Coronary Atherosclerosis:Past, Present and Future

Harisios Boudoulas, MD, Dr, Dr Hon.Professor of Medicine/Cardiovascular Medicine and Pharmacy (emeritus)

The Ohio State University, Columbus, Ohio USAHonorary Professor, Academician (an. mem.)

Coronary Atherosclerosisin Time Past

Coronary Atherosclerosisin Time Past

Coronary Atherosclerosis in Antiquity

• Coronary artery atheroma and calcification inEgyptian mummies 1580 BC – 525 BC

• Hippocrates 460 BC – 377 BC

• Coronary artery atheroma and calcification inEgyptian mummies 1580 BC – 525 BC

• Hippocrates 460 BC – 377 BC

“And I will tell my soul, Soul, you have many goods laid up formany years. Take your ease, eat, drink, and be merry. But Godsaid to him, Fool! This night your soul will be required of you”

- Luke 12:19-20

Life Expectancy from 1850 to 2000(Incidence of coronary atherosclerosis was

low when life expectancy was short)

Influenza epidemic

Coronary Atherosclerosis in the 1950s – 1960s

• In the late fifties to mid sixties, coronaryarteriography, echocardiography, IVUS, nuclearcardiology, thrombolysis, angioplasty, stents,biomarkers of inflammation or myocardialnecrosis indices of left ventricular function werenot available for clinical use at that time.

• Electrocardiogram and chest x-ray were the hightechnology at that time.

• Only nitroglycerin, morphine and bed rest wereused for the management of coronaryatherosclerosis at the time.

• In the late fifties to mid sixties, coronaryarteriography, echocardiography, IVUS, nuclearcardiology, thrombolysis, angioplasty, stents,biomarkers of inflammation or myocardialnecrosis indices of left ventricular function werenot available for clinical use at that time.

• Electrocardiogram and chest x-ray were the hightechnology at that time.

• Only nitroglycerin, morphine and bed rest wereused for the management of coronaryatherosclerosis at the time.

Management of AMI• Morphine

• Heparin

• Warfarin

Selective Injection in the Right Coronary Arteryin October 30, 1958 by F. Mason Sones

Cine coronary arteriography. Modern ConceptsCardiovascular Dis 1962; 31: 735

Chest Pain with Angiographically NormalCoronary Arteries: A New Syndrome

Myocardial lactate production in patientswith angina-like chest pain andangiographically normal coronary arteriesand left ventricle.

Boudoulas H, et al. Clin Res 1973Am J Cardiol 1974; 30: 501

Myocardial lactate production in patientswith angina-like chest pain andangiographically normal coronary arteriesand left ventricle.

Boudoulas H, et al. Clin Res 1973Am J Cardiol 1974; 30: 501

Coronary Atherosclerosis inTime Present

Genetic and environmental risk factors

SedentaryLife

SmokingInflammatory

Process

StressDiabetes

Hyper-tension Inhibitory

Genes

PromotorGenes

SedentaryLife Stress

FattyDiet

Other

RenalDisease

PromotorGenes

Other

Coronary Atherosclerosis

Genetics in Coronary Atherosclerosis

• More than 55 genetic risk variants• Chromosome 9p21 locus• LDL receptor (discovery of statins)• PCSK9 mutation (monoclonal, antibodies

evolucubam, other)• Variation in ANGPTL4 (lipoprotein lipase

pathway)• Blood groups A and B are risk variants for

AMI compared to group 0 (higher vWF complex)

• More than 55 genetic risk variants• Chromosome 9p21 locus• LDL receptor (discovery of statins)• PCSK9 mutation (monoclonal, antibodies

evolucubam, other)• Variation in ANGPTL4 (lipoprotein lipase

pathway)• Blood groups A and B are risk variants for

AMI compared to group 0 (higher vWF complex)

Coronary Atherosclerosis: Development andProgression

• Remodeling• Progression• Inflammation, neo-vessel (v-v)• Unstable plaque-rupture - thrombosis• Stabilization-regression

Coronary Atherosclerosis: Progression and Clinical Manifestations

LipidPool

Plaque Rupture and Thrombosis

Thrombosis/Progression/

AnginaAsymptomaticStable Disease

(± Angina)

Myopathy,CHF/MR

AMI

Normal

Years

Plaquerupture

Chest Pain(Atypical)

ThrombosisOcclusion

Death/SCD

AsymptomaticStable Disease

(± Angina)AMI

Angina(Unstable)

Prognosis is Related to Overall Disease andNot to a Specific Lesion

Coronary atherosclerosis is a systemicproblem that requires systemic treatment.

