If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MassachusettsThe National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MassachusettsDepartment of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig Maximilians University, Munich, Germany
The National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MassachusettsDivision of Endocrinology, Metabolism, and Diabetes, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
The National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MassachusettsSection of Cardiovascular Medicine, Boston University, School of Medicine, Boston, Massachusetts
The National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MassachusettsSection of Preventive Medicine, Evans Memorial Department of Medicine, Boston University, School of Medicine, Boston, MassachusettsSection of Cardiology, Evans Memorial Department of Medicine, Boston University, School of Medicine, Boston, Massachusetts
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MassachusettsCardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts
The National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MassachusettsSection of Preventive Medicine, Evans Memorial Department of Medicine, Boston University, School of Medicine, Boston, MassachusettsSection of Cardiology, Evans Memorial Department of Medicine, Boston University, School of Medicine, Boston, Massachusetts
Heart failure, a strong risk factor for atrial fibrillation (AF), is often accompanied by elevated liver transaminases. The aim of this study was to test the hypothesis that elevated transaminases are associated with the risk for incident AF in the community. A total of 3,744 participants (mean age 65 ± 10 years, 56.8% women) from the Framingham Heart Study Original and Offspring cohorts, free of clinical heart failure, were studied. Cox proportional-hazards models adjusted for standard AF risk factors (age, gender, body mass index, systolic blood pressure, electrocardiographic PR interval, antihypertensive treatment, smoking, diabetes, valvular heart disease, and alcohol consumption) were examined to investigate associations between baseline serum transaminase levels (alanine transaminase and aspartate transaminase) and the incidence of AF over up to 10 years (29,099 person-years) of follow-up. During follow-up, 383 subjects developed AF. The 2 transaminases were significantly associated with greater risk for incident AF (hazard ratio expressed per SD of natural logarithmically transformed biomarker: alanine transaminase hazard ratio 1.19, 95% confidence interval 1.07 to 1.32, p = 0.002; aspartate transaminase hazard ratio 1.12, 95% confidence interval 1.01 to 1.24, p = 0.03). The associations between transaminases and AF remained consistent after the exclusion of participants with moderate to severe alcohol consumption. However, when added to known risk factors for AF, alanine transaminase and aspartate transaminase only subtly improved the prediction of AF. In conclusion, elevated transaminase concentrations are associated with increased AF incidence. The mechanisms by which higher mean transaminase concentrations are associated with incident AF remain to be determined.
Heart failure is 1 of the strongest risk factors for atrial fibrillation (AF)
Liver function abnormalities and outcome in patients with chronic heart failure: data from the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program.
We hypothesized that elevations of liver transaminases may also be a marker of subclinical heart failure and thus an indirect marker of AF risk. In addition, the current guidelines for the management of patients with AF of the American College of Cardiology, the American Heart Association, and the European Society of Cardiology recommend the assessment of liver function for the evaluation of patients with initial, incident diagnoses of AF, at least if their heart rates are difficult to control.
ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation).
presumably, the guidelines recommend the assessment of liver function for pharmacodynamic reasons. With the present study, we therefore sought to assess whether transaminases are associated with risk for new-onset AF in a community-based sample.
Methods
The Framingham Heart Study was founded in 1948 by enrolling 5,209 subjects, who were followed regularly every 2 years.
For the present study, we examined 1,401 participants who attended the 20th examination cycle (1986 to 1990). Starting in 1971, the offspring of the Original cohort and their spouses were enrolled in the Framingham Offspring Study (n = 5,124) and were followed every 4 to 8 years. Offspring participants who attended the 7th examination cycle (1998 to 2001) were eligible (n = 3,539). We combined participants from the Original and the Offspring cohorts and excluded 1,196 participants for the following indications (detailed in Supplemental Table 1): age <45 years at examination (because the incidence of AF below this threshold is very low, and to make the age distribution of the 2 cohorts more comparable), did not attend the examination on site, incomplete or missing follow-up, incomplete covariate information, prevalent AF or heart failure, and transaminases >3 times the upper limit of normal (>120 U/L) (suggestive of prevalent liver disease; values ≤120 U/L are considered only mildly elevated
). The Boston University Medical Center Institutional Review Board approved the study protocols, and participants provided written informed consent at each examination.
