10/17/16. Assessing cardiovascular risk through use of inflammation testing

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1 Assessing cardiovascular risk through use of inflammation testing Anthony L. Lyssy, DO Medical Director and Managing Partner Diamond Physicians Dallas, TX Response to Injury Hypothesis Injury Response to Injury Lipids 50% of individuals who experience a heart attack or stroke have normal lipid levels Inflammation Response to Injury Hypothesis Injury Lipids Blood Pressure Blood Glucose Oxidation Smoking Age/Gender 50% of individuals who experience a heart attack or stroke have normal lipid levels Response to Injury Inflammation 1

2 The benefits of a multi-marker approach Individuals with impaired fasting glucose have a higher incidence of unrecognized myocardial infarctions. 1 Silent heart attacks account for over 45% of all heart attacks. 2 A multi-marker strategy that combines biomarkers across various pathobiological axes provides incremental prognostic information for prediction of cardiovascular death. 3 1 Stacey RB et al. Prediabetes and the association with unrecognized myocardial infarction in the Multi-Ethnic Study of Atherosclerosis (MESA). Am Heart J. (2015) 2 Zhang ZM et al. Race and sex differences in the incidence and prognostic significance of silent myocardial infarction in the Atherosclerosis Risk in Communities (ARIC) Study. Circulation. (2016) 3 O Donoghue ML et al. Multimarker risk stratification in patients with acute myocardial infarction. J Am Heart Assoc. (2016) The standard of care utilizes a risk factor approach to identify risk Things That Damage the Body Patient High Blood High Blood High Pressure Sugar Cholesterol INTERHEART Study Risk for Myocardial Infarction* Risk Factor Odds Ratio (adj. for all other risk factors (99% CI) Smoker 2.9 Diabetes 2.4 High BP 1.9 Abdominal Obesity 1.4 Lack of Exercise 1.1 High Cholesterol 3.3 Yusuf et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364:

3 The standard of care utilizes a risk factor approach to identify risk Things That Damage the Body Inflammation Tests that Examine the Body's Response to Damage Patient 1 High Blood High Blood High Pressure Sugar Cholesterol Possible Presence of Disease Vascular Inflammation Inside the Artery wall Vascular Inflammation Outside the Artery Wall Inflammation testing can identify: Those with hidden risk Those at greatest risk Those who are worried well Inflammation testing Low Risk Moderate Risk High Risk Inflammation testing Low Risk 3

4 F 2-Isoprostanes (F 2-IsoPs) Risk of Disease Prostaglandin-like compounds formed from free radical mediated oxidation of arachidonic acid and excreted in the urine. The gold standard for measuring oxidative stress in the body. F 2-Isoprostanes (F 2-IsoPs) Lifestyle markers (inversely related to conditioning) Exercise daily & eat healthy Sedentary lifestyle, eat poorly & smoke Low F2-IsoPs High F2-IsoPs Smoking increases F 2-IsoPs production levels which can be reduced with cessation 3 cigarettes smoked over 30 minutes 2 weeks of smoking abstinence Case-controlled study 10 smokers >1.5 packs/day 10 non-smokers Matched for age and sex Morrow et al. Increase in circulating products of lipid peroxidation (F2-Isoprostanes) in smokers. N Engl J Med. 1995; 332:

5 Oxidized LDL (OxLDL) Risk of Disease Measures protein damage due to oxidative modification of the ApoB subunit on LDL cholesterol LDL Oxidation is the initiating event for foam cell formation High OxLDL levels precede development of metabolic syndrome and insulin insensitivity Oxidized LDL (OxLDL) OxLDL Poor Diet Lack of Exercise Metabolic syndrome Diabetes Cardiovascular Disease Lifestyle Risks Early Onset Disease Chronic Disease OxLDL is beyond F 2-IsoPs which marks lifestyle risk and identifies altered LDL biology increasing risk for chronic disease Inflammation testing Moderate Risk 5

6 ADMA/SDMA Presence of Disease Asymmetric dimethylarginine (ADMA) Symmetric dimethylarginine (SDMA) A measurement of endothelial dysfunction due to NO deficiency Nitric oxide maintains endothelial health and is cardioprotective Reduced LDL oxidation Improved dilation of blood vessels Reduced artery wall thickening Nitric Oxide Reduced blood clotting Reduced free radical formation Reduced inflammation in artery wall Measuring endothelial health Past and present Microalbumin Examines endothelial health in the kidneys due to reduced vascular integrity Structural damage Low Microalbumin = CV risk High Microalbumin = Renal risk ADMA/SDMA Examines systemic endothelial health associated with reduced NO production Chemical damage High ADMA = CV risk High SDMA = Renal risk Use as a surrogate for endothelial health in other vascular beds 6

