Abstract
Objectives
To examine the association between chronotropic incompetence and incident atrial fibrillation (AF).
Background
Patients with inadequate heart rate response during exercise may have abnormalities in sinus node function or autonomic tone that predispose to the development of AF.
Methods
We examined the association between heart rate response and incident AF in 57,402 (mean age=54±13 years, 47% female, 64% white) patients free of baseline AF who underwent exercise-treadmill stress testing from the Henry Ford ExercIse Testing (FIT) Project. Age-predicted maximum heart rate (pMHR) values <85% and chronotropic index values <80% were used to define chronotropic incompetence. Cox regression, adjusting for demographics, cardiovascular risk factors, medications, coronary heart disease, heart failure, and metabolic equivalent of task achieved, was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association between chronotropic incompetence and incident AF.
Results
Over a median follow-up of 5.0 years (25th-75th percentiles=2.6, 7.8), a total of 3,395 (5.9%) participants developed AF. pMHR values <85% were associated with an increased risk for AF development (HR=1.33, 95%CI=1.22, 1.44). Chronotropic index values <80% also were associated with an increased risk of AF (HR=1.28, 95%CI=1.19, 1.38). The associations of pMHR and chronotropic index with AF remained significant with varying cut-off points to define chronotropic incompetence.
Conclusions
Our analysis suggests that patients with inadequate heart rate response during exercise have an increased risk for developing AF.
Keywords: chronotropic incompetence, atrial fibrillation, risk factors
INTRODUCTION
Exercise stress testing is widely used to detect the presence of obstructive coronary artery disease (1). Additionally, such testing is used to assess heart rate and atrioventricular conduction response (2). During exercise, heart rate increases linearly with workload and oxygen demand, and can be expected to rise 10 bpm per metabolic equivalent of task (MET) achieved (1). The inability of heart rate to augment cardiac output to match metabolic demands during exercise has been defined as chronotropic incompetence and its presence is associated with an increased risk of coronary heart disease and mortality (3-5).
Chronotropic incompetence is commonly described in individuals with underlying sinus node dysfunction and conduction abnormalities. It also has been suggested that an increased prevalence of chronotropic incompetence exists in patients with chronic atrial fibrillation (AF) (6). Potentially, those with chronotropic incompetence have sinus node dysfunction or abnormalities in autonomic tone that precede the development of arrhythmias such as AF (7). However, to our knowledge this hypothesis has not been fully explored. Therefore, the purpose of this analysis was examine the association between chronotropic response during exercise and incident AF in the Henry Ford ExercIse Testing (FIT) Project, a racially diverse registry of men and women aimed to elucidate the association between cardiorespiratory fitness and cardiovascular outcomes.
METHODS
Study Population
Details of the design, procedures, and methods used in FIT have been previously described (8). Briefly, the project population included 69,885 consecutive patients who underwent physician-referred exercise treadmill stress testing in the Henry Ford Health System affiliated hospitals and ambulatory care centers throughout the metropolitan area of Detroit, Michigan, between 1991 and 2009. Data regarding treadmill testing, medical history, and medications were collected by laboratory staff at the time of testing. Follow-up data were collected from electronic medical records and an administrative claims database. Patients <18 years old at the time of testing or those who underwent pharmacological stress testing, modified Bruce, and other non-Bruce protocol tests were excluded from the database. The FIT Project was approved by the Henry Ford Health System institutional review board.
In this analysis, we examined the association between chronotropic incompetence and the risk of new-onset AF. Patients with a history of AF (n=1,975) or valve surgery (n=579) were excluded. We also excluded patients with missing baseline characteristics, medication data, and/or follow-up data (n=9,929).
Patient Characteristics
Demographics and clinical characteristics were obtained at the time of treadmill testing. Age, race, sex, and smoking status were self-reported. Diabetes mellitus was defined as a prior diagnosis of diabetes, use of hypoglycemic medications including insulin, or a database-verified diagnosis of diabetes. Obesity was identified by the clinician at the time of the test. Hypertension was defined as a prior diagnosis of hypertension or a database-verified diagnosis. The blood pressure at the time of the test was not used to diagnose hypertension. Hyperlipidemia was defined by prior diagnosis of any major lipid abnormality or a database-verified diagnosis of hypercholesterolemia or dyslipidemia. Coronary heart disease was defined as a history of prior myocardial infarction, coronary angioplasty or coronary artery bypass grafting surgery. Heart failure was defined as prior clinical diagnosis of systolic or diastolic heart failure.
