Criteria to Meet before Applying Emerging Biomarkers of CVD Risk

Emerging Risk Factors for CVD:How to Assess Residual RiskRyan Bradley ND, MPHAssociate Director | Bastyr University Research InstituteCore Clinical Faculty | Bastyr University CaliforniaDirector | Center for Diabetes & Cardiovascular Wellness

• Assessing CVD event riskOverview• Traditional risk classification- Framingham & (now) Reynolds• Residual risk- How much is there?• INTERHEART• Emerging risk factors- How do you evaluate them?• Criteria for evaluating emerging biomarkers• Evaluation of select emerging risk factors• Lipoprotein measures: Apo B100: Apo A1, particle characteristics (i.e.,number; density; size)• Methylation: Homocysteine, [MTHFR polymorphism]• Inflammation/ acute phase reactants: CRP, fibrinogen [SAA]• Atherosclerosis: Lp-PLA 2 [sICAM-1; IL-6]• Oxidative stress: oxLDL, GGT [f2-isoprostanes, etc.]• Endothelial function: Reactive Hyperemia Index (RHI)• Renovascular function: cystatin C

Traditional Cardiovascular Risk Assessment• Framingham Risk Score:• Age• Gender• Total cholesterol• HDL• Smoking status• SBP• Resource: http://hp2010.nhlbihin.net/atpiii/calculator.asp• Reynolds Risk Score:• Framingham under estimates risk in women• Reynolds re-classifies risk in 40%• Reynolds adds: hsCRP & A1c (if diabetes)• Resource: www.reynoldsriskscore.org/ 3

Impact of adding CRP in women4Mora et al., Am J Cardiol. 2006

Population Attributable Risk of First MI:INTERHEARTRisk Factors:• Elevated ApoB:ApoA1• OR=3.25 (5th vs. 1st quin);PAR=49.2%• Smoking• OR=2.87; PAR=35.7%• HTN• OR=1.91; PAR=17.9%• Abdominal obesity• OR=1.12 (top vs.lowest tertile);PAR=20.1%• Diabetes• OR=2.37; PAR=9.9%• Psychosocial factors• OR=2.67; PAR=32.5%Protective Factors:• Daily F&V Consumption• OR=0.70; PAR=13.7%• Moderate alcoholconsumption• OR=0.91; PAR=6.7%• Regular Physical Activity• OR=0.86; PAR=12.2%Total Population Attributable Risk (PAR): 90% in women & 94% in menYusuf et al., Lancet, 2004

Contribution of Multiple Risk Factors: INTERHEARTYusuf et al., Lancet, 2004

The Contribution of Lifestyle toAll-Cause Mortality in CAD *• Smoking Cessation:• RR= 0.64 (0.58, 0.71)• Healthy Diet ** :• RR= 0.56 (0.42, 0.74)• Moderate Alcohol:• RR= 0.80 (0.78, 0.83)• Physical Activity:• RR= 0.76 (0.59, 0.98)* CAD= Past MI, Angina, PCTA, CABG** Healthy Diet=Low Sat’d Fat, Regular Fish, Whole Grains, Nuts,F&V, reduced salt (

Contribution of Lifestyle: INTERHEARTYusuf et al., Lancet, 2004

• Assessing CVD event riskOverview• Traditional risk classification- Framingham & (now) Reynolds• Residual risk- How much is there?• INTERHEART• Emerging risk factors- How do you evaluate them?• Criteria for evaluating emerging biomarkers• Evaluation of select emerging risk factors• Lipoprotein properties: Apo B100: Apo A1, particle characteristics (i.e.,number; density; size)• Methylation: Homocysteine, [MTHFR polymorphism]• Inflammation/ acute phase reactants: CRP, fibrinogen [SAA]• Atherosclerosis: Lp-PLA 2 [sICAM-1; IL-6]• Oxidative stress: oxLDL, GGT [f2-isoprostanes, etc.]• Endothelial function: Reactive Hyperemia Index (RHI)• Renovascular function: cystatin C

