Heart rate (HR) at rest has been associated inversely with mortality risk. However, fitness is inversely associated with mortality risk and both increased fitness and β-blockade therapy affect HR at rest. Thus, both fitness and β-blockade therapy should be considered when HR at rest–mortality risk association is assessed. From 1986 to 2011, we assessed HR at rest, fitness, and mortality in 18,462 veterans (mean age = 58 ± 11 years) undergoing a stress test. During a median follow-up period of 10 years (211,398 person-years), 5,100 died, at an average annual mortality of 24.1 events/1,000 person-years. After adjusting for age, body mass index, cardiac risk factors, medication, and exercise capacity, we noted approximately 11% increase in risk for each 10 heart beats. To assess the risk in a wide and clinically relevant spectrum, we established 6 HR at rest categories per 10 heart beat intervals ranging from <60 to ≥100 beats. Mortality risk was significantly elevated at a HR at rest of ≥70 beats/min (hazard ratio 1.14, confidence interval 1.04 to 1.25; p <0.006) and increased progressively to 49% (hazard ratio 1.49, confidence interval 1.29 to 1.73; p <0.001) for those with a HR at rest of ≥100 beats/min. Similar trends were noted when for subjects aged <60 and ≥60 years and those treated with β blockers. In all assessments, mortality risk was consistently overestimated when fitness was not considered. In conclusion, HR at rest–mortality risk association was direct and independent. A progressive increase in risk was noted >70 beats/min for the entire cohort, those treated with β blockers, and those aged <60 and ≥60 years. Mortality risk was overestimated slightly when fitness status was not considered.
Elevated heart rate (HR) at rest has been associated inversely with cardiovascular and overall mortality in general populations and in subjects with established heart disease, hypertension, and diabetes mellitus. Evidence suggests that reduction in HR at rest may improve endothelial function and delay the progression of coronary atherosclerosis. HR at rest is affected by fitness status and β blockers. Furthermore, exercise capacity is inversely associated with mortality risk regardless of age, gender, or risk factors. Thus, fitness status and β-blockade therapy must be considered when the HR–mortality risk association is assessed. Previous studies assessing the HR at rest–mortality risk association accounted for fitness based on self-reported levels of physical activity. However, questionnaires are highly subjective and can be unreliable. In some studies, β-blockade therapy was not considered and HR at rest was assessed manually by radial pulse rate. These factors increase the likelihood for inconsistent findings. Therefore, in the present study, we assessed the HR at rest–mortality risk association, adjusted for exercise capacity as determined during an exercise tolerance test. In addition, we considered those treated with β blockers separately and those aged <60 and ≥60 years.
Methods
From 1986 to 2011, symptom-limited exercise tolerance tests were performed on >20,000 veterans at the Veterans Affairs Medical Centers in Washington, DC and Palo Alto, California, either as part of routine evaluations or to assess exercise-induced ischemia. This information along with the subject’s medical history was electronically stored. We excluded those with any of the following: (1) history of an implanted pacemaker, (2) left bundle branch block, (3) subjects unable to complete the test for any reason or required emergent intervention, (4) those who were not treated with β blockers and did not achieve at least 85% of age-predicted heart, (5) those with a body mass index (BMI) of <16 kg/m 2 , and (6) those with chronic obstructive pulmonary disease. After these exclusions, the participant cohort comprised a total of 18,462 subjects (18,033 men and 429 women; mean age 58.3 ± 11.4 years). Of those, 8,427 (46%) approximately were African-American (mean age 58 ± 11.2 years), 8,963 (49%) were Caucasian (mean age 59.2 ± 11.5 years), and 1,072 (6%) were other races (i.e., Native Americans and Asians; mean age 57.2 ± 11.4 years). The study was approved by the institutional review board at each institution, and all subjects gave written informed consent before undergoing exercise tolerance test.
All demographic, clinical, and medication information was obtained from the subject’s computerized medical records just before their exercise tolerance test. Each subject was asked to verify the computerized information, including history of chronic disease, current medications, and smoking habits. Body weight and height were assessed by a standardized scale and recorded before the test. BMI was calculated as weight (kg) divided by height squared (m 2 ). Demographic data are listed in Table 1 .
