Contemporary Reviews in Cardiovascular Medicine

Chronotropic IncompetenceCauses, Consequences, and Management

Peter H. Brubaker, PhD; Dalane W. Kitzman, MD

Chronotropic incompetence (CI), broadly defined as theinability of the heart to increase its rate commensurate

with increased activity or demand, is common in patients withcardiovascular disease, produces exercise intolerance thatimpairs quality of life, and is an independent predictor ofmajor adverse cardiovascular events and overall mortality.However, the importance of CI is underappreciated, and CI isoften overlooked in clinical practice. This may be due in partto multiple definitions, the confounding effects of aging andmedications, and the need for formal exercise testing fordefinitive diagnosis. This review discusses the definition,mechanisms, diagnosis, and treatment of CI, with particularemphasis on its prominent role in heart failure (HF). CI iscommon and can be diagnosed by objective, widely available,inexpensive methods; it is potentially treatable, and itsmanagement can lead to significant improvements in exercisetolerance and quality of life.

Contribution of Heart Rate toExercise Performance

The ability to perform physical work is an important deter-minant of quality of life,1 and is enabled by an increase inoxygen uptake (V̇O2).2 During maximal aerobic exercise inhealthy humans, V̇O2 increases approximately 4-fold.2 This isachieved by a 2.2-fold increase in heart rate (HR), a 0.3-foldincrease in stroke volume, and a 1.5-fold increase in arterio-venous oxygen difference.2 Thus, the increase in HR is thestrongest contributor to the ability to perform sustainedaerobic exercise.3 It is therefore not surprising that CI can bethe primary cause of or a significant contributor to severe,symptomatic exercise intolerance.

HR ControlHR at any moment in time reflects the dynamic balancebetween the sympathetic and parasympathetic divisions of theautonomic nervous system. Although the intrinsic rate of thesinoatrial node is approximately 100 beats per minute (bpm),resting HR in humans is generally much lower (60 to 80 bpm)owing to the predominant influence of the parasympatheticnervous system efferent vagus nerve. Increased resting HRlevels due to increased sympathetic and/or decreased para-sympathetic “tone” have been associated with increased

cardiovascular death, ischemic heart disease, and suddencardiac death in both asymptomatic men and women.4,5

Furthermore, a resting HR �70 bpm has been associated withincreased mortality in patients with stable coronary arterydisease and left ventricular (LV) dysfunction.6,7

An intact HR response is vital for tight matching of asubject’s cardiac output to metabolic demands during exer-tion.4 Failure to achieve maximal HR, inadequate submaxi-mal HR, or HR instability during exertion are all examples ofimpaired chronotropic response. These conditions are rela-tively common in patients with sick sinus syndrome, atrio-ventricular block, coronary artery disease, and HF.4

Immediately after the termination of exertion, sympatheticwithdrawal and increased parasympathetic tone to the sino-atrial node combine to cause a rapid decline in HR. A delayedrecovery of HR after exertion has been associated withincreased all-cause mortality risk in a variety of asymptom-atic and diseased populations,8 even after adjustment forseverity of cardiovascular disease, LV function, and exercisecapacity.9 Although there are a number of methods availableto evaluate HR recovery, the most widely used threshold forincreased risk of all-cause mortality has been a decrease inHR from peak exercise to 1 minute of passive supine recoveryof �12 bpm (or �18 bpm if recovery was “active,” eg,unloaded cycling or slow walking) or a decrease in HR frompeak exercise to 2 minutes of recovery of �42 bpm.10

In contrast, highly trained athletes often display a rapid andprofound drop in HR of �30 to 50 beats during the firstminute of recovery from strenuous exertion.11 The rate andmagnitude of HR recovery after exertion appear to be directlyrelated to the level of parasympathetic tone. The associationbetween early HR recovery and parasympathetic nervoussystem function was elegantly demonstrated in a study of 3groups of subjects: athletes, normal subjects, and patientswith HF. Among athletes and normal subjects, there was abiexponential pattern of HR during early recovery, with asteep nonlinear decrease during the first 30 seconds followedby a more shallow decline (Figure 1A). When the samesubjects were given atropine and exercise testing was re-peated, the initial steep decrease in HR observed amongathletes and normal subjects disappeared (Figure 1B).11

From the Department of Health and Exercise Science (P.H.B.), Wake Forest University, and Department of Internal Medicine (Cardiology) (D.W.K.),Wake Forest University School of Medicine, Winston-Salem, NC.

Correspondence to Dalane W. Kitzman, MD, Cardiology Section, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem,NC 27157-1045. E-mail dkitzman@wfubmc.edu

(Circulation. 2011;123:1010-1020.)© 2011 American Heart Association, Inc.