Coronary Atherosclerosis: Progression and Clinical Manifestations

LipidPool

Plaque Rupture and Thrombosis

Thrombosis/Progression/

AnginaAsymptomaticStable Disease

(± Angina)

Myopathy,CHF/MR

AMI

Normal

Years

Plaquerupture

Chest Pain(Atypical)

ThrombosisOcclusion

Death/SCD

AsymptomaticStable Disease

(± Angina)AMI

Angina(Unstable)

Coronary Atherosclerosis: Therapy for the Plaque

To Prevent

Progression

Rupture

Thrombosis

Infarction

Death

D/CSmoking ↓ LDL-C Anti-

plateletβ-

Blocker ACEI

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

To Prevent

Progression

Rupture

Thrombosis

Infarction

Death

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+• Moderate exercise; Mediterranean diet• Ezetamibe• New drugs, Evolocumab• The role of vitamin D• Other

Coronary Atherosclerosis: Clinical Significance ofLeft Ventricular (LV) Function

• LV systolic function is a stronger prognostic indicatorcompared to number of diseased vessels.

• Coronary bypass surgery and/or β-blockade therapyincreased survival only in patients with abnormal leftventricular systolic function. Boudoulas, O’Neil,Weissler, et al. Circulation 1981, Am J Cardiol 1981,Circulation 1982.

• CASS (Coronary Artery Surgery Study).Circulation 1983

• LV systolic function is a stronger prognostic indicatorcompared to number of diseased vessels.

• Coronary bypass surgery and/or β-blockade therapyincreased survival only in patients with abnormal leftventricular systolic function. Boudoulas, O’Neil,Weissler, et al. Circulation 1981, Am J Cardiol 1981,Circulation 1982.

• CASS (Coronary Artery Surgery Study).Circulation 1983

Coronary Atherosclerosis: Therapy to Preserve /Improve LV Function

Goal

Stabilize PlaquePrevent Rupture,Thrombosis, MI

↓ Infract size

ImproveFunction

Therapyfor plaque

β-Blocker ACEI

Revascul-arization Cell

+ +

+

+

+

+

+

?

+

+

Thrombo-lysis

Goal

Stabilize PlaquePrevent Rupture,Thrombosis, MI

↓ Infract size

ImproveFunction

+

+

+

+

+

+

?

+

+

+

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+

• Triggers of MI• Preconditioning, Postconditioning?

Cell Based Therapy / Biomaterial• Intracoronary

injection

• Direct injection– Epicardial (Surgery)– Endocardial

(Percutaneous)

• Intracoronaryinjection

• Direct injection– Epicardial (Surgery)– Endocardial

(Percutaneous)

Coronary Atherosclerosis: Medical Therapy vs.Revascularization for the Individual Patient

PharmacologicAgents

Bypass

Stent

The Superior PhysicianHe is skeptical toward the data of his ownprofession, welcomes discoveries which upset hisprevious hypothesis, and still animated by humansympathy and understanding.

- Alfred North Whitehead, Dialogues (Lucien Press) 1954

Coronary Atherosclerosis:Medical Therapy vs. Revascularization

• Medical management improves symptoms, increases survival and inmost instances is not inferior to revascularization.

• As medical therapy is getting better, revascularization looks betteras well (“free ride”) since all patients with coronary atherosclerosisare on optimal medical management.

• Medical therapy for most patients with chronic stable angina shouldbe the initial approach.

