Anemia and Reduced Kidney Function as Risk Factors for New Onset of Atrial Fibrillation (from the Ibaraki Prefectural Health Study)

doi:10.1016/j.amjcard.2014.10.041

The American Journal of Cardiology

Volume 115, Issue 3, 1 February 2015, Pages 328-333

https://doi.org/10.1016/j.amjcard.2014.10.041 Get rights and content

Chronic kidney disease (CKD) is a potential independent risk factor for atrial fibrillation (AF). It remains unclear whether anemia is synergistically associated with increased risk of AF onset in subjects with CKD. We evaluated the association of kidney function, hemoglobin (Hb), and their combination with new-onset AF in a population-based cohort study. We conducted a 15-year prospective cohort study of 132,250 Japanese subjects aged 40 to 79 years who participated in annual health checkups from 1993. Kaplan-Meier survival analysis was used to compare freedom from new-onset AF between groups classified by estimated glomerular filtration rate grade, Hb grade, and their combination. Cox proportional hazard model analysis was used to estimate hazard ratios (HRs) for new-onset AF. During a 13.8-year mean follow-up period, 1,232 (0.93%) subjects with new-onset AF were identified. Lower estimated glomerular filtration rate and lower Hb grades were significantly associated with a higher incidence of new-onset AF. Multivariate HRs and 95% confidence intervals (CIs) of new-onset AF were 1.38 (1.21 to 1.56) for mild CKD group, 2.56 (2.09 to 3.13) for CKD group, and 1.50 (1.24 to 1.83) for anemia group. Borderline Hb level was not significantly associated with increased risk for new-onset AF (HR 1.07, CI 0.91 to 1.25, p = 0.4284). In the model with interaction term between CKD and anemia, the risk was significantly higher (p = 0.0343 for the interaction) than that predicted by each factor independently. In conclusion, decreased kidney function and lower Hb level are associated with increased risk for new-onset AF, especially when both are present.

Section snippets

Methods

In 1993, the Ibaraki prefectural government initiated a large community-based cohort study, known as the Ibaraki Prefectural Health Study, to obtain information on health status for the purposes of health education and policy making. The cohort included 194,333 subjects (63,865 men and 130,468 women aged 40 to 79 years) living in Ibaraki Prefecture, Japan, who completed an annual health checkup in 1993.

We excluded 58,022 subjects who did not participate in the 1994 health checkup because they

Results

The baseline characteristics of the subjects according to eGFR and Hb grades are listed in Table 1. Mean age was significantly higher in subjects with lower eGFR and lower Hb values. BP, BMI, TC, and TG were higher in subjects with lower eGFR and inversely lower in those with lower Hb. Smokers were more predominant and drinkers rather less predominant in the CKD group. DM was also more prevalent in the CKD group but less prevalent in anemia group.

During the 15-year (mean 13.8 years) follow-up

Discussion

We found that both anemia and CKD were independently associated with increased risk for new-onset AF. Moreover, we also demonstrated that combination of CKD with anemia was a synergistic risk factor for AF onset. To our best knowledge, this is the first study to show that a combination of anemia and CKD confers a particularly high risk for the incidence of AF. Furthermore, we showed that subjects with a borderline Hb level were at risk for new-onset AF in the CKD group but not in the normal

Disclosures

This research was supported by a Grant-in-Aid from the Ministry of Health, Labor and Welfare, and Health and Labor Sciences Research Grants, Japan (Research on Health Services: H17-Kenkou-007; Comprehensive Research on Cardiovascular and Life-Style Related Diseases: H18-Junkankitou[Seishuu]-Ippan-012; Comprehensive Research on Cardiovascular and Life-Style Related Diseases: H20-Junkankitou[Seishuu]-Ippan-013; Intractable Diseases Conquest Research: H21-Nanchi-Ippan-059; Intractable Diseases

References (23)

