Ischemic Heart Disease

Front 1

Coronary Arteries' Normal Anatomy:

Back 1

Very first arteries coming off the aorta are the coronaries. Impacts the timing of coronary blood flow. As soon as LV ejects, blood goes to coronary arteries while contraction is still happening.

Front 2

Basic Principles of ischemia/MI:
normal state oxygen extraction--
stenotic state oxygen extraction--

Back 2

*Myocardial cells have to do only 2 things: contract and relax; BOTH are aerobic, energy 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).

*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.

Front 3

When does Myocardial Ischemia occur?
Discuss from a supply/demand of oxygen perspective--

Back 3

Occurs when myocardial oxygen demand exceeds myocardial oxygen supply.

Front 4

What determines MVO2? 3

Back 4

*MVO2 = Myocardial Oxygen Demand.

*MVO2 determined by:
-Heart Rate
-Contractility
-Wall Tension

Front 5

What does MVO2 (Myocardial Oxygen Demand) increase with? 3

Back 5

*Increases directly in proportion to heart rate.
*Increases with increased contractility.
*Increases with increased Wall Tension; i.e. increases with increasing preload or afterload.

Front 6

Plot of MVO2 as a function of ∆ in HR:

Back 6

*Linear relationship.

Front 7

Plot of MVO2 as a function of ∆ in contractility:

Back 7

*Y-intercept is shifted up compared to controls.

Front 8

Discuss Wall Tension:
what is it?
equation for it?
what's it increased by?

Back 8

*It's related to (Pressure x Radius)/(Wall thickness).

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

Increased by:
*Higher Afterload - LV systolic pressure
*Higher Preload - LV end-diastolic pressure or volume

Front 9

Myocardial Oxygen Supply is Determined by:

Back 9

*Increase in perfusion pressure increases flow.
*Resistance decreases it.

Front 10

Coronary Blood Flow is Proportional to:

Back 10

Coronary Blood Flow is Proportional to perfusion pressure / resistance.

Front 11

Timing of Coronary Blood Flow:

Back 11

*Most coronary blood flow occurs during diastole! This is why LVEDP = perfusion pressure.

Front 12

Discuss Autoregulatory Resistance of coronary perfusion:

Back 12

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

*Metabolic control of coronary perfusion is with:
-Oxygen
-Adenosine , ADP
-NO (nitric oxide)
-Lactate , H+ (pH)
-Histamine, Bradykinin

Front 13

Autoregulatory Resistance: Describe the 3 different cells involved:

Back 13

*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).

Front 14

Autoregulation of Coronary Blood Flow: discuss roles of Oxygen and Adenosine--

Back 14

*If you have enough O2, you don't need any more. Therefore, it's a constrictor.
*Adenosine is the most important. It has a really short (seconds) half life, so it's great as a messenger for rapid changes.

Front 15

Discuss Adenosine's role during hypoxia:

Back 15

*During hypoxemia, aerobic metabolism in mitochondria is inhibited.
*There is accumulation of ADP and AMP (from ATP).
*Production of adenosine--> breakdown product of aerobic metabolism.
*Adenosine vasodilates arterioles.
*Increased coronary blood flow.

Front 16

Autoregulatory Resistance: plot of coronary perfusion pressure vs. flow:

Back 16

*Adenosine gets clinically used to increase perfusion pressure.

Front 17

What endothelial-derived factors contribute to autoregulation?
dilators--
constrictors--

Back 17

*Other endothelial- derived factors contribute to autoregulation:

*Dilators include:
1) EDRF (endothelial-derived relaxation factor: it's actually just NO)
2) Prostacyclin: increases cAMP.

*Constrictors include:
1) Endothelin-1; goes up during an MI.

Front 18

Discuss Coronary Flow Reserve

How much can people increase their coronary blood flow?

Back 18

*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...athletes/marathoners).

~ 2.25 - 3 (when measured clinically...normal people).

Front 19

Discuss Coronary Flow Reserve during stenosis of vessels:

What is the critical level and what happens when you pass it?

Back 19

*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 is “maxxed out”), any further decrease in Perfusion pressure OR increase in MVO2 results in ischemia.

Front 20

Coronary Flow Reserve: what's the relationship of coronary blood flow to % diameter stenosis?

