Ischemic Heart Disease and Myocardial Infarction

Pathophysiology of Myocardial Ischemia

Bio-Med 350

September 2004

Physiology and Pathophysiology of Coronary Blood Flow / Ischemia

Basic Physiology / Determinants of MVO2

Autoregulatory Mechanisms / Coronary Flow Reserve Pathophysiology of Coronary Ischemia and Atherosclerosis Clinical Syndromes

Stable Angina Acute Coronary Syndromes

– Unstable Angina– Acute MI (UA, AMI)

Coronary ArteriesNormal Anatomy

Basic Principles

myocardial cells have to do only 2 things: contract and relax; both are aerobic, O2 requiring processes

oxygen extraction in the coronary bed is maximal in the baseline state; therefore to increase O2 delivery, flow must increase

large visible epicardial arteries are conduit vessels not responsible for resistance to flow (when normal)

Basic Principles

small, distal arterioles make up the major resistance to flow in the normal state

atherosclerosis (an abnormal state) affects the proximal, large epicardial arteries

once arteries are stenotic (narrowed) resistance to flow increases unless distal, small arterioles are able to dilate to compensate

Myocardial Ischemia:Occurs when myocardial oxygen demand exceeds

myocardial oxygen supply

Myocardial Ischemia:Occurs when myocardial oxygen demand exceeds

myocardial oxygen supply

MVO2 = Myocardial Oxygen Demand

MVO2 determined by:

Heart RateContractilityWall Tension

MVO2 (Myocardial Oxygen Demand)

Increases directly in proportion to heart rate

Increases with increased contractility Increases with increased Wall Tension:

i.e. increases with increasing preload or afterload

Heart Rate

100 150 200

cc/min/100g

MVO2

2

10

6

8

4

Heart Rate (BPM)

Contractility

Peak Developed Tension (g/cm2)

MVO2(cc/min/100g)

10

0

5

Norepinephrine

Control

Wall Tension

Is related to Pressure x Radius

Wall Thickness

Defined as: Force per unit area generated in the LV throughout the cardiac cycle

Afterload - LV systolic pressurePreload - LV end-diastolic pressure or volume

Myocardial Ischemia:Occurs when myocardial oxygen demand exceeds

myocardial oxygen supply

Myocardial Oxygen Supply

Determined by:

Coronary Blood Flow & O2 Carrying Capacity

Oxygen saturation of the blood

Hemoglobin content of the blood

( Flow = Pressure / Resistance)

Coronary perfusion pressure

Coronary vascular resistance

Coronary Blood FlowProportional to perfusion pressure / resistance

Coronary Perfusion pressure

=

Diastolic blood pressure, minus LVEDP

Coronary Vascular resistance

external compression intrinsic regulation

Local metabolites Endothelial factors Neural factors (esp.

sympathetic nervous system)

Endocardium and CFR

Diastole

Systole

Endocardium vs Epicardium

Greater shortening / thickening, higher wall tension: increased MVO2

Greater compressive resistance ? Decreased Perfusion Pressure Less collateral circulation Net Result is more compensatory

arteriolar vasodilatation at baseline and therefore decreased CFR

Autoregulatory Resistance

Major component of resistance to flow Locus at arteriolar level Adjusts flow to MVO2

Metabolic control Oxygen Adenosine , ADP NO (nitric oxide) Lactate , H+

Histamine, Bradykinin

Autoregulatory Resistance

Myocardial muscle cell - produces byproducts of aerobic metabolism (lactate,adenosine, etc)

Vascular endothelial cell (arteriole) - reacts to metabolic byproducts

Vascular smooth muscle cell (arteriole) - signaled by endothelial cell to contract (vessel constriction) or relax (vessel dilation)

Involves 3 different cells

Autoregulation of Coronary Blood Flow

Oxygen Acts as

vasoconstrictor As O2 levels drop

during ischemia: pre-capillary vasodilation and increased myocardial blood supply

Adenosine Potent vasodilator Prime mediator of

coronary vascular tone

Binds to receptors on vascular smooth muscle, decreasing calcium entry into cell

Adenosine

During hypoxemia, aerobic metabolism in mitochondria is inhibited

Accumulation of ADP and AMP Production of adenosine Adenosine vasodilates arterioles Increased coronary blood flow

