Emerging Cardiac Risk Factors

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Emerging Cardiac Risk Factors

• Jon W. Wahrenberger, MD FACC

DHMC Cardiology Update Symposium 2003 December 1,
2003
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Traditional Risk Factors

• Tobacco Exposure
• Hypertension
• Diabetes Mellitus
• Lipid Disorders
• Family History

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Audience Response Question 1

• Question Traditional risk factors are present
  in what percentage of patients with coronary
  heart disease
• A. Less than 50
• B. Greater than 50
• C. Conflicting data

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Total Cholesterol Distribution CHD vs Non-CHD
Population
Framingham Heart Study26-Year Follow-up
No CHD
35 of CHD Occurs in People with TClt200 mg/dL
CHD
150
250
300
200
Total Cholesterol (mg/dL)
Castelli WP. Atherosclerosis. 1996124(suppl)S1-S
9.
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Prevalence of Risk Factors in Patients with
Coronary Heart Disease
Khot, et al. JAMA 2003290898-904
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Prevalence of Risk Factors in CHD
4
0
3
2
1
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Emerging Cardiac Risk Factors
The Four Big Ones

• C-Reactive Protein
• Lipoprotein (a)
• Fibrinogen
• Homocysteine

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Atherosclerosis

• Current Understanding

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Atherosclerosis and Inflammation
Ross R. N Engl J Med 1999340115-126.
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Atherosclerosis and Inflammation
Ross R. N Engl J Med 1999340115-126.
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Anatomy of the Mature Plaque
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Matrix Metabolism and Integrity of the Plaques
Fibrous Cap
Synthesis
Breakdown
Collagen-degrading Proteinases
Fibrouscap
IFN-?

CD-40L




IL-1TNF-?MCP-1M-CSF


Lipid core
Tissue Factor Procoagulant
Libby P. Circulation 1995912844-2850.
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Plaque Rupture with Thrombosis
From A Slide Atlas Atherosclerosis Progression
and Regression, Parthenon Publishing, 1999
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Emerging Cardiac Risk Factors
The Four Big Ones

• C-Reactive Protein
• Lipoprotein (a)
• Fibrinogen
• Homocysteine

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Characteristics of an Ideal Screening Test

• Presence of reliable assay
• Independence from other risk factors
• Presence of populations norms to allow
  interpretation of test
• Clear statistical association of test and
  clinical endpoint
• Ability to improve prediction beyond traditional
  risk factors
• Ability to generalize results to other groups
• Acceptable cost for assay

Circulation 2003107499-511
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C-reactive Protein

• Circulating acute phase reactant
• Many-fold increase with injury infection
• Synthesized in liver, induced primarily by
  interleukin-6 (IL-6)
• Stable levels in circulation, not affected by
  meals, no circadian levels
• Level within normal range predicts CVD risk

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Hs-CRP predicts first events
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hs-CRP and Risk of Future MI in Apparently
Healthy Men
P Trend lt0.001
P lt 0.001
P lt 0.001
P 0.03
Relative Risk of MI
1lt0.055
20.0560.114
30.1150.210
4gt0.211
Quartile of hs-CRP (range, mg/dL)
Ridker PM et al. N Engl J Med 1997336973-979.
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hs-CRP and Risk of Future MI Analysis Stratified
by Smoking Status
All Patients
Nonsmokers
Relative Risk of Future MI
1
2
3
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Quartile of CRP
Ridker PM et al. N Engl J Med 1997336973-979.
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CRP and Risk Overview of 18 Studies
Ridker PM. Circulation 2003107363-9
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C-Reactive Protein and CHD
Danesh, et al. BMJ. 2000321199-204
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CRP and Cardiovascular Risk
CRP will Predict

• MI
• Stroke
• Peripheral arterial disease
• Sudden cardiac death
• Recurrent ischemia and death in
• Unstable Angina
• Myocardial Infarction
• Percutaneous intervention

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hs-CRP and Risk of T2DM
P value for trend 0.001
Pradhan, et al. JAMA 2001286327-34
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hs-CRP and Risk of Metabolic Syndrome