• Revascularization: persistent symptoms - large area of myocardiumat risk

• The greater the severity of ischemia, extent of disease and LVdysfunction the greater the benefit on survival from revascularizationover medical therapy.

• Medical management improves symptoms, increases survival and inmost instances is not inferior to revascularization.

• As medical therapy is getting better, revascularization looks betteras well (“free ride”) since all patients with coronary atherosclerosisare on optimal medical management.

• Medical therapy for most patients with chronic stable angina shouldbe the initial approach.

• Revascularization: persistent symptoms - large area of myocardiumat risk

• The greater the severity of ischemia, extent of disease and LVdysfunction the greater the benefit on survival from revascularizationover medical therapy.

Coronary Atherosclerosis: PCI versus CABGAvailable Information Should be Applied to the Individual Patient

• Left main or equivalent

• 3 VD with EF < 50%or large area of ischemia

• 3 VD (prox. LAD), normal EFespecially in diabetics

• 2 VD (prox. LAD), EF < 50%or large area of ischemia

• Proximal LAD

Consider CABG Consider PCI

• Proximal LAD

• 1-2 VD (no prox. LAD), LVdysfunction or large area of ischemia

• 2-3 VD (prox. LAD),normal LV, no diabetes

• Symptom control

• Restenosis, large area of ischemia

Operating Room Catheterization Lab

Hybrid Cardiovascular Operating Room

Vanderbilt University, First Adult OR/Lab in USA

Coronary Atherosclerosis: Available Information Should be Applied to theIndividual Patient

PharmacologicAgents

BypassStent

Coronary Atherosclerosis in Time Future

Quo Vadis

Coronary Atherosclerosis in Time Future

Quo Vadis

Halfway Technology and Cost ofMedicine

–

–

MedicalCost

–

–No Therapy

MedicalCost

HalfwayTechnology

Prevention/Cure

Translational research

René Magritte. La Clairvoyance, 1936

Certain Infections Diseases

–

–

• Rheumatic fever

• Syphilis

• Tuberculosis

• Peptic ulcer

• Other

Frequency

Mortality from CardiovascularDisease

UnitedStates

USA

BritianUSA

Finland

Northwestern Europe,Australia, Canada, New

Zealand, USA–

–Time

• Rheumatic fever

• Syphilis

• Tuberculosis

• Peptic ulcer

• Other

Frequency

Japan

“Time present and time pastAre both perhaps present in time future,

And time future contained in time past.”- T. S. Eliot, Four Quartets

Genome Atlas• Coronary atherosclerosis• Other

Immunology - Inflammation

• Developing medicines that mimic thenatural successes of the human genome

• Pharmacogenetics/Pharmacogenomics• Other

Vaccines for prevention:• Atherosclerosis• Other

Epigenetics

Epigenetics link genetics and environment throughmodification of gene expression

GeneEnvironment A Disease

Environment B No Disease

Pathologic effects of tobacco(cigarette smoke/secondhand smoke)

Environment A Disease

Environment B No Disease

Coronary Atherosclerosis: Early treatment mayprevent the clinical manifestations of the disease

↓ LDL-C (Statin), Other

LDL-C< 45 mg/dl (Statin)

No therapy

Frequency ofclinical

manifestationsof coronary

atherosclerosis

Birth 20 40 60 80

Age (years)

LDL-C< 45 mg/dl (Statin)

Statin + PCSK9i

Vaccine, Other

0 –

Frequency ofclinical

manifestationsof coronary

atherosclerosis

Coronary Atherosclerosis in Time Past, Time Presentand Time Future

Dev

elop

men

ts PharmacologicAgents

Prevention/Cure

1950 2010Time

Dev

elop

men

ts

BypassStent

PharmacologicAgents

Microbiome and Chronic Disease

• Antibiotics and obesity• Diabetes• Coronary atherosclerosis• Other

Mild to Moderate Coronary ArteryStenosis is Responsible for Most of the

Myocardial Infarctions

• Little WC, et al. Circulation. 1988

• Abrose JA, et al. J Am Coll Cardiol. 1988

• Little WC, et al. Circulation. 1988

• Abrose JA, et al. J Am Coll Cardiol. 1988

Davies. Pathology

Optical Coherence Tomography

Tanaka, et al. Eur Heart J 2009; 30: 1348-1355

Thermographic catheter

Stefanadis, Ch.

