NOVEL BIOMARKERS and CARDIOVASCULAR DISEASE

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  • Slide 5. Is there clinical evidence that inflammatory markers predict future coronary events and provide additional predictive information? In this discussion, we are going to focus on the clinical question of whether there is clinical evidence that inflammatory markers can be used to predict future coronary events, and if so, whether they provide additional predictive information to that obtained from traditional risk factors. Keywords: inflammation, inflammatory markers Slide type: text
  • This slide depicts the molecular helices which together form the C-reactive protein (CRP) pentamer. This structure is highly stable, provides for a long half-life, and results in an easily measured biomarker of inflammation. CRP is a key component of the innate immune response and participates in a number of processes related to the development of atherosclerosis including a role in the oxidation of LDL. The role of CRP as a marker for underlying inflammation and its contribution to cardiovascular risk lie at the heart of the rationale for the JUPITER trial.
  • Slide 25. CRP vs hs-CRP The standard CRP test is inadequate for detecting the low grade levels of inflammation measured with the hs-CRP test. CRP is an acute phase protein produced in the liver in response to cytokine production. The levels will increase several hundredfold if not a thousandfold during acute infection and tissue injury. High sensitivity assays are needed to detect the CRP levels within the normal range that have been used to predict vascular risk. Keyword: C-reactive protein, measurement Slide type: text
  • In fact, as shown here, CRP has now been evaluated as a novel risk factor for future myocardial infarction, stroke, peripheral arterial disease, and sudden cardiovascular death in over a dozen major epidemiologic studies. The association between CRP and cardiovascular risk has been consistently observed over a wide array of patient populations.
  • A critical clinical question has been whether or not CRP levels add to information based upon cholesterol evaluation. As shown here, high sensitivity evaluation for CRP (hs-CRP) clearly adds to the predictive value of the total to HDL cholesterol ratio. As also shown, risk is high for those with elevated levels of CRP but average cholesterol values. Such patients, however, are largely missed by current screening protocols.
  • When directly compared with many other novel risk factors including homocysteine, lipoprotein(a), and standard lipid measures, hs-CRP has proven to be the single strongest predictor of risk, as is shown here in further data from the Women’s Health Study. It is important to note that CRP levels do not correlate well with cholesterol levels. Thus, as also shown in this slide, the addition of CRP evaluation to cholesterol screening greatly improves risk prediction.
  • Slide 2. Is there clinical evidence that inflammation can be modified by preventive therapies?   Keywords: inflammation Slide type: text
  • Slide 6. Elevated CRP levels in obesity: NHANES 1988–1994 Probably the simplest mechanism to modify CRP levels is weight reduction. In the third U.S. National Health and Nutrition Examination Survey (NHANES III), as individuals increased from normal weight to overweight to frankly obese, the proportion of individuals with elevated CRP dramatically increased. These data are not surprising, because fat cells, or adipocytes, are a major source of IL-6 production and hence will lead to increased levels of CRP. From a preventive cardiologist's standpoint, exercise and weight loss are likely to be fundamental mechanisms by which we can reduce the impact of the inflammatory process.   Reference: Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. JAMA 1999;282:2131-2135. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10591334&dopt=Abstract   Keywords: C-reactive protein, NHANES, obesity Slide type: graph
  • Slide 7. Effects of weight loss on CRP concentrations in obese healthy women In 83 healthy obese women (mean BMI 33.8 ± 0.4 kg/m 2 , range 28.2–43.8 kg/m 2 ), CRP was positively associated with BMI at baseline (r=0.281, p=0.01). Subjects with CRP below the median of 5.8 mg/L had significantly lower BMI at baseline (33.0 ± 0.5 kg/m 2 ) than subjects with CRP above the median (BMI 34.8 ± 0.6 kg/m 2 ; p=0.02). BMI accounted for 7.7% of variability in baseline CRP (p=0.01). After 12 weeks on a very low fat, energy-restricted diet (mean 5700 ± 60 kJ/d, 14.2 ± 0.2% fat), CRP was reduced by 26% (p<0.001). Average weight loss was 7.9 ± 0.3 kg and was associated with change in CRP. Change in CRP was also correlated with change in total cholesterol (r=0.240, p=0.03) but not changes in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), or glucose. At 12 weeks, CRP concentration was highly correlated with triglyceride concentration (r=0.287, p=0.009), but not with other lipids or glucose at baseline or 12 weeks.   Reference: Heilbronn LK, Noakes M, Clifton PM. Energy restriction and weight loss on very-low-fat diets reduce C-reactive protein concentrations in obese, healthy women. Arterioscler Thromb Vasc Biol 2001;21:968-970. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11397705&dopt=Abstract   Keywords: C-reactive protein, diet, obesity, weight loss Slide type: text
  • Slide 12. Effect of HRT on hs-CRP: the PEPI study Another preventive therapy that seems to impact upon CRP is hormone-replacement therapy (HRT). The Postmenopausal Estrogen/Progestin Interventions (PEPI) study randomized postmenopausal women to placebo or to four different estrogen or estrogen plus progesterone regimens: conjugated equine estrogens (CEE) 0.625 mg/d, CEE 0.625 mg/d plus medroxyprogesterone acetate (MPA) 10 mg/d for days 1–12 each month (cyclic), CEE 0.625 mg/d plus MPA 2.5 mg/d (continuous), or CEE plus micronized progesterone (MP) 200 mg/d, days 1–12 each calendar month. Regardless of the HRT preparation, CRP levels markedly increased following initiation of HRT. These data have been confirmed elsewhere and have raised the possibility that part of the early thrombotic hazard that might be associated with initiation of HRT may relate in some way to a proinflammatory effect.   Reference: Cushman M, Legault C, Barrett-Connor E, Stefanick ML, Kessler C, Judd HL, Sakkinen PA, Tracy RP. Effect of postmenopausal hormones on inflammation‑sensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Study. Circulation 1999;100:717-722. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10449693&dopt=Abstract   Keywords: C-reactive protein, estrogen, PEPI, progesterone Slide type: graph
  • Moreover, it was also shown in the CARE trial for the first time that statin therapy could lower plasma levels of CRP. This is now known to be a class effect of all statins. It is important to note that the magnitude of CRP reduction associated with statin use is not closely linked to the magnitude of LDL reduction.
