Inflammation, Cholesterol, Lipoprotein(a), and 30-Year Cardiovascular Outcomes in Women

Abstract

Background: High-sensitivity C-reactive protein (CRP), low-density lipoprotein (LDL) cholesterol, and lipoprotein(a) levels contribute to 5-year and 10-year predictions of cardiovascular risk and represent distinct pathways for pharmacologic intervention. More information about the usefulness of these biomarkers for predicting cardiovascular risk over longer periods of time in women is needed because early-life intervention represents an important risk-reduction method.

Methods: We measured high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) levels at baseline in 27,939 initially healthy U.S. women who were subsequently followed for 30 years. The primary end point was a first major adverse cardiovascular event, which was a composite of myocardial infarction, coronary revascularization, stroke, or death from cardiovascular causes. We calculated the adjusted hazard ratios and 95% confidence intervals across quintiles of each biomarker, along with 30-year cumulative incidence curves adjusted for age and competing risks.

Results: The mean age of the participants at baseline was 54.7 years. During the 30-year follow-up, 3662 first major cardiovascular events occurred. Quintiles of increasing baseline levels of high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) all predicted 30-year risks. Covariable-adjusted hazard ratios for the primary end point in a comparison of the top with the bottom quintile were 1.70 (95% confidence interval [CI], 1.52 to 1.90) for high-sensitivity CRP, 1.36 (95% CI, 1.23 to 1.52) for LDL cholesterol, and 1.33 (95% CI, 1.21 to 1.47) for lipoprotein(a). Findings for coronary heart disease and stroke appeared to be consistent with those for the primary end point. Each biomarker showed independent contributions to overall risk. The greatest spread for risk was obtained in models that incorporated all three biomarkers.

Conclusions: A single combined measure of high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) levels among initially healthy U.S. women was predictive of incident cardiovascular events during a 30-year period. These data support efforts to extend strategies for the primary prevention of atherosclerotic events beyond traditional 10-year estimates of risk. (Funded by the National Institutes of Health; Women's Health Study ClinicalTrials.gov number, NCT00000479.).

Figure 1.

30-year age and competing risk adjusted cumulative incidence of first major cardiovascular events among initially healthy women according to baseline levels of hsCRP, LDL-C, and Lp(a). Quintile 1 (Blue), Quintile 2 (Red), Quintile 3 (Green), Quintile 4 (Black), Quintile 5 (Purple).

Figure 1.

30-year age and competing risk adjusted cumulative incidence of first major cardiovascular events among initially healthy women according to baseline levels of hsCRP, LDL-C, and Lp(a). Quintile 1 (Blue), Quintile 2 (Red), Quintile 3 (Green), Quintile 4 (Black), Quintile 5 (Purple).

Figure 1.

30-year age and competing risk adjusted cumulative incidence of first major cardiovascular events among initially healthy women according to baseline levels of hsCRP, LDL-C, and Lp(a). Quintile 1 (Blue), Quintile 2 (Red), Quintile 3 (Green), Quintile 4 (Black), Quintile 5 (Purple).

Figure 2.

Joint effects of hsCRP, LDL-C, and Lp(a) on 30-year age and competing risk adjusted cumulative incidence of first major cardiovascular events among initially healthy women. Data are shown for values of hsCRP ≥ or < 2 mg/L; for LDLC ≥ or < 130 mg/dL, and Lp(a) ≥ or < 40 mg/dL. Alternative use of Lp(a) thresholds of 30 or 50 mg/dL had minimal impact on these observations.

Figure 2.

Joint effects of hsCRP, LDL-C, and Lp(a) on 30-year age and competing risk adjusted cumulative incidence of first major cardiovascular events among initially healthy women. Data are shown for values of hsCRP ≥ or < 2 mg/L; for LDLC ≥ or < 130 mg/dL, and Lp(a) ≥ or < 40 mg/dL. Alternative use of Lp(a) thresholds of 30 or 50 mg/dL had minimal impact on these observations.

Figure 2.

Joint effects of hsCRP, LDL-C, and Lp(a) on 30-year age and competing risk adjusted cumulative incidence of first major cardiovascular events among initially healthy women. Data are shown for values of hsCRP ≥ or < 2 mg/L; for LDLC ≥ or < 130 mg/dL, and Lp(a) ≥ or < 40 mg/dL. Alternative use of Lp(a) thresholds of 30 or 50 mg/dL had minimal impact on these observations.

Figure 2.

Joint effects of hsCRP, LDL-C, and Lp(a) on 30-year age and competing risk adjusted cumulative incidence of first major cardiovascular events among initially healthy women. Data are shown for values of hsCRP ≥ or < 2 mg/L; for LDLC ≥ or < 130 mg/dL, and Lp(a) ≥ or < 40 mg/dL. Alternative use of Lp(a) thresholds of 30 or 50 mg/dL had minimal impact on these observations.

Figure 2.

Joint effects of hsCRP, LDL-C, and Lp(a) on 30-year age and competing risk adjusted cumulative incidence of first major cardiovascular events among initially healthy women. Data are shown for values of hsCRP ≥ or < 2 mg/L; for LDLC ≥ or < 130 mg/dL, and Lp(a) ≥ or < 40 mg/dL. Alternative use of Lp(a) thresholds of 30 or 50 mg/dL had minimal impact on these observations.

Figure 2.

Joint effects of hsCRP, LDL-C, and Lp(a) on 30-year age and competing risk adjusted cumulative incidence of first major cardiovascular events among initially healthy women. Data are shown for values of hsCRP ≥ or < 2 mg/L; for LDLC ≥ or < 130 mg/dL, and Lp(a) ≥ or < 40 mg/dL. Alternative use of Lp(a) thresholds of 30 or 50 mg/dL had minimal impact on these observations.

Figure 3.

Combined effects of hsCRP, LDL-C, and Lp(a) on 30-year age and competing risk adjusted cumulative incidence of first major cardiovascular events, coronary heart disease events, and stroke events among initially healthy women according to the number of baseline biomarker levels in the top quintile (0, 1, 2, or 3).

Figure 3.

Combined effects of hsCRP, LDL-C, and Lp(a) on 30-year age and competing risk adjusted cumulative incidence of first major cardiovascular events, coronary heart disease events, and stroke events among initially healthy women according to the number of baseline biomarker levels in the top quintile (0, 1, 2, or 3).

Figure 3.

Combined effects of hsCRP, LDL-C, and Lp(a) on 30-year age and competing risk adjusted cumulative incidence of first major cardiovascular events, coronary heart disease events, and stroke events among initially healthy women according to the number of baseline biomarker levels in the top quintile (0, 1, 2, or 3).