Criteria to Meet before Applying EmergingBiomarkers of CVD Risk• Measurement provides independent risk prediction notcaptured by current standards/clinical norms.• Treatment is available, validated and unique.• Treatment improves clinical outcomes.• Measurement and treatment are risk-balanced and costeffective.©2013 Ryan Bradley, ND, MPH

Criteria Scoring Exercise• Criteria:• Met: 2 points• Partially met: 1 point• Not met: 0 points• Weighting based on your values:• E.g., Independent risk prediction & improves clinical outcomes >>unique treatment & risk-balanced and cost effective.• Met: 4 points• Partially met: 2 point• Not met: 0 points©2013 Ryan Bradley, ND, MPH

Overview• Assessing CVD event risk• Traditional risk classification- Framingham & (now) Reynolds• Residual risk- How much is there?• INTERHEART• Emerging risk factors- How do you evaluate them?• Criteria for evaluating emerging biomarkers• Evaluation of select emerging risk factors• Lipoprotein properties• Methylation: Homocysteine, [MTHFR polymorphism]• Inflammation/ acute phase reactants: CRP, fibrinogen [SAA]• Atherosclerosis: Lp-PLA 2 [sICAM-1; IL-6]• Oxidative stress: oxLDL, GGT [f2-isoprostanes, etc.]• Endothelial function: Reactive Hyperemia Index (RHI)• Renovascular function: cystatin C

What properties oflipoproteins (LDL) can bemeasured?• Calculated particle concentration (i.e., LDL-C)• Apoprotein concentrations (ApoA, ApoB)• Particle number (LDL-P)• Physical size (nm or Å)• > or < 255 Å• Density• Cholesterol ester content• Triglyceride (TG) content• Oxidation state (oxLDL)

A Few Comments on LDL• 1% reduction in LDL results in a 1-1.7%reduction in event RR 1,2,3• Caveats:• LDL at birth: ~50 mg/dl 4• Estimates of LDL requirement for peripheralcholesterol needs: ~25 mg/dl 51. Brown et al, Curr Opin Lipidol. 2006.2. Wilson et al. Am J Med. 1991.3. Pederon et al. Circulation. 1998.4. Brown. Science. 1986.5. O’Keefe et al. AJCC. 2004.

A Few Comments on HDL• Plaque scavenger- “reverse cholesterol transport”• ApoA corresponding lipoprotein• 1% increase in HDL = 1% reduction in risk 1,2• Caveats:• Difficult to increase if TG not normalized first• Evidence for drug-increased HDL leading to eventprotection is waning (especially when combined withstatins)1. Brown et al. Curr Opin Lipidol. 2006.2. Gordon et al. Circulation. 1989.

ApoB• Apoprotein on lipoprotein micelle, i.e. LDL• ApoB100 vs. ApoB48• B100: hepatic synthesis- endogenously produced LDL &VLDL• B48: intestinal synthesis- packing of dietary cholesterolin chylomicrons• Proxy for “non-HDL cholesterol”• Strong correlation with LDL particle number, esp.with normal triglycerides• B100 binds LDL receptor• B48 may not bind LDL receptor

ApoA• Apoprotein on HDL lipoprotein micelle• Strong correlation with HDL particle number

ApoB: ApoA• Elevated ApoB:ApoA1: OR=3.25 (5th vs. 1st quin); PAR=49.2%(INTERHEART)OR (MI)8.04.02.0ApoB: ApoA0.430.721.28Yusuf et al., Lancet, 2004

Unique Treatment?• Lowering LDL lowers apoB100• Raising HDL increases apoA• Lowering triglycerides lowers apoB100 via lowering VLDL

Criteria to Meet before Applying EmergingBiomarkers of CVD Risk: Apo B: Apo A• Measurement provides unique independent risk assessmentnot captured by measurement per current standards/clinicalnorms• Treatment is available, validated and unique• Treatment improves hard clinical outcomes• Measurement and treatment are risk-balanced and costeffective©2013 Ryan Bradley, ND, MPH

