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European Journal of Heart Failure 2008 10(1):96-101; doi:10.1016/j.ejheart.2007.11.006
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© 2008 European Society of Cardiology

Chronotropic incompetence, beta-blockers, and functional capacity in advanced congestive heart failure: Time to pace?

Ulrich P. Jordea,*, Timothy J. Vittoriob, Michael E. Kasperb, Emma Arezzia, Paolo C. Colomboa, Rochelle L. Goldsmitha, Kartikya Ahujab, Chi-Hong Tsengb, Francois Haasb and David S. Hirshb

a Division of Cardiology, New York Presbyterian Hospital, Columbia University College of Physicians and Surgeons United States
b Heart Failure Program, Leon Charney Division of Cardiology, New York University School of Medicine United States

* Corresponding author. College of Physicians & Surgeons, Columbia University, Department of Medicine, Division of Cardiology, 630 West 168th Street, Box #93, New York, NY 10032, United States. Tel.: +1 212 305 4736; fax: +1 212 305 4825. E-mail address: upj1{at}columbia.edu (U. P. Jorde).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Chronotropic incompetence (CI) is often seen in subjects with chronic congestive heart failure (CHF). The prevalence of CI, its mechanisms and association with beta-blocker use as well as exercise capacity have not been clearly defined.

Methods and results: Cardiopulmonary exercise tolerance testing data for 278 consecutive patients with systolic CHF was analyzed. CI, defined as the inability to reach 80% of maximally predicted heart rate was present in 128 of 278 subjects (46%). The prevalence of CI was highest in those with most impaired exercise capacity (72, 48, and 24% for subjects with a VO2 of <14.0, 14.0–20.0, and >20.0ml/kg/min respectively; p=0.001). While subjects with CI had lower peak exercise heart rate (114 vs. 152 bpm), and lower peak VO2 (15.4 vs. 19.9 ml/kg/min), they were equally likely to be on chronic beta-blocker therapy (74% vs. 71%; p=0.51).

Heart rate and norepinephrine (NE) levels were measured during exercise in a separate cohort of 24 subjects with CHF. There was no difference in beta-blocker dose between subjects with and without CI, however, exercise induced NE release and Chronotropic Responsiveness Index, a measure of post-synaptic beta-receptor sensitivity to NE, were lower in subjects with CI (1687±911 vs. 2593±1451pg/ml p=0.08; CRI 12.7±5.7 vs. 22.1±4.7, p=0.002).

Conclusions: CI occurs in >70% of subjects with advanced systolic CHF irrespective of beta-blocker use and is associated with a trend toward impaired NE release, post-synaptic beta-receptor desensitization and reduced exercise capacity.

Key Words: CHF • Chronotropic Incompetence • Beta-blocker • Exercise

Received May 2, 2007; Revised September 10, 2007; Accepted November 14, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Activation of the sympathetic nervous system (SNS) is a hallmark in the syndrome of chronic congestive heart failure (CHF) and evidenced by increased circulating catecholamine levels as well as altered adrenergic receptor densities [1-4]. The physiological response to exercise is modified in systolic CHF and recent observations suggest that 30-50% of patients are unable to reach 80% of the age-adjusted maximum predicted heart rate (MPHR), thus manifesting Chronotropic Incompetence (CI) [5-7]. CI has been identified as a factor limiting exercise capacity and proposed as a therapeutic target [8,9]. The precise mechanism of CI and its relevance in the reduction of exercise capacity in systolic CHF, particularly in the presence of beta-blockade, is unknown.

Heart rate changes during exercise are in principle modulated by withdrawal of vagal tone, increases in sympathetic outflow, and the relative sensitivity of the sinoatrial node to catecholamines [3,10]. In patients with systolic CHF, chronically elevated sympathetic nervous outflow as well as reduced cardiac beta-receptor density may alter heart rate regulation during exercise [2,11]. Beta-blockers, a mainstay in the treatment of systolic CHF, may further attenuate the exercise induced increase in heart rate, although it is equally possible that chronic beta-blockade, through beta-1 receptor upregulation, might increase heart rate responsiveness [3]. In any event, an inadequate heart rate response during exercise, i.e. CI, may lead to inadequate cardiac output [12], resulting in a mismatch of metabolic demand and supply, thus limiting exercise capacity. In patients with CHF and CI, resynchronizing heart rate requirements with metabolic demands might therefore be a useful therapeutic intervention [8]. Conversely, CI might be a protective mechanism partially conferred by beta-blockade.