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.110.940577

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In the Framingham Offspring Study, nearly 3000 healthymen and women were followed up for an average of 15 years.Individuals in the top quintile of HR recovery at 1 minuteafter exercise had the lowest risk of coronary heart diseaseand cardiovascular disease (hazard ratios of 0.54 and 0.61,respectively) compared with those in the lower 4 quintiles ofHR recovery.12 The Multiple Risk Factor Intervention Trial(MRFIT) also demonstrated that a delayed HR recovery (�50bpm after 3 minutes) was an independent predictor ofall-cause death in asymptomatic men.13 In a long-term,23-year follow-up study of asymptomatic working men whounderwent exercise stress testing,14 factors independentlyassociated with increased risk of fatal myocardial infarctionwere a resting HR �75 bpm, an increase in HR from rest topeak exercise of �89 bpm, and a decrease in HR of �25 bpmafter cessation of exercise. In conclusion, the autonomicimbalance of sympathetic and parasympathetic activity, ob-servable through HR responses at rest and both during andafter exercise, is strongly associated with increased risk ofadverse cardiovascular outcomes and sudden death.8

Effect of Age and Gender on the HR Responseto ExerciseThere is no change in resting HR with adult aging; however,in healthy humans, there is a marked age-related decrease inmaximum HR in response to exercise that is inexorable,highly predictable, and occurs in other mammalian species aswell as humans.3,15,16 The age-related decline in maximal HRis the most substantial age-related change in cardiac function,

both in magnitude and consequence.3,15,18 It is primarilyresponsible for the age-related decline in peak aerobic exer-cise capacity.3,18 Starting from early adulthood, maximal HRdeclines with age at a rate of approximately 0.7 bpm per yearin healthy sedentary, recreationally active, and enduranceexercise–trained adults.19 Although the mechanisms are notfully understood, dual-blockade studies show that intrinsicHR declines by 5 to 6 bpm for each decade of age such thatresting HR in an 80-year-old is not much slower than theintrinsic HR.15 This indicates that at rest, there is minimalparasympathetic tone. In support of this, the increase in HRafter atropine in an older person is less than half that in theyoung.15 There are also significant alterations in the sympa-thetic influence on HR response to exercise with aging, withincreased circulating catecholamines and reduced responsive-ness.15 Doses of isoproterenol that increase HR by 25 bpm inhealthy young men produce an increase of only 10 bpm inolder persons.15

The normal age-related decline in maximal HR duringexercise is not significantly modified by vigorous exercisetraining, which suggests that it is not due to the age-relateddecline in physical activity level.15 Also, it does not appear tobe due to inadequate sympathetic stimulation, because bothserum norepinephrine and epinephrine are increased ratherthan decreased at rest in healthy elderly persons. Further-more, with exertion or stress, catecholamines increase evenmore than in young persons under the same stress conditions.

The traditional equation to predict maximal HR (220bpm�age) was developed on the basis of studies primarilyconducted in middle-aged men, some of whom had knowncoronary artery disease and were taking �-blockers.19,20 Thisequation has been associated with tremendous intersubjectvariability, with a standard deviation of �11 bpm21 thatincreases to �40 bpm in patients with coronary heart diseasewho are taking �-blockers.22 Consequently, an alternative for-mula from Tanaka et al (208�0.7�age) is gaining acceptancefor determination of age-predicted maximal HR (APMHR),even though it may still underpredict APMHR in older adults(Figure 2).21

Several earlier studies suggested that gender affected theHR trajectory during exercise and recovery and that thetraditional equation (220�age) overestimated maximal HR inyounger women but underestimated it in older women.19,21 Ameta-analysis indicated that maximal HR was unaffected bygender.21 A recent large prospective study in �5000 asymp-tomatic women showed that the traditional equation signifi-cantly overestimated maximal HR and thus proposed a newequation in which maximal HR�206�0.88�age.19 Brawneret al22 demonstrated that the 220�age equation is not valid inpatients with coronary heart disease taking �-adrenergicblockade therapy and developed the equation 164�0.7[time]age for this population.

All of the aforementioned studies improve on estimationsof maximal HR versus the traditional 220�age approach butstill produce substantial standard deviation of the estimate (10to 22 bpm). Given the inherent variability in maximal HR,regression equations that use a single predictor variable, suchas age, are unlikely to be 100% accurate, and increasing thenumber of predictor variables adds little improvement and

Figure 1. Influence of parasympathetic tone on heart rate recov-ery. A, Absolute heart rates (after log transformation) during thefirst 3 minutes after exercise in 3 groups of subjects. Amongathletes and normal subjects, there is a biexponential relation-ship that is absent in heart failure patients. B, After atropine, theinitial steep slope is absent. Reproduced with permission fromLauer.8 © 2009.

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reduces practicality for clinical use. Thus, for estimation ofpredicted maximal HR, we suggest the selection of an equationthat was generated in a population that most closely matches thepopulation of interest. In this regard, the equation suggested byTanaka et al19 is recommended for apparently healthy persons,and the equation of Brawner et al22 is recommended for thosewith known or suspected cardiovascular disease. Although thesealso are imperfect, they are superior to the traditional 220�ageequation and are practical.