Exercise Stress Testing
Exercise treadmill stress testing was conducted using the Bruce protocol (9). Resting heart rate was measured from the baseline electrocardiogram and blood pressure was manually measured prior to each stress test with each participant in the upright position. Heart rate was measured continuously during testing and blood pressure values were measured every 3 minutes. Peak heart rate and blood pressure were the values recorded closest to the end of the exercise test for each participant. Initial treadmill speed was set at 2.7 km/h and increased to 4.0, 5.4, 6.7, 8.0, 8.8 km/h on minutes 3, 6, 9, 12, and 15, respectively. Peak METs were calculated by the treadmill/electrocardiogram control based on peak exercise workload.
Chronotropic Incompetence
Age-predicted maximum heart rate (pMHR) was computed as a percentage of the maximum predicted value according to the following formula: % predicted = (peak heart rate∕ (220 – age)) × 100%. Chronotropic incompetence for our main analysis was defined as <85% of the pMHR. The presence of chronotropic incompetence also was evaluated and defined using different values varying between 60% and 95% of the pMHR with 5% incremental steps (<95%, <90%, <85%, <80%, <75%, <70%, <65%, <60%). We also examined chronotropic index using the following formula: ((peak heart rate-resting heart rate)/((220 – age) – resting heart rate)) × 100%. Chronotropic index values <80% are considered significant for chronotropic incompetence (4).
Incident Atrial Fibrillation
AF events were ascertained though linkage with administrative claim files from services delivered by the system-affiliated group practice and/or reimbursed by the system’s health plan. These files included the appropriate International Classification of Disease Code Ninth Revision (ICD-9) for AF. A new diagnosis was considered present when the appropriate ICD-9 code (427.31) was identified in at least 3 separate follow-up encounters. Patients were censored when they lost contact with the health system.
Statistical Analysis
Categorical variables were reported as frequency and percentage while continuous variables were reported as mean ± standard deviation. Follow-up time was defined as the date of exercise stress testing until the date of AF, death, censoring, or end of follow-up (March, 2010). Kaplan-Meier estimates were used to compute cumulative incidence curves for AF by chronotopic incompetence and the differences in estimates were compared using the log-rank procedure. Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI). We also constructed a restricted cubic spline model to examine the graphical dose-response relationship between pMHR and AF at the 5th, 50th, and 95th percentiles (10). Multivariable models were constructed as follows: Model 1 adjusted for age, sex, and race; Model 2 adjusted for Model 1 covariates plus resting heart rate, smoking, hypertension, diabetes, obesity, hyperlipidemia, coronary heart disease, heart failure, antihypertensive medication use, lipid-lowering medication use, aspirin, and METs achieved. We tested for interactions between our main effect variable and age (stratified by median age), sex, race (white vs. non-white), hypertension, and coronary heart disease. A secondary analysis was performed to examine the association between pMHR and AF with varying cut-off points as lower values have been suggested among populations taking medications that influence heart rate and among older adults (11,12). Additionally, we examined the association between chronotropic incompetence and AF using chronotropic index with similar cut-off points (<95%, <90%, <85%, <80%, <75%, <70%, <65%, <60%). We also examined the association between chronotropic incompetence and AF after excluding participants who reported the use of heart rate-modifying therapies (beta-blockers, calcium channel blockers, digoxin, or amiodarone) to determine if the association between chronotropic incompetence and AF was materially altered. The test statistic of Grambsch and Therneau was used to check the proportional hazards assumption (13). Statistical significance was defined as p <0.05 for the main effect model and tests for interaction. SAS® Version 9.3 (Cary, NC) was used for all analyses.