Autoregulatory Resistance

Coronary Perfusion Pressure (mmHg)

Flowcc/100g/min

60 130100 11580

Control

Adenosine

0

200

100

Autoregulators

Other endothelial- derived factors contribute to autoregulation Dilators include:

EDRF (NO)Prostacyclin

Constrictors include:Endothelin-1

Coronary Flow Reserve

Arteriolar autoregulatory vasodilatory capacity in response to increased MVO2 or pharmacologic agents

Expressed as a ratio of Maximum flow / Baseline flow

~ 4-5 / 1 (experimentally) ~ 2.25 - 2.5 (when measured clinically)

Coronary Flow Reserve

Stenosis in large epicardial (capacitance) vessel decreased perfusion pressure arterioles downstream dilate to maintain normal resting flow

As stenosis progresses, arteriolar dilation becomes chronic, decreasing potential to augment flow and thus decreasing CFR

Endocardial CFR < Epicardial CFR As CFR approaches 1.0 (vasodilatory capacity

“maxxed out”), any further decrease in PP or increase in MVO2 ischemia

Coronary Flow Reserve

1

5

3

4

2

Epicardial % Diameter Stenosis

1000 50 7525

Maximum Flow

Resting Flow

CoronaryBloodFlow

Endocardium and Collaterals

Epicardium

Endocardium

Coronary Steal

Vasodilator Rx (Ado) R2 decreases Flow increases to A R3 - no reserve Increased flow across

R1 GRT P1-2 No change in P1 P2 Flow to B is dependant

on P2 and

A

B

Sub-epicardium

Sub-endocardium

0

10

20

30

40

50

60

70

<25

25-40

>40

Age(years)

25%

50%

70%

% Donors

Clevelend Clinic Cardiac TransplantDonor IVUS Data-Base

Prevalence of CAD in Modern Society

Risk Factors

family History cigarette smoking diabetes mellitus hypertension hyperlipidemia sedentary life-style obesity elevated homocysteine, LP-a ?

Coronary lesions in Men and Women,Westernized and non-Westernized diets

Relationship between fat in diet and serum cholesterol

Atherosclerotic PlaqueEvolution from Fatty Streak

Fatty streaks present in young adults

Soft atherosclerotic plaques most vulnerable to fissuring/hemorrhage

Complex interaction of substrate with circulating cells (platelets, macrophages) and neurohumoral factors

Plaque progression….

Fibrous cap develops when smooth muscle cells migrate to intima, producing a tough fibrous matrix which glues cells together

Intra-vascular Ultrasound (IVUS)

Atherosclerotic Plaque

Physiologic Remodeling

Coronary atherosclerosis

Stable Angina - Symptoms

mid-substernal chest pain squeezing, pressure-like in quality (closed fist =

Levine’s sign) builds to a peak and lasts 2-20 minutes radiation to left arm, neck, jaw or back associated with shortness of breath, sweating, or

nausea exacerbated by exertion, cold, meals or stress relieved by rest, NTG

Symptoms and Signs:Coronary Ischemia

Stable Angina - DiagnosisExercise Treadmill Test

Stable Angina - DiagnosisThallium Stress Test

Stable Angina - Treatment

Risk factor modification (HMG Co-A Reductase inhibitors = Statins)

Aspirin Decrease MVO2

nitrates beta-blockers calcium channel blockers ACE-inhibitors

Anti-oxidants (E, C, Folate, B6)?

Stable Angina - TreatmentMechanical Dilation:

Angioplasty, Stent, etc.

Treatment of Stable Angina -STENTS

Stable Angina - TreatmentCoronary Artery Bypass Grafting Surgery

(CABG)

Schematic of an Unstable PlaqueSchematic of an Unstable Plaque

Unstable Plaque:

More Detail…….