Definition, Criteria, and Measurement of CIA barrier to progress in studies of CI and its clinicalmanagement has been a lack of consistent methodology fordetermining CI. The lack of standardized criteria likelyaccounts for the wide range in reported prevalence of CI (9%to 89%) in the literature.23–26 In an evaluation of �1500 CIpatients referred for pacemaker implantation, the use of 5different definitions of CI resulted in a prevalence of CI of34% to 87%.27 CI has been most commonly diagnosed whenHR fails to reach an arbitrary percentage (either 85%, 80%,or, less commonly, 70%) of the APMHR (usually based onthe 220�age equation described above) obtained during anincremental dynamic exercise test.28–30 CI has also beendetermined from change in HR from rest to peak exerciseduring an exercise test, commonly referred to as the HRreserve. Because the proportion of actual HR achieved duringexercise depends in part on the resting HR level, the chrono-tropic response to exercise can also be assessed as the fractionof HR achieved at maximal effort. Thus, adjusted (percent)HR reserve, determined from the change in HR from rest topeak exercise divided by the difference of the resting HR andthe APMHR, commonly has been used.31 The majority ofstudies in the literature have used failure to attain �80% ofthe HR reserve, measured during a graded exercise test, as theprimary criterion for CI.

However, before one concludes that a patient has CI, it isimportant to consider the patient’s level of effort and reasons

for terminating the exercise test. Patients should be encour-aged to continue on the exercise modality until true symptom-limited (exhaustive) maximal levels are achieved. Symptomsand subjective ratings of perceived exertion can provide anestimate of exertion level and are an acceptable method. Therespiratory exchange ratio (RER; ie, volume of carbondioxide produced divided by volume of oxygen consumed)obtained from expired respiratory gas analysis at peak exer-tion during the exercise test is the most definitive andobjective clinically available measure of physiological levelof effort during exercise. RER is reliable, and although itsmeasurement requires expired gas analysis equipment,current-generation equipment is automated and is moderate incost. RER is a continuous variable, ranging from �0.85 atquiet rest to �1.20 during intense, exhaustive exercise.Higher RER values indicate increasing confidence of maxi-mal effort. It is generally accepted that an RER �1.05 at peakexercise suggests submaximal effort or that the test wasterminated prematurely, which should lead to caution indiagnosing CI.

Wilkoff et al32 used the expired gas analysis technique tomore objectively evaluate CI using the relationship between HRand V̇O2 during exercise. In this approach, the metabolic-chronotropic relationship (MCR; also known as the chronotropicindex) is calculated from the ratio of the HR reserve to themetabolic reserve during submaximal exercise. The advantageof using the MCR is that it adjusts for age, physical fitness, andfunctional capacity and appears to be unaffected by the exercisetesting mode or protocol. In normal adults, the percentage of HRreserve achieved during exercise equals the percentage ofmetabolic reserve achieved. This physiological concept allowsfor a single HR achieved at any point during an exercise study(HRstage) to be determined as consistent or inconsistent withnormal chronotropic function. This is accomplished by use of thefollowing formula, in which metabolic equivalents (METS)�V̇O2 (in mL � kg�1 � min�1)/3.5:

Estimated HRstage��(220�age�HRrest)��[(METsstage�1)/(METSpeak�1)]HRrest

The Wilkoff model predicts the MCR slope of the normalsinus response to be 1.0, with a 95% confidence intervalbetween 0.8 and 1.3.32 An MCR slope or any single MCRvalue (from 1 stage) �0.80 is considered indicative of CI.

Consequently, the information that should be recorded foreach patient during an exercise test to evaluate CI includes thefollowing: Age; resting HR (HRrest); APMHR (defined as 220bpm�patient’s age in years); age-predicted HR reserve(APHRR), defined as APMHR�HRrest; observed maximalHR during exercise test (HRmax); oxygen consumption (V̇O2,in mL � kg�1 � min�1) at each stage and at peak effort; andRER. For example, in a 60-year-old subject who onlyachieved an RER of 0.96 at peak exertion (ie, submaximaleffort), the following data from a submaximal stage (25 W) ofexercise (HRrest 67 bpm; HRpeak 100 bpm; HR@25W 97 bpm,METS@25W 3.3, METSpeak 3.7) when entered into theWilkoff equation would result in a CI index of 0.66 (actualHRstage of 97/estimated HRstage of 147), which is well belowthe CI cutoff of �0.80. The Wilkoff approach32 can becombined with other methods to determine the presence of CI

Figure 2. Relationship between age and maximal heart rate in�5000 asymptomatic women, with 95% confidence limits. Fromthese data, a new prediction equation was proposed: Peakheart rate�206�0.88�age. Reproduced from Tanaka et al.21

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in challenging situations, such as the following: (1) If despitereaching a peak exercise RER �1.05 (which suggests ade-quate effort), the patient fails to achieve an HRmax �80% to85% of APHRR (or 80% to 85% HR reserve), or (2) if RERdoes not reach 1.05 (which suggests submaximal effort), anMCR relationship of �0.80 can be used.

