PACING
Predictors of chronotropic incompetence in the pacemaker patient population
Charité-Campus Mitte, Medizinische Klinik mit Schwerpunkt Kardiologie Angiologie, Pneumologie, Schumannstrasse 20/21, D-10117 Berlin Germany ; Medtronic, Inc. Minneapolis, MN USA
Manuscript submitted 17 October 2003. Accepted after revision 21 August 2005.
Corresponding author. Tel: +49 30 450 513 148; fax: +49 30 450 513 915. E-mail address: christoph.melzer{at}charite.de
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Abstract |
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Aims We prospectively evaluated results from cardiopulmonary exercise testing for chronotropic incompetence (CI) in a cohort of 292 pacemaker patients. In addition, we evaluated comorbidity and antiarrhythmic patient data as indicators of CI.
Methods and results On the basis of exercise stress testing and application of the definition of CI by Wilkoff, 51% of our cohort was categorized as having CI. Indications for pacemaker implant for this patient group were 42% atrioventricular block, 56% sinus node disease, and 59% atrial fibrillation. Maximum oxygen uptake (VO2 max) and exercise duration were significantly reduced among CI pacemaker patients, whereas oxygen uptake at the anaerobic threshold remained unchanged. The following clinical characteristics were significant predictors of CI: existence of coronary artery disease (P=0.038), presence of an acquired valvular heart disease (P=0.037), and former cardiac surgery (P=0.041). Age, gender, arterial hypertension, cardiomyopathy, congenital heart disease, left ventricular ejection fraction, and time period between stress-exercise examination and pacemaker implantation were not significant predictors of CI. Chronic antiarrhythmic therapy with digitalis (P=0.013), beta blockers (P=0.036), and amiodarone (P=0.045) were significant predictors of CI. In contrast, medication with class I and IV antiarrhythmics had no significant correlation with CI.
Conclusion We found the following characteristics predictive of CI in this pacemaker patient population: VO2 max, existence of coronary artery disease or acquired valvular heart disease, previous cardiac surgery, as well as medication with digitalis, beta blockers, and amiodarone.
Key Words: Chronotropic incompetence, Pacemaker, Cardiopulmonary exercise testing
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Introduction |
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Chronotropic incompetence (CI) is the inability of the sinus node to respond appropriately to varying physical workload.1
The term ‘chronotropic incompetence’ first appeared in conjunction with markers for myocardial ischaemia.2–5
CI has attained clinical significance as a result of the introduction of rate-adaptive pacemakers. Evaluation of various sensors and rate-adaptive pacing systems requires a definition of appropriate heart rate response to varying workloads.6,7
The majority of previous studies have demonstrated the beneficial effects of rate-adaptive pacing on exercise capacity and cardiovascular response to exercise.8–11 Other studies, however, have failed to establish benefits of rate-adaptive pacing in comparison with conventional pacing.1,12 However, the current ACC/AHA/NASPE Guidelines (2002) recommend the implantation of rate-responsive pacemakers for CI patients.13
Despite considerable effort, it has not yet been proved possible to arrive at a uniform definition of CI.14 The prevalence of CI patients has likewise proved to be a topic of dispute in the literature: estimates range between 9 and 84%.15–22The definition of CI by Wilkoff23 is based on age, physical fitness, and resting heart rate.24 This method is well established in patients with heart failure and coronary artery disease.24,25 Published data on pacemaker patients include fewer than 50 patients.1
Previous studies investigating CI in the pacemaker patient population have not carefully monitored the administration of antiarrhythmic medication. The increasing prescription of beta blockers and amiodarone in the treatment of heart failure patients may have significant implications for the occurrence of CI in pacemaker and implanted defibrillator patient populations.26–29 The relationship between left ventricular ejection fraction and CI remains to be studied, and may be especially important for heart failure patients receiving pacing therapy.
The goal of our study was therefore to investigate heart rate response to exercise stress testing, as well as the relationships among CI, chronic antiarrhythmic therapy, underlying heart disease, and left ventricular ejection fraction, especially with application of Wilkoff's definition.
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Methods |
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Patient characteristics
From a total of 1268 pacemaker patients, data were prospectively collected in our pacemaker clinic for 110 women (age 62.1±12.5) and 182 men (age 59.9±13.8) from 1995 to 2000. Inclusion criteria were physical capability to perform a symptom-limited stress test and informed patient consent. Of these patients, 127 with pacemaker replacement (mean±SD: 4.5±5.5 years after implant) and 165 with initial implantation completed treadmill tests. All pacemakers were programmed to non-rate-adaptive modes during treadmill stress testing, which allowed evaluation of native sinus node response. Before and during cardiopulmonary evaluation, antiarrhythmic therapy was maintained as previously prescribed. Among patients with DDD pacemakers, we programmed the upper rate limit to 150–160/min in order to provide 1 : 1 synchronization between atrium and ventricle at higher pacing rates.