• ATP III Definition of the Metabolic Syndrome
• Three of the following five characteristics
• Midline obesity
• Elevated TG
• Low HDL
• Hypertension
• Glucose Intolerance

P value for trend lt 0.0001
Ridker, et al. Circulation 2003107391-7
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CRP, Metabolic Syndrome and CV Events
Ridker, et al. Circulation 2003107391-7
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Elevated CRP Levels in Obesity NHANES 1988-1994
Percent with CRP ?0.22 mg/dL
Normal
Overweight
Obese
Visser M et al. JAMA 19992822131-2135.
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Does CRP provide predictive information beyond
existing global predictors?
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CRP and Framingham Risk Score
Ridker PM. Circulation 2003107363-9
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CRP and LDL Cholesterol
Ridker PM. Circulation 2003107363-9
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Relative Risks of Future MI among Apparently
Healthy Middle-Aged Men Physicians Health Study
Relative Risk for Future MI
Ridker PM. Ann Intern Med 1999130933-937.
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CRP and Risk of MI Rotterdam Study
van der Meer, et al Arch Intern Med
20031641323-8
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Can intervention lower CRP levels?

• Statins? Yes
• Weight loss ??
• Smoking cessation??
• Physical activity??
• No studies to date have shown CRP lowering in
  itself is associated with reduced event rates!

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Effect of Statin Therapy on hs-CRP Levels at 6
Weeks
6 5 4 3 2 1 0
plt0.025 vs. Baseline
hs-CRP (mg/L)
Baseline
Prava(40 mg/d)
Simva(20 mg/d)
Atorva(10 mg/d)
Jialal I et al. Circulation 20011031933-1935. ?2
001 Lippincott Williams Wilkins.
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Routine screening with c-reactive protein?
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CRP Limitations

• Most studies limited to North American and
  European population -- limited ability to
  extrapolate to Native American, African and South
  Asian
• Not good indicator of extent of disease burden
• Most studies have not adjusted for
  body-mass-index
• Strength of association lessoned in some studies
  when adjusting for other risk factors

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AHA/CDC Consensus Panel
Hs-CRP Recommendations

• Class I None
• Class IIa
• In primary prevention, CRP measurement may be
  useful in those at intermediate risk (10-20
  10-year CHD risk), to help direct further
  evaluation and treatment.
• In patients with stable CAD or ACS, CRP may be
  useful as an independent marker of recurrent
  events, including death, MI and restenosis
  following PCI.

Circulation 2003107499-511
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AHA/CDC Consensus Panel
Hs-CRP Recommendations

• Class IIa
• Measurement should be done twice (two weeks
  apart) and results averaged.
• If level gt 10 mg/L, test should be repeated and
  patient examined for sources of infection or
  inflammation
• Classify risk as follows
• Low lt 1 mg/L
• Average 1.0 3.0 mg/L
• High gt 3.0 mg/L

Circulation 2003107499-511
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AHA/CDC Consensus Panel
Hs-CRP Recommendations

1. Screening of the population as a whole is NOT
   recommended
2. Application of secondary prevention measures
   should not depend upon hs-CRP results
3. Application of management guidelines for acute
   coronary syndromes should not be dependent upon
   hs-CRP level
4. Serial CRP levels should not be used to monitor
   effects of treatment

Circulation 2003107499-511
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Emerging Cardiac Risk Factors
The Four Big Ones

• C-Reactive Protein
• Lipoprotein (a)
• Fibrinogen
• Homocysteine

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Lipoprotein (a)

• LDL-like particle consisting of apolipoprotein
  moiety attached to apoB-100
• Levels under genetic control and dont vary with
  diet or exercise
• Acute phase reactant, doubling in concentration
  after IL-6 stimulation
• Structural similarities to plasminogen

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Lipoprotein (a)
Danesh, et al. Circulation 20001021082-5
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Lipoprotein (a)

• Lp(a) levels not affected by usual lipid lowering
  drugs lowered only by high-dose niacin
• No prospective trials showing reduction of
  cardiac endpoints with Lp(a) lowering
• Not recommended for general screening

