Beyond Framingham: Contemporary Evolution of Individualized Coronary Heart Disease Risk Assessment

Jeffrey L. Anderson, MDProfessor of Medicine, University of Utah

Associate Chief of Cardiology, Intermountain Medical Center

Salt Lake City, UT

www.medscape.comhttp://www.medscape.com/infosite/cardiodx/article-2

Introduction

• Cardiovascular (CV) disease is the leading cause of death and disability in the United States and has grown to become the leading health issue globally.

• The majority of first myocardial infarctions occur in subjects without a known history of CHD and in whom proven preventive therapies would not have been indicated—according to current guidelines based on the Framingham Risk Score (FRS)—prior to the event.

• The FRS performs reasonably well at a population level in differentiating groups at differing risk, but its deficiencies at the level of individual risk assessment have been increasingly recognized.3 Thus, a major goal of contemporary CV medicine is to discover and validate additional markers of CHD risk that might identify individuals with pre-clinical disease or assess the likelihood of CHD in patients who might be candidates for intervention.

Beyond Framingham

• Three specific areas that promise to increase early detection of disease or improve on discovery of disease predisposition are

• (1) biomarkers, • (2) vascular imaging, and• (3) genomics.

Biomarkers

• High sensitivity C-reactive protein (hsCRP)

• Lipoprotein-associated phospholipase A2 (LpPLA2)

High sensitivity C-reactive protein (hsCRP)

• Atherothrombosis is an inflammatory disease, and hsCRP has been proposed as a circulating systemic marker of vascular disease activity.

• A report from the Physician's Health Study, now a decade old, demonstrated a linear relationship between hsCRP levels, even within the "normal range", and subsequent risk of a first CV event.

JUPITER

• In the JUPITER study, elevated hsCRP was successfully used to select patients from the large "low-risk" pool of subjects without clinical CHD and with average or "normal" LDL-C levels (<130 mg/dL), a group not currently targeted for lipid-lowering.

• In this >17,000 patient study, intensive lipid-lowering to an average LDL-C level of 55 mg/dL resulted in an approximate 50% reduction in major adverse atherothrombotic events, including CV death

JUPITER

Lipoprotein-associated phospholipase A2 (LpPLA2)

• LpPLA2 represents a second biomarker of vascular inflammation more recently found to enhance risk prediction of CHD and stroke. LpPLA2 appears to overcome several of the limitations of hsCRP.

• It resides on and travels with LDL in the plasma, hence is more vascular specific than hsCRP, it does not act as an acute phase reactant or rise in response to therapies such as hormone replacement, and it is found in abundance and is generated within active atherosclerotic plaque

• Predictive value for primary and secondary prevention now has been shown consistently in over 2 dozen studies, with top quantile (e.g., tertile or quartile) LpPLA2 predicting a 2-fold increase in coronary and cerebrovascular disease risk.

LaPLA2

• In addition, a low LpPLA2 (< 200 ng/mL) has been associated with excellent negative predictive value (i.e., ≤ 1% annual event risk).

• A small increment in AUC over traditional risk factors has been claimed for LpPLA2, and LpPLA2 levels decrease with lipid-lowering therapies (statins, fibrates, niacin),

• Although its use as a selection criterion or as a target for treatment has not been specifically tested yet.

Vascular Imaging Carotid intima-media thickening (CIMT) • A number of studies have demonstrated the

predictive value of CIMT measurements for assessing primary CHD risk.

• Advantages of CIMT include its non-invasive nature and its non-dependence on ionizing radiation. These features make it an applicable tool for refining stratification in those with low to intermediate Framingham risk, particularly in younger subjects in whom coronary calcium testing is poorly predictive.

Disadvantages of CIMT

• include its operator dependence and inter-test variability.

• Also, results, though correlated with coronary atherosclerosis, are taken in a different vascular bed and hence indirect for CHD.

• Finally, its use as a surrogate marker to assess therapeutic effect of lipid-lowering is complex and controversial, especially if trial entry does not require a clearly abnormal baseline study.

Coronary artery calcium scoring (CACS)

• Calcification within plaque is an integral part of the evolution of atherosclerosis, particularly in advanced lesions. Focal calcification can be readily detected with low-dose radiation exposure and quantified using electron beam or, more recently, multidetector coronary CT scanners.

• A large database of observational information has now accumulated that supports the independent predictive value of CACS for primary risk assessment.

• A meta-analysis of 6 studies included 27,622 subjects followed for up to 10 years and documented 395 CV events. CACS distinguished groups at greatly distinct (11- fold) differing risk categories from very low (CACS = 0) to very high (CACS ≥ 1000 Agatston U) risk.

• Further, CACS has been found to be largely independent of traditional risk factors assessed in the FRS. Its use in risk assessment for those in the intermediate risk category now is supported as a reasonable risk refinement option by AHA/ACC scientific statements (Class II).

Genomic Markers

• Genetic basis for CHD. A number of studies have suggested a strong heritable contribution to CHD. At our institution, Williams and colleagues investigated the familial basis of CHD. Families with a positive family history of CHD (i.e., onset of clinical CHD at age ≤ 55 in a male or ≤ 65 in a woman first degree relative) accounted for 14% of the general population, but 48% of those with CHD and 72% of those with premature CHD.

• However, CHD is a chronic disease whose etiology is complex and incompletely understood.

• It is clear that CHD is multifactorial with multiple genetic and environmental factors interacting to determine disease progression and clinical manifestation

• Genetic markers of CHD risk. Investigations into the genetic basis of common varieties of CHD have usually assumed a "common-disease, common-polymorphism" hypothesis, which implies that modest incremental effects of common variants, i.e.,

• with minor allele frequencies of >10%, in genes operating in pathways postulated to be central to vascular health and disease, may explain complex diseases such as CHD.

• These pathways may include those related to lipid metabolism, vascular integrity/endothelial function, vascular inflammation, and thrombosis, among others.

• However, studies of common single nucleotide polymorphisms (SNPs) in over 100 of these candidate genes have been fraught with failures of replication.