Inflammation Infection and CHD 051106

Inflammation Infection and CHD 051106 - Inflammation,...

Info iconThis preview shows page 1. Sign up to view the full content.

View Full Document Right Arrow Icon
This is the end of the preview. Sign up to access the rest of the document.

Unformatted text preview: Inflammation, Thrombosis, Infection, and Inflammation, Thrombosis, Infection, and CARDIOVASCULAR DISEASE Nathan D Wong, PhD, FACC Professor and Director Heart Disease Prevention Program University of California, Irvine Beyond Cholesterol: Predicting Beyond Cholesterol: Cardiovascular Risk In the 21st Century Cardiovascular Risk Cardiovascular Risk Lipids Lipids HTN HTN Diabetes Diabetes Behavioral Behavioral Hemostatic Hemostatic Thrombotic Thrombotic Inflammatory Inflammatory Genetic Genetic Inflammation and Atherosclerosis Inflammation and Atherosclerosis Inflammation may determine plaque stability ­ Unstable plaques have increased leukocytic infiltrates ­ T cells, macrophages predominate rupture sites ­ Cytokines and metalloproteinases influence both stability and degradation of the fibrous cap Lipid lowering may reduce plaque inflammation ­ Decreased macrophage number ­ Decreased expression of collagenolytic enzymes (MMP­1) ­ Increased interstitial collagen ­ Decreased expression of E­selectin ­ Reduced calcium deposition Libby P. Circulation 1995;91:2844­2850. Ross R. N Engl J Med 1999;340:115­126. Is there clinical evidence that inflammatory Is there clinical evidence that inflammatory markers predict future coronary events and provide additional predictive information beyond traditional risk factors? Evaluating Novel Risk Factors for CAD Evaluating Novel Risk Factors for CAD Consistency of prospective data Strength of association Independence of association Improve predictive value Standardized measure Low variability High reproducibility Biologic plausibility Low cost Modifiable Biomarkers for Venous and Arterial Biomarkers for Venous and Arterial Thrombosis Parameter Venous Arterial Fibrinogen – +++ Factor VII – + vWF: ag – ++ tPA: ag – +++ PAI­1: ag – ++ Platelet function – ++ Lp(a) – + hs­CRP / SAA / IL­6 / TNF – +++ Biomarkers for Venous and Arterial Biomarkers for Venous and Arterial Thrombosis (cont’d) Parameter Venous Arterial Factor V Leiden +++ – Prothrombin mutation ++ – Prothrombin + – Factor VIII ++ – Anti­thrombin III ++ – Protein C + – Protein S + – Homocysteine ++ ++ D­dimer ++ ++ Thrombosis and Cardiovascular Risk Thrombosis and Cardiovascular Risk Thrombus formation is a crucial factor in the precipitation of unstable angina or myocardial infarction, as well as occlusion during or following angioplasty. Often preceded by platelet aggregation and activation of the coagulation system. A thrombus may develop at sites of only mild to moderate coronary stenosis. The majority of coronary events occur where there is less than 70% stenosis. Occlusive coronary thrombosis plays a role in over 80% of myocardial infarctions and about 95% of sudden death victims. Fibrinogen and Atherosclerosis Fibrinogen and Atherosclerosis Promotes atherosclerosis Essential component of platelet aggregation Relates to fibrin deposited and the size of the clot Increases plasma viscosity May also have a proinflammatory role Measurement of fibrinogen, incl. Test variability, remains difficult. No known therapies to selectively lower fibrinogen levels in order to test efficacy in CHD risk reduction via clinical trials. Fibrinogen and CHD Risk: Epidemiologic Fibrinogen and CHD Risk: Epidemiologic Studies Recent meta­analysis 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) ARIC study in 14,477 adults aged 45­64 showed relative risks of 1.8 in men and 1.5 in women, attenuated to 1.5 and 1.2 after risk factor adjustment. Scottish Heart Health Study of 5095 men and 4860 women showed