BEYOND FRAMINGHAM

1. Beyond Framingham: Contemporary Evolution of
Individualized Coronary Heart Disease Risk Assessment
Jeffrey L. Anderson, MD
Professor of Medicine, University of Utah
Associate Chief of Cardiology, Intermountain Medical Center
Salt Lake City, UT
www.medscape.com
http://www.medscape.com/infosite/
cardiodx/article-2

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.

3. • 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.

4. 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.

5. Biomarkers
• High sensitivity C-reactive protein (hsCRP)
• Lipoprotein-associated phospholipase A2
(LpPLA2)

6. 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 quot;normal rangequot;, and subsequent
risk of a first CV event.

7. JUPITER
• In the JUPITER study, elevated hsCRP was
successfully used to select patients from the large
quot;low-riskquot; pool of subjects without clinical CHD
and with average or quot;normalquot; 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

8. JUPITER

9. 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

10. • 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. • 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.

16. • 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).

17. 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.

18. • 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

19. • Genetic markers of CHD risk. Investigations into
the genetic basis of common varieties of CHD
have usually assumed a quot;common-
disease, common-polymorphismquot;
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.

20. • 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.