RESULTS
A total of 57,402 (mean age=54±13 years, 47% female, 64% white) patients were included in this analysis. A total of 13,013 (23%) patients did not reach 85% of the pMHR and were classified as having chronotropic incompetence. Baseline characteristics stratified by chronotropic incompetence are shown in Table 1.
Table 1. Baseline Characteristics by Chronotropic Incompetence (N=57,402)*.
| Characteristics | Chronotropic Incompetence (n=13,013) |
No Chronotropic Incompetence (n=44,389) |
P-value |
|---|---|---|---|
| Age, mean (SD), years | 57 (13) | 53 (12) | <0.001 |
| White (%) | 7,694 (59) | 29,134 (66) | <0.001 |
| Male (%) | 7,160 (55) | 23,081 (52) | <0.001 |
| Smoker (%) | 6,482 (50) | 18,145 (41) | <0.001 |
| Obesity (%) | 3,221 (25) | 10,632 (24) | 0.061 |
| Diabetes (%) | 3,700 (28) | 7,758 (17) | <0.001 |
| Hypertension (%) | 11,140 (86) | 25,913 (58) | <0.001 |
| Hyperlipidemia (%) | 11,112 (85) | 35,830 (81) | <0.001 |
| Coronary heart disease (%) | 3,754 (29) | 2,864 (6.5) | <0.001 |
| Heart failure (%) | 559 (4.3) | 420 (1.0) | <0.001 |
| Aspirin (%) | 4,333 (33) | 7,406 (17) | <0.001 |
| Antihypertensive medications (%) | 9,638 (74) | 17,070 (38) | <0.001 |
| Beta-blockers | 6,604 (51) | 5,350 (12) | <0.001 |
| Calcium channel blockers (%) | 2,641 (20) | 4,619 (10) | <0.001 |
| Digoxin (%) | 387 (3.0) | 323 (0.7) | <0.001 |
| Amiodarone (%) | 20 (0.2) | 11 (0.02) | <0.001 |
| Lipid-lowering therapies (%) | 4,570 (35) | 9,637 (22) | <0.001 |
| METs achieved, mean (SD) | 7.3 (2.8) | 9.5 (2.8) | <0.001 |
| Resting heart rate, mean (SD), bpm | 68 (12) | 74 (12) | <0.001 |
| Maximum heart rate, mean (SD), bmp | 122 (17) | 157 (14) | <0.001 |
Chronotropic incompetence was defined as <85% of the age-predicted maximum heart rate.
Bpm=beats per minutes; MET=metabolic equivalent of task; SD=standard deviation.
Over a median follow-up of 5.0 years (25th-75th percentiles=2.6, 7.8), a total of 3,395 (5.9%) participants developed AF. AF developed in 11% (n=1,398) of patients with chronotropic incompetence and 4.5% (n=1,997) of patients without chronotropic incompetence. A higher incidence rate (per 1000 person-years) was observed for patients with chronotropic incompetence (incidence rate=20.6, 95%CI=19.6, 21.7) than those without (incidence rate=8.0, 95%CI=7.7, 8.4). The cumulative incidence curves of AF events by chronotropic incompetence are shown in Figure 1 (log-rank: p<0.0001). The cumulative incidence of AF increased with decreasing cut-off points to define chronotropic incompetence (Figure 2).
Figure 1. Unadjusted Cumulative Incidence of Atrial Fibrillation by Chronotropic Incompetence*.
*Chronotropic incompetence was defined as <85% of the age-predicted maximum heart rate. Cumulative incidence curves are statistically different (log-rank p<0.0001).
Figure 2. Unadjusted Cumulative Incidence of Atrial Fibrillation with Varying Chronotropic Incompetence Cut-off Points*.
*Chronotropic incompetence was defined using age-predicted maximum heart rate.
Chronotropic incompetence was associated with a 33% increase in the risk for AF development after adjustment for demographics and potential confounders (Table 2). Each 10% decrease in pMHR was associated an 8% increase in the risk for AF (Table 2). The results remained similar when stratified by sex, race, and hypertension. The association between chronotropic incompetence and AF was stronger for younger compared with older patients (Table 2). The relationship also was stronger for those without coronary heart disease than those with coronary heart disease (Table 2). The proportional hazards assumption was not violated in our analysis.
