Author + information
- Received October 20, 2015
- Revision received February 8, 2016
- Accepted February 9, 2016
- Published online April 26, 2016.
- Haqeel A. Jamil, PhDa,
- John Gierula, BScb,
- Maria F. Paton, BSc, MSca,
- Roo Byrom, BSca,
- Judith E. Lowry, BSc, MSca,
- Richard M. Cubbon, PhDa,
- David A. Cairns, PhDb,
- Mark T. Kearney, MDa and
- Klaus K. Witte, MDa,∗ ()
- aLeeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
- bClinical Trials Research Unit, Leeds Institute of Clinical Trials Research, Leeds, United Kingdom
- ↵∗Reprint requests and correspondence:
Dr. Klaus K. Witte, Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre (MCRC), Leeds Institute of Cardiovascular and Metabolic Medicine, LIGHT building, University of Leeds, Clarendon Way, Leeds LS2 9JT, United Kingdom.
Background Limited heart rate (HR) rise (HRR) during exercise, known as chronotropic incompetence (CI), is commonly observed in chronic heart failure (CHF). HRR is closely related to workload, the limitation of which is characteristic of CHF. Whether CI is a causal factor for exercise intolerance, or simply an associated feature remains unknown.
Objectives This study sought to clarify the role of the HR on exercise capacity in CHF.
Methods This series of investigations consisted of a retrospective cohort study and 2 interventional randomized crossover studies to assess: 1) the relationship between HRR and exercise capacity in CHF; and 2) the effect of increasing and lowering HR on exercise capacity in CHF as assessed by symptom-limited treadmill exercise testing and measurement of peak oxygen consumption in patients with CHF due to left ventricular systolic dysfunction.
Results The 3 key findings were: 1) the association of exercise capacity and HRR is much weaker in severe CHF compared to normal left ventricular function; 2) increasing HRR using rate-adaptive pacing (versus fixed-rate pacing) in unselected patients with CHF does not improve peak exercise capacity; and 3) acutely lowering baseline and peak HR by adjusting pacemaker variables in conjunction with a single dose of ivabradine does not adversely affect exercise capacity in unselected CHF patients.
Conclusions The data refute the contention that CI contributes to impaired exercise capacity in CHF. This finding has widespread implications for pacemaker programming and the use of heart-rate lowering agents. (The Influence of Heart Rate Limitation on Exercise Tolerance in Pacemaker Patients [TREPPE]; NCT02247245)
Chronic heart failure (CHF) due to left ventricular systolic dysfunction (LVSD) is associated with greatly reduced exercise tolerance due to fatigue or shortness of breath (1). A common additional feature is chronotropic incompetence (CI), a failure of the heart rate (HR) to increase during exercise. CI is proposed by many to be a major contributor to exercise intolerance (2,3). CI is defined as either a failure of the peak heart rate (PHR) to reach an arbitrary percentage (usually 80% or 90%) of the age-predicted maximum, or a reduction in the ratio of HR reserve to metabolic reserve (chronotropic index) (4), where a ratio below 0.8 indicates CI, irrespective of age, fitness, or functional capacity (5).
Rate-adaptive cardiac pacing was developed to treat CI (6,7). In patients receiving standard pacemakers for bradycardia without CHF, this programming mode is associated with an increase in cardiac output during exercise (8), and better quality of life (9–11), but inconsistent improvements in exercise capacity, compared to fixed-rate pacing (12,13). Additionally, rate-adaptive pacing in CHF patients may worsen prognosis and cardiac function (14,15).
Despite evidence showing benefits on all-cause mortality with pharmacologically reduced resting heart rate (RHR) (16,17), many patients do not reach optimal doses of HR lowering agents, possibly because of a fear of inducing more exercise intolerance and worsening symptoms (17,18).
Previous studies exploring the relationship between CI and exercise capacity have conflicting results because of difficulties in adjusting HR independently of other potential contributing factors. Although there seems to be a strong association, definite causation is unproven (19–21). The aim of this investigation was to clarify the effect of HR on exercise capacity in patients with LVSD.
This work describes the findings of 1 observational and 2 interventional studies.
