In this study, we investigated the association between SUA and LA size in a total of 5392 healthy subjects in a single-center database. We determined that SUA was positively correlated with LA size after the adjustment for other important factors. SUA levels and blood pressure had a superposition effect on LA size. The effect of HU on LA size was similar to that of blood pressure on LA size. After adjustment for blood pressure, HU was an independent risk factor of LA enlargement.
Uric acid (UA) is the final product of purine metabolism. The main enzyme involved in the pathway is xanthine oxidoreductase, which exists in two interconvertible isoforms: xanthine dehydrogenase and xanthine oxidase. Only xanthine oxidase creates reactive oxygen species. This latter isoform is more active in ischemic conditions, after extensive surgery or physiologic stress, and is mainly expressed by the liver, intestine, and vascular wall. UA is primarily excreted by the kidney (85%) as a poorly soluble substance in urine and by the small bowel[17]. UA acts as an antioxidant and represents more than 60% of the antioxidant capacity of plasma. It scavenges oxidant radicals, reacts with peroxynitrite, and stabilizes endothelial nitric oxide synthase activity[18]. Importantly, extremely low UA levels are associated with endothelial dysfunction[19], and there is a J-shaped relationship between cardiovascular events and UA levels in primary hypertensive men and women[20].
UA is considered an independent factor for the development of a wide variety of microvascular and macrovascular disorders: hypertension[21], metabolic syndrome[22, 23], coronary artery disease(CAD)[24], diabetes[25], cerebrovascular disease [26, 27] and chronic kidney disease(CKD) [28] as well as other cardiovascular diseases(CVDs) [29, 30] and, conversely, these comorbidities increase the incidence of HU[31]. Some studies reported a relation between SUA level and CVD not only in patients with clearly diagnosed HU but also with values considered as normal to high, i.e., > 5.2–5.5 mg/dL[32–34]. Notably, since a high SUA concentration is associated with inflammatory markers, i.e., C-reactive protein or neutrophil count, inflammation seems to be a major link between HU and CVD and kidney diseases[31]. The increased risk of death was reported among patients with a high SUA level and heart failure(HF)[35]. A large retrospective analysis of patients with symptomatic HF revealed that HU was significantly associated with increased HF events or death[36]. Animal experiments have confirmed that the expression level and activity of xanthine oxidase in chronic heart failure(CHF) model animals are significantly increased[37]. Clinical trials have also found that HU increases the risk of atrial remodeling and CHF[38]. Although SUA has been regarded as an emerging risk factor of cardiovascular diseases[39], the association between SUA and LA size has not been clearly investigated in previous reports. In the study performed by Letsas et al., which enrolled a total of 86 AF and 48 non-AF patients, SUA level was significantly correlated with LA diameter (P < 0.001)[6]. However, the sample of the previous study was not from healthy population, the size was very small, and the correlation was not adjusted for other clinical factors which may confound the result. In another study, Tze-Fan Chao et al.[40] demonstrated the significant relationship between SUA and LA dimension in a large cohort(n = 3043). HU is associated with larger LA diameter. However, they defined patients as having HU only when they suffered at least one episode of a gout attack which necessitated long-term treatment of UA-lowering agents. Consistent with the above results, in the present study, we demonstrated the significant positive correlation between SUA and LA dimension in a larger cohort. Besides, the linear correlation between LA diameter and SUA levels remained significant in stepwise regression models adjusted for multiple variables (Age, BMI, systolic blood pressure, diastolic blood pressure, TC, TG, LDL-C, HDL-C, FBG, and white blood cell count). Different from Tze-Fan Chao’s definition of HU,the definition of HU in our study is that in a regular purine diet, fasting SUA levels in males are higher than 420 µmol/L, in females are higher than 360 µmol/L or take xanthine oxidase inhibitors). We believe that the findings of the present study provided a reliable evidence to support the viewpoint that the SUA level was positively correlated with LA diameter, which may reflect the degree of structural remodeling of LA.
