Incidence and risk factors associated with atrioventricular block in the general population: the atherosclerosis risk in communities study and Cardiovascular Health Study

Abstract

Objectives

To identify risk factors correlated with atrioventricular block (AVB) in the general population.

Methods

Participants in the Atherosclerosis Risk in Communities study (ARIC) and the Cardiovascular Health study (CHS) were enrolled. The presence of AVB was confirmed at an electrocardiogram (ECG) reading center using Minnesota ECG Classification. Cox proportional hazards models were performed to investigate potential risk factors of AVB, after adjustment for age, sex, race and traditional cardiovascular risk factors.

Results

During the 17 years of follow-up, a total of 731 high-degree AVB cases were identified. Age and sex-standardized rate of AVB was 2.79 and 2.35 per 1000 person-years in the white and the black population, respectively. With the increase of the geriatric population, the incidence of high-degree AVB will increase from 378,816 in 2020 to 535,076 in 2060, and most increment would occur among the elderly. Older age, male sex, the white race, overweight, comorbidities, declined forced vital capacity (FVC), elevated inflammation biomarkers, left bundle branch block and bifascicular block were independently associated with the incidence of high-degree AVB.

Conclusion

To conclude, older age, male sex, white population, overweight, combined diabetes or chronic kidney disease, impaired FVC, elevated inflammation biomarkers, left bundle branch block and bifascicular block were independent predictors for high-degree AVB. The next 40 years would witness a dramatic increase in the incidence of high-degree AVB.

Introduction

Atrioventricular block (AVB) is a common conduction system disorder, characterized by the delay or interruption in the transmission of an impulse from the atrium to the ventricle. According to previous studies, high grade AVB, including second-degree Mobitz type II AVB and third-degree AVB, was associated with severe bradycardia and hemodynamic instability, which might result in higher risk of syncope, asystole, ventricular tachycardia and sudden cardiac death, thus requiring the implantation of permanent pacemaker [1].

Common causes for AVB include the age-related fibrosis and degeneration of the cardiac conduction system, coronary artery disease, cardiomyopathy, congenital heart diseases, autoimmune disorders, previously received cardiac surgery such as transcatheter aortic valve replacement, ventricular septal defect repair or valve replacement and atrioventricular-nodal blocking agents application. Nevertheless, in a large majority of young patients, the aetiology of AVB remained unknown [2,3,4,5,6,7]. Additionally, most previous studies concerning AVB risk factors focused on particular population with underlying diseases, thus could not be extrapolated to the general population. Thus, the potential mechanisms and modifiable risk factors for AVB in the general population warrant further study.

The aim of this study was to identify risk factors correlated with the occurrence of AVB in a large-scale general population, thus providing potential therapeutic targets in the early prevention and treatment of AVB.

Methods

Enrolled population

Participants in the Atherosclerosis Risk in Communities study (ARIC) and the Cardiovascular Health Study (CHS) were enrolled, with an average follow-up of 17 years. The ARIC study is a population-based prospective cohort which enrolled Caucasian and African-American participants aged 45 to 64 years at baseline(Visit 1, 1987–1989) and free of prevalent cardiovascular disease (CVD) from 4 U.S communities, and focused on the etiology, clinical sequelae and risk factors of atherosclerosis [8]. The CHS study is a population-based longitudinal study which recruited participants aged 65 years or older at baseline (Visit 1, 1989–1990, original cohort and visit 2, 1992–1993, supplemental cohort) from 4 U.S communities, in order to identify risk factors linked to the prevalence and natural history of coronary heart disease, stroke and other cardiovascular diseases [9]. Participants were excluded from the current study if they had incomplete baseline data, missed or poor electrocardiographic (ECG) data, if they had second degree AVB or complete AVB or atrial or ventricular pacing at baseline (Fig. 1). Details concerning design, eligibility criteria and procedures of the ARIC and CHS study have been reported [8,9,10].

Fig. 1

Flowchart of study participants ARIC indicates Atherosclerosis Risk in Communities; AVB, atrioventricular block; CHS: Cardiovascular Health study; ECG: electrocardiogram

We chose these cohorts because they were designed to investigate risk factors and natural history of cardiovascular diseases in the general population, and their methodology for the ascertainment of AVB was rigorous, comparable, and validated [11]. Furthermore, these enrolled communities varied in terms of education, income level, urbanization and medical care. Both studies were approved by the institutional review boards at all participating institution, and all participants provided written informed consent at enrollment.