Retrospective cohort analysis was performed for consecutive patients referred for cardiopulmonary exercise testing (CPX) from Leeds Outpatient Services between August 2011 and August 2012. All patients underwent a transthoracic echocardiogram (TTE) to exclude untreated valvular disease. Inclusion in the study required the ability to perform an exercise test. Exclusion criteria included exertion-limiting angina pectoris and musculoskeletal limitation to exercise. Patients in whom we suspect heart failure with preserved ejection fraction (EF) due to abnormalities of diastolic function do not routinely undergo CPX testing and were excluded.
We divided patients into groups based on resting left ventricular function. The “no LVSD” group had a normal resting echocardiogram, no evidence of systolic or diastolic dysfunction using British Society of Echocardiography criteria, EF >50%, and no identified cause for exercise intolerance. Patients with LVSD and no other cause of exercise limitation were divided into those with “mild-moderate LVSD” (resting EF >35% but ≤50%) and “severe LVSD” (resting EF ≤35%).
We undertook 2 randomized crossover studies in patients with stable CHF and pacemakers or defibrillators. Patients and physicians were blinded to both pacemaker settings and test results. The first study examined whether rate-adaptive pacing in CHF patients increased exercise capacity, and the second study examined whether HR limitation using a pure HR lowering agent (in patients with sinus rhythm [SR]) or pacemaker programming (in patients with atrial fibrillation [AF]) impaired exercise capacity.
Patients invited to take part in both interventional studies had stable CHF due to moderate-severe LVSD (left ventricular EF ≤45%), persistent symptoms of breathlessness or fatigue and either a cardiac resynchronization therapy (CRT) device or a standard right ventricular pacemaker or defibrillator. Devices had stable lead variables, and either >95% bi-ventricular pacing (in CRT devices) or 0% ventricular pacing (in non-CRT devices), and all had been implanted for standard indications at least 3 months before the study. Patients also had to be receiving optimally tolerated medical therapy with no change in medication or other invasive cardiac procedures for at least 3 months.
We excluded patients who were dependent on atrial pacing or were unable to give informed consent. Other exclusions were significant cardiovascular comorbidities limiting exercise capacity, such as uncontrolled angina, peripheral vascular disease, severe valvular dysfunction, and noncardiac conditions such as significant airway disease and musculoskeletal abnormalities that could restrict walking on a treadmill.
Patients currently receiving ivabradine, or with contraindications to ivabradine, such as severe hepatic impairment, significant renal impairment (creatinine clearance <15 ml·min−1) and long QT syndrome, were also excluded.
Ethical approval was granted by the Health Research Authority (National Research Ethics Service Centre: South Yorkshire REC: 13/YH/0144). Written informed consent was obtained from all participants.
Interventional study 1: increasing exercise HR
Subjects were tested on 2 occasions at the same time of the day, 1 week apart. Before each test, their pacemakers were interrogated and randomly assigned to rate-adaptive pacing (augmented HR rise: rate-response programmed “on”) or fixed-rate pacing (intrinsic HR rise: rate response “off”). Sensor sensitivity was set to maximum, and peak paced HR was determined using the “220 − age” method (22).
Interventional study 2: reducing exercise HR
Subjects were tested on 2 occasions at the same time of the day, 1 week apart. As the peak plasma concentration time after a single oral dose of ivabradine is between 60 min and 120 min, patients in SR were randomized to receive either a single 7.5-mg dose of ivabradine or matching placebo 2 h before each CPX test (23). Patients with AF were randomized by the unblinded cardiac physiologist to either a base rate of 30 beats/min or usual settings (base rate of 60 beats/min).
Laboratory arrangement and exercise protocol
Subjects for both interventional studies were exercised using the Bruce protocol, modified by the addition of a “stage 0” at onset consisting of 3 min of exercise at 1.61 km·h−1 (1 mile·h−1) with a 5% gradient. Expired air was collected and metabolic gas exchange analysis performed (Vmax 29, Sensormedics, Yorba Linda, California) throughout the test. HR, oxygen uptake (Vo2) (ml·kg·min−1) and carbon dioxide output (Vco2) (ml·kg·min−1) were recorded as 15-s averages. Anaerobic threshold (AT) was calculated using the Vo2/Vco2 slope method.