  • Slide 26. Effect of statin therapy on hs-CRP levels at 6 weeks Each statin studied significantly reduced CRP levels. Median percent reduction in hs-CRP did not differ significantly among statins; atorvastatin reduced hs-CRP by a median of 28.3%, pravastatin by 20.3%, and simvastatin by 22.8%. With the respective statins, CRP was reduced in 81.8%, 72.7%, and 81.8% of patients; CRP was reduced with all three statins in 54.6% of patients. Change in CRP level was not significantly correlated with change in LDL-C or HDL-C but was correlated with triglyceride (r=0.59, p=0.005).   Reference: Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S. Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation 2001;103:1933-1935. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11306519&dopt=Abstract   Keywords: atorvastatin, C-reactive protein, pravastatin, simvastatin, statins Slide type: graph
  • This slide provides the key excerpt from the AHA/CDC Scientific Statement on CRP that was published in January, 2003 encapsulating the essence of how CRP should be applied for clinical cardiovascular risk assessment in primary prevention populations : Measurement of hs-CRP is an independent marker of risk and may be used at the discretion of the physician as part of global coronary risk assessment in adults without known cardiovascular disease. Weight of evidence favors use particularly among those judged at intermediate risk by global risk assessment. Recall that those with an intermediate global risk– a Framingham Score between 5 and 20%/10yrs– defines the population being recruited for participation in the JUPITER trial.
  • As outlined in a recent clinical overview of CRP, the Centers for Disease Control also established a set of cut points to be used in routine clinical practice. As shown here, levels of CRP < 1mg/L, 1 to 3 mg/L, and > 3 mg/L correspond to low, moderate, and high vascular risk. CRP levels >10mg/L likely may indicate an acute phase response and should be remeasured in 2 to 3 weeks. Values that remain in this range are true positives and again reflect high vascular risk. CRP levels do not require fasting and can be measured at any time of the day.
  • Inflammatory cytokines: interleukin-6 (IL-6), IL-8, etc. Cellular adhesion molecules: integrins, selectins, NCAM (neural cell adhesion molecule), VCAM (vascular cellular adhesion molecule), etc. Acute-phase reactants: C-reactive protein (CRP) Plaque destabilization and rupture biomarkers: Myeloperoxidase (MPO) and possibly matrix metalloproteinase-9 (MMP-9), although it is not well defined. Biomarkers of ischemia: ischemia modified albumin (IMA) Biomarkers of myocardial stretch: BNP
  • References Cannon CP. Optimizing the treatment of unstable angina. J Thromb Thrombolysis . 1995;2:205-218. The theories behind the development of coronary artery disease (CAD) have revealed a strong component of inflammation. This is where MPO can be useful, as predictive of CAD and also in the acute phase as an early marker of plaque rupture. The necrosis markers are only seen hours after the damage has been done. Ideally we want to identify patients before this occurs. There are many markers of inflammation but few have been truly shown to be of use in ACS
  • Hypochlorous acid- (chemical) an oxyacid of chlorine containing monovalent chlorine that acts as an oxidizing or reducing agent Lymphocytes -identify foreign substances and produce antibodies and cells that specifically target them Neutrophils -made in bone marrow and move from blood vessels into infected tissue to attack bacteria. Leukopenia -low WBC count Leukocytosis -high WBC count Atherogenic -capacity to accelerate the process of atherogenesis (formation of lipid deposits in arteries)
  • Monocytes- one of three types of WBCs, monocytes are precursors to macrophages. Macrophage- type of WBC that ingests foreign material. Important in the immune response to foreign invaders. Blood monocytes migrate into tissue and then differentiate into macrophages. Foam cells- lipid laden macrophages originating from monocytes or from smooth muscle cells. Oxidize- To combine with oxygen, or subject to the action of oxygen, or of an oxidizing agent.
