The Impact of Serum Uric Acid Levels on New-onset Atrioventricular Block: a Prospective Cohort Study

doi:10.12114/j.issn.1007-9572.2024.0638

Abstract

Abstract:

Background

Previous studies have shown that elevated serum uric acid (SUA) level is associated with various cardiovascular diseases, such as hypertension, atrial fibrillation, heart failure, and coronary artery disease, but its relationship with cardiac conduction system disorders remains unclear.

Objective

The present community-based cohort study aimed to elucidate the effects of SUA on the risk of developing atrioventricular (AV) block.

Methods

Kailuan Study was a prospective cohort study based on a community population. A total of 87 913 eligible participants who participated in health examination at Kailuan Group between 2006 and 2007 were included as the study cohort. The participants were divided into non-hyperuricemia group (SUA≤420 µmol/L) and hyperuricemia group (SUA>420 µmol/L). Follow-ups were conducted every two years until December 31, 2019. The endpoint event was defined as new-onset AV block. Multivariate Cox proportional hazard models were used to analyze the impact of different SUA levels and each 1 standard deviation (SD) increase in SUA on new-onset AV block.

Results

Among the 87 913 participants, 69 101 males (78.60%) and 18 812 females (21.40%), with a mean age of (50.7±12.0) years. Dring a median follow-up of 11.89 (9.06-12.83) years, 1 037 AV block cases developed. After adjusting for confounding factors, the hyperuricemia group showed a 26% increased risk of incident AV block compared to the non-hyperuricemia group (HR=1.26, 95%CI=1.02-1.54, P=0.030). For each 1 SD increase in SUA level, the risk of incident AV block increased by 12% (HR=1.12, 95%CI=1.05-1.19, P<0.001). Specifically, the hyperuricemia group had a 29% increased risk of incident first-degree AV block compared to the non-hyperuricemia group (HR=1.29, 95%CI=1.05-1.60, P=0.017), and each 1 SD increase in SUA level was associated with a 12% increased risk of incident first-degree AV block (HR=1.12, 95%CI=1.05-1.20, P<0.001). The restricted cubic spline analysis showed a nonlinear relationship between serum UA levels and the risk of developing AV block (P<0.001).

Conclusion

High SUA level is an independent risk factor for AV block, and SUA level is dose-dependently associated with the risk of AV block.

Key words: Atrioventricular block, First-degree atrioventricular block, Serum uric acid, Hyperuricemia, Cohort studies, Prospective studies

摘要：

背景

既往研究表明血尿酸（SUA）水平与多种心血管疾病相关，比如高血压、心房颤动、心力衰竭和冠心病。但其与房室传导阻滞的关系目前尚不清楚。

目的

探讨SUA水平对新发房室传导阻滞的影响。

方法

本研究为前瞻性队列研究。选取2006—2007年参加开滦集团健康体检且符合纳排标准的人群87 913例作为研究队列，根据基线SUA水平将其分为非高尿酸血症组（SUA≤420 μmol/L）82 418例和高尿酸血症组（SUA>420 μmol/L）5 495例，每2年随访1次。以新发房室传导阻滞为终点事件，研究随访至2019-12-31。采用多因素Cox逐步回归模型分析不同SUA水平分组及SUA每增加1个标准差（SD）对新发房室传导阻滞的影响。

结果

入选的87 913人中男69 101例（78.60%）、女18 812例（21.40%），平均年龄（50.7±12.0）岁。中位随访11.89（9.06~12.83）年，共有1 037人发生房室传导阻滞。校正了年龄、性别等因素后，高尿酸血症组新发房室传导阻滞的风险较非高尿酸血症组增加26%（HR=1.26，95%CI=1.02~1.54，P=0.030），SUA水平每增加1个SD新发房室传导阻滞的风险增加12%（HR=1.12，95%CI=1.05~1.19，P<0.001）；高尿酸血症组新发Ⅰ度房室传导阻滞的风险较非高尿酸血症组增加29%（HR=1.29，95%CI=1.05~1.60，P=0.017），SUA水平每增加1个SD新发Ⅰ度房室传导阻滞的风险增加12%（HR=1.12，95%CI=1.05~1.20，P<0.001）。样条函数曲线分析结果显示SUA水平与新发房室传导阻滞存在非线性相关（P<0.001）。

结论

高尿酸血症是新发房室传导阻滞的独立危险因素，且两者呈剂量-反应关系。

关键词: 房室传导阻滞, Ⅰ度房室传导阻滞, 血尿酸, 高尿酸血症, 队列研究, 前瞻性研究

CLC Number:

R 541.76

ZHU Chenrui,LI Na,WU Yuntao, et al. The Impact of Serum Uric Acid Levels on New-onset Atrioventricular Block: a Prospective Cohort Study[J]. Chinese General Practice, 2026, 29(05): 583-590. DOI: 10.12114/j.issn.1007-9572.2024.0638.
朱辰蕊,李娜,吴云涛等. 血尿酸水平对新发房室传导阻滞的影响：一项前瞻性队列研究[J]. 中国全科医学, 2026, 29(05): 583-590. DOI: 10.12114/j.issn.1007-9572.2024.0638.

Figures/Tables 8

References 31

[1]	CHENG S S, KEYES M J, LARSON M G, et al. Long-term outcomes in individuals with prolonged PR interval or first-degree atrioventricular block[J]. JAMA, 2009, 301(24): 2571-2577. DOI: 10.1001/jama.2009.888.
[2]	CRISEL R K, FARZANEH-FAR R, NA B, et al. First-degree atrioventricular block is associated with heart failure and death in persons with stable coronary artery disease: data from the Heart and Soul Study[J]. Eur Heart J, 2011, 32(15): 1875-1880. DOI: 10.1093/eurheartj/ehr139.
[3]	ARO A L, ANTTONEN O, KEROLA T, et al. Prognostic significance of prolonged PR interval in the general population[J]. Eur Heart J, 2014, 35(2): 123-129. DOI: 10.1093/eurheartj/eht176.
[4]	KNABBEN V, CHHABRA L, SLANE M. Third-degree atrioventricular block[M]. In: StatPearls. edn. Treasure Island (FL): StatPearls Publishing LLC, 2024.
[5]	SHAN R Q, NING Y, MA Y, et al. Prevalence and risk factors of atrioventricular block among 15 million Chinese health examination participants in 2018: a nation-wide cross-sectional study[J]. BMC Cardiovasc Disord, 2021, 21(1): 289. DOI: 10.1186/s12872-021-02105-3.
[6]	FRIMODT-MØLLER E K, GOTTDIENER J S, SOLIMAN E Z, et al. Inflammation and incident conduction disease[J]. J Am Heart Assoc, 2023, 12(1): e027247. DOI: 10.1161/JAHA.122.027247.
[7]	MARUHASHI T, HISATOME I, KIHARA Y, et al. Hyperuricemia and endothelial function: from molecular background to clinical perspectives[J]. Atherosclerosis, 2018, 278: 226-231. DOI: 10.1016/j.atherosclerosis.2018.10.007.
[8]	CULLETON B F, LARSON M G, KANNEL W B, et al. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study[J]. Ann Intern Med, 1999, 131(1): 7-13. DOI: 10.7326/0003-4819-131-1-199907060-00003.
[9]	FANG J, ALDERMAN M H. Serum uric acid and cardiovascular mortality the NHANESⅠ epidemiologic follow-up study, 1971-1992. National Health and Nutrition Examination Survey[J]. JAMA, 2000, 283(18): 2404-2410. DOI: 10.1001/jama.283.18.2404.
[10]	SAITO Y, TANAKA A, NODE K, et al. Uric acid and cardiovascular disease: a clinical review[J]. J Cardiol, 2021, 78(1): 51-57. DOI: 10.1016/j.jjcc.2020.12.013.
[11]	EPSTEIN A E, DIMARCO J P, ELLENBOGEN K A, et al. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (writing committee to revise the ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons[J]. J Am Coll Cardiol, 2008, 51(21): e1-62. DOI: 10.1016/j.jacc.2008.02.032.
[12]	POTTEL H, DELANAYE P, SCHAEFFNER E, et al. Estimating glomerular filtration rate for the full age spectrum from serum creatinine and cystatin C[J]. Nephrol Dial Transplant, 2017, 32(3): 497-507. DOI: 10.1093/ndt/gfw425.
[13]	THYGESEN K, ALPERT J S, JAFFE A S, et al. Fourth universal definition of myocardial infarction (2018)[J]. Circulation, 2018, 138(20): e618-e651. DOI: 10.1161/CIR.0000000000000617.
[14]	SWEDBERG K, CLELAND J, DARGIE H, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): the Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology[J]. Eur Heart J, 2005, 26(11): 1115-1140. DOI: 10.1093/eurheartj/ehi204.
[15]	Corrigendum to: 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS[J]. Eur Heart J, 2018, 39(13): 1109. DOI: 10.1093/eurheartj/ehx039.