fibrinogen to be an independent risk factor for new events­­RRs 2.2­3.4 for coronary death and all­ cause mortality. Fibrinogen and CHD Risk Factors Fibrinogen and CHD Risk Factors Fibrinogen levels increase with age and body mass index, and higher cholesterol levels Smoking can reversibly elevated fibrinogen levels, and cessation of smoking can lower fibrinogen. Those who exercise, eat vegetarian diets, and consume alcohol have lower levels. Exercise may also lower fibrinogen and plasma viscosity. Studies also show statin­fibrate combinations (simvastatin­ciprofibrate) and estrogen therapy to lower fibrinogen. Other Thrombotic Factors and CHD Other Thrombotic Factors and CHD Mixed reports of coagulation factor VIIc in cardiovascular disease. PROCAM study showed no association with CHD events, CHS also showed no relation to subclinical CVD. Endogenous tissue­type plasminogen activator (tPA) shown in some studies to relate to increased cardiovascular risk­­Physician’s Health Study showed RR for MI 2.8, stroke 3.5 in those in 5th vs. 1st quintile of tPA. Plasminogen activitor inhibitor type 1 (PAI­1) shown associated with increased cardiovascular risk, esp in diabetic patients. Aspirin and Cardiovascular Risk: Clinical Aspirin and Cardiovascular Risk: Clinical Trial Evidence for Primary Prevention US Physician’s Health Study­ 22,071 male physicians ­ 44% reduction in MI risk, 13% nonsignificant increase in risk of stroke British Doctor’s Study of 5139 male physicians showed nonsignificant 3% reduction in MI risk,13% nonsignificant increase in stroke Hypertension Optimal Treatment (HOT) study among 18,790 pts w/htn showed 15% reduction in CVD events, 36% reduction in MI Women’s Health Study (n=39,876 women aged 45+) randomized to 100 mg asprin/day vs placebo, 10 years follow­ up – results recently released and asprin preventive only for stroke (17% reduction overall, p=0.04; 24% ischemic stroke, p<.001); nonfatal MI RR=1.02, CVD death 0.95, ns) (NEJM 2005; 352: 1366­8). Aspirin and Cardiovascular Risk: Clinical Aspirin and Cardiovascular Risk: Clinical Trial Evidence for Secondary Prevention Antiplatelet Trialists Collaboration of 54,000 patients with cardiovascular disease (10 trials post­MI) showed 31% reduction in MI, 42% reduction in stroke, 13% reduction in total vascular mortality International Study of Infarct Survival of 17,187 pts w/evolving MI showed 49% reduction in reinfarction, 26% reduction in nonfatal stroke, and 23% reduction in total vascular mortality Antiplatelet Therapy: Targets Antiplatelet dipyridamole clopidogrel bisulfate ticlopidine hydrochloride phosphodiesterase ADP ADP Gp 2b/3a Inhibitors Gp IIb/IIIa (Fibrinogen Receptor) Activation COX Collagen Thrombin TXA2 TXA2 aspirin ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase Schafer AI. Am J Med 1996;101:199–209 Antiplatelet Therapy: Common Oral Agents Antiplatelet Acetylsalicylic acid (ASA) Class Formulation Maintenance Dose Major Bleeding Risk (%) Ticlopidine hydrochloride* Aspirin Plavix® Ticlid® Salicylate Thienopyridine Thienopyridine Active Drug Pro­Drug Active Drug 75­325 mg daily 75 mg daily 250 mg twice daily 2.4­3.3%1 1.0­3.7% alone2,3 1.0% alone5 3.0­4.9% w/ ASA4 Trade Name Clopidogrel bisulfate* 1.7­5.5% w/ ASA6,7 Topol EJ et al. Circulation. 2003;108:399-406 Diener H-C et al. Lancet 2004;364;331-7 3 Plavix® package insert. www.sanofi-synthelabo.us 4 Peters RJ et al. Circulation 2003;108:1682-7 5 Hass WK. NEJM 1989;321:501-7 6 Urban P. Circulation. 