U-shaped association between serum uric acid concentration and mortality in hypertrophic cardiomyopathy patients ARTICLE U-shaped association between serum uric acid concentration and mortality in hypertrophic cardiomyopathy patients Ziqiong Wang, Ying Xu, Hang Liao, Xiaoping Chen and Sen He Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China ABSTRACT Background. No study has examined the effect of low serum uric acid (SUA) concentrations on mor- tality in hypertrophic cardiomyopathy (HCM) patients. The aim of the present study was to assess the relations between both low and high SUA concentrations and the risk of mortality across the full range of SUA concentrations in a retrospective cohort of HCM patients. Methods. A total of 454 HCM patients were enrolled in the study, and SUA concentrations were meas- ured at baseline. The primary and secondary endpoints were all-cause mortality and HCM-related mor- tality, respectively. The associations between SUA concentrations and endpoints were analysed. Results. During a median follow-up of 3.8 years, there were 80 (17.6%) all-cause mortality events, and 52 of them (11.5%) were ascribed to HCM-related mortality. Patients with SUA concentrations of 250–350mmol/L had the lowest all-cause mortality rate (11.8%) and HCM-related mortality rate (5.0%). Both low and high SUA concentrations were associated with increased all-cause and HCM-related mor- tality. Adjusted HRs were 2.52 (95% CI 1.13–5.61, p ¼ 0.024) and 4.86 (95% CI 1.74–13.58, p ¼ 0.003) for all-cause mortality and HCM-related mortality in the lowest SUA group (<250 mmol/L) when compared with the reference group (250–350mmol/L), respectively. The corresponding HRs in the highest SUA group (�450mmol/L) were 2.73 (95% CI 1.42–5.23, p ¼ 0.003) and 4.14 (95% CI 1.70–10.13, p ¼ 0.002), respectively. Conclusions. Both low and high SUA concentrations were significantly associated with increased risk of all-cause mortality and HCM-related mortality, which supported a U-shaped association between SUA concentrations and mortality in HCM patients. ARTICLE HISTORY Received 13 January 2020 Accepted 16 January 2020 KEYWORDS Hypertrophic cardiomyop- athy; mortality; serum uric acid; U-shaped association Introduction Uric acid is the end product of purine metabolism (1). It has been reported that high serum uric acid (SUA) concentra- tions are associated with increased risk of cardiovascular dis- eases and death (2,3). However, the role of SUA in this constellation still remains controversial (4,5). Recently, several studies have also indicated that low SUA concentrations could predict cardiovascular death and all-cause mortality, which supports a J- or U-shaped association between SUA concentrations and mortality (6–9). Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease with marked heterogeneity in clinical expression, nat- ural history, and prognosis (10). Some factors have been identified for risk stratification in HCM patients, such as New York Heart Association (NYHA) class, atrial fibrillation (AF), maximal wall thickness (MWT), and left ventricular outflow tract obstruction (LVOTO), etc. (11). In a retrospective cohort study, Zhu et al. illustrated that high SUA concentrations were associated with adverse outcomes in HCM patients (12). However, no longitudinal studies have evaluated the risk of all-cause and HCM-related mortality across the full range of SUA concentrations in HCM patients while considering both low and high SUA concentrations. Therefore, the purpose of the present study was to evaluate the association between both low and