The definition of HU varies widely in different studies, which makes the epidemiological reports somewhat inconsistent[13]. The prevalence of HU depends on sex, age and ethnicity, reaching a plateau at the age of 70[13]. In this study, 20.3% of individuals were diagnosed as HU (27.6% for men and 8.5% for women) in South China. The prevalence of men is about 3.25 times higher than that of women. While in the Taiwanese aboriginals, a very high prevalence (41%) has been found[41]. The United States National Health and Nutrition Examination Survey (NHANES) study estimated the HU prevalence to be 21.4% (21.2% for men and 21.6% for women)[42]. Reports are also available of ethnic difference such as, in the USA, a higher prevalence among African Americans than among non-African Americans(25.7%,22.1%, respectively)[31]. Over the ten years, epidemiological data consistently show an increase in the prevalence of both HU and gout. This might be caused by rapid economic development and a change of dietary habits and lifestyle and among patients with a higher socioeconomic status[43, 44]. Interestingly, SUA levels are higher in subsets of subjects at high cardiovascular(CV) risk, including postmenopausal women, non-white patients with hypertension or CKD.
Since the SUA was correlated with LA size which was a well-known determinant of AF development, and several studies have reported an association between HU and AF[5, 6, 8, 9], including the Atherosclerosis Risk In Communities (ARIC) study, it is reasonable to suppose that HU may be a risk factor of LA enlargement, may lead to AF through LA remodeling. Our study showed that the incidence of LA enlargement was significantly greater in subjects with HU than in those with a normal SUA level. HU increases the risk of LA enlargement by 2.09 times. Especially in women, the risk of LA enlargement by 3.50 times due to HU, suggesting that high SUA in women is a susceptible factor for LA enlargement. The ARIC study and Suzuki et al. demonstrated that HU was associated with AF only in females[5, 9]. We observe a significant gender difference regarding the HU-related LA enlargement risk, may explain the gender differences in the HU-related AF risk. However, further studies are needed.
Recent preclinical and clinical studies consistently support the hypothesis that increased levels of SUA may lead to hypertension[13]. HU is likewise independent risk factor of hypertension[17]. To avoid the possible influence of blood pressure on analysis, we stratified blood pressure in the HU group and normal SUA group. The stratified analysis suggested that SUA levels and blood pressure had a superposition effect on LA size. The risk of LA enlargement in the HU group with hypertension was 7.90 times higher than in normal SUA group with ideal blood pressure. The risk of LA enlargement was similar between the HU group with high normal blood pressure and the normal SUA group with hypertension. The higher blood pressure and SUA, the greater the risk of LA enlargement. The effect of HU on LA size was similar to that of blood pressure on LA size. After adjustment for blood pressure, HU was an independent risk factor of LA enlargement. The association between an increase in the risk of LA enlargement and HU remains independent of hypertension. Therefore, in children, adolescents and young adults with a family history of prehypertension (120–139/80–89 mmHg) or hypertension (≥ 140/90 mmHg), especially if other comorbidities(obesity, diabetes) are present, we recommend monitoring and maintaining SUA levels below the upper limit of normal (330, 360, and 420 µmol/l for children, women and men, respectively). Specific diets and uricosuric anti-hypertensive drugs (losartan) can be used as first choice therapy in these patients; diuretics should be avoided. Large-scale interventional studies are needed to determine whether a reduction in SUA levels and blood pressure can prevent LA enlargement and AF, especially in young patients with prehypertension.
The current study has some limitations. First, because of the cross-sectional study, we only studied the correlation between SUA levels and LA, the mechanism of SUA levels linking LA enlargement was not well explored. Second, the study population was mainly selected from Wenzhou, a city in southern China. Therefore, selection bias may limit the present conclusion to apply to the entire population of China. Finally, further prospective clinical trials are warranted to validate the predictive value of hyperuricemia for LA enlargement in different populations, and for making decisions on HU treatment.