Clinical features

Demographic characteristics including age, sex, race and body mass index, traditional cardiovascular risk factors, co-morbidities, lab parameters such as estimated GFR, renal function, lung function and ECG variables were obtained through self-report, physical examination and blood tests during baseline study visit, while several cardiac biomarkers and thyroid function parameters were measured at later visits. In ARIC study, plasma concentration of Troponin T and N-terminal pronatriuretic peptide (NT-proBNP) were measured between 2010 and 2011 using blood samples collected at visit 4(1996–1997), and also measured at visit 5 (2012–2013). Between 2010 and 2011, ARIC investigators measured plasma concentrations of hs-cTnT and NTproBNP using blood samples that were collected at visit 4(1996–1998) and stored at 70 ℃ until the assay was performed. Thyroid function parameters such as thyroid-stimulating hormone (TSH), total triiodothyronine (TT3) and free thyroxin (FT4) were measured at study visit 5. In CHS study, NT-proBNP were measured between 2007 and 2008, while Troponin T concentrations and thyroid parameters were analyzed in 2010.

Current smoking status and alcohol drinking were ascertained according to their questionnaires. Hypertension was defined as systolic blood pressure more than or equal to 140mmHg, or diastolic blood pressure more than or equal to 90mmHg, or reported the use of antihypertensive medications. The diagnosis of diabetes was ascertained when the participant meets one of the following: the fasting glucose ≥ 126 mg/dL, 2-hour glucose ≥ 200 mg/dL, with an A1C value of more than or equal to 6.5%, or use of oral antidiabetic agents or insulin [12]. Estimated glomerular filtration rate (eGFR) was calculated using cystatin C based CDK-EPI equation, and chronic kidney disease was defined as eGFR less than 60mL/min/1.73 m² or the presence of proteinuria.

Identification of AVB

In both CHS and ARIC study, ECG recordings were performed during each study visits and further analyzed at an ECG reading center. Presence of AVB was identified using Minnesota ECG Classification standard. Mobitz type II second degree AVB (Minnesota code 6.2.1) was characterized as the occurrence of intermittent non-conducted P waves, with constant PR intervals, while complete AVB (Minnesota code 6.1) was defined as the absence of AV nodal conduction, with independent P waves and unrelated QRS complexes. High-degree AVB was described as the presence of Mobitz type II second degree AVB or complete AVB. The incidence of AVB was taken into consideration when the medical records included the diagnosis of AVB, symptoms and consistent ECG characteristics.

ECG parameters

12-lead ECG of each participant were performed during every scheduled visit and then read centrally using the Minnesota ECG Classification, and those with missing lead or technical errors were excluded. ECG parameters including the heart rate, PR interval, QRS interval and QTc interval were analyzed at an ECG read center. Furthermore, other conduction disorders including right bundle branch block (RBBB), left bundle branch block (LBBB) and bifascicular block were also confirmed.

Statistical analysis

Clinical characteristics of the enrolled population were compared between the white and the black population. Continuous variables were expressed as mean (SD) or median (range), while categorical variables were described as frequency and percentage. One-way ANOVA test or Nonparametric Kruskal Walls test was used to make comparisons for continuous variables, while Chi-square or Fisher exact-test were applied for categorical variables. The annual incidence of AVB occurring in the U.S. population older than 45 years of age during 2020 to 2060 was estimated, by applying age-specific incidence rates from the ARIC and CHS cohorts to the U.S. Census Bureau population projections [13] through 2060, on condition that no other risk factors would affect the distribution of AVB incidence in different age groups. To illustrate the potential impact of race and sex on the incidence of AVB, age and sex standardized incidence rate of AVB was calculated among the white and the black population, then age and race standardized rate was also calculated in both sexes.

In order to identify potential risk factors of high-degree AVB and complete AVB, Cox proportional hazards models were applied to calculate the hazard ratios (HRs) and 95% confidence interval (CI) after adjustment for age, sex, race and traditional cardiovascular risk factors. Variables such as age, sex, BMI, lipid profiles, renal function, lung function, inflammation biomarkers, thyroid function, ECG features and cardiac biomarkers were analyzed using a stepwise backward process. Missing values on all socio-demographic covariates were handled by Markov Chain Monte Carlo multiple imputation method before their inclusion in the full adjusted models. All analysis was performed using Stata 15.0 (College Station, TX). A 2-tailed p-value < 0.05 was considered as statistically significant for all analysis executed.