LDL Particle Number (LDL-P)• Criteria met:• Independent risk prediction?: Valid and better discriminates CVD riskthan LDL-C 1-4 major CVD case-control studies and prospective cohortstudies• Treatment improves outcomes• Criteria not met:• Unique treatment?: LDL-lowering treatment lowers LDL-P• Independent risk prediction?: Strong correlations with LDL and VLDL(therefore triglycerides), therefore testing less valuable for the costdue to high correlation with LDL and VLDL• Cost effective?1. Mora et al. Atherosclerosis. 20072. Kuller et al. Arterioscler Thromb Vasc Biol. 2002.3. Rosenson Am J Cardiol. 20024. Blake et al. Circulation. 2002.5. Otvos. Circulation. 2006.

Criteria to Meet before Applying EmergingBiomarkers of CVD Risk: LDL-P• Measurement provides unique/independent riskassessment not captured by measurement per currentstandards/clinical norms• Treatment is available, validated and unique• Treatment improves hard clinical outcomes• Measurement and treatment are risk-balanced and costeffective©2013 Ryan Bradley, ND, MPH

Does [LDL-P] Size Matter????

What causes differences in size ?1. Diet: sat’d fat & CHOincrease triglycerides (TG)packaged in VLDLs2. Genes: Cholesterol estertransport protein (CETP)transfers cholesterol estersto VLDL (removed from LDL)3. CETP transfers TAGs to LDL(removed from VLDL)4. Lipoprotein lipase acts onLDL and…Voilá! small, dense LDLs26#Roheim and Asztalos. Clinical Chemistry. 41(1). 1995.

How many patterns are there?© Berkeley Heart LabsPattern AIntermediatePattern B

What predicts “Pattern B”?• Cross-sectional study of 131apparently health adults• Associations with Pattern B?• +non-fasting TGs• -HDLs• Prediction variables• Two-variable model:• HDL and total TG• Three-variable model:• HDL• Total cholesterol and• Total apoBSwinkels et al. Arteriosclerosis. 1989.

Do small, dense LDLs reallyincrease IHD Risk?“Small, dense LDL” OR: 2.5 (95% CI: 1.2-5.2)• Quebec Cardiovascular Study• 5-yr. cohort 4637 men• Nest case-control• Evaluated sdLDL and IHD• Outcomes: new angina, coronaryinsufficiency, nonfatal MI, coronarydeath• Controls matched for age, BMI,smoking, alcohol use• OR: 2.5 (95% CI: 1.2-5.2)• Did adjust for SBP, med use, FHx• Did not adjust for TG, HDL, or LDLparticle number

Relative RiskLDL Pattern & IHD: More in QCS76543X median210TAGS LDL ApoBRisk Factor• Increased prediction when LDL size was added to model (BMI, systolic BP,diabetes, meds, age, HDL, LDL, log(TAG), log (Apo-a)& FHx)• as proportion of LDL

LDL pattern & carotid atherosclerosis: MESA• MESA: Multiethnic Study of Atherosclerosis• 5538 participants• Evaluated associations between carotid atherosclerosis (measuredby IMT) and LDL pattern• First to adjust for interclass correlations between small and largeLDL particle number (LDL-P)• Small and Large LDL-P were:• sdLDL and ldLDL negatively correlated with each other (r= -0.63)• sdLDL negatively correlated with HDL (r= -0.65, 0.67)• sdLDL positively correlated with TAGS (r= +0.57, -0.40)Mora et al. Artheroslcerosis. 2007.

cIMT & LDL pattern: MESAMora et al. Artheroslcerosis. 2007.

sdLDL & ldlLDL: MESAIMTMora et al. Artheroslcerosis. 2007.

LDL Pattern & CAD: EPI-Norfolk• 25,663 participants for 6 years• Nested case-control eval. LDL size as predictor of CAD• Case definition: ICD-9 or CVD death• 1003 cases and 1885 CAD-free controlsEl Harchaoui et al. J Am Coll Cardiol. 2007.