| Heart Rate Categories | |||||||
|---|---|---|---|---|---|---|---|
| Entire Cohort (%) | <60 (%) | 60–69 (%) | 70–79 (%) | 80–89 (%) | 90–99 (%) | ≥100 (%) | |
| Number of participants | 18,462 | 2,823 (15) | 4,847 (26) | 4,928 (27) | 3,461 (19) | 1,634 (9) | 769 (4) |
| Age (yrs) ∗ | 58 ± 11 | 60 ± 12 | 59 ± 11 | 58 ± 11 | 58 ± 11 | 57 ± 11 | 57 ± 11 |
| <60 | 9,758 | 1,276 | 2,444 | 2,660 | 1,948 | 979 | 451 |
| ≥60 | 8,704 | 1,547 | 2,403 | 2,268 | 1,513 | 655 | 318 |
| Weight (kg) ∗ | 89 ± 18 | 87 ± 16 | 88 ± 16 | 89 ± 18 | 91 ± 19 | 90 ± 19 | 90 ± 19 |
| Body mass index (kg/m 2 ) | 28.7 ± 5 | 28.1 ± 5 | 28.4 ± 5 | 28.8 ± 5 | 29.3 ± 6 | 29.3 ± 6 | 29 ± 6 |
| Resting Heart Rate (beats/min) ∗ | 74 ± 14 | 54 ± 4 | 65 ± 3 | 74 ± 3 | 84 ± 3 | 94 ± 3 | 105 ± 5 |
| Systolic blood pressure at rest (mm Hg) | 131 ± 20 | 131 ± 21 | 130 ± 20 | 131 ± 20 | 132 ± 20 | 131 ± 20 | 132 ± 20 |
| Diastolic blood pressure at rest (mm Hg) ∗ | 80 ± 12 | 78 ± 12 | 79 ± 11 | 80 ± 11 | 82 ± 12 | 82 ± 12 | 83 ± 12 |
| Peak metabolic equivalents ∗ | 7.6 ± 3 | 7.7 ± 3 | 7.8 ± 3 | 7.6 ± 3 | 7.5 ± 3 | 7.4 ± 3 | 7.0 ± 3 |
| Black ∗ | 46 | 15 | 26 | 27 | 19 | 9 | 4 |
| White ∗ | 49 | 12 | 23 | 28 | 22 | 10 | 5 |
| Unknown ∗ | 5 | 8 | 21 | 29 | 22 | 14 | 7 |
| Cardiovascular disease ∗ | 21 | 26 | 22 | 20 | 18 | 17 | 14 |
| Family history of cardiovascular disease ∗ | 17 | 15 | 17 | 18 | 18 | 18 | 17 |
| Smokers ∗ | 23 | 23 | 21 | 23 | 24 | 23 | 24 |
| Hypertension ∗ | 50 | 51 | 50 | 50 | 50 | 52 | 53 |
| Type 2 diabetes Mellitus ∗ | 38 | 28 | 34 | 40 | 43 | 45 | 46 |
| β Blocker ∗ | 16 | 28 | 21 | 13 | 8 | 7 | 7 |
| Calcium channel blocker ∗ | 19 | 19 | 18 | 20 | 18 | 20 | 19 |
| Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers ∗ | 17 | 17 | 16 | 17 | 17 | 18 | 17 |
| Diuretics ∗ | 12 | 12 | 12 | 12 | 11 | 12 | 11 |
| Nitrates or vasodilators ∗ | 8 | 10 | 8 | 8 | 7 | 9 | 8 |
| Statins ∗ | 11 | 12 | 12 | 11 | 11 | 9 | 8 |
Dates of death were verified from the Veterans Affairs Beneficiary Identification and Record Locator System File. This system is used to determine benefits to survivors of veterans and has been shown to be 95% complete and accurate. Vital status was determined as of December 28, 2011.
Exercise capacity was assessed by a standard treadmill test using the Bruce protocol at the Veterans Affairs Medical Center, Washington, DC, and an individualized ramp protocol as described elsewhere for men assessed at the Veterans Affairs Medical Center, Palo Alto, California. Peak exercise time was recorded in minutes. Peak exercise capacity (metabolic equivalents [METs]) was estimated using standardized equations based on peak speed and grade for the ramp protocol and on peak exercise time for the Bruce protocol. One MET is defined as the energy expended at rest, which is approximately equivalent to an oxygen consumption of 3.5 ml/kg of body weight per minute. Subjects were encouraged to exercise until volitional fatigue in the absence of symptoms or other indications for stopping. The use of handrails was discouraged but allowed when necessary for balance and safety. Age-predicted peak exercise HR was determined based on a population-specific equation. Medications were not altered before testing.
We formed the following 6 HR categories based on the HR at rest recorded on an electrocardiogram before the exercise test: (1) HR at rest of <60 beats/min (n = 2,823), (2) HR of 60 to 69 beats/min (n = 4,847), (3) HR of 70 to 79 beats/min (n = 4,928), (4) HR of 80 to 89 beats/min (n = 3,461), (5) HR of 90 to 99 beats/min (n = 1,634), and (6) HR of ≥100 beats/min (n = 769). For those treated with β blockers, we formed 4 HR at rest categories (<60 to ≥80 beats/min) to maintain adequate number of subjects in each category and preserve statistical power.