Back 20

*75% before you really start to decrease flow.
*At ~90%, resting flow = maximal flow. This is the state where you can't move without pain.
*~95% = resting angina.

Front 21

Endocardium and Coronary Flow Reserve:
in diastole:
in systole:

Back 21

*Heart thickens in systole. Less blood flow to endocardium when this happens! Endocardial surface is most vulnerable part of the heart for this reason.

Front 22

Compare Endocardium vs. Epicardium:
What factors make the endocardium vulnerable?

Back 22

Endocardium:
*Greater shortening / thickening, higher wall tension: increased MVO2 in endocardium.

*Greater compressive resistance.

*Decreased Perfusion Pressure.

*Less collateral circulation.

*Net Result is more compensatory arteriolar vasodilatation at baseline and therefore DECREASED CFR.

Front 23

Prevalence of CAD in Modern Society by age:

Back 23

>40 = you pretty much have it.

Front 24

Risk Factors for CAD:

Back 24

*family History
*cigarette smoking (doubles risk)
*diabetes mellitus
*HTN
*hyperlipidemia (especially LDL)
*sedentary life-style (minor he says)
*obesity (minor he says)
*elevated homocysteine
*LP-a (lipoprotein a)

Front 25

Coronary lesions in Men and Women with Westernized and non-Westernized diets:

Back 25

*He points to LDL cholesterol as the culprit.
*Kyushu is a remote island in Japan.

Front 26

Relationship between fat in diet and serum cholesterol:

Back 26

*Different points = different countries.

Front 27

Discuss the Atherosclerotic Plaque Evolution from Fatty Streak:

Back 27

*Fatty streaks are present in young adults.
*Soft atherosclerotic plaques are most vulnerable to fissuring/hemorrhage.
*Complex interaction of substrate with circulating cells (platelets, macrophages) and neurohumoral factors.

Front 28

Discuss the Plaque progression to the fibrous cap:

Back 28

*Fibrous cap develops when smooth muscle cells migrate to intima, producing a tough fibrous matrix which glues cells together. More stable when there's a fibrous cap.
*Vessel remodeling = vessel outer wall expands to accommodate the plaque.

Front 29

Back 29

Intra-vascular Ultrasound (IVUS). White area is endothelial lining. These are normal vessels.

Front 30

Back 30

Atherosclerotic Plaque. US on right side shows crescent shaped plaques (typical).

Front 31

Back 31

*Physiologic Remodeling of arteries with plaques. Vessel wall is expanded outward.
*Angiogram doesn't show this. IVUS does.

Front 32

Stable Angina - Describe Symptoms:
What makes it worse?

Back 32

*Mid-substernal chest pain.
*Squeezing, pressure-like in quality (closed fist over chest = Levine’s sign). NOT SHARP!
*Builds to a peak and lasts 2-20 minutes.
*RADIATION to left arm, neck, jaw or back.
*Associated with SOB, sweating, or nausea.

*Exacerbated by exertion, cold, meals, or stress
relieved by rest, NTG. Things that increase MVO2!

*Why meals? Blood is going to the gut; it is shunted away from your heart. So if you have HD, don't go exercise after a meal.

Front 33

WTF is going on here?

Back 33

*Stable Angina - Diagnosis Exercise Treadmill Test.
*Left: resting
*Middle shows ST depression with exercise.

Front 34

Back 34

*Stable Angina - Diagnosis with Thallium Stress Test
*Nuclear isotope shows decreased blood flow during exercise; less prominent at rest.

Front 35

Stable Angina - Treatment
most important meds?
which ones decrease MVO2?

Back 35

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

*Aspirin--reduces platelet aggregation; less clot formation. BEST most important med.

*Decrease MVO2 with
-nitrates
-beta-blockers (really important too! Slow the HR and lower the BP!
-calcium channel blockers
-ACE-inhibitors

*Anti-oxidants (E, C, Folate, B6)? NO!!!! No evidence that they do anything.

Front 36

Aspirin Therapy's effects on MI and death risk:

Back 36

THE STUFF WORKS-- 81mg is sufficient.

Front 37

Discuss treatment of Stable Angina with STENTS:

Back 37

*Stent prevents artery from re-occluding.
*Right shows expanded vs. non-expanded stent.
*Chemical Coating inhibits cell growth.