Results

Clinical features of the enrolled population

A total of 18,547 participants in the Atherosclerosis Risk in Communities study (ARIC, n = 13125) and the Cardiovascular Health Study (CHS, n = 5422) were enrolled, with an average follow-up of 17 years. Clinical features of these participants were shown in Table 1. The average age was 59.8 years, and males consisted 45.32% of the whole population. In comparison to ARIC participants, population in CHS was older, with higher incidence of coronary artery disease, stroke, chronic kidney disease and left bundle branch block, while the incidence of hypertension, smoking history and forced vital capacity was lower.

Table 1 Clinical characteristics in the enrolled population

Furthermore, the black population exhibited a higher prevalence of traditional cardiovascular risk factors, including hypertension, diabetes, heart failure, stroke, chronic kidney disease, overweight and smoking history, while the white population were with higher incidence of coronary artery disease and more alcohol consumption. Regarding laboratory parameters, lower level of HDL-cholesterol, eGFR, C-reactive protein (CRP), interleukin-6 (IL-6), NT-proBNP and Troponin T, as well as higher forced vital capacity (FVC), TSH, FT4 and TT3 were observed in the white population. Additionally, ECG features varied between both races. Shorter PR interval and prolonged QRS interval, lower incidence of LBBB and higher prevalence of bifascicular block were observed in the white, when compared with the black population.

Estimated incidence of high-degree AVB

During the 17 years of follow-up, a total of 731 high-degree AVB cases were identified. According to Table 2, the incidence of AVB increased significantly with age in both races (Table 2). In the whole population, the age and sex-standardized rate of AVB was 2.79 per 1000 person-years in the white, and 2.35 per 1000 person-years in the black population. Likewise, age and race-standardized rate of AVB was 3.73 per 1000 person-years in males and 1.93 per 1000 person-years in females.

Table 2 Estimated incidence of AVB in different sex and races

As shown in Fig. 2, it was estimated that the incidence of high-degree AVB would be 378,816 per year in 2020 (95%CI: 353562–408280), and it might increase to approximately 535,076 per year by 2060 (95%CI: 499404–576693). Most increment would occur among the elderly population, especially in those aged more than 75 years.

Fig. 2

Estimated incidence of high-degree AVB from 2020 to 2060 The incidence of high-degree AVB would be 378,816 per year in 2020 (95%CI: 353562–408280), and it might increase to approximately 535,076 per year by 2060 (95%CI: 499404–576693). The shaded area represents the range of 95% confidence intervals for the estimated incidence of high-degree AVB

Risk factors associated with high-degree AVB

As shown in Fig. 3, a total of 731 high-degree AVB cases (including 556 complete AVB patients) were diagnosed during the follow-up of 17 years. Above all, older age (HR per 10-year increment 2.23, 95% CI 2.04–2.44), male sex (HR 1.74, 95%CI 1.46–2.06), white race (HR 1.28, 95%CI 1.04–1.57), overweight (HR 1.36, 95%CI 1.12–1.63), obese (HR 1.49, 95%CI 1.20–1.84), combined with diabetes (HR 1.14, 95%CI 1.05–1.25), occurrence of cardiovascular events (HR 1.54, 95%CI 1.29–1.84), impaired forced vital capacity (HR for FVC < 2.81 L 1.74, 95%CI 1.28–2.37, HR for 2.81 L ≤ FVC < 3.44 L 1.48, 95%CI 1.14–1.92) were associated with AVB. Furthermore, chronic kidney disease (HR 1.37, 95%CI 1.04–1.80) was also correlated with the increased incidence of AVB. It was estimated that a 10mL/min decrease in eGFR might result in 6% increased risk in AVB (HR 1.06, 95%CI 1.01–1.11), and a 2-fold increase in cystatin C was associated with 30% increased risk of AVB (HR 1.33, 95%CI 1.03–1.71). Likewise, inflammation biomarkers CRP (HR 1.07, 95%CI 1.01–1.13) and IL-6 (HR 1.16, 95%CI 1.01–1.32), cardiac injury biomarkers such as NT-proBNP (HR 1.11, 95%CI 1.05–1.18) and Troponin T (HR 1.30, 95%CI 1.13–1.49) were also associated with AVB. In terms of other conduction system disorders, prolonged PR interval (HR per 30ms increment 1.24, 95%CI 1.16–1.33), QRS interval (HR per 15 ms increase 1.38, 95%CI 1.31–1.46), QTc interval (HR per 40ms increment 1.14, 95%CI 1.02–1.26), left bundle branch block (HR 1.91, 95%CI 1.51–2.42), bifascicular block (HR 2.83, 95%CI 1.34–5.98) were independently associated with high-degree AVB.