7 Regulation of NO production by ADMA and SDMA ADMA directly blocks enos to inhibit NO production SDMA indirectly blocks NO production by inhibiting the availability of free L-Arginine. ADMA and SDMA are excreted/degraded by distinct mechanisms, and therefore manifest differently ADMA is cleared gradually by degradation while SDMA is cleared rapidly through the urine Therefore, ADMA identifies endothelial dysfunction and CV risk whereas SDMA identifies renal insufficiency and subsequent renal failure Individuals with elevated ADMA are 1.5x more likely to experience all-cause mortality Framingham Offspring Study Asymptomatic individuals (n = 3,320) Follow-up: ~11 yrs. Death rates decreased across increasing quartiles of Arginine and the Arg/ADMA ratio Böger RH et al. Circulation. 2009;119(12):

8 Individuals with known CAD and elevated ADMA are 2.5x more likely to experience a CV-related event AtheroGene Study Individuals w/ known CAD (n=1,874) Individuals who went on to have an event (n=114; or 6%) Follow-up: ~3 yrs. Schnabel R et al. Circ Res. 2005; 97(5):e53-9. Individuals with unstable CAD plus elevated ADMA are 2.5x more likely to experience CV-related mortality LURIC Study Individuals w/ & w/o CAD (n=3,238) Follow-up: 6 yrs. Meinitzer A et al. Clin Chem. 2007; 53(2): Measuring endothelial health Past and present Microalbumin Examines endothelial health in the kidneys due to reduced vascular integrity Structural damage Low Microalbumin = CV risk High Microalbumin = Renal risk ADMA/SDMA Examines systemic endothelial health associated with reduced NO production Chemical damage High ADMA = CV risk High SDMA = Renal risk Use as a surrogate for endothelial health in other vascular beds 8

9 Microalbumin Presence of Disease The quantification of small amounts of albumin in the urine that can identify microvascular integrity and endothelial dysfunction. May suggest the presence of systemic endothelial dysfunction an early indicator of heart disease Individuals with microalbumin levels above the genderspecific median had a nearly 3-fold increased risk of CVD The Framingham Heart Study 1,568 nonhypertensive, nondiabetic offspring participants free of CVD Mean age 55 yrs. (58% women) ~6 yrs. follow-up Median: Men: 3.9 μg/mg Women: 7.5 μg/mg CHL reports the aforementioned gender-specific cut-offs Arnlöv J et al. Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: The Framingham Heart Study. Circulation. 2005; 112: Elevated levels of microalbumin are a robust independent continuous risk factor for CV events and death The HOPE Study 5,545 (w/o DM ; history of CVD) 3,498 (w/ DM + at lease 1 risk factor) Gerstein HC et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and non-diabetic individuals. JAMA. 2001; 286:

10 High-sensitivity C-reactive Protein (hscrp) A highly sensitive quantification of C-reactive protein - an acute phase protein - that may be associated with the presence of heart disease hscrp Presence of Disease To date, increased hscrp levels have not been associated with vulnerable plaque suggesting that it is a marker of atheroma burden more so than plaque activity. hscrp An acute-phase protein released into the blood by the liver during inflammation Compared to standard CRP testing, hscrp testing can more accurately detect lower concentrations of CRP making it more useful in predicting a healthy person s risk for cardiovascular disease hscrp is a well documented clinical marker of general and cardiac-related inflammation 10

11 Interpreting hscrp results hscrp mg/dl Relative Risk Interpretation <1.0 Low Risk Reflect low CV risk Moderate Risk Doubles risk for coronary events (compared with levels <1 mg/l) High Risk Elevated vascular risk, 4-6x risk of diabetes >10.0 High Risk Can reflect acute infection Acute Infection - hscrp > 10.0 mg/dl Viral infections (10-40 mg/l) Active inflammation and bacterial infections ( mg/l) Severe bacterial infections/burns (>200 mg/l) Ridker PM Circ 2003;108:e81-e85. Toth PP Expert Rev Cardiovasc. Ther. 2010;8: How to Interpret hscrp results Elevated levels should be confirmed at least 1 month later To date, increased hscrp levels have not been associated with vulnerable plaque suggesting that it is a marker of atheroma burden more so than plaque activity. Ridker PM Circ 2003;108:e81-e85. Toth PP Expert Rev Cardiovasc. Ther. 2010;8: Baseline hscrp levels in apparently healthy men can predict the risk of first MI or ischemic stroke Physicians Health Study 1,086 men (>8 yrs) hscrp measured at baseline Ridker PM et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997; 336:

12 hscrp is a stronger predictor of cardiovascular events in women than LDL-C Women s Health Study 28,345 women (8 yrs.; 15,745 were not on HRT) hscrp and LDL-C measured at baseline Ridker PM et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002; 347: Inflammation testing High Risk The two sides of vulnerable plaque 12