  • Risk significantly increased with increasing MPO level. The risk elevated quickly for 72 hr outcome, and then appears to stabilize over 6 months. The difference in the tertiles was significant as indicated on the graph. This data includes the 547 pts in the placebo arm of the CAPTURE trial.
  • NOVEL BIOMARKERS and CARDIOVASCULAR DISEASE

    1. 1. NOVEL BIOMARKERS and CARDIOVASCULAR DISEASE Nathan D Wong, PhD, FACC Professor and Director Heart Disease Prevention Program University of California, Irvine
    2. 2. ATP III Assessment of CHD Risk <ul><li>For persons without known CHD, other forms of atherosclerotic disease, or diabetes: </li></ul><ul><li>Count the number of risk factors: </li></ul><ul><ul><li>Cigarette smoking </li></ul></ul><ul><ul><li>Hypertension (BP  140/90 mmHg or on antihypertensive medication) </li></ul></ul><ul><ul><li>Low HDL cholesterol (<40 mg/dL) † </li></ul></ul><ul><ul><li>Family history of premature CHD </li></ul></ul><ul><ul><ul><li>CHD in male first degree relative <55 years </li></ul></ul></ul><ul><ul><ul><li>CHD in female first degree relative <65 years </li></ul></ul></ul><ul><ul><li>Age (men  45 years; women  55 years) </li></ul></ul><ul><li>Use Framingham scoring for persons with  2 risk factors* (or with metabolic syndrome) to determine the absolute 10-year CHD risk. (downloadable risk algorithms at www.nhlbi.nih.gov) </li></ul>Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486-2497. © 2001, Professional Postgraduate Services ® www.lipidhealth.org
    3. 3. Assessing CHD Risk in Men Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486-2497. Step 2: Total Cholesterol TC Points at Points at Points at Points at Points at (mg/dL) Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79 <160 0 0 0 0 0 160-199 4 3 2 1 0 200-239 7 5 3 1 0 240-279 9 6 4 2 1  280 11 8 5 3 1 Point Total 10-Year Risk Point Total 10-Year Risk <0 <1% 11 8% 0 1% 12 10% 1 1% 13 12% 2 1% 14 16% 3 1% 15 20% 4 1% 16 25% 5 2%  17  30% 6 2% 7 3% 8 4% 9 5% 10 6% Step 7: CHD Risk ATP III Framingham Risk Scoring http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm © 2001, Professional Postgraduate Services ® www.lipidhealth.org Step 1: Age Years Points 20-34 -9 35-39 -4 40-44 0 45-49 3 50-54 6 55-59 8 60-64 10 65-69 11 70-74 12 75-79 13 HDL-C (mg/dL) Points  60 -1 50-59 0 40-49 1 <40 2 Step 3: HDL-Cholesterol Systolic BP Points Points (mm Hg) if Untreated if Treated <120 0 0 120-129 0 1 130-139 1 2 140-159 1 2  160 2 3 Step 4: Systolic Blood Pressure Step 5: Smoking Status Points at Points at Points at Points at Points at Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79 Nonsmoker 0 0 0 0 0 Smoker 8 5 3 1 1 Age Total cholesterol HDL-cholesterol Systolic blood pressure Smoking status Point total Step 6: Adding Up the Points
    4. 4. Modified approach to CHD risk assessment <ul><li>LOW RISK designated as <0.6% CHD risk per year (<6% in 10 years) </li></ul><ul><li>INTERMEDIATE RISK designated as a CHD risk of 0.6%-2.0% per year (6-20% over 10 years) </li></ul><ul><li>HIGH RISK designated as a CHD risk of >2% per year (20% in 10 years) (CHD risk equivalent), including those with CVD, diabetes, and PAD </li></ul>Greenland P et al. Circulation 2001; 104: 1863-7
    5. 5. Presentation <ul><li>Examination: </li></ul><ul><ul><li>Height: 6 ft 2 in </li></ul></ul><ul><ul><li>Weight: 220 lb (BMI 28 kg/m 2 ) </li></ul></ul><ul><ul><li>Waist circumference: 41 in </li></ul></ul><ul><ul><li>BP: 150/88 mm Hg </li></ul></ul><ul><ul><li>P: 64 bpm </li></ul></ul><ul><ul><li>RR: 12 breaths/min </li></ul></ul><ul><li>Cardiopulmonary exam: normal </li></ul><ul><li>Laboratory results: </li></ul><ul><ul><li>TC: 220 mg/dL </li></ul></ul><ul><ul><li>HDL-C: 36 mg/dL </li></ul></ul><ul><ul><li>LDL-C: 140 mg/dL </li></ul></ul><ul><ul><li>TG: 220 mg/dL </li></ul></ul><ul><ul><li>FBS: 120 mg/dL </li></ul></ul>
    6. 6. What is WJC’s 10-year absolute risk of fatal/nonfatal MI? <ul><li>A 12% absolute risk is derived from points assigned in Framingham Risk Scoring to: </li></ul><ul><ul><li>Age: 6 </li></ul></ul><ul><ul><li>TC: 3 </li></ul></ul><ul><ul><li>HDL-C: 2 </li></ul></ul><ul><ul><li>SBP: 2 </li></ul></ul><ul><ul><li>Total: 13 points </li></ul></ul>In 1992 he exercised 14 minutes in a Bruce protocol exercise stress test to 91% of his maximum predicted heart rate without any abnormal ECG changes. He started on a statin in 2001. But in Sept 2004, he needed urgent coronary bypass surgery .