We studied AF risk over up to 10 years of follow-up from the baseline examinations (cohort 20th [1986 to 1990] and Offspring 7th [1998 to 2001] examination). An AF diagnosis was based on AF or atrial flutter on electrocardiography or medical record information from routinely collected Framingham Heart Study examinations and inpatient or outpatient medical visits. Health history updates during examination visits and between examinations also contained a routine question regarding AF. If any cardiovascular, cancer, or orthopedic diagnosis or AF was indicated, all available medical records to substantiate diagnoses were reviewed. All incident AF electrocardiograms were individually reviewed by ≥2 Framingham cardiologists.
Clinical covariates were routinely ascertained during the Framingham Heart Study examination visits. Physicians performed interviews and physical examinations and collected data on self-reported medication use (e.g., hypertension and statins), smoking status, and alcohol consumption. Participants were considered current smokers if they reported smoking cigarettes during the preceding year. Alcohol consumption was categorized as light or moderate to heavy drinking for men, if they consumed 1 to 14 or >14 drinks per week, respectively, and for women if they consumed 1 to 7 or >7 drinks per week, respectively. Systolic blood pressure was assessed as the average of 2 seated measurements. A systolic murmur of grade ≥3 on a scale of 6, or any diastolic murmur, was considered a clinically significant heart murmur. A dedicated end point committee adjudicated all diagnoses of heart failure on the basis of criteria published elsewhere.
Fasting blood samples were drawn and processed immediately for storage at −70°C during the examination visits. Liver function tests assessed at the baseline examination included alanine transaminase (ALT; previously referred to as alanine aminotransferase or serum glutamic pyruvic transaminase) and aspartate transaminase (AST; previously referred to as aspartate aminotransferase or serum glutamic oxaloacetic transaminase). In the Original cohort, ALT and AST were measured using a Cobas Mira Analyzer using Roche Diagnostics reagents (Roche Diagnostics Corporation, Indianapolis, Indiana). In the Offspring cohort, ALT and AST were determined enzymatically using a Roche Hitachi 911 analyzer (Roche Diagnostics Corporation). For ALT, the intra- and interassay coefficients of variation were 3.8% and 4.4%, respectively. For AST, the intra- and interassay coefficients of variation were 3.1% and 4.5%, respectively. Details on the distribution of ALT and AST are provided in Supplemental Table 2 and Supplemental Figure 1. The 2 assays had comparable detection ranges. C-reactive protein (CRP) was available only in the Offspring cohort and was determined using the Dade Behring BN 100 high-sensitivity CRP reagent kit (Dade Behring, Deerfield, Illinois). Intra- and interassay coefficients of variation were 3.2% and 5.3%, respectively.
All discrete variables are expressed as frequencies and percentages. Untransformed biomarkers are expressed as medians with 25th and 75th percentiles; all other continuous variables, including natural logarithmically transformed ALT, AST, and CRP, are summarized as mean ± SD. Log-transformed ALT and AST were standardized to a mean of 0 and an SD of 1.
Interaction testing did not suggest effect modification by gender, so Cox models are gender pooled. We used Cox proportional-hazards models to assess the relations between ALT and AST and the incidence of AF. The follow-up time was up to 10 years; participants were followed from their baseline examinations until the development of AF. Censoring occurred at the time of death or at the end of follow-up. All models adjusted for age, gender, and cohort. Further multivariable models additionally adjusted for baseline risk factors included in the Framingham AF risk prediction model: body mass index, systolic blood pressure, electrocardiographic PR interval, antihypertensive treatment, smoking, diabetes, and valvular heart disease.
To account for its potential involvement in liver pathology, we also incorporated alcohol consumption into the model. We assessed the assumption of proportional hazards by calculating a supremum test on the basis of the cumulative sums of Martingale-based residuals.
