Dr. Tabas Atherosclerosis - Columbia UniversityAtherosclerosis Ira Tabas, M.D., Ph.D. Richard J. Stock Professor of Medicine, Cell Biology, and Physiology [email protected] •Overview

Cardiovascular Pathophysiology Course

College of Physicians & Surgeons

January 14, 2009

Atherosclerosis

Ira Tabas, M.D., Ph.D.

Richard J. Stock Professor of Medicine,

Cell Biology, and Physiology

[email protected]

• Overview of atherosclerosis and

atherothrombotic vascular disease

• Theories of atherogenesis and advanced lesion

progression

• The macrophage foam cell

• Clinical implications

Atherosclerosis

Of all the ailments that might blow

out life's little candle, heart disease

is the chief.

William Boyd (1885-1972)

Pathology for the Surgeon

Coronary Arteries

Unoccluded Coronary Artery

Necroticatherosclerotic

lesion

Thrombus

Occluded Coronary Artery

Progression of Atherothrombotic Vascular Events

Abrams (2005) NEJM 352:2524

YEARS

Progression of Atherothrombotic Vascular Events

Abrams (2005) NEJM 352:2524

YEARS MINUTES




progression



Atherosclerosis

Atherogenesis

Abrams (2005) NEJM 352:2524

Tabas et al., Circulation, 2007



Subendothelial Lipoprotein Aggregationand Matrix-Retention

J. Frank





Plaque necrosisPlaque necrosis


Plaque necrosisPlaque necrosis


(Circulation. 2005;112:3348-3353.)

© 2005 American Heart Association, Inc.

Special Report

Atherosclerosis 2005

Recent Discoveries and Novel Hypotheses

Oxidation, lipoproteins, and atherosclerosis: which

is wrong, the antioxidants or the theory?

Current Opinion in Clinical Nutrition & Metabolic Care. 8(2):139-146

March 2005

Maladaptive Responses to Lipoprotein Retention are Key Processes

in Lesion Progression . . . But They Can't Explain Lesion Initiation

Don't Forget the Root Cause!

Atherosclerosis: the role of endothelial injury, smooth

muscle proliferation and platelet factors

Regression: The "Orange Arrows"

Maladaptiveinflammatory

response

Regression of Atherosclerosis

Reverse Cholesterol

Transport

ABCA1

ABCG1

Role of LXR

ABCA1

ABCG1

Acute AtherothrombosisThe Trigger for Acute Coronary Syndromes

Abrams (2005) NEJM 352:2524

YEARS MINUTES

The Plaque Rupture Theory of Acute Atherothrombosis

necroticcore

Plaque Morphology is More Important than Plaque SizeMild-to-Moderate Lesions that Rupture

are the Most Common Cause of Cardiac Events

Thin fibrous cap

Necrotic core

Inflammatory milieu

Plaque Rupture

ThrombusThrombus

Rupturedplaque

at area of thinned

fibrous cap Necrotic CoreNecrotic Core

Constantinides

The Problem

"Benign" atherosclerotic

lesion

Ruptured"vulnerable"

plaque

Crawford et al. ATVB 1998; Constantinides

?

The Importance of Advanced Lesional Mφφφφ Death

"graveyard of dead Mφφφφs"Necrotic Core

"graveyard of dead Mφφφφs"Necrotic Core

inflammation coagulation

thrombosis

proteases stress onfibrous cap

The Importance of Advanced Lesional Mφφφφ Death

Tabas ATVB Nov 2005

Mφφφφ Death in Advanced Atherosclerosis




progression PICTURE GALLERY



Atherosclerosis

The Fatty StreakFocal Accumulations of Cholesterol

"Foam Cells"The Cellular Component of the Fatty Streak

lumen

intima

media

SMCsMφφφφs

Fibrous Lesion

Fibrous cap

Fibrous Lesion with Necrotic Core

Necroticcore

Fibrouscap

Fibrous Lesion with Necrotic Core

Plaque Rupture




progression



Atherosclerosis

The Macrophage Foam Cell

foamcells

"Nature and Origin of the Xanthoma ('Foam') Cell"L.W. Plewes (1934) Archiv. Pathol. 17:177-186

EM of atherosclerotic aortic intima from a patient given Thorotrast prior to death

"I believe that the origin of the [foam cell] is from the

reticulo-endothelial system, and that the foam cell is

an evidence of [a] specific reaction . . . to certain

lipoids, especially cholesterol and its esters, when

conditions favorable for their deposition in tissues are

present."