Table 2. Risk of Atrial Fibrillation with Chronotropic Incompetence (N=57,402)*.
| Events/ No at risk |
Model 1† HR (95%CI) |
P-value | Model 2‡ HR (95%CI) |
P-value | Interactionδ P-value |
|
|---|---|---|---|---|---|---|
| No Chronotropic Incompetence | 1,997/44,389 | 1.0 | - | 1.0 | - | |
| Chronotropic Incompetence | 1,398/13,013 | 1.96 (1.83, 2.10) | <0.0001 | 1.33 (1.22, 1.44) | <0.0001 | |
| Age-predicted maximum heart rate per 10% decrease | 3,395/57,402 | 1.29 (1.25, 1.32) | <0.0001 | 1.08 (1.05, 1.12) | <0.0001 | |
| Age¶ | ||||||
| <53 years | 692/28,267 | 3.02 (2.59, 3.53) | <0.0001 | 1.36 (1.11, 1.65) | 0.0024 | 0.0014 |
| ≥53 years | 2,703/29,135 | 2.02 (1.87, 2.18) | <0.0001 | 1.12 (1.02. 1.22) | 0.017 | |
| Sex | ||||||
| Female | 1,372/27,161 | 1.81 (1.62, 2.02) | <0.0001 | 1.34 (1.18, 1.53) | <0.0001 | 0.56 |
| Male | 2,023/30,241 | 2.06 (1.89, 2.26) | <0.0001 | 1.33 (1.19, 1.48) | <0.0001 | |
| Race | ||||||
| Non-White | 929/20,574 | 2.19 (1.92, 2.49) | <0.0001 | 1.33 (1.14, 1.56) | 0.0003 | 0.17 |
| White | 2,466/36,828 | 1.87 (1.72, 2.03) | <0.0001 | 1.31 (1.19, 1.45) | <0.0001 | |
| Hypertension | ||||||
| No | 580/20,349 | 1.93 (1.56, 2.40) | <0.0001 | 1.57 (1.23, 1.99) | 0.0002 | 0.29 |
| Yes | 2,815/37,053 | 1.78 (1.65, 1.92) | <0.0001 | 1.30 (1.19, 1.41) | <0.0001 | |
| Coronary heart disease | ||||||
| No | 2,374/50,784 | 1.84 (1.69, 2.01) | <0.0001 | 1.39 (1.26, 1.53) | <0.0001 | 0.014 |
| Yes | 1,021/6,618 | 1.42 (1.25, 1.62) | <0.0001 | 1.19 (1.02, 1.37) | 0.024 |
Chronotropic incompetence was defined as >85% of the age-predicted maximum heart rate.
Adjusted for age, sex, and race.
Adjusted for Model 1 covariates plus resting heart rate, smoking, hypertension, diabetes, obesity, hyperlipidemia, coronary heart disease, heart failure, antihypertensive medication use, lipid-lowering medication use, aspirin, and METs achieved.
interactions tested using Model 2.
Dichotomized at the median age for study population.
CI=confidence interval; HR=hazard ratio; MET=metabolic equivalent of task; SD=standard deviation.
A dose-response relationship was observed between pMHR and AF with the risk increasing for lower values of pMHR (Figure 3). Chronotropic incompetence remained a significant predictor of incident AF with varying cut-off points of pMHR to define chronotropic incompetence (Table 3). Similar results were obtained with chronotropic index to define chronotropic incompetence (Table 3).
Figure 3. Risk of Atrial Fibrillation across Age-Predicted Maximum Heart Rate*.
*Each hazard ratio was computed with the median value for age-predicted maximum heart rate achieved of 91% as the reference and was adjusted for age, sex, race, heart rate, smoking, hypertension, diabetes, obesity, hyperlipidemia, coronary heart disease, heart failure, antihypertensive medication use, lipid-lowering medication use, aspirin, and METs achieved. Dotted-lines represent the 95% confidence interval.
MET=metabolic equivalent of task.