high SUA concentrations with all-cause and HCM-related mortality in a cohort of HCM patients. Methods Study population This was a retrospective and longitudinal study. A total of 508 patients with a diagnosis of HCM were consecutively enrolled in the study from December 2008 to May 2016 at West China Hospital of Sichuan University (a tertiary referral centre). The diagnosis of HCM was based on the echocardio- graphic demonstration of an increase in wall thickness of �15 mm in any left ventricular myocardial segment, which was not solely explained by abnormal load conditions (13). Nine patients with inherited metabolic disease or syndromic causes of HCM were excluded from the study (cardiac CONTACT Sen He hesensubmit@163.com Department of Cardiology, West China Hospital, Sichuan University, 37 Guo Xue Xiang, Chengdu, 610041 Sichuan Province, China Ziqiong Wang and Ying Xu contributed equally to this work. � 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. UPSALA JOURNAL OF MEDICAL SCIENCES 2020, VOL. 125, NO. 1, 44–51 https://doi.org/10.1080/03009734.2020.1719245 http://crossmark.crossref.org/dialog/?doi=10.1080/03009734.2020.1719245&domain=pdf&date_stamp=2020-02-19 http://creativecommons.org/licenses/by/4.0/ https://doi.org/10.1080/03009734.2020.1719245 http://www.tandfonline.com amyloidosis n ¼ 5, restrictive cardiomyopathy n ¼ 2, dilated cardiomyopathy n ¼ 1, myocarditis n ¼ 1). We also excluded patients who were lost to follow-up after the first evaluation (n ¼ 41), as well as patients with incomplete biochemistry data (n ¼ 4). The final sample size consisted of 454 HCM patients. Detailed information about those patients has been reported elsewhere (14,15). The study was approved by the Ethics Committee on Medical Research of West China Hospital of Sichuan University, and performed according to the principles of the Declaration of Helsinki. Due to the retro- spective nature of the study, informed consent was waived. Data collection Blood samples were obtained at admission for all patients. SUA concentrations were measured by the uricase method. Estimated glomerular filtration rate (eGFR) was calculated using the four-variable Modification of Diet in Renal Disease study equation: eGFR (mL/min/1.73 m2) ¼ 186.3 � (serum creatinine)�1.154� age�0.203 (� 0.742 if female) (16). Normal kidney function was defined as eGFR � 60 ml/min/1.73 m2 (6). All patients underwent standard two-dimensional trans- thoracic echocardiography examinations by standard techni- ques (17). The presence of LVOTO was defined as a gradient >30 mmHg at rest. Other data of baseline characteristics were collected from medical records. Follow-up and outcomes Follow-ups were carried out by clinical consultations, medical records, or telephone interviews. The primary endpoint was all-cause mortality, and the secondary endpoint was HCM- related mortality, which included: (1) sudden cardiac death, (2) heart failure-related death, (3) stroke-related death, and (4) perioperative death due to septal myectomy. Statistical analysis Patients were divided into four groups according to concen- trations of SUA: <250 mmol/L (n ¼ 43), �250 mmol/L and <350 mmol/L (n ¼ 161), �350 mmol/L and <450 mmol/L (n ¼ 148), and �450 mmol/L (n ¼ 102). Descriptive statistics were used to summarise baseline characteristics. Baseline characteristics among the four groups were ana- lysed by ANOVA for parametric variables, Kruskal–Wallis test for non-parametric variables, and chi-square or Fisher exact tests for categorical variables. A Kaplan–Meier method was used to estimate the survival in each