1998;98:2126-32 7 Ticlid® package insert. www.rocheusa.com 1 2 *Clopidogrel is generally given preference over Ticlopidine because of a superior safety profile Aspirin: Mechanism of Action Aspirin: Membrane Phospholipids ARACHIDONIC ACID COX-1 Aspirin Prostaglandin H2 Thromboxane A2 ↑ Platelet Aggregation Vasoconstriction Prostacyclin ↓ Platelet Aggregation Vasodilitation Aspirin Recommendations Aspirin I IIa IIb III Primary Prevention Aspirin (75­162 mg daily) for intermediate risk men with a 10 year risk of CHD >10%. I IIa IIb III I IIa IIb III Aspirin (75­162 mg daily) for intermediate risk women with a 10 year risk of CHD >10%. Aspirin for low risk women with a 10 year risk of CHD<10%. Aspirin (75­325 mg daily) for those with known CHD. I IIa IIb III Secondary Prevention Rader, NEJM 2000; 343: 1181. P. Ridker CRP vs hs­CRP CRP vs hs­CRP CRP is an acute­phase protein produced by the liver in response to cytokine production (IL­6, IL­1, tumor necrosis factor) during tissue injury, inflammation, or infection. Standard CRP tests determine levels which are increased up to 1,000­fold in response to infection or tissue destruction, but cannot adequately assess the normal range High­sensitivity CRP (hs­CRP) assays (i.e. Dade Behring) detect levels of CRP within the normal range, levels proven to predict future cardiovascular events. Potential Mechanisms Linking CRP to Potential Mechanisms Linking CRP to Atherothrombosis Confounding by cigarette consumption Innocent bystander ­ Acute phase response Cytokine surrogate ­ IL­6, TNF­α, IL­1β Direct effects of CRP ­ Innate immunity ­ Complement activation ­ CAM induction Prior infection ­ Chlamydia, H pylori, CMV Marker for subclinical atherosclerosis ­ EBCT / IMT / ABI Marker for insulin resistance/ obesity Marker for endothelial dysfunction Marker for dysmetabolic syndrome Marker for plaque vulnerability hs­CRP and Risk of Future MI in Apparently hs­CRP and Risk of Future MI in Apparently Healthy Men P Trend <0.001 Trend Relative Risk of MI 3 P<0.001 P<0.001 2 P=0.03 1 0 1 2 3 Quartile of hs-CRP Ridker et al, N Engl J Med. 1997;336:973–979. 4 hs­CRP and Risk of Future Stroke in hs­CRP and Risk of Future Stroke in Apparently Healthy Men P Trend <0.03 Trend P=0.02 Relative Risk of Ischemic Stroke 2 P<0.02 3 4 1 0 1 2 Quartile of hs-CRP Ridker et al, N Engl J Med. 1997;336:973–979. hs­CRP as a Risk Factor For Future CVD : Primary hs­CRP as a Risk Factor For Future CVD : Primary Prevention Cohorts 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 0 Ridker PM. Circulation 2003;107:363­9 1.0 2.0 3.0 4.0 5.0 Relative Risk (upper vs lower quartile) 6.0 hs­CRP Adds to Predictive Value of TC:HDL Ratio in hs­CRP Adds to Predictive Value of TC:HDL Ratio in Determining Risk of First MI Relative Risk 5.0 4.0 3.0 2.0 1.0 0.0 High Medium High Medium Low Total Cholesterol:HDL Ratio Ridker et al, Circulation. 1998;97:2007–2011. Low RP s-C h Risk Factors for Future Cardiovascular Events: Risk Factors for Future Cardiovascular Events: WHS Lipoprotein(a) Homocysteine IL­6 TC LDLC sICAM­1 SAA Apo B TC: HDLC hs­CRP hs­CRP + TC: HDLC 0 1.0 2.0 4.0 6.0 Relative Risk of Future Cardiovascular Events Ridker et al, N Engl J Med. 2000;342:836-43 Is there clinical evidence that inflammation Is there clinical evidence that inflammation can be modified by preventive therapies? Percent with CRP ≥ 0.22 mg/dL Elevated CRP Levels in Obesity: NHANES 1988­1994 25 20 15 10 5 0 Normal Overweight Visser M et al. JAMA 1999;282:2131­2135. Obese Effects of Weight Loss on CRP Effects of Weight Loss on CRP Concentrations in Obese Healthy Women 83 women (mean BMI 33.8, range 28.2­43.8 kg/m2) placed on very low fat, energy­restricted diet (6.0 MJ, 15% fat) for 12 weeks Baseline CRP positively associated with BMI (r=0.281, p=0.01) CRP reduced by 26% (p<0.001) Average weight loss 7.9 kg, associated with change in CRP Change in CRP correlated with change in TC (r=0.240, p=0.03) but not changes in LDL­C, HDL­C, or glucose At 12 weeks, CRP concentration highly correlated with TG (r=0.287, p=0.009), but not with other lipids or glucose Heilbronn LK et al. Arterioscler Thromb Vasc Biol 2001;21:968­970. Effect of HRT on hs­CRP: the PEPI Study Effect of HRT on hs­CRP: hs­CRP (mg/dL) 3.0 CEE + MPA cyclic CEE + MPA continuous CEE + MP CEE 2.0 Placebo 1.0 0 12 Months Cushman M et al. Circulation 1999;100:717­722. © 1999 Lippincott Williams & Wilkins. 