The CPX equipment was recalibrated before every exercise test. All test subjects were encouraged to exercise to exhaustion before starting the test, and no further motivation or instructions were given. Participants indicated a score for dyspnea and fatigue from 0 (no symptoms) to 10 (maximal symptoms) using the standardized Borg scoring system after each stage (24).
To maintain blinding, the continuous 12-lead electrocardiogram (ECG) monitor was obscured throughout the test (and recovery phase) from subjects and the supervising physician. Only the cardiac physiologist was aware of the programming mode or testing arm for the duration of the studies. He monitored the ECG throughout the study and reprogrammed the pacemaker to its original settings at the end of every visit.
Sample size calculation
For study 1, we calculated that to detect a clinically important peak Vo2 (pVo2) increase of 1.5 ml·kg·min−1 (an increase of 10%) with 80% power, and a 2-sided alpha of 0.05, we would need a minimum of 22 subjects in the CHF patients with AF, and a minimum of 38 in those with SR. To allow for dropouts, recruitment targets were 25 with AF and 50 with SR.
For study 2, the predicted group size to demonstrate a clinically important change was revised after post hoc analysis of study 1 demonstrated higher pVo2 values for both SR and AF than expected. A minimum of 12 subjects was needed in the AF group, and a minimum of 20 in the SR group. To allow for dropouts, recruitment targets were 15 with AF and 25 with SR.
Data were analyzed using the Statistical Package for the Social Sciences (SPSS version 21, IBM Corporation, Armonk, New York), R: A Language and Environment for Statistical Computing (version 3.2.3, R Development Core Team, Vienna, Austria), and SAS (version 9.4, SAS Institute Inc., Cary, North Carolina).
Normality for all continuous variables was tested using the Shapiro-Wilk test. Normally distributed continuous variables were reported as mean ± SD, and non-normally distributed continuous variables as median (interquartile range [IQR]). Subsequently, associations between groups or interventions and baseline characteristics were assessed using either analysis of variance (ANOVA) and the 2-sample Student t test for normally distributed values, or the Kruskal-Wallis H test (1-way ANOVA of ranks) for non-normally distributed data. Similar associations with categorical variables were analyzed using the chi-square test for contingency tables.
The observational study was analyzed using a linear mixed model with random intercepts and slope parameters and compared with the model with only random intercepts using the likelihood ratio test. Linear models regressing peak oxygen consumption on HR rise (HRR) were estimated using least squares for inclusion in graphical displays.
Once a familiarization test has been performed, a peak exercise test is not a training stimulus. We have previously performed up to 5 exercise tests in consecutive weeks in patients with CHF and controls, with no longitudinal effects (25). However, to account for any carryover effects, the interventional crossover studies were analyzed using a linear mixed model with a random effect for patient. For each endpoint Yijk (e.g., pVo2) under consideration in the study:where εijk ∼ N(0,σ2ε), αk ∼ N(0,σ2α), μ is the overall mean, τ is the treatment effect, π is the period effect, and λ is the carryover effect (which is mathematically identical to an interaction term between treatment and period). This model was estimated using PROC MIXED in SAS and least squares means estimated for each of these terms and their differences.
All statistical tests were 2-sided and any p value <0.05 was called as statistically significant.
During the prospective data collection period, 214 patients underwent outpatient clinical assessment, 12 lead ECG, CPX testing, and echocardiography. Of these, 19 were excluded because of significant comorbidities (n = 12) and poor quality tests (n = 7) leaving 195 patients. There were 48 participants in the “no LVSD” group, 57 in the “mild-moderate LVSD” group, and 90 in the “severe LVSD” group. Baseline characteristics are shown in Table 1.
