Inflammation and Heart Disease in Women Inflammation and Heart Disease What is the link between een inflammation and atherosclerotic disease? What is the role of biomarkers in predicting cardiovascular events? Should biomarkers be a target for therapy? 1
Factors Affecting hs-crp levels Increased Levels Hypertension Obesity Cigarette smoking Metabolic syndrome/diabetes Estrogen/Progesterone hormone use Chronic infections (gingivitis, bronchitis) Chronic inflammation (rheumatoid arthritis) Decreased Levels Exercise Weight Loss Moderate alcohol consumption Medications Statins Fibrates Niacin Pearson et al, Markers of Inflammation and CVD (AHA Statement); Circulation 2003 Risk Factors, Inflammation, and CVD HTN, Hyperlipidemia, DM, Smoking Activation of Inflammatory Cells Formation of Plaque Acute Rupture Formation of Thrombus 2
Adhesion Molecules OxLDL Foam Cells v v Fibrous Cap T T T LDL Rupture Macrophages Extracellular matrix molecules, collagen Activated macrophage released mediators (eg MMP) Inflammation and Plaque Rupture Hansson G, NEJM 2005 3
Innate Immunity and Atherosclerosis Libby P et al, JACC 2009 Systemic Inflammation and Vascular Endothelial Function: Periodontitis Tonetti et al, NEJM 2007 4
Inflammation and CVD: It s Complicated O'Connor, C. M. et al. JAMA 2003;290:1459-1466 Grayston et al,. NEJM 2005; 352: 1637 Inflammatory Markers and Risk of CHD death, Nonfatal MI or Stroke, or Revascularization in Healthy Postmenopausal Women Ridker et al, NEJM 2000 5
Inflammatory Markers and CHD Risk in Healthy Postmenopausal Women Ridker et al, NEJM 2000; 342: 836 Inflammatory Markers and Prediction of CHD in the Reykjavik Study Danesh et al, NEJM 2004 6
EPIC-Norfolk Study Prospective Case Control Healthy Men and Women ALL CHD FATAL CHD Boekholdt et al, Atherosclerosis 2006 AFCAPS/TexCAPS Ridker et al, NEJM 2001 7
CRP and Risk of Nonfatal MI or Fatal CHD (Nurses Health Study/Health Professionals Follow-up Study) Women Age 30-55 Men Age 40-75 Pai et al, NEJM 2004 CRP Percentile Levels in Women and Men: MESA Study M F Lakoski et al, Am Heart J, 2006 8
CRP Levels in Women and Men Adjusted for Risk Factors in MESA Lakoski et al, Am Heart J 2006 Subclinical CHD by CAC in Women with Low Risk FHS Score Michos et al, Am Heart J 2005: 150: 1276 9
Reynolds Risk Score Women without DM or known CVD Systolic Blood Pressure Total Cholesterol HDL Cholesterol Parent with CVD age<60 years CRP Ridker et al, JAMA 2007; 297 Reynolds Risk Score Characteristics Age, years (IQR) 52 (48-58) Race (%White/Other) 95/5 BMI (IQR) 25 (23-28) DM (%) 1 HTN (%) 1.5 +Family History (%) 13 Menopausal (%) 54 Median LDL, mg/dl (IQR) 121 (100-144) Median HDL, mg/dl (IQR) 52 (43-63) Median CRP, mg/dl (IQR) 2 (0.8-4.3) Ridker et al, JAMA 2007 10
55 year old woman with no risk factors FHS 1% www.reynoldsriskscore.org 55 year old woman with 2 Risk Factors FRS 2% www.reynoldsriskscore.org 11
FRS 7-10% Reynolds Risk Score Woman at Age 75: FRS 10-yr risk: 5% 12
Reynolds Risk Score Woman at Age 75: FRS 10-yr risk: 5-7% 70 year old woman FRS 11-16% 13
Individual Biomarkers and Incident Cardiovascular and Coronary Events Melander, O. et al. JAMA 2009;302:49-57. Reclassification of 10-Year Predicted Risk Melander, O. et al. JAMA 2009;302:49-57. 14
WHI: Prediction of CHD Events (Nonfatal MI, CHD Death) Postmenopausal women ages 50-79 Nested case control study IL-6, d-dimer, coagulation factor Factor VIII, VFW, homocysteine CRP did not significantly improve CHD prediction alone or in combination with other biomarkers C-statistic FRS 0.699 TRF 0.729 ABM 0.751 P=0.001 P<0.001 Kim et al, Circulation 2009; 120: S424 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 No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dl hscrp >2 mg/l Rosuvastatin 20 mg (N=8901) Placebo (N=8901) Baseline LDLC Baseline HDLC Baseline hscrp 104 mg/dl 49 mg/dl 4.2 mg/l Women 6,800 Non-Caucasian 5,000 MI Stroke Unstable Angina CVD Death CABG/PTCA Ridker et al, NEJM 2008:359:2195-07 15
