Transcript VASCULAR BIOLOGY AND CARDIOVASCULAR RISK FACTORS …
UltraPrevention: Living Heart Attack Free
Joel Kahn MD, FACC, FSCAI Clinical Professor of Medicine Wayne State University School of Medicine Medical Director, Preventive Cardiology Detroit Medical Center
Heart Attack Prevention: Don’t Help Fat People?
“Rosie O’Donnell Suffered a Heart Attack After Helping a Fat Lady Get Out of a Car”
Gawker.com
Vascular Biology in Clinical Practice, Oct. 2000; Mark C. Houston,MD
21
Endothelium
The endothelium serves a critical role as a barrier and primary sensor of physiological and chemical changes in the blood stream.
Traditional Cardiovascular Risk Factors
Hypertension
Dyslipidemia
Diabetes Mellitus
Smoking
Obesity
Figure 1
Fig 1 Rudolph Ludwig Carl Virchow, 1821-1902. Source: Photograph reproduced from Ref. No. 2 (public domain)
Atherosclerosis Pathogenesis: “Endarteritis Deformans” “Atheroma is a product of an inflammatory process within the intima” - 1845 Atherosclerosis is a reaction to injury and inflammation within the arterial wall
Step 1: Age
Assessing CHD Risk in Men
Step 4: Systolic Blood Pressure Step 6: Adding Up the Points Years Points 20-34 -9 Systolic BP (mm Hg) Points Points if Untreated if Treated 35-39 -4 Age Total cholesterol <120 0 0 40-44 0 HDL-cholesterol 120-129 0 1 45-49 3 Systolic blood pressure 130-139 1 2 50-54 6 Smoking status 55-59 8 140-159
160 1 2 60-64 10 2 3 Point total 65-69 70-74 75-79 11 12 13 Step 7: CHD Risk Risk 10-Year <0 <1% TC at Points at (mg/dL) 70-79 <160 0 160-199 200-239 4 7 240-279
280 9 11 Step 3: HDL-Cholesterol HDL-C (mg/dL)
60 Points -1 50-59 40-49 Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 0 1 Points at 0 3 5 6 8 Nonsmoker Smoker Points at 0 2 3 4 5 Step 5: Smoking Status Points at Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79 0 8 Points 0 1 1 2 3 Points at 0 5 0 0 0 1 1 Points at 0 3 0 1 2 3 4 5 6 7 8 9 10 Points at 0 1 1% 1% 1% 1% 1% 2% 2% 3% 4% 5% 6% Points at 0 1 11 12 13 14 15 16
17 8% 10% 12% 16% 20% 25%
30% <40 2
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.
© 2001, Professional Postgraduate Services ® www.lipidhealth.org
Framingham Score approach to CHD risk assessment
LOW RISK
designated as <0.6% CHD risk per year (<6% in 10 years)
INTERMEDIATE RISK
designated as a CHD risk of 0.6%-2.0% per year (6-20% over 10 years)
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 Greenland P et al. Circulation 2001; 104: 1863-7
Estimated 10-Year CHD Risk in 55-Year-Old Adults According to Levels of Various Risk Factors
Framingham Heart Study 40 35 30 25 20 15 10 5 0 5 5 13 8 25 A B
Blood Pressure (mm Hg) Total Cholesterol (mg/dL) HDL Cholesterol (mg/dL) Diabetes Cigarettes
mm Hg = millimeters of mercury mg/dL = milligrams per deciliter of blood
A 120/80 200 50 No No
Source: Circulation 1998;97:1837-1847.
B 140/90 240 50 No No
C 20
C 140/90 240 40 Yes No
37 27 D
D 140/90 240 40 Yes Yes
Men Women
Not all individuals with coronary heart disease have traditional risk factors
3 RF 9% 4 RF 1% 0 RF 19% 2 RF 28% 1 RF 43%
Khot et al. JAMA 2003
17 daggers (or 400) of heart risk
A Multimarker Approach Should Focus on Multiple Mechanisms / Pathologies
Circulation 108: 250-252
Potential Components of a “Multimarker” Approach
Daniels LB. Curr CV Risk Rep 2009.
Multiple Biomarkers for Prediction of CV Death in Older Adults
Variables
Established risk factors + cTnI + NT-proBNP + cystatin C + CRP + all biomarkers
C statistic
0.66
0.72
0.75
0.69
0.69
0.77
P value
Ref 0.002
<0.001
0.07
0.07
<0.001
Zethelius B et al. N Engl J Med 2008;358:2107-2116
Rader NEJM 2000
hs-CRP and Risk of Future MI in Apparently Healthy Men
3
P Trend <0.001
P<0.001
P<0.001
2
P=0.03
1 0 1 0.055
2 0.056
–0.114
3 0.115
–0.210
Quartile of hs-CRP (range, mg/dL)
4 0.211
Ridker PM et al.