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Emerging Cardiac Risk Factors
The Four Big Ones

• C-Reactive Protein
• Lipoprotein (a)
• Fibrinogen
• Homocysteine

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Fibrinogen

• Circulating glycoprotein involved in final steps
  of coagulation
• Other actions
• Regulation of cell adhesion, chemotaxis and
  proliferation
• Vasoconstriction at sites of vascular injury
• Stimulation of platelet aggregation
• Influence on blood viscosity

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Fibrinogen

• Acute phase reactant, increasing up to 4-fold
  after infectious or inflammatory stimuli
• Levels also increased by
• Cigarette smoking
• Diabetes
• Hypertension
• Obesity
• Sedentary lifestyle
• Levels lowered with fibrates and niacin no
  effect from statins or aspirin

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Emerging Cardiac Risk Factors
The Four Big Ones

• C-Reactive Protein
• Lipoprotein (a)
• Fibrinogen
• Homocysteine

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Causes of elevated Homocysteine

• Homozygous homocysteinurias
• MTHFR mutations
• Others
• Renal failure
• Hypothyroidism
• Drugs interfering with folate metabolism (niacin)

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Clinical Consequences of Elevated Homocysteine

• Clinical studies show increased risk of
• CHD
• Stroke
• Peripheral vascular disease

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MTHFR Homozygous Abnormal
General Population
Wald et al. BMJ 20023251202-9
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Homocyteine Meta-analysis
Population Outcome Odds Ratio Confidence Intervals
MTHFR Mutation CHD 1.21 1.06-1.31
General Population CHD 1.23 1.14-1.32
General Population Stroke 1.42 1.21-1.66
Wald et al. BMJ 20023251202-9
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Homocystine and Risk of CHD ARIC Study
ARIC Study. Circulation 199898204-10
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Homocystine and Risk of CHD ARIC Study
P 0.24
P 0.14
P 0.001
P 0.29
Plasma Homocysteine
Dietary Folate
Plasma PLP (B6)
Dietary Vitamin B12
ARIC Study. Circulation 199898204-10
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Secondary Prevention with Homocysteine Lowering

• 593 patients with stable CAD (documented MI, gt 60
  lesion on cath, PCI/CABG)
• Prospective, open label
• Mean follow-up 24 months

Leim, et al. J Am Coll Cardiol 2003412105-13
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Secondary Prevention with Homocysteine Lowering
Clinical Events
Leim, et al. J Am Coll Cardiol 2003412105-13
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Secondary Prevention with Homocysteine Lowering
Survival Analysis
Leim, et al. J Am Coll Cardiol 2003412105-13
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Homocysteine Reduction After PCI

• Prospective double-blind, placebo controlled
  trial
• 205 patients undergoing PCI randomized to
  receive
• Folate 1 mg, Vit. B12 400 mcg, Pyridoxine 10 mg
• OR
• Placebo
• Primary endpoint angiographic restenosis at 6
  months

Schnyder et al. NEJM 20013451593-600
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Folate Supplementation and Renstenosis
P lt 0.001
P 0.01
P 0.32
Schnyder et al. NEJM 20013451593-600
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Homocysteine Reduction After PCI
Schnyder et al. NEJM 20013451593-600
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Problems with Homocysteine as a Vascular Disease
Risk Factor

• Recent prospective studies in low risk
  populations have shown little or no risk
  association between tHcy and CVD
• Traditional risk factors are often associated
  with tHcy and may confound results
• Mutations of MTHFR cause a moderate elevation of
  tHcy but little or no increased CVD risk

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AHA Science Advisory

• Widespread population screening not advised
• Selective screening should be considered in those
  with
• Strong family history
• Suspected elevated risk
• Pending results of large clinical trials,
  treatment to lower homocysteine should be
  considered experimental

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Conclusions

• The majority of those with CHD have traditional
  risk factors
• Novel risk factors add little to existing global
  risk predictors such a Framingham risk score
• CRP may provide useful information in those at
  intermediate risk
• Routine screening of homocysteine levels is not
  recommended
• Fibrinogen and Lp(a) screening not recommended