This Article Extract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ellestad, M. H. Search for Related Content PubMed PubMed Citation Articles by Ellestad, M. H.

(Circulation. 1996;93:1485-1487.)
© 1996 American Heart Association, Inc.

Articles

Chronotropic Incompetence

The Implications of Heart Rate Response to Exercise (Compensatory Parasympathetic Hyperactivity?)

Myrvin H. Ellestad, MD

From Memorial Heart Institute, Long Beach Memorial Medical Center, Long Beach, Calif, and University of California, Irvine, School of Medicine.

Correspondence to Myrvin H. Ellestad, MD, Memorial Heart Institute, Long Beach Memorial Medical Center, 2801 Atlantic Ave, Long Beach, CA 90801.

Key Words: Editorials • heart rate • exercise

	Introduction

Top Introduction History of the Concept Physiological Mechanism References

 
The report in this issue by Lauer et al¹ provides more fascinating data on the possible predictive value of a reduced response of the sinus node to exercise. They exploited the opportunity to study this important response in 1575 healthy participants in the Framingham Offspring Study who had exercise tests on entry in the 1970s. The mortality and morbidity of the men in this study were extracted from the Framingham follow-up data as well as during follow-up examinations 8, 12, and 16 years after their entry.

These investigators correlated the mortality and incident coronary disease with the subject's ability or failure to reach 85% of maximum predicted heart rate, actual increase in heart rate from rest to maximum, and a ratio of heart rate to metabolic reserve achieved by stage 2 of the Bruce exercise protocol. This ratio compensates for the differences in age and physical fitness and provides a chronotropic index.

During a mean follow-up of 7.7 years, the inability to achieve the target heart rate in 21% of the subjects was correlated with total mortality and with the incidence of coronary disease including myocardial infarction. Similar correlations occurred with a reduced heart rate increase with exercise and with the chronotropic response index calculated as previously mentioned. The data suffer from the fact that exercise was arbitrarily terminated at 85% of age-predicted heart rate, a highly artificial value that had considerable adherence in the 1970s. However, previous work suggests that if their patients had been exercised to a symptom-limited end point, the correlations with coronary events would have been even stronger.

The reason the magnitude of the increase in heart rate during an exercise test would be predictive of subsequent events and mortality is an intriguing one. Lauer and colleagues'¹ report reaches the same conclusions as the recently published report by Sandvik and colleagues² from Oslo who followed 2014 apparently healthy men aged 40 to 59 years who were exercised to maximum capacity. The follow-up period in their study was in excess of 16 years and revealed that the heart rate increase during exercise testing was inversely correlated with survival and that a reduction in the heart rate increase was a stronger predictor of mortality from cardiovascular disease than any other variable available to them. The Figure illustrates the cardiovascular mortality in Sandvik and coworkers' study² stratified by heart rate during exercise. Quartile 1 represents those with the least increase in heart rate.

View larger version (16K): [in this window] [in a new window]   Figure 1. Cardiovascular mortality is shown by follow-up years for the four quartiles of heart rate. Quartile 1, which has the lowest heart rate, has the highest mortality. (Sandvik et al,2 with permission.)

	History of the Concept

Top Introduction History of the Concept Physiological Mechanism References

 
In the early 1970s, we tested a 51-year-old man who had a good exercise tolerance and no ST depression or pain but was only able to reach a maximum heart rate of 110 beats per minute. When I commented on this, he stated that his heart rate had always been slow, probably because of his athletic background. Shortly thereafter he died suddenly, and the autopsy revealed advanced coronary disease with 80% narrowing in both the left anterior descending and the circumflex arteries.

This event caused me to examine our treadmill computer database and to label this type of heart rate response as inappropriate bradycardia. When we analyzed the follow-up results of 2700 patients, we found that those with a slow heart rate response were at greater risk for a cardiac event than those with ischemic ST depression. As we finalized the manuscript for submission, I felt the need for a better label and at the last minute decided on the term chronotropic incompetence, which has subsequently been broadly applied to a number of different patient cohorts with a reduced heart rate response to exercise.³

In preparation of the manuscript in 1974, we found that Hinkle et al⁴ had already reported in 1972 that the inability to reach an expected heart rate on a standard exercise protocol, recorded with Holter equipment, identified a group of 301 men who had an increased number of cardiac events after a 7-year follow-up. They termed the syndrome sustained relative bradycardia.