Follow-up time is presented as mean and SD and median years. Mortality rate was calculated as the ratio of events by the person-years of observation. Continuous variables are presented as mean values and SD and categorical variables as relative frequencies (percentage). Baseline associations between categorical variables were tested using chi-square analysis. One-way analysis of variance was applied to evaluate mean differences between age and BMI among fitness categories. Post hoc procedures (Bonferroni) were performed for multiple comparisons. Equality of variances between groups was tested by Levene’s test.
The hazard ratio for all-cause mortality was calculated for the HR at rest categories for the entire cohort, for the 2 age groups (<60 and ≥60 years), and for those treated with β blockers. The HR at rest category of <60 beats/min comprised the reference group. The analyses were adjusted for age, systolic and diastolic blood pressures, BMI, exercise capacity (peak METs), ethnicity, and history of cardiovascular disease, atrial fibrillation or flutter, cardiovascular medications (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, β blockers, calcium channel blocker, diuretics, and vasodilators), hypoglycemic agents, lipid-lowering agents, alcohol or drug abuse, risk factors (hypertension, type 2 diabetes mellitus, and smoking), dyslipidemia, sleep apnea, and muscle-wasting diseases (cancer, human immunodeficiency virus/acquired immunodeficiency syndrome, and renal failure). The assumption of proportionality for all Cox proportional hazard analyses was graphically tested and fulfilled the criteria. p Values of <0.05 using 2-sided tests were considered statistically significant. All statistical analyses were performed using SPSS software version 19.0 (SPSS Inc., Chicago, Illinois).
Results
The median follow-up period was 10.8 years (6.4 and 15.8 for the twenty-fifth and seventy-fifth percentiles, respectively), comprising a total of 211,398 person-years. There were 5,100 deaths (∼28%) with an average annual mortality of 24.1 events per 1,000 person-years. There was no interaction between site-by-METs (p = 0.53), or race-by-METs (p = 0.10), or race-by-heart rate (p <0.11), and therefore, the data were not stratified by site or race.
Demographic and clinical characteristics for the entire cohort and the 6 HR at rest categories are listed in Table 1 . Significant differences were noted in all variables assessed except systolic blood pressure. Hazard ratios for the predictors of mortality risk are listed in Table 2 . With HR at rest introduced in the model as a continuous variable, Cox proportional hazards analysis adjusted for age revealed that mortality risk was approximately 1% higher for each heart beat (hazard ratio 1.01, confidence interval [CI] 1.008 to 1.013) or 11% higher for every 10 heart beats. The risk remained unchanged when the model was fully adjusted and when subjects with fibrillation or flutter were excluded from the analysis.
| Variables | Hazard Ratio (95% CI) | p |
|---|---|---|
| Age (yrs) | 1.06 (1.05–1.06) | <0.001 |
| HR at rest (per 1 heart beat) | ||
| Adjusted for age | 1.01 (1.008–1.012) | <0.001 |
| Adjusted for age, blood pressure, body mass index, hypertension, diabetes mellitus, smoking, dyslipidemia, atrial fibrillation or flutter, cardiovascular disease, cardiac medications, alcohol or drug abuse, ethnicity, lipid-lowering agents, hypoglycemic agents, sleep apnea, and muscle-wasting disease | 1.011 (1.009–1.013) | <0.001 |
| Adjusted for age, blood pressure, body mass index, hypertension, diabetes mellitus, smoking, dyslipidemia, atrial fibrillation or flutter, cardiovascular disease, cardiac medications, alcohol or drug abuse, ethnicity, lipid-lowering agents, hypoglycemic agents, sleep apnea, muscle-wasting disease, and exercise capacity (METs) | 1.009 (1.006–1.011) | <0.001 |
| Age <60 yrs | 1.010 (1.006–1.014) | <0.001 |
| Age ≥60 yrs | 1.009 (1.006–1.011) | <0.000 |
| Body mass index | 0.98 (0.97–0.99) | <0.001 |
| Smoke | 1.24 (1.16–1.32) | <0.001 |
| Diabetes mellitus | 1.23 (1.16–1.31) | <0.001 |
| Hypertension | 1.17 (1.10–1.25) | <0.001 |
| Cardiovascular disease | 1.40 (1.32–1.49) | <0.001 |
| Muscle-wasting disease | 1.90 (1.75–2.05 | <0.001 |
| Peak metabolic equivalents | 0.89 (0.88–0.90) | <0.001 |
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