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Observational Study
. 2021 Sep 14;78(11):1083-1094.
doi: 10.1016/j.jacc.2021.07.016.

High-Sensitivity C-Reactive Protein Modifies the Cardiovascular Risk of Lipoprotein(a): Multi-Ethnic Study of Atherosclerosis

Wei Zhang  1 , Jaime Lynn Speiser  2 , Fan Ye  3 , Michael Y Tsai  4 , Miguel Cainzos-Achirica  5 , Khurram Nasir  5 , David M Herrington  3 , Michael D Shapiro  6
Affiliations
Observational Study

High-Sensitivity C-Reactive Protein Modifies the Cardiovascular Risk of Lipoprotein(a): Multi-Ethnic Study of Atherosclerosis

Wei Zhang et al. J Am Coll Cardiol. .

Abstract

Background: Little is known about the relationship between lipoprotein (a) [Lp(a)] and high-sensitivity C-reactive protein (hsCRP) and their joint association with atherosclerotic cardiovascular disease (ASCVD).

Objectives: The purpose of this study was to assess whether Lp(a)-associated ASCVD risk is modified by hsCRP in the context of primary prevention.

Methods: The current study included 4,679 participants from the MESA (Multi-Ethnic Study of Atherosclerosis) Apolipoprotein ancillary data set. Cox proportional hazards models and Kaplan-Meier curves were used to assess the association among Lp(a), hsCRP, and time to cardiovascular disease (CVD) events.

Results: During a mean follow-up of 13.6 years, 684 CVD events occurred. A significant interaction was observed between Lp(a) and hsCRP (P = 0.04). With hsCRP <2 mg/L, no significant CVD risk was observed at any level of Lp(a) from <50 mg/dL to >100 mg/dL. However, with hsCRP ≥2 mg/L, a significant CVD risk was observed with Lp(a) of 50-99.9 mg/dL (HR: 1.36; 95% CI: 1.02-1.81) and Lp(a) ≥100 mg/dL (HR: 2.09; 95% CI: 1.40-3.13). Isolated elevations of either Lp(a) or hsCRP were not associated with increased CVD risk. In contrast, the combination of elevated Lp(a) (≥50 mg/dL) and hsCRP (≥2 mg/L) was independently associated with significant CVD risk (HR: 1.62; 95% CI: 1.25-2.10) and all-cause mortality (HR: 1.39; 95% CI: 1.12-1.72).

Conclusions: Lp(a)-associated ASCVD risk is observed only with concomitant elevation of hsCRP. Individuals with concomitant presence of elevated Lp(a) and systemic inflammation have greater ASCVD risk and all-cause mortality, and thus may merit closer surveillance and more aggressive ASCVD risk management.

Keywords: ASCVD; Multi-Ethic Study of Atherosclerosis (MESA); cardiovascular risk; high-sensitivity C-reactive protein (hsCRP); inflammation; lipoprotein(a).

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Conflict of interest statement

Funding Support and Author Disclosures MESA is supported by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute; and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from National Center for Advancing Translational Sciences. The MESA Air ancillary study was supported by a grant from the US Environmental Protection Agency’s Science to Achieve Results (STAR) program. Assistance Agreement number RD831697 awarded by the U.S. Environmental Protection to the University of Washington. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

Figure 1.
Figure 1.. Cardiovascular Risk across Clinical Strata of Lipoprotein(a).
A: Hazard Ratios for Cardiovascular Events. Cox proportional hazards model was adjusted for age, gender, race/ethnicity, hypertension, use of hypertension medications, diabetes, smoking status, HDL-C, triglycerides, total cholesterol and renal function (eGFR). Point estimates of hazard ratios are represented by the black dot and 95%CI by the horizontal lines. B: Kaplan-Meier curves of Cumulative Incidence of Cardiovascular Events. Lp(a)<50mg/L was used as the reference group. Lp(a), lipoprotein(a); hsCRP, high-sensitivity C-reactive protein; HR, hazard ratio; CI, Confidence Interval; NA, not applicable.
Figure 1.
Figure 1.. Cardiovascular Risk across Clinical Strata of Lipoprotein(a).
A: Hazard Ratios for Cardiovascular Events. Cox proportional hazards model was adjusted for age, gender, race/ethnicity, hypertension, use of hypertension medications, diabetes, smoking status, HDL-C, triglycerides, total cholesterol and renal function (eGFR). Point estimates of hazard ratios are represented by the black dot and 95%CI by the horizontal lines. B: Kaplan-Meier curves of Cumulative Incidence of Cardiovascular Events. Lp(a)<50mg/L was used as the reference group. Lp(a), lipoprotein(a); hsCRP, high-sensitivity C-reactive protein; HR, hazard ratio; CI, Confidence Interval; NA, not applicable.
Figure 2.
Figure 2.. Cardiovascular Risk Classified by Lipoprotein(a) and high-sensitivity C-Reactive Protein.
A: Hazard Ratios for Cardiovascular Events. Cox proportional hazards model was adjusted for age, gender, race/ethnicity, hypertension, use of hypertension medications, diabetes, smoking status, HDL-C, triglycerides, total cholesterol and renal function (eGFR). B: Kaplan-Meier curves of Cumulative Incidence of Cardiovascular Events. Lp(a), lipoprotein(a); hsCRP, high-sensitivity C-reactive protein; HR, hazard ratio; CI, Confidence Interval; NA, not applicable; Lp(a)<50mg/dL & hsCRP<2mg/L was used as the reference group. P-value for interaction between Lp(a) and hsCRP =0.04 (as continuous variable) or 0.17 (as a dichotomous variable).
Figure 3.
Figure 3.. Cumulative Incidence of Cardiovascular Events in African-Americans and Non-African-Americans.
Kaplan-Meier curves of the cumulative incidence of CVD events are shown. In both African-American and Non-African-American, greater cumulative risk of CVD was observed only in individuals with concomitant elevation of Lp(a) (≥ 50 mg/dL) and hsCRP (≥ 2 mg/L).
Central Illustration.
Central Illustration.. Cumulative Incidence of Cardiovascular Events in Female and Male.
Kaplan-Meier curves of the cumulative incidence of CVD events are shown. In both female and male, greater cumulative risk of CVD was observed only in individuals with concomitant elevation of Lp(a) (≥ 50 mg/dL) and hsCRP (≥ 2 mg/L). Lp(a), lipoprotein(a); hsCRP, high-sensitivity C-reactive protein.
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