A further search revealed that Rubinstein et al⁵ had described abnormalities in autonomic function in patients with sick sinus syndrome who often had slow exercise heart rates and that Eckberg et al⁶ had described a reduced vagal influence in cardiac patients in general. Subsequently, many investigators examined the heart rate response to exercise, and it became common knowledge that many patients with angina and those with other coronary syndromes were unable to reach normal predicted heart rates.^{7 8 9} A reduction in exercise heart rate also has been correlated with the severity of coronary artery disease and with the presence of collaterals in stable angina patients.^{10 11}

	Physiological Mechanism

Top Introduction History of the Concept Physiological Mechanism References

 
The term chronotropic incompetence implies that the heart's response to exercise is not physiological. It is well known that most of myocardial perfusion is a diastolic event and that as the heart rate increases, diastole is reduced from about 70% of the cardiac cycle at rest to approximately 20% at maximum heart rate.^{12 13} One might propose that reducing the heart rate in a patient with narrowed coronary arteries will allow more time during diastole for myocardial perfusion and thus be a protective physiological response. It is believed that this is the principal reason why ß-blockers are beneficial in coronary artery disease.¹⁴

This idea is supported by the fact that some of our patients with this syndrome returned to normal after successful revascularization. We also were able to show that ischemia of the sinus node was not necessary to produce the syndrome but did find that the intrinsic heart rate (after complete autonomic blockade with propranolol and atropine) was reduced in 28 patients studied.¹⁵ It has been shown that patients with congestive heart failure have a reduced exercise heart rate and a reduced chronotropic response to norepinephrine infusion,¹⁶ probably the result of downregulations of the ß-receptors in the myocardium. Could this mechanism be a factor in our patients with slow heart rates?

There has been a tendency in the recent literature for sick sinus syndrome to be labeled as chronotropic incompetence.^{17 18} Jordan et al¹⁹ found that patients with a delayed sinus node recovery time also had a reduced intrinsic heart rate, although their sick sinus syndrome patients with normal sinus node recovery times had normal intrinsic heart rates. We do not have at this time a clear understanding of whether we should separate patients with chronotropic incompetence from those labeled with sick sinus syndrome.

The parasympathetic response mediated by mechanoreceptors in the left ventricular wall, the Bezold-Jarisch reflex, might also play a role in patients with coronary artery disease.^{20 21} It might be postulated that as the ischemic heart fails to contract normally, these receptors are activated. We do know that vasodilation, as well as bradycardia, also occurs in this syndrome and would thus be another way to achieve a protective response. Recent work has provided evidence that vagal tone, once thought to be completely withdrawn at onset of exercise, continues to modulate not only heart rate but coronary flow.²²

Recent interest in the evaluation of autonomic activity by the measurement of heart rate variability suggests that most patients have less parasympathetic drive as coronary artery disease becomes more severe.²³ Hayano et al²⁴ have proposed that decreased vagal activity might even be the cause of atherosclerosis rather than a result. Thus, it would follow that cardiac patients, known to have inadequate vagal drive, usually would have a higher heart rate. How is it that our patients under discussion have a reduced heart rate response to exercise but a faster resting heart rate? Dyer et al²⁵ and others have shown that a rapid resting heart rate is a risk factor for subsequent cardiac events.

Not long ago, it seemed that those with chronotropic incompetence might be making a more physiological adaptation to decreased myocardial perfusion, and thus the syndrome might be labeled compensatory parasympathetic hyperactivity. This hypothesis has become less tenable with the recent work by Lauer et al¹ and Sandvik et al² demonstrating that a slow exercise heart rate precedes the clinical events for years. It seems very unlikely that the participants of both of these studies had significant coronary disease on entry or certainly not enough to need the protective mechanism described, although we cannot completely exclude this possibility because extensive coronary disease has been described in young, apparently healthy soldiers killed in the Korean War.²⁶

The syndrome of chronotropic incompetence grows more fascinating as time goes by. It is hoped that the recent reports will stimulate others to help us explain the reasons for these confusing and conflicting observations.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editor or of the American Heart Association.

	References

Top Introduction History of the Concept Physiological Mechanism References

 

1. Lauer MS, Okin PM, Larson MG, Evans JC, Levy D. Impaired heart rate response to graded exercise: prognostic implications of chronotropic incompetence in the Framingham Heart Study. Circulation. 1996;93:1520-1526. [Abstract/Free Full Text]
   
2. Sandvik L, Erikssen J, Ellestad M, Erikssen G, Thaulow E, Mundal R, Rodahl K. Heart rate increase and maximal heart rate during exercise as predictors of cardiovascular mortality: a 16-year follow-up study of 1960 healthy men. Coron Artery Dis. 1995;6:667-678. [Medline] [Order article via Infotrieve]
   
3. Ellestad MH, Wan MK. Predictive implications of stress testing: follow-up of 2700 subjects after maximum treadmill stress testing. Circulation. 1975;51:363-369. [Abstract/Free Full Text]
   
4. Hinkle LE, Carver ST, Plakum A. Slow heart rates and increased risk of cardiac death in middle aged men. Arch Intern Med. 1972;129:5-8.
   