Accordingly, we investigated the association of CI with beta-blockade and exercise capacity in a large cohort of patients with CHF and attempted to identify mechanisms underlying CI in subjects on chronic beta-blockade.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study populations
Cohort 1 (Prevalence of CI in CHF): Seven hundred and fifty-five consecutive patients with CHF underwent initial cardiopulmonary exercise tolerance testing (CPETT) as part of routine clinical testing and/or evaluation for orthotopic heart transplantation. Data was abstracted from the records in the exercise physiology laboratory where left ventricular ejection fraction (LVEF) is recorded by convention as severely reduced (<30%) moderately reduced (30-39%), mildly reduced (40-54%) or normal. After exclusion of subjects who failed to achieve a respiratory exchange ratio (RER) >1.0, had an LVEF ≥40%, a permanent pacemaker, or atrial fibrillation, data of 278 patients was analyzed.

Cohort 2: Thirty subjects aged 18 or older, with LVEF ≤40%, CHF for at least 6 months, New York Heart Association (NYHA) functional class II-IV, chronic beta-blocker therapy with carvedilol for at least 3 months, and ability to provide written informed consent were asked to participate in a prospective study on exercise induced NE release. Patients who had a hospitalisation within 3 months for CHF or any other cardiovascular event, uncontrolled hypertension (>160/90 mm Hg), marked resting bradycardia (<50 bpm) or tachycardia (>100 bpm), a permanent pacemaker, or any non-cardiac condition limiting exercise ability (i.e. severe rheumatoid arthritis or osteoarthritis, chronic pulmonary disease requiring beta-agonists) were excluded.

Both investigations were approved by the institutional review board. Data collected retrospectively was fully de-identified. Informed consent was obtained prior to CPETT for Cohort 2.

2.2. Cardiopulmonary exercise tolerance testing
Peak-oxygen consumption (peak VO2 [ml/kg/min]) was assessed during graded treadmill exercise using a SensorMedics metabolic cart (SensorMedics, Yorba Linda, CA). Expired gases were collected throughout exercise, and oxygen consumption was recorded on a breath-by-breath basis. The instruments were calibrated before every test and were corrected for humidity, room temperature and barometric pressure according to the manufacturer's protocol. The work-rate increased continuously as a ramp function by augmenting the speed and grade of the treadmill according to the Naughton protocol. Patients exercised to a symptom-limited maximum. Heart rate and electrocardiogram were recorded continuously during exercise and blood pressure was measured at rest, every 2 min during exercise, and upon completion of exercise. Peak-oxygen consumption was defined as the highest value of oxygen uptake attained in the final 20 s of exercise when the respiratory exchange ratio was >1.0.

2.3. Chronotropic Incompetence
We employed a commonly applied definition for CI, which is an inability to reach 80% of MPHR6. Maximal predicted heart rate was calculated using Astrand's formula which quantifies MPHR in the following manner: 220-age [13].

The Chronotropic Responsiveness Index (CRI) was calculated using the following formula: (baseline heart rate–peak heart rate)/Log (baseline norepinephrine–peak norepinephrine) [12,14].

2.4. Measurement of norepinephrine
Following an overnight fast including medications, an 18- or 20-gauge angiocatheter was inserted into a forearm vein without the use of a tourniquet. A total of 30 cm3 of venous blood was collected in EDTA vials: 15 cm3 after 30 min of supine rest and an additional 15 cm3 during peak exercise. Samples were stored on ice until centrifugation and then frozen immediately at –80 °C. Norepinephrine was measured using high performance liquid chromatography [15].

2.5. Statistical analysis
All analyses were performed using SAS software. Data are expressed as means±SD for continuous variables and frequency distributions for categorical variables. Student's t-test or Wilcoxon rank sum test was used to compare continuous variables of two groups, and ANOVA was used to compare continuous variables of 3 or more groups. Trend analysis was performed using Cochran-Armitage test. To compare categorical data, Chi-square test or Fisher's exact test was used as appropriate. Multiple logistic regression analysis was used to demonstrate the association between VO2 and CI while adjusting for other confounders. All tests are 2-sided, and a p-value <0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Prevalence of CI and association with beta-blockade and exercise capacity (Cohort 1)
CI was present in 128 of the 278 subjects (46%). Baseline demographic and clinical data as well as the frequency of beta-blocker use (74% vs. 71%, p=0.51) were comparable in subjects with and without CI. However, peak VO2 was significantly lower in subjects with CI (15.4 vs. 19.9 ml/kg/min, p=0.002, Table 1). This relationship was the same in ischaemic and non-ischaemic subjects.


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  		Table 1 Baseline characteristics for Cohort 1 stratified by CI

 
When stratifying subjects according to peak VO2, prevalence of CI was highest among subjects with the most impaired exercise capacity (72%, 48%, and 24% for peak VO2<14.0, 14.0-20.0, and >20.0 ml/kg/min respectively, (p<0.0001; Fig. 1). Subjects with lower peak VO2 were slightly older, more likely to be female, have ischaemic cardiomyopathy and less likely to be on chronic beta-blockade (Table 2). After adjusting for these variables in multiple logistic regression analysis, the association of peak VO2 and CI remained highly significant (p<0.001).


