Methods

The Institute for Preventive Medicine of the Chaim Sheba Medical Center performs approximately 9,000 annual screening examinations. All participants are interviewed at the time of each annual examination using standard questionnaires that gather information about demographic characteristics, medical history, and health-related habits. Thereafter, blood samples are drawn after a 12-hour fast and analyzed immediately. A physician at the center performs a complete physical examination, including blood pressure measurement. All subjects undergo a standard exercise stress test each year and are instructed not to take β blockers in the morning of their visit. A computerized database of all the annual examinations performed in this center was established in the year 2000 and is the source of data for the study. The Institutional Review Board of the Sheba Medical Center approved this study on the basis of strict maintenance of participants’ anonymity during database analyses. Data from subjects were recorded anonymously. No individual consent was obtained.

The study population comprised Caucasian men and women >34 years of age, free of ischemic heart, cerebrovascular diseases, or diabetes mellitus and with plasma fasting glucose <126 mg/dl. Subjects with pathologic, abnormal, or inconclusive exercise stress test in their first visit were excluded. Additionally, follow-up data must have been available from at least 1 subsequent visit (average number of visits per subject, 5; range, 2 to 9). A total of 18,034 subjects with available data were included in the database. The final study sample comprised 10,323 subjects ( Figure 1 ). Baseline characteristics, cardiovascular risk factors, and HR response of the 3,020 subjects who had a single visit were not statistically different from the characteristics of the included subjects (data not shown).

Study flow diagram. DM = diabetes mellitus.

At each annual visit, each participant had a treadmill exercise test according to the Bruce protocol in the presence of a board-certified cardiologist. Participants were instructed not to take β blockers in the morning of the visit. APMHR was defined as (220−age) for all subjects. Maximal HR was defined as the maximal HR during the stress test, as documented by the cardiologist during the test. HR response was defined as the maximal HR in beats/min divided by the APMHR and is presented in percentage in all statistical analyses. Study population was divided into 3 prespecified tertiles based on the percent APMHR reached at the baseline stress test (60.5% to 96.5%, 96.6% to 98.8%, and 98.9% to 130.6% of APMHR).

Diagnosis of cardiovascular disease (CVD) was the primary end point of the study. The outcome was defined as significant coronary heart disease (angiographically proved stenosis of >50% in at least 1 coronary artery), myocardial infarction, or acute coronary syndrome reported at the yearly visit and approved by the attending physician as well as cerebrovascular disease (see later). All-cause mortality was defined as a secondary end point of the study. Cerebrovascular outcome included cerebrovascular events or transient ischemic attacks, which were diagnosed based on a clinically significant neurologic deficit, self-reported, or based on the participants’ medical record and approved by the attending physician.

End points for termination of the exercise test were clinically significant ST-segment depression (>2 mm depression in 2 contiguous leads measured 80 ms after the J point), intolerable symptoms of angina, and exhaustion or achievement of the APMHR without such findings. All cases with a pathologic stress test were referred for coronary angiography. In participants with a borderline stress test or when participants reported angina symptoms without diagnostic electrocardiographic changes, stress perfusion imaging with thallium-201 was performed. Those with a pathologic thallium-201 cardiac scan underwent coronary angiography. For subjects with a positive stress test for whom data on coronary angiography or thallium-201 cardiac scan were not available, a positive stress test was considered as confirmation for a positive coronary heart disease.

Baseline clinical characteristics by percent APMHR tertiles were compared by either using 1-way analysis of variance for continuous variables or chi-square test for categorical variables to calculate the statistical significance of the independent variables’ trend of means across HR response tertiles. The probability of the development of a first CVD event during follow-up was estimated and graphically displayed according to the method of Kaplan and Meier, with comparison of cumulative events across strata by the log-rank test. Multivariate Cox proportional hazards regression modeling was carried out to evaluate baseline factors independently associated with the development of the composite CVD outcome. Prespecified covariates in the multivariate models included HR response (categorized to 3 tertiles), age (continuous), gender, systolic blood pressure (continuous), low-density lipoprotein cholesterol (continuous), current smoking status (yes or no), obesity (body mass index >30 or ≤30 kg/m ² ), regular physical activity (yes or no), family history of coronary disease (yes or no), the use of β blockers, the total number of cardioprotective medication groups used out of 5 predefined groups (antiplatelets, inhibitors of the renin-angiotensin axis, diuretics, rate-control, and lipid-lowering drugs), HR at rest (continuous), HR recovery (continuous), the level of activity during the exercise (categorized into 3 tertiles) and the cardiologists’ final conclusion of the exercise stress test (normal, inconclusive, or suspected of ischemia). All statistical analyses were performed with SPSS (version 20.0) statistical software (IBM Corporation, Armonk, New York).

Results

Data of 10,323 men and women free of diabetes or CVD were analyzed in this study. The study population included 7,579 men (73%) and 2,744 women (27%). Mean age was 50.4 ± 9.2 years, mean body mass index was 26.1 ± 3.7 kg/m ² , and mean low-density lipoprotein cholesterol was 125.6 ± 28.3 mg/dl. A total of 13.5% of the study population had hypertension and 16% were active smokers ( Table 1 ).

Maximal HR during the baseline exercise stress test was documented in all 10,323 subjects. Five hundred seven subjects (5%) failed to achieve 85% of the APMHR (mean HR response was 95.7 ± 6.0%). The baseline clinical characteristics of study patients by tertiles of percent APMHR reached at the baseline stress test are presented in Table 1 . Average HR response was 90.5 ± 6.5% in the first tertile, 98.2 ± 0.93% in the second tertile, and 102 ± 2.4% in the third tertile. Mean age was greater in the first HR response tertile and similar in the upper 2 tertiles. The frequency of men increased with increasing tertiles of HR response, whereas mean body mass index, the frequency of hypertension and of smokers were all inversely correlated with 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%) documented incident cases of CVD end points (936 cases of coronary artery disease, 79 cases of cerebrovascular events). One hundred two subjects died during the follow-up period (1%).

Compared with the upper tertile (98.9% to 130.6% of APMHR), patients in the lowest tertile (60.5% to 96.5% of APMHR) had a significant 61% (p <0.001) increase in the unadjusted risk for the development of CVD outcomes during follow-up and patients in the middle tertile had a corresponding 24% (p = 0.02) risk increase ( Table 2 ). Consistent with those findings, Kaplan-Meier survival analysis showed that the cumulative probabilities for the development of CVD at 4-year follow-up were 6.6% among subjects in the upper HR response tertile, 8.5% among those in the middle tertile, and 10.4% among those in the lowest tertile (log-rank p value <0.001 for the overall difference during follow-up; Figure 2 ).

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

The fully adjusted multivariate model showed that compared with the upper tertile of HR response, the lower tertile was independently associated with a significant 35% (p = 0.001) increased hazard ratio for the development of CVD during follow-up and the middle tertile was associated with a corresponding 23% (p = 0.01) increase of hazard ratio ( Table 3 ). Additional factors in the multivariate model independently associated with increased hazard ratio for CVD events were gender, age, low-density lipoprotein cholesterol, systolic blood pressure at rest, regular physical activity, family history of CVD, the use of cardioprotective drugs, and the cardiologist’s final conclusion of the exercise stress test. Notably, HR recovery during the index exercise test was not shown to be significantly associated with outcome after adjustment for HR response, suggesting that the latter measure may have more important prognostic implications.

Table 3

Cox proportional hazards regression model for study primary outcome

Variable	Hazard Ratio	95% Confidence Interval	p Value	p Value for Interaction ∗
HR response
Upper tertile	1
Middle tertile	1.23	1.04–1.45	0.01
Lower tertile	1.35	1.14–1.6	0.001
Age (1-yr increment)	1.05	1.04–1.56	<0.001	0.51
Men	1.74	1.47–2.06	<0.001	0.33
Current smoking	1.13	0.95–1.34	0.16	0.60
Body mass index ≤30 kg/m 2	0.87	0.72–1.06	0.16	0.86
Low-density lipoprotein cholesterol (1 mg/dl increment)	1.004	1.002–1.006	0.001	0.60
SBP (1-mm Hg increment)	1.005	1.001–1.008	0.007	0.48
Regular physical activity	0.38	0.33–0.46	<0.001	0.03
Family history of ischemic heart disease	1.25	1.10–1.42	0.001	0.05
β Blockers	1.27	0.97–1.66	0.09	0.43
HR at rest (1 beat/min increment)	0.997	0.993–1.002	0.24	0.59
HR during recovery (1 beat/min increment)	1.000	0.997–1.004	0.85	0.1
Cardioprotective drugs
None	1
1	0.71	0.59–0.85	0.003	0.36
2	0.65	0.52–0.82	0.002	0.18
3	0.53	0.37–0.75	0.003	0.71
4	0.10	0.04–0.28	<0.001	0.53
5	0.08	0.01–0.56	.014	0.98
METs (kcal·kg −1 h −1 )
1.1–10.1	1
10.2–12.9	0.84	0.71–0.98	0.030	0.25
>13	0.82	0.64–1.06	0.125	0.43
Missing data	0.88	0.74–1.04	0.131	0.46
Ergometry results
Normal	1
Inconclusive	2.688	2.19–3.30	<0.001	0.06
Suspected	5.330	3.23–8.79	<0.001	0.67
Missing	2.744	2.37–3.19	<0.001	0.37

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