In subjects with no LVSD there was a strong correlation between HRR and pVo2 (linear regression, r2 = 0.420, ANOVA F value <0.01), but this relationship was much less obvious in patients with CHF (r2 = 0.366, ANOVA F value <0.01 for mild-moderate LVSD and r2 = 0.179, ANOVA F value <0.01 for severe LVSD). These associations are further demonstrated by the differing slope terms in linear models for each group (Figure 1). A linear mixed model with random intercepts and slopes for each group compared with a mixed model with only random intercepts was shown to fit the observational study data better (likelihood ratio test chi-square = 19.0, p < 10−4). This indicates that the slope varies between the groups, suggesting distinctions in this relationship even within the CHF cohort—with a less steep slope in those with severe LVSD compared to those with mild-moderate LVSD and no LVSD (Figure 1).
Chronotropic index <0.8 was present in 107 of the heart failure cohort. Patients with CI had lower exercise time (477 s, 95% CI: 425 to 539 vs. 382 s, 95% CI: 342 to 422; p < 0.001), pVo2 (16.3 ml·kg·min−1, 95% CI: 14.9 to 17.7 vs. 15.9 ml·kg·min−1, 95% CI: 14.8 to 17.0; p < 0.001) and AT (13.7 ml·kg·min−1, 95% CI: 13.0 to 14.3 vs. 12.1 ml·kg·min−1, 95% CI: 11.5 to 12.7; p < 0.001), despite similar EF, comorbidities, and medications (Figure 2).
Interventional study 1: increasing exercise HR
Seventy-nine patients were enrolled; 53 with SR and 26 with AF. Baseline characteristics are shown in Table 2 and analysis for primary and all secondary endpoints are shown in Online Table 1 (SR) and Online Table 2 (AF).
In subjects with SR, rate-adaptive pacing led to higher HR at submaximal (p = 0.003) and maximal exercise (p < 0.001) (Figure 3), but no changes in any CPX variables including pVo2 (17.0 ml·kg·min−1, 95% CI: 15.6 to 18.5 vs. 16.6 ml·kg·min−1, 95% CI: 15.2 to 18.1; p = 0.350), exercise time (459 s, 95% CI: 390 to 526 vs. 464 s, 95% CI: 397 to 533; p = 0.644), AT (12.8 ml·kg·min−1, 95% CI: 11.8 to 13.8 vs. 12.2 ml·kg·min−1, 95% CI: 11.2 to 13.2, p = 0.075), Ve/Vco2 slope (to peak: 35.7, 95% CI: 32.8 to 38.5 vs. 36.3, 95% CI: 33.4 to 39.1; p = 0.533; to AT: 30.4, 95% CI: 28.1 to 32.9 vs. 31.5, 95% CI: 29.1 to 33.9; p = 0.353), respiratory exchange ratio (RER; 1.09, 95% CI: 1.05 to 1.12 vs. 1.09, 95% CI: 1.06 to 1.12; p = 0.806), mean oxygen pulse (12.4 [3.5] vs. 11.7 [3.5]), p = 0.605), end-tidal oxygen tension (PETo2; 111 mm Hg, 95% CI: 107.9 to 114.0 vs. 112 mm Hg, 95% CI: 109.0 to 115.2; p = 0.287), or perceived exertion level (Borg) scores (for shortness of breath; 4.2, 95% CI: 3.8 to 4.6 vs. 4.1, 95% CI: 3.6 to 4.5; p = 0.458; and leg weakness; 4.6, 95% CI: 4.0 to 5.3 vs. 4.8, 95% CI: 4.2 to 5.5; p = 0.494).
All patients had peak exertional HR <90% peak predicted HR. There was no heterogeneity in change in exercise response between those patients with significant CI at baseline (chronotropic index <0.8; n = 66) versus those without (n = 13).