Figure 01
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  		Fig. 1 Cohort 1: Prevalence of Chronotropic Incompetence.

 


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  		Table 2 Baseline characteristics of Cohort 1 stratified by peak-oxygen consumption

 
Recognizing that CI is a categorical variable arbitrarily defined here as the inability to reach 80% MPHR, we also performed linear regression analysis using the continuous variables %MPHR and peak VO2 to examine the association of CI and exercise capacity. This analysis revealed a significant interaction (MPHR%=60.2+1.1*VO2, p<0.0001).

To examine whether subjects with a lower VO2 had lower peak exercise heart rates (i.e. CI) simply due to shorter exercise times, we compared exercise times and generated two point acceleration slopes for subjects and without CI stratified by beta-blocker use (Fig. 2). While exercise time was indeed shorter in subjects with CI, heart rate acceleration slopes were less steep (p<0.001) in subjects with CI irrespective of beta-blocker use.


Figure 02
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  		Fig. 2 Heart rate slope is abnormal in CI irrespective of beta-blockade. p<0.001 for the difference in slope between subjects with CI and those without CI. CI: Chronotropic Incompetence. BB: Beta-blocker.

 
3.2. Prospective investigation of NE release and Chronotropic Responsiveness Index to investigate mechanisms of CI in subjects on chronic beta-blocker therapy (Cohort 2)
Thirty subjects met inclusion criteria and agreed to participate in this study; six subjects did not reach an RER >1.0 and were excluded from further analysis. CI was present in 12 of 24 subjects. Demographic and clinical characteristics including beta-blocker dose were not different between subjects with and without CI (Table 3). However, exercise induced NE release trended to be lower (1687±911 vs. 2593±1451 pg/ml p=0.08) and Chronotropic Responsiveness Index, a measure of post-synaptic beta-receptor sensitivity to NE, was significantly lower in subjects with CI (CRI 12.7±5.7 vs. 22.1±4.7, p=0.002).


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  		Table 3 Demographics and clinical characteristics for Cohort 2

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
We examined the association of CI, beta-blockers and functional capacity in 278 subjects with systolic CHF and explored the mechanisms of CI in 24 separate subjects on chronic beta-blockade. Our principal findings are as follows. First, the prevalence of CI is highest in subjects with most advanced CHF and occurs in >70% of subjects with peak VO2 <14.0 ml/kg/min. Second, CI is equally prevalent in subjects receiving and not receiving chronic beta-blocker therapy. Third, in subjects treated chronically with beta-blockers, (and similar to findings by others in subjects not receiving beta-blockers [3,16]) attenuated NE release as well as post-synaptic beta-receptor desensitization are associated with and may mechanistically underlie CI. Fourth, the association of CI and peak VO2 is not simply explained by shorter exercise times, rather heart rate slope is blunted in subjects with CI irrespective of beta-blocker use.

To our knowledge, the current study is the largest to date examining the prevalence of CI in CHF. Our findings regarding the prevalence of CI in the group of subjects with VO2 ≥14.0 ml/kg/min are concordant with prior studies reporting CI to occur in 30-50% of subjects with CHF. However, the low mean peak VO2 of our cohort allowed us to evaluate a substantial number of subjects (n=75) with markedly reduced VO2 (<14.0 ml/kg/min). When examining this group of subjects with more advanced disease, CI was present in 72% and thus appears to be much more common than previously thought.

Regarding the absence of an interaction between CI and treatment with beta-blockers: Chronic use of beta-1 selective agents in subjects with CHF is associated with improved LV function, haemodynamics, and mortality [17] and it has been proposed that these changes are mediated through an increase in beta-1 receptor density [18]. The upregulation of myocardial beta-1 receptors has been shown to re-sensitize the myocardium to adrenergic stimulation with dobutamine [19] and, if a similar upregulation of sinoatrial beta-1 receptors took place, may partially or fully restore chronotropic competence. CI should then be less prevalent in subjects chronically treated with beta-blockers. Our results in 278 patients with CHF, albeit cross-sectional, are not consistent with such an hypothesis but corroborate the (to our knowledge only) longitudinal study examining this topic by Castro et al. [20] in which 6 months treatment with carvedilol increased LVEF, but had no effect on noradrenaline release or chronotropic responsiveness. This data could be consistent with upregulation of myocardial (thereby increasing LVEF) but not sinoatrial beta-1 receptors during chronic beta-blockade in CHF, although some uncertainty exists as to whether the non-selective beta-blocker carvedilol upregulates myocardial beta-receptors at all [21]. Furthermore, given the strong association of peak VO2 and CI, it is important to recognize that subjects in Castro's study had a mean peak VO2 of 17.1 ml/kg/min and at baseline reached 89% of MPHR, leaving little room for improvement. Whether different results could have been obtained with a selective beta-blocker is unknown. Lastly, our results are in contrast to findings by Witte et al. who reported that CI is more prevalent in subjects receiving chronic beta-blockade [6]. Importantly, their population had an average peak VO2 of 20 ml/kg/min and average % MPHR of 80-87% and in subjects classified as NYHA class III, or more advanced heart failure, there indeed did not seem to be a difference in the prevalence of CI between groups taking or not taking beta-blockers; the latter finding is in good agreement with our data. A prospective longitudinal study in subjects with advanced CHF and significant CI should be conducted to definitively answer whether or not long term beta-blockade modulates CI in advanced CHF. Until such a study is conducted, the prevailing evidence does not suggest a profound effect.

