Nathan D. Wong, PhD, FACC, FAHA, FNLA, FASPC

Professor and Director, Heart Disease Prevention Program

Division of Cardiology, UC Irvine

Past President, American Society for Preventive Cardiology

Past President, Pacific Lipid Association

Assessing Cardiovascular Risk: The Foundation of Preventive Cardiology

Disclosures

Dr. Wong reports research funding through

UC Irvine from Amarin, Amgen, Novartis,

Novo Nordisk, and Boehringer Ingelheim

Dr Wong is also on the speakers bureau for

Esperion and Amarin and a consultant for

Novartis

Two words “risk factors” began the field of preventive cardiology

Kannel et al, Ann Intern Med 1961

Age, sex, hypertension, hyperlipidemia,

smoking, diabetes, (family history), (obesity)

Why Use Risk Scores?

1) As early as 1976, former Framingham director Dr. William

Kannel had noted risk functions provide an “economic

and efficient method of identifying persons at high

cardiovascular risk who need preventive treatment…”

(AJC 1976)

2) The ACC Bethesda

Conf. noted the intensity

of treatment should match

a person’s risk

(Califf RM, JACC 1996)

Framingham Heart Study: Kannel et al., 1961

Key Risk Scores Used in CHD and CVD Prediction

Risk Score (year) Endpoint Definition

Framingham, 1991 (Anderson) 10-year all CHD CHD death, MI, unstable

angina, angina

Framingham, 1998 (Wilson) 10-year all CHD and

hard CHD

CHD death, MI, unstable

angina, angina

ATP III, 2001 (Framingham) 10-year hard CHD CHD death, nonfatal MI

PROCAM 2002 (Germany) 10-year hard CHD CHD death, non-fatal MI

European SCORE 2003 and

after

10-year CVD death CVD death only (country

and region specific)

QRISK 2007 (England and

Wales)

10-year global CVD CVD death, MI, stroke,

revascularization

Reynolds women (2007) and

men (2008) (Boston, USA)

10-year global CVD CHD death, MI, stroke,

revascularization

Framingham Global CVD 2008 10-year global CVD CVD death, all CHD, stroke,

heart failure, claudication

Pooled Cohort Equations 2013

(USA)

10-year and lifetime

ASCVD

Nonfatal/fatal MI & stroke

Joint British Societies (JBS) CVD

Risk Score

10-year and lifetime

ASCVD

CHD (incl MI, angina) and

stroke

ASCVD Risk Estimator Plus

• Estimates 10-year hard ASCVD (nonfatal MI, CHD death, stroke) for ages 40-79 and lifetime risk for ages 20-59

• Intended to promote patient-provider risk discussion and best ways to reduce risk

• Used as a starting point in risk assessment, consider risk enhancing factors to refine risk

tools.acc.org/ascvd-risk-estimator-plus

Estimates risk

reduction from BP

reduction or

smoking cessation

Lifetime Risks of Cardiovascular Disease Death by Number of Risk Factors and Attained Age (Berry et al. , 2012)

Men Women

Optimal risk factors: total cholesterol <180 mg/dl, blood pressure <120/80, non-

smoking, non-diabetic.

Major risk factors: current smoker, diabetes, treated cholesterol or untreated

cholesterol >=240 mg/dl, treated hypertension or untreated systolic BP >=160 mmHg or

diastolic BP>=100 mmHg.

