Heart rate (HR) at rest is associated with adverse cardiovascular events; however, the biologic mechanism for the relation is unclear. We hypothesized a strong association between HR at rest and subclinical inflammation, given their common interrelation with the autonomic nervous system. HR at rest was recorded at baseline in the Multi-Ethnic Study of Atherosclerosis, a cohort of 4 racial or ethnic groups without cardiovascular disease at baseline and then divided into quintiles. Subclinical inflammation was measured using high-sensitivity C-reactive protein, interleukin-6, and fibrinogen. We used progressively adjusted regression models with terms for physical activity and atrioventricular nodal blocking agents in the fully adjusted models. We examined inflammatory markers as both continuous and categorical variables using the clinical cut point of ≥3 mg/L for high-sensitivity C-reactive protein and the upper quartiles of fibrinogen (≥389 mg/dl) and interleukin-6 (≥1.89 pg/ml). Participants had a mean age of 62 years (SD 9.7), mean resting heart rate of 63 beats/min (SD 9.6) and were 47% men. Increased HR at rest was significantly associated with higher levels of all 3 inflammatory markers in both continuous (p for trend <0.001) and categorical (p for trend <0.001) models. Results were similar among all 3 inflammatory markers, and there was no significant difference in the association among the 4 racial or ethnic groups. In conclusion, an increased HR at rest was associated with a higher level of inflammation among an ethnically diverse group of subjects without known cardiovascular disease.
It has been suggested that an elevated heart rate (HR) may reflect an imbalance of the autonomic nervous system, favoring a sympathetic dominance. This autonomic imbalance may also contribute to increased inflammation, which is a central process in the development, progression, and destabilization of atherosclerotic plaques. Previous studies investigating the association between HR at rest and inflammation have been limited because of either missing important covariates such as physical activity and restriction to a single ethnic group or by the inclusion of participants with cardiovascular disease. Therefore, whether there is a consistent and independent association among an ethnically diverse group of subjects without known cardiovascular disease has not been demonstrated. We hypothesized that HR at rest would be independently associated with inflammation as measured by 3 different markers (high-sensitivity C-reactive protein [hs-CRP], interleukin-6 [IL-6], and fibrinogen) and that this association would be consistent across racial or ethnic groups.
Methods
We used participant data from the baseline visit (2000 to 2002) of the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were excluded if they did not have a HR at rest value (n = 49) or were missing all inflammatory markers investigated in this analysis (n = 31), which resulted in a total of 6,735 participants included in this analysis.
Participant HR at rest was recorded from a 12-lead electrocardiography performed at rest at the baseline examination. Participants were fasting for at least 12 hours and were instructed to avoid heavy exercise before the examination. Hs-CRP was measured using the Behring Nephelometer-2 (N High Sensitivity CRP; Dade Behring Inc., Deerfield, Illinois; interassay coefficient of variation 2.1% to 5.7%), IL-6 was measured using an ultrasensitive ELISA assay (Quantikine HS Human IL-6 Immunoassay; R&D Systems, Minneapolis, Minnesota; interassay coefficient of variation 6.3%), and fibrinogen was measured using immunoprecipitation of fibrinogen antigen using the BNII nephelometer (N-Antiserum to Human Fibrinogen; Dade Behring Inc, Deerfield, Illinois; interassay coefficient of variation 2.6%). Blood samples were stored at −70°C and analyzed at a central laboratory (University of Vermont, Burlington, Vermont).
All other covariates were obtained from the baseline MESA clinical examination. Hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or the use of a blood pressure–lowering medication; diabetes was defined as a fasting blood glucose level ≥126 mg/dl or a self-report of diabetes or taking glucose-lowering medications. Physical activity was measured in MESA using the Typical Week Physical Activity Survey, which assessed the frequency and time spent engaging in various physical activities. There were 28 questions about the typical weekly time spent and frequency engaged in activities including household chores, yard work, leisure time, sports, and occupational activity. This included questions about light, moderate, and vigorous physical activities. Time spent in each activity was multiplied by the MET level to obtain MET-h/week. We divided participants into approximate quartiles based on reported moderate and vigorous physical activities. Socioeconomic status was based on total household income and the highest attained level of education. Family history of coronary heart disease (CHD) was defined as a positive history of CHD in a parent, sibling, or child.
Participants were divided into HR at rest quintiles as per most previous HR studies. Inflammation was examined as a continuous variable using linear regression models with robust error variance. Hs-CRP, fibrinogen, and IL-6 were not normally distributed and were therefore log transformed for continuous analyses.
In categorical analyses of the inflammatory variables, we used the clinical cut point for a normal hs-CRP <1 mg/L as the reference group and an elevated hs-CRP of ≥3 mg/L. We used cut points of the upper quartile for fibrinogen (389 mg/dl) and IL-6 (1.89 pg/ml) in our population, with the lowest quartile as the reference group. This approximately corresponds to the definition of hyperfibrinogenemia (400 mg/dl); there is no commonly used clinical cut point for IL-6. For our secondary analyses, we used these categorical cut points to calculate prevalence ratio (PR) regression models. Results of these models are interpreted as the PR of having an elevated inflammatory level (as defined previously) compared with a nonelevated level for each HR quintile, with the lowest HR quintile as the reference.
We used progressively adjusted models, with model 1 including age, gender, and race or ethnicity. Model 2 added body mass index, waist circumference, total household income, highest attained level of education, systolic blood pressure, diastolic blood pressure, pulse pressure, antihypertensive medication use, smoking status, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, lipid-lowering medication use, and a family history of CHD. Model 3 added physical activity level and atrioventricular nodal medication use.
We performed subgroup sensitivity analyses modeling the PR of being in the highest inflammatory group (hs-CRP ≥3 mg/L or quartile with the highest inflammation) per 10-beats/min change in HR at rest, which corresponded to approximately 1 SD (9.7). In addition, because an hs-CRP ≥10 mg/L is likely due to an acute inflammatory reaction, we investigated our 2 primary analyses excluding these participants (n = 591).
Results
At the baseline examination, participants with higher HR at rest were more likely to have a family history of premature CHD, have higher blood pressure, triglycerides, body mass index, diabetes, metabolic syndrome, and use a lipid-lowering medication ( Table 1 ). Median values of hs-CRP and mean values of IL-6 and fibrinogen were higher among those with higher HR at rest. Participants with lower HR at rest were more likely to be men, take an atrioventricular nodal blocker medication, have a higher total household income, have more than a high school education, and have a higher reported physical activity level (p <0.001).
| Characteristic | Baseline HR Quintile | p Value for Trend | ||||
|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | ||
| Resting heart rate (beats/min) ∗ | 50.9 (36–55) | 58.1 (56–60) | 62.9 (61–65) | 68.3 (66–71) | 78 (72–130) | <0.001 |
| Age (yrs) | 62.9 ± 10.1 | 61.9 ± 10.3 | 61.8 ± 10.2 | 61.6 ± 10.1 | 62.5 ± 10.2 | 0.09 |
| Men | 60.2 | 47.1 | 43.3 | 43.1 | 41.2 | <0.001 |
| Race | ||||||
| White | 38.9 | 38.5 | 39.2 | 37.5 | 37.3 | 0.81 |
| Black | 30.9 | 26.2 | 25.1 | 27.1 | 29.0 | 0.01 |
| Hispanic | 19.9 | 22.7 | 22.5 | 22.5 | 23.1 | 0.26 |
| Chinese | 10.2 | 12.6 | 13.2 | 19.9 | 10.6 | 0.04 |
| Current smoker | 12.1 | 13.6 | 12.2 | 14.0 | 13.2 | 0.49 |
| Family history coronary heart disease | 41.6 | 42.6 | 40.3 | 41.8 | 48.0 | 0.01 |
| Systolic blood pressure (mm Hg) | 126.9 ± 24 | 124.7 ± 21 | 126.2 ± 21 | 125.9 ± 20 | 129.7 ± 20 | <0.001 |
| Diastolic blood pressure (mm Hg) | 70.3 ± 10 | 70.7 ± 10 | 71.9 ± 10 | 72.9 ± 10 | 74.2 ± 10 | <0.001 |
| Low-density lipoprotein (mg/dl) | 115.8 ± 30 | 118.8 ± 30 | 116.8 ± 33 | 116.8 ± 32 | 117.9 ± 33 | 0.46 |
| High-density lipoprotein (mg/dl) | 50.8 ± 14 | 51.5 ± 15 | 51.3 ± 15 | 50.7 ± 15 | 50.3 ± 15 | 0.16 |
| Triglycerides † (mg/dl) | 101 (72, 146) | 105 (76, 151) | 114 (78, 162) | 118 (80, 170) | 124 (85, 181) | <0.001 |
| Body mass index (kg/m 2 ) | 27.5 ± 4.9 | 27.9 ± 5.2 | 28.2 ± 5.3 | 28.7 ± 5.8 | 29.6 ± 5.9 | <0.001 |
| Waist circumference (cm) | 96.1 ± 13.3 | 97.1 ± 14.2 | 97.6 ± 13.9 | 98.8 ± 14.8 | 101.7 ± 15.2 | <0.001 |
| Hypertension medication | 40.3 | 33.7 | 33.9 | 36.5 | 41.6 | <0.001 |
| AV blocker medication | 20.7 | 12.9 | 11.7 | 9.6 | 8.0 | <0.001 |
| Lipid-lowering medication | 15.0 | 14.2 | 16.1 | 16.7 | 19.1 | 0.01 |
| Diabetes mellitus | 7.5 | 8.8 | 10.4 | 15.0 | 23.3 | <0.001 |
| Metabolic syndrome | 28.7 | 30.4 | 33.6 | 40.3 | 49.7 | <0.001 |
| Moderate and vigorous physical activities ‡ | 105 ± 101 | 100 ± 104 | 95 ± 102 | 92 ± 92 | 84 ± 89 | <0.001 |
| ≥$40,000 income | 55.4 | 51.4 | 52.9 | 48.8 | 48.4 | <0.001 |
| ≥High school education | 68.6 | 65.6 | 64.2 | 60.4 | 59.5 | <0.001 |
| Hs-CRP † (mg/L) | 1.4 (0.7–3.1) | 1.7 (0.7–3.9) | 2.0 (0.9–4.3) | 2.2 (0.9–4.7) | 2.8 (1.2–5.7) | <0.001 |
| IL-6 (mg/L) | 1.4 ± 1.1 | 1.5 ± 1.1 | 1.5 ± 1.1 | 1.7 ± 1.3 | 1.9 ± 1.5 | <0.001 |
| Fibrinogen (mg/dl) | 334 ± 69 | 339 ± 68 | 344 ± 72 | 350 ± 71.7 | 370 ± 85 | <0.001 |
| D-dimer (pg/ml) | 0.4 ± 0.7 | 0.3 ± 0.7 | 0.4 ± 0.8 | 0.4 ± 1.2 | 0.4 ± 0.9 | 0.02 |
∗ Mean and minimum to maximum values.
† Median and interquartile range.
For all 3 inflammatory markers, an increase in HR at rest was associated with an increased percentage of subjects who had an elevated inflammatory level. The absolute percentage of subjects classified with an elevated inflammatory level was highest for hs-CRP (48% in quintile 5) and similar for fibrinogen (36% in quintile 5) and IL-6 (36% in quintile 5; Figure 1 ).
In linear regression models, hs-CRP, fibrinogen, and IL-6 increased with increasing HR even after multivariate adjustment including physical activity and atrioventricular nodal blocker medication use (p for trend <0.001 for all 3 markers; Table 2 ). The relative increase of the regression term from the lowest to highest HR at rest quintile was similar for all 3 inflammatory variables.
| Marker | Resting Heart Rate Quintile, β Coefficient | p for Trend | ||||
|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | ||
| Hs-CRP (mg/L) | ||||||
| Unadjusted | Reference | 0.15 † | 0.31 † | 0.42 † | 0.61 † | <0.001 |
| Model 1 | Reference | 0.13 † | 0.28 † | 0.37 † | 0.53 † | <0.001 |
| Model 2 | Reference | 0.11 † | 0.24 † | 0.30 † | 0.37 † | <0.001 |
| Model 3 | Reference | 0.11 † | 0.24 † | 0.30 † | 0.37 † | <0.001 |
| Fibrinogen (mg/dl) | ||||||
| Unadjusted | Reference | 0.02 | 0.03 † | 0.05 † | 0.10 † | <0.001 |
| Model 1 | Reference | 0.01 | 0.02 † | 0.04 † | 0.08 † | <0.001 |
| Model 2 | Reference | 0.01 | 0.02 † | 0.03 † | 0.06 † | <0.001 |
| Model 3 | Reference | 0.01 | 0.02 † | 0.03 † | 0.06 † | <0.001 |
| IL-6 (pg/ml) | ||||||
| Unadjusted | Reference | 0.07 † | 0.07 † | 0.19 † | 0.29 † | <0.001 |
| Model 1 | Reference | 0.09 † | 0.09 † | 0.21 † | 0.29 † | <0.001 |
| Model 2 | Reference | 0.09 † | 0.08 † | 0.18 † | 0.22 † | <0.001 |
| Model 3 | Reference | 0.09 † | 0.08 † | 0.18 † | 0.22 † | <0.001 |
∗ Hs-CRP, fibrinogen, and IL-6 are presented using log-transformed values.
Participants with higher HR at rest also had a progressively increased risk of having an elevated inflammatory marker compared with those with lower HR at rest (p for trend <0.001 for all 3 markers; Table 3 ). In the fully adjusted model, the prevalence of having an elevated inflammatory marker was significantly increased for all HR at rest quintiles, except for the second quintile of fibrinogen, although the PR of 1.11 (95% confidence interval [CI] 0.95 to 1.29) was consistent with the overall graded relation. For the highest quintile of HR at rest, the PR for having an elevated inflammatory marker was similar across the 3 inflammatory markers (PR 1.34, 95% CI 1.21 to 1.49 for hs-CRP; PR 1.51, 95% CI 1.31 to 1.75 for fibrinogen; and PR 1.45, 95% CI 1.27 to 1.67 for IL-6). The association between HR at rest and all 3 inflammatory markers showed some attenuation, but overall, the association was similar when participants with an hs-CRP ≥10 mg/L were excluded from the analyses (data not shown).
| Marker | Resting Heart Rate Quintile | p for Trend | ||||
|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | ||
| Hs-CRP (mg/L) | ||||||
| Unadjusted | Reference | 1.21 (1.08–1.36) ∗ | 1.40 (1.26–1.57) ∗ | 1.57 (1.41–1.75) ∗ | 1.80 (1.62–2.00) ∗ | <0.001 |
| Model 1 | Reference | 1.16 (1.01–1.30) ∗ | 1.29 (1.16–1.44) ∗ | 1.42 (1.28–1.58) ∗ | 1.57 (1.42–1.74) ∗ | <0.001 |
| Model 2 | Reference | 1.13 (1.02–1.25) ∗ | 1.24 (1.12–1.37) ∗ | 1.31 (1.18–1.45) ∗ | 1.33 (1.20–1.47) ∗ | <0.001 |
| Model 3 | Reference | 1.14 (1.02–1.27) ∗ | 1.25 (1.13–1.38) ∗ | 1.33 (1.20–1.47) ∗ | 1.34 (1.21–1.49) ∗ | <0.001 |
| Fibrinogen (mg/dl) | ||||||
| Unadjusted | Reference | 1.17 (1.07–1.36) ∗ | 1.37 (1.19–1.58) ∗ | 1.46 (1.27–1.69) ∗ | 2.01 (1.76–2.30) ∗ | <0.001 |
| Model 1 | Reference | 1.10 (0.95–1.28) | 1.25 (1.08–1.44) ∗ | 1.33 (1.15–1.53) ∗ | 1.68 (1.47–1.93) ∗ | <0.001 |
| Model 2 | Reference | 1.08 (0.93–1.26) | 1.22 (1.05–1.41) ∗ | 1.27 (1.10–1.46) ∗ | 1.47 (1.28–1.70) ∗ | <0.001 |
| Model 3 | Reference | 1.11 (0.95–1.29) | 1.23 (1.07–1.43) ∗ | 1.31 (1.13–1.51) ∗ | 1.51 (1.31–1.75) ∗ | <0.001 |
| IL-6 (pg/ml) | ||||||
| Unadjusted | Reference | 1.16 (1.02–1.34) ∗ | 1.15 (0.99–1.32) | 1.49 (1.31–1.70) ∗ | 1.71 (1.50–1.94) ∗ | <0.001 |
| Model 1 | Reference | 1.19 (1.04–1.36) ∗ | 1.14 (0.99–1.31) | 1.47 (1.29–1.68) ∗ | 1.64 (1.44–1.86) ∗ | <0.001 |
| Model 2 | Reference | 1.16 (1.02–1.33) ∗ | 1.16 (1.01–1.33) ∗ | 1.39 (1.22–1.59) ∗ | 1.42 (1.24–1.62) ∗ | <0.001 |
| Model 3 | Reference | 1.18 (1.03–1.35) ∗ | 1.17 (1.02–1.34) ∗ | 1.42 (1.25–1.63) ∗ | 1.45 (1.27–1.67) ∗ | <0.001 |
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