Chronotropic incompetence and functional capacity in cardiovascular disease






Dalane W. KITZMAN, MD
Cardiology Section Wake Forest University
School of Medicine Winston-Salem USA

Chronotropic incompetence and functional capacity in cardiovascular disease


by D. W. Kitzman, USA



The important role of heart rate (HR) in cardiovascular disease is well established, but attention to HR has often been limited to discussion of resting HR or HR at peak exercise. This paper highlights the importance of evaluating HR profiles during and after exercise. The ability of the heart to increase HR to tightly match cardiac output to metabolic demand during exercise is critical to physical performance. The increase in HR during exercise is the largest contributor to the ability to perform physical work and therefore is an important determinant of quality of life. The high prevalence of impaired exercise HR response and its easy assessment in clinical practice provides the rationale for screening for inadequate HR responses during exercise testing and recovery after exercise. This condition is potentially treatable, and its management can lead to significant improvements in exercise tolerance and quality of life.

Medicographia. 2012;34:400-406 (see French abstract on page 406)


Contribution of heart rate to exercise performance

The ability to perform physical work is an important determinant of quality of life1 and is enabled by an increase in oxygen uptake (VO2).2 During maximal aerobic exercise in healthy persons, VO2 increases approximately 4-fold.2 This is achieved by a 2.2-fold increase in heart rate (HR), a 0.3-fold increase in stroke volume, and a 1.5-fold increase in arteriovenous oxygen difference.2 The increase in HR is thus the largest contributor to the ability to perform sustained aerobic exercise.3 Therefore, an abnormal HR response to exercise can be the primary cause of, or a significant contributor to, severe, symptomatic exercise intolerance.

Heart rate control and recovery

Instantaneous HR reflects the dynamic balance between the sympathetic and parasympathetic divisions of the autonomic nervous system. An intact HR response is critical to tightly match a subject’s cardiac output to metabolic demands during exertion.4 Failure to achieve maximal HR, inadequate submaximal HR, or HR instability during exertion are all examples of impaired chronotropic response. These conditions are relatively common in patients with sick sinus syndrome, atrioventricular block, coronary artery disease, and heart failure (HF).4 Immediately after the termination of exertion, sympathetic withdrawal and increased parasympathetic tone to the sinoatrial node combine to cause a rapid decline in HR. A delayed recovery of HR after exertion is independently associated with increased all-cause mortality in a variety of asymptomatic and diseased populations.5,6 In contrast, highly trainedathletes often display a rapid and profound drop in HR of ≥30 to 50 beats during the first minute of recovery from strenuous exertion.7 The Framingham Offspring study and the MRFIT study (Multiple Risk Factor Intervention Trial) demonstrated that a delayed HR recovery is an independent predictor of all-cause death in asymptomatic persons.8 In an important recent study, Jolly et al showed that exercise training improved HR recovery in a group of over 1000 patients with cardiovascular disease undergoing phase 2 cardiac rehabilitation.9 Patients with abnormal HR recovery at baseline and whose HR recovery was normalized with exercise training had a mortality similar to that of individuals with normal baseline HR recovery.


Figure 1
Figure 1. Relationship between age and maximal heart rate (group mean values) obtained from a meta-analysis including 18 712 subjects.

From these data, a new prediction equation was proposed: peak heart rate =
206 – (0.88 × age).
Adapted from reference 17: Tanaka et al. JACC. 2001;37:153-156. © 2001, American College of Cardiology.


Effect of age and gender on the maximal HR response to exercise

There is no change in resting HR with adult aging. However, in healthy men and women, there is a marked age-related decrease in maximum HR in response to exercise that is inexorable and predictable and occurs in other mammalian species as well as humans.3,10,11 The age-related decline in maximal HR is the most substantial biological age–related change in cardiac function, both in magnitude and consequence.3,12,13 It is primarily responsible for the age-related decline in peak aerobic exercise capacity.3,13 Starting from early adulthood, maximal HR declines with age at a rate of approximately 0.7 beats per minute (bpm) per year in healthy sedentary, recreationally active, and endurance exercise–trained adults.14 Though the mechanism(s) of this decline are not fully understood, dual-blockade studies show that intrinsic HR declines by 5 to 6 bpm for each decade of age such that the resting HR of an 80-year-old is not much slower than the intrinsic HR.10 This indicates that there is reduced and minimal parasympathetic tone at rest. This is supported by the fact that the increase in HR after atropine in an older person is less than half that in the young.12