"Nature and Origin of the Xanthoma ('Foam') Cell"L.W. Plewes (1934) Archiv. Pathol. 17:177-186

Immunohistochemical Identification of

Atherosclerotic Macrophage Foam Cells

hematoxylin and eosin mAB to Mφφφφ surface antigen

expanded intima

filled with"foam cells"

lumen

subendothelium

The Life Cycle of the Macrophage Foam Cell

Monocyte Chemotaxis

*** * * *

chemokines*

adhesionmolecule

matrix-retained and modified lipoproteins

lumen

subendothelium


Diapedesis

lumen

subendothelium


Differentiation

lumen

subendothelium


? Proliferation

subendothelium

The Life Cycle of the Macrophage Foam CellContinued Macrophage Recruitment

lumen

subendothelium


Cholesteryl Ester Accumulation

lumen

Macrophage Foam Cell Formation

monocyte

endothelial cell

foam cellCE droplets foam cell

extension ofendothelial cell

Lumen

lumen

subendothelium


Cholesterol Efflux

HDL

ApoA1/E

lumen

subendothelium


? Macrophage Egress

? dendriticcell

subendothelium


Apoptosis

apoptotic Mφφφφ

lumen

cholesterol, oxidized lipids,

growth factor depletion

subendothelium


? Phagocytosis of Apoptotic Body

lumen

lumen

subendothelium


? Disposal of Apoptotic Body

lumen

subendothelium


Mφφφφ "Necrosis" or "Aponecrosis"

necrotic Mφφφφ

lumen

subendothelium


Lesional Necrosis: The Lipid (or Necrotic) Core

Mφφφφ debris

lumen

subendothelium


Plaque Rupture

lumen

Mφφφφ debris

subendothelium


Acute Thrombosis and Vascular Occlusion

lumen

Mφφφφ debris

Tabas ATVB Nov 2005

Mφφφφ Death in Atherosclerosis

Tabas ATVB Nov 2005


Tabas ATVB Nov 2005


living Mφφφφs




progression



Atherosclerosis

Lowering Plasma LDL Decreases

Coronary Artery Disease

Adapted from Illingworth. Med Clin North Am. 2000;84:23.

At: http://www.hpsinfo.org.

50 21070 19017015013011090

0

5

10

15

20

25

% w

ith

CA

D e

ven

t

LDL-C (mg/dL)

HPS

WOSCOPS

AFCAPS

CARE

4S

LIPID

HPS

Primarypreventiontrials

Secondarypreventiontrials

Lowering Plasma LDL Decreases

Coronary Artery Disease

50 21070 19017015013011090

0

5

10

15

20

25%

wit

h C

AD

ev

en

t

LDL-C (mg/dL)

HPS

WOSCOPS

AFCAPS

CARE

4S

LIPID

HPS



50 21070 19017015013011090

0

5

10

15

20

25%

wit

h C

AD

ev

en

t

LDL-C (mg/dL)

HPS

WOSCOPS

AFCAPS

CARE

4S

LIPID

HPS



HPS

WOSCOPS

AFCAPS

CARE

4S

LIPID

HPS



WOSCOPS

AFCAPS

WOSCOPS

AFCAPS

CARE

4S

LIPIDCARE

4S

LIPID

HPS



Why?


response

Atherogenesis

"High" levels of apoB-lipoproteins

in the bloodstream

+

A "susceptible" arterial wall

(i.e., susceptible to apoB-LP retention or responses to retention)

"High" levels of ApoB-lipoproteins

in the bloodstream

Therapeutic Approach to Prevent and

Reverse Atherosclerosis

↓↓↓↓ Probability of ApoB-LP entry and then

retention in the subendothelium

(Circulation. 2005;112:3348-3353.)

© 2005 American Heart Association, Inc.

Special Report

Atherosclerosis 2005

Recent Discoveries and Novel Hypotheses

Oxidation, lipoproteins, and atherosclerosis: which

is wrong, the antioxidants or the theory?

Current Opinion in Clinical Nutrition & Metabolic Care. 8(2):139-146

March 2005

Don't Forget the Root Cause!

Atherosclerosis: the role of endothelial injury, smooth

muscle proliferation and platelet factors

Don't Get Fooled!

Don't Forget the Time Frame!