Fig. 3

Risk factors independently associated with complete AVB and high-degree AVB According to multivariate Cox regression analysis, older age, male sex, white race, overweight, combined with diabetes, impaired FVC, elevated inflammation biomarkers, other conduction disorders including LBBB and bifascicular block were independent predictors of complete AVB or high-degree AVB LDL-cholesterol indicates low density lipoprotein cholesterol; HDL-cholesterol, high density lipoprotein cholesterol; CV event, cardiovascular event; BMI, body mass index; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; FVC, forced vital capacity; CRP, C-reactive protein; TSH, thyroid-stimulating hormone; TT3, total triiodothyronine; FT4, free thyroxin; NT-proBNP, N-terminal pronatriuretic peptide

Discussion

In this study, we found that the incidence of AVB increased significantly with age in both the black and the white population. The year 2020 to 2060 would witness a dramatic increase in the occurrence of high-degree AVB, and most increment would occur among the elderly, especially in those aged more than 75 years. Furthermore, older age, male sex, white race, overweight, combined with diabetes, declined forced vital capacity, elevated inflammation biomarkers or cardiac injury biomarkers were confirmed to be correlated with the incidence of high-degree AVB or complete AVB. The prolongation of the PR interval, QRS interval and QTc interval might slightly increase the risk of AVB. In addition, conduction disorders such as left bundle branch block and bifascicular block were associated with higher incidence of AVB (Figure 4). Nevertheless, it’s crucial to note that further research is required to establish any causal relationships and determine if improved management of these risk factors may potentially contribute to a lower incidence of high-degree AVB.

Fig. 4

Central illustration. Demographic characteristics, such as older age, male sex and white race, cardiovascular risk factors (obesity, diabetes, impaired lung function, chronic kidney disease) may affect the conductive system and promote the pathological changes. Variables in the electrocardiogram (ECG) and blood tests could be used to characterize the conductive disorder. Eventually, alterations in the conductive system lead to signs and symptoms of AVB, thus resulting in a clinical diagnosis of AVB. CV indicates cardiovascular; CRP, C-reactive protein; NT-proBNP, N-terminal pronatriuretic peptide; IL-6, interleukin-6; AVB, atrioventricular block

As far as we know, most previous studies concerning AVB risk factors focused on specific population such as patients undergoing congenital heart surgery, transcatheter aortic valve replacement or percutaneous coronary intervention, thus could not be extrapolated to the general population. Only a few population-based studies focusing on AVB risk factors have been conducted. In Kerola et al. study [14], which enrolled 6146 community-dwelling individuals, older age, male sex, history of myocardial infarction and congestive heart failure, increasing blood pressure and fast glucose level were independently related to AVB. In Shan R et al. study, the prevalence and risk factors of AVB among large-scale Chinese health examination adults were evaluated. Similarly, older age, male gender and several metabolic factors were correlated with the incidence of AVB [15]. The HORIZON-AMI trial [6] enrolled patients with ST-segment elevation myocardial infarction and it was revealed that older age, diabetes mellitus, right coronary artery occlusion and baseline thrombolysis in Myocardial Infarction flow 0/1 were independently associated with high-grade AVB. In Pollari et al. study [3], risk factors correlated with AVB and permanent pacemaker implantation included baseline right bundle branch block, overweight, previous PCI and left ventricular outflow tract calcification. In patients received congenital heart surgery [2], especially in those received congenitally-corrected TGA repair, ventricular septal defect repair, tricuspid valve replacement or Nikaidoh procedure, the prolongation of cardiopulmonary bypass was independently associated with AVB.

Older age is a crucial risk factor in AVB occurrence, which might be partially explained by age-related conduction system fibrosis. In our study, a 10-year increment in age resulted in more than 2-fold risk increase in complete AVB or high-degree AVB. Thus, with the rapid increase in the geriatric population, the incidence of AVB would rise significantly, which might exert much burden on global health. Although permanent pacemaker implantation has been regarded as an effective treatment choice for high-degree AVB, complications such as bleeding, pneumothorax, lead failure, pacemaker dysfunction or battery depletion at early stage, pacemaker migration, erosion, pace system related endocarditis could not be ignored [16], and the risk of pacemaker implantation related infection remained higher in the elderly despite of antibiotics use prior to surgery [17]. According to our study, particular attention should be paid to the elderly patients, especially those aged more than 75 years, and patients with renal insufficiency. Regular ECG or 24-hour holter monitoring might be useful for early detection of high-degree AVB, and timely intervention might improve their prognosis and life quality, as well as reduce mortality.

