Effect of Mildly Attenuated Heart Rate Response During TreadmillExercise Testing on Cardiovascular Outcome in Healthy Men

and Women

Elad Maor, MD, PhDa,b,c,d,*, Eran Kopel, MD, MPHb,g, Yechezkel Sidi, MDb,f, Ilan Goldenberg, MDd,f,Shlomo Segev, MDe, and Shaye Kivity, MDa,b,c,f

Attenuated heart rate (HR) response during exercise is associated with adverse cardio-

Departments oDr. Pinchas BorenLeviev Heart CentMedical Center, TAviv University,Ministry of Healtrevised manuscrip

Drs. Maor, KoThis work was

for Medical Researesearch.

See page 1378*CorrespondinE-mail addres

0002-9149/13/$ -http://dx.doi.org/1

vascular outcome. The acceptable value for HR response is 85% of the age-predictedmaximal HR (APMHR). This study hypothesized that mild attenuation of HR responseduring exercise among healthy subjects is associated with increased cardiovascular risk.The study population comprised 10,323 healthy men and women without known cardio-vascular disease (CVD) or diabetes mellitus who underwent a yearly screening program andwere followed up during a mean period of 4.3 years. Participants were grouped to 3 tertilesbased on the percentage of their APMHR reached at the baseline stress test. The primaryend point was the occurrence of CVD or cerebrovascular disease. A total of 1,015 incidentcases of CVD occurred during follow-up. A multivariate Cox proportional hazardsregression model showed that the CVD risk of subjects who reached 60% to 96% of theirAPMHR was 35% greater compared with those who reached their APMHR (p [ 0.001).A subgroup analysis among subjects who reached 85% of their APMHR showed that evenmildly attenuated heart response (in the range of 85% to 96% APMHR) was independentlyassociated with 36% increase in CVD risk (p <0.001). In conclusion, attenuated HRresponse during exercise is a powerful and independent predictor of adverse cardiovascularevents during long-term follow-up among healthy men and women. The prognosticimplications of attenuated HR response in this population are apparent even with a minordecrease of the maximal HR to <96% of the APMHR. � 2013 Elsevier Inc. All rightsreserved. (Am J Cardiol 2013;112:1373e1378)

Attenuated maximal heart rate (HR) during maximal exer-cise, termed chronotropic incompetence, is a strong predictorof cardiovascular morbidity andmortality. It is independent ofother confounding factors, including ST-segment changesduring exercise or coronary artery disease.1,2 Chronotropicincompetence predicts adverse cardiovascular outcomesamong different populations, including healthy men andwomen,3 patients with known coronary artery disease,4 andpatients with heart failure.5 Chronotropic incompetence lacksstandard definition, with most studies using 85% of the age-predictedmaximalHR (APMHR) as the acceptable threshold.6

Some definitions of chronotropic incompetence require otherparameters in addition to themaximalHR, includingHRat restor METs at different stages of the exercise.7,8 The exact

f aInternal Medicine A and bInternal Medicine C, cThestein Talpiot Medical Leadership Program 2012, dTheer, and eInstitute for Preventive Medicine, Chaim Shebael Hashomer, Israel; fSackler Faculty of Medicine, TelTel Aviv, Israel; and gTel Aviv District Health Office,h, Tel Aviv, Israel. Manuscript received June 1, 2013;t received and accepted June 25, 2013.pel, and Sidi contributed equally to the study.supported in part by a grant from the Shalvi Foundationrch and by the contribution of Nathan Hetz for medical

for disclosure information.g author: Tel/fax: (þ972) 03-5302642.s: Elad.Maor@sheba.health.gov.il (E. Maor).

see front matter � 2013 Elsevier Inc. All rights reserved.0.1016/j.amjcard.2013.06.028

threshold below which healthy subjects can be considered tohave increased risk for adverse cardiovascular events duringlong-term follow-up is not known. Therefore, the aims of thepresent study were to (1) describe the association between theHR response during exercise and subsequent cardiovascularmorbidity in a large cohort of asymptomatic men and womenfree of diabetes or ischemic heart disease and (2) identify thedegree of chronotropic incompetence associated with long-term adverse cardiovascular events in this population.

