other relevant financial relationships to disclose.

Acknowledgments

Editorial assistance for this supplement was provided by Content Ed Net funded by Fondazione Menarini.