Cross section of acomplicated plaque

Journey down a coronary…

Angiogram in unstable angina:eccentric, ulcerated plaque

Angiogram in unstable angina: after stent deployment

Acute Coronary SyndromeTerminology

Pathophysiology of all 3 is the same Unstable Angina (UA)

ST depression, T Wave inversion or normal No enzyme release

Non-Transmural Myocardial Infarction (NTMI or SEMI) ST depression, T Wave inversion or normal No Q waves CPK, LDH + Troponin release

Transmural Myocardial Infarction (AMI) ST elevation + Q waves CPK, LDH + Troponin release

Pathophysiology of the Acute Coronary Syndrome (UA,MI)

Plaque vulnerability and extrinsic triggers result in plaque rupture

Platelet adherence, aggregation and activation of the coagulation cascade with polymerization of fibrin

Thrombosis with sub-total (UA, NTMI) or total coronary artery occlusion (AMI)

Pathophysiology of Acute Coronary Syndromes

Pathophysiology of Acute Coronary Syndromes

“Vulnerable Plaque”

>70

50-70

<50

% Stenosis68%

18%

14%

Coronary Stenosis Severity Prior to Myocardial Infarction

Falk et al, Circulation 1995; 92: 657-71

Acute Coronary SyndromeUnstable Angina / Myocardial Infarction

Symptoms

new onset angina increase in frequency, duration or

severity decrease in exertion required to provoke any prolonged episode (>10-15min) failure to abate with >2-3 S.L. NTG onset at rest or awakening from sleep

Unstable Angina - High Risk Features

prolonged rest pain dynamic EKG changes (ST depression) age > 65 diabetes mellitus left ventricular systolic dysfunction angina associated with congestive heart

failure, new murmur, arrhythmias or hypotension

elevated Troponin i or t

Unstable Angina / NTMI Pharmacologic Therapy

ASA and Heparin beneficial for acute coronary syndromes ( UA, NTMI, AMI)

Decrease MVO2 with Nitrates, Beta-blockers, Ca channel blockers, and Ace inhibitors

consider platelet glycoprotein 2b / 3a inhibitor and / or low molecular weight heparin

Anti-Platelet Therapy

Three principle pathways of platelet activation with >100 agonists: ( TXA2, ADP, Thrombin )

Final common pathway for platelet activation / aggregation involves membrane GP II b / III A receptor

Fibrinogen molecules cross-bridge receptor on adjacent platelets to form a scaffold for the hemostatic plug

Platelet GP IIB/ IIIA Inhibitors with Acute Coronary Syndromes

Odds Ratios and 95% CI for Composite Endpoint

( Death,Re- MI at 30days )

0.2 1 4

PURSUIT

PRISM (vs Heparin)

PRISM PLUS (+ Heparin)

PARAGON (high dose)

15.7 14.2

7.1 5.8

11.9 8.7

11.7 12.0

Placebo (% ) Rx ( % )

Rx better Placebo better

Low Molecular Weight Heparin in Acute Coronary Syndromes

Odds Ratios and 95% CI for Composite Endpoint( Death, MI, Re-angina or Revasc at 6-14 days )

0.2 1 4

FRISC

FRIC

ESSENCE

TIMI 11b

10.3 5.4

7.6 9.3

19.8 16.6

16.6 14.2

UH / Placebo Rx (%) (%)

LMWH Better UH Better

Acute Myocardial Infarction

total thrombotic occlusion of epicardial coronary artery onset of ischemic cascade

prolonged ischemia altered myocardial cell structure and eventual cell death (release of enzymes - CPK, LDH, Troponin)

altered structure altered function (relaxation and contraction)

consequences of altered function often include exacerbation of ischemia (ischemia begets ischemia)

Acute Myocardial Infarction

wavefront phenomenon of ischemic evolution - endocardium to epicardium

If limited area of infarction homeostasis achieved If large area of infarction (>20% LV ) Congestive heart

failure If larger area of infarction (>40% LV) hemodynamic collapse

AMI - Wavefront Phenomenon

Acute Myocardial Infarction

Non-transmural / sub-endocardial Non-occlusive

thrombus or spontaneous re-perfusion

EKG – ST depression Some enzymatic

release – troponin i most sensitive

Transmural total, prolonged

occlusion EKG - ST elevation Rx - Thrombolytic

Therapy or Cath Lab / PTCA

Cardiac enzymes: overview

Legend: A. Early CPK-MB isoforms after acute MI B. Cardiac troponin after acute MI C. CPK-MB after acute MI D. Cardiac troponin after unstable angina