Methods

The Institute for Preventive Medicine of the ChaimSheba Medical Center performs approximately 9,000 annualscreening examinations. All participants are interviewed atthe time of each annual examination using standard ques-tionnaires that gather information about demographic char-acteristics, medical history, and health-related habits.Thereafter, blood samples are drawn after a 12-hour fast andanalyzed immediately. A physician at the center performsa complete physical examination, including blood pressuremeasurement. All subjects undergo a standard exercisestress test each year and are instructed not to take b blockersin the morning of their visit. A computerized database of allthe annual examinations performed in this center wasestablished in the year 2000 and is the source of data for thestudy. The Institutional Review Board of the Sheba MedicalCenter approved this study on the basis of strict maintenanceof participants’ anonymity during database analyses. Data

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Figure 1. Study flow diagram. DM ¼ diabetes mellitus.

1374 The American Journal of Cardiology (www.ajconline.org)

from subjects were recorded anonymously. No individualconsent was obtained.

The study population comprised Caucasian men andwomen >34 years of age, free of ischemic heart, cerebro-vascular diseases, or diabetes mellitus and with plasmafasting glucose <126 mg/dl. Subjects with pathologic,abnormal, or inconclusive exercise stress test in their firstvisit were excluded. Additionally, follow-up data must havebeen available from at least 1 subsequent visit (averagenumber of visits per subject, 5; range, 2 to 9). A total of18,034 subjects with available data were included in thedatabase. The final study sample comprised 10,323 subjects(Figure 1). Baseline characteristics, cardiovascular riskfactors, and HR response of the 3,020 subjects who hada single visit were not statistically different from the char-acteristics of the included subjects (data not shown).9

At each annual visit, each participant had a treadmillexercise test according to the Bruce protocol in the presenceof a board-certified cardiologist. Participants were instructednot to take b blockers in the morning of the visit. APMHRwas defined as (220�age) for all subjects. Maximal HR wasdefined as the maximal HR during the stress test, as docu-mented by the cardiologist during the test. HR response wasdefined as the maximal HR in beats/min divided by theAPMHR and is presented in percentage in all statisticalanalyses. Study population was divided into 3 prespecifiedtertiles based on the percent APMHR reached at the baselinestress test (60.5% to 96.5%, 96.6% to 98.8%, and 98.9% to130.6% of APMHR).

Diagnosis of cardiovascular disease (CVD) was theprimary end point of the study. The outcome was defined assignificant coronary heart disease (angiographically provedstenosis of >50% in at least 1 coronary artery), myocardialinfarction, or acute coronary syndrome reported at the yearlyvisit and approved by the attending physician as well ascerebrovascular disease (see later). All-cause mortality wasdefined as a secondary end point of the study. Cerebrovas-cular outcome included cerebrovascular events or transientischemic attacks, which were diagnosed based on a clini-cally significant neurologic deficit, self-reported, or based

on the participants’ medical record and approved by theattending physician.

End points for termination of the exercise test were clini-cally significant ST-segment depression (>2 mm depressionin 2 contiguous leads measured 80 ms after the J point),intolerable symptoms of angina, and exhaustion or achieve-ment of the APMHR without such findings. All cases witha pathologic stress test were referred for coronary angiog-raphy. In participants with a borderline stress test or whenparticipants reported angina symptoms without diagnosticelectrocardiographic changes, stress perfusion imaging withthallium-201 was performed. Those with a pathologic thal-lium-201 cardiac scan underwent coronary angiography. Forsubjects with a positive stress test for whom data on coronaryangiography or thallium-201 cardiac scan were not available,a positive stress test was considered as confirmation fora positive coronary heart disease.