Correlation between the clinically related transaminases was assessed using Pearson's correlation; models including the 2 transaminases were not assessed, because of potential collinearity. Instead, we forced the inclusion of previously established AF risk factors and used a stepwise, automated selection process with p = 0.05 to determine which transaminase would be selected. Effect estimates and confidence intervals for ALT and AST are shown for a 1-SD increase in the log-transformed biomarker values. For graphical presentation, we used cumulative hazard plots and spline plots with 3 knots around the untransformed median biomarker values of 18.0 U/L for ALT and 21.0 U/L for AST.
In secondary analyses, we assessed whether inflammation as measured by CRP might partially mediate the risk associated with elevated transaminases. As sensitivity analyses, we restricted our association analysis to subjects at the baseline examination with transaminases within the reference range (transaminase values ≤40 U/L), and we excluded participants with moderate or heavy alcohol consumption. We also adjusted for the competing risk for death during follow-up. Further analyses additionally adjusted for the interim occurrence of heart failure and myocardial infarction, respectively.
In supplemental analyses, we assessed the ability of the transaminases to improve risk prediction of AF. To ensure complete follow-up for all subjects, we calculated all prediction analyses restricted to 8-year risk for AF. We calculated C-statistics and the difference in the C-statistic between the models with and without the respective transaminase.
Reclassification of AF cases on the basis of the risk score including transaminases versus the score without the biomarkers was determined using a continuous and a user-defined net reclassification improvement analysis.
Eight-year risk categories for net reclassification improvement were selected as 5%, 5% to 10%, and 10%. Confidence intervals for prediction analyses were calculated using bootstrapping and 1,000-times resampling.
Results
Our overall study consisted of 3,744 participants, 875 of whom were derived from the Original cohort and 2,869 from the Offspring cohort. Clinical characteristics and the distributions of biomarkers are provided in Table 1. The mean follow-up duration was 7.77 ± 2 years (minimum 0.04, maximum 10.00) in 29,099 person-years of observation. During follow-up, 383 participants developed AF (Table 2). The mean age at the time of AF diagnosis was 76 years. At baseline, participants who subsequently developed AF were on average 6.8 years older than those who remained AF free.
Table 1Baseline characteristics of the study sample (n = 3,744)
In an age-, gender-, and cohort-adjusted model, ALT was significantly associated with incident AF; AST slightly missed statistical significance. In the multivariable-adjusted model, ALT and AST were significantly associated with incident AF (Table 3). Cumulative hazard curves illustrate the incidence of AF for subjects with baseline transaminase levels within reference limits (≤40 U/L) compared to those with elevated levels (>40 U/L) (Figure 1). Spline plots illustrate the increased risk for AF by increased transaminase values (Supplemental Figure 2). For ALT, a hazard ratio of 2 was reached at untransformed values of about 80 U/L, a hazard ratio of 3 at about 120 U/L, and a hazard ratio of 4 at about 150 U/L. ALT and AST were highly correlated (r = 0.73). In the Offspring cohort, neither of the transaminases was significantly correlated with CRP (ALT r = −0.07, and AST r = 0.05). By stepwise regression, ALT but not AST reached statistical significance for risk for AF once established risk factors were considered.
Table 3Cox proportional-hazards models relating transaminases to incidence of AF
Adjustments
ALT
AST
HR (95% CI)
p Value
HR (95% CI)
p Value
Primary models
Age and gender
1.21 (1.09–1.34)
<0.001
1.11 (1.00–1.23)
0.05
Multivariable
1.19 (1.07–1.32)
0.002
1.12 (1.01–1.24)
0.03
Secondary models
Multivariable model with additional adjustments
CRP
1.18 (1.04–1.35)
0.01
1.10 (0.98–1.24)
0.12
Competing risk for death during follow-up
1.21 (1.08–1.35)
<0.001
1.12 (1.01–1.25)
0.03
Interim heart failure
1.19 (1.06–1.32)
0.002
1.12 (1.01–1.24)
0.03
Interim myocardial infarction
1.20 (1.07–1.34)
0.002
1.10 (0.99–1.22)
0.08
Restricting to transaminases ≤40U/L
1.14 (0.99–1.32)
0.07
1.06 (0.93–1.22)
0.39
Excluding moderate to heavy alcohol consumption
1.28 (1.10–1.39)
<0.001
1.18 (1.05–1.32)
0.005
Multivariable adjustment included age, gender, body mass index, alcohol consumption, smoking status, diabetes mellitus, antihypertensive treatment, cardiac murmur, PR interval, and systolic blood pressure. HRs are expressed per 1 SD of loge ALT or loge AST.