In subjects with AF, rate-adaptive pacing led to higher HR at AT (p = 0.035) and peak exercise (p < 0.001) (Figure 3). Although this was associated with a small increase in pVo2 (15.3 ml·kg·min−1, 95% CI: 13.8 to 16.7 vs. 14.2 ml·kg·min−1, 95% CI: 12.7 to 15.8; p = 0.058), there was no change in the exercise time (417 s, 95% CI: 323 to 511 vs. 401 s, 95% CI: 307 to 495; p = 0.396), the relationship between ventilation and carbon dioxide output (Ve/Vco2 slope) (to peak: 37.3, 95% CI: 33.3 to 41.2 vs. 39.2, 95% CI: 35.3 to 43.2, p = 0.152; to AT: 31.3 ml·kg·min−1, 95% CI: 27.2 to 35.4 vs. 33.1 ml·kg·min−1, 95% CI: 29.0 to 37.2; p = 0.092), RER (1.15, 95% CI: 1.08 to 1.21 vs. 1.13, 95% CI: 1.06 to 1.19; p = 0.568), oxygen pulse (12.9, 95% CI: 11.2 to 14.6 vs. 14.9, 95% CI: 13.2 to 16.6; p = 0.012), PETo2 (114 mm Hg, 95% CI: 110 to 117 vs. 117 mm Hg, 95% CI: 113 to 120; p = 0.060) or perceived exertion level (Borg) scores for shortness of breath (4.9, 95% CI: 4.1 to 5.7 vs. 4.4, 95% CI: 3.6 to 5.1; p = 0.0636) and leg weakness (5.2, 95% CI: 4.5 to 6.0 vs. 4.9, 95% CI: 4.1 to 5.6; p = 0.327).
Interventional study 2: lowering exercise HR
Forty patients were enrolled in this study; 26 with SR and 14 with AF. Baseline characteristics are shown in Table 3 and analyses for primary and secondary endpoints are shown in Online Table 3 for SR and Online Table 4 for AF.
In patients with SR, the use of ivabradine resulted in an HR reduction at rest (p < 0.001), submaximal exercise (p = 0.035), and at peak (p < 0.001) (Figure 4), with no effect on HRR (48 beats/min, 95% CI: 38 to 58 vs. 49 beats/min, 95% CI: 41 to 59; p = 0.588). There was no change in the overall exercise time (534 s, 95% CI: 431 to 639 vs. 554 s, 95% CI: 450 to 658; p = 0.396), oxygen pulse (14.4, 95% CI: 12.7 to 16.0 vs. 13.9, 95% CI: 12.2 to 15.5; p = 0.286), PETo2 (110 mm Hg, 95% CI: 107 to 113 vs. 111 mm Hg, 95% CI: 109 to 115; p = 0.560), oxygen consumption at AT (p = 0.700), and at peak (p = 0.588) (Figure 4). The symptom score profiles and all other measured CPX variables were similar in both tests.
In CHF patients with AF, reducing the pacemaker base rate resulted in significant differences in resting HR (p = 0.002) and HRR (p = 0.030) with no change in the chronotropic index (0.61, 95% CI: 0.46 to 0.76 vs. 0.66, 95% CI: 0.48 to 0.84; p = 0.6). When randomized to a lower resting HR, patients achieved a longer exercise time (434 s, 95% CI: 308 to 561 vs. 482 s, 95% CI: 356 to 609; p = 0.042) with no change in pVo2 (p = 0.207) or PETo2 (113 mm Hg, 95% CI: 110 to 117 vs. 114 mm Hg, 95% CI: 111 to 117; p = 0.061) (Figure 4). Symptoms score profiles and other measured CPX variables were not significantly different across the 2 tests.
Our study shows that CI is common in patients with CHF, and the prevalence is related to the severity of the LVSD. We have also shown that increasing HR in unselected patients with CHF does not improve exercise tolerance or improve symptoms, and conversely, that lowering HR does not worsen exercise tolerance or exercise-related symptoms (Central Illustration).
Among unselected patients with CHF due to LVSD, we found the prevalence of CI to be 73%, and even higher in patients with more severe disease as described by cardiac function. However, although our observational data demonstrate a strong positive correlation between HRR and peak oxygen consumption in patients without CHF, this relationship is much weaker in the CHF cohort, and flat in those with the most severe disease, suggesting that correcting the CI might not lead to improved exercise tolerance particularly in these most limited patients.
Previous studies have provided conflicting results. Although Al-Najjar et al. (2) and Jorde et al. (26) reported a relationship between exercise capacity on CPX testing and the presence of CI in stable CHF patients, this association was not seen by Roche et al. (19) and Clark et al. (27) who reported no significant difference in important exercise variables between CHF subjects with and without CI. We have also previously described a poor correlation between peak HR and exercise capacity in CHF patients (r = 0.003; p = 0.98), in contrast to the strong relationship seen in control subjects (r = 0.85, p < 0.001) (28).