There are also significant alterations in the sympathetic influence on HR response to exercise with aging, with increased circulating catecholamines and reduced responsiveness.12 Doses of isoproterenol that increase HR by 25 bpm in young healthy men produce an increase of only 10 bpm in older persons.12 The normal, age-related decline in maximal HR during exercise is not significantly modified by vigorous exercise training, suggesting that it is not due to the age-related decline in physical activity level.10 It also does not appear to be due to inadequate sympathetic stimulation, since both serum norepinephrine and epinephrine are increased rather than decreased at rest in healthy elderly individuals. Furthermore, with exertion or stress, catecholamines increase even more than in young persons under the same stress conditions.

The traditional equation to predict normal maximal HR (220 – age), was developed based on studies primarily conducted in middle-aged men, some of whom had known coronary artery disease and were taking β-blockers.15,16 This equation has large intersubject variability with a standard deviation of 11 bpm17 that increases to 40 bpm in patients with coronary heart disease receiving β-blockers.18 An alternative formula from Tanaka et al (208 – 0.7 × age) is becoming more accepted for determining age-predicted maximal HR (APMHR) even though it may still underpredict APMHR in older adults (Figure 1).17

Several earlier studies suggested that gender affects the HR trajectory during exercise and recovery, and that the traditional equation (220 – age) overestimates maximal HR in younger women, but underestimates it in older women.15,17 A meta- analysis indicated that maximal HR is unaffected by gender.17 A large prospective study in over 5000 asymptomatic women showed that the traditional equation significantly overestimates maximal HR and thus proposed a new equation where maximal HR = 206 – (0.88 × age).15

Brawner et al18 demonstrated that the 220 – age equation is not valid in patients with coronary heart disease taking β-adrenergic blockade therapy and subsequently developed the equation [164 – (0.7 × age)] for this population.





Figure 2
Figure 2. Relationship between exercise-induced change in heart rate (ΔHR) and peak oxygen consumption (peak VO2) in β-blocked and not β-blocked patients.

There is a significant relationship between ΔHR during exercise and peak VO2 in patients with heart failure and severely reduced ejection fraction (HFrEF), but there is no significant difference in this relationship between patients taking -blockers (right panel) and those not taking them (left panel). “r” values are for Spearman analysis.
Adapted from reference 24: Magri et al. Cardiovasc Ther. 2012;30:100-108. © 2010, Blackwell Publishing Ltd.


Definition, criteria, and measurement of chronotropic incompetence

Chronotropic incompetence (CI) is most commonly diagnosed when HR fails to reach an arbitrary percentage (either 85%, 80%, or less commonly, 70%) of the APMHR (usually based on the 220 – age equation described earlier) obtained during an incremental dynamic exercise test.14,19,20 CI can also be determined by the HR reserve, which is the change in HR from rest to peak exercise during an exercise test. Since the proportion of HR achieved during exercise depends in part on the resting HR, the chronotropic response to exercise can also be assessed as the fraction of the HR achieved at maximal effort. Thus, adjusted HR reserve, determined from the change in HR from rest to peak exercise divided by the difference between resting HR and APMHR has been commonly used.21 The majority of studies have used failure to obtain ≥80% of the HR reserve obtained during a graded exercise test as the primary criterion for CI.

However, before concluding that a patient has CI, it is important to consider their level of effort and reasons for terminating the exercise test. Patients should be encouraged to continue exercising until true symptom-limited (exhaustive) maximal levels are achieved. Symptoms and subjective ratings of perceived exertion (RPE) can provide an estimate of exertion levels. However, the respiratory exchange ratio (RER, ie, volume of carbon dioxide produced/volume of oxygen consumed) obtained from expired respiratory gas analysis at peak exertion during the exercise test, is the most definitive, objective, reliable, clinically available measure of the physiological level of effort during exercise. RER is a continuous variable, ranging from <0.85 at quiet rest to >1.20 during intense, exhaustive exercise. Higher RER values increase confidence that maximal effort was achieved while RER <1.05 at peak exercise suggests submaximal effort and should lead to caution in diagnosing CI.

Figure 3
Figure 3. Heart rate slopes for subjects with heart failure with and without chronotropic incompetence stratified by β-blocker use.

In patients with heart failure, β-blockers (BB) do not significantly impact the relationship between heart rate and exercise time, regardless of whether chronotropic incompetence (CI) is present.
Adapted from reference 25: Jorde et al. Eur J Heart Fail. 2008;10:96-101. © 2007, European Society of Cardiology.



Wilkoff et al utilized the expired gas analysis technique to more objectively evaluate CI using the relationship between HR and VO2 during exercise.22 With this approach, the metabolic chronotropic relationship (MCR) is calculated from the ratio of the HR reserve to the metabolic reserve during submaximal exercise. The advantage of using the MCR is that it adjusts for age, physical fitness, and functional capacity and it appears to be unaffected by the exercise testing mode or protocol. In normal adults, the percentage of HR reserve achieved during exercise equals the percentage of metabolic reserve achieved. This physiological concept allows determination of whether a single HR achieved at any point during an exercise study is consistent with normal chronotropic function. A specific CI exercise testing protocol that evaluates the MCR relationship from 2 stages of a treadmill protocol has been employed in some laboratories.22

Effect of medications and other confounding influences on chronotropic incompetence

Many commonly used cardiovascular medications including β-blockers, digitalis, calcium channel blockers, amiodarone, and others can confound the determination of CI. β-Blockers may result in pharmacologically induced CI and obscure identificationof an underlying intrinsic abnormality in neural balance. In one study,23 a suitable threshold for CI in HF patients using β-blockers was found to be ≤62% of APHRR. Using this lower HR threshold, CI could be reliably identified and was found to be an independent predictor of death.23 Care should be taken before applying these criteria to ensure that the patient is on a nontrivial dose and is compliant with the medication. The use of separate CI criteria for patients taking β-blocker medications has been challenged by other studies that failed to demonstrate any effect of β-blockers, including at high dose, on the occurrence of CI.24 Figure 2 shows the similar relationship between HR reserve and VO2 at peak exercise (peak VO2) in HF patients who were either taking or not taking β-blockers. Similarly, Jorde and colleagues examined the relationship between exercise time and HR during treadmill exercise testing in HF patients.25 As seen in Figure 3, the HR slope is abnormal in HF patients with CI, yet β-blockers have no impact on this relationship in these patients.26 Chronic treatment of HF patients with β-blockers may paradoxically improve chronotropic response by decreasing sympathetic tone and/or by increasing β-receptor activity.27 Furthermore, there appears to be potentially important differences between β-blockers in the relationship between HR reduction and exercise capacity.28

Criteria for the diagnosis of CI in the presence of atrial fibrillation have not been established. Exercise testing can be used to assess the adequacy of response following pacemaker insertion for CI by reprogramming or suspending the device with a magnet, taking care to ensure the patient is not completely pacemaker-dependent beforehand.

Contribution of impaired HR response to exercise intolerance in HF

A hallmark of chronic HF is a markedly reduced capacity for physical exertion, with a subsequent 15% to 40% reduction in peak VO2 compared with healthy matched controls.29 We have shown that patients with HF and preserved ejection fraction (HFpEF) have similar reductions in peak VO2, exercise time, ventilatory anaerobic threshold, and 6-minute walk distance as patients with HF and severely reduced ejection fraction (HFrEF).30


Figure 4
Figure 4. Relationship of heart rate reserve (HRR) to peak exercise oxygen consumption (peak VO2) in older patients with heart failure and either severely reduced (HFrEF) or preserved ejection fraction (HFpEF), with and without chronotropic incompetence (CI).

There is a significant correlation between HRR and peak VO2 in those with CI (R=0.39; P=0.04) and those without CI (R=0.41; P=0.01).
Adapted from reference 33: Brubaker et al. J Cardiopulm Rehabil. 2006;26: 86-89. © 2006, Lippincott Williams & Wilkins Inc.



Reduced peak VO2 in HFrEF as well as HFpEF patients is due to a combination of reduced peak cardiac output and arterial venous oxygen content difference.31 The latter is related to abnormalities of skeletal muscle and vascular function that limit the exercise intolerance associated with HF. The reduced cardiac output response in HF patients can be due to reduced stroke volume and reduced HR during peak exercise. In HFpEF patients, reduced peak HR appears to be a stronger contributor to reduced peak VO2 than stroke volume.31 Whereas maximal HR during exercise may be only mildly reduced, HR reserve is often blunted more substantially in HF patients owing to the sympathetically driven increase in resting HR.32

