#1 killer of human

beings in the 21st century?

Fatal Heart Attack!

What causes heart attack?

Vulnerable Plaque

The short answer is:

What is vulnerable plaque?

Dangerous forms of atherosclerotic plaques

that can rupture or induce thrombosis and

lead to critical disruption of blood flow.

The short answer is:

Everybody has atherosclerosis, the question is who has vulnerable plaque

Sudden Cardiac DeathAcute MI

What Do We Know About Vulnerable Plaque?

Morteza Naghavi, MD

Center for Vulnerable Plaque ResearchUniversity of Texas at Houston

Texas Heart InstituteOctober 2001

Mohammad Madjid, MD Silvio Litovsky, MD Alireza Zarrabi, MDMaziar Azadpour, MD Parsa Mirhaji, MD Cornelius Nwora, MD

Ward Casscells, MD James Willerson, MD

Salute to Pioneers

Carl von Rokitansky (1804-1878)

Rokitansky gave early detailed descriptions of arterial disease. He

is alleged to have performed 30,000

autopsies.

Rokitansky in 1841 championed the Thrombogenic Theory. He proposed that the deposits observed in the inner layer of the arterial wall

derived primarily from fibrin and other blood elements rather than being the result of a purulent process. Subsequently, the atheroma resulted from the

degeneration of the fibrin and other blood proteins as a result of a preexisting crasis of the blood, and finally these deposits were modified toward a pulpy

mass containing cholesterol crystals and fatty globules. This theory came under attack by Virchow

First studies on inflammation of vessels, particularly phlebitis, Started at a time when Cruveilhier2had just stated: La phlebite domine toute la pathologie.3 First a great number of preparatory studies on fibrin, leukocytes, meta-morphosis of blood, published separately. …

Rudolf Virchow 1821-1902

The Father of Cellular Pathology

Virchow appreciates prior works.

Virchow presented his inflammatory theory. He utilized the name of "endarteritis deformans." By this he meant that the atheroma was a product of an inflammatory process within the intima with the fibrous thickening evolved as a consequence of a reactive fibrosis induced by proliferating connective tissue cells within the intima.

Olcott 1931 “plaque rupture”

Leary 1934 “rupture of atheromatous abscess”

Wartman 1938 “rupture-induced occlusion”

Horn 1940 “plaque fissure”

Helpern 1957 “plaque erosion”

Crawford 1961 “plaque thrombosis”

Gore 1963 “plaque ulceration”

Friedman 1964 “macrophage accumulation”

Byers 1964 “thrombogenic gruel”

Chapman 1966 “plaque rupture”

Plaque Fissure in Human Coronary Thrombosis (Abstract) Fed. Proc. 1964, 23, 443 Paris Constantinidis

“The destruction of the hyalinized wall separating lumen from the atheroma was almost always observed to be preceded by or associated with its invasion by lipid containing macrophages.”

Friedman and van den Bovenkamp 1965

Unheralded Pioneers

N Engl J Med 1999

“Atherosclerosis; an inflammatory disease”

Ross R.

Russell Ross

Atherosclerosis; arterial “Response to Injury”

N Engl J Med 1976 Aug 12;295(7):369-77 The pathogenesis of atherosclerosis (first of two parts).Ross R, Glomset JA.

James T. Willerson 1981N Engl J Med 1981 Mar 19;304(12):685-91

Plaque Thrombosis

Erling Falk Michael Davies

Autopsy Series

Thin Fibrous Cap + Large Lipid Core + Dense Macrophage

A culprit ruptured plaque

1981-1990

Seymour GlagovCompensatory enlargement of human atherosclerotic coronary arteries N Engl J Med 1987 May

28;316(22):1371-5

<50% stenosis

Luminal area is not endangered until more than 40% of IEL is destructed and occupied by plaque

Coronary artery disease is a disease of arterial wall disease not lumen.

Angiographic progression of coronary artery disease and the development of myocardial infarction.Ambrose JA, Tannenbaum MA, Alexopoulos D, Hjemdahl-Monsen CE, Leavy J, Weiss M, Borrico S, Gorlin R, Fuster V.

Department of Medicine, New York Cardiac Center, Mount Sinai Medical Center, New York 10029.

Simultaneously, Little et al, Haft et al reported that majority of culprit lesions are found on previously non-critical stenosis plaques.

Conclusion: “Myocardial infarction frequently develops from non-severe lesions.”

J Am Coll Cardiol 1988 Jul;12(1):56-62

Ambrose, Fuster, and colleagues

Angiographically Invisible Plaques

Falk E., Shak P.K., Fuster V. Circulation 1995

Non-stenotic (<75%) plaques cause about 80% of deadly MI

Macrophage- driven MMPs soften plaque cap and prompt it to rupture

P.K. Shah

Peter LibbyAtherosclerosis and its thrombotic complication is governed by immune

cells.

Goran Hansson…

Allard van der Wal

Muller JE, Abela GS, Nesto RW, Tofler GH.

Triggers, acute risk factors and vulnerable plaques: the lexicon of a new frontier.

J Am Coll Cardiol. 1994 Mar 1;23(3):809-13

James E. Muller 1994

Muller coined the term of “Vulnerable” Plaque

Muller likened Vulnerable Plaques to American nuclear missiles stored underground in Nevada desert where they could be vulnerable to Russians’ long-range missile attack!

•Eroded Plaque

Rupture-prone plaques are not the only type of vulnerable plaque

•Calcium Nodulevan der Wal - Netherlands

Renu Virmani -USA

Thiene - Italy

Kolodgie F., Burk A.P., Farb A., and Virmani R.

“Who is Who” on

www.VP.org

The field of vulnerable plaque is best owed to many known and unknown

scientists who have worked hard to shed light on our way to prevent and

eradicate heart attacks in the future. To see a more complete list please visit:

Natural History ofVulnerable Plaques

Illustrated:

~65%

Percent of stenosis

Frequency of plaques

“Risk” per each plaque

Culprit Risk per each type of Vulnerable Plaque

(Log)

Culprit lesions found in autopsy series of acute MI

Different Types of Plaque Vulnerable to Thrombosis

All

Male

Female

~10% <5% ~20%

50%

Angiography

~70% <5% ~20%

~55% ~20%

<5%

<5% ~20%

Rupture Prone Eroded Calcified NoduleHemorrhage

Positive Remodeling

Fissured /Healed

Natural History of Vulnerable Atherosclerotic Plaques

Ruptured Plaques (~70%)1. Stenotic (~20%)2. Non-stenotic (~50%)

Non-ruptured Plaques (~ 30%)1.Erosion (~20%)2.Calcified Nodule (~5%)3.Others / Unknown (~5%)

Plaque Pathology Responsible for Coronary Thrombotic Death

In summary:

Culprit Plaque; a retrospective terminology 

Vulnerable Plaque; a prospective terminology

Vulnerable Plaque = Future Culprit Plaque

Clarification of Terminologies

Rupture-Prone Plaque

Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001

Macrophage

Necrotic Lipid Core

Thin Fibrous Cap

Eroded Plaque

Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001

Fissured / Healed Plaque

Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001

Plaque with a Subluminal Calcified Nodule

Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001

Intra-Plaque Hemorrhage with Intact Cap

Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001

Critically Stenotic but Asymptomatic Plaque

Naghavi et al, Cur Ath Rep 2001Vulnerable Plaque