Markers of MI: Troponin I

Diagnosis of MI:Role of troponin i

Troponin I is highly sensitive

Troponin I may be elevated after prolonged subendocardial ischemia

See examples below

Causes of Troponin elevation

Any cause of prolonged (>15 – 20 minutes) subendocardial ischemia Prolonged angina pectoris Prolonged tachycardia in setting of CAD Congestive heart failure (elevated LVEDP

causing decreased subendocardial perfusion)

Hypoxia, coupled with CAD “aborted” MI (lytic therapy or spontaneous

clot lysis)

EKG diagnosis of MI

ST segment elevation

ST segment depression

T wave inversion Q wave formation

Consequences of Ischemia(Ischemia begets Ischemia)

chest pain systolic dysfunction (loss of contraction)

decrease cardiac output decrease coronary perfusion pressure

diastolic dysfunction (loss of relaxation) higher pressure (PCWP) for any given volume dyspnea, decrease pO2, decrease O2 delivery increased wall tension (increased MVO2)

All 3 give rise to stimulation of sympathetic nervous system with subsequent catecholamine release- increased heart rate and blood pressure (increased MVO2)

Ischemic Cycle

Ischemia / infarction

chest pain

Diastolic Dysfunction Systolic Dysfunction

cardiac output

catecholamines

MVO2

wall tension

LV diastolic pressurepulmonarycongestionpO2

(heart rate, BP)

Treatment of Acute Myocardial Infarction

aspirin, heparin, analgesia, oxygen reperfusion therapy

thrombolytic therapy (t-PA, SK, n-PA, r- PA) new combinations ( t-PA, r-PA + 2b / 3a inhib) cath lab (PTCA, stent)

decrease MVO2 nitrates, beta blockers and ACE inhibitors for high PCWP - diuretics for low Cardiac Output - pressors (dopamine, levophed,

dobutamine; IABP; early catheterization

TIMI Flow Grades

TIMI 0 Flow = no penetration of contrast beyond stenosis (100% stenosis, occlusion)

TIMI 1 Flow = penetration of contrast beyond stenosis but no perfusion of distal vessel

(99% stenosis, sub-total occlusion)

TIMI 2 Flow = contrast reaches the entire distal vessel but either at a decreased rate of filling or clearing versus the other coronary arteries (partial perfusion)

TIMI 3 Flow = contrast reaches the distal bed and clears at an

equivalent rate versus the other coronary arteries (complete perfusion)

GUSTO

7.2 7.46.3

7.0

0

2

4

6

8

10

SK + SQHeparin

SK + IVHeperan

Accel. t-PA t-PA + SK

N: 9,796 10,376 10,344 10,327

p-values t-PA vs. t-PA + SK 0.04t-PA vs. SK (IV) 0.003t-PA vs. SK (SQ) 0.009t-PA vs. Combo SK 0.001

30 Day Mortality

GUSTO

0

20

40

60

80

100

SK+ SQHeparin

SK + IVHeparin

Accel. t-PA t-PA + SK

TIMI 3 TIMI 2

p < 0.001 p < 0.001

56 % 61 %

81 % *73 %

% of Patients

N: 295 282 291 297

p = < 0.001 for Accelerated t-PA vs. all other arms

90 min Patency

TIMI Flow Grade Versus Mortality (GUSTO)

0

12

6

3

9% ofPatients

TIMI 0 TIMI 1 TIMI 2 TIMI 3

N 259 81 342 447

Mortality

4.3

7.9

9.99.7

p=0.01

p=0.05

Coronary Steal Role of Collaterals

P1 P1P2 P2

Rest AdenosineAssumptionsCollateral resistanceP1 drops with vasodilP2 bed with no vaso dilator reserve

Flow Flow

collateral collateral

Changing Paradigm – The Concept of Physiologic Remodeling