group, and a log-rank test was used for comparisons. To assess the role of SUA as an independent predictor of mortality, Cox proportional haz- ard regression analysis was used. The lowest mortality inci- dence group was defined as the reference group. Age and gender were forced into five multivariable models. Other var- iables entered a model on the basis of clinical relevance and a univariate relation with mortality (p < 0.05). For the final model, the predictors were sought using a stepwise back- ward modelling approach (p ¼ 0.05 for inclusion, p ¼ 0.10 for exclusion) including all variables from models 1 to 4. The proportional hazard assumption was verified by means of multivariate Cox regressions. Restricted cubic splines were used to further explore the shape of the dose–response rela- tion between SUA concentrations and risk of all-cause mor- tality and HCM-related mortality. Finally, we assessed the relation between SUA concentrations and mortality in the patients who did not take hydrochlorothiazide and patients with normal kidney function as sensitivity analyses. All analyses were performed by EmpowerStats software (www.empowerstats.com, X&Y Solutions, Inc., Boston, MA, USA) and SPSS version 25.0 (SPSS Inc., Chicago, IL, USA). All statistical testing was two-sided. Results Baseline characteristics The median age was 57.5 (interquartile range: 46.0–67.0) years (Table 1). Male patients accounted for 55.7%. SUA con- centrations ranged from 42.0 to 913.0 mmol/L. Patients with higher SUA concentrations had higher male percentage (p < 0.001), higher serum creatinine (p < 0.001), larger left atrium (LA) and left ventricle sizes (p ¼ 0.006 and p ¼ 0.001, respectively), but lower eGFR (p ¼ 0.046), high-density lipo- protein–cholesterol (p < 0.001), and left ventricular ejection fraction (LVEF) (p < 0.001). Other variables did not differ between the four groups. Clinical outcomes During a median follow-up of 3.8 years (range: 0.1–9.4), there were 80 (17.6%) all-cause mortality events, and 52 (11.5%) were ascribed to HCM-related mortality. Patients with SUA concentrations in the interval 250–350 mmol/L had the lowest mortality rate (Table 2). Likewise, a Kaplan–Meier analysis showed that the survival freedom of all-cause mortality and HCM-related mortality was highest in this group of patients (p ¼ 0.014 and 0.002, respectively, Figure 1). A further decrease or increase of SUA was associated with higher risk of mortality. Relation of SUA to all-cause mortality and HCM- related mortality Table 3 presents the results of univariate Cox proportional hazard analysis. The lowest SUA group (<250 mmol/L) was found to have an increased risk of all-cause and HCM-related mortality. The corresponding HRs for all-cause and HCM- related mortality, comparing <250 mmol/L SUA with 250–350 mmol/L SUA, were 2.11 (95% confidence interval [CI]: 0.98–4.55, p ¼ 0.056) and 3.98 (95% CI: 1.49–10.62, p ¼ 0.006), respectively. The highest SUA group (�450 mmol/L) was sig- nificantly associated with increased risk of all-cause and HCM-related mortality. Among the remaining variables, NYHA III/IV, AF, warfarin, serum glucose, and LA were also identified as significant risk factors for both all-cause mortal- ity and HCM-related mortality, while triglycerides, low-density UPSALA JOURNAL OF MEDICAL SCIENCES 45 http://www.empowerstats.com lipoprotein–cholesterol (LDL-C), and LVEF were protect- ive factors. After adjusting for potential confounding factors, the association between SUA concentrations and endpoints remained consistent. In the final model—after adjusting for age, sex, NYHA