Table 3. Risk of Atrial Fibrillation with varying Chronotropic Incompetence Cut-off Points.
| Age-Predicted Maximum Heart Rate |
HR* (95%CI) |
P-value | Chronotropic Index |
HR* (95%CI) |
P-value |
|---|---|---|---|---|---|
| <95% predicted | 1.13 (1.04, 1.23) | 0.0049 | <95% predicted | 1.13 (1.03, 1.24) | 0.013 |
| <90% predicted | 1.27 (1.17, 1.37) | <0.001 | <90% predicted | 1.11 (1.02, 1.21) | 0.011 |
| <85% predicted | 1.33 (1.23, 1.44) | <0.001 | <85% predicted | 1.20 (1.11, 1.30) | <0.001 |
| <80% predicted | 1.21 (1.11, 1.32) | <0.001 | <80% predicted | 1.28 (1.19, 1.38) | <0.001 |
| <75% predicted | 1.22 (1.10, 1.34) | <0.001 | <75% predicted | 1.33 (1.23, 1.43) | <0.001 |
| <70% predicted | 1.17 (1.04, 1.31) | 0.0074 | <70% predicted | 1.29 (1.19, 1.40) | <0.001 |
| <65% predicted | 1.09 (0.95, 1.26) | 0.20 | <65% predicted | 1.20 (1.11, 1.31) | <0.001 |
| <60% predicted | 1.17 (0.98, 1.40) | 0.081 | <60% predicted | 1.22 (1.12, 1.34) | <0.001 |
Adjusted for age, sex, race, resting heart rate, smoking, hypertension, diabetes, obesity, hyperlipidemia, coronary heart disease, heart failure, antihypertensive medication use, lipid-lowering medication use, aspirin, and METs achieved.
CI=confidence interval; HR=hazard ratio; MET=metabolic equivalent of task.
When we examined the association between chronotropic incompetence and AF after excluding participants who reported heart rate-modifying therapies (n=17,310), pMHR (<85%: HR=1.25, 95%CI=1.09, 1.43) and chronotropic index: <80%: HR=1.19, 95%CI=1.07, 1.33) remained significantly associated with AF. The association between chronotropic incompetence and AF after excluding partients who reported heart rate-modifying therapies is shown in Supplemental Tables 1 and 2.
DISCUSSION
In this analysis from the FIT registry, we have shown that the inability to achieve adequate heart rate response during exercise is independently associated with an increased risk for the development of AF. The risk of AF remained after excluding participants who reported taking heart rate-modifying therapies. Additionally, we explored several cut-off points to define chronotropic incompetence and all were associated with AF development. To our knowledge, our findings are the first to report that chronotropic incompetence is associated the development of AF. Our data also alert practitioners to the increased risk for AF development in patients with chronotropic incompetence.
Several reports have examined the predictive ability of chronotropic incompetence. Data from the Framingham Heart Study have shown that the inability to achieve 85% of the pMHR during exercise is predictive of incident coronary heart disease and total mortality (3). Additionally, a cohort of adults referred for symptom-limited exercise treadmill stress testing at the Cleveland Clinic observed an increased risk of death (HR=1.84, 95%CI=1.13, 3.00) among those failing to achieve 85% of the pMHR (4). Similarly, an increased risk of death was observed in adults with chronotropic incompetence (<85% pMHR) independent of coronary artery disease in a cohort of adults who were not receiving beta-blockers (5).
Prior reports have largely focused on all-cause mortality and neglected the risk of arrhythmia development. An examination of patients undergoing exercise testing to determine the indication for rate-responsive pacing before primary pacemaker implantation or pacemaker replacement observed an increased prevalence of chronotropic incompetence in patients with chronic AF (6). However, no studies have explored the AF risk associated with chronotropic incompetence. Our findings also indicate that younger individuals with chronotropic incompetence have a higher risk for AF compared with older adults. Maximum heart rate decreases with age and the higher risk in younger participants likely reflects that younger persons are more likely to be labeled as having chronotropic incompetence at higher cut-off points (12). Additionally, a stronger association between chronotropic incompetence and AF was observed among those without coronary heart disease. This possibly reflects the increased likelihood of chronotropic incompetence to detect autonomic dysfunction in persons without coronary heart disease rather than chronotropic incompetence due to ventricular dysfunction in persons with coronary artery disease (14).