    7. 7. Not all individuals with coronary heart disease have traditional risk factors Khot et al. JAMA 2003
    8. 8. The Detection Gap in CHD <ul><li>“ Despite many available risk assessment approaches, a substantial gap remains in the detection of asymptomatic individuals who ultimately develop CHD” </li></ul><ul><li>“ The Framingham and European risk scores… emphasize the classic CHD risk factors…. is only moderately accurate for the prediction of short- and long-term risk of manifesting a major coronary artery event…” </li></ul>Pasternak and Abrams et al. 34 th Bethesda conf. JACC 2003; 41: 1855-1917
    9. 9. Is there clinical evidence that novel risk markers predict future coronary events and provide additional predictive information beyond traditional risk factors?
    10. 10. Fibrinogen and Atherosclerosis <ul><li>Promotes atherosclerosis </li></ul><ul><li>Essential component of platelet aggregation </li></ul><ul><li>Relates to fibrin deposited and the size of the clot </li></ul><ul><li>Increases plasma viscosity </li></ul><ul><li>May also have a proinflammatory role </li></ul><ul><li>Measurement of fibrinogen, incl. Test variability, remains difficult. </li></ul><ul><li>No known therapies to selectively lower fibrinogen levels in order to test efficacy in CHD risk reduction via clinical trials. </li></ul>
    11. 11. Fibrinogen and CHD Risk: Epidemiologic Studies <ul><li>Recent meta-analysis of 18 studies involving 4018 CHD cases showed a relative risk of CHD of 1.8 (95% CI 1.6-2.0) comparing the highest vs lowest tertile of fibrinogen levels (mean .35 vs. .25 g/dL) </li></ul><ul><li>ARIC study in 14,477 adults aged 45-64 showed relative risks of 1.8 in men and 1.5 in women, attenuated to 1.5 and 1.2 after risk factor adjustment. </li></ul><ul><li>Scottish Heart Health Study of 5095 men and 4860 women showed fibrinogen to be an independent risk factor for new events--RRs 2.2-3.4 for coronary death and all-cause mortality. </li></ul>
    12. 12. Fibrinogen and CHD Risk Factors <ul><li>Fibrinogen levels increase with age and body mass index, and higher cholesterol levels </li></ul><ul><li>Smoking can reversibly elevated fibrinogen levels, and cessation of smoking can lower fibrinogen. </li></ul><ul><li>Those who exercise, eat vegetarian diets, and consume alcohol have lower levels. Exercise may also lower fibrinogen and plasma viscosity. </li></ul><ul><li>Studies also show statin-fibrate combinations (simvastatin-ciprofibrate) and estrogen therapy to lower fibrinogen. </li></ul>
    13. 13. P. Ridker
    14. 14. CRP vs hs-CRP <ul><li>CRP is an acute-phase protein produced by the liver in response to cytokine production (IL-6, IL-1, tumor necrosis factor) during tissue injury, inflammation, or infection. </li></ul><ul><li>Standard CRP tests determine levels which are increased up to 1,000-fold in response to infection or tissue destruction, but cannot adequately assess the normal range </li></ul><ul><li>High-sensitivity CRP (hs-CRP) assays (i.e. Dade Behring) detect levels of CRP within the normal range, levels proven to predict future cardiovascular events. </li></ul>
    15. 15. C-Reactive Protein: Risk Factor or Risk Marker? <ul><li>CRP previously known to be a marker of high risk in cardiovascular disease </li></ul><ul><li>More recent data may implicate CRP as an actual mediator of atherogenesis </li></ul><ul><li>Multiple hypotheses for the mechanism of CRP-mediated atherogenesis: </li></ul><ul><ul><li>Endothelial dysfunction via ↑ NO synthesis </li></ul></ul><ul><ul><li>↑ LDL deposition in plaque by CRP-stimulated macrophages </li></ul></ul>
    16. 16. hs-CRP as a Risk Factor For Future CVD : Primary Prevention Cohorts 0 1.0 2.0 3.0 4.0 5.0 6.0 Kuller MRFIT 1996 CHD Death Ridker PHS 1997 MI Ridker PHS 1997 Stroke Tracy CHS/RHPP 1997 CHD Ridker PHS 1998,2001 PAD Ridker WHS 1998,2000,2002 CVD Koenig MONICA 1999 CHD Roivainen HELSINKI 2000 CHD Mendall CAERPHILLY 2000 CHD Danesh BRHS 2000 CHD Gussekloo LEIDEN 2001 Fatal Stroke Lowe SPEEDWELL 2001 CHD Packard WOSCOPS 2001 CV Events* Ridker AFCAPS 2001 CV Events* Rost FHS 2001 Stroke Pradhan WHI 2002 MI,CVD death Albert PHS 2002 Sudden Death Sakkinen HHS 2002 MI Relative Risk (upper vs lower quartile) Ridker PM. Circulation 2003;107:363-9
    17. 17. hs-CRP Adds to Predictive Value of TC:HDL Ratio in Determining Risk of First MI Total Cholesterol:HDL Ratio Ridker et al, Circulation. 1998;97:2007–2011. hs-CRP Relative Risk
    18. 18. Risk Factors for Future Cardiovascular Events: WHS 0 1.0 2.0 4.0 6.0 Lipoprotein(a) Homocysteine IL-6 TC LDLC sICAM-1 SAA Apo B TC: HDLC hs-CRP hs-CRP + TC: HDLC Relative Risk of Future Cardiovascular Events Ridker et al, N Engl J Med. 2000;342:836-43
    19. 19. Is there clinical evidence that inflammation can be modified by preventive therapies?