13 Lp-PLA 2 Activity Disease Activity A vascular-specific inflammatory enzyme implicated in the formation of atherosclerotic plaque Bound primarily to small, dense LDL - highly atherogenic In arterial wall, Lp-PLA 2 releases chemicals that generate an immune response to damaged LDL Lp-PLA 2 is associated with risk of CHD and all vascular mortality Less distinct associations with ischemic stroke and the aggregate of non-vascular mortality were documented. Coronary Heart Disease Ischemic Stroke Risk ratio (95% CI) Risk ratio (95% CI) Lp-PLA2 Activity Lp-PLA2 mass Lp-PLA2 Activity Lp-PLA2 mass The Lp-PLA2 Studies Collaboration. Lipoprotein-associated phospholipase A2 and risk of coronary artery disease, stroke, and mortality: Collaborative analysis of 32 prospective studies. Lancet. 2010; 375: The two sides of vulnerable plaque 13

14 Myeloperoxidase (MPO) Disease Activity Enzyme produced and stored within polymorphonuclear (PMNs) leukocytes and monocytes Generates anti-microbial oxidants that: invade PMN leukocytes and monocytes to kill bacteria and other pathogens damage surrounding vasculature are enriched within human atherosclerotic plaque Myeloperoxidase (MPO) An enzyme synthesized and stored within polymorphonuclear (PMNs) leukocytes and monocytes MPO generates potent anti-microbial oxidants that invade PMN leukocytes and monocytes to kill bacteria and other pathogens that can also damage surrounding vasculature that are enriched within human atherosclerotic plaque Myeloperoxidase (MPO) MPO contributes to endothelial dysfunction Diminishes nitric oxide bioavailability MPO contributes to cholesterol accumulation Modifies LDL = atherogenic Modifies HDL = dysfunctional Specific marker of arterial vulnerable plaque/erosions/fissures Contributes to plaque instability by activating protease cascades that ultimately degrade the collagen cap Increasing levels signify increasing risk for cardiac events Hazen, Arterioscler Thromb Vasc Biol. 2004;24:

15 Time release of various inflammatory biomarkers EPIC/Norfolk Study: MPO levels predict the risk of CAD in subjects otherwise associated with low risk Meuwese MC et al. Serum myeloperoxidase levels are associated with the future risk of coronary artery disease in apparently healthy individuals: The EPIC-Norfolk Prospective Study. J Am Coll Cardiol. 2007; 2: MPO levels are independently associated with incident CHD in a healthy population The MONIKA/KORA Augsburg Study Population-based case-cohort study Middle-aged, healthy men and women 333 subjects with incident CHD (non-cases: 1727) Mean follow-up: ~10 years Karakas M et al. Myeloperoxidase is associated with incident CHD independently of traditional risk factors: Results from the MONICA/KORA Augsburg study. J Intern Med. 2012; 271:

16 MPO levels increase with the severity of CAD Case-controlled Study 847 patients with angiographically proven CAD Ndrepepa G et al. Myeloperoxidase level in patients with stable coronary artery disease and acute coronary syndromes. Eur J Clin Invest. 2008; 38: MPO and CRP have combined utility in predicting CV mortality risk in patients with evidence of CAD Patients with either a high MPO or high CRP elevated had 5.3-fold higher mortality risk Patients with high levels of both MPO and CRP had a 4.3-fold risk vs. patients with only one elevated marker Log-rank test: p<0.001 for trend MPO CRP Low and Low High or High High and High Modified from Heslop CL et al. Myeloperoxidase and C-reactive protein have combined utility for long-term prediction of cardiovascular mortality after coronary angiography. J Am Coll Cardiol. 2010; 55: Elevated MPO levels can predict the incidence of death or MI in individuals with ACS The CAPTURE Trial 1,090 patients with ACS Follow-up 6 months Modified from Baldus S et al. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation. 2003; 108:

17 The two sides of vulnerable plaque Clinical Interpretation Low Lp-PLA 2 and High MPO Less active artery wall, but an unstable collagen cap High Lp-PLA 2 and Low MPO Active artery wall, but a stable collagen cap High Lp-PLA 2 and High MPO Active artery wall, and an unstable collagen cap Anatomical and biological assessment of CV risk Anatomy (structure) Important, but may be hard to follow Biology (pathophysiology) Important, and can be measured routinely Together, both provide additive insight into a patient s risk for heart disease Wong ND et al. Myeloperoxidase, subclinical atherosclerosis, and cardiovascular disease events. J Am Coll Cardiol Img. 2009; 2: Elevated MPO levels predict a significantly higher incidence of cardiovascular events in patients with PAD MPOx >183.7 pm had higher hscrp levels versus MPOx pm Brevetti G et al. Myeloperoxidase, but not C-reactive protein, predicts cardiovascular risk in peripheral arterial disease. Eur Heart J. 2008; 29:

18 Measurement of MPO, in addition to ABI, improved the ability to identify PAD patients at risk for MI and stroke Brevetti G et al. Myeloperoxidase, but not C-reactive protein, predicts cardiovascular risk in peripheral arterial disease. Eur Heart J. 2008; 29: Inflammation testing Low Risk Moderate Risk High Risk 18

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