Although a variety of exercise testing protocols (Bruce,RAMP, etc) and modes of testing can be used, a specific CIexercise testing protocol has been used in some laboratoriesthat evaluates the MCR relationship from 2 stages on atreadmill protocol (stage 1�1.3 mph and 0.5% grade andstage 2�3.0 mph and 1.5% grade). The process of datacollection and analysis described above is subsequently usedto determine the adequacy of the chronotropic responses.32

Savonen et al33,34 have proposed methods that attempt toseparate the effects of parasympathetic withdrawal versussympathetic stimulation on the HR response to exercise. Thisis based on physiological observations that the HR increasebelow 100 bpm is predominantly controlled by gradualwithdrawal of parasympathetic tone, whereas from 100 bpmto maximum, the HR increase is predominantly the result ofincreasing sympathetic nervous system activity. Savonen et alhave termed this a “delineational” approach. Their workindicates that in men with and without coronary heart disease,an increase in HR from 40% to 100% of maximal workcapacity on the exercise test predicts mortality and acutemyocardial infarction better than the peak HR or HR reserveapproaches. Similarly, another study35 demonstrated that ablunted HR increase from rest to 33% of maximal workcapacity was not as strong of a predictor of death as a low HRreserve in patients referred for exercise testing. Althoughprovocative, these innovative approaches for assessing chro-notropic response to exercise will require further validationbefore clinical application.

Effect of Medications and Other ConfoundingInfluences on CI

A number of commonly used cardiovascular medications,including �-blockers, digitalis, certain calcium channel

blockers, amiodarone, and others, can confound the determi-nation of CI.36,37 �-Blockers may result in pharmacologicallyinduced CI and obscure identification of an underlyingintrinsic abnormality in neural balance.37 In one study,38 asuitable threshold for CI among HF patients using �-blockerswas found to be �62% of APHRR. With this lower HRthreshold, CI could be identified reliably and was an inde-pendent predictor of death.38 These modified criteria havebeen used to design clinical trials.39 Care should be takenbefore these modified threshold criteria are applied to ensurethat the patient is taking a nontrivial dose and is compliantwith the medication.

The use of separate CI criteria for patients taking �-blockermedications has been challenged by other studies that failedto demonstrate any effect of �-blockers, including at a highdose, on the occurrence of CI.40 Figure 3 shows the similarrelationship between HR reserve and V̇O2 peak in HF patientswho were either taking or not taking �-blockers. Similarly,Jorde and colleagues41 examined the relationship betweenexercise time and HR during treadmill exercise testing in HFpatients. As seen in Figure 4, the HR slope was abnormal inHF patients with CI, yet �-blockers had no impact on thisrelationship in these patients.42 Although still an evolving

Figure 3. There is a significant relationship between change in heart rate (HR) during exercise and V̇O2peak in patients (pts) with heartfailure with reduced ejection fraction, but there is no significant difference in this relationship between those patients taking �-blockersand those not taking them. Reproduced from Magri et al.40

Figure 4. In patients with heart failure, �-blockers (BB) do notsignificantly impact the relationship between heart rate andexercise time, regardless of whether chronotropic incompetence(CI) is present. Reproduced from Jorde et al.41

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concept, chronic treatment of HF patients with �-blockersmay paradoxically improve chronotropic response by de-creasing sympathetic tone or increasing �-receptor activity.43

Chronic atrial fibrillation confounds the assessment of CI,and criteria for its diagnosis have not been established.Exercise testing can be used to assess adequacy of responseafter pacemaker insertion for CI. Intrinsic HR response can beassessed in patients with existing pacemakers by reprogram-ming or suspending the device with a magnet, taking care toensure the patient is not completely pacemaker dependentbeforehand.

Relationship Between CI and MortalityThe relationship between CI and increased cardiac andall-cause mortality was first reported more than 30 years agoby Hinkle et al.44 They described a group of men who wereunable to reach an expected HR on a standard exerciseprotocol and who subsequently experienced an increasedfrequency of cardiac events during 7-year follow-up. Theseinvestigators initially termed this inadequate HR response a“sustained relative bradycardia.” Subsequently, others45,46 de-scribed a relationship between this phenomenon and auto-nomic dysfunction. Ellestad et al47 confirmed the finding ofincreased risk of cardiac events during long-term follow-upand showed that the risk of cardiac events associated with anabnormal HR response during exercise was greater than thatassociated with ischemic ST-segment depression. He sug-gested the term “chronotropic incompetence” to describe thisabnormal HR response during exercise.

Subsequently, a number of studies expanded on thesefindings and reported that an attenuated HR response toexercise is predictive of increased mortality and coronaryheart disease risk, independent of a variety of other confound-ing factors, including age, gender, physical fitness, traditionalcardiovascular risk factors, and ST-segment changes duringexercise.19,28,48,49 In �5000 asymptomatic women, those withpeak exercise HR �1 SD below the predicted mean hadmarkedly increased mortality during long-term follow-up(Figure 5).19 An attenuated HR response was found to be

predictive of myocardial perfusion defects.28 A combinationof CI and a myocardial perfusion defect during exercise stresstesting defined a particularly high-risk group of patients aspotential candidates for heightened treatment.28 The prognos-tic value of an impaired HR response to exercise appears topersist even after the adverse effects of coronary arterydisease or LV dysfunction are considered.29