Patient exclusion criteria were New York Heart Association (NYHA) class III–IV, unstable angina pectoris, and physical inability to undergo exercise testing.
Indications for pacemaker implantation were AV block (AVB) (119 patients, 41%), sinus node disease (SND) (100 patients, 34%), and atrial fibrillation (AF) (73 patients, 25%) (Figure 1). Pacemaker modes were programmed as follows: AAI (16 patients, 5%), DDD (203 patients, 70%), and VVI (73 patients, 25%) (Figure 2).
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Exercise testing
Symptom-limited treadmill evaluations were completed in 292 patients with cardiopulmonary exercise (CPX) testing according to the Bruce protocol.30
The exercise tests were performed under controlled conditions: stable clinical status, post-absorptive state, and controlled temperature and humidity. Data collected for each CPX exercise period were maximum oxygen uptake (VO2 max, mL/min/kg) and oxygen uptake at the anaerobic threshold (VO2 AT, mL/min/kg). In addition, exercise duration and maximum heart rate achieved were recorded.
Wilkoff's definition of CI23
Chronotropic response is assessed by calculating the ratio of used percent heart rate reserve (%HRR) to percent metabolic reserve (%MR). A patient is referred as a CI patient if the resulting chronotropic index is <0.8. This method allows definition of CI for each exercise-stress stage:
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Statistics
All data are presented as mean±standard deviation. We additionally performed longitudinal regression analysis,31 with P<0.05 defined as statistically significant.
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Results |
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Incidence of CI
Determination of CI on the basis of Wilkoff was effectively applied for the patients who were examined before their first pacemaker implantation. Among those patients who underwent pacemaker replacement, it was not possible to determine HRrest for 46 patients (16%), as the intrinsic rate was less than the lowest programmable pacemaker rate. For those patients with complete AVB, the atrial rate was defined as HRrest.
Application of Wilkoff's definition resulted in classification of 125 (51%) of the 246 patients as CI patients. The following distribution resulted with reference to the basic arrhythmia: AVB 45/106 (42%), SND 42/76 (56%), and AF 38/64 (59%) (Figure 3). A significant difference in the prevalence of CI became apparent between AVB and SND (P=0.036) and between AVB and AF (P=0.018). The frequency of CI between SND and AF was not significant.
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Predictors of CI
Patients with coronary artery disease (P=0.038) or acquired valvular heart disease (P=0.037) or patients who had undergone cardiac surgery (P=0.041) demonstrated CI significantly more often than those without these conditions. The following factors were not correlated with elevated frequency of CI: age, gender, arterial hypertension, cardiomyopathy, congenital heart disease, left ventricular ejection fraction, and period of time between exercise testing and pacemaker implantation.
Patients receiving chronic therapy with digitalis (P=0.013), beta blockers (P=0.036), or amiodarone (P=0.045) experienced CI significantly more often than other antiarrhythmics. In comparison, class I and class IV antiarrhythmics had no significant correlation with CI (Table 1).
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Exercise testing
We did not observe significant differences in VO2 AT between chronotropically competent (CC) and CI patients for any of the patient arrhythmia classifications (Figure 4).
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Using Wilkoff's definition, 29 (23%) of the 125 CI patients did not reach the anaerobic threshold. In comparison, only 13 of the 121 CC patients (11%) failed to reach the anaerobic threshold during exercise. The resulting difference between the two patient groups is significant (P=0.023). There was significant reduction in VO2 max in CI patients (Figure 5). The difference in average exercise duration between CI and CC patients was significant (Figure 6).
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Discussion |
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Prevalence of CI
Application of Wilkoff's definition23
disclosed that 51% of the patients examined by us showed CI. Our patient cohort represents the largest population of pacemaker patients for whom this definition was applied. For 46 patients (16% of the total), it was not possible to apply Wilkoff's formula, as the resting heart rate could not be determined: the intrinsic rate was less than the lowest programmable pacemaker rate. Haywood et al.1 were not able to apply Wilkoff's formula for the majority of the patients in their pacemaker population, as the resting sinus rate could also not be determined. Studies with the largest cohorts of CI among pacemakers patients have been by Lukl et al.32 (211 patients) and Lamas et al.22 (985 patients). Although both of these studies applied similar criteria for CI, Lukl: 
0.7×(220–age) and Lamas: 0.8×(220–age), the resulting numbers of CI patients appreciably differed. Lukl et al.32 indicated prevalence of CI of 42% and Lamas, 84%.
Crook et al.18 reported the lowest incidence of CI: only 9% of patients with sick sinus syndrome met their CI definition. The authors defined CI on the basis of intercepts and slopes of the regression lines of sinus heart rate response to exercise. Patients were categorized as CI when the intercept lay below twice the standard deviation of the control group. This study was conducted with withdrawal of ongoing oral medication, and the majority of the patients investigated did not suffer from structural heart disease.
Prevalence of CI as a function of basic arrhythmia
For application of Wilkoff's definition, there was no significant difference in the prevalence of CI between patients with an SND and an AF.