Figure 1Cumulative hazard curves for the incidence of AF depicted by transaminase values ≤40 U/L versus >40 U/L; p values are derived from log-rank tests. (Left) ALT, (right) AST.
Secondary analyses are presented in Table 3. We additionally adjusted our model for CRP (available in the Offspring cohort only); the effect estimates minimally changed, and ALT remained significantly associated with new-onset AF, but AST did not. Consideration of death as a competing risk did not affect the associations. The incorporation of interim heart failure into the multivariable-adjusted model did not change the association of transaminases with AF risk. After the inclusion of interim myocardial infarction during follow-up, hazard ratios were slightly diminished; ALT remained significantly associated, but AST was not statistically significantly associated with AF. Restricting our analyses to subjects with transaminases within normal limits at baseline, the effect estimates for ALT and AST remained in the same direction but failed to reach statistical significance. Finally, we excluded participants with moderate to severe alcohol consumption, and both assessed transaminases remained significantly associated with incident AF after multivariable adjustment.
We assessed the ability of transaminases to improve AF risk prediction after 8 years of follow-up as supplemental analyses (Supplemental Tables 3 and 4). Models showed good calibration for ALT and AST. The predictive ability of ALT and AST, determined by an increase in the C-statistic, the absolute and relative integrated discrimination improvement, and the user-defined net reclassification improvement, failed to reach significance. Only the continuous net reclassification improvement metric suggested modest significant prediction improvement (17.8% for ALT, 16.3% for AST).
Discussion
In our study, we found evidence that impaired liver function as assessed by elevation of transaminases was significantly associated with incident AF over a 10-year follow-up period with multivariable adjustment for risk factors from a widely validated AF risk score. We further report that ALT and AST only subtly improved the prediction of AF when added to risk factors from an established AF risk score.
To date, numerous risk factors for AF have been described,
but the published research on AF and liver function is sparse. Only 1 case report describes a relation between the occurrence of AF in the context of manifest liver disease.
Another study reported that almost 28% of outpatients with AF presented with transaminase elevations >40 U/L; however, no suggestion was made regarding the causality or temporality of this observation.
We found that transaminase elevation was associated with a moderate increased risk for incident AF. However, we are uncertain why ALT appeared to be more consistently associated with AF than AST. ALT is highly liver specific and localized in the cytosol,
The 2 biomarkers indicate disintegration of liver cells, but ALT may be released more readily and thus occur more frequently.
Whereas we found an association between transaminases and AF, the underlying pathophysiological pathways remain unclear, and there are several plausible possibilities. The association might be due to preclinical heart failure. Heart failure and AF are closely related and share the burden of risk factors. Transaminase elevation is common in heart failure,
Liver function abnormalities and outcome in patients with chronic heart failure: data from the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program.
We excluded subjects with clinical heart failure at baseline. Also, adjustment for clinically relevant interim heart failure during follow-up did not change our effect estimates for ALT or AST. Yet we hypothesize, but cannot prove, that alterations in hepatic function presage heart failure. Regarding other potentially involved pathways, several investigations consistently found increased concentrations of transaminases in the context of the metabolic syndrome,
Association of serum alanine aminotransferase and gamma-glutamyltransferase levels within the reference range with metabolic syndrome and nonalcoholic fatty liver disease.
the significance of the association with AF diminished for ALT and vanished for AST. Other factors possibly linking nonalcoholic fatty liver disease, oxidative stress or inflammation, and AF are a deranged adipokine profile, hypercoagulability, endothelial dysfunction, and accelerated progression of atherosclerosis.
was a last mechanism we considered to explain the relation between transaminase elevation and AF risk. To reflect the importance of alcohol, all of our multivariable models incorporated adjustment for alcohol consumption. Our sensitivity analysis excluded all participants with moderate or heavy alcohol intake, and the associations between transaminases and AF risk remained largely unchanged. Yet it is possible that the true extent of alcohol use was misclassified because of participants' nondisclosure of their true drinking habits.