E.Z. Soliman et al.
Chronic kidney disease and prevalent atrial fibrillation: the Chronic Renal Insufficiency Cohort (CRIC)
Am Heart J
(2010)
Y. Iguchi et al.
Relation of atrial fibrillation to glomerular filtration rate
Am J Cardiol
(2008)
H. Watanabe et al.
Close bidirectional relationship between chronic kidney disease and atrial fibrillation: the Niigata Preventive Medicine Study
Am Heart J
(2009)
R.N. Foley et al.
The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease
Am J Kidney Dis
(1996)
A. Al-Ahmad et al.
Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction
J Am Coll Cardiol
(2001)
D.D. McManus et al.
Relation of kidney function and albuminuria with atrial fibrillation (from the Heart and Soul Study)
Am J Cardiol
(2009)
Y. Naruse et al.
Concomitant chronic kidney disease increases the recurrence of atrial fibrillation after catheter ablation of atrial fibrillation: a mid-term follow-up
Heart Rhythm
(2011)
A. Goette et al.
Increased expression of extracellular signal-regulated kinase and angiotensin-converting enzyme in human atria during atrial fibrillation
J Am Coll Cardiol
(2000)
K. Kumagai et al.
Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation
J Am Coll Cardiol
(2003)
J.L. Abramson et al.
Chronic kidney disease, anemia, and incident stroke in a middle-aged, community-based population: the ARIC Study
Kidney Int
(2003)

M.J. Sarnak et al.

Anemia as a risk factor for cardiovascular disease in the Atherosclerosis Risk in Communities (ARIC) study

J Am Coll Cardiol

(2002)

Cited by (47)

Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors on Outcomes After Catheter Ablation for Atrial Fibrillation
2022, JACC: Clinical Electrophysiology
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently been a significant focus of attention because of their multiple pleiotropic effects. However, the impact of SGLT2i on atrial fibrillation (AF) remains unclear.
The goal of this study was to examine the effects of SGLT2i on AF after catheter ablation (CA).
This prospective, randomized controlled study compared the suppressive effect of SGLT2i vs dipeptidyl peptidase-4 inhibitors on AF recurrence after CA. Eighty AF patients with type 2 diabetes mellitus were randomized (by a computer-generated random sequence) to the tofogliflozin group (20 mg/d) or the anagliptin group (200 mg/d) stratified according to left atrial diameter and AF type (paroxysmal AF [PAF] or non-paroxysmal atrial fibrillation [PAF]) at screening. The primary outcome was AF recurrence at 12 months after CA.
Seventy patients were analyzed (mean age 70.3 ± 8.1 years; 48 male; 30 with paroxysmal AF; 38 tofogliflozin treated). Recurrent AF was detected in 24 (34.3%) of 70 patients, and the AF recurrence ratio was higher in the anagliptin group than in the tofogliflozin group (15 of 32 patients [47%] vs 9 of 38 patients [24%]; P = 0.0417). Moreover, univariate analysis revealed that compared with the nonrecurrence group (n = 46), the recurrence group (n = 24) had a higher prevalence rate of non-PAF, elevated brain natriuretic peptide, higher urinary albumin-creatinine ratio, lower rate of SGLT2i use, larger left atrial diameter, elevated E wave, lower left ventricular ejection fraction, and lower rate of cryoballoon pulmonary vein isolation.
Compared with anagliptin, tofogliflozin achieved greater suppression of AF recurrence after CA in patients with type 2 diabetes mellitus.
Disentangling the association between kidney function and atrial fibrillation: a bidirectional Mendelian randomization study
2022, International Journal of Cardiology
Citation Excerpt :
Moreover, we found causal effects of AF on various kidney function assessments and CKD including eGFRcreat, CKD stage ≥G3 and microalbuminuria, and a suggestive causal effect of AF on eGFRcys. Our study therefore extends our knowledge about the unidirectional and bidirectional association that has been suggested by previous observational studies [8,21–27]. Our results confirm that CKD, in particular its more severe forms such as CKD stage ≥G3 and increased urinary albumin excretion defined as microalbuminuria, are independent risk factors for AF and vice versa.
The potential bidirectional causal association between kidney function and atrial fibrillation (AF) remains unclear.
We conducted a bidirectional two-sample Mendelian randomization (MR) analysis. From multiple genome-wide association studies (GWAS), we retrieved genetic variants associated with kidney function (estimated glomerular filtration rate based on creatinine (eGFRcreat), blood urea nitrogen (BUN), chronic kidney disease (CKD stage ≥G3): n = 1,045,620, eGFR based on cystatin C: n = 24,063-32,861, urine albumin-to-creatinine ratio (UACR), and microalbuminuria: n = 564,257), and AF (n = 1,030,836). The inverse-variance weighted method was used as our main analysis.
MR analyses supported a causal effect of CKD (n = 9 SNPs, odds ratio (OR): 1.10, 95% confidence interval (CI): 1.04–1.17, p-value = 1.97 × 10⁻⁰³), and microalbuminuria (n = 5 SNPs, OR: 1.26, 95% CI: 1.10–1.46, p-value = 1.38 × 10⁻⁰³) on AF risk. We also observed a causal effect of AF on eGFRcreat (n = 97 SNPs, OR: 1.00, 95% CI: 1.00–1.00, p-value = 6.78 × 10⁻⁰³), CKD (n = 107 SNPs, OR: 1.06, 95% CI: 1.03–1.09, p-value = 2.97 × 10⁻⁰⁴), microalbuminuria (n = 83 SNPs, OR: 1.07, 95% CI: 1.04–1.09, p-value = 2.49 × 10⁻⁰⁸), and a suggestive causal effect on eGFRcys (n = 103 SNPs, OR: 0.99, 95% CI: 0.99–1.00, p-value = 4.61 × 10⁻⁰²). Sensitivity analyses, including weighted median estimator, MR-Egger, the MR pleiotropy residual sum and outlier test, and excluding genetic variants associated with possible confounders and/or horizontal mediators (myocardial infarction/coronary artery disease, heart failure) indicated that these findings were robust.
Our results supported a bidirectional causal association between kidney function and AF. The shared genetic architecture between kidney dysfunction and AF might represent potential important therapeutic targets to prevent both conditions in the general population.
A proposed interval for evaluation of renal function during anticoagulation therapy using direct oral anticoagulants in patients with atrial fibrillation
2022, Journal of Cardiology
Citation Excerpt :
In general, a creatinine clearance (CCr) of 50 mL/min is recognized as an appropriate cut-off value to select standard or low doses of DOACs for patients with AF [9]. Several investigators have reported that AF increases the risk of developing chronic kidney disease (CKD), and CKD increases the risk of new-onset AF [10–15]. AF and CKD are closely associated, and one can be a cause but also a result of the other.
Direct oral anticoagulants (DOACs) have been used to prevent cardiogenic embolism in patients with atrial fibrillation (AF). No evidence has been established for the follow-up renal function evaluation intervals. We hypothesized that a proposed follow-up interval of renal function can be estimated by patient's baseline characteristics including creatinine clearance (CCr).
We conducted a single-center retrospective study at Kindai University Hospital from May 2011 to December 2017. Patients were screened and they were enrolled if baseline CCr of ≥50 mL/min. To provide a periodical synchronization for measurements of CCr in all patients, these were evaluated at four different time points (approximately at 3, 6, 9, and 12 months). Primary endpoint was defined as a CCr value of <50 mL/min during the follow-up period. We analyzed associations between the cumulative risk for renal endpoint and baseline characteristics by the Kaplan–Meier method and the Cox proportional hazards model.
Renal endpoint was associated with age (95% CI: 0.07 to 0.21, p<0.01), body weight (95% CI: -0.09 to -0.01, p<0.01), CCr (95% CI: -0.18 to -0.07, p<0.01), and CHA2DS2-VASc score (95% CI: 0.14 to 0.63, p<0.01). Combining baseline CCr of <60 mL/min and other risk factors, acceptable intervals for 5% risk levels were 78 days (age ≥75 years old), 100 days (CHA2DS2-VASc score of> 4 points), and 90 days (body weight <60kg), respectively. Under conditions of baseline CCr of <60 mL/min, age ≥75 years old, CHA2DS2-VASc score of> 4 points, or body weight <60 kg, an increased risk of renal endpoints is 4.85, 3.29, 1.24, 2.44 fold, respectively.