• 2-yr "risk"

• Post-ACS studies

• CIMT studies

• 10-yr risk

• Framingham risk score

• Lifetime risk

• Most meaningful metric for risk assessment of

CAD, a disease that takes decades to develop


response

Clinical Predictions

Cases of CAD"Low"*High

Cases of no

CADHighLow

HighAverageAverage

Lifelong Risk of

CADPlasma LDL

Arterial Wall

Susceptibility

(genes; lifestyle)

*low end of the bell-shaped curve for modern industrialized societies

Case Study

Mrs. M

• 64 y/o female with 20-yr hx of type 2 diabetes and HTN

• smokes one ppd cigarettes

• moderately obese

• Het FH: LDL = upper 200's; HDL = upper 30's; TG = low 300's

• on Rx for diabetes, hypertension, and dyslipidemia but is non-compliant

• refuses to stop smoking, engage in an exercise program, or lose weight

• no clinical hx of CAD, CVA, or PAD; EKG and stress test normal

Clinical Predictions

Cases of CAD"Low"*High

Cases of no

CADHighLow

HighAverageAverage

Lifelong Risk of

CADPlasma LDL

Arterial Wall

Susceptibility

(genes; lifestyle)

*low end of the bell-shaped curve for modern industrialized societies

Current ATP III Treatment GuidelinesLast updated 2004

-C

≤1 RF

≥2 RFs

equivalent• high Framingham risk

• symptomatic athero d.

• diabetes

CAD or

CAD risk

Risk Category

<160

<130-100

<100-70

LDLGoal

(mg/dL)

Non-HDL-C

Goal*

(mg/dL)

<190

<160-130

<130-100

*Post-hoc TNT & IDEAL: for subjects on statins,

better predictor than LDL (Circ 2008)

NCEP ATP III Treatment Guidelines

Therapeutic

Lifestyle Change (TLC)

Improve diet

Weight reduction

Physical activity

Pharmacologic

Treatment

Statins (HMG-CoA reductase inhibitors)

Fibrates

Niacin

Bile acid sequestrants

Cholesterol absorption inhibitors

Combinations of the above

It Ain't Happening

Am Heart J. July 2008: NHANES → only 37%

of those with CVD were at target LDL goals in

2003-2004

Circulation July 2008: If goals were actually

met, MI and strokes would be lowered by 63%

and 31%, respectively, and 224 million quality-

adjusted life-years would be added over the

next 30 yrs

Current ATP III Treatment GuidelinesLast updated 2004

-C

≤1 RF

≥2 RFs

equivalent• high Framingham risk

• symptomatic athero d.

• diabetes

CAD or

CAD risk

Risk Category

<160

<130-100

<100-70

LDLGoal

(mg/dL)

Non-HDL-C

Goal

(mg/dL)

<190

<160-130

<130-100}Ongoingdevelopments:

• Lower is better

• Earlier is better

Circulation 2008;118;672-677

Lower is BetterCholesterol Levels Among Different Human Populations

50 70 90 110 130 150 170 190 210

Adult American

San

Pygmy

!Kung

Inuit

Hazda

Hunter-

gatherer

humans

Mean total cholesterol, mg/dLMean total cholesterol, mg/dL

Adapted from O’Keefe JH Jr et al. J Am Coll Cardiol. 2004;43(11):2142–2146.

Lower is Better and "Safe"

• Hunter-gatherer societies (and other mammals)

• Cord blood

• Familial hypobetalipoproteinemia

• "Zero-risk" extrapolation of LDL-lowering trials

• PROVE-IT subgroup

• LDL receptor is 50% saturated at 10 mg/dl

Earlier is Better

Gore I et al. Am J Clin Nutr. 1959;7(1):50–54.

Age, Decades

Su

bje

cts

%

fattystreaks

fibrousplaques

0

20

40

60

80

100

0 2 4 6 8 10

advancedlesions


response

Regression is More Robust When Starting With Earlier Lesions

• Adolescents

• Life-long low risk by 50 y/o = very low future risk

• Best predictor of CAD = risk profile 15 yrs prior

• PCSK9

• Children with FH

• 2007 AHA/AAP guidelines

Earlier is Better

Ferranti et al. 2008 NEJM 359:1309

Is Long-Term Use of High-Dose Statins Completely Safe?

Dolichol

Of all the ailments that might blow

out life's little candle, heart disease

is the chief.

William Boyd (1885-1972)

Pathology for the Surgeon


response

Documents

Dr. Tabas Atherosclerosis - Columbia UniversityAtherosclerosis Ira Tabas, M.D., Ph.D. Richard J. Stock Professor of Medicine, Cell Biology, and Physiology [email protected] •Overview