Summary: Small, dense LDL & CVD Risk

Lp(a)• Lipoprotein a: ApoB covalently bound toglycylated Apo(a) through a disulfide bond• Acts as an acute-phase reactant

Lp(a) & CVD Risk• Levels > 30mg/dl increase risk approximately 3-foldin men (CHS) 1 ; Higher risk in:• males,• young patients w/ familial hypercholesterolemia &• high risk patients (based on traditional risk factors) 1• No evidence in females or older adults after adj. forother risk factors 1• LDL reduction may offset risk 1• Unique treatment?• Niacian lowers ~30% 1 ;• L-Carnitine: ~13% reduction; 2g qd 2; and• CoQ10 : ~22% reduction; 120mg Qgel 31. Tsimikas et al. JACC. 2006; 2. Solfrizzi et al. Atherosclerosis. 2006; 3. Singh et al. Int. J. Cardio. 1999.

Criteria to Meet before Applying EmergingBiomarkers of CVD Risk• Measurement provides independent risk assessment notcaptured by measurement per current standards/clinicalnorms [in select populations]• Treatment is available, validated and unique• Treatment improves hard clinical outcomes• Measurement and treatment are risk-balanced and costeffective©2013 Ryan Bradley, ND, MPH

Homocysteine (Hcy)• Metabolic byproduct of dietary methionine• Vitamin B12, folic acid or vitamin B6 required forconversion of Hcy back into methionine (B12 & folicacid) or to cysteine (B6)• Data in genetic “homocystinurics” suggests strongassociation with thromboembolic events

Austin et al. Cell Death Differentiation. 2004.

Homocysteine & IHD RiskOR=1.0OR=0.8The Homocysteine Studies Collaboration. JAMA. 2002.

Hcy & Stroke RiskOR=0.8The Homocysteine Studies Collaboration. JAMA. 2002.

% of CHD AttributedHcy & PARPopulation Attributable Risk2520151050Total Cholesterol LDL-C HomocysteineRisk FactorJAMA. 1995. 274. 1049

NORVIT• RCT of 3749 with +1st MI; 40months f/u; Primaryendpoint: 2nd MI, stroke ordeath• Randomized to four arms:• 0.8mg folic acid, 0.4 mg B12 &40 mg B6• 0.8mg folic acid and 0.4mgB12• 40mg B6• Placebo• Hcy lowered 27% in groupsgiven folic acid + B12• No effect on primaryoutcomeBenaa, et al., JAMA. 2006.

NORVITBenaa, et al., JAMA. 2006.

HOPE2• RCT 5522 patients with vascular dzor diabetes; primary endpoint MI,stroke or CV-related death• Randomized to 2.5 mg folic acid, 50mg B6 and 1 mg B12 or placebo• No difference in primary outcome• Reduced risk of stroke in active txarm: RR=0.75 (95% CI: 0.59-0.97)• Active arm had increasedhospitalization for angina: RR=1.24(95% CI: 1.04-1.49)Heart Outcomes Prevention and Evaluation 2 Investigators, NEJM. 2006.

HOPE 2Heart Outcomes Prevention and Evaluation 2 Investigators, NEJM. 2006.

Summary: Homocysteine• PAR for Hcy is very low, if present• Testing should be selective & treatment more so(>15)• Unknowns:• Primary prevention data not available and mayprove significant• Possible benefit for stroke prevention• Some design issues remain, i.e. B12 absorption in anelderly population

Criteria to Meet before Applying EmergingBiomarkers of CVD Risk: Homocysteine• Measurement provides independent risk assessment notcaptured by measurement per current standards/clinicalnorms• Treatment is available, validated and unique• Treatment improves hard clinical outcomes (except possiblystroke)• Measurement and treatment are risk-balanced and costeffective©2013 Ryan Bradley, ND, MPH

C-reactive protein & Fibrinogen• Acute phase reactants indicative of inflammation• Chronic elevations (lower levels) also impact CVD risk• High co-linearity/correlation between CRP and fibrinogen(therefore no reason to ever measure both for residual riskassessment)• Difficult to separate CRP reduction independent of LDLreduction

