Chronotropic response is the ability to adapt heart rate (HR) to the level of activity or demand1 and is frequently impaired in patients with cardiovascular (CV) disease.2 This physiologic reflex is a strong and independent predictor of functional capacity and CV morbidity and mortality.1,3 It is usually represented by the chronotropic index (Ci), defined as the fraction of the age-predicted maximal HR (APMHR) or, more commonly, of the age-predicted HR reserve achieved at maximal effort.4 Wider use of Ci has been limited by the lack of consensus on the appropriate definition and cut-off points to establish chronotropic incompetence (CI), with most studies suggesting failure to attain a Ci ≥80%, measured during a graded exercise test, as the primary criterion for CI,1 although other thresholds have been used (either 85% or 70%, for example).5

Chronotropic index produces exercise intolerance and, although the increase in HR is the strongest contributor to aerobic performance,6 other factors should be considered, such as failure to achieve maximal HR, inadequate submaximal HR, HR instability during exertion and the rate of HR recovery after exertion, which is also an important indicator of risk of all-cause mortality.1,7,8 HR responses at rest, during and after exercise are thus strongly associated with increased risk of adverse CV outcomes.2,9 Moreover, confounding effects of gender, age and medication (particularly beta blockers (BB)) in HR should be considered when diagnosing CI, as these factors influence the maximal HR attained during exertion.

The conventional equation to predict APMHR (220 – age in years), which is based on the physiological decrease in maximal HR with aging, was established in a cohort of healthy young men, shows a large variability between subjects and may not be adequate in patients with coronary artery disease (CAD), particularly those taking BB, with standard deviations of ±40 beats per minute (bpm) in some cases.10,11 In fact, maximal HR is expected to be lower in patients on BB therapy irrespective of age, suggesting the need to use alternative equations and different CI thresholds in those taking BB. Brawner proposed using APMHR (164 – 0.7(age in years)) and the ≥80% threshold to define CI, while others suggest using the conventional formula with a lower threshold of Ci ≤62% for diagnosing CI.11,12 However, having multiple criteria and a lack of standardization can dampen practicality for Ci clinical use. This indicator is, therefore, frequently overlooked, particularly in the setting of cardiac rehabilitation programs (CRP), where it can stand as a useful tool to assess the outcomes after an acute coronary syndrome (ACS). CRP programs tend to enhance chronotropic response and when CI is correctly managed, functional capacity and quality of life of the individual are strongly improved.1

Chronotropic response to exercise is a strong predictor of CV morbidity and mortality both in healthy subjects and in those with CAD. In this study we found that engaging in a CRP is associated with a short and long-term improvement in chronotropic response, irrespective of age, gender and use of BB.

Exercise testing is usually performed to determine whether new or worsening myocardial ischemia is present, but it may also be performed to evaluate a therapeutic regimen and/or develop an exercise prescription.12 In this context, assessing HR response to exercise and defining CI based on baseline exercise testing performance is cumbersome since there are different accepted definitions and cut-offs for chronotropic response and no consideration for the level of effort achieved and reason for exercise test termination. These may be some of the reasons why evaluation of HR response and CI is often overlooked in clinical practice,3 The end of the exercise test must be guided by symptoms and subjective perception of effort when other methods are not available, but the patient must be encouraged to continue until possible,1 as an abnormal chronotropic response provides prognostic information that is independent of myocardial perfusion – the combination of a myocardial perfusion abnormality and an abnormal Ci suggests a worse prognosis than either abnormality alone.13

Chronotropic index is common in patients with CV disease and is an important predictor of major adverse events and overall mortality. It reflects an imbalance in the autonomic nervous system,3 common in the early stages after ACS, as demonstrated by experimental and clinical studies.14 It has been well established that physical exercise promotes beneficial autonomic adaptations in patients after myocardial infarction including reduced resting HR, increased HR reserve and a steeper decrease in HR at 1 and 3 minutes after exercise termination. BB therapy seems to enhance these effects by promoting a shift in CV autonomic tone toward lower sympathetic and increased parasympathetic activity.15 Therefore, the combination of exercise training with BB therapy seems promising for CI improvement following ACS. Nevertheless, BB influence on HR response to exercise hinders interpretation and comparability of chronotropic response to exercise and renders the use of APMHR equations imprecise.12,16,17

Higher resting HR is associated with higher total and CV mortality and risk for major CV events.2,18 It has been suggested that the magnitude of increased CV mortality risk is higher than ischemic ST depression19 and that it is independent of other factors such as age, gender, functional capacity, other CV risk factors and even ST-segment changes during exercise.20 On the other hand, blunted HR response to exercise also has a prognostic value, independent of the presence of CAD or left ventricular disfunction.9,21 Despite the high rate of BB use in outpatients with stable CAD and post-ACS, most patients have, as in our study, a resting HR>70 bpm,16,22 reflecting an underdosing of BB possibly due to worries regarding patient tolerance and/or clinician decision.

Concerning the definition of CI, the use of different criteria for patients taking BB has been contradicted by some studies, based on the possible absence of any effect of this medication on the occurrence of CI, including at high doses.23 Nevertheless, we found that the prevalence of CI is highly dependent on the definition used, with values up to 73.7%, when using the APMHR and the CCi>80% cut-off at baseline, to 11.2%, when using the BCi equation and the BCi>80% cut-off at baseline. On the other hand, adding more variables would reduce applicability to clinical use. The BCi equation is found to be superior to the conventional equation for those with known or suspected CV disease11 and it appears to be a valid application in the setting of CRP. Chronotropic adaptations to exercise with increased HR variability seem to be independent of BB use and may in fact be potentiated by its use.14

There is substantial variability in the individual effect of BB on maximal HR and on functional capacity in CVD patients.24 Not considering the negative effect of BB on maximal HR, including the impact of dose modification, may lead to overtraining and increased risk of exercise-related adverse events.11,16 Overall, besides the effects on CV events and mortality, CRP improves exercise capacity with most benefit obtained in those more severely limited. We found that improvements in exercise capacity positively correlates to improvements in CCi, independent of age, gender and BB therapy or BB dose modification. Nevertheless, more studies are needed to calibrate the APMHR for those with CV disease and taking BB as well as to establish a universal threshold for diagnosis of CI in this patient population.

There were some limitations in this study. First of all, it is a descriptive study, with a relatively small sample and no control group. There was no information regarding the reasons for BB use and BB dose modification throughout the study period. Disease severity in our patients was somewhat mild, in accordance with the CRP admission criteria, and the NYHA functional classification was low. No information regarding physical activity habits outside the CRP exercise sessions was collected. Since our objective was the short-term effect of exercise training on chronotropic response, we did not collect information on major cardiovascular events.

We found that Ci significantly improves with CRP after an ACS, irrespective of BB dose changes, and that CCi is more closely related to improvement in functional capacity than BCi. However, it is unclear which maximal predicted HR equation is more appropriate to use when BB therapy is held prior to exercise stress testing. This data supports the need for an appropriate screening for HR responses during exercise testing and recovery, as it can be helpful for risk stratification and prognosis definition.

The author has no conflicts of interest to declare.