N Engl J Med.
1997;336:973 –979.
Inadequate Monitoring of Vascular Response to Treatments
<$100 for # 1 killer >$1000 for # 2 Killer
The Vulnerable Patient Consensus Statement Preceding the SHAPE Initiative Review: Current Perspective From Vulnerable Plaque to Vulnerable Patient
A Call for New Definitions and Risk Assessment Strategies: Part I Morteza NagilaNi. MD: Peter Libby. MD: Erling Falk. MD. PhD; S. Ward Casscells, MD: Silvio Litovsky.
MD: John Rut-nix:Ter. MD: Juan Jose Badimon. PhD: Christodoulos Stelanadis, MD; Pedro Moreno, MD: Gerald Pasterkamp. MD. PhD: Zahi Fayad. PhD: Peter H. Stone. MD Sergio Waxman. MD: Paolo Raggi.
MD: Mohammad Madjid. MD; Alireza Zarrabi. MD Allen Burke, Ma Chun Yuan. PhD; Peter J. Fitzgerald.
MD. PhD: David S. Siscovick. MD: Chris L. de Korte. PhD: Masanori Aikawa, MD. PhD: K.E. Jukuii Nuaksinen. MD: Gerd Assmann. MD: Christoph R. Becker. MD: James H. Chesebro. MD: Andrew Farb.
MD: Zorina S. Galls. PhD: Chris Jackson. PhD: lk-Kyung king. MD. PhD: Wolfgang Koenig. MD. PhD: Robert A. Lodder. PhD: Keith March. MD. PhD: Jasenka Deminwic. MD. PhD. Mohamad Navab. PhD: Silvia G. Priori. MD. PhD; Mark D. Rekhter. PhD: Raymond Bahr. MD: Scott NI. Gmndy, MD. PhD: Roman Mehran. MD: Antonio Colombo. MD: Eric Boerwinkle. PhD: Christie Ballantyne. MD: William Insult. Jr.
MD: Robert S. Schwartz. MD: Robert Vogel. MD: Patrick W. Sermys. MD. PhD: Gana) K. Ruisson. MD.
PhD: David P. Fawn, MD; Sanjay Kalil. MD: Fleh»ut Drexler. MD: Philip Greenland. MD: James E. Muller.
MD: Renu Vinnani, Ma Paul M Ricker. MD: Douglas P. Zipes, MD; Prediman K. Shah, MD; James T.
Willerson, MD Naghavi et. al. Circulation Journal Vol108, No14; October 7, 2003
SHAPE vs. Status Quo
• •
Existing Guidelines (Status Quo):
Screen for Risk Factors of Atherosclerosis Treat Risk Factors of Atherosclerosis • •
The SHAPE Guidelines:
Screen for Atherosclerosis (the Disease) Regardless of Risk Factors Treat based on the Severity of the Disease and its Risk Factors
The 1 st S .
H .
A .
P .
E .
Guideline
Conceptual Flow Chart
Apparently Healthy At-Risk Population Step 1
Test for Presence of the Disease
Atherosclerosis Test Negative No Risk Factors + Risk Factors <75 th Percentile Positive 75 th
-
90 th Percentile Step 2
Stratify based on the Severity of the Disease and Presence of Risk Factors
≥90 th Percentile Step 3
Treat based on the Level of
Risk Lower Risk Moderate Risk Moderately High Risk High Risk Very High Risk
The 1 st SHAPE Guidelines Step 1 Step 2 Negative Test
• CACS =0 • CIMT <50 th percentile No Risk Factors 5 + Risk Factors
Step 3 Apparently Healthy Population Men>45y Women>55y
1 Very Low Risk 3 All >75y receive unconditional treatment 2 Exit Exit
Atherosclerosis Test
•
Coronary Artery Calcium Score (CACS)
•
or Carotid IMT (CIMT) & Carotid Plaque 4 Lower Risk Moderate Risk
• CACS <100 & <75 th % • CIMT <1mm & <75 th % & no Carotid Plaque
Positive Test
• CACS ≥1 • CIMT 50 th percentile or Carotid Plaque • CACS 100-399 or >75 th % • CIMT 1mm or >75 th % or <50% Stenotic Plaque • CACS >100 & >90 th % or CACS 400 • 50% Stenotic Plaque 6
Moderately High Risk
ABI<0.9
CRP>4 mg Optional
High Risk Very High Risk LDL Target Re-test Interval <160 mg/dl
5-10 years
<130 mg/dl
5-10 years
<130 mg/dl <100 Optional
Individualized
<100 mg/dl <70 Optional
Individualized
<70 mg/dl
Individualized Follow Existing Guidelines Angiography Myocardial IschemiaTest Yes No
Carotid B-Mode Ultrasonography: CIMT
Measurement of intimal medial thickness
Non-invasive, inexpensive, no radiation
Well-established as an indicator of cardiovascular risk from epidemiologic studies
ACCF/AHA 2010 Guideline: CIMT measurement may be reasonable for CV risk assessment in asymptomatic adults at intermediate risk (Class IIa-B)
Cardiovascular Health Study: Combined intimal-medial thickness predicts total MI and stroke
Cardiovascular Health Study (CHS) (aged 65+): MI or stroke rate 25% over 7 years in those at highest quintile of combined IMT (O’Leary et al. 1999)
Common carotid intima-media thickness measurements in cardiovascular risk prediction: : A meta-analysis.