Mora et al., Am J Cardiol. 2006

Mora et al., Am J Cardiol. 2006

REVERSAL• RCT (n=654)• 40 mg/d pravastatin (PS) or• 80 mg/d atorvastatin (AS)• x 18 months• PS:• 27% LDL reduction• 5.2% reduction in hSCRP• Progression of atheroma• AS:• 47% LDL reduction• 36.4% reduction in hsCRP• Regression of atheroma in ASgroupNissen et al., JAMA. 2004

hsCRP & Regression of CADNissen et al., JAMA, 2004 reprinted in Mora et al., Am J Cardiol., 2006

Justification for Use of Statins in Primary Prevention: An InterventionTrial Evaluating Rosuvastatin (JUPITER)55Ridker et al., NEJM, 2008

Reclassification with CRP & Fibrinogen• Evaluation of reclassification of CVD risk adding CRP and/orfibrinogen to determine incremental MI risk• 52 prospective studies analyzed including 246,669 participants• Results adjusted for statin indication based on traditional risk• Further adjustment for additional measures of acuteinflammation via WBC count• Reclassification index improved (statistically, but clinically?)• 1.52% for CRP• 0.83% for fibrinogen• 30 events prevented over 10 years by measuring in 13,199people• Prevent 1 event/10 years/400-500 people screened56The Emerging Risk Factors Collaboration, NEJM, 2012

Unique treatment? hsCRP• Some statins (e.g. rosuvastatin)• Niacin• Fiber (30g/d) 1• Pomegranate ?• High AOX Capacity Diet? 2• Smoking cessation1. King et al. Arch Int. Med. 20072. Valtuena et al. Am. J. Clin. Nutr. 2008.

Criteria to Meet before Applying EmergingBiomarkers of CVD Risk: CRP/Fibrinogen• Measurement provides independent risk assessment notcaptured by measurement per current standards/clinicalnorms• Treatment is available, validated and unique• Treatment improves hard clinical outcomes• Measurement and treatment are risk-balanced and costeffective©2013 Ryan Bradley, ND, MPH

Lipoprotein-associated Phospholipase A 2 (Lp-PLA 2)• Secreted by macrophages, T cells and mast cells• Resides in and is transported by lipoproteins (mostly LDL)• Hydrolyzes oxidized phospholipids into two inflammatorymediators:• free oxidized lipid• lysophosphotidylcholine• Conflicting data:• too little (due to genetic deficiency) increases risk• too much may also increase risk• Highly correlated with LDL-C (adjustment for LDL-C inMONICA & WHI attenuated increased risk)• Studies showing independence suggest limited usefulness(LDL

Tsimikas et al. JACC. 2006

Criteria to Meet before Applying EmergingBiomarkers of CVD Risk: Lp-PLA2• Measurement provides unique/independent risk assessmentnot captured by measurement per current standards/clinicalnorms• Treatment is available, validated and unique• Treatment improves hard clinical outcomes• Measurement and treatment are risk-balanced and costeffective©2013 Ryan Bradley, ND, MPH

Oxidative Stress Biomarkers are Stressful• F2-isoprostanes?• Limited measure of lipid peroxidation• Expensive to measure by GC-MS• Unreliable to measure by ELISA• 8-hydroxydeoxyguanosine? (8-OHdG)• Limited measure of DNA oxidation• Overestimated by ELISA• Protein carbonyls?• Limited measure of protein modification• Rapidly metabolized by kidneys• Nitrotyrosine?• Limited measure of peroxynitrite activity• Expensive to measure by GC-MS• Unreliable to measure by ELISA• RBC GSH?• Few population-based cohorts (ex. HIV+)• Cannot be measured from stored samples• Moderately expensive• oxLDL?• GGT?©2013 Ryan Bradley, ND, MPH

oxLDL• Formed from peroxidation of PUFA in the LDL• Not a single entity• Research is heterogeneous due to differences in measurementmethods• Debate continues re: whether it exists• oxLDL (MDA-epitope) predictive of CAD in numerous studies• Correlates with LDL + hsCRP

oxLDL + Traditional Risk Factors?• Holvoet et al. conducted a case-control study in 178 CADpatients + 126 controls• 3.11 +/- 1.19 mg/dl (Cases) vs. 1.30 +/- 0.88 mg/dl (Controls);p

oxLDL: Sens/Spec/PPV/NPVAdapted from Holvoet et al. Arterioscler. Thromb. Vasc. Bio. 2001.