With regard to the mechanisms that underlie CI in patients chronically treated with beta-blockers, our data suggests that CI can at least in part be attributed to both an attenuated norepinephrine release during exercise and post-synaptic beta-receptor desensitization. Colucci et al. demonstrated almost two decades ago that post-synaptic beta-receptors are desensitized in subjects with CHF [3]. In a population of subjects not receiving beta-blockers, they reported that "the ratio of exercise increments in heart rate and norepinephrine, an indirect index of sinoatrial node sympathetic responsiveness, was markedly reduced in CHF patients and was inversely related to the severity of exercise impairment". Our data obtained in the modern era in subjects receiving chronic beta-blockade are concordant with Colucci et al.'s findings. Thus, it appears that CI is an intrinsic component of disease progression in systolic CHF and, especially in advanced stages, occurs irrespective of beta-blockade. Given the substantial morbidity and mortality benefits associated with beta-blockade in systolic CHF [22], this observation is of particular relevance when contemplating discontinuation of beta-blockade to restore chronotropic competence. The latter has been suggested for subjects with CI and heart failure with preserved systolic function [8].

What is the contribution of CI to exercise intolerance in CHF and is it conceivable that successful modulation of CI, possibly by atrial pacing, would improve exercise capacity? When comparing subjects with and without CI we observed a significantly lower peak VO2 in those subjects with CI and this may imply that CI significantly contributes to exercise intolerance. Indeed, Kindermann et al. have previously shown that it is possible to increase peak VO2 in subjects with CHF and CI by force pacing to 75% of MPHR [23]. Tse et al. reported improvements in exercise capacity activating a DDD-R mode in heart failure patients with CI receiving cardiac resynchronization therapy [9]. In our study, approximately one in three patients failed to reach 75% of MPHR and this occurred in 62% of subjects with a peak VO2 less than 14.0 ml/kg/min. Thus, our data suggests that CI is a potential therapeutic target in the majority of patients with advanced systolic CHF.

Importantly, whether CI represents a protective or maladaptive response to severe heart failure remains to be fully elucidated prior to investigating the effects of pharmacological or pacing-based interventions. Simply increasing heart rates may not be advantageous in the long term in subjects with CHF as was powerfully illustrated in the DAVID trial [24]. Here, investigators found significant increases in mortality when comparing a VVI-40 mode to DDD-R70. In the former group, ventricular backup pacing accounted for 1% of heart beats whereas subjects in the DDD-R70 group where paced nearly 60% of the time at a minimum rate of 70. Subjects randomised to the DDD-R70 mode had significantly higher morbidity and mortality. Higher heart rates, but also induction of ventricular dyssynchrony with ventricular pacing may explain this adverse finding.

Our data and their interpretation are in principle limited by the cross-sectional nature of this study and absence of randomisation to beta-blockade. With these limitations in mind, we report that CI occurs in >70% of subjects with advanced CHF, is equally prevalent in subjects receiving/not receiving chronic beta-blockade, and is associated with impaired exercise induced NE release as well as post-synaptic beta-receptor desensitization. Modulation of CI using atrial pacing without induction of dyssynchrony should be further explored and may prove to be a worthy therapeutic intervention in a large proportion of patients with advanced CHF. Prior studies have demonstrated that force pacing up to 75% of MPHR, but not above this level, increases peak VO2 in subjects with CHF and CI [23]. Consequently, pacer based CI modulation may be most beneficial when limited to low levels of exercise. Furthermore, given the substantial morbidity and mortality benefit conferred by beta-blockers in systolic CHF, possible differential effects of beta-blockers on sinoatrial and myocardial beta-receptors, as well as the absence of a strong association between beta-blockade and CI reported here, treatment of CI should be attempted in the presence of beta-blockade.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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H. Nagele, W. Rodiger, and M. A. Castel
Rate-responsive pacing in patients with heart failure: long-term results of a randomized study
Europace, October 1, 2008; 10(10): 1182 - 1188.
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