Baseline clinical characteristics by percent APMHR ter-tiles were compared by either using 1-way analysis ofvariance for continuous variables or chi-square test forcategorical variables to calculate the statistical significanceof the independent variables’ trend of means across HRresponse tertiles. The probability of the development ofa first CVD event during follow-up was estimated andgraphically displayed according to the method of Kaplanand Meier, with comparison of cumulative events acrossstrata by the log-rank test. Multivariate Cox proportionalhazards regression modeling was carried out to evaluatebaseline factors independently associated with the devel-opment of the composite CVD outcome. Prespecifiedcovariates in the multivariate models included HR response(categorized to 3 tertiles), age (continuous), gender, systolicblood pressure (continuous), low-density lipoprotein cho-lesterol (continuous), current smoking status (yes or no),obesity (body mass index >30 or �30 kg/m2), regularphysical activity (yes or no), family history of coronarydisease (yes or no), the use of b blockers, the total numberof cardioprotective medication groups used out of 5predefined groups (antiplatelets, inhibitors of the renin-angiotensin axis, diuretics, rate-control, and lipid-loweringdrugs), HR at rest (continuous), HR recovery (continuous),the level of activity during the exercise (categorized into3 tertiles) and the cardiologists’ final conclusion of theexercise stress test (normal, inconclusive, or suspected ofischemia). All statistical analyses were performed withSPSS (version 20.0) statistical software (IBM Corporation,Armonk, New York).

Results

Dataof10,323menandwomen freeofdiabetes orCVDwereanalyzed in this study. The study population included 7,579men(73%) and2,744women (27%).Mean agewas50.4� 9.2years,mean body mass index was 26.1 � 3.7 kg/m2, and mean low-density lipoprotein cholesterol was 125.6� 28.3 mg/dl. A totalof 13.5% of the study population had hypertension and 16%were active smokers (Table 1).

Maximal HR during the baseline exercise stress testwas documented in all 10,323 subjects. Five hundredseven subjects (5%) failed to achieve 85% of the APMHR(mean HR response was 95.7 � 6.0%). The baseline clinical

Table 2Unadjusted effect of heart rate response on study outcomes

Event Unadjusted Hazard Ratio (95% CI) Number of Events

Lower Tertile Middle Tertile Upper Tertile(Reference)

Lower Tertile Middle Tertile Upper Tertile

Cardiovascular or cerebrovascular disease 1.61 (1.38e1.86) 1.24 (1.06e1.46) 1 428 338 249CVD 1.53 (1.30e1.80) 1.22 (1.03e1.45) 1 385 315 236Cerebrovascular disease 3.09 (1.66e5.75) 1.58 (0.81e3.14) 1 43 23 13All-cause mortality 1.72 (1.03e2.86) 0.95 (0.54e1.66) 1 50 30 22

Figure 2. Kaplan-Meier curve showing the cumulative survival of subjectsfree from CVD or cerebrovascular disease. The percentage of patients freefrom CVD as a function of time of follow-up in years. The lower tertile is inblue color, the middle tertile is in green color, and the upper tertile is inyellow color (log-rank p value <0.001 for the overall difference duringfollow-up; for interpretation of the references to color in this figure legend,the reader is referred to the web version of this article.).

Table 1Baseline characteristics of study population (n ¼ 10,323)

Characteristic* All First Tertile, n ¼ 3,452(60.5%e96.5%)

Second Tertile, n ¼ 3,462(96.6%e98.8%)

Third Tertile, n ¼ 3,409(98.9%e130.6%)

HR response (%)† 95.7 � 5.9 90.5 � 6.5 98.2 � 0.93 102.0 � 2.4Age (yrs)† 50 � 9 52 � 10 49 � 8 50 � 8Men† 73 67 76 78Body mass index (kg/m2)† 26 � 4 27 � 4 26 � 3 25 � 4Systolic blood pressure (mm Hg)† 120 � 20 122 � 22 121 � 19 117 � 18HR at rest (beats/min)† 76 � 16 73 � 16 77 � 16 79 � 17Low-density lipoprotein cholesterol (mg/dl)† 126 � 28 125 � 28 127 � 28 124 � 28Hypertension† 14 21 11 8Current smoker† 16 20 14 13Physical activity 63 61 62 64Family history of ischemic heart disease 33 33 32 32

* All values are reported as percentages or means � SD.† p Value for trend <0.001.

Preventive Cardiology/Attenuated Heart Rate Response During Exercise 1375

characteristics of study patients by tertiles of percentAPMHR reached at the baseline stress test are presented inTable 1. Average HR response was 90.5 � 6.5% in the firsttertile, 98.2 � 0.93% in the second tertile, and 102 � 2.4%

in the third tertile. Mean age was greater in the first HRresponse tertile and similar in the upper 2 tertiles. Thefrequency of men increased with increasing tertiles of HRresponse, whereas mean body mass index, the frequency ofhypertension and of smokers were all inversely correlatedwith increasing tertiles of percent APMHR reached(Table 1).

During 44,806 person-years of follow-up (mean follow-up of 4.3 years), there were 1,015 (9.8%) documentedincident cases of CVD end points (936 cases of coronaryartery disease, 79 cases of cerebrovascular events). Onehundred two subjects died during the follow-up period (1%).

Compared with the upper tertile (98.9% to 130.6% ofAPMHR), patients in the lowest tertile (60.5% to 96.5% ofAPMHR) had a significant 61% (p <0.001) increase in theunadjusted risk for the development of CVD outcomesduring follow-up and patients in the middle tertile hada corresponding 24% (p ¼ 0.02) risk increase (Table 2).Consistent with those findings, Kaplan-Meier survivalanalysis showed that the cumulative probabilities for thedevelopment of CVD at 4-year follow-up were 6.6% amongsubjects in the upper HR response tertile, 8.5% among thosein the middle tertile, and 10.4% among those in the lowesttertile (log-rank p value <0.001 for the overall differenceduring follow-up; Figure 2).

The fully adjusted multivariate model showed thatcompared with the upper tertile of HR response, the lowertertile was independently associated with a significant 35%(p ¼ 0.001) increased hazard ratio for the development ofCVD during follow-up and the middle tertile was associated

Table 3Cox proportional hazards regression model for study primary outcome

Variable Hazard Ratio 95% Confidence Interval p Value p Value for Interaction*

HR responseUpper tertile 1Middle tertile 1.23 1.04e1.45 0.01Lower tertile 1.35 1.14e1.6 0.001

Age (1-yr increment) 1.05 1.04e1.56 <0.001 0.51Men 1.74 1.47e2.06 <0.001 0.33Current smoking 1.13 0.95e1.34 0.16 0.60Body mass index �30 kg/m2 0.87 0.72e1.06 0.16 0.86Low-density lipoprotein cholesterol (1 mg/dl increment) 1.004 1.002e1.006 0.001 0.60SBP (1-mm Hg increment) 1.005 1.001e1.008 0.007 0.48Regular physical activity 0.38 0.33e0.46 <0.001 0.03Family history of ischemic heart disease 1.25 1.10e1.42 0.001 0.05b Blockers 1.27 0.97e1.66 0.09 0.43HR at rest (1 beat/min increment) 0.997 0.993e1.002 0.24 0.59HR during recovery (1 beat/min increment) 1.000 0.997e1.004 0.85 0.1Cardioprotective drugsNone 11 0.71 0.59e0.85 0.003 0.362 0.65 0.52e0.82 0.002 0.183 0.53 0.37e0.75 0.003 0.714 0.10 0.04e0.28 <0.001 0.535 0.08 0.01e0.56 .014 0.98

METs (kcal$kg�1 h�1)1.1e10.1 110.2e12.9 0.84 0.71e0.98 0.030 0.25>13 0.82 0.64e1.06 0.125 0.43Missing data 0.88 0.74e1.04 0.131 0.46

Ergometry resultsNormal 1Inconclusive 2.688 2.19e3.30 <0.001 0.06Suspected 5.330 3.23e8.79 <0.001 0.67Missing 2.744 2.37e3.19 <0.001 0.37

SBP ¼ systolic blood pressure.* For interaction with HR response.

1376 The American Journal of Cardiology (www.ajconline.org)

with a corresponding 23% (p ¼ 0.01) increase of hazard ratio(Table 3). Additional factors in the multivariate model inde-pendently associated with increased hazard ratio for CVDevents were gender, age, low-density lipoprotein cholesterol,systolic blood pressure at rest, regular physical activity,family history of CVD, the use of cardioprotective drugs, andthe cardiologist’s final conclusion of the exercise stress test.Notably, HR recovery during the index exercise test was notshown to be significantly associated with outcome afteradjustment for HR response, suggesting that the lattermeasure may have more important prognostic implications.

Of the entire study cohort, 102 subjects (1%) died duringthe follow-up period. Of the subjects who died, 50 were inthe lower tertile of HR response, 30 were in the middletertile, and 22 were in the upper tertile. The mean HRresponse during the baseline stress test among the 102subjects who died was less compared with that of thesurvivors (91.4 � 6.2% vs 95.8 � 10.1%, p <0.001).Unadjusted hazard ratio for all-cause mortality was higheramong subjects in the lower tertile compared with the uppertertile of the HR response (1.72, 95% confidence interval[CI] 1.03 to 2.86, p ¼ 0.04; Table 2). Kaplan-Meier survivalanalysis showed that the cumulative probabilities for deathat 4-year follow-up were 0.8% among subjects in the lower

HR response tertile, 0.5% among those in the middle tertile,and 0.6% among those in the upper tertile (log-rankp value ¼ 0.006 for the overall difference during follow-up).

A subgroup analysis of 9,754 subjects (95% of thepopulation study) with APMHR of �85% was performed.Subjects were categorized again into 3 tertiles based ontheir maximal HR during exercise (85% to 96.0%, 96.1%to 98.8%, and 98.9% to 130.6%). A multivariate modeladjusted for the same variables aforementioned showed thatthe hazard ratio for CVD outcome was significantly higheramong subjects in the lower tertile compared with the uppertertile (hazard ratio 1.35, 95% CI 1.15 to 1.63, p <0.001;Figure 3) and to a lesser extent for subjects in the middletertile (hazard ratio 1.23, 95% CI 1.04 to 1.45, p ¼ 0.015).

To validate the consistency of those findings, we carriedout an additional analysis among 8,693 subjects withAPMHR of 85% to 100% in which the HR response wasused as a continuous measure. A multivariate modeladjusted for the same variables aforementioned showedthat for subjects with a maximal HR response in the range of85% to 100% of APMHR, each 1% reduction in HRresponse was associated with a corresponding 3% increasein CVD outcome (hazard ratio 1.03, 95% CI 1.01 to 1.05,p ¼ 0.001).

Figure 3. Forest plot of subjects with HR response of �85%. The figureshows graphically the fully adjusted Cox proportional hazards regressionmodel for the primary cardiovascular outcome of the subgroup of subjectswith an HR response of �85% (n ¼ 9,754). LDL ¼ low-density lipopro-tein; SBP ¼ systolic blood pressure.

Preventive Cardiology/Attenuated Heart Rate Response During Exercise 1377

Discussion

The present study shows that even a small reduction inthe maximal HR response, to the range of 85% to 96% ofthe APMHR, is associated with adverse CVD outcome andincreased all-cause mortality. Furthermore, the study showsthat even within the group of subjects with HR response inthe range of 85% to 100%, each 1% reduction in theAPMHR is independently associated with a corresponding3% increase in CVD outcomes. The results regarding theprognostic implications of HR response persisted afteradjustment for multiple clinical and laboratory covariatesand HR recovery during the index exercise test. Thesefindings stress the importance of assessing HR response toexercise among healthy subjects undergoing routinescreening with an exercise test and suggest that a thresholdgreater of the acceptable 85% APMHR value should be usedfor risk assessment in this population.

Attenuated maximal HR during exercise lacks standard-ized criteria. Previous reports arbitrarily defined chrono-tropic insufficiency as the inability to reach 70%, 80%, or85% of the APMHR.7 To the best of our knowledge, our

cohort is the largest to date to focus on the subject of chro-notropic incompetence among healthy asymptomaticsubjects. In our cohort, only 5% were unable to reach 85% ofAPMHR. This percentage is less than in previous reports andstresses the healthy nature of the present study population.For example, Elhendy et al10 in a cohort of 512 patientsreferred for dobutamine stress test found that 38% failed toreach 85% of APMHR. In another study, Lauer et al3 foundthat 21% of the subjects in a study of 1,575 young maleparticipants who were free of coronary heart disease failed toreach 85% of the APMHR. In another report by Lauer et al4

of patients referred for treadmill exercise testing, 11% of the2,953 patients did not achieve 85% of the APMHR. Gulatiet al, in their study of 5,932 asymptomatic women, showedthat the inability to achieve 85% of APMHR was not anindependent predictor of mortality, but being �1 SD belowthe mean APMHR was an independent predictor ofmortality.3 In another important and relatively large study of5,713 men, Jouven et al11 demonstrated that subjects witha difference of <89 beats/min between the resting andmaximum HRs had an increased risk of sudden cardiac death.

In our analysis, subjects in the lower tertile had a signif-icant increase in the risk for adverse CVD outcomes.However, it included a relatively wide range of HR response(60.5% to 96.6%). Therefore, we further analyzed onlythose patients who achieved a maximal HR of at least 85%of their APMHR. This analysis of 9,754 patients similarlyshowed that patients with maximal HR percentage of 85%to 96% had an adverse CVD outcome compared withpatients in the upper tertile. Our findings challenge thecommonly used thresholds and show that even the mildattenuations of the HR response are correlated with worsecardiovascular outcome in a healthy population of adult menand women. Furthermore, we have shown that assessmentof APMHR percentage as a continuous measure, even in therange of 85% to 100% of the APMHR, has importantclinical implications in this population.

Chronotropic incompetence is a reflection of dysfunctionof the autonomic nervous system.11 Other examples for suchdysfunction include HR at rest, HR variability, or HRrecovery after exercise. All have been correlated withcardiovascular risk.12,13 Our findings are consistent withthese previous observations. The adjustment for HR at restand HR recovery in this study was used to show that thecorrelation between HR response and CVD risk was inde-pendent and stronger than the other 2 parameters.

We used the traditional formula for the expectedAPMHR (220�age). This formula was the acceptableformula during the time of this study. Tanaka et al14

demonstrated in their meta-analysis that this traditionalformula is an underestimation of the true APMHR. Ourfinding, that even patients with an HR very close to theAPMHR were still at an increased cardiovascular risk,supports observation by Tanaka et al that the commonlyused formula is indeed an underestimation.

The strengths of our study include the relatively largecohort size, the young and apparently healthy population,and the subanalysis of patients with HR >85% of theAPMHR. Despite these strengths, our study has severallimitations: First, this is a retrospective observational study,and therefore, there is risk of residual confounding. Second,

1378 The American Journal of Cardiology (www.ajconline.org)

the study consisted of relatively young, healthy and of highsocioeconomic background population. Third, abnormalstress test result was used as a proxy for the diagnosis of CVDin the absence of coronary angiography or a thallium stress,despite the reduced sensitivity and specificity of this test inmiddle-age healthy population. Finally, we did not havecomplete information regarding the breakdownof the primaryoutcomes for all study subjects. However, among subjects forwhom these data were available, subanalysis showed thatcardiovascular events comprised myocardial infarction in 7%of cases, angiographically proved coronary disease in 50%,and a positive noninvasive test result in the remaining cases,whereas cerebrovascular events comprised stroke in 38% andtransient ischemic attack in the remaining cases.

We believe that to enable the use of chronotropicincompetence as predictive clinical tool, further prospectivestudies should focus on finding validated and widelyaccepted greater threshold for chronotropic incompetence.At present, our findings suggest that among healthy subjectsundergoing stress testing, greater than conventionalAPMHR thresholds should be used for risk assessment.

Disclosures

The authors have no conflicts of interest to disclose.

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