[16]	HAXHA S, HALILI A, MALMBORG M, et al. Type 2 diabetes mellitus and higher rate of complete atrioventricular block: a Danish Nationwide Registry[J]. Eur Heart J, 2023, 44(9): 752-761. DOI: 10.1093/eurheartj/ehac662.
[17]	KAWASOE S, KUBOZONO T, YOSHIFUKU S, et al. Uric acid level and prevalence of atrial fibrillation in a Japanese general population of 285, 882[J]. Circ J, 2016, 80(12): 2453-2459. DOI: 10.1253/circj.CJ-16-0766.
[18]	CHEN N, MUHAMMAD I F, LI Z B, et al. Sex-specific associations of circulating uric acid with risk of diabetes incidence: a population-based cohort study from Sweden[J]. Diabetes Metab Syndr Obes, 2020, 13: 4323-4331. DOI: 10.2147/DMSO.S273387.
[19]	SUGIURA T, DOHI Y, TAKAGI Y, et al. Increased impact of serum uric acid on arterial stiffness and atherosclerosis in females[J]. J Atheroscler Thromb, 2022, 29(11): 1672-1691. DOI: 10.5551/jat.63368.
[20]	LOU Y M, QIN P, WANG C Y, et al. Sex-specific association of serum uric acid level and change in hyperuricemia status with risk of type 2 diabetes mellitus: a large cohort study in China[J]. J Diabetes Res, 2020, 2020: 9637365. DOI: 10.1155/2020/9637365.
[21]	BEN SALEM C, SLIM R, FATHALLAH N, et al. Drug-induced hyperuricaemia and gout[J]. Rheumatology (Oxford), 2017, 56(5): 679-688. DOI: 10.1093/rheumatology/kew293.
[22]	SPIES F, KNECHT S, ZELJKOVIC I, et al. First-degree atrioventricular block in patients with atrial fibrillation and atrial flutter: the prevalence of intra-atrial conduction delay[J]. J Interv Card Electrophysiol, 2021, 61(2): 421-425. DOI: 10.1007/s10840-020-00838-3.
[23]	JIA Z R, ZHANG Y A, DENG J P, et al. A novel LMNA indel mutation identified in a family with atrioventricular block and atrial fibrillation[J]. Medicine (Baltimore), 2021, 100(19): e25910. DOI: 10.1097/MD.0000000000025910.
[24]	NIKOLAIDOU T, CAI X J, STEPHENSON R S, et al. Congestive heart failure leads to prolongation of the PR interval and atrioventricular junction enlargement and ion channel remodelling in the rabbit[J]. PLoS One, 2015, 10(10): e0141452. DOI: 10.1371/journal.pone.0141452.
[25]	WALLER B F, GERING L E, BRANYAS N A, et al. Anatomy, histology, and pathology of the cardiac conduction system: Part Ⅴ[J]. Clin Cardiol, 1993, 16(7): 565-569. DOI: 10.1002/clc.4960160710.
[26]	YANNI J, MACZEWSKI M, MACKIEWICZ U, et al. Structural and functional alterations in the atrioventricular node and atrioventricular ring tissue in ischaemia-induced heart failure[J]. Histol Histopathol, 2014, 29(7): 891-902. DOI: 10.14670/HH-29.891.
[27]	YU M N, SÁNCHEZ-LOZADA L G, JOHNSON R J, et al. Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction[J]. J Hypertens, 2010, 28(6): 1234-1242.
[28]	WOLLERT K C, DREXLER H. The renin-angiotensin system and experimental heart failure[J]. Cardiovasc Res, 1999, 43(4): 838-849. DOI: 10.1016/s0008-6363(99)00145-5.
[29]	WANG D Y, SUN L, ZHANG G W, et al. Increased susceptibility of atrial fibrillation induced by hyperuricemia in rats: mechanisms and implications[J]. Cardiovasc Toxicol, 2021, 21(3): 192-205. DOI: 10.1007/s12012-020-09611-4.
[30]	BERGAMINI C, CICOIRA M, ROSSI A, et al. Oxidative stress and hyperuricaemia: pathophysiology, clinical relevance, and therapeutic implications in chronic heart failure[J]. Eur J Heart Fail, 2009, 11(5): 444-452. DOI: 10.1093/eurjhf/hfp042.
[31]	YAN M L, CHEN K K, HE L, et al. Uric acid induces cardiomyocyte apoptosis via activation of calpain-1 and endoplasmic reticulum stress[J]. Cell Physiol Biochem, 2018, 45(5): 2122-2135. DOI: 10.1159/000488048.