Overall, the association between transaminases and AF is likely to be multifactorial. We acknowledge that residual confounding may partially or completely explain the association. For instance, natriuretic peptides (which were unavailable at the index examination) are a valuable diagnostic and predictive marker of cardiac dysfunction,
Increased circulating pro-brain natriuretic peptide (proBNP) and brain natriuretic peptide (BNP) in patients with cirrhosis: relation to cardiovascular dysfunction and severity of disease.
We were also interested in the association between transaminases and AF because of guideline-based recommendation to assess liver function in patients with incident first episodes of AF.
ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation).
We note that the recommendation is undoubtedly for pharmacodynamic reasons. Almost all antiarrhythmic and anticoagulant drugs are at least partly eliminated hepatically, and their half-lives and clearance are affected in the setting of impaired liver function.
Impaired liver function constitutes an increased risk for bleeding complications, a circumstance that led to the incorporation of liver function into clinical scores such as HAS-BLED to assess the risk for bleeding.
In our supplemental analysis, we also aimed to identify the potential of transaminases to contribute to AF risk prediction. ALT and AST subtly improved the prediction of AF beyond previously established factors. The discrepancy between a transaminase-AF association and weak predictive abilities requires careful interpretation. One reason might be that transaminases only are an imperfect marker of a truly underlying condition.
Our study results benefit from a well-phenotyped sample with highly systematic follow-up and detailed outcome ascertainment. However, a number of limitations need to be considered. Our sample was predominantly of European descent. We thus cannot comment on subjects of different ethnic and racial backgrounds. Despite careful assessment of each AF event, the arrhythmia is often asymptomatic and might thus have been missed during case ascertainment. Furthermore, different subtypes of AF exist. We investigated overall AF only and therefore cannot comment on the association of transaminases depending on AF type (e.g., paroxysmal AF, permanent AF, or atrial flutter). Also, we cannot comment on whether transaminase levels influence the progression of AF from a paroxysmal to a permanent type. Our study was limited by a fixed sample size, the lack of a validation sample, and the availability of CRP in the Offspring cohort only. Liver function in its entirety is only partly reflected by transaminases. Other liver related biomarkers, in particular bilirubin, alkaline phosphate, and γ-glutamyltransferase, were not consistently available in the investigated examination cycles. Also, transaminases were assessed at baseline only; we could not investigate the relation of variation in transaminases over time to incident AF risk. Furthermore, complete 10-year follow up was not available for all participants; we thus had to restrict our risk prediction analysis to 8 years of follow-up. We cannot exclude residual confounding.
Liver function abnormalities and outcome in patients with chronic heart failure: data from the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program.
ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation).
Association of serum alanine aminotransferase and gamma-glutamyltransferase levels within the reference range with metabolic syndrome and nonalcoholic fatty liver disease.
Increased circulating pro-brain natriuretic peptide (proBNP) and brain natriuretic peptide (BNP) in patients with cirrhosis: relation to cardiovascular dysfunction and severity of disease.
This work was supported by Grants N01-HC25195 and 6R01-NS17950, Grant 1RO1HL092577 to Dr. Benjamin and Dr. Ellinor, Grants 1RC1HL101056, 1R01HL102214, and 1R01AG028321 to Dr. Benjamin, Grants 5R21DA027021, 1RO1HL104156, and 1K24HL105780 to Dr. Ellinor, and Grant 1K08DK090150-01 to Dr. Calderwood from the National Institutes of Health, Bethesda, Maryland; by the German Heart Foundation, Frankfurt-am-Main, Germany (to Dr. Sinner); by Grant 09FTF2190028 to Dr. Magnani from the American Heart Association, Dallas, Texas; and partially by the Evans Center for Interdisciplinary Biomedical Research (http://www.bumc.bu.edu/evanscenteribr/) ARC on Atrial Fibrillation at Boston University, Boston, Massachusetts (to Drs. Benjamin and Magnani).
02199-6&id=gr1.jpg){kind=link}