European Heart Journal Advance Access originally published online on March 21, 2006
European Heart Journal 2006 27(8):897-898; doi:10.1093/eurheartj/ehi712
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Chronotropic incompetence: are the carotid arteries to blame?
1Department of Cardiology, University Hospital Gent, De Pintelaan 185, 9000 Gent, Belgium
2Department of Cardiology, AZ Groeninge, Loofstraat 43, 8500 Kortrijk, Belgium
* Corresponding author. Tel: +32 9 240 58 26; fax: +32 9 240 44 32. E-mail address: johan.desutter{at}ugent.be
This editorial refers to ‘Chronotropic response to exercise testing is associated with carotid atherosclerosis in healthy middle-aged men’
by S.Y. Jae et al., on page 954
Jae et al.1 report on the association between the chronotropic response during exercise testing and carotid atherosclerosis in a large cohort of 8959 healthy middle-aged men. Importantly, the association between an attenuated heart rate (HR) response to exercise and a measurement of sub-clinical atherosclerosis by ultrasonography was independent of age, conventional cardiac risk factors, and parameters of inflammation.
The HR response to exercise is related to several parameters including age, resting HR, functional capacity, cardiac function, extent of coronary artery disease, and the autonomic nervous system. A common definition of an abnormal HR response during exercise is the failure to achieve 85% of the age-predicted maximal HR (defined by 220 bpm minus the patient's age). This method may, however, be confounded by the resting HR and functional capacity. Therefore, the concept of HR reserve was introduced. The HR reserve is defined as the difference between maximal predicted HR (or 220 bpm minus the patient's age) and resting HR. Failure to use 80% of HR reserve is considered as chronotropic incompetence. To take into account the functional capacity, the chronotropic index can be calculated as HR reserve/metabolic reserve percentage, with metabolic reserve measured by gas analysis. A marker of abnormal HR response during exercise is then defined as a chronotropic index <0.8 in the absence of beta-blocker therapy.2
In most laboratories, failure to reach 85% of age-predicted maximum HR during exercise is considered as a sub-maximal response that is associated with a decreased sensitivity to detect coronary artery disease. Thus, studies have shown that an abnormal HR reserve is not diagnostic for coronary artery disease.3 Therefore, in the clinical setting, abnormal HR responses should not be used to establish a diagnosis of coronary artery disease. However, the HR information obtained during the test can further help in the risk stratification of an individual patient. Recent large-scale studies have found that an abnormal chronotropic index or HR reserve <80% is associated with increased long-term mortality in asymptomatic subjects and in lower and higher risk patients referred for exercise testing. Most importantly, the prognostic information obtained from HR during exercise appears to be incremental to pre-test information, such as the Framingham risk score, and to post-test information, such as functional capacity or information obtained from nuclear perfusion imaging, treadmill exercise echocardiography, or coronary angiography.3–8 Recently, Khan et al. reported in a series of 3736 patients referred for symptom-limited exercise testing and taking either metoprolol tartrate or atenolol that chronotropic incompetence remained an independent predictor of death. Of note, Khan et al.9 defined a cut-off of HR reserve 
62% to define chronotropic incompetence in patients taking beta-blockers.
Although several large-scale studies have established the prognostic value of the chronotropic response during exercise, the underlying mechanisms are not very clear. Chronotropic incompetence is generally believed to reflect an underlying autonomic nervous system imbalance. Individuals with dysfunctional autonomic HR responses may be more predisposed to lethal cardiac arrhythmias and thus increased mortality regardless of the presence or extent of coronary artery disease.
A possible explanation for the association between chronotropic incompetence and carotid artery atherosclerosis as documented by Jae et al.1 can be found in the area where the common carotid artery bifurcates. Pioneer work by Hering and Heymans10 has shown that the carotid sinuses and the walls of the large arteries arising from the carotid artery contain receptors that, by a reflex mechanism, act upon and regulate the activity of the cardiovascular and respiratory centres. Arterial blood pressure is constantly monitored by baroreceptor nerve endings that are sensitive to stretching of the vessel wall and are connected with the central nervous system through the glossopharyngeal nerve. Under normal physiological conditions, baroreceptor firing exerts a tonic inhibitory influence on sympathetic outflow from the medulla. Hypotension results in a disinhibition of the medullary centres, leading to an increasing sympathetic outflow and a decreasing parasympathetic outflow. These autonomic changes cause vasoconstriction (increase in total peripheral resistance), tachycardia, and positive inotropy, thus restoring arterial blood pressure.