    20. 20. Elevated CRP Levels in Obesity: NHANES 1988-1994 Visser M et al. JAMA 1999;282:2131-2135. Normal Percent with CRP  0.22 mg/dL Overweight Obese
    21. 21. Effects of Weight Loss on CRP Concentrations in Obese Healthy Women <ul><li>83 women (mean BMI 33.8, range 28.2-43.8 kg/m 2 ) placed on very low fat, energy-restricted diet (6.0 MJ, 15% fat) for 12 weeks </li></ul><ul><li>Baseline CRP positively associated with BMI (r=0.281, p=0.01) </li></ul><ul><li>CRP reduced by 26% (p<0.001) </li></ul><ul><li>Average weight loss 7.9 kg, associated with change in CRP </li></ul><ul><li>Change in CRP correlated with change in TC (r=0.240, p=0.03) but not changes in LDL-C, HDL-C, or glucose </li></ul><ul><li>At 12 weeks, CRP concentration highly correlated with TG (r=0.287, p=0.009), but not with other lipids or glucose </li></ul>Heilbronn LK et al. Arterioscler Thromb Vasc Biol 2001;21:968-970.
    22. 22. Effect of HRT on hs-CRP: the PEPI Study 3.0 2.0 1.0 hs-CRP (mg/dL) Months 0 12 36 Cushman M et al. Circulation 1999;100:717-722.  1999 Lippincott Williams & Wilkins. CEE + MPA cyclic CEE + MPA continuous CEE + MP CEE Placebo
    23. 23. Long-Term Effect of Statin Therapy on hs-CRP: Placebo and Pravastatin Groups Pravastatin Placebo Median hs-CRP Concentration (mg/dL) -21.6% ( P =0.004) 0.18 0.19 0.20 0.21 0.22 0.23 0.24 0.25 Baseline 5 Years Ridker et al, Circulation. 1999;100:230-235.
    24. 24. Effect of Statin Therapy on hs-CRP Levels at 6 Weeks hs-CRP (mg/L) Jialal I et al. Circulation 2001;103:1933-1935.  2001 Lippincott Williams & Wilkins. 6 5 4 3 2 1 0 Baseline Prava (40 mg/d) Simva (20 mg/d) Atorva (10 mg/d) *p<0.025 vs. Baseline * * *
    25. 25. However, while intriguing and of potential public health importance, the observation in AFCAPS/TexCAPS that statin therapy might be effective among those with elevated hsCRP but low cholesterol was made on a post hoc basis. Thus, a large-scale randomized trial of statin therapy was needed to directly test this hypotheses. Ridker et al, New Engl J Med 2001;344:1959-65 Low LDL, Low hsCRP Low LDL, High hsCRP Statin Effective Statin Not Effective 1.0 2.0 0.5 [A] [B] Low LDL, Low hsCRP Low LDL, High hsCRP Statin Effective Statin Not Effective 1.0 2.0 0.5 AFCAPS/TexCAPS Low LDL Subgroups RR AFCAPS/TEXCAPS showed statins to be effective in lowering risk in the setting of normal LDL-C, but only when inflammation was present
    26. 26. A Randomized Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among 17,802 Apparently Healthy Men and Women With Elevated Levels of C-Reactive Protein (hsCRP): The JUPITER Trial Paul Ridker*, Eleanor Danielson, Francisco Fonseca*, Jacques Genest*, Antonio Gotto*, John Kastelein*, Wolfgang Koenig*, Peter Libby*, Alberto Lorenzatti*, Jean MacFadyen, Borge Nordestgaard*, James Shepherd*, James Willerson, and Robert Glynn* on behalf of the JUPITER Trial Study Group An Investigator Initiated Trial Funded by AstraZeneca, USA * These authors have received research grant support and/or consultation fees from one or more statin manufacturers, including Astra-Zeneca. Dr Ridker is a co-inventor on patents held by the Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease that have been licensed to Dade-Behring and AstraZeneca.