We recently demonstrated that HR reserve was significantly correlated (r=0.40) with peak VO2 in elderly HF patients with either HFrEF or HFpEF (Figure 4).33 Furthermore, the increase in HR during exercise accounted for an appreciable portion (ie, 15%) of the observed differences in peak VO2. This was unchanged even after accounting for medications, including β-blockers. These findings were confirmed and expanded by Borlaug et al, who reported that HFpEF patients also had a slower HR rise and impaired HR recovery, indicating abnormal autonomic function (Figure 5).34


Figure 5
Figure 5. Heart rate profiles during and after cycle ergometry in patients with heart failure and preserved ejection fraction (HFpEF) compared with age- and gender-matched subjects with similar comorbidities including left ventricular hypertrophy (control).

These data demonstrate the delayed and attenuated heart rate response often
seen in chronotropically impaired heart failure patients.
Adapted from reference 34: Borlaug et al. Circulation. 2006;114:2138-2147. © 2006, American Heart Association, Inc.


Prevalence of chronotropic incompetence in heart failure

The reported prevalence of CI within the HF population has varied considerably, with a range of 25% to 70%. This substantial variability is likely to be influenced by the criteria employed to determine CI as well as differing patient characteristics. In older HFrEF patients, Witte et al found that 103 of 237 (43%) HF patients met the criterion of <80% of APMHR, whereas 170 of 237 (72%) met the criterion of <80% of APHRR.35 Patients taking β-blockers were more likely to have CI than those not taking β-blockers when <80% APMHR was used (49% vs 32%, respectively) or <80% APHRR was used (75% vs 64%, respectively). When the criterion of ≤62% APHRR was used for HF patients on β-blocker therapy, a significantly smaller percentage (22%) of patients were diagnosed with CI.23

We evaluated the prevalence of CI in older (≥60 years) HFrEF and HFpEF patients as well as in age-matched healthy subjects using ≤80% of APMHR and the Wilkoff approach.33 While CI was uncommon in healthy older adults (just 2 out of 28 subjects, or 7%), the prevalence of CI was relatively similar between older HFrEF (12 of 46, or 26%) and HFpEF (11 of 56, or 19%) patients. Phan et al reported that the prevalence of CI increased to 63% of HFpEF patients when the criterion of 80% of HR reserve was used as the definition of CI.26 Thus, a significant portion (one-third or more depending on the criteria employed) of both HFrEF and HFpEF patients have significant CI, which contributes to their exercise intolerance.

Mechanisms of chronotropic incompetence in heart failure

CI in HF is associated with a 50% reduction in β-adrenergic receptor density in the left ventricular myocardium, downregulation of β-receptors, and desensitization assessed by decreased responsiveness to norepinephrine infusion and exercise.36 HF patients also have significant sinus node remodeling.37 The relationship between change in HR and change in plasma norepinephrine is significantly correlated with anaerobic threshold, peak VO2, and ventilatory efficiency (ventilatory equivalent to carbon dioxide output slope [VE/VCO2]).38

Effect of exercise training on chrotropic incompetence in heart failure

In addition to many other health benefits, endurance exercise training in healthy individuals results in favorable changes in chronotropic function such as decreased resting and submaximal exercise HR, as well as a more rapid decline in postexercise HR. Most of these HR adaptations appear to be related to an alteration in the balance of the sympathetic and parasympathetic influence of the autonomic nervous system.

Endurance exercise training generally improves exercise tolerance in HF patients through a variety of potential central and peripheral mechanisms. A meta-analysis of 35 randomized studies of exercise training in HFrEF patients indicated that peak HR increased by an average of 4 bpm, or 2.5% of the pretraining level.39 Keteyian et al demonstrated that after 24 weeks of endurance exercise training, peak exercise HR increased by 7% (approximately 9bpm) yet remainedunchanged in a nonexercise control group.40 Furthermore, the traininginduced increase in peak HR accounted for 50% of the increase in peak VO2 in the exercise training group.

While alterations in β-adrenergic receptor sensitivity may explain these findings, the mechanisms responsible for the improved chronotropic response with exercise training in HFrEF are not known. We recently reported that exercise training in HFpEF patients improved peak HR, but this was counterbalanced by a reduced stroke volume response, such that cardiac output did not change with training.41 Thus, in HFpEF, improved CI may not contribute to improved exercise capacity, which appears to be primarily due to improved peripheral mechanisms. More information is needed regarding the impact of exercise training on the chronotropic response of HFrEF and HFpEF patients.

Effect of rate-adaptive pacing on chronotropic incompetence and exercise performance in heart failure

There is a linear relationship between HR and VO2 during exercise in a variety of patient populations, including patients with HF.42 Not surprisingly, rate-adaptive pacing has been shown to enhance functional capacity in a variety of patients with CI.22,43 However, despite the prominent role of abnormal HR responses in HF, there has been relatively little attention to rate-adaptive pacing in this specific population.44,45

Tse et al examined the potential benefit of rate-adaptive pacing, in conjunction with cardiac resynchronization therapy, on exercise performance in HFrEF patients.46 A total of 20 HFrEF patients with CI with an implanted cardiac resynchronization device underwent exercise testing with measurement of VO2. In the overall group, rate-adaptive pacing during cardiac resynchronization therapy increased peak exercise HR and exercise time, but did not increase peak exercise VO2. However, in the 11 (55%) HF patients with more severe CI (those achieving <70% APMHR), rate-adaptation significantly increased peak HR, exercise time, and peak VO2. Further, in the majority (82%) of these patients, the improvement in chronotropic response was associated with an approximately 20% increase in peak VO2. But in patients with less severe CI there was little or no benefit, and one-third of the patients experienced a reduction in exercise capacity with rate-adaptive pacing.46 Thus, while it appears that rate-adaptive pacing may have potential benefits in carefully selected patients with HFrEF, advances in this area are hindered by the lack of standardized, accepted definitions and selection criteria. Furthermore, at this time it is unclear if CI is causal or simply a marker of advanced disease and if treating it with a pacemaker would improve functional status in HFrEF patients. Clearly, this issue will require further investigation in the future.

Even less is known regarding pacing in patients with HFpEF, despite the significant prevalence of CI in this population and the contribution of impaired chronotropic response to their objectively measured exercise intolerance.26,33,34 One trial was designed to help determine if rate-responsive pacing can potentially improve exercise function in HFpEF.patients with overt CI.47

A recent report noted that CI is common in clinical HF patients who already have implanted pacemakers and is associated with worse exercise capacity.48 Further, the authors recommended periodic optimization of pacemaker settings and reevaluation of β-blocker dosages.

Summary

CI is a common and important cause of exercise intolerance, and an independent predictor of major adverse cardiovascular events and mortality. The diagnosis of CI should take into account the confounding effects of aging, physical condition, and medications, but can be achieved objectively with widely available exercise testing methods and standardized definitions. If CI is found to be present, a search for potentially reversible causes is warranted.

In HF, β-adrenergic blockade may have a less detrimental effect on exercise capacity than previously thought, and may even paradoxically improve exercise performance. The potential of more novel β-blockers to reduce the prevalence of CI in HF patients is unclear. While exercise training and rateadaptive pacing have been shown to improve chronotropic responses and exercise capacity in HF, more research is needed to fully evaluate the impact of these therapies on key clinical outcomes.

CI is a common, easily diagnosed, and potentially treatable cause of exercise intolerance and merits more attention by clinicians when they encounter patients with symptoms of effort intolerance.

Acknowledgments. Supported in part by National Institutes of Health grant R37AG18915. The sponsor had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.


