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HIV Positive People with Elevated C-reactive Protein Have Higher Cardiovascular Risk, but It May Not Be a Good Predictor of Heart Disease

A widely used biomarker of inflammation, C-reactive protein (CRP), is associated with cardiovascular risk in people with HIV, according to a large study reported in the July 2009 Journal of Acquired Immunodeficiency Syndromes. HIV positive people with elevated CRP had more than 4 times the risk of acute myocardial infarction (MI) than HIV negative people with normal CRP. But two other recent general population studies suggest CRP may not be a causal factor or a good predictor of heart disease.

Researchers from Massachusetts General Hospital investigated whether elevated C-reactive protein levels and HIV infection are independently associated with acute MIs, or heart attacks.

Prior research, including the large SMART treatment interruption trial, found that HIV positive people who interrupted antiretroviral therapy had a higher incidence of MIs and also more elevated CRP and other inflammatory proteins than patients who remained on continuous therapy. These results, the investigators wrote, "suggest a possible association between acute episodic inflammation and cardiovascular events."

The current study included 487 HIV positive and 69,870 HIV negative participants receiving care through Partners HealthCare, a large U.S. health system, between January 1997 and December 2006 who had undergone CRP testing within the past 3 years.

The investigators measured both CRP and high-sensitivity CRP (hsCRP), and assessed the relationship between these biomarker, HIV status, and occurrence of acute MI, after adjusting for demographic characteristics and other cardiovascular risk factors including high blood pressure, diabetes, and blood lipid abnormalities.

Results

• In a univariate analysis, elevated CRP and being HIV positive were both significantly associated with more than double the rate of acute MI:

o   Elevated CRP: odds ratio (OR) 2.51 (P < 0.0001);

o   Having HIV: OR 2.07 (P = 0.001).

• In a combined model looking at both factors together, CRP and HIV were both still significant predictors of acute MI:

o   Elevated CRP: OR 2.50 (P < 0.0001);

o   Having HIV: OR 1.74 (P = 0.01).

• In a fully adjusted model controlling for age, sex, race/ethnicity, and the other cardiovascular risk factors, CRP and HIV remained independently associated with acute MI:

o   Elevated CRP: OR 2.13 (P < 0.0001);

o   Having HIV: OR 1.93 (P = 0.004).

• The risk of acute MI increased more than 4-fold among HIV positive people with elevated CRP compared with HIV negative people with normal CRP levels

"Elevated CRP and HIV are independently associated with increased acute MI risk, and patients with HIV with increased CRP have a markedly increased relative risk of acute MI," the study authors concluded.

"Although these data cannot establish causality, they highlight the need for further in-depth evaluation of the prognostic value of CRP for acute MI in the HIV population," they continued in their discussion. "Developing HIV-specific cardiovascular risk assessment strategies is important for the long-term health of the HIV population."

CRP as a Cardiovascular Marker

Two recent studies looking at the general population, however, cast doubt on the value of CRP and other biomarkers as causal factors or predictors of cardiovascular disease.

As reported in the July 1, 2009 Journal of the American Medical Association, Olle Melander from Lund University and colleagues assessed the usefulness of a variety of cardiovascular biomarkers -- including CRP, cystatin C, N-terminal pro-B-type natriuretic peptide (N-BNP), lipoprotein-associated phospholipase-2 (Lp-PLA2), midregional proadrenomedullin (MR-proADM), and midregional proatrial natriuretic peptide (MR-proANP) -- as predictors of cardiovascular events, both individually and in combination.

The analysis included 5067 participants in Malmö, Sweden, who did not have heart disease when they enrolled in the study between 1991 and 1994. Based on data from the Swedish national hospital discharge and cause-of-death registers and the Stroke in Malmö register, 648 first-time cardiovascular/coronary events including heart attacks and strokes occurred during a median 13 years of follow-up.

The researchers found that while 5 of the 6 biomarkers considered individually predicted future cardiovascular events, using multiple biomarkers only slightly improved predictive accuracy compared with traditional risk factors such as elevated blood lipids, high blood pressure, diabetes, and smoking. CRP, for example, had a hazard ratio for first cardiovascular events of just 1.19 (where a ratio of 1 equals no difference in risk). Furthermore, consideration of biomarkers reclassified few participants from high-risk to low-risk or vice versa.

"Our data indicate that a relatively small proportion of individuals are moved to new risk categories by the addition of biomarkers -- 8% fewer when both upward and downward risk category movement are included and fewer than 1% when only the movements likely to lead to changes in therapy according to the Adult Treatment Panel III [cholesterol] guidelines are included," they wrote. "Furthermore, these reclassifications result in only modest improvements in the overall concordance between risk categories and actual event rates, as measured by the net reclassification improvement."

In another study described in the same issue, Paul Elliott from Imperial College London and colleagues looked at the link between genetic variations that influence CRP levels and risk of coronary heart disease.

The investigators first performed a genome-wide association study with 17,967 participants to identify gene locations associated with plasma CRP concentrations and replicated the findings in another cohort of 13,615 patients. They then conducted a Mendelian randomization study of the most closely associated CRP single-nucleotide polymorphism (SNP), or variation at a single gene position, as well as a meta-analysis of published data about other CRP variants involving a total of 28,112 people with coronary heart disease and 100,823 control subjects without the condition.

In the randomization study, common genetic variations in the LEPR, IL6R, CRP, and HNF1A locations, as well as the APOE-CI-CII cluster, were linked with coronary heart disease risk. However, the minor allele of SNP rs7553007 and other variants in the CRP locus were not associated with altered risk. Overall, the genetic variants included in the Mendelian randomization study were associated with CRP levels about 20% lower than average, corresponding to about a 6% reduction in the predicted risk of coronary heart disease based on data from the meta-analysis of observational studies.

"[O]ur Mendelian randomization study of more than 28,000 cases and 100,000 controls found no association of variants in the CRP locus and coronary heart disease, arguing against a causal role for CRP in atherosclerosis," the researchers concluded.

"The lack of association with coronary heart disease of genetic variants in the CRP locus suggests that the observational data linking CRP levels and coronary heart disease may be confounded by association with other risk factors, or reflect a secondary inflammatory response associated with atherosclerosis (reverse causation), rather than indicate a causal relationship," they continued.

With regard to clinical applications, they wrote, 'this study suggests that development of therapeutic strategies targeting specific reductions in plasma levels of CRP are unlikely to be fruitful."

In an accompanying editorial, Svati Shah from Duke University Medical Center and James de Lemos from the University of Texas Southwestern Medical Center noted that the findings from these 2 studies are "in sharp distinction to other, population-based studies." They suggested that biomarkers do not perform as well for populations with low overall cardiovascular risk (as was the case for participants in the present studies), and do not predict non-fatal coronary events and strokes as well as heart failure and cardiovascular death.

Researchers will continue to explore novel biomarkers, since a large proportion of people who experience MIs and other cardiovascular events have none or only 1 conventional risk factor.

"Ideally, biomarkers would also be risk factors and could be used for both risk assessment and to individualize specific therapies," they commented. "In the future, better biomarkers and more creative strategies for combining them will be needed, along with comprehensive statistical and functional evaluation of causality, to fulfill the promise of biomarkers for personalized medicine."

7/17/09

References

V Triant, J Meigs, and SK Grinspoon. Association of C-Reactive Protein and HIV Infection With Acute Myocardial Infarction. Journal of Acquired Immune Deficiency Syndromes 51(3): 268-273. July 2009.

O Melander, C Newton-Cheh, P Almgren, and others. Novel and Conventional Biomarkers for Prediction of Incident Cardiovascular Events in the Community: "Minimal Benefit in Predicting CVD Compared To Traditional Risk Factors." Journal of the American Medical Association (JAMA) 302(1): 49-57. July 1, 2009.

P Elliott, JC Chambers, W Zhang, and others. Genetic Loci Associated with C-Reactive Protein Levels and Risk of Coronary Heart Disease. JAMA 302(1): 37-48. July 1, 2009.

SH Shah and JA de Lemos. Biomarkers and Cardiovascular Disease Determining Causality and Quantifying Contribution to Risk Assessment. JAMA 302(1): 92-93. July 1, 2009.