III/IV, chronic obstructive pulmonary disease, AF, triglycerides, LDL-C, and LA—HRs for all-cause mortality and HCM-related mortality, comparing �450 mmol/L SUA with 250–350 mmol/L SUA, were 2.73 (95% CI: 1.42–5.23, p ¼ 0.003) and 4.14 (95% CI: 1.70–10.13, p ¼ 0.002), respect- ively. The corresponding adjusted HRs in SUA <250 mmol/L for all-cause mortality and HCM-related mortality were 2.52 (95% CI: 1.13–5.61, p ¼ 0.024) and 4.86 (95% CI: 1.74–13.58, p ¼ 0.003) (Table 4). Restricted cubic spline In the multivariable-adjusted spline (adjusted for the same variables as in model 5), there was a U-shaped association between SUA concentrations and all-cause mortality and HCM-related mortality, with a nadir of risk at SUA around 300 mmol/L. Deviation of SUA from 300 mmol/L was signifi- cantly associated with higher mortality risk (Figure 2(A,B)). For SUA concentrations higher than 300 mmol/L, a 10 mmol/L increase of SUA showed a 4.6% (p < 0.001) increase of all- cause mortality and 5.2% (p ¼ 0.001) increase of HCM-related mortality. For SUA concentrations less than 300 mmol/L, a 10 mmol/L decrease of SUA showed a 9.4% (p ¼ 0.03) increase of all-cause mortality and 15.6% (p ¼ 0.004) increase of HCM- related mortality. Sensitivity analyses When including patients with normal kidney function (n ¼ 384), there were 56 (14.6%) all-cause mortality and 38 (9.9%) HCM-related mortality events. The adjusted HRs main- tained a U-shaped relation, with a nadir of risk at SUA around 300 mmol/L (Figure 3(A,B)). For SUA concentrations higher than 300 mmol/L, a 10 mmol/L increase of SUA was associated with a 2.6% (p ¼ 0.213) increase of all-cause Table 2. Primary and secondary endpoint of the present study. Endpoints Whole cohort Serum uric acid concentration (mmol/L) <250 �250, <350 �350, <450 �450 No. of patients 454 43 161 148 102 All-cause mortality No. of deaths 80 10 19 25 26 Mortality rate (%)a 17.6 23.3 11.8 16.9 25.5 HCM-related mortality No. of deaths 52 8 8 17 19 Mortality rate (%)a 11.5 18.6 5.0 11.5 18.6 aBinary event rate. Table 1. Baseline characteristics of the study cohort. Variables Whole cohort (n ¼ 454) Serum uric acid concentration (mmol/L) p Value<250 (n ¼ 43) �250, <350 (n ¼ 161) �350, <450 (n ¼ 148) �450 (n ¼ 102) Basic information Age (y) 57.5 (46.0–67.0) 59.0 ± 15.1 59.0 (46.0–68.0) 56.5±±4.8 52.1 ± 16.6 0.067 Gender (male) 253 (55.7%) 10 (23.3%) 72 (44.7%) 95 (64.2%) 76 (74.5%) <0.001 FHHCM 42 (9.3%) 2 (4.7%) 15 (9.3%) 15 (10.1%) 10 (9.8%) 0.739 FHSCD 18 (4.0%) 2 (4.7%) 4 (2.5%) 6 (4.1%) 6 (5.9%) 0.579 NYHA III/IV 156 (34.4%) 20 (46.5%) 49 (30.4%) 47 (31.8%) 40 (39.2%) 0.121 Medical history Hypertension 141 (31.1%) 9 (20.9%) 46 (28.6%) 51 (34.5%) 35 (34.3%) 0.280 Diabetes 37 (8.1%) 5 (11.6%) 14 (8.7%) 13 (8.8%) 5 (4.9%) 0.517 COPD 29 (6.4%) 6 (14.0%) 11 (6.8%) 5 (3.4%) 7 (6.9%) 0.092 AF 77 (17.0%) 5 (11.6%) 23 (14.3%) 23 (15.5%) 26 (25.5%) 0.067 Medications/devices/procedures Aspirin/clopidogrel 98 (21.6%) 10 (23.3%) 29 (18.0%) 37 (25.0%) 22 (21.6%) 0.512 Warfarin 41 (9.0%) 2 (4.7%) 8 (5.0%) 13 (8.8%) 18 (17.6%) 0.004 Statins 123 (27.1%) 10 (23.3%) 37 (23.0%) 48 (32.4%) 28 (27.5%) 0.279 Beta-blockers 325 (71.6%) 29 (67.4%) 109 (67.7%) 117 (79.1%) 70 (68.6%) 0.109 ACEI/ARB 88 (19.4%) 8 (18.6%) 30 (18.6%) 27 (18.2%) 23 (22.5%) 0.837 HCTZ 27 (5.9%) 3 (7.0%) 10 (6.2%) 9 (6.1%) 5 (4.9%) 0.959 ICD/pacemaker 59 (13.0%) 5 (11.6%) 23 (14.3%) 17 (11.5%) 14 (13.7%) 0.393 Obstruction intervention 41 (9.0%) 4 (9.3%) 13 (8.1%) 19 (12.8%) 5 (4.9%) 0.091 Laboratory test eGFR (mL/min/1.73 m2) 82.8 (68.6–100.7) 94.2 (79.3–110.3) 88.5 (74.5–107.0) 80.0 ± 24.3 74.4 (56.0–91.2) 0.046 Creatinine (mmol/L) 80.6 (67.0–94.7) 63.1 (55.0–75.0) 74.0 ± 16.7 84.6 (74.0–99.2) 94.7 (80.3–115.3) <0.001 Glucose (mmol/L) 5.4 (4.9–6.5) 5.4 (4.6–6.7) 5.4 (4.7–6.2) 5.4 (5.0–6.3) 5.5 (5.0–6.8) 0.437 Triglycerides (mmol/L) 1.2 (0.9–1.9) 1.2 (0.9–1.4) 1.2 (0.9–1.6) 1.4 (1.0–2.0) 1.2 (0.9–2.1) 0.054 HDL-C (mmol/L) 1.3 (1.0–1.6) 1.3 (1.1–1.5) 1.4 (1.1–1.7) 1.2 (1.0–1.5) 1.1 (1.0–1.5) <0.001 LDL-C (mmol/L) 2.4 ± 0.8 2.6 ± 0.9 2.4 ± 0.8 2.4 ± 0.7 2.4 ± 0.8 0.597 Echocardiographic data LA (mm) 40.0 (35.0–46.0) 39.2 ± 6.6 38.0 (34.0–45.0) 40.4 ± 6.7 42.6 ± 8.0 0.006 LV (mm) 43.0 (40.0–46.0) 40.0 (36.3–43.0) 43.0 (39.3–46.0) 43.5 (40.0–47.0) 44.0 (40.0–49.0) 0.001 MWT (mm) 19.0 (16.0–22.0) 19.1 ± 5.0 19.0 (17.0–22.0) 20.0 (16.3–22.0) 19 (16.0–21.0) 0.309 LVEF (%) 68.0 (63.0–72.0) 69.0 (65.0–73.0) 70.0 (65.0–73.0) 68.0 (63.0–71.0) 65.0 (59.0–71.0) <0.001 LVOTO 181 (39.9%) 20 (46.5%) 72 (44.7%) 57 (38.5%) 32 (31.4%) 0.165 ACEI: angiotensin-converting-enzyme inhibitor; AF: atrial fibrillation; ARB: angiotensin receptor blocker; COPD: chronic obstructive pulmonary disease; eGFR: esti- mated glomerular filtration rate; FHHCM: family history of hypertrophic cardiomyopathy; FHSCD: family history of sudden cardiac death; HCM: hypertrophic car- diomyopathy; HCTZ: hydrochlorothiazide; HDL-C: high-density lipoprotein–cholesterol; ICD: implantable cardioverter defibrillator; LA: left atria; LDL-C: low-density lipoprotein–cholesterol; LV: left ventricle; LVEF: left ventricular ejection fraction; LVOTO: left ventricular outflow tract obstruction; MWT: maximal wall thickness; NYHA: New York Heart Association; TG: triglycerides. 46 Z. WANG ET AL. mortality and 6.3% (p ¼ 0.008) increase of HCM-related mor- tality. For SUA concentrations less than 300 mmol/L, a 10 mmol/L decrease of SUA was associated with a 11.1% (p ¼ 0.026) increase of all-cause mortality and 19.3% (p ¼ 0.002) increase of HCM-related mortality. Upon excluding patients who were taking hydrochloro- thiazide, 427 patients remained. There were 75 (17.5%) all- cause mortality and 49 (11.4%) HCM-related mortality events. The association between SUA concentrations and mortality did not change materially (Figure 3(C,D)). For SUA concentra- tions higher than 300 mmol/L, the risk of all-cause mortality and HCM-related mortality increased 4.5% (p ¼ 0.001) and 5.0% (p ¼ 0.003) with each 10 mmol/L increase in SUA con- centrations, respectively. For SUA less than 300 mmol/L, the risk of all-cause mortality and HCM-related mortality increased 9.9% (p ¼ 0.029) and 15.6% (p ¼ 0.006) with each 10 mmol/L decrease in SUA concentration, respectively. Discussion In the present study, patients with either low or high SUA concentrations were found to have a higher risk of all-cause mortality and HCM-related mortality. Our study is the first study to reveal a U-shaped association between SUA concentrations and all-cause mortality and HCM-related mor- tality in HCM patients. The inflection point is approximately 300 mmol/L SUA. Our findings have some similarities with previous studies but also presented with certain differences (6–9). In a general US population, it was reported that there was a U-shaped association between SUA concentrations and cardiovascular mortality. However, this relation was no longer statistically significant after adjusting for eGFR and albumin–creatinine ratio (ACR) (6). In our study, the association remained stable after adjusting for eGFR. We were unable to examine the effect of ACR due to data unavailability. In another study comprising Korean adults with normal kidney function, Kang et al. found that the overall mortality rate had a U-shaped association with SUA concentrations in males but not in females (7). Furthermore, in a large cohort study of Korean general populations, the authors demonstrated that low SUA concentrations were independently associated with increased risk of all-cause mortality in both genders and increased risk of cardiovascular disease in females only (9). There was no gender-specific relation in our study. To our knowledge, only one study has been carried out to illustrate the relation between SUA concentrations and all- cause mortality and cardiovascular death in HCM patients (12). In that study, SUA was categorised into tertiles. The adjusted HRs for all-cause mortality and cardiovascular death of subjects in the highest tertile of SUA were 2.33 (95% CI: 1.11–4.89, p ¼ 0.025) and 3.10 (95% CI: 1.37–7.04, p ¼ 0.007) when compared to that of subjects in the lowest tertile. There was no statistical difference between the second tertile versus the first tertile with regard to the aforementioned out- comes. The cut-off points overlapped but not the same when categorising patients into different groups between that study and our study. By grouping SUA into tertiles, intracategory variations in mortality risk could not be detected, probably leading to a failure of examining the influence of very low and very high SUA concentrations on mortality. In vitro and animal studies have revealed that high SUA concentrations might produce an inflammatory reaction, as evidenced by increased expression of inflammation cyto- kines, such as interleukin (IL)-6, IL-8, and tumour necrosis fac- tor-a (TNF-a) in endothelial cells. This process was associated with activation of transcription factor NF-jB (18). High SUA concentrations could also stimulate monocyte chemoattract- ant protein-1 in vascular smooth muscle cells through mito- gen-activated protein kinase and cyclooxygenase-2 (19). A clinical study based on community-dwelling older per- sons revealed a positive and significant association between SUA concentrations and several inflammatory markers, including neutrophil count, C-reactive protein (CRP), IL-6, IL- 18, and TNF-a (20). The above findings supported a role of high SUA concentrations in the process of inflammation. Recently, Wang et al. reported that elevated high-sensitivity CRP was associated with increased risk of adverse outcomes in patients with HCM, suggesting a possible association of an inflammatory state and the clinical progression of HCM (21). Therefore, these inflammatory events induced by SUA might Figure 1. Freedom from all-cause mortality (A) and HCM-related mortality (B) according to different serum uric acid (SUA) concentrations during follow-up period in HCM patients. UPSALA JOURNAL OF MEDICAL SCIENCES 47 partially explain the poor prognosis of HCM patients with high SUA concentrations in the present study. In addition, the impaired nitro-oxide bioavailability and oxidative stress produced by xanthine oxidase may also be mechanisms behind high SUA-related all-cause and HCM-related mortal- ity (22,23). The mechanism underlying the increased risk of mortality related to low SUA is not fully understood. SUA acting as an antioxidant may be one of the possible explanations. It has been reported that SUA may exert antioxidant protection against the damage of free radical and reactive oxygen species in ischaemic brain tissue, illustrating the protective effect of SUA for the central nervous system (24). There is also one previous study showing that extremely low SUA concentrations were associated with endothelial dysfunction and vascular damage (25). Therefore, when SUA decreased even more, antioxidant defense might contribute to the rela- tively high risk of all-cause mortality and HCM-related mortal- ity in HCM patients with low SUA in our study. This study has several limitations. First, we did not adjust for urate-lowering medications. There were 39.4% of patients diagnosed as having hyperuricaemia (>420 mmol/L for male Table 3. Univariate cox proportional hazard analysis for all-cause mortality and HCM-related mortality in HCM patients. Variables Change All-cause mortality HR (95% CI), p HCM-related mortality HR (95% CI), p Age Per 1-year increase 1.02 (1.01–1.04), 0.006 1.01 (0.99–1.03), 0.219 Gender Female vs male 1.12 (0.72–1.73), 0.625 1.33 (0.77–2.30), 0.302 FHHCM Yes vs no 0.71 (0.31–1.63), 0.419 0.94 (0.37–2.36), 0.893 FHSCD Yes vs no 1.51 (0.61–3.73), 0.376 1.38 (0.43–4.46), 0.582 NYHA III/IV Yes vs no 2.91 (1.87–4.53), <0.001 2.44 (1.41–4.20), 0.001 Hypertension Yes vs no 0.81 (0.49–1.33), 0.405 0.76 (0.40–1.42), 0.387 Diabetes Yes vs no 1.04 (0.48–2.27), 0.913 0.91 (0.33–2.53), 0.861 COPD Yes vs no 3.18 (1.75–5.76), <0.001 2.13 (0.91–4.99), 0.083 AF Yes vs no 2.23 (1.39–3.58), 0.001 3.59 (2.07–6.23), <0.001 Warfarin Yes vs no 2.38 (1.33–4.24), 0.003 3.77 (2.01–7.07), <0.001 HCTZ Yes vs no 1.09 (0.44–2.71), 0.846 1.01 (0.31–3.23), 0.993 Devices None 1 1 Pacemaker 1.55 (0.67–3.57), 0.304 2.49 (1.06–5.86), 0.036 ICD 0.56 (0.20–1.53), 0.257 0.69 (0.21–2.22), 0.529 Procedures None 1 1 Alcohol septal ablation 0.48 (0.15–1.53), 0.216 0.25 (0.03–1.77), 0.163 Septal myectomy 1.06 (0.15–7.60), 0.957 1.64 (0.23–11.87), 0.627 eGFR Per 1 unit increase 0.99 (0.98–0.99), 0.004 0.99 (0.98–1.00), 0.128 Glucose Per 1 mmol/L increase 1.12 (1.03–1.22), 0.008 1.11 (0.99–1.24), 0.070 Triglycerides Per 1 mmol/L increase 0.67 (0.49–0.93), 0.015 0.55 (0.35–0.87), 0.010 LDL-C Per 1 mmol/L increase 0.64 (0.48–0.85), 0.002 0.67 (0.46–0.96), 0.029 LA Per 1 mm increase 1.04 (1.01–1.07), 0.016 1.06 (1.03–1.10), <0.001 MWT Per 1 mm increase 1.01 (0.96–1.05), 0.826 0.98 (0.92–1.04), 0.439 EF Per 1 percent increase 0.97 (0.95–0.99), 0.004 0.96 (0.94–0.98), 0.002 LVOTO Yes vs no 1.07 (0.68–1.69), 0.757 1.10 (0.63–1.92), 0.749 serum uric acid (mmol/L) <250 2.11 (0.98–4.55), 0.056 3.98 (1.49–10.62), 0.006 �250, <350 1 1 �350, <450 1.65 (0.91–3.00), 0.098 2.65 (1.14–6.14), 0.023 �450 　 2.56 (1.42–4.64), 0.002 4.43 (1.94–10.15), <0.001 Abbreviations as in Table 1. Table 4. Multivariate cox proportional hazard models for all-cause mortality and HCM-related mortality in HCM patients. Models serum uric acid concentration (mmol/L) <250 �250, <350 �350, <450 �450 All-cause mortality, HR (95% CI), p Model 1 1.64 (0.75–3.58), 0.215 1 1.86 (1.01–3.43), 0.047 2.73 (1.47–5.07), 0.001 Model 2 1.58 (0.71–3.50), 0.261 1 1.91 (1.04–3.54), 0.038 2.75 (1.47–5.15), 0.002 Model 3 2.02 (0.93–4.41), 0.076 1 1.73 (0.94–3.20), 0.080 2.59 (1.39–4.84), 0.003 Model 4 2.72 (1.21–6.10), 0.016 1 1.72 (0.92–3.24), 0.091 2.53 (1.26–5.06), 0.009 Model 5 2.52 (1.13–5.61), 0.024 1 1.99 (1.06–3.72), 0.031 2.73 (1.42–5.23), 0.003 HCM-related mortality, HR (95% CI), p Model 1 3.10 (1.14–8.40), 0.026 1 3.13 (1.33–7.36), 0.009 5.16 (2.19–12.18), <0.001 Model 2 3.16 (1.17–9.06), 0.024 1 3.27 (1.38–7.76), 0.007 4.63 (1.94–11.09), 0.001 Model 3 4.13 (1.52–11.25), 0.005 1 3.03 (1.28–7.18), 0.012 4.20 (1.77–9.96), 0.001 Model 4 4.68 (1.71–12.81), 0.003 1 2.97 (1.24–7.09), 0.014 4.38 (1.77–10.85), 0.001 Model 5 4.86 (1.74–13.58), 0.003 1 3.18 (1.33–7.61), 0.010 4.14 (1.70–10.13), 0.002 Model 1: adjusted for age, sex, FHHCM, FHSCD, NYHA. Model 2: adjusted for age, sex, hypertension, diabetes, COPD, AF. Model 3: adjusted for age, sex, warfarin, HCTZ, obstruction intervention and devices. Model 4: adjusted for age, sex, eGFR, glucose, triglycerides, LDL-C, LA, EF. Model 5: adjusted for age, sex, NYHA, COPD, AF, TG, LDL-C, LA. Abbreviations as in Table 1. 48 Z. WANG ET AL. Figure 2. U-shaped association between serum uric acid concentration and all-cause mortality (A) and HCM-related mortality (B). Figure 3. Sensitivity analyses including patients with normal kidney function (A,B) or excluding patients taking hydrochlorothiazide (C,D). U-shaped association between serum uric acid concentration and all-cause mortality (A,C) and HCM-related mortality (B,D). UPSALA JOURNAL OF MEDICAL SCIENCES 49 and >360 mmol/L for female (26)). Some of them might take urate-lowering agents, which in turn would reduce the effect of high SUA on endpoints in our study. However, patients with SUA concentrations less than 250 mmol/L might not be affected by the treatment. And thus the U-shaped associ- ation between SUA concentrations and all-cause mortality and HCM-related mortality in HCM patients is credible to some extent. Second, the mortality rate in the present study is higher than in previous studies (11), which might be par- tially explained by collection bias of patients. All patients were enrolled at the inpatient department of a tertiary refer- ral hospital, and their diseases might be more severe than general HCM populations. Patients with NYHA class �3 accounted for 34.1% in the present study. Third, there is a relatively small number of patients (n ¼ 43) with SUA level <250 mmol/L in our study. Fourth, some unknown covariates could not be excluded, although extensive adjustment was performed for many important covariates. Fifth, this is a retrospective study from a single centre. Multicentre-based prospective studies are needed to confirm and extend the present findings. Disclosure statement No potential conflict of interest was reported by the author(s). Funding This study was supported by the National Natural Science Foundation of China [grant number: 81600299]. Notes on contributors Ziqiong Wang is a resident from the Cardiology Department in Sichuan University at West China Hospital. Ying Xu is a chief nurse from the Cardiology Department in Sichuan University at West China Hospital. Hang Liao is an attending doctor from the Cardiology Department in Sichuan University at West China Hospital. Xiaoping Chen is a cardiologist. She is the head of Cardiology Department in Sichuan University at West China Hospital. Sen He is an associate professor from the Cardiology Department in Sichuan University at West China Hospital. References 1. Muiesan ML, Agabiti-Rosei C, Paini A, Salvetti M. Uric acid and car- diovascular disease: an update. 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JAMA. 2000;283:2404–10. doi:10.1001/jama.283.18.2404 UPSALA JOURNAL OF MEDICAL SCIENCES 51 https://doi.org/10.1007/s11926-010-0084-3 https://doi.org/10.1016/j.jjcc.2012.01.013 https://doi.org/10.1016/j.jjcc.2012.01.013 https://doi.org/10.1093/qjmed/hcr159 https://doi.org/10.1253/circj.CJ-15-0232 https://doi.org/10.1001/jama.283.18.2404 Abstract Introduction Methods Study population Data collection Follow-up and outcomes Statistical analysis Results Baseline characteristics Clinical outcomes Relation of SUA to all-cause mortality and HCM-related mortality Restricted cubic spline Sensitivity analyses Discussion Disclosure statement References