References

1. Kitzman DW. Exercise intolerance. Prog Cardiovasc Dis. 2005;47:367-379.
2. Higginbotham MB, Morris KG, Williams RS, McHale PA, Coleman RD, Cobb FR. Regulation of stroke volume during submaximal and maximal upright exercise in normal man. Circ Res. 1986;58:281-291.
3. Higginbotham MB, Morris KG, Williams RS, et al. Physiologic basis for the agerelated decline in aerobic work capacity. Am J Cardiol. 1986;57:1374-1379.
4. Orso F, Baldasseroni S, Maggioni A. Heart rate in coronary syndromes and heart failure. Prog Cardiovasc Dis. 2009;52:38-45.
5. Lauer MS. Autonomic function and prognosis. Cleve Clin J Med. 2009;76:S18- S22.
6. Vivekananthan DP, Blackstone EH, Pothier CE, Lauer MS. Heart rate recovery after exercise is a predictor of mortality, independent of angiographic severity of coronary disease. J Am Coll Cardiol. 2003;42:831-838.
7. Imai K, Sato H, Hori M, et al. Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure. J Am Coll Cardiol. 1994;24:1529-1535.
8. Adabag AS, Grandits GA, Prineas RJ, Crow RS, Bloomfield HE, Neaton JD; MRFIT Research Group. Relation of heart rate parameters during exercise test to sudden death and all-cause mortality in asymptomatic men. Am J Cardiol. 2008;101:1437-1443.
9. Jolly MA, Brennan DM, Cho L. Impact of exercise on heart rate recovery. Circulation. 2011;124:1520-1526.
10. Kitzman DW, Taffet G. Effects of aging on cardiovascular structure and function. In: Halter JB, Ouslander JG, Tinetti ME, Studenski SA, High KP, Asthana S, eds. Hazzard’s Geriatric Medicine and Gerontology. New York, NY: McGraw Hill. 2009:883-895.
11. Haidet GC. Dynamic exercise in senescent beagles: oxygen consumption and hemodynamic responses. Am J Physiol. 1989;257:H1428-H1437.
12. Tate CA, Taffet GE, Hudson EK, Blaylock SL, McBride RP, Michael LH. Enhanced calcium uptake of cardiac sarcoplasmic reticulum in exercise-trained old rats. Am J Physiol Heart Circ Physiol. 1990;258:H431-H435.
13. Ogawa T, Spina RJ, Martin WH, Kohrt WM, Schechtman KB. Effect of aging, sex, and physical training on cardiovascular responses to exercise. Circulation. 1992;86:494-503.
14. Dresing TJ, Blackstone EH, Pashkow FJ. Usefulness of impaired chronotropic response to exercise as a predictor of mortality, independent of the severity of coronary artery disease. Am J Cardiol. 2000;86:602-609.
15. Gulati M, Shaw LJ, Thisted RA, Black HR, Bairey CN, Arnsdorf MF. Heart rate response to exercise stress testing in asymptomatic women. The St. James Women Take Heart Project. Circulation. 2010;122:130-137.
16. Astrand PO. Physical performance as a function of age. JAMA. 1968;205: 729-733.
17. Tanaka H, Monahan KD, Seals DR. Age-predicted maximal heart rate revisited. J Am Coll Cardiol. 2001;37:153-156.
18. Brawner CA, Ehrman JK, Schairer JR, Cao JJ, Keteyian SJ. Predicting maximum heart rate among patients with coronary heart disease receiving betaadrenergic blockade therapy. Am Heart J. 2004;148:910-914.
19. Lauer MS, Francis GS, Okin PM, Pashkow FJ, Snader CE, Marwick TH. Impaired chronotropic response to exercise stress testing as a predictor of mortality [see comments]. JAMA. 1999;281:524-529.
20. Elhendy A, van Domburg RT, Bax JJ, et al. The functional significance of chronotropic incompetence during dobutamine stress test. Heart. 1999;81: 398-403.
21. Okin PM, Lauer MS, Kligfield P. Chronotropic response to exercise. Improved performance of ST-depression criteria after adjustment for heart rate reserve. Circulation. 1996;94:3226-3231.
22. Wilkoff BL, Miller RE. Exercise testing for chronotropic assessment. Cardiol Clin. 1992;10:705-717.
23. Khan ME, Pothier CE, Lauer MS. Chronotropic incompetence as a predictor of death among patients with normal electrocardiograms taking beta blockers. Am J Cardiol. 2005;96:1328-1333.
24. Magri D, Palermo P, Cauti FM, et al. Chronotropic incompetence and functional capacity in chronic heart failure: no role of β-blockers and β-blocker dose. Cardiovasc Ther. 2012;30:100-108.
25. Jorde UP, Vittorio T, Kasper ME, et al. Chronotropic incompetence, beta-blockers, and functional capacity in advanced congestive heart failure: time to pace? Eur J Heart Fail. 2008;10:96-101.
26. Phan T, Shivu G, Weaver R, Ahmed I, Frenneaux M. Impaired heart rate recovery and chronotropic incompetence in patients with heart failure with preserved ejection fraction. Circ Heart Fail. 2010;3:29-34.