The underlying mechanisms that explain the association between inadequate heart rate response and AF are currently unknown. A potential mechanism includes an inappropriate autonomic response that favors parasympathetic dominance (15). This is supported by observations of increased AF risk in those with low resting heart rates, suggesting that underlying sinus node dysfunction predisposes to AF (7,16-18). Therefore, it is plausible that patients who are unable to appropriately increase their heart rate during exercise represent a group with sinus node dysfunction that predisposes to AF development. Additionally, persons with chronotropic incompetence possibly have increased myocardial fibrosis and abnormal left atrial remodeling, and both of these conditions have been associated with AF (15,19-22). Several AF risk factors (e.g., older age, hypertension) have been associated with sinus node dysfunction and this is another explanation to link both conditions (23-25). However, our findings remained statistically significant after adjusting for several of these common risk factors.
Current guidelines recommend the use of exercise stress testing to assess chronotropic competence, arrhythmias, and response to implanted device therapy (1). This report largely focuses on abnormalities regarding impulse initiation and conduction during exercise to identify individuals who will benefit from rate-responsive therapies. Our data suggest that exercise stress testing also is able to identify those who are more likely to develop AF. Also, the observed increased mortality risk associated with chronotropic incompetence potentially is partially related to undetected AF and its well-known thromboembolic complications (26). In addition to the mortality risk associated with chronotropic incompetence, our findings alert practitioners to a group of patients in which targeted programs to identify AF events possibly are beneficial. Therefore, the identification of AF in patients with chronotropic incompetence potentially will reduce mortality by providing this high risk group with therapies that are known to influence survival in AF, such as anticoagulation (27).
The current study should be interpreted in the context of several limitations. AF events were identified using administrative claim files that are specific to the Henry Ford Health System and any cases that occurred in other health systems possibly were missed. However, given that many patients were followed in this health maintenance organization, it is likely that a very small number of AF episodes were missed. Additionally, non-permanent cases (e.g., paroxysmal) potentially were missed. We were unable to ascertain AF events using Holter monitors or event recorders as this data was not collected in our dataset. Our results suggest that an increased risk for AF exists with varying cut-off points to define chronotropic incompetence and the criteria used. Unfortunately, we were unable to determine a specific cut-off point to label patients as high risk and further research is needed to determine the clinical value in which AF risk is greatest. Although other definitions exist to define pMHR during exercise, the definitions used were clinically relevant and allow for easy comparison with prior work (28). Furthermore, we included several covariates in our multivariable models that likely influenced the development of AF but we acknowledge that residual confounding remains a possibility. For example, we were unable to account for left atrial size in our analysis.
In conclusion, we have shown that chronotropic incompetence is associated with an increased AF risk. In addition to assessing sinus node function and conduction defects, exercise stress testing is able to identify patients who are at risk for developing this common arrhythmia. Further research is needed to determine the clinically relevant cut-off point to define chronotropic incompetence in which a closer evaluation for the detection of AF is warranted.
Supplementary Material
COMPETENCY IN MEDICAL KNOWLEDGE.
Patients with chronotropic incompetence detected on exercise stress testing have an increased risk for the development of atrial fibrillation.
TRANSLATIONAL OUTLOOK.
The well-known increased mortality associated with chronotropic incompetence possibly is related to undetected atrial fibrillation and its well-known thromboembolic complications. Our findings alert practitioners to a group of patients in which targeted programs to identify atrial fibrillation events are beneficial.
ACKNOWLEDGEMENTS
The authors would like to thank the patients and support staff who participated in The FIT Registry.
FUNDING
WTQ is funded by Ruth L. Kirschstein NRSA Institutional Training Grant 5T32HL076132-10.
ABBREVIATIONS
- AF
atrial fibrillation
- FIT
Henry Ford ExercIse Testing Project
- MET
metabolic equivalent of task
- pMHR
age-predicted maximum heart rate
Footnotes
Disclosures: The authors declare no conflicts of interest.
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