组别	例数	年龄（±s，岁）	性别（男/女）	吸烟[例（%）]	饮酒[例（%）]	体育锻炼[例（%）]	BMI （±s，kg/m²）	SBP （±s，mmHg）
非高尿酸血症组	82 418	50.5±11.9	63 953/18 465	32 009（38.80）	32 886（39.90）	12 373（15.00）	25.0±3.4	130±20
高尿酸血症组	5 495	53.2±13.3	5 148/347	3 120（56.80）	3 405（62.00）	1 190（21.70）	26.5±3.4	135±21
检验统计量值		-15.34^a	792.86	691.18	1 034.61	174.26	-32.07^a	-18.79^a
P值		<0.001	<0.001	<0.001	<0.001	<0.001	<0.001	<0.001
组别	DBP （±s，mmHg）	FBG （±s，mmol/L）	TG[M（P₂₅，P₇₅），mmol/L]	TC （±s，mmol/L）	LDL-C （±s，mmol/L）	hs-CRP[M（P₂₅，P₇₅），mg/L]	SUA（±s，μmol/L）
非高尿酸血症组	83±11	5.45±1.56	1.25（0.88，1.88）	4.93±1.09	2.35±0.88	0.80（0.30，2.16）	275.40±67.19
高尿酸血症组	86±12	5.39±1.41	1.80（1.20，2.81）	5.23±1.12	2.38±0.89	1.29（0.55，3.10）	473.66±49.27
检验统计量值	-16.39^a	3.00^a	1 553.54^b	-19.83^a	-2.68^a	573.47^b	-281.37^a
P值	<0.001	0.003	<0.001	<0.001	0.007	<0.001	<0.001
组别	eGFR[±s，mL·min^-1·（1.73 m²）^-1]	高血压[例（%）]	糖尿病[例（%）]	基线心肌梗死[例（%）]	服用降压药[例（%）]	服用降糖药[例（%）]	服用降脂药[例（%）]	服用利尿剂[例（%）]
非高尿酸血症组	82.81±20.72	34 543（41.90）	7 319（8.88）	834（1.01）	7 719（9.37）	1 798（2.18）	688（0.83）	726（0.88）
高尿酸血症组	77.20±21.12	2 982（54.30）	441（8.03）	110（2.00）	1 209（22.00）	132（2.40）	74（1.35）	199（3.62）
检验统计量值	19.09^a	321.45	4.68	47.52	901.52	1.17	15.71	371.65
P值	<0.001	<0.001	0.031	<0.001	<0.001	0.280	<0.001	<0.001

组别	例数	年龄（±s，岁）	性别（男/女）	吸烟[例（%）]	饮酒[例（%）]	体育锻炼[例（%）]	BMI （±s，kg/m²）	SBP （±s，mmHg）
非高尿酸血症组	82 418	50.5±11.9	63 953/18 465	32 009（38.80）	32 886（39.90）	12 373（15.00）	25.0±3.4	130±20
高尿酸血症组	5 495	53.2±13.3	5 148/347	3 120（56.80）	3 405（62.00）	1 190（21.70）	26.5±3.4	135±21
检验统计量值		-15.34^a	792.86	691.18	1 034.61	174.26	-32.07^a	-18.79^a
P值		<0.001	<0.001	<0.001	<0.001	<0.001	<0.001	<0.001
组别	DBP （±s，mmHg）	FBG （±s，mmol/L）	TG[M（P₂₅，P₇₅），mmol/L]	TC （±s，mmol/L）	LDL-C （±s，mmol/L）	hs-CRP[M（P₂₅，P₇₅），mg/L]	SUA（±s，μmol/L）
非高尿酸血症组	83±11	5.45±1.56	1.25（0.88，1.88）	4.93±1.09	2.35±0.88	0.80（0.30，2.16）	275.40±67.19
高尿酸血症组	86±12	5.39±1.41	1.80（1.20，2.81）	5.23±1.12	2.38±0.89	1.29（0.55，3.10）	473.66±49.27
检验统计量值	-16.39^a	3.00^a	1 553.54^b	-19.83^a	-2.68^a	573.47^b	-281.37^a
P值	<0.001	0.003	<0.001	<0.001	0.007	<0.001	<0.001
组别	eGFR[±s，mL·min^-1·（1.73 m²）^-1]	高血压[例（%）]	糖尿病[例（%）]	基线心肌梗死[例（%）]	服用降压药[例（%）]	服用降糖药[例（%）]	服用降脂药[例（%）]	服用利尿剂[例（%）]
非高尿酸血症组	82.81±20.72	34 543（41.90）	7 319（8.88）	834（1.01）	7 719（9.37）	1 798（2.18）	688（0.83）	726（0.88）
高尿酸血症组	77.20±21.12	2 982（54.30）	441（8.03）	110（2.00）	1 209（22.00）	132（2.40）	74（1.35）	199（3.62）
检验统计量值	19.09^a	321.45	4.68	47.52	901.52	1.17	15.71	371.65
P值	<0.001	<0.001	0.031	<0.001	<0.001	0.280	<0.001	<0.001

