Myocardial Infarction and Reperfusion (Goldhaber)

Question 1

Ischemia vs. Infarction

Answer 1

Ischemia: O2 supply doesn’t meet demand

Infarction: when ischemia causes necrosis

Question 2

Using PET to look for MI

Answer 2

NH3 is tracer showing perfusion

FDG is tracer showing metabolism

In MI, get metabolism but no perfusion

(and in scar, have no metabolism and reduced flow)

Question 3

Sequence of failure during MI

Answer 3

1a) Impaired rate of relaxation
1b) Impaired force generation
1c) Rapid K+ leak and Na+ gain
2) Onset of contracture (rigor)
3) Na/K pump failure

Question 4

Creatine phosphate

Answer 4

Phