Elevated hs-CRP as a Risk Marker of Cardiovascular Events
Elevated hs-CRP as a Risk Marker of Cardiovascular Events
The relationship between cholesterol and coronary heart disease (CHD) is attenuated at older age. We analyzed cholesterol level as a predictor of CHD in 8,947 participants from the Atherosclerosis Risk in Communities (ARIC) Study, a large multicenter cohort study that enrolled participants in 1987–1989 at 4 field centers in Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and Minneapolis, Minnesota. Participants in the present analysis had no history of CHD and were stratified by age (<65 or ≥65 years) and high-sensitivity C-reactive protein (hs-CRP) level (<2 or ≥2 mg/L). Visit 4 (1996–1997) was the baseline for this analysis, with follow-up through 2008. Cholesterol level was significantly associated with CHD among younger participants, and cholesterol level was similarly predictive of CHD among older participants with an hs-CRP level of <2 mg/L. In contrast, among older participants with an hs-CRP level of 2 mg/L or higher, the association of CHD with total cholesterol level was borderline significant (hazard ratio = 1.14, 95% confidence interval: 1.00, 1.29), and the association of CHD with low-density lipoprotein cholesterol level was nonsignificant (hazard ratio = 1.10; 95% confidence interval: 0.96, 1.26). Among older persons with an elevated hs-CRP level, cholesterol level was significantly less predictive of CHD (P < 0.05), whereas for those with an hs-CRP level of <2 mg/L, there was no significant difference compared with younger participants. In conclusion, we found that among the young-old, the association of cholesterol level with CHD was strong when hs-CRP level was not elevated and weak when hs-CRP level was elevated. Therefore, hs-CRP level could be useful for stratifying the young-old to assess the strength of cholesterol level in CHD risk prediction.
Elevated serum cholesterol level is a well-established risk factor for coronary heart disease (CHD), and the use of cholesterol-lowering medications has been shown to be effective in the primary prevention of cardiovascular disease at all ages. However, the relationship between elevated serum cholesterol level and adverse cardiac events is attenuated at older age. Although the reason for cholesterol's decreased contribution to CHD risk in older age is unclear, it is possible that comorbid conditions that become more common with age could compete with traditional risk factors for CHD risk prediction and in some circumstances could lower the serum cholesterol level through inflammation or other processes. Therefore, methods for distinguishing which subset of older adults retains the strong association of cholesterol level with CHD and which subset does not would be useful in making progress toward improved risk prediction.
High-sensitivity C-reactive protein (hs-CRP) is a nonspecific inflammatory marker, elevated levels of which have been strongly associated with adverse cardiovascular events. Additionally, in the Justification for the Use of Statins in Primary Prevention trial, participants with an elevated hs-CRP level and a normal serum cholesterol level had a lower rate of major cardiovascular events after treatment with rosuvastatin. An elevated hs-CRP level has also been associated with many conditions beyond vascular inflammation, including malignancy, infection, heart failure, chronic kidney disease, airway disease, and general physical decline. Overall, these pathological states are more common in the elderly and could effectively compete with traditional risk factors for CHD risk prediction. It is also possible that the systemic inflammation associated with these conditions results in a lower serum cholesterol level because of associated poor nutrition or increased catabolism. Increased systemic inflammation also could exacerbate preexisting coronary artery disease, leading to a greater risk of clinical events. In extreme cases, such as end-stage renal disease, this can lead to a reversal of the expected relationship between serum cholesterol level and CHD.
We hypothesize that an elevated hs-CRP level will be a nonspecific but useful predictive marker that can integrate many pathological processes and can distinguish the elderly population into subgroups: 1) older adults with an elevated hs-CRP level in whom an elevated serum cholesterol level is weakly associated with or not associated with an increased risk of CHD, and 2) older adults with a normal hs-CRP level in whom the cholesterol level–CHD association is largely unchanged from that at younger ages.
Abstract and Introduction
Abstract
The relationship between cholesterol and coronary heart disease (CHD) is attenuated at older age. We analyzed cholesterol level as a predictor of CHD in 8,947 participants from the Atherosclerosis Risk in Communities (ARIC) Study, a large multicenter cohort study that enrolled participants in 1987–1989 at 4 field centers in Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and Minneapolis, Minnesota. Participants in the present analysis had no history of CHD and were stratified by age (<65 or ≥65 years) and high-sensitivity C-reactive protein (hs-CRP) level (<2 or ≥2 mg/L). Visit 4 (1996–1997) was the baseline for this analysis, with follow-up through 2008. Cholesterol level was significantly associated with CHD among younger participants, and cholesterol level was similarly predictive of CHD among older participants with an hs-CRP level of <2 mg/L. In contrast, among older participants with an hs-CRP level of 2 mg/L or higher, the association of CHD with total cholesterol level was borderline significant (hazard ratio = 1.14, 95% confidence interval: 1.00, 1.29), and the association of CHD with low-density lipoprotein cholesterol level was nonsignificant (hazard ratio = 1.10; 95% confidence interval: 0.96, 1.26). Among older persons with an elevated hs-CRP level, cholesterol level was significantly less predictive of CHD (P < 0.05), whereas for those with an hs-CRP level of <2 mg/L, there was no significant difference compared with younger participants. In conclusion, we found that among the young-old, the association of cholesterol level with CHD was strong when hs-CRP level was not elevated and weak when hs-CRP level was elevated. Therefore, hs-CRP level could be useful for stratifying the young-old to assess the strength of cholesterol level in CHD risk prediction.
Introduction
Elevated serum cholesterol level is a well-established risk factor for coronary heart disease (CHD), and the use of cholesterol-lowering medications has been shown to be effective in the primary prevention of cardiovascular disease at all ages. However, the relationship between elevated serum cholesterol level and adverse cardiac events is attenuated at older age. Although the reason for cholesterol's decreased contribution to CHD risk in older age is unclear, it is possible that comorbid conditions that become more common with age could compete with traditional risk factors for CHD risk prediction and in some circumstances could lower the serum cholesterol level through inflammation or other processes. Therefore, methods for distinguishing which subset of older adults retains the strong association of cholesterol level with CHD and which subset does not would be useful in making progress toward improved risk prediction.
High-sensitivity C-reactive protein (hs-CRP) is a nonspecific inflammatory marker, elevated levels of which have been strongly associated with adverse cardiovascular events. Additionally, in the Justification for the Use of Statins in Primary Prevention trial, participants with an elevated hs-CRP level and a normal serum cholesterol level had a lower rate of major cardiovascular events after treatment with rosuvastatin. An elevated hs-CRP level has also been associated with many conditions beyond vascular inflammation, including malignancy, infection, heart failure, chronic kidney disease, airway disease, and general physical decline. Overall, these pathological states are more common in the elderly and could effectively compete with traditional risk factors for CHD risk prediction. It is also possible that the systemic inflammation associated with these conditions results in a lower serum cholesterol level because of associated poor nutrition or increased catabolism. Increased systemic inflammation also could exacerbate preexisting coronary artery disease, leading to a greater risk of clinical events. In extreme cases, such as end-stage renal disease, this can lead to a reversal of the expected relationship between serum cholesterol level and CHD.
We hypothesize that an elevated hs-CRP level will be a nonspecific but useful predictive marker that can integrate many pathological processes and can distinguish the elderly population into subgroups: 1) older adults with an elevated hs-CRP level in whom an elevated serum cholesterol level is weakly associated with or not associated with an increased risk of CHD, and 2) older adults with a normal hs-CRP level in whom the cholesterol level–CHD association is largely unchanged from that at younger ages.
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