36 Long­Term Effect of Statin Therapy on Long­Term Effect of Statin Therapy on hs­CRP: Placebo and Pravastatin Groups Placebo 0.25 Median hs-CRP Concentration (mg/dL) 0.24 0.23 -21.6% (P=0.004) 0.22 0.21 0.20 Pravastatin 0.19 0.18 Baseline Ridker et al, Circulation. 1999;100:230-235. 5 Years Effect of Statin Therapy on hs­CRP Levels at 6 Weeks 6 *p<0.025 vs. Baseline hs­CRP (mg/L) 5 * 4 * * Prava (40 mg/d) Simva (20 mg/d) Atorva (10 mg/d) 3 2 1 0 Baseline Jialal I et al. Circulation 2001;103:1933­1935. © 2001 Lippincott Williams & Wilkins. Change at 24 weeks, % Effect of Bezafibrate with and without Fluvastatin on Effect of Bezafibrate with and without Fluvastatin on Plasma Fibrinogen, PAI­1, and CRP in Patients with CAD and Mixed Hyperlipidemia 15 10 5 0 ­5 ­10 ­15 ­20 Fibrinogen PAI­1 CRP 70 72 63 83 80 75 n: 81 80 74 * * P<0.05 vs. baseline * Beza 400 mg/d Beza 400 mg/d + fluva 20 mg/d Cortellaro M et al. Thromb Haemost 2000;83:549­553. Beza 400 mg/d + fluva 40 mg/d JUPITER Randomized Trial of Rosuvastatin in the Primary Prevention of Cardiovascular Events Among Individuals with Low Levels of LDL­C and Elevated Levels of hs­CRP Rosuvastatin (N =7500) No History of CAD Men > 55, Women > 65 LDL­C <130 mg/dL hs­CRP >2 mg/L Screening Screening Visit 1 Visit 2 hs­CRP Lipids hs­CRP LFTs HbA1C 4 week Run­in Randomization Visit Placebo (N =7500) Safety Visit hs­CRP LFTs UA Bi­Annual Follow­Up Visits MI Stroke Unstable Angina CVD Death CABG/PTCA End of Study Visit hs­CRP LFTs UA Lipids HbA1C N Engl J Med. 2002;347:1157-1165 Event­Free Survival According to Baseline Quintiles of C­Reactive Protein and LDL Cholesterol Quintiles of LDL 0. 99 0. 99 1 1 3 2 0. 98 0. 98 2 3 4 0. 97 0. 97 4 5 0. 96 5 0. 96 CVD Event-Free Survival Probability 1. 00 1. 00 Quintiles of CRP 0 2 4 6 Years of Follow-Up Ridker et al, N Engl J Med. 2002;347:1157-1165. 8 0 2 4 6 Years of Follow-Up 8 CV Event-Free Survival Using Combined CV hs-CRP and LDL-C Measurements hs-CRP Probability of Event-free Survival Median LDL 124 mg/dl Median CRP 1.5mg/l 1.00 Low CRP-low LDL 0.99 Low CRP-high LDL 0.98 High CRP-low LDL 0.97 0.96 0.00 High CRP-high LDL 0 2 4 6 Years of Follow-up Ridker et al, N Engl J Med. 2002;347:1157-1165. 8 hs-CRP Adds Prognostic Information at all Levels of LDL-C and at all Levels of the Framingham Risk Score LDL-C <1.0 1.0-3.0 >3.0 C-Reactive Protein (mg/L) 3 Multivariable relative risk 25 Relative risk 20 15 10 5 0 <1.0 0 -1 2- 4 5- 9 10-20 Framingham estimate of 10-year risk (%) Ridker et al, N Engl J Med. 2002;347:1557. 1.0-3.0 >3.0 C-Reactive Protein (mg/L) 2 1 0 <130 130-160 >160 LDL cholesterol (mg/dL) What is the role of hs­CRP with What is the role of hs­CRP with regard to diabetes and the metabolic syndrome? Circulation. 2003;107:391-397. Plasma hs­CRP Levels According to Severity of the Metabolic Syndrome C-reactive protein (mg/L) 8 6 4 2 0 0 1 2 3 4 5 Number of Components of the Metabolic Syndrome Ridker et al, Circulation 2003;107:391-7 Event Free Survival According to hs-CRP Levels: Analysis Event Limited to Participants with Metabolic Syndrome at Baseline with Metabolic 1.00 CVD Event-Free Survival Probability 0.99 0.98 CRP <1 mg/L 0.97 CRP 1-3 mg/L 0.96 CRP >3 mg/L 0.95 0 2 4 6 Years of Follow-Up Ridker et al, Circulation 2003;107:391-7 8 AHA / CDC Scientific Statement AHA 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 cardiovascular particularly among those judged at intermediate risk by particularly global risk assessment”. Clinical Application of hs-CRP for Cardiovascular Risk Prediction Cardiovascular 1 mg/L Low Risk 3 mg/L Moderate Risk Ridker PM. Circulation 