Estimate Absolute 10-year ASCVD Risk

Low Risk

0 - <5%

High Risk

≥20%

Intermediate Risk

7.5% - <20%

Lifestyle

and drug therapy

Lifestyle

modification

Borderline Risk

5% - <7.5%

Clinician-patient discussion considering

risk-enhancing factors and net benefit of therapy

Refining Risk Estimates for Individual Patients

Refining Risk Estimates for Individual Patients

Risk-Enhancing Factors for Clinician–Patient Risk Discussion

Family history of premature ASCVD; (males, age <55 y; females, age <65 y)

Primary hypercholesterolemia (LDL-C, 160-189 mg/dL [4.1- 4.8 mmol/L]; non-HDL-C 190-219 mg/dL [4.9-5.6

mmol/L])*

Metabolic syndrome (increased waist circumference, elevated triglycerides [>175 mg/dL], elevated blood

pressure, elevated glucose, and low HDL-C [<40 mg/dL in men; <50 in women mg/dL] are factors; tally of 3 makes

the diagnosis)

Chronic kidney disease (eGFR 15-59 mL/min/1.73 m2 with or without albuminuria, not treated with dialysis or

kidney transplantation)

Chronic inflammatory conditions such as psoriasis, RA, or HIV/AIDS

History of premature menopause (before age 40 y) and history of pregnancy-associated conditions that

increase later ASCVD risk such as pre-eclampsia

High-risk race/ethnicities (e.g. South Asian ancestry)

Lipid/biomarkers: Associated with increased ASCVD risk

-Persistently* elevated, primary hypertriglyceridemia ( 175mg/dL);

-If measured:

o Elevated high-sensitivity C-reactive protein (≥2.0 mg/L

o Elevated Lp(a) A relative indication for its measurement is family history of premature ASCVD. An Lp(a) ≥

50 mg/dL or ≥125 nmol/L constitutes a risk enhancing factor especially at higher levels of Lp(a)

o Elevated apoB 130 mg/dL - A relative indication for its measurement would be triglyceride ≥ 200 mg/dL.

A level ≥ 130 mg/dL corresponds to an LDL-C >160 mg/dL and constitutes a risk enhancing factor

o ABI (ABI) <0.9

TOM

Age: 56

• 56 year old Caucasian

male

• No family history

• Vague symptoms

• Lipids normal

• Framingham Risk normal

• American College of

Cardiology Risk Calculator

normal

Patient Medical History

Age/Sex 56 y/o Male

Smoke /

Substance

No

Family History No

Medication No

BMI Normal

Blood Pressure Normal

Case Study

Clinical Work-

Up

Results

ASCVD

Calculation

(10 year)

5.4% - Normal

FRS

Calculation

(10 year)

7.1% - Normal

>90% LCx

lesion

The challenge in diagnosis of coronary heart disease

“The majority of people destined to die

suddenly will not have a positive exercise

test. The likely reason that they will die

suddenly is that only a mild, non-flow -

limiting coronary plaque will have been

present before the sudden development

of an occlusive thrombus.”- Stephen Epstein

New England Medical Journal 1989

Most Myocardial Infarctions Are Causedby Low-Grade Stenoses

Pooled data from 4 studies: Ambrose et al, 1988; Little et al, 1988; Nobuyoshi et al, 1991; and Giroud et al, 1992.(Adapted from Falk et al.)Falk E et al, Circulation, 1995.

Criteria required for a good screening test

• Provides an accurate determination of the

likelihood that an asymptomatic person has the

condition (accuracy)

• Reproducible results (reliability)

• Detect individuals where early intervention is

likely to have a beneficial impact

• Should provide incremental value to risk

predicted by office-based risk assessment

Redberg and Vogel et al., 34th Bethesda Conf. JACC 2003; 41: 1855-1917

Carotid B-Mode Ultrasonography

• Measurement of intimal medial thickness

• Non-invasive, inexpensive, no radiation

• Well-established as an indicator of cardiovascular risk

from epidemiologic studies

• Published clinical trials on utility of carotid IMT as

measure of atherosclerosis and effects of therapy

• Accuracy of assessments depends on experience of those

interpreting scans

• Both the 2013 ACC/AHA guidelines and ESC 2016

guidelines do not recommend CIMT measurement for

risk assessment.

Cardiovascular Health Study: Combined intimal-medial thickness predicts total MI and stroke in older adults

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)

Date of download: 1/9/2014Copyright © 2014 American Medical

Association. All rights reserved.