It is interesting in this context that more than one-third of our patients with AVB were CI patients and presumably manifested additional disease of the sinoatrial node. Lukl et al.32 similarly revealed a high incidence (30%) of accompanying sinus node disease among their patients with higher grade AVB.
In our patient population, and in concurrence with the literature, the prevalence of CI among patients with AF was higher than that among patients with SND. Lukl et al.,32 accordingly, found CI in 67% of patients with AF and in only 49% of patients with SND. Corbelli et al.20 reported a prevalence of 58% of CI in 19 patients with implanted VVI pacemakers and concomitant AF.
In our SND patient subgroup, the prevalence of CI, in the range of 40–50%, was consistent with previous investigations.1,33 The only divergence among these findings is in the study by Crook et al.,18 which reported a very low incidence of 9%.
Predictors of CI
With regard to the clinical characteristics of the CI patient population, the following factors correlated significantly with occurrence of CI: presence of coronary artery disease, existence of acquired valvular heart disease, and former cardiac surgery. In 81% of cases, the indication for cardiac surgery was coronary heart disease. The finding that coronary heart disease is associated with elevated incidence of CI among ICD patients correlates with the early reports published on CI. The designation ‘chronotropic incompetence’ was accordingly used for the first time in the early 1970s in conjunction with markers for myocardial ischaemia and predictors for coronary disease.3,34–36 In their studies, Rubenstein et al.37 determined that coronary heart disease represents the primary aetiological explanation of CI.
The time duration between pacemaker implantation and exercise testing showed no correlation with CI. A study published by Gwinn et al.38 categorized patients into two groups: those with pacemakers for fewer than 2 years and those with pacemakers for longer than 4 years. They reported a significant increase in CI in the latter group. The Lukl et al.32 study found no significant difference regarding the intervals between pacemaker implantation and the point in time of exercise testing, a finding consistent with those of the present investigation.
In previous studies, antiarrhythmic therapy was routinely terminated before exercise testing; indeed, patients were rarely tested at prescribed antiarrhythmic therapeutic levels.18,38 Corbelli et al.20 also suspended antiarrhythmic therapy on the day of examination. Exercise testing without ongoing antiarrhythmic therapy represents an artificial state in comparison with the normal conditions experienced by patients. We consequently believe that this approach impairs the validity of the results of exercise testing as a measure of normal patient response. Furthermore, increasing numbers of pacemaker patients are currently receiving beta-blocker therapy as a result of recent insights gained into the treatment of cardiac insufficiency.26,27
Chronic antiarrhythmic therapy with digitalis as well as beta blockers and amiodarone produced significant influence on CI among our patients.
On the basis of its mechanism of action, therapy with beta blockers leads to a reduction in resting and exercise heart rates. Gauri et al.39 investigated the relationship between medication with beta blockers and CI: of the 355 patients in his study treated with a beta blocker, 303 (85%) were CI patients.
We are not aware of studies on the influence of amiodarone therapy on CI. Two publications, however, have reported that amiodarone reduces the resting heart rate among patients. Nul et al.40 examined the effects of amiodarone therapy on the heart rate of 516 patients in the GESICA study. In the patient group with initial heart rate >90 b.p.m., the rate after 6 months of amiodarone therapy was 12.7±16 b.p.m. slower than the initial rate. Likewise, Takemura et al.41 demonstrated a reduction in heart rate in patients after 1 month of amiodarone therapy (81±12 vs. 65±7 b.p.m.). Depression of sinus node automaticity and slowing of atrioventricular node conduction have been discussed as causes of heart-rate reduction with amiodarone therapy.42,43
CPX testing
Chronotropically competent patients reach the anaerobic threshold significantly more frequently than do CI patients; CI patients likewise demonstrate significantly reduced maximum oxygen uptake and exercise capacities.
Our results concur with several studies that have evidenced the fact that CI is associated with reduced exercise capacity.44,45 We are not aware of large studies (i.e. >100 patients) that have applied CPX for the definition of CI among pacemaker patients. One reason for this lack could be the additional expense involved in comparison with standard exercise testing.32
One of the most recent studies on CPX in a pacemaker patient population was conducted by Meine et al.46 As a result of their study of 16 patients with CI, and with 15 control subjects, they proposed a new definition of CI on the basis of heart rate at the time of the anaerobic threshold. In addition, a recently published study by Kindermann et al.47 examined optimization of the upper heart rate limit among patients with chronic heart failure. These authors defined CI determined by CPX as follows: heart rate increase of <2 b.p.m. per oxygen consumption (mL/kg/min).
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Conclusion |
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Application of Wilkoff's definition for determining CI, 51% of our patients showed CI. We were able to define the following predictive factors for CI: coronary artery disease; acquired valvular heart disease; cardiac surgery; and medication with digitalis, beta blockers, or amiodarone. In addition, CI patients demonstrated lower exercise capacity, reduced maximum oxygen uptake, and a restricted ability to reach the anaerobic threshold when compared with CC patients.
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