The findings from our observational data stimulated the hypotheses for the subsequent intervention studies; that CI is not a contributor to exercise intolerance in unselected patients with CHF.
The first of the interventional studies demonstrated that increasing PHR to “correct” CI does not improve oxygen consumption, exercise time, or symptoms in CHF. In the presence of AF we found pVo2 to be a little higher but without change in exercise time or AT. CI thus seems to be a bystander rather than a contributor to exercise intolerance in patients with CHF. Tse et al. (29) found in 20 patients with CRT that rate-adaptive pacing led to an incremental benefit only in those with severe CI, but a worsening of exercise capacity in those with less severe CI. In contrast, our data do not allude to a heterogeneity of response to rate adaptive pacing across degrees of CI. Whether increasing heart rate by rate adaptive pacing leads to worse metabolic efficiency (as hinted at in our AF patients) is worthy of further exploration.
In our second interventional study, we found that reducing RHR did not result in worsening exercise capacity in either the SR or AF cohorts. In fact, starting at a lower RHR in AF resulted in higher HRR and longer exercise time, with similar pVo2, implying an increase in overall metabolic efficiency, and achieving greater workload for similar oxygen consumption.
Our findings are consistent with the results of a randomized placebo-controlled trial reported by Sarullo et al. (30). In that study, HR reduction by ivabradine in 60 CHF patients with LVSD resulted in dramatic increases in both endurance exercise time during a constant workload test (14.8 min vs. 28.2 min; p <0.05) and pVo2 on a graded maximal exercise test (13.5 ml/kg/min vs. 17.9 ml/kg/min; p <0.05). The CARVIVA HF (Effect of Carvedilol, Ivabradine or their combination on exercise capacity in patients with Heart Failure) trial using ivabradine alone or in combination with a beta-blocker also described greater walk distance in 6 minutes in CHF patients (31).
Patients with CHF have impaired biomechanical efficiency compared to controls (32). Reducing RHR may reduce the oxygen requirement per unit of work by reducing myocardial oxygen demand, and thereby increase overall metabolic efficiency (33). This may also be a mechanism by which HR reduction improves outcomes in patients with CHF (34,35).
The mechanical dysfunction and loss of metabolic capability that is characteristic of CHF is closely linked to the degree of abnormal myocardial calcium handling (36). Calcium cycling is a major determinant of cardiac contractility, and abnormalities thereof lead to reduction in the force-frequency relationship and impairment of the Bowditch effect (37,38). Calcium cycling is both dependent on, and a determinant of, HR (39). There may be an optimal HR range in CHF beyond which the limit for effective calcium handling is exceeded. A lower HR range could restore calcium homeostasis and improve myocardial energetics (40), and may be the mechanistic basis for our findings.
Our data suggest that the improved exercise capacity seen as a result of rate adaptive pacing in patients without heart failure (41) cannot be extrapolated into patients with heart failure, in whom there are strong prognostic benefits of HR limitation (42,43).
Patients with advanced HF symptoms, or who have other comorbidities that preclude treadmill-based exercise testing may not be referred for a CPX test by the clinician responsible for their care, leading to bias in patient selection. Our non-CHF group was younger than our CHF group; a common problem with comparisons of this type is finding enough “normal” older people.
Resting ventricular function was used to divide cohorts into groups of no LVSD, mild-moderate LVSD, and severe LVSD. EF has been shown to correlate poorly with exercise capacity. A better way to discriminate LVSD severity may have been to use questionnaires that assess the activities of daily living, 6-min walk tests, New York Heart Association (NYHA) functional class status or dose of diuretics required to control the LVSD symptoms. Nonetheless, LVSD treatment guidelines rely on echocardiographic EF measurements to stratify CHF severity and to guide treatment decisions. Hence, EF was chosen as the measure with which to separate the cohorts.
The groups in our observational study were not matched for height, weight, age, or level of training; all of which can affect pVo2. Although we cannot exclude the possibility of systematic differences in the level of motivation or encouragement from the technicians running the tests between subject groups, we believe that this is unlikely and was not borne out in the metabolic gas data, where the RER was >0.99 in all 3 groups.