Common Carotid Intima-Media Thickness Measurements in

Cardiovascular Risk Prediction:

A Meta-analysis: 14 cohorts, 45,828 subjects, 11 year follow-up

JAMA. 2012;308(8):796-803. doi:10.1001/jama.2012.9630

A, Individuals without and with events classified according

to their 10-year absolute risk to develop a myocardial

infarction or stroke predicted with the Framingham Risk

Score variables or classified according to their 10-year

absolute risk to develop a first-time myocardial infarction

or stroke predicted with the Framingham Risk Score and a

common carotid intima-media thickness (CIMT)

measurement. B, Observed Kaplan-Meier absolute risk

estimates for all individuals (with and without events). The

observed risk in reclassified individuals is significantly

different from the observed risk of the individuals in the

gray cells.

CIMT w/w/o Plaque and CHD Incidence: ARIC Study (Nambi et al., JACC 2010)

23% of 13,145 eligible subjects were reclassified by adding CIMT and plaque information over traditional risk factors

ESC 2016 Prevention Guidelines: IIb-B recommendation for carotid plaque assessment

Improvement in Net Reclassification of

Subjects by CIMT and plaque over risk

factors (Nambi et al., JACC 2010)

Ankle- Brachial Index (ABI)Measure of lower-extremity

occlusive peripheral arterial disease

Ankle SBP *

ABI < 0.90 is abnormal

Sensitivity = 90% specificity= 98% for stenosis >50%.

Can detect asymptomatic disease.

Brachial Artery SBP

* dorsalis pedis or posterior tibial artery by doppler probe

ABI

ABI and Total Mortality (ABI Collaboration, JAMA 2008)

19% of men and 38% of women would be reclassified in

their risk category from addition of ABI.

Risk enhancing factor in ACC/AHA guidelines; IIb-B

recommendation by ESC

Coronary Calcium and Atherosclerosis: Pathology Evidence

• Coronary calcium invariably

indicates the presence of

atherosclerosis, but

atherosclerotic lesions do not

always contain calcium (1-3).

• Calcium deposition may occur

early in life, as early as the

second decade, and in lesions

that are not advanced (4-5).

• Correlates with plaque burden;

highly sensitive for angiographic

disease

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.

The extent of CAC roughly correlates with the

amount of overall atherosclerotic plaque, but there

is great variability around this relationship

Radiation dose

• “dose [EBT dose 0.7 mSv, MDCT dose 1.5

mSv]”

– AHA Scientific Statement Circulation

2005

• CAC Dose = 1 mSv (Gerber AHA Scient

Statement on Ionizing Radiation 2009)

– Similar to Mammogram

– Similar to long distance air flight

– 1/3 annual background radiation

Cumulative Incidence of Any Coronary Event: MESA Study (Detrano et al., NEJM 2008)

ACC/AHA Risk Assessment Work Group notes that “assessing CAC is likely

to be the most useful of the current approaches to improving risk

assessment among individuals found to be at intermediate risk after formal

risk assessment.”

ACC/AHA Class IIa recommendation; ESC Class IIb-B recommendation

Ten-year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the multi-ethnic study of atherosclerosis (MESA) (Budoff et al., Eur Heart J 2018)• At 10 years of follow-

up, all participants with

CAC > 100 were

estimated to have

>7.5% risk regardless

of demographic

subset.

• Ten-year ASCVD

event rates increased

steadily across CAC

categories regardless

of age, sex, or

race/ethnicity.