0.08 JUPITER: Primary Trial Endpoint (MI, Stroke, UA/Revascularization, CV Death) HR 0.56, 95% CI 0.46-0.69 P < 0.00001 Number Needed to Treat (NNT 5 ) = 25 Placebo 251 / 8901 Cumulative Incidence 02 0.04 0.06 0.00 0.0-44 % Rosuvastatin 142 / 8901 0 1 2 3 4 Number at Risk Follow-up (years) Rosuvastatin 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 Placebo 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174 Ridker et al, NEJM 2008:359:2195-07 JUPITER: All Cause Mortality Cumulative Incidence 5 0.06 0.02 0.03 0.04 0.0 HR 0.80, 95%CI 0.67-0.97 P= 0.02 Placebo 247 / 8901-20 % Rosuvastatin 198 / 8901 0.00 0.01 0 1 2 3 4 Number at Risk Follow-up (years) Rosuvastatin 8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 227 Placebo 8,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246 Ridker et al, NEJM 2008:359:2195-07 16
JUPITER: Primary Endpoint Understudied or Low Risk Subgroups Understudied Subgroups Women Age > 70 Black, Hispanic, Other Low Risk Subgroups Framingham Risk < 10 % LDLC < 100 mg/dl BMI < 25 mg/m2 No Hypertension N HR (95%CI) 6,801 0.54 (0.37-0.80) 5,695 0.61 (0.46-0.82) 5,117 0.63 (0.41-0.98) 8,882 0.56 (0.38-0.83) 6,269 0.66 (0.47-0.92) 4,073 0.59 (0.40-0.87) 7,586 0.62 (0.44-0.87) No metabolic Syndrome 10,296 0.49 (0.37-0.65) Elevated hscrp Only 6,375 0.63 (0.44-0.92) All Participants 17,802 0.56 (0.46-0.69) Ridker et al, NEJM 2008:359:2195-07 0.25 0.5 1.0 2.0 4.0 Rosuvastatin Superior Rosuvastatin Inferior JUPITER: Achieved LDL, Achieved hscrp Analysis Baseline Clinical Characteristics (N=15,548) Placebo Rosuvastatin LDL>70 LDL<70 hscrp>2 hscrp<2 Age, (years) 66 65 66 66 66 BMI, (kg/m2) 28.4 27.8 28.5 29.0 27.7 Blood pressure Systolic 134 134 135 135 134 Diastolic 80 80 80 80 80 Smoker, (%) 15.6 17.9 14.5 17.2 13.3 Fam His, (%) 11.8 11.3 11.7 11.0 12.4 Met Syn, (%) 41.5 38.3 42.2 43.5 37.8 hscrp, mg/l 4.2 4.2 4.2 5.4 3.2 LDLC, mg/dl 108 112 106 108 109 HDLC, mg/dl 49 50 49 49 49 TG, mg/dl 118 115 119 120 116 ApoB:ApoA 0.7 0.7 0.7 0.7 0.7 HbA1c 5.7 5.7 5.7 5.7 5.7 Ridker et al, Lancet, 374 (9670): 1175 17
JUPITER: Dual Target Analysis: LDLC<70 mg/dl, hscrp<2 mg/l Cumulative Incidence 06 0.08 0.02 0.04 0.0 0.00 0 1 2 3 4 Placebo HR 1.0 (referent) LDL > 70 mg/dl and / or hscrp > 2 mg/l HR 0.64 (0.49-0.84) LDL < 70 mg/dl and hscrp < 2 mg/l HR 0.35 (0.23-0.54) Number at Risk Rosuvastatin Placebo Follow-up (years) 7,716 7,699 7,678 6,040 3,608 1,812 1,254 913 508 145 7,832 7,806 7,777 6,114 3,656 1,863 1,263 905 507 168 P < 0.0001 Ridker et al; Lancet, 374 (9670): 1175 Mendelian Randomization If the relationship between an outcome and biomarker, than the biomarker genotype should associate with outcome The magnitude of the relationship should be predicted by the association between genotype and biomarker Shah, DeLemos, JAMA 2009 18
Associations of SNPs rs1130864 and rs1205 With CRP Levels, CRP Levels With CHD, and SNPs With CHD Elliott, P. et al. JAMA 2009;302:37-48. Associations of SNPs in LEPR (rs6700896), IL6R (rs4537545), and HNF1A (rs1183910) Loci and APOE-CI-CII (rs4420638) Cluster in the Genetic Association Study With CHD Elliott, P. et al. JAMA 2009;302:37-48. 19
hcrp-tg rabbits developed hypercholesterolemia similar to that of non-tg rabbits during cholesterol diet feeding Koike, T. et al. Circulation 2009;120:2088-2094 Conclusion Inflammation plays a key role in the development of atherosclerosis Elevated levels of inflammatory markers are associated with increased risk of CVD events 20
Future Directions Further examination of the relationship between CRP and CVD and women Do inflammatory markers present a potential target for therapeutic interventions? Do therapies specifically targeted at reducing inflammation improve CVD risk? 21