5. Rubinstein JJ, Schulman CL, Yurchak PM, DeSanctis RW. Clinical spectrum of the sick sinus syndrome. Circulation. 1972;46:5-13. [Abstract/Free Full Text]
   
6. Eckberg DL, Brabinsky M, Braunwald E. Defective cardiac parasympathetic control in patients with heart disease. N Engl J Med. 1971;285:877-883.
   
7. Bruce RA, Gey GO, Cooper MN, Fisher LD, Peterson DR. Seattle heart watch: initial clinical, circulatory and electrocardiographic responses to maximal exercise. Am J Cardiol. 1974;33:459-469. [Medline] [Order article via Infotrieve]
   
8. McNeer JF, Margolis JR, Lee KL, Kisslo JA, Peter RH, Kong Y, Behar VS, Wallace AG, McCants CB, Rosati RA. The role of the exercise test in the evaluation of patients for ischemic heart disease. Circulation. 1978;57:64-70. [Abstract/Free Full Text]
   
9. Hammond HK, Kelly TL, Froelicher V. Radionuclide imaging correlatives of heart rate impairment during maximal exercise testing. J Am Coll Cardiol. 1983;2:826-833. [Abstract]
   
10. Brenner SJ, Pashkow FJ, Harvey SA, Lauer MS. Chronotropic impairment predicts angiographic severity of coronary disease. Circulation. 1995;92(suppl I):I-736. Abstract.
    
11. Erickssen UH, Nielsen TT, Bagger JP, Egeblad H. Exercise stress testing in relation to coronary collaterals. Circulation. 1995;92(suppl I):I-736. Abstract.
    
12. Ferro G, Spinelli L, Spinelli L, Duilio C, Spadafora M, Guarnaccia F, Condorelli M. Diastolic perfusion time at ischemic threshold in patients with stress-induced ischemia. Circulation. 1991;84:49-56. [Abstract/Free Full Text]
    
13. Boudoulas H, Rittgers S, Lewis RP, Leier CV, Weissler AM. Changes in diastolic time with various pharmacologic agents: implication for myocardial perfusion. Circulation. 1979;60:164-169. [Medline] [Order article via Infotrieve]
    
14. Kobinger W, Lillie C, Pichier L. N-Allyl-derivative of clonidine, a substance with specific bradycardic action at a cardiac site. Naunyn Schmiedebergs Arch Pharmacol. 1979;306:255-262. [Medline] [Order article via Infotrieve]
    
15. Chin C-F, Messenger JC, Greenberg PS, Ellestad MD. Chronotropic incompetence in exercise testing. Clin Cardiol. 1979;2:12-18. [Medline] [Order article via Infotrieve]
    
16. Colucci WS, Ribeiro J, Rocco MB, Quigg RJ, Creager MA, Marsh JD, Gauthier DF, Hartley LH. Impaired chronotropic response to exercise in patients with congestive heart failure: role of postsynaptic ß-adrenergic desensitization. Circulation. 1989;2:314-323.
    
17. Corbelli R, Masterson M, Wilkoff BI. Chronotropic response to exercise in patients with atrial fibrillation. PACE. 1990;13:179-187.
    
18. Sutton R. DDDR pacing. PACE. 1990;13:385. Editorial.
    
19. Jordan JL, Yamaguchi I, Mandel WJ. Studies on the mechanism of sinus node dysfunction in the sick sinus syndrome. Circulation. 1978;57:217-222. [Abstract/Free Full Text]
    
20. Mark AL. The Bezold-Jarisch reflex revisited: clinical implications of inhibitory reflexes originating in the heart. J Am Coll Cardiol. 1983;1:90-102. [Abstract]
    
21. von Bezold A, Hirt L. Uber die physiologischen Wirkungen des essigsauren veratrins. Untersuchungen aus dem physiologischen laboratorium Wurzburg. 1867;1:75-156.
    
22. Marraccini P, Orsini E, Nassi G, L'Abbate A. Effects of parasympathetic blockade on ischemic threshold in patients with exercise-induced myocardial ischemia. Am J Cardiol. 1991;68:539-542. [Medline] [Order article via Infotrieve]
    
23. Kleiger RE, Mieler JP, Krone RJ, Bigger JT, for the Multicenter Postinfarction Research Group. The independence of cycle length variability and exercise testing on predicting mortality of patients surviving acute myocardial infarction. Am J Cardiol. 1990;65:408-411. [Medline] [Order article via Infotrieve]
    
24. Hayano J, Yamada A, Mukai S, Sakakibara Y, Yamada M, Ohte N, Hashimoto T, Fujinami T, Takata K. Severity of coronary atherosclerosis correlates with the respiratory component of heart rate variability. Am Heart J. 1991;121:1070-1079. [Medline] [Order article via Infotrieve]
    
25. Dyer AR, Persky V, Stamler J, Paul O, Shekelle RB, Berkson DM, Lepper M, Schoenberger MA, Lindberg HA. Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies. Am J Epidemiol. 1980;112:736-749. [Abstract/Free Full Text]
    
26. Enos WF, Holmes RH, Beyer J. Coronary disease among United States soldiers killed in action in Korea. JAMA. 1953;152:1090-1093.
    

This article has been cited by other articles:

				K. P. Savonen, V. Kiviniemi, J. A. Laukkanen, T. A. Lakka, T. H. Rauramaa, J. T. Salonen, and R. Rauramaa Chronotropic incompetence and mortality in middle-aged men with known or suspected coronary heart disease Eur. Heart J., June 13, 2008; (2008) ehn269v1. [Abstract] [Full Text] [PDF]

				J A Laukkanen, S Kurl, J T Salonen, T A Lakka, and R Rauramaa Peak oxygen pulse during exercise as a predictor for coronary heart disease and all cause death Heart, September 1, 2006; 92(9): 1219 - 1224. [Abstract] [Full Text] [PDF]

				H C Routledge and J N Townend Why does the heart rate response to exercise predict adverse cardiac events? Heart, May 1, 2006; 92(5): 577 - 578. [Abstract] [Full Text] [PDF]

				K. P. Savonen, T. A. Lakka, J. A. Laukkanen, P. M. Halonen, T. H. Rauramaa, J. T. Salonen, and R. Rauramaa Heart rate response during exercise test and cardiovascular mortality in middle-aged men Eur. Heart J., March 1, 2006; 27(5): 582 - 588. [Abstract] [Full Text] [PDF]

				M. S. Lauer Chronotropic incompetence: Ready for prime time J. Am. Coll. Cardiol., July 21, 2004; 44(2): 431 - 432. [Full Text] [PDF]

				A. Elhendy, D. W. Mahoney, B. K. Khandheria, K. Burger, and P. A. Pellikka Prognostic significance of impairment of heart rate response to exercise: Impact of left ventricular function and myocardial ischemia J. Am. Coll. Cardiol., September 3, 2003; 42(5): 823 - 830. [Abstract] [Full Text] [PDF]

				B. R. Chaitman Abnormal heart rateresponses to exercise predict increased long-term mortality regardless of coronary disease extent: The question is why? J. Am. Coll. Cardiol., September 3, 2003; 42(5): 839 - 841. [Full Text] [PDF]

				W. Kannel On checking the pulse Eur. Heart J., January 2, 2000; 21(2): 97 - 98. [PDF]

				A Elhendy, R T van Domburg, J J Bax, P R Nierop, M L Geleijnse, M M Ibrahim, and J R T C Roelandt The functional significance of chronotropic incompetence during dobutamine stress test Heart, April 1, 1999; 81(4): 398 - 403. [Abstract] [Full Text]

				M. S. Lauer, G. S. Francis, P. M. Okin, F. J. Pashkow, C. E. Snader, and T. H. Marwick Impaired Chronotropic Response to Exercise Stress Testing as a Predictor of Mortality JAMA, February 10, 1999; 281(6): 524 - 529. [Abstract] [Full Text] [PDF]

				M. S. Lauer, R. Mehta, F. J. Pashkow, P. M. Okin, K. Lee, and T. H. Marwick Association of chronotropic incompetence with echocardiographic ischemia and prognosis J. Am. Coll. Cardiol., November 1, 1998; 32(5): 1280 - 1286. [Abstract] [Full Text] [PDF]

This Article Extract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ellestad, M. H. Search for Related Content PubMed PubMed Citation Articles by Ellestad, M. H.