• For each doubling of

CAC, there was a 14%

increment in ASCVD

risk

UKPDS Risk Engine for Diabetes

• T2DM specific risk calculator

• Based on 53,000 patients years of

data from the UK Prospective

Diabetes Study

• Risk estimates and 95%

confidence intervals in

individuals with type 2 diabetes

not known to have heart disease,

for:

- Non-fatal and fatal

coronary heart disease

- Fatal coronary heart

disease

- Non-fatal and fatal stroke

- fatal stroke

http://www.dtu.ox.ac.uk/riskengine/

Diabetes-Specific Risk Enhancers That Are Independent of Other Risk Factors in Diabetes Mellitus

Risk Enhancers

Long duration (≥10 years for type 2 diabetes mellitus (S.4.3-20) or ≥20

years for type 1 diabetes mellitus)

Albuminuria ≥30 mcg of albumin/mg creatinine

eGFR <60 mL/min/1.73 m2

Retinopathy

Neuropathy

ABI <0.9

Coronary Artery Calcium (CAC)?

Annual CHD Event Rates (in %) by Calcium Score Events by CAC Categories in Subjects with DM, MetS, or Neither Disease(Malik and Wong et al., Diabetes Care 2011)

Coronary Heart Disease

Coronary Artery Calcium Score

ACCF/AHA 2010 Guideline: CAC Scoring for CV risk

assessment in asymptomatic adults aged 40 and over with

diabetes (Class IIa-B)

01-99

100-399400+

Neither MetS/DM

MetS

DM

0.4

1.5 1.9

4

0.20.8

2.1

3.5

0.1 0.41.3

2.2

00.5

11.5

22.5

33.5

4

Annual

CHD

Event

Rate

Intermediate Risk

MESA Subjects

(n=1330)

C-statistics:

FRS alone 0.623

FRS+CAC 0.784 (p<0.001)

FRS+CIMT 0.652 (p=0.01)

FRS+FMD 0.639 (p=0.06)

FRS+CRP 0.640 (p=0.03)

FRS+FamHx 0.675

(p=0.001)

FRS+ABI 0.650 (p=0.01)

Yeboah J et al, JAMA 2012

Risk Stratification in

Secondary Prevention:

Implications of Recent

Guidelines

Secondary Prevention

Table 4. Very High-Risk* of Future ASCVD Events

Major ASCVD Events

Recent ACS (within the past 12 mo)

History of MI (other than recent ACS event listed above)

History of ischemic stroke

Symptomatic peripheral arterial disease (history of claudication

with ABI <0.85, or previous revascularization or amputation)

* Very High-Risk is defined as multiple major

ASCVD events or one major ASCVD event

and multiple high risk conditions (next slide)

Table 4 continued

High-Risk Conditions

Age ≥65 y

Heterozygous familial hypercholesterolemia

History of prior coronary artery bypass surgery or percutaneous coronary

intervention outside of the major ASCVD event(s)

Diabetes mellitus

Hypertension

CKD (eGFR 15-59 mL/min/1.73 m2)

Current smoking

Persistently elevated LDL-C (LDL-C ≥100 mg/dL [≥2.6 mmol/L]) despite maximally

tolerated statin therapy and ezetimibe

History of congestive HF

Why Does Very High Risk Status Matter?

Role for a Complementary Approach Predicting ASCVD Risk

Adapted from Kullo IJ, et al. Mayo Clin Proc. 2005;80:219-230.

Arterial

imaging/

function

Metabolic syndrome

Biomarkers

Pooled 10 yr ASCVD Risk Equation

Family history

• global risk

assessment

w/family hx and

other measures

• biomarkers (ideally

predicting near-term

risk)

• subclinical disease

imaging for

atherosclerotic

burden

The Future of Cardiovascular Risk Assessment: The Four Ps

• Predictive: Optimizing identification of persons

at increased risk for CVD

• Preventive: Increasing focus on delaying or

preventing the onset of CVD

• Pre-emptive: Applying preventive strategies long

before clinically apparent disease

• Personalized: Using accurate markers based on

improved understanding of CV pathophysiology

to tailor preventive strategies to individual needs E. Nabel, NHLBI

Thank You !

www.aspconline.org