    27. 27. To investigate whether rosuvastatin 20 mg compared to placebo would decrease the rate of first major cardiovascular events among apparently healthy men and women with LDL < 130 mg/dL (3.36 mmol/L) who are nonetheless at increased vascular risk on the basis of an enhanced inflammatory response, as determined by hsCRP > 2 mg/L. To enroll large numbers of women and individuals of Black or Hispanic ethnicity, groups for whom little data on primary prevention with statin therapy exists. J ustification for the U se of statins in P revention: an I ntervention T rial E valuating R osuvastatin Ridker et al NEJM 2008
    28. 28. Rosuvastatin 20 mg (N=8901) MI Stroke Unstable Angina CVD Death CABG/PTCA JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP 4-week run-in Ridker et al, Circulation 2003;108:2292-2297. No Prior CVD or DM Men > 50, Women > 60 LDL <130 mg/dL hsCRP > 2 mg/L JUPITER Trial Design Placebo (N=8901) Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay, United States, Venezuela
    29. 29. JUPITER Baseline Blood Levels (median, interquartile range) Rosuvastatin Placebo (N = 8901) (n = 8901) hsCRP, mg/L 4.2 (2.8 - 7.1) 4.3 (2.8 - 7.2) LDL, mg/dL 108 (94 - 119) 108 (94 - 119) HDL, mg/dL 49 (40 – 60) 49 (40 – 60) Triglycerides, mg/L 118 (85 - 169) 118 (86 - 169) Total Cholesterol, mg/dL 186 (168 - 200) 185 (169 - 199) Glucose, mg/dL 94 (87 – 102) 94 (88 – 102) HbA1c, % 5.7 (5.4 – 5.9) 5.7 (5.5 – 5.9) All values are median (interquartile range). [ Mean LDL = 104 mg/dL ] Ridker et al NEJM 2008
    30. 30. hsCRP (mg/L) LDL (mg/dL) Months 0 12 24 36 48 TG (mg/dL) HDL (mg/dL) Months JUPITER Effects of rosuvastatin 20 mg on LDL, HDL, TG, and hsCRP LDL decrease 50 percent at 12 months hsCRP decrease 37 percent at 12 months HDL increase 4 percent at 12 months TG decrease 17 percent at 12 months Ridker et al NEJM 2008
    31. 31. JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Placebo 251 / 8901 Rosuvastatin 142 / 8901 HR 0.56, 95% CI 0.46-0.69 P < 0.00001 Number Needed to Treat (NNT 5 ) = 25 - 44 % 0 1 2 3 4 0.00 0.02 0.04 0.06 0.08 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174 Ridker et al NEJM 2008
    32. 32. JUPITER Secondary Endpoint – All Cause Mortality Placebo 247 / 8901 Rosuvastatin 198 / 8901 HR 0.80, 95%CI 0.67-0.97 P= 0.02 - 20 % 0 1 2 3 4 0.00 0.01 0.02 0.03 0.04 0.05 0.06 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 227 8,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246 Ridker et al NEJM 2008
    33. 33. JUPITER Implications for Primary Prevention Among men and women age 50 or over : If diabetic, treat If LDLC > 160 mg/dL, treat If hsCRP > 2 mg/L, treat A simple evidence based approach to statin therapy for primary prevention. Ridker et al NEJM 2008
    34. 34. AHA / CDC Scientific Statement Markers of Inflammation and Cardiovascular Disease: Applications to Clinical and Public Health Practice Circulation January 28, 2003 “Measurement of hs-CRP is an independent marker of risk and may be used at the discretion of the physician as part of global coronary risk assessment in adults without known cardiovascular disease. Weight of evidence favors use particularly among those judged at intermediate risk by global risk assessment”.