The role of the carotid baroreceptors on the exercise HR response is far more complex, involving resetting of the arterial baroreflex to a higher operating point and interaction with muscle chemoreceptors and baroreceptors.11 As the carotid sinus baroreceptors are ‘stretch’ receptors, increased stiffness of the vessel wall associated with carotid artery atherosclerosis will most likely affect the ability of the receptors to respond to pressure changes. Other baroreceptors are located in the aortic arch, operating at pressure levels 
30 mmHg higher. As atherosclerosis of the carotid arteries is often associated with aortic atherosclerosis and reduced aortic compliance, the sensitivity of aortic baroreceptors may also be influenced. Jae et al.1 demonstrated nicely that the presence of carotid atherosclerosis was associated with chronotropic incompetence, but the conclusion would have been stronger if the analysis of the carotid arteries had included an evaluation of the vessel wall elasticity. Wall tracking techniques can be easily combined with carotid artery intima-media thickness measurements and allow a non-invasive evaluation of arterial compliance.12 Also, as no outcome data were available, the independent prognostic information of carotid artery atherosclerosis vs. chronotropic incompetence in a population of healthy individuals remains unclear.
In conclusion, the authors have to be congratulated for this well-documented and large-scale study on chronotropic incompetence. Further studies are now needed to unravel the pathophysiological mechanisms that produce the abnormal response in individual patients, including down-regulation of beta-adrenergic receptors, central nervous system effects, and baroreflex abnormalities, with their potential relationship to carotid atherosclerosis.13 Also, additional studies on how to modulate chronotropic incompetence by interventions are awaited. In the meantime, the HR response during exercise can be easily measured during exercise testing and can help, based on a large amount of clinical data, in the risk stratification of asymptomatic individuals as well as patients with established coronary artery disease.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehi832 
References
- Jae SY, Fernhall B, Heffernan KS, Kang M, Lee MK, Choi YH, Park WH. Chronotropic response to exercise testing is associated with carotid atherosclerosis in healthy middle-aged men. Eur Heart J 2006;27:954–959. First published on March 14, 2006, doi:10.1093/eurheartj/ehi832.
[Abstract/Free Full Text] - Lauer MS. Chronotropic incompetence. Ready for prime time. J Am Coll Cardiol 2004;21:431–432.
- Vivekananthan DP, Blackstone EH, Pothier CE, Lauer MS. Heart rate recovery after exercise is a predictor of mortality, independent of the angiographic severity of coronary artery disease. J Am Coll Cardiol 2003;42:831–838.
[Abstract/Free Full Text] - Azarbal B, Hayes SW, Lewin HC, Hachamovitch R, Cohen I, Berman DS. The incremental prognostic value of percentage of heart rate reserve achieved over myocardial perfusion single-photon emission computed tomography in the prediction of cardiac death and all-cause mortality: superiority over 85% of maximal age-predicted heart rate. J Am Coll Cardiol 2004;44:423–430.
[Abstract/Free Full Text] - Elhendy A, Mahoney DW, Khandheria BK, Burger K, Pellikka PA. Prognostic significance of impairment of heart rate response to exercise: impact of left ventricular function and myocardial ischemia. J Am Coll Cardiol 2003;42:823–830.
[Abstract/Free Full Text] - Lauer MS, Francis GS, Okin PM, Pashkow FJ, Snader CE, Marwick TH. Impaired chronotropic response to exercise stress testing as a predictor of mortality. JAMA 1999;281:524–529.
[Abstract/Free Full Text] - Balady GJ, Larson MG, Vasan RS, Leip EP, O'Donnell CJ, Levy D. Usefulness of exercise testing in the prediction of coronary disease risk among asymptomatic persons as a function of the Framingham Risk Score. Circulation 2004;110:1920–1925.
[Abstract/Free Full Text] - Jouven X, Empana JP, Schwartz PJ, Desnos M, Courbon D, Ducimetière P. Heart-rate profile during exercise as a predictor of sudden death. N Engl J Med 2005;352:1951–1958.
[Abstract/Free Full Text] - Khan MN, Pothier CE, Lauer MS. Chronotropic incompetence as a predictor of death among patients with normal electrograms taking beta-blockers. Am J Cardiol 2005;96:1328–1333.[CrossRef][ISI][Medline]
- Heymans CJF. The part played by vascular presso- and chemo-receptors in respiratory control. Nobel Lecture, 12 December 1945.
- O'Leary DS. Heart rate control during exercise by baroreceptors and skeletal muscle afferents. Med Sci Sports Exerc 1996;28:210–217.[ISI][Medline]
- Reneman RS, Meinders JM, Hoeks AP. Non-invasive ultrasound in arterial wall dynamics in humans: what have we learned and what remains to be solved. Eur Heart J 2005;26:960–969.
[Abstract/Free Full Text] - Fukuma N, Oikawa K, Aisu N, Kato K, Kimura-Kato Y, Tuchida T, Mabuchi K, Takano T. Impaired baroreflex as a cause of chronotropic incompetence during exercise via autonomic mechanism in patients with heart disease. Int J Cardiol 2004;97:503–508.[CrossRef][ISI][Medline]
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- Chronotropic response to exercise testing is associated with carotid atherosclerosis in healthy middle-aged men
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