Ischemic Heart Disease and Myocardial Infarction

Pathophysiology of Myocardial Ischemia Bio-Med 350 September 2005

Physiology and Pathophysiology of Coronary Blood Flow / Ischemia • • • • Basic Physiology / Determinants of MVO 2 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, O 2 requiring processes oxygen extraction in the coronary bed is maximal in the baseline state; therefore to increase O 2 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 MVO 2 = Myocardial Oxygen Demand MVO 2 determined by: Heart Rate Contractility Wall Tension

MVO 2 (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 6 4 2 100 150 200 Heart Rate (BPM)

Contractility

10 Norepinephrine Control MVO2 (cc/min /100g) 5 0 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) & O 2 Carrying Capacity  Coronary perfusion pressure  Coronary vascular resistance  Oxygen saturation of the blood  Hemoglobin content of the blood

•

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

Diastole Systole

Endocardium vs Epicardium

• • • • • Greater shortening / thickening, higher wall tension: increased MVO 2 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 MVO 2 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) metabolic byproducts reacts to Vascular smooth muscle cell (arteriole) signaled by endothelial cell to contract (vessel constriction) or relax (vessel dilation)

Autoregulation of Coronary Blood Flow

• Oxygen  Acts as vasoconstrictor  As O 2 supply levels drop during ischemia: pre capillary vasodilation and increased myocardial blood • 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

200 Flow cc/100g /min 100 Adenosine Control 0 60 80 100 115 130 Coronary Perfusion Pressure (mmHg)

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 MVO 2 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 MVO 2  ischemia

Coronary Flow Reserve

5 4 Maximum Flow

Coronary Blood Flow

3 2 Resting Flow 1 0 25 50 75 Epicardial % Diameter Stenosis 100

Prevalence of CAD in Modern Society

70 60 50

% Donors

40 30 20 10 0 25% 50% 70%

Age(years)

<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 = 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 - 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 Syndromes:

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

Pathophysiology of Acute Coronary Syndromes

Pathophysiology of Acute Coronary Syndromes

“Vulnerable Plaque”

Coronary Stenosis Severity Prior to Myocardial Infarction

68% 14% 18%

% Stenosis

>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, 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 ) Placebo (% ) Rx ( % ) 15.7 14.2

PURSUIT 7.1 5.8

PRISM (vs Heparin) PRISM PLUS (+ Heparin) PARAGON (high dose) 11.9 8.7

11.7 12.0

0.2

Rx better

1 4

Placebo better

Low Molecular Weight Heparin in Acute Coronary Syndromes FRISC Odds Ratios and 95% CI for Composite Endpoint ( Death, MI, Re-angina or Revasc at 6-14 days ) UH / Placebo Rx (%) (%) 10.3 5.4

7.6 9.3

FRIC 19.8 16.6

ESSENCE 16.6 14.2

TIMI 11b 0.2

LMWH Better

1

UH Better

4

Acute Myocardial Infarction

• • • • total thrombotic occlusion of epicardial coronary artery  onset of ischemic cascade prolonged ischemia  structure and eventual cell death (release of enzymes - CPK, LDH, Troponin) altered myocardial cell altered structure contraction)  altered function (relaxation and 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 )  failure If larger area of infarction (>40% LV)  collapse Congestive heart hemodynamic

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 Diastolic Dysfunction chest pain Systolic Dysfunction pulmonary congestion pO2 LV diastolic pressure wall tension cardiac output 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