27. Vittorio T, Lanier G, Zolty R, et al. Association between endothelial function and chronotropic incompetence in subjects with chronic heart failure receiving optimal medical therapy. Echocardiography. 2010;27:294-299.
28. Volterrani M, Cice G, Caminiti G, Vitale C, D’Isa S, Perrone Filardi P, Acquistapace F, Marazzi G, Fini M, Rosano GM. Effect of carvedilol, ivabradine or their combination on exercise capacity in patients with heart failure (the CARVIVA HF trial). Int J Cardiol. 2011;151:218-224.
29. Sullivan MJ, Hawthorne M. Exercise intolerance in patients with chronic heart failure. Prog Cardiovasc Dis. 1995;28:1-22.
30. Kitzman DW, Little WC, Brubaker PH, et al. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA. 2002;288:2144-2150.
31. Haykowsky MJ, Brubaker PH, John JM, Stewart KP, Morgan TM, Kitzman DW. Determinants of exercise intolerance in elderly heart failure patients with preserved ejection fraction. J Am Coll Cardiol. 2011;58:265-274.
32. Pina IL, Apstein CS, Balady GJ, et al. Exercise and heart failure: A statement from the American Heart Association Committee on exercise, rehabilitation, and prevention. Circulation. 2003;107:1210-1225.
33. Brubaker PH, Joo KC, Stewart KP, Fray B, Moore B, Kitzman DW. Chronotropic incompetence and its contribution to exercise intolerance in older heart failure patients. J Cardiopulm Rehabil. 2006;26:86-89.
34. Borlaug BA, Melenovsky V, Russell SD, et al. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation. 2006;114:2138-2147.
35. Witte KK, Cleland J, Clark AL. Chronic heart failure, chronotropic incompetence, and the effects of beta blockade. Heart. 2006;92:481-486.
36. Bristow MR, Hershberger RE, Port JD, et al. Beta-adrenergic pathways in nonfailing and failing human ventricular myocardium. Circulation. 1990;82:12-25.
37. Sanders P, Kistler PM, Morton JB, Spence SJ, Kalman JM. Remodeling of sinus node function in patients with congestive heart failure: reduction in sinus node reserve. Circulation. 2004;110:897-903.
38. Samejima H, Omiya K, Uno M, et al. Relationship between impaired chronotropic response, cardiac output during exercise, and exercise tolerance in patients with chronic heart failure. Jpn Heart J. 2003;44:515-525.
39. van Tol BA, Huijsmans RJ, Kroon DW, Schothorst M, Kwakkel G. Effects of exercise training on cardiac performance, exercise capacity and quality of life in patients with heart failure: a meta-analysis. Eur J Heart Fail. 2006;8:841-850.
40. Kavanaugh T, Myers MG, Baigrie R, et al. Quality of life and cardiorespiratory function in chronic heart failure: effects of 12 months of aerobic training. Heart. 1996;76:42-49.
41. Haykowsky MJ, Brubaker PH, Stewart KP, Morgan TM, Eggebeen J, Kitzman DW. Effect of endurance training on the determinants of peak exercise oxygen consumption in elderly patients with stable compensated heart failure and preserved ejection fraction. J Am Coll Cardiol. 2012;60:120-128.
42. Keteyian SJ, Brawner CA, Schairer JR, et al. Effects of exercise training on chronotropic incompetence in patients with heart failure. Am Heart J. 1999; 138:233-240.
43. Kappenberger L, Herpers L. Rate responsive dual chamber pacing. Pacing Clin Electrophysiol. 1986;9:987-991.
44. Buckingham TA. Effects of ventricular function on exercise hemodynamics of variable rate pacing. J Am Coll Cardiol. 1998;11:1269-1277.
45. Freedman RA. Assessment of pacemaker chronotropic response: implementation of the Wilkoff mathematical model. Pacing Clin Electrophysiol. 2001;24: 1748-1754.
46. Tse HF, Siu CW, Lee KLF, Fan K, Chan HW, Tang MO, Tsang V, Lee SWL, Lau CP. The incremental benefit of rate-adaptive pacing on exercise performance during cardiac resynchronization therapy. J Am Coll Cardiol. 2005;46:2292- 2297.
47. Kass DA, Kitzman DW, Alvarez GE. The restoration of chronotropic competence in heart failure patients with normal ejection fraction (RESET) study: rationale and design. J Card Fail. 2010;16:17-24.
48. Ujeyl A, Stevenson LW, West EK, Kato M, Liszkowski M, Campbell P, Forman DE. Impaired heart rate responses and exercise capacity in heart failure patients with paced baseline rhythms. J Card Fail. 2011;17:188-195.


Keywords: aging; chronotropic incompetence; ejection fraction; exercise; heart failure; heart rate