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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 Arteries Normal 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 Rate Contractility Wall 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
10 8 MVO2 cc/min /100g

4 2 100 150 Heart Rate (BPM) 200



MVO2 (cc/min /100g)

Peak Developed Tension (g/cm2)

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 pressure Preload - 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
( Flow = Pressure / Resistance)


O2 Carrying Capacity
Oxygen saturation of the blood Hemoglobin content of the blood

Coronary perfusion pressure Coronary vascular resistance

Coronary Blood Flow

Proportional 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



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
Involves 3 different cells

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)

Autoregulation of Coronary Blood Flow



Acts as vasoconstrictor As O2 levels drop during ischemia: precapillary vasodilation and increased myocardial blood supply

Potent vasodilator Prime mediator of coronary vascular tone Binds to receptors on vascular smooth muscle, decreasing calcium entry into cell

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
200 Flow cc/100g /min 100






Coronary Perfusion Pressure (mmHg)


Other endothelialderived factors contribute to autoregulation

Dilators include:
EDRF (NO) Prostacyclin

Constrictors include:

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

5 4
Coronary 3 Blood Flow

Maximum Flow


Resting Flow





Epicardial % Diameter Stenosis

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

Prevalence of CAD in Modern Society

70 60 50



% Donors

40 30 20 10 0

<25 25-40 >40


Clevelend Clinic Cardiac Transplant Donor IVUS Data-Base

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 Plaque Evolution 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 = Levines 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 - Diagnosis Exercise Treadmill Test

Stable Angina - Diagnosis Thallium 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 - Treatment Mechanical Dilation: Angioplasty, Stent, etc.

Treatment of Stable Angina STENTS

Stable Angina - Treatment Coronary Artery Bypass Grafting Surgery (CABG)

Schematic of an Unstable Plaque

Unstable Plaque:
More Detail.

Cross section of a complicated plaque

Journey down a coronary

Angiogram in unstable angina: eccentric, ulcerated plaque

Angiogram in unstable angina: after stent deployment

Acute Coronary Syndrome Terminology

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

Coronary Stenosis Severity Prior to Myocardial Infarction

% Stenosis


14% 18%

>70 50-70 <50

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

Acute Coronary Syndrome Unstable 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, Betablockers, 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 )

Placebo (% ) Rx ( % )




(vs Heparin)



(+ Heparin)



(high dose)



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 )

UH / Placebo (%)

Rx (%)










TIMI 11b 0.2



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 reperfusion EKG ST depression Some enzymatic release troponin i most sensitive

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


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 Diastolic Dysfunction Systolic Dysfunction

chest pain

pulmonary congestion pO2

LV diastolic pressure

cardiac output

wall tension

catecholamines (heart rate, BP) MVO2

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)

30 Day Mortality
10 8 6 4 2 0 SK + SQ H e p a r in S K + IV H epera n A c c e l. t-P A t-P A + S K 7 .2 7 .4 6 .3 7 .0

t-PA vs. t-PA + SK t-PA vs. SK (IV) t-PA vs. SK (SQ) t-PA vs. Combo SK

0.04 0.003 0.009 0.001






% of Patients
100 80 60 40 20 0 SK + SQ H epa rin

90 min Patency

81 % * 73 % 56 % 61 %

p < 0.001
SK + IV H epa rin

p < 0.001
t-P A + SK

A ccel. t-P A






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

TIMI Flow Grade Versus Mortality (GUSTO)

% of Patients Mortality p=0.01 9.7 9.9

9 6


3 4.3 0 TIMI 0 TIMI 1 TIMI 2 TIMI 3





Coronary Steal Role of Collaterals



Assumptions Collateral resistance P1 drops with vasodil P2 bed with no vaso dilator reserve







Changing Paradigm The Concept of Physiologic Remodeling