分组	模型1		模型2		模型3
分组	HR（95%CI）	P值	HR（95%CI）	P值	HR（95%CI）	P值
房室传导阻滞
高尿酸血症组（以非高尿酸血症组为参考）	1.31（1.07~1.60）	0.010	1.31（1.07~1.61）	0.010	1.26（1.02~1.54）	0.030
SUA每增加1个SD	1.14（1.07~1.21）	<0.001	1.14（1.07~1.21）	<0.001	1.12（1.05~1.19）	<0.001
Ⅰ度房室传导阻滞
高尿酸血症组（以非高尿酸血症组为参考）	1.35（1.09~1.66）	0.006	1.35（1.09~1.67）	0.005	1.29（1.05~1.60）	0.017
SUA每增加1个SD	1.14（1.07~1.21）	<0.001	1.14（1.07~1.21）	<0.001	1.12（1.05~1.20）	<0.001
Ⅱ度及以上房室传导阻滞
高尿酸血症组（以非高尿酸血症组为参考）	0.85（0.35~2.12）	0.721	0.84（0.33~2.09）	0.700	0.76（0.30~1.92）	0.567
SUA每增加1个SD	1.11（0.88~1.39）	0.382	1.10（0.87~1.38）	0.437	1.06（0.84~1.34）	0.640

分组	模型1		模型2		模型3
分组	HR（95%CI）	P值	HR（95%CI）	P值	HR（95%CI）	P值
房室传导阻滞
高尿酸血症组（以非高尿酸血症组为参考）	1.31（1.07~1.60）	0.010	1.31（1.07~1.61）	0.010	1.26（1.02~1.54）	0.030
SUA每增加1个SD	1.14（1.07~1.21）	<0.001	1.14（1.07~1.21）	<0.001	1.12（1.05~1.19）	<0.001
Ⅰ度房室传导阻滞
高尿酸血症组（以非高尿酸血症组为参考）	1.35（1.09~1.66）	0.006	1.35（1.09~1.67）	0.005	1.29（1.05~1.60）	0.017
SUA每增加1个SD	1.14（1.07~1.21）	<0.001	1.14（1.07~1.21）	<0.001	1.12（1.05~1.20）	<0.001
Ⅱ度及以上房室传导阻滞
高尿酸血症组（以非高尿酸血症组为参考）	0.85（0.35~2.12）	0.721	0.84（0.33~2.09）	0.700	0.76（0.30~1.92）	0.567
SUA每增加1个SD	1.11（0.88~1.39）	0.382	1.10（0.87~1.38）	0.437	1.06（0.84~1.34）	0.640

分组	模型1		模型2		模型3
分组	HR（95%CI）	P值	HR（95%CI）	P值	HR（95%CI）	P值
房室传导阻滞
非高尿酸血症组	1.00		1.00		1.00
高尿酸血症组	1.41（1.30~1.53）	<0.001	1.42（1.31~1.54）	<0.001	1.38（1.27~1.50）	<0.001
Ⅰ度房室传导阻滞
非高尿酸血症组	1.00		1.00		1.00
高尿酸血症组	1.44（1.32~1.56）	<0.001	1.45（1.33~1.57）	<0.001	1.41（1.30~1.54）	<0.001
Ⅱ度及以上房室传导阻滞
非高尿酸血症组	1.00		1.00		1.00
高尿酸血症组	1.05（0.74~1.49）	0.779	1.05（0.74~1.49）	0.788	1.02（0.72~1.45）	0.894