Our interventional studies included only patients with pacemaker devices who may exhibit a different chronotropic response compared to those without indications for pacing, although CI had not been an indication in any of the CHF patients.
Our data are also limited by the bias introduced by enrolling patients who have previously completed a good quality exercise test. However, the observational data were collected in consecutive patients. Our use of a modified version of the Bruce protocol was dictated by a desire to use a consistent protocol for all patients, to allow us to compare exercise times rather than just metabolic gas analysis data, and the fact that treadmill-based activity is associated with greater upper body movement required for activation of the rate-response algorithms in pacemakers. We acknowledge that this exercise modality and protocol might not have been ideal for all of our patients, but on balance we feel the protocol choice did not materially alter our results. The early, low workload stage allowed even patients with the greatest limitation in exercise capacity to complete at least the first stage, reducing the bias towards less limited patients.
Finally, small increases in HR were seen in all tests, and we are unable to comment whether our observations would have been the same had there been no HR increases at all.
We found that the degree of HRR during exercise in patients with heart failure due to LVSD may not be important in determining exercise capacity. This has clinical implications for pharmacological and device treatment strategies. Although CI and exercise tolerance are related, correcting this in CHF patients is unnecessary and might have adverse metabolic effects. Physicians and their patients should be reassured that optimal doses of HR-lowering agents with the aim of achieving the best prognostic outcomes are unlikely to objectively worsen exercise capacity.
COMPETENCY IN MEDICAL KNOWLEDGE: Although chronotropic incompetence in patients with CHF is associated with functional limitation, medications that limit the HR range response to exercise do not compromise exercise capacity.
TRANSLATIONAL OUTLOOK: Further work is needed to define the optimum HR range for individual patients with heart failure and determine whether tailoring the HR response with a combination of medications and pacemaker settings can improve exercise tolerance.
The authors acknowledge the consistent administrative support provided by Mrs. Andrea Marchant and Miss Lisa Trueman that made this research possible. This research took place in the National Institute for Health Research Leeds Cardiovascular Clinical Research Facility at Leeds Teaching Hospitals NHS Trust.
For supplemental tables, please see the online version of this article.
The study was supported through an unrestricted research grant from Servier (UK) to Drs. Jamil and Witte. Dr. Kearney has received an unrestricted research grant from Medtronic Ltd. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Jamil and Gierula contributed equally to this work.
- Abbreviations and Acronyms
- atrial fibrillation
- anaerobic threshold
- chronic heart failure
- chronotropic incompetence
- cardiopulmonary exercise test
- heart rate
- heart rate rise
- left ventricular systolic dysfunction
- peak heart rate
- peak oxygen consumption
- resting heart rate
- sinus rhythm
- Received October 20, 2015.
- Revision received February 8, 2016.
- Accepted February 9, 2016.
- American College of Cardiology Foundation
- Hobbs F.D.,
- Kenkre J.E.,
- Roalfe A.K.,
- et al.
- Brubaker P.H.,
- Kitzman D.W.
- Trappe H.J.,
- Klein H.,
- Frank G.,
- Lichtlen P.R.
- Nagele H.,
- Rodiger W.,
- Castel M.A.
- Lele S.S.,
- Macfarlane D.,
- Morrison S.,
- Thomson H.,
- Khafagi F.,
- Frenneaux M.
- Witte K.K.,
- Cleland J.G.,
- Clark A.L.
- Witte K.K.,
- Thackray S.D.,
- Nikitin N.P.,
- et al.
- Tse H.F.,
- Siu C.W.,
- Lee K.L.,
- et al.
- Sarullo F.M.,
- Fazio G.,
- Puccio D.,
- et al.
- Boerth R.C.,
- Covell J.W.,
- Pool P.E.,
- Ross J. Jr..
- Mulieri L.A.,
- Hasenfuss G.,
- Leavitt B.,
- Allen P.D.,
- Alpert N.R.
- Haywood G.A.,
- Katritsis D.,
- Ward J.,
- Leigh-Jones M.,
- Ward D.E.,
- Camm A.J.
- Levine H.J.