In another study30 of 3221 patients who underwent tread-mill exercise echocardiography with a median follow-up of3.2 years, failure to achieve 85% of maximal predicted HRwas associated with increased mortality and cardiac deatheven after adjustment for LV function and exercise-inducedmyocardial ischemia. Azarbal et al50 showed that a lowpercentage of HR reserve was a superior predictor comparedwith an inability to achieve 85% of APMHR, because thelatter method identified 2.2 times more individuals at in-creased risk of cardiac death. An attenuated HR response toexercise also predicts major adverse cardiac events amongpersons with known or suspected cardiovascular disease.51

Furthermore, in HF patients not taking �-blockers, the pres-ence of CI appears to increase mortality risk.52

Thus, the HR profiles both during and after exercise arestrong predictors of sudden death in asymptomatic andselected clinical populations, including those with coronaryartery disease or HF. Collectively, these findings provide therationale for increased screening for inappropriate or inade-quate HR responses during exercise testing and recovery toassist with more effective risk stratification and prognosis.

Mechanisms of Exercise Intolerance in HFIn contrast to most other forms of heart disease, the incidenceof HF, a debilitating disorder, is increasing, with 500 000 newcases in the United States per year and a 175% increase in thenumber of hospital discharges for HF over the past 20 years.53

It has been shown that a majority of persons with HF livingin the community have a preserved LV ejection fraction(HFpEF).54–56 A hallmark characteristic of chronic HF, eitherHF with reduced ejection fraction (HFrEF) or HFpEF, is amarkedly reduced capacity for physical exertion, with asubsequent reduction in V̇O2peak that is 15% to 40% belowthat of age-matched control subjects.57 Work from our groupand others has shown that patients with HFpEF have similarreductions in exercise tolerance, measured as peak exerciseoxygen consumption (V̇O2peak), and have similar reducedsubmaximal exercise measures, ventilatory anaerobic thresh-old, 6-minute walk distance, quality of life, and markers ofprognosis, including V̇E/V̇CO2 slope, as those withHFrEF.58–61 These findings have been replicated by Smartet al62 and others.

According to the Fick equation, an appropriate increase inV̇O2peak during exertion is dependent on both an increase incardiac output and concomitant widening of the arterial-venous oxygen content difference.63,64 The latter is related toabnormalities of skeletal muscle and vascular function thatlimit exercise intolerance associated with HF.57,63,65 In addi-tion, patients with HF often achieve �50% of the maximalcardiac output achieved by healthy individuals at peak exer-cise.57 The impairment in cardiac output response of HFpatients correlates significantly with reductions in V̇O2peak.66

Figure 5. Markedly reduced survival during long-term follow-upamong asymptomatic women with peak heart rate (HR) �1standard deviation (SD) below average. Reproduced from Gulatiet al.19

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The reduced cardiac output response of HF is often attributedto an attenuated stroke volume, subsequent to either systolicor diastolic LV dysfunction. Stroke volume, already dimin-ished at rest in the HF patient subsequent to systolic ordiastolic abnormalities, rises only modestly to a peak of 50 to65 mL versus �100 mL in healthy subjects.67 Consequently,HF patients must rely to a greater extent on increases in HRto augment cardiac output to compensate for their inadequatestroke volume during physical exertion. Although maximalHR during exercise may be reduced only mildly at peakexertion, HR reserve (ie, degree of HR augmentation aboveresting levels) is often blunted more substantially in HFpatients owing to the sympathetically driven elevation inresting HRs.67

Contribution of Impaired HR Response toExercise Intolerance in HF

As described previously, the Fick equation dictates that anincrease in cardiac output during exertion is dependent on anincrease in stroke volume, HR, or both. In HFrEF and HFpEFpatients, the primary limiting factor during exertion is gen-erally assumed to be an inability to increase the strokevolume commensurate with the degree of effort. Yet, giventhe potential impact of HR responsiveness on cardiac outputand subsequent V̇O2peak, it is surprising there has not beenmore interest in CI in a patient population in which exerciseintolerance is so problematic. We68 recently demonstratedthat in a group of 102 elderly patients with either HFrEF orHFpEF, HR reserve (the difference between resting and peakHR achieved on a bicycle exercise test) was significantlycorrelated (r�0.40) with V̇O2peak (Figure 6). Moreover,these findings indicated that the increase in HR duringexercise accounted for an appreciable portion (ie, 15%) of theobserved differences in V̇O2peak in these older HF patients.This means that in a patient population with an averageV̇O2peak of 14 mL � kg�1 � min�1, abnormal HR accounts forapproximately 2 mL � kg�1 � min�1 (�16%) and thereforehas significant functional and prognostic ramifications.

Similarly, Witte et al37 found, using �80% of eitherAPMHR or HR reserve, that the average V̇O2peak wassignificantly lower (�2.6 mL � kg�1 � min�1, or 14%, and�4.6 mL � kg�1 � min�1, or 25%, respectively) in HFrEFpatients with CI than in those without CI. Furthermore, Witteet al37 reported a correlation between V̇O2peak and HR(peak exercise HR�rest HR) of 0.56 and 0.60 for �-blockedand non–�-blocked HF patients, which further supports thesignificance and impact of an inadequate HR increase duringexertion in this population.