2003;107:363-9 10 mg/L High Risk >100 mg/L Acute Phase Response Ignore Value, Repeat Test in 3 weeks Inflammatory and Infections Agents in CHD Inflammatory and Infections Agents in CHD Belgian epidemiologic study included 446 of 16307 male workers aged 35­39 who had evidence of CHD vs. 892 controls. CRP, but none of the infectious agents (H. pylori, C. pneumoniae, CMV, and EBV) were associated with CHD, even after adjustment for other risk factors. De Backer et al. Atherosclerosis 2002; 160: 457-63. Infection and CHD ­ is there a connection? Infection and CHD ­ is there a connection? Local or systemic infections resulting from gram negative bacteria such as Chlamydia pneumoniae and Helicobacter pylori, including cytomegalovirus (CMV) have been implicated in atheroscelosis While several case control studies have shown increased titers of C.pneumoniae and H. Pylori in those with vs. without CHD, convincing evidence from prospective studies is lacking. Prospective Studies of CHD and Infectious Prospective Studies of CHD and Infectious Pathogens Physician’s Health Study (nested case­control) shows RR 1.1 (0.8­1.5) for C. Pneumoniae, 0.94 (0.7­1.2) for cytomegalovirus, and 0.72 (0.6­0.9) for Herpes simplex virus. H. pylori also shows mixed results. Whincup showed a nonsignificant 1.3 OR when adjusted for other risk factors, the large ARIC study showed no relation, and the Caerphilly Prospective study showed RR=1.05 in 1796 men followed 14 years. Other Studies of Infectious Agents Other Studies of Infectious Agents In South Asian persons with CHD vs. controls, C. pneumoniae specific IgG antibody was seropositive in similar proportions; risk factors appeared to mediate any relations (Mendis et al. Int J Cardiol 2001; 79: 191­6). Cross­sectional survey of 704 individuals of C. pneumoniae and CMV with risk factors did nto show significant associations (Danesh et al., J Cardiovasc Risk 1999; 6: 387­90). Meta­analysis of 24 articles involving H. pylori infection and CHD showed a pooled odds ratio of 1.55 (95% CI: 1.38­1.74) (p<0.001), suggested a weak relation, but high hetrogeneity between studies precludes clear demonostration (Pellicano et al., Eur J Epidemiol 1999; 15: 611­9). ARIC Study failed to show clear relation between IgG antibodies for C. pneumoniae and incident CHD occurring over average 3.3 years. (Nieto et al. Am J Epidemiol 1999; 150: 149­56). Clinical Trial Evidence for Antibiotic Clinical Trial Evidence for Antibiotic Treatment and Prevention of CVD ACADEMIC Study of 302 patients with CHD seropositive to C. Pneumoniae randomized to azithromycin 500 mg/wk or placebo for 3 months showed no significant treatment difference (HR=0.89, p=0.74) for recurrent events (Muhlestein et al., Circulation 2000; 102: 1755­60). AZACS Multicenter study of 1439 pts with unstable angina randomized to 250 mg azithromycin/day for up to 6 months showed no significant benefit for death, recurrent MI, or recurrent ischemia (Cercek et al., Lancet 2003; 361: 809­13). WIZARD trial of 7,747 pts post­MI randomized to 12 week of therapy with azithromycin or placebo showed no significant reduction in reinfarction, revascularization, hospitalization for angina, or death (O’Connor et al., JAMA 2003; 290: 1459­66). Infectious Agents and the Future Infectious Agents and the Future Individuals with greater infectious burdens may be at greater risk, because they are older, have poorer health habits, less access to care. Observed associations often may be due to selection biases or confounding from age and other factors Prospective clinical trials under way examining role of certain antibiotics such as azithromycin on reduction of recurrent events in CHD patients. Until these data are available, no role for measurement or treatment of infectious burden. ...
View Full Document

Ask a homework question - tutors are online