Front 38

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

Back 38

*One end sewed to aorta; one end sewed to coronary artery.
*Lasts 20-30 years. Left internal Mammary artery (LIMA) is used--for some reason, it doesn't develop atherosclerosis. No one knows why.

Front 39

Back 39

*Schematic of an Unstable Plaque.
*Arrows indicate abnormal flow.

Front 40

Back 40

Unstable Plaque. Note fissure, tissue factor causing thrombus --> angina and/or MI.

Front 41

Back 41

Cross section of a complicated plaque. Note fissure and interplaque hemorrhage. Not that obstructive, but still killed the guy. This is autopsy specimen.

Front 42

Back 42

*Angiogram in unstable angina: eccentric, ulcerated plaque.
*Oval area is plaque. Clot is downstream of the plaque. Treat with stent!

Front 43

Back 43

*Angiogram in unstable angina: after stent deployment.
*You can see the struts of the stent.

Front 44

Acute Coronary Syndromes: discuss Terminology:

Back 44

Pathophysiology of all 3 is the same:

*Unstable Angina (UA):
-ST depression, T Wave inversion or normal
-No enzyme release

*Non-ST elevation Myocardial Infarction (non-STEMI):
-ST depression, T Wave inversion or normal
-No Q waves
-CPK, LDH + Troponin release

*ST-elevation (“transmural”) Myocardial Infarction (STEMI):
ST elevation
+ Q waves
CPK, LDH + Troponin release

Front 45

Discuss Pathophysiology of the Acute Coronary Syndromes (UA,MI):

Back 45

*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 or total coronary artery occlusion (if total --usually causing a “STEMI”)

Front 46

Pathophysiology of Acute Coronary Syndromes

Back 46

*activation and aggregation of platelets is important!

Front 47

Back 47

“Vulnerable Plaque”

Front 48

Coronary Stenosis Severity Prior to Myocardial Infarction:

Back 48

*Actually, most MIs occur with <50% stenosis of lumen.

Front 49

Discuss Acute Coronary Syndrome: Unstable Angina / non-STEMI Symptoms:

Back 49

*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 SLNTG (nitro under tongue)
*onset at rest or awakening from sleep

Front 50

Unstable Angina - Discuss High Risk Features:

Back 50

*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

Front 51

Unstable Angina / non-STEMI Pharmacologic Therapy:

Back 51

*Anti-platelet therapy
-Aspirin
-Thienopyridine drugs (super aspirin)

*Heparin

*Decrease MVO2 with Nitrates, Beta-blockers, and ACE inhibitors

*consider platelet glycoprotein IIb / IIIa inhibitor and / or low molecular weight heparin

**Skipped all but the aspirin part**

Front 52

Anti-Platelet Therapy

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Back 52

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

Front 53

Acute Myocardial Infarction

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Back 53

*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)

Front 54

Discuss Acute Myocardial Infarction:

Back 54

*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

Front 55

SKIPPED

Back 55

AMI - Wavefront Phenomenon

Front 56

Acute Myocardial Infarction
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Back 56

Front 57

Cardiac enzymes: overview; HOW DO WE KNOW SOMEONE IS HAVING AN MI?

Back 57

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

Troponin I is key.

Front 58

Markers of MI: Discuss Troponin I:

Back 58

*Pretty small molecule.

Front 59

Diagnosis of MI: Discuss Role of troponin I:

Back 59

*Troponin I is highly sensitive.

*Troponin I may be elevated after prolonged subendocardial ischemia.

Front 60

Discuss Causes of Troponin elevation: 5

Back 60

*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).

Front 61

EKG diagnosis of MI

SKIPPED

Back 61

Front 62

Consequences of Ischemia (Ischemia begets Ischemia)

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Back 62

*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, decreased pO2, decreased 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).

Front 63

Ischemic Cycle

SKIPPED

Back 63

Front 64

Treatment of Acute Myocardial Infarction
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Back 64

aspirin, thienopyridine, heparin, analgesia, oxygen
reperfusion therapy
cath lab (drug-coated or bare-metal stent)
thrombolytic therapy
decrease MVO2
nitrates, beta blockers and ACE inhibitors
for high PCWP - diuretics
for low Cardiac Output - pressors (dopamine, levophed, dobutamine); IABP; early catheterization

Front 65

Back 65

*Thrombectomized material.
*About the size of fingernail clippings.