Borlaug et al69 evaluated parameters of exercise tolerancein HFpEF patients versus a control group without HF butmatched on age, gender, important comorbidities, and LVhypertrophy (controls). At peak exertion, the HFpEF patientshad significant reductions in V̇O2peak (9.0�3.4 versus14.4�3.4 mL � kg�1 � min�1, respectively) and HR (87�20versus 115�22 bpm, respectively) compared with controls.Exercise capacity, expressed as V̇O2peak, correlated directlywith cardiac output but was determined primarily by HR andafterload responses during exercise. In contrast, changes inend-diastolic volume and stroke volume were not correlatedwith exercise capacity. Furthermore, HFpEF patients had aslower HR rise, lower peak exercise HR, and impaired HRrecovery, which indicates abnormal autonomic function inthese patients (Figure 7).69

Prevalence of CI in HFThe reported prevalence of CI within the HF population hasvaried considerably, with a range of 25% to 70%. Thissubstantial variability is likely influenced by the criteria usedto determine CI, as well as differing patient characteristics(age, disease severity, type/dose of medications). In one ofthe earliest papers to evaluate the prevalence of CI in HF,Clark and Coates,70 using �80% of APMHR as the criterion,found that approximately 28% of stable, non–�-blockedsystolic HFrEF patients (mean age 59 years) demonstratedCI. In contrast, Roche et al,71 using achievement of �80% ofAPHRR as the predetermined criterion, determined that 14(67%) of 21 stable, non–�-blocked HFrEF patients (mean age

Figure 6. Relationship of heart rate reserve(HRR) to peak exercise oxygen consumption(V̇O2peak) in older patients with heart failurewith reduced ejection fraction and those withheart failure with preserved ejection fraction,with (E) and without (F) chronotropic incompe-tence (CI). There is a significant correlationbetween HRR and V̇O2peak in those with(R�0.39 P�0.04) and without CI (R�0.41P�0.01). Reproduced from Brubaker et al.68

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54�10 years) demonstrated CI. Furthermore, Roche et al71

found no significant difference in age, HR, peak oxygenuptake, or LV ejection fraction between patients with andwithout CI. In a slightly older group of HFrEF patients, Witteet al37 found that 103 (43%) of 237 HF patients met thecriterion of �80% of APMHR, whereas 170 (72%) of 237met the criterion of �80% of APHRR. Witte et al did indicatethat patients taking �-blockers were more likely to have CIthan those not taking �-blockers when �80% APMHR wasused (49% versus 32%, respectively) or �80% APHRR wasused (75% versus 64%, respectively). In contrast, when thecriterion of �62% APHRR was used for HF patients taking�-blocker therapy, a significantly smaller percentage (22%)of patients were identified with CI.38

We evaluated the prevalence of CI in older (�60 years)HFrEF and HFpEF patients and in age-matched healthysubjects using �80% of APMHR and the Wilkoff approach.68

Although CI was uncommon in healthy older adults (just 2 of28 subjects, or 7%), the prevalence of CI was relativelysimilar between older HFrEF (12 of 46, or 26%) and HFpEF(11 of 56, or 20%) patients. A more recent unpublishedanalysis of 207 older HFpEF patients tested in our laboratoryindicated that 28% of these patients met the CI criteria asdescribed previously. Phan et al42 also observed abnormal HRresponses to exercise in HFpEF patients versus age-matchedhypertensive and healthy control subjects. Using the criterionof �80% APMHR, Phan et al observed a similar prevalenceof CI among HFpEF patients of 35%. As in other studies thatused multiple criteria, the prevalence of CI increased to63% of HFpEF patients when 80% of HR reserve was usedas the definition of CI.42 Consequently, in addition to thecentral and peripheral pathophysiological derangementsobserved in HF patients, a significant portion (one third ormore depending on criteria used) of both HFrEF andHFpEF populations also have significant CI that contrib-utes to their exercise intolerance.

Mechanisms of CI in HFStudies in the 1980s by Bristow et al72 and Colucci et al73

were the first to associate CI in HF with downregulation of

�-receptors and desensitization in the presence of increasedcirculating catecholamine levels. Bristow and colleagues72

found a 50% or greater reduction in �-adrenergic receptordensity in the LV myocardium of failing hearts explantedduring transplant surgery. Colucci et al73 demonstrated thatnorepinephrine infusion results in a reduced HR response inHF patients versus healthy subjects. During maximal isopro-terenol stimulation, Bristow et al72 observed a 45% reductioncompared with normal in adenylate cyclase elaboration andup to a 73% reduction in muscle contraction. These findingssuggest that in HF patients, a decrease in �-receptor densityleads to a diminished sensitivity of the �-adrenergic pathwayand a decrease in �-agonist–stimulated muscle contractility.72

