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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

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ischemic heart disease and myocardial infarction

Ischemic Heart Disease and Myocardial Infarction

Pathophysiology of Myocardial Ischemia

Bio-Med 350

September 2005

physiology and pathophysiology of coronary blood flow ischemia
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)
basic principles
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 principles5
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 supply7
Myocardial Ischemia:Occurs when myocardial oxygen demand exceeds myocardial oxygen supply

MVO2 = Myocardial Oxygen Demand

MVO2 determined by:

Heart Rate

Contractility

Wall Tension

mvo 2 myocardial oxygen demand
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
Heart Rate

10

8

MVO2

cc/min

/100g

6

4

2

100 150 200

Heart Rate (BPM)

contractility
Contractility

10

Norepinephrine

Control

MVO2

(cc/min

/100g)

5

0

Peak Developed Tension (g/cm2)

wall tension
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 oxygen supply
Myocardial Oxygen Supply

Determined by:

Coronary Blood Flow & O2 Carrying Capacity

( Flow = Pressure / Resistance)

  • 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)

Coronary Blood FlowProportional to perfusion pressure / resistance
endocardium and cfr
Endocardium and CFR

Diastole

Systole

endocardium vs epicardium
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
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 resistance18
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

Autoregulation of Coronary Blood Flow
adenosine
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 resistance21
Autoregulatory Resistance

200

Adenosine

Flow

cc/100g

/min

Control

100

0

60

80

100

115

130

Coronary Perfusion Pressure (mmHg)

autoregulators
Autoregulators
  • Other endothelial- derived factors contribute to autoregulation
    • Dilators include:
      • EDRF (NO)
      • Prostacyclin
    • Constrictors include:
      • Endothelin-1
coronary flow reserve
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 reserve24
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 reserve25
Coronary Flow Reserve

5

Maximum Flow

4

Coronary

Blood

Flow

3

2

Resting Flow

1

0

25

50

75

100

Epicardial % Diameter Stenosis

prevalence of cad in modern society
Prevalence of CAD in Modern Society

70

60

Age(years)

50

70%

<25

40

% Donors

25-40

50%

30

>40

20

25%

10

0

Clevelend Clinic Cardiac Transplant

Donor IVUS Data-Base

risk factors
Risk Factors
  • family History
  • cigarette smoking
  • diabetes mellitus
  • hypertension
  • hyperlipidemia
  • sedentary life-style
  • obesity
  • elevated homocysteine, LP-a ?
atherosclerotic plaque evolution from fatty streak
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
Plaque progression….
  • Fibrous cap develops when smooth muscle cells migrate to intima, producing a tough fibrous matrix which glues cells together
stable angina symptoms
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
slide37

Symptoms and Signs:

Coronary Ischemia

stable angina treatment
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)?
slide45

Unstable Plaque:

More Detail…….

acute coronary syndromes terminology
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
slide51

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 sub-total (UA, NTMI) or total coronary artery occlusion (AMI)
slide55

Coronary Stenosis Severity Prior to

Myocardial Infarction

% Stenosis

14%

68%

>70

18%

50-70

<50

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

acute coronary syndrome unstable angina myocardial infarction symptoms
Acute Coronary SyndromeUnstable Angina / Myocardial InfarctionSymptoms
  • 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
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
slide58

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
slide59

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
slide60

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

7.1 5.8

11.9 8.7

11.7 12.0

PURSUIT

PRISM

(vs Heparin)

PRISM PLUS

(+ Heparin)

PARAGON

(high dose)

0.2

4

1

Rx better

Placebo better

slide61

Low Molecular Weight Heparin in Acute Coronary Syndromes

UH / Placebo Rx

(%) (%)

Odds Ratios and 95% CI for Composite Endpoint

( Death, MI, Re-angina or Revasc at 6-14 days )

10.3 5.4

7.6 9.3

19.8 16.6

16.6 14.2

FRISC

FRIC

ESSENCE

TIMI 11b

0.2

4

1

LMWH Better

UH Better

acute myocardial infarction
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 infarction63
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
acute myocardial infarction65
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

Acute Myocardial Infarction
slide66

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

slide68

Diagnosis of MI:Role of troponin i

  • Troponin I is highly sensitive
  • Troponin I may be elevated after prolonged subendocardial ischemia
  • See examples below
slide69

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)
slide70

EKG diagnosis of MI

  • ST segment elevation
  • ST segment depression
  • T wave inversion
  • Q wave formation
consequences of ischemia ischemia begets ischemia
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
Ischemic Cycle

Ischemia / infarction

Diastolic Dysfunction

Systolic Dysfunction

chest pain

LV diastolic pressure

cardiac output

pulmonary

congestion

pO2

wall tension

catecholamines

(heart rate, BP)

MVO2

treatment of acute myocardial infarction
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