We propose a risk-stratified follow-up interval for renal evaluation in patients with AF and DOACs therapy according to a combination of baseline CCr and other risk factors.
Hematologic and Infectious Complications of Chronic Kidney Disease
2019, Chronic Renal Disease
Chronic kidney disease (CKD) is associated with an array of secondary abnormalities of blood cell lines: red blood cells, white blood cells, and platelets. Anemia in CKD becomes more common as CKD progresses and is associated with significant all-cause as well as cardiovascular morbidity and mortality. CKD also results in progressive platelet dysfunction and impaired primary hemostasis. Furthermore, CKD is associated with impaired immune homeostasis, with abnormalities in both innate and adaptive immunity, and their effector cells as well as humoral components, promoting infection and a state of chronic sterile inflammation. The latter is associated with increased risk of cardiovascular disease. We review the hematological and infectious complications of CKD, and their interconnectedness with cardiovascular disease and infection, the two major causes of mortality and morbidity in this patient population.
Simple risk model and score for predicting of incident atrial fibrillation in Japanese
2019, Journal of Cardiology
Citation Excerpt :
We assessed potential risk predictors for incident AF during 7 years using Cox proportional hazards regression model, which accounts for the discrepancy in follow-up time. Candidate predictors for our model were selected based on previous prospective findings for AF [6,7,11,20–26], including age, sex, physical measurements, blood pressure, fasting plasma glucose, treatment for hypertension, diabetes mellitus and dyslipidemia, eGFR, blood cholesterol, triglycerides, smoking, alcohol drinking, physical exercise, heart rate, ECG findings, history of heart disease and stroke. First, age and sex-adjusted univariate associations of incident AF with the above candidate predictors were evaluated using Cox proportional hazards models.
Investigating regarding a predicted risk score of incident atrial fibrillation (AF) for an Asian general population has not been enough. Whether addition of electrocardiogram (ECG) variables to risk factors improves prediction of incident AF is unclear in a context that ECGs are extensively used at medical check-ups and outpatient clinics in Japan.
Participants undergoing periodic health check-ups during 2008–2014 followed-up by December 2015 including 96,841 (65.1% male) aged 40–79 years were pooled to derive prediction models and risk scores for incident AF. Multivariable Cox regression identified clinical risk factors associated with incident AF in 7 years among 65,984 eligible participants including 349 AF cases.
A 7-year prediction model (“Simple-model”) including the variables of age, waist circumference, diastolic blood pressure, alcohol consumption, heart rate, and cardiac murmur, had good discrimination (C-statistic, 0.77), requiring no blood sampling. Addition model of the ECGs variables (“Added-model”) including left ventricular hypertrophy, atrial enlargement, atrial premature contraction, and ventricular premature contraction, improved significantly the overall model discrimination (C-statistic, 0.78; categorical net reclassification improvement, 0.063; 95%CI, 0.031–0.099). The risk scores derived from the two models respectively showed an approximation of the observed and predicted probability for each score. Participants with score ≤4 or ≥9 points had, respectively, ≤1% and ≥5% predicted probability of incident AF in 7 years. The receiver-operating characteristics curve for the risk score of the added-model was significantly higher than the simple-model (0.769 vs 0.753, p < 0.001). Atrial enlargement on ECG and the highest age group were the highest risk points of the significant predictors.
We developed 7-year risk scores for incident AF using usually available clinical factors including ECGs in primary care. These risk scores could identify individuals with high risk of incident AF at health check-up and outpatient clinics.
Risk factors for new-onset atrial fibrillation: A focus on Asian populations
2018, International Journal of Cardiology
Citation Excerpt :
In the Catanzaro AF project, in which new cases of AF was 546 (15.4%), renal dysfunction was independently related to NOAF [65]. In Asia population, a 15-year prospective cohort study on 132,250 Japanese subjects demonstrated a significantly higher AF incidence in CKD group [66]. Further, multivariate adjusted HR for NOAF were significantly higher in the mild and moderate CKD groups (HR:1.38, 95%CI 1.21–1.56 and HR:2.56, 95%CI 2.09–3.13, respectively) [66].
The incidence of new-onset atrial fibrillation (NOAF) is increasing both in the Asian populations and Western countries. Several demographic and clinical risk factors were independently associated with NOAF, including ageing, male sex, obesity, obstructive sleep apnea syndrome, hypertension, coronary artery disease, renal dysfunction and heart failure. However, some differences in the incidence of NOAF, the prevalence of some risk factors and lifestyle or environmental conditions may exist between Asian and Western countries. Early recognition and holistic management of risk factors in an integrated manner may help reduce the burden of NOAF and its complications. While some risk scores have been developed to predict the risk of NOAF, thus far none are currently recommended or adequately validated to be used as a screening tool especially in the Asian population.
The present semi-systematic review article aims to provide a comprehensive overview on the risk factors associated to NOAF, focusing on those explored in the Asian populations.

View all citing articles on Scopus

: See page 332 for disclosure information.

View full text

Arrhythmias and Conduction DisturbancesAnemia and Reduced Kidney Function as Risk Factors for New Onset of Atrial Fibrillation (from the Ibaraki Prefectural Health Study)

Section snippets

Methods

Results

Discussion

Disclosures

Am Heart J

Am J Cardiol

Am Heart J

Am J Kidney Dis

J Am Coll Cardiol

Am J Cardiol

Heart Rhythm

J Am Coll Cardiol

J Am Coll Cardiol

Kidney Int

J Am Coll Cardiol

Arrhythmias and Conduction Disturbances
Anemia and Reduced Kidney Function as Risk Factors for New Onset of Atrial Fibrillation (from the Ibaraki Prefectural Health Study)