Samejima et al74 demonstrated that the ratio of change in HRto change in log of norepinephrine (HR/log NE), an indexof sinoatrial node sympathetic responsiveness, decreasedprogressively with the severity of HF. Furthermore, theHR/log NE ratio during exercise was significantly corre-lated with anaerobic threshold, V̇O2peak, and VE/VCO2

slope.74 An electrophysiology study75 of symptomatic HFrEFpatients and age-matched normal subjects undergoing radio-frequency ablation for atrioventricular tachycardia or atrio-ventricular nodal tachycardia demonstrated that comparedwith non-HF subjects, HF patients with no prior atrialarrhythmias have significant sinus node remodeling charac-terized by (1) anatomic and structural changes along the cristaterminalis, (2) prolonged sinus node recovery and sinoatrialconduction, and (3) caudal localization of the sinus nodecomplex with circuitous propagation of the sinus impulse.This reduction in sinus node reserve appears to be responsi-ble, at least in part, for the bradycardia and possibly the CIcommonly seen in HF.75

Management of CI in HFExercise TrainingIn addition to many other health benefits, endurance exercisetraining in healthy individuals results in favorable changes inchronotropic function, such as decreased resting and sub-maximal exercise HRs, as well as a more rapid decline inpostexercise HRs. Most of these HR adaptations appear to berelated to an alteration in the balance of the sympathetic andparasympathetic influence of the autonomic nervous system.Moreover, endurance exercise training generally improvesexercise tolerance in HFrEF patients through a variety ofpotential central and peripheral mechanisms. The specificeffects of exercise training on autonomic dysfunction andneurohormonal activation in chronic HF include increasedbaroreflex sensitivity and HR variability and reduced sympa-thetic outflow and plasma levels of catecholamines, angio-tensin II, vasopressin, and brain natriuretic peptides atrest.76,77 Consequently, it appears that exercise training mod-ifies the abnormal afferent stimuli from the failing heart thattend to increase sympathetic outflow, which leads to auto-nomic derangement and neurohumoral activation.76 More-over, Hasking et al78 found that plasma norepinephrineconcentrations sampled during supine rest were increased inpatients with asymptomatic LV dysfunction and increasedfurther with the progression to overt HF; at the later stages of

Figure 7. Heart rate profiles during and after cycle ergometry inpatients with heart failure with preserved ejection fraction(HFpEF) compared with age- and gender-matched subjects whopossessed similar comorbidities to the HFpEF group, includingleft ventricular hypertrophy (control). These data demonstrate thedelayed and attenuated heart rate response often seen in chrono-tropically impaired heart failure patients. From Borlaug et al.69

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overt HF, total body spillover was on average double that ofcontrol subjects, and norepinephrine clearance was reducedby one third. Although beneficial, the specific mechanismresponsible for modification of the neurohumoral activationand autonomic derangement in HF patients during exercisetraining is yet to clarified.

Several exercise training studies79–81 have demonstratedthat peak exercise HR increases 5% to 7% and contributes tothe increase in cardiac output and V̇O2peak usually observedin HF patients with exercise training. A meta-analysis of 35randomized studies of exercise training in HF patients82

indicated that peak HR increased by an average of 4 bpm, or2.5% of the pretraining level. Keteyian et al83 demonstratedthat after 24 weeks of endurance exercise training, peakexercise HR increased by 7% (�9 bpm) yet remainedunchanged in a nonexercise control group. Furthermore, thetraining-induced increase in peak HR accounted for 50% ofthe increase in V̇O2peak (2 mL � kg�1 � min�1, or 14%) in theexercise training group. Although alterations in �-adrenergicreceptor sensitivity may explain these findings, other mech-anisms responsible for or contributing to the improvedchronotropic response in HF patients cannot be excluded.Further information is needed regarding the impact of exer-cise training on the chronotropic response of HFrEF andHFpEF patients.

Rate-Adaptive PacingThere is a linear relationship between HR and V̇O2 duringexercise in a variety of patient populations, including HF,83 inwhich a 2- to 6-bpm increase in HR is associated with a1-mL � kg�1 � min�1 increase in V̇O2 during exercise. Conse-quently, rate-adaptive pacing has been shown to enhancefunctional capacity in patients with an inadequate chrono-tropic response84 and those meeting formal definitions ofCI.32,85 Despite the potential to improve HR, cardiac output,and subsequently V̇O2 during exertion in HF patients withchronotropic impairment, rate-adaptive pacing in this popu-lation has received minimal attention.86,87 Furthermore, itmay be counterintuitive for some clinicians to believe certainHF patients may benefit from a pacemaker, particularly in theabsence of bradycardic/heart block.