Pomegranate & oxLDL• 90% reduction in oxLDL and 21% reduction in systolic BP• Dose:2 oz. juice per day for 3 years! 1• 141% increase in antioxidant defenses (GSH), 56% reduction in lipidperoxides, reduced oxLDL uptake by macrophages by 39%• Dose: ~2oz. Juice per day x 3 months; Type 2 DM! 21. Aviram et al. 20042. Rosenblat et al. 2006

Criteria to Meet before Applying EmergingBiomarkers of CVD Risk: oxLDL• Measurement provides independent risk assessment notcaptured by measurement per current standards/clinicalnorms• Treatment is available, validated and unique• Treatment improves hard clinical outcomes• Measurement and treatment are risk-balanced and costeffective©2013 Ryan Bradley, ND, MPH

Dickinson and Forman. Ann. N.Y. Acad. Sci. 2002. 973. P. 491

Serum GGT activity: A validbiomarker of oxidative stress?• No “gold standard” for systemic ox stress• GGT activity increased in response to oxidative stressand demand for reduced GSH• Other correlates with GGT:• + correlated with serum iron 1 & heme iron intake, e.g. meat (prooxidant)2• + correlated with F2-isoprostanes• - correlated with AOX and dietary patterns associated withprotection• + correlated with HOMA-measured insulin resistance in DM,Pre-DM, and non-DM 3,4• Predicts incident T2DM, HTN, CHF, CV events and totalmortality1. Forouhi et al. Diabetologia. 2007.2. Lee et al. Am. J. Clin. Nutr. 2003.3. Lim et al. Clin. Chem. 2007.4. Bradley et al. Biomarkers in Med. 2013

Multi-Ethnic Study ofAtherosclerosis (MESA)• N=6814, 44-84 yoa w/o known CVD but prevalentmetabolic disease (DM2:11% and MetS:28%)• Caucasian: n=2,622• Chinese-American: n=803• Black: n=1,893• Hispanic/Latino-American: n=1,496• GGT measurement: microplate assay, calibrated to 2independent labs (r=0.99)• All within 95 th percentile included in analyses

GGT & Cardiometabolic Risk

Odds Ratio for Metabolic SyndromeOdds Ratio for Metabolic SyndromeGGT & Composite Metabolic RiskOdds Ratio for Type 2 DiabetesOdds Ratio for Type 2 Diabetes10Figure 1a. Odds Ratio* of the Metabolic Syndromeby GGT Quintile in Ethnic Subgroups10Figure 1b. Odds Ratio* of Type 2 Diabetesby GGT Quintile in Ethnic Subgroups99876Entire Cohort (n=852)White (n=158)Chinese (n=105)Black (n=330)Hispanic (n=259)876Entire Cohort (n=1,935)White (n=698)Chinese (n=221)Black (n=462)Hispanic (n=554)P

Interleukin - 6 (pg/ml)C-reactive protein (mg/L)oxLDL (mg/dl)sICAM-1 (ng/ml)GGT: Inflammation, Oxidation & Endothelial Dysfunction6Figure 1a. Trends in C-reactive Protein (CRP)by GGT Quintile320Figure 1b. Trends in Soluble Intercellular AdhesionMolecule-1 (sICAM-1) by GGT Quintile3105300290428027032602502402230All (n=6,415)22010Q1 = 45.2 U/LWhite (n=2,506)Chinese (n=771)Black (n=1,392)Hispanic (n=1,404)210200190180Q1 = 45.2 U/LGGT Quintilep