Common carotid intima-media thickness (CIMT) measurement did not add clinically meaningful information to the Framingham risk score for predicting a person's 10-year risk of first MI or stroke, according to a meta-analysis of relevant studies "Our results suggest that common CIMT measurements should not routinely be performed in the general population, as the overall added value may be too limited to result in health benefits," the authors say.
Coronary Calcium as a marker for Atherosclerosis
Coronary calcium invariably indicates the presence of atherosclerosis, but atherosclerotic lesions do not always contain calcium
Calcium deposition may occur early in life, as early as the second decade, and in lesions that are not advanced
1) Wexler et al., Circ 1996; 94: 1175-92, 2) Blankenhorn and Stern, Am J Roentgenol 1959; 81: 772-7, 3) Blankenhorn and Stern, Am J Med Sci 1961; 42: 1-49, 4) Stary, Eur Heart J 1990; 11(suppl E): 3-19, 5) Stary, Arteriosclerosis 1989; 9 (suppl I): 19-32.
Cumulative Incidence of Any Coronary Event: MESA Study (Detrano et al., NEJM 2008)
Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals.
Association of risk markers with incident coronary heart disease* Risk marker Hazard ratio (95% CI)
Ankle-brachial index
Brachial flow-mediated dilation
0.79 (0.66-0.96) 0.93 (0.74-1.16) Coronary artery calcium 2.60 (1.94-3.50)
Carotid intima-media thickness
Family history
High-sensitivity CRP
1.17 (0.96-1.45) 2.18 (1.38-3.42) 1.28 (1.00-1.64)
JAMA
2012; 308: 788-795.
Indications for CAC Assessment
(Greenland et al., ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults (Circulation, 2010)
•
CV risk assessment in asymptomatic adults at intermediate risk (10-20% 10-year risk) (Class IIa, Level of Evidence B)
•
CV risk assessment in persons at low to intermediate risk (6-10% 10-year risk) (Class IIb, Level of Evidence B)
•
CV risk assessment in asymptomatic adults with diabetes (Class IIa-B)
•
Persons at low risk (<6% 10-year risk) should not undergo CAC measurement for CV risk assessment (Class III, Level of Evidence B)
Does coronary artery screening by electron beam computed tomography motivate potentially beneficial lifestyle behaviors?
In 703 men and women aged 28-84 who received scanning for coronary calcium by EBCT, calcium score remained independently associated with: new aspirin usage new cholesterol medication consulting with a physician losing weight decreasing dietary fat …but also increased worry …..potentially important risk-reducing behaviors may be reinforced by the knowledge of a positive coronary artery scan, independent of preexisting coronary risk factor status.
Wong ND et al, Am J Cardiol. 1996 Dec 1;78(11):1220-3.
0 Calcium Score 1-10 11-100 101-400 > 400
Calcium Score Guidelines
Plaque Burden No identifiable Plaque Minimal identifiable plaque burden Probability of Significant CAD Very low, generally <5% Very unlikely <10% Implications for CV Risk Very low Low Recommendations Reassure patient. Discuss general public health guidelines for primary prevention of CV disease.
Discuss general public health guidelines for primary prevention of CV disease.
Moderate Definite, at least mild atherosclerotic placque burden Mild or minimal coronary stenoses likely Definite, at least moderate atherosclerotic plaque burden Non-obstructive CAD highly likely although obstructive disease possible Moderately High Counsel about risk factor modification, strict adherence with primary prevention goals. Daily ASA.
Institute risk factor modification and secondary prevention goals. Consider exercise testing for further risk stratification. Daily ASA.
Extensive atherosclerotic plaque burden High likelihood >50% of at least one significant coronary stenosis High Institute very aggressive risk factor modification. Consider exercise for pharmacologic nuclear stress testing to evaluate for inducible ischemia. Daily ASA.