In our study, impaired renal function, characterized as declined eGFR and increased cystatin C, was independently associated with high-degree AVB. It was universally acknowledged that cardiovascular disease has become the leading cause of death in patients with chronic kidney disease. Furthermore, about 25 to 30% sudden cardiac death in patients receiving dialysis was caused by arrhythmia [18]. In a study which enrolled 923 patients with type 2 diabetes mellitus [19], the correlation between declined eGFR and risk of cardiac conduction defects was reported. In patients with eGFR less than 30 ml/min/1.73 m², the risk of cardiac conduction disorders such as atrioventricular block, LBBB, RBBB and left anterior hemi-block reached almost 3.6 folds after adjustment for traditional cardiovascular risk factors.

In recent years, the link between lung function and cardiovascular diseases has aroused much concern. Our study added the evidence that impaired FVC were independently associated with complete AVB or high-degree AVB. Previous studies have demonstrated that abnormal FVC, forced expiratory volume in 1s(FEV1) and FEV1/FVC ratio might be correlated with a higher incidence of cardiovascular diseases [20, 21]. In Waheed et al. study [22], impaired pulmonary function significantly increased the risk of heart failure and cardiovascular mortality in the elderly population with left ventricular systolic dysfunction. Declined FEV1 was also correlated with higher atrial fibrillation incidence, according to an analysis in 15,004 participants from the ARIC study [23]. Nevertheless, current research is insufficient to establish a causal relationship. Possible explanations were the triggered inflammatory state originated from smoking, air pollution or infection, which linked pulmonary function and cardiac dysfunction.

Chronic inflammatory state, often defined as the elevation in systemic cytokines such as IL-1, IL-6, CRP and TNF-a, has been regarded as a crucial contributor for cardiovascular disease for a long time. In our study, overweight or obese, in combination with diabetes, elevated systemic inflammation biomarkers IL-6 and CRP were associated with higher incidence of AVB. Previous studies have illustrated that impaired energy homeostasis were observed in overweight patients and those with diabetes, which participated in the development of metabolic inflammation [24, 25]. Inflammatory state played crucial roles in the activation of leukocytes, endothelial and vascular smooth muscle cells, then participating in the process of atherosclerosis and inducing plaque destabilization [25,26,27]. Our study indicated that inflammation was also linked to complete AVB or high-degree AVB, but the potential mechanisms warrant further study.

ECG characteristics might also provide hints for the potential risk of AVB. In our study, left bundle branch block and bifascicular block were independently associated with AVB, while no significant correlation was observed between RBBB and AVB. According to previous studies, left bundle branch block was associated with higher risk of heart failure and myocardial infarction, thus presenting poorer cardiovascular prognosis and higher mortality. In contrast, right bundle branch block, despite of the relatively higher incidence, was with conflicting results [28]. In the Copenhagen City Heart Study [29], RBBB was associated with increased risk or myocardial infarction and pacemaker implantation, but no significant correlation was observed between RBBB and chronic heart failure. In Meyer et al. study [30], higher incidence of major adverse cardiovascular events and death during hospitalization was shown in ST-segment elevation myocardial infarction patients with LBBB, when compared with those with RBBB. Previous studies in patients received transcatheter aortic valve replacement (TAVR) demonstrated that patients with preexisting LBBB or BBB had a higher risk of developing high-degree AVB and requiring pacemaker implantation [31, 32].

This study has several advantages. On one hand, while most previous studies were small and focused on particular population, our study added valuable evidence regarding AVB risk factors in a large-scale general population. On the other hand, early identification of risk factors might provide potential therapeutic targets for the prevention and treatment of AVB, thus improving the clinical outcomes. Nevertheless, there is no doubt that a few limitations existed. This study enrolled only the white and the black population, therefore, these findings could not be extrapolated to other ethnic groups. Furthermore, since the participants of the ARIC and CHS study were drawn from several U.S communities, the estimated trend of AVB and potential risk factors might not represent the entire population. In addition, these studies didn’t provide data on drug treatment during follow-up, which might be correlated with the incidence of AVB.

To conclude, older age, male sex, white population, overweight, combined with diabetes or chronic kidney disease, impaired FVC, elevated inflammation biomarkers, other conduction system disorders including left bundle branch block and bifascicular block were independent predictors for high-degree AVB. The next 40 years would witness a dramatic increase of the incidence of high-degree AVB.