Criteria to Meet before Applying EmergingBiomarkers of CVD Risk• Measurement provides independent risk assessment notcaptured by measurement per current standards/clinicalnorms• Treatment is available, validated and unique• Treatment improves hard clinical outcomes• Measurement and treatment are risk-balanced and costeffective©2013 Ryan Bradley, ND, MPH

Endothelial Dysfunction• Early, continuousdisease process ofvascular inflammationand reduced NO• Effects accumulate andresult in:• ischemia,• plaque formation,and• modified metabolicsignaling

EndoPAT Procedure• 3 Phases:• Pre-occlusive,• Occlusive, and• Post-occlusive/re-perfusion• Final result = ReactiveHyperemia Index (RHI)• post-occlusive diameter :pre-occlusive diameter

EndoPAT, RHI and Risk

Sensitivity: RHI vs. cIMTTonari et al. Hypertens Res. 2003

RHI adds to Reynolds Risk Score to IdentifyIschemic Heart Disease in WomenMatsuzawa Y., et al. JACC. 2010.

RHI & Plaque CompositionSchoenenberger et al. Am. J. Cardiology. 2012

RHI & Plaque CompositionSchoenenberger et al. Am. J. Cardiology. 2012

Criteria to Meet before Applying EmergingBiomarkers of CVD Risk: RHI• Measurement provides independent risk assessment notcaptured by measurement per current standards/clinicalnorms• Treatment is available, validated and unique• Treatment improves hard clinical outcomes• Measurement and treatment are risk-balanced and costeffective©2013 Ryan Bradley, ND, MPH

Cystatin C• Biomarker for glomerular filtration rate (GFR)• Unlike creatinine-estimated GFR, Cystatin C isindependent of age, sex & lean muscle mass• Cysteine protease inhibitor produced & excreted byall human cells• Freely filtered by glomerulus & metabolized in prox.tubule• May be elevated in hypothyroidism & depressed inhyperthyroidismShlipak et al. NEJM. 2005

Renal Function & MortalityShlipak et al. NEJM. 2005

Cystatin C & CVD-related Mortality• Highest quintile (after adj. for traditional risk factors):• CV-related Death: HR=2.27 (95% CI: 1.73-2.97)• MI: HR=1.48 (95% CI: 1.08-2.02)• Stroke: HR=1.47 (95% CI: 1.09-1.96)Shlipak et al. NEJM. 2005

Cystatin C & Death in those w/o CKD?Shlipak et al. Annals Int. Med. 2006

Cystatin C +/- CKD: CV-events & deathShlipak et al. NEJM. 2005

Criteria to Meet before Applying EmergingBiomarkers of CVD Risk: Cystatin C• Measurement provides unique/independent risk assessmentnot captured by measurement per current standards/clinicalnorms• Treatment is available, validated and unique• Treatment improves hard clinical outcomes• Measurement and treatment are risk-balanced and costeffective©2013 Ryan Bradley, ND, MPH

Summary of Emerging Risk Factors for CVD89©2013 Ryan Bradley, ND, MPH

Conclusions: Assessing CVD Risk• Start here:• Traditional risk factors of CVD are important, deserve detection and treatmentfor reduction• LDL, HDL, and BP still account for 67.1% of PAR for MI• The go here:• Total INTERHEART factors (smoking, stress, lifestyle, etc.) account for 90-94%• Until lifestyle factors in place, and treatment goals met, why do anything else?• Then consider:• First tier:• CRP• Endothelial function assessment (RHI)• Lipoprotein particle number (although consider waiting until LDL:HDLoptimized)• Second tier:• oxLDL• GGT (although co-linear with CRP and oxLDL)• Cystatin C• Select ordering:• Hcy for stroke risk assessment• Lp(a) in select high-risk populations• Emerging risk factors should be incorporated cautiously until validated byprospective data on outcomes, co-lateral risk, and costs.

HEART DISEASE RISKDiet, Stress, LDL, HDL,Triglycerides & Blood Pressure