Rumberger et al. Mayo Clin Proc 1999; 74: 243-52
Ankle Brachial Index as a Predictor of Cardiovascular Mortality in the CHS Study
Newman A et al ATVB 1999
ABI and Total Mortalty (ABI Collaboration, JAMA 2008)
LDL Particle Number (LDL-P) in the Clinical Management of Heart Disease
Framingham Heart Study Indicates that Measuring Cholesterol Does Not Tell Us Enough
• 80% of subjects with cardiac events had lipid levels similar to subjects that were event free • 35% of CHD occurs in people with TC<200
20/100 40/100 90/100
Evidence of Residual CVD Risk
• 136,905 hospitalizations for (non-CHF) CAD and lipids w/in 24 hrs of admit (at 541 hospitals) • Over 50% of patients with LDL-C <100 mg/dL and 17.6% with LDL-C <70 mg/dL • For patients without h/o CAD, 72.1% with LDL-C <130 mg/dL and 41.5% with LDL-C <100 mg/dL Sachdeva A, et al. Am Heart J 2009; 157:111-7.e2.
From AHA’s Get with The Guidelines (GWTG) CAD Program and database; 2000 -2006.
LDL-C can vary with particle size
At the same LDL cholesterol, more small LDL vs. large LDL particles present Up to 70% More Particles
100 mg/dL Large LDL
Otvos JD et al. Am J Cardiol 2002;90(suppl):22i-29i Cromwell WC et al. J Clin Lipidology. 2007;1(6):583-592.
Cholesterol Balance 100 mg/dL Small LDL
LDL-C can vary, even in particles of the same size
With the same-size LDL particles (at any triglyceride level), the cholesterol content per LDL particle is highly variable.
More Particles 100 mg/dL Normal Cholesterol Carried Per Particle
Otvos JD et al. Am J Cardiol 2002;90(suppl):22i-29i Cromwell WC et al. J Clin Lipidology. 2007;1(6):583-592.
Cholesterol Balance 100 mg/dL Less Cholesterol Carried Per Particle
Multiple Outcome Studies Demonstrate Difference Between LDL-P and LDL-C
CHD Event Associations of LDL-P versus LDL-C Framingham Offspring Study
Cromwell WC et al. J Clin Lipidology 2007;1(6):583-592.
LDL-C and LDL-P Correlations in MESA (n=5,598)
3000 r = 0.75
2500 2000 1500 1000 500 50 100 150 200 250 LDL-C (mg/dL) 300 Otvos et al. J Clin Lipidol 2011;5:105-13
MESA: LDL-P and LDL-C Discordance Relations with Incident CVD Events (n=319)
0.08
LDL-C LDL-P 0.06
LDL-P > LDL-C Concordant LDL-P < LDL-C MetSyn 54% 33% 16% 104 1372 0.04
LDL-C underestimates LDL-attributable risk
117 1249 0.02
0
LDL-C overestimates LDL-attributable risk
5 5 6 130 mg/dL 1117 nmol/L Otvos et al. J Clin Lipidol 2011;5:105-13
ENDO-PAT: Endothelial dysfunction before atherosclerosis
JACC 2010;55:1688 JACC 2004;44:2137 Circulation 2008;117:2467
Measures reactive hyperemia and ED. FDA approved. 5 minute occlusion of brachial artery with BP cuff
Measure pre and post occlusion ratio index
Index of 1.67 has sensitivity of 82% and specificity of 77% to diagnose coronary ED and highly correlates to brachial artery FMD(r=.0.33 to 0.55)
Occluded arm Control arm Reactive hyperemia
ENDOPAT Good and poor results
Normal EF Poor EDF
ENDOPAT AND FRAMINGHAM RISK SCORE AND CHD RISK
EndoPAT vs. Framingham Risk Score
Mayo Clinic, 2010
Low risk but with endothelial dysfunction Low risk & normal endothelial function
1-May-20 5/1/2020 n=270, Intermediate risk patients Mayo Clinic & Tufts Medical Center 49
ENDO-PAT AND CVD OUTCOMES
Eur Heart J 2010 ;31:1142
270 patients over 7 years : ED and Framingham risk score
Abnormal Index predicted cardiac events such as cardiac death, MI cardiac hospitalization and CABG: 48% vs 28% (p=0.03). This was independent of Framingham risk score.
Also correlates with risk factors
The more severe the CVD the worse the index
Conclusions
Standard risk factors alone or in combination do not predict global risk well enough
Too many events in too many lower risk individuals
Modest screening performance
Measurement of certain biomarkers such as hs-CRP and advanced lipid profiles may be useful in conjunction with global risk assessment to improve risk classification.
Screening tests for subclinical atherosclerosis should provide incremental risk prediction for CHD events over global risk assessment
Guidelines suggest intermediate risk subjects may be suitable for such screening that may help identify those needing more aggressive risk factor intervention.