0.35 –

0.3 –

0.25 –

0.2 –

0.15 –

0.1 –

0.05 –

0.0 –

∆TºC

Plaque Temperature in Acute Coronary Syndromes (ACS)and Stable Angina (SA)

0.35 –

0.3 –

0.25 –

0.2 –

0.15 –

0.1 –

0.05 –

0.0 –

ACS SA

∆TºC

Stefanadis et al. Atherosclerosis 2006.

Opening of the Coronary Artery Stenosis RelievesSymptoms

• Gruentzig AR, Angioplasty 1977

• Sigwart U, Stents 1987

• Stefanadis Ch, Covered stents 1996

• Serruys PW, Heparin coated stents 1998

• Gruentzig AR, Angioplasty 1977

• Sigwart U, Stents 1987

• Stefanadis Ch, Covered stents 1996

• Serruys PW, Heparin coated stents 1998

Antiplatelet Therapy

Atherosclerotic plaques as Defined by Coronary Arteriographyand Intravascular Ultrasound

ACCSAP 2009

Progression of Coronary Atherosclerosis

Ischemia (angina, acutecoronary syndromes)

Years

Ischemia (angina, acutecoronary syndromes)

• β-Blockers• Calcium blockers• Coronary bypass surgery

“Since we did not find any thrombi without fissuresor any fissures without thrombi we are forced toconclude that there was a causal associationbetween these two findings in the cases weexamined.”

Constantinides P. Am Soc Exp Pathol. Chicago, April 16, 1964Atheroscl Res 1966; 6: 1-7

Pathologists View of Thrombosis in AcuteMyocardial Infarction

“Since we did not find any thrombi without fissuresor any fissures without thrombi we are forced toconclude that there was a causal associationbetween these two findings in the cases weexamined.”

Constantinides P. Am Soc Exp Pathol. Chicago, April 16, 1964Atheroscl Res 1966; 6: 1-7

Coronary Thrombosis in AMIDetermined by Coronary Arteriography

Dewood, et al. N Engl J Med. 1980

• ACE inhibitors• β-Blockers• Thrombolysis• Biomarkers• Rehabilitation

• CCU• PCI• ICD

• ACE inhibitors• β-Blockers• Thrombolysis• Biomarkers• Rehabilitation

• CCU• PCI• ICD

Screening of Ruptured Plaque byIntravascular Ultrasound

Ge, Erbel, Boudoulas, et al. Heart 1999; 81: 621-627

Fibrous cap

The Shortcomings of Diagnosing CoronaryAtherosclerosis Based on Stress -Induced Ischemia

Stress ECG

Stress NuclearStress Echo

“We had the experiencebut missed the meaning.”

- T.S. Eliot

Multislice CT

Information Available Related to CoronaryAtherosclerosis in the Late Fifties - Early Sixties

• Angina pectorisHeberden W. Royal College of Physicians 1768

• Coronary artery occlusion produces myocardial infarctionHerrick JB. Association of American Physicians, Chicago 1912

JAMA 1912; 54: 2015

Nitroglycerin

• Angina pectorisHeberden W. Royal College of Physicians 1768

• Coronary artery occlusion produces myocardial infarctionHerrick JB. Association of American Physicians, Chicago 1912

JAMA 1912; 54: 2015

Nitroglycerin

Regression of Coronary Artery Disease as a Result ofIntensive Lipid-Lowering Therapy in Men with High levels

of Apolipoprotein B

Brown, G, et al. N Engl J Med 1990; 323: 1289-98.

The Role of Statins

PRESENTPAST

Therapy of Peptic Uncer: Past and PresentTherapy of Coronary Atherosclerosis: Present and Future

FUTURE(Prevention, Cure)

Imaging of the Entire Cardiovascular System / Molecular Imaging

MRI PET/MRI