The potential benefit of rate-adaptive pacing, in conjunc-tion with cardiac resynchronization therapy, for exerciseperformance in HFrEF patients was assessed by Tse et al.88

Twenty HFrEF patients with CI (defined as achieving �85%APMHR and �80% APHRR) with an implanted cardiacresynchronization device (�6 months) underwent treadmillexercise testing with measurement of V̇O2. During the exer-cise testing, the cardiac resynchronization device was pro-grammed to (1) DDD mode with fixed AVI (DDD-off), (2)DDD mode with AVI algorithm on (DDD-on), and (3)DDDR mode. None of the 20 patients in the study achieved�85% APMR, and 11 (55%) failed to reach �70% APMHR,a level indicative of severe CI. In the overall group, rate-adaptive pacing during cardiac resynchronization therapyincreased peak exercise HR and exercise time but did nothave an incremental benefit on peak exercise V̇O2peak.However, in the HF patients with more severe CI (thoseachieving �70% APMHR), rate adaptation significantly

increased peak HR, exercise time, and V̇O2peak. Furthermore,in the majority (82%) of these patients, the improvement inchronotropic response with rate-adaptive pacing was associ-ated with an �20% increase in V̇O2peak.

For the majority of patients with less severe CI (thoseachieving 70% to 85% of APMHR), there was little or nobenefit, and one third of the patients experienced a reductionin exercise capacity with rate-adaptive pacing.88 Although itappears that rate-adaptive pacing has potential benefit incarefully selected patients with HFrEF, advances in this areaare hindered by lack of standardized, accepted definitions,and selection criteria. Furthermore, at this time, it is unclearwhether CI is causal or simply a marker of advanced diseaseand whether treating this with a pacemaker would improvefunctional status in HFrEF patients. Clearly, this issue re-quires further investigation.

Even less is known regarding pacing in patients withHFpEF. The current RESET trial (Restoration of Chrono-tropic Competence in Heart Failure Patients With NormalEjection Fraction) is designed to evaluate the effect ofrate-adaptive pacing in HFpEF patients with overt CI.39 Therationale for this intervention is based on observations that�30% of this population have CI and that impairment inchronotropic function contributes significantly to their objec-tively measured exercise intolerance.42,68,69 The outcome ofthis randomized controlled trial has the potential to helpdetermine whether rate-responsive pacing is an effectiveapproach for improving exercise functional in this patientpopulation.

Conclusions and Suggested Approach toAssessment and Management

Chronotropic incompetence is common, an important causeof exercise intolerance, and an independent predictor of majoradverse cardiovascular events and mortality. It is present inup to one third of patients with HF and contributes to theirprominent exertional symptoms and reduced quality of life.Although the underlying mechanisms for CI in HF and otherdisorders are incompletely understood, available data suggestroles for reduced �-receptor density and sensitivity secondaryto increased sympathetic drive.89

The diagnosis of CI should take into account the confound-ing effects of aging, physical condition, and medications butcan be achieved objectively with the use of widely availableexercise testing methods and standardized definitions. A3-step approach to assessment is suggested. First, a progres-sive, exhaustive, symptom-limited exercise test should beperformed. If practical, this should include automated expiredgas analysis with a standard, commercially available systemfor assessment of RER, which objectively verifies level ofeffort, and peak V̇O2. Then, a formula for peak HR that isrelevant to the patient’s profile should be applied. In general,this will be the Tanaka formula for apparently healthypersons21 and the Brawner formula for those with cardiovas-cular disease or taking �-blockers.22 If the patient fails toachieve 80% of APMHR on this test despite good/maximaleffort (judged by rating of perceived exertion, symptoms, andRER levels), then the Wilkoff chronotropic index should be

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calculated. If CI is found to be present, a search for poten-tially reversible causes is warranted.

In HF, �-adrenergic blockade may have a less detrimentaleffect on exercise capacity than previously thought and mayeven paradoxically improve exercise performance.�-Blockers and other negative inotropes do not appear tohave a major impact on HR response to exercise in HFpatients, and thus, the use of separate CI criteria for thesepatients does not appear necessary. Furthermore, it appearsthat �-blockers may not increase the prevalence of CI in HFpatients substantially. The potential of more novel �-blockersto reduce the prevalence of CI in HF patients is unclear.

Although exercise training and rate-adaptive pacing havebeen shown to improve chronotropic responses and exercisecapacity in HF, it is clear that more research is needed to fullyevaluate the impact of these therapies on key clinical out-comes. CI is a common, easily diagnosed, and potentiallytreatable cause of exercise intolerance and merits moreattention by clinicians when they encounter patients withsymptoms of effort intolerance.

AcknowledgmentsWe gratefully acknowledge Rickie Henderson, MD, for criticalreview of the manuscript and Belinda Youngdahl for administrativeassistance.

Sources of FundingThis work was supported in part by National Institutes of Healthgrants R37AG18915 and P30AG21332.

DisclosuresDr Brubaker has received a research grant from Boston Scientific. DrKitzman has received research grants from Synvista Therapeutics,Bristol-Myers Squibb, Novartis, Boston Scientific, Relypsa, andForest Laboratories. Both authors participated in drafting of themanuscript, reviewed and edited the manuscript for critical intellec-tual content, and approved the final version for submission. Thesponsor had no role in design and conduct of the study; collection,management, analysis, and interpretation of the data; or preparation,review, or approval of the manuscript.

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KEY WORDS: heart rate � exercise � aging � heart failure � exercise test� cardiac chronotropy

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Peter H. Brubaker and Dalane W. KitzmanChronotropic Incompetence: Causes, Consequences, and Management

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