    35. 35. Clinical Application of hs-CRP for Cardiovascular Risk Prediction 1 mg/L 3 mg/L 10 mg/L Low Risk Moderate Risk High Risk Acute Phase Response Ignore Value, Repeat Test in 3 weeks >100 mg/L Ridker PM. Circulation 2003;107:363-9
    36. 36. Homocysteine <ul><li>Intermediary amino acid formed by the conversion of methionine to cysteine </li></ul><ul><li>Moderate hyperhomocysteinemia occurs in 5-7% of the population </li></ul><ul><li>Recognized as an independent risk factor for the development of atherosclerotic vascular disease and venous thrombosis </li></ul><ul><li>Can result from genetic defects, drugs, vitamin deficiencies, or smoking </li></ul>
    37. 37. Homocysteine <ul><li>Homocysteine implicated directly in vascular injury including: </li></ul><ul><ul><li>Intimal thickening </li></ul></ul><ul><ul><li>Disruption of elastic lamina </li></ul></ul><ul><ul><li>Smooth muscle hypertrophy </li></ul></ul><ul><ul><li>Platelet aggregation </li></ul></ul><ul><li>Vascular injury induced by leukocyte recruitment, foam cell formation, and inhibition of NO synthesis </li></ul>
    38. 38. Homocysteine <ul><li>Elevated levels appear to be an independent risk factor, though less important than the classic CV risk factors </li></ul><ul><li>Screening recommended in patients with premature CV disease (or unexplained DVT) and absence of other risk factors </li></ul><ul><li>Treatment includes supplementation with folate, B6 and B12 </li></ul>
    39. 39. The Future of Cardiac Biomarkers <ul><li>Many experts are advocating the move towards a multimarker strategy for the purposes of diagnosis, prognosis, and treatment design </li></ul><ul><li>As the pathophysiology of ACS is heterogeneous, so must be the diagnostic strategies </li></ul>
    40. 40. Multiple Biomarkers for the Prediction of First CVD Events and Death (Wang TJ et al., NEJM 2006; 355: 2631-9) <ul><li>10 biomarkers examined in 3209 pts of the Framingham Heart Study </li></ul><ul><li>CRP, BNP, N-T pro-ANP, aldosterone, renin, fibrinogen, d-dimer, PAI-1, homocysteine, and urine albumin/creatinine ratio. </li></ul><ul><li>7.4 years medial follow-up </li></ul><ul><li>Adjusted HR’s per SD: BNP 1.4, CRP 1.4, albumin/creatinine 1.2, homocysteine 1.2, renin 1.5 for death, and BNP 1.25, albumin/creatinine 1.2 for CVD events </li></ul><ul><li>Multimarker scores in highest quintile vs. lowest two quintiles had adjusted HR for death of 4.1, p<0.001 and CVD events of 1.8, p=0.02 </li></ul><ul><li>Only moderate increases in C-statistic seen from biomarkers over standard risk factors </li></ul>
    41. 41. Multiple biomarkers and C-statistics (discrimination) Death First CVD Age, sex 0.75 0.68 Risk factors alone 0.80 0.76 RF plus biomarkers 0.82 0.77
    42. 42. Multiple biomarkers and reclassification Standard risk factors alone Standard risk factors plus multimarker score <10% 10-20% >20% <10% 79% 3% 0% 10-20% 3% 9% 1% >20% 0% 1% 3%
    43. 43. Use of Multiple Biomarkers to Improve Prediction of CVD Death (Zethelius B et al., NEJM 2008; 358: 2107-16) <ul><li>1135 elderly men from the Uppsala Longitudinal Study of Adult Men, mean age 71 years at baseline, 10 years median follow-up </li></ul><ul><li>Examined role of multiple markers reflecting myocardial cell damage—troponin I, LV dysfunction– N-T pro BNP, renal failure—cystatin C, and inflammation – CRP </li></ul><ul><li>C-statistic increased significantly when the four biomarkers were put in a model with established risk factors (0.77 vs. 0.66, p<0.0001) in the whole cohort and in those without CVD at baseline (0.748 vs. 0.688, p=0.03). </li></ul><ul><li>Among elderly men, multiple biomarkers may significantly improve risk for death from CVD causes beyond standard risk factors. </li></ul>
    44. 44. Current Biomarkers for ACS <ul><li>Biomarker assessment of high risk patients may include: </li></ul><ul><ul><li>Inflammatory cytokines </li></ul></ul><ul><ul><li>Cellular adhesion molecules </li></ul></ul><ul><ul><li>Acute-phase reactants </li></ul></ul><ul><ul><li>Plaque destabilization and rupture biomarkers </li></ul></ul><ul><ul><li>Biomarkers of ischemia </li></ul></ul><ul><ul><li>Biomarkers of myocardial stretch (BNP) </li></ul></ul><ul><ul><li>Biomarkers of myocardial necrosis (Troponin, CK-MB, Myoglobin) </li></ul></ul>Apple Clinical Chemistry March 2005
    45. 45. Progression of Biomarkers in ACS ACS, acute coronary syndrome; UA, unstable angina; NSTEMI, non–ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction Adapted from: Apple Clinical Chemistry March 2005 STEMI UA/NSTEMI STABLE CAD PLAQUE RUPTURE MPO CRP IL-6 MPO ICAM sCD40L PAPP-A MPO D-dimer IMA FABP TnI TnT Myoglobin CKMB Inflammation has been linked to the development of vulnerable plaque and to plaque rupture
    46. 46. Stefan Blankenberg, MD; Renate Schnabel, MD; Edith Lubos, MD, et al., Myeloperoxidase Early Indicator of Acute Coronary Syndrome and Predictor of Future Cardiovascular Events 2005
    47. 47. History: Troponin <ul><li>Troponin I first described as a biomarker specific for AMI in 1987 1 ; Troponin T in 1989 2 </li></ul><ul><li>Now the biochemical “gold standard” for the diagnosis of acute myocardial infarction via consensus of ESC/ACC </li></ul><ul><li>1 Am Heart J 113: 1333-44 </li></ul><ul><li>2 J Mol Cell Cardiol 21: 1349-53 </li></ul>
    48. 48. Troponins <ul><li>Elevated serum levels are an independent predictor of prognosis, morbidity and mortality </li></ul><ul><li>Meta-analysis of 21 studies involving ~20,000 patients with ACS revealed that those with elevated serum troponin had 3x risk of cardiac death or reinfarction at 30 days 1 </li></ul><ul><li>1 Am J Heart (140): 917 </li></ul>
    49. 49. All-Cause Mortality by Cardiac Troponin T (n=733) CP1090800-14 Circulation 106:2944, 2002 Time since blood draw (years) Cumulative survival (%) Patients at risk (no.) Baseline 1 yr 2 yr 2.5 yr cTnT <0.01  g/L 132 106 25 12 cTnT  0.01 to <0.04  g/L 214 166 41 15 cTnT  0.04 to <0.10  g/L 239 180 63 18 cTnT  0.10  g/L 148 93 20 8 cTnT <0.01  g/L cTnT  0.04  g/L cTnT  0.10  g/L cTnT  0.04 to 0.10  g/L
    50. 50. cTnT and Survival (Rancho Bernardo) Daniels et al: JACC 52:450, 2008 CP1322078-9 Survival (%) Years All Subjects Survival (%) Years Subjects Without Baseline CHD P<0.001 TnT  0.01 ng/mL TnT undetectable P<0.001 TnT undetectable TnT  0.01 ng/mL
    51. 51. BNP <ul><li>BNP has also shown utility as a prognostic marker in acute coronary syndrome </li></ul><ul><li>It is associated with increased risk of death at 10 months as concentration at 40 hours post-infarct increased </li></ul><ul><li>Also associated with increased risk for new or recurrent MI </li></ul>
    52. 52. BNP as a Predictor of Risk in Asymptomatic Adults: The Framingham Heart Study Wang et al., NEJM 2004
    53. 53. Association of increasing BNP levels and outcomes SD=standard deviation Wang TJ et al. N Engl J Med 2004; 350:655-63. 0.37 1.1 CHD event 0.002 1.53 Stroke or TIA <0.001 1.66 Atrial fibrillation <0.001 1.77 HF 0.03 1.28 First major CV event 0.009 1.27 Death p Hazard ratio for 1 SD increment in log BNP value End point
    54. 54. Conjoint Effects of cTnT and NT-proBNP on Prognosis (Rancho Bernardo) Daniels et al: JACC 52:450, 2008 CP1322078-12 Survival (%) Years All Subjects P<0.001 for all comparisons Survival (%) Years P<0.001 for all comparisons Subjects Without Baseline CHD Low NT-proBNP (n=758) High NT-proBNP, low TnT (n=171) High NT-proBNP, high TnT (n=27) Low NT-proBNP (n=667) High NT-proBNP, low TnT (n=122) High NT-proBNP, high TnT (n=16)
    55. 55. Myeloperoxidase <ul><li>MPO is an enzyme that aids white blood cells in destroying bacteria and viral particles </li></ul><ul><li>MPO catalyzes the conversion of hydrogen peroxide and chloride ions (Cl-) into hypochlorous acid </li></ul><ul><li>Hypochlorous acid is 50 times more potent in microbial killing than hydrogen peroxide </li></ul><ul><li>MPO is released in response to infection and inflammation </li></ul><ul><li>EPIC Norfolk Study showed its predictive value for future cardiovascular disease events in asymptomatic adults. </li></ul>Sugiyama Am J Pathology 2001
    56. 56. Summary of MPO and ACS <ul><li>MPO leads to oxidized LDL cholesterol </li></ul><ul><ul><li>Oxidized LDL is phagocytosed by macrophages producing foam cells* </li></ul></ul><ul><li>MPO leads to the consumption of nitric oxide </li></ul><ul><ul><li>Vasoconstriction and endothelial dysfunction </li></ul></ul><ul><li>MPO can cause endothelial denuding and superficial platelet aggregation </li></ul><ul><li>MPO indicates activated immune cells </li></ul><ul><ul><li>Activated immune cells and inflammation lead to unstable plaque* </li></ul></ul><ul><li>Inflammatory plaque is inherently less stable </li></ul><ul><ul><li>Thin fibrous cap/fissured/denuded </li></ul></ul>Brennan, NEJM 2003 *Hansson, NEJM 2005
    57. 57. MPO and MI in Asymptomatic Subjects: EPIC-NORFOLK <ul><li>Tertile 1 MPO < 222 ug/L </li></ul><ul><li>Tertile 2 MPO 222 – 350 ug/L </li></ul><ul><li>Tertile 3 MPO > 350 ug/L </li></ul>Death or MI (%) Baldus, et al. Circulation 2003;108: 1440-5.
    58. 58. MPO and CVD Event Risk (%) P-trend = 0.05 (Wong et al. JACC Cardiovasc Img 2009 ) Figure 2
    59. 59. Combined MPO-CAC Groups and CVD Event Risk (%) Log-rank test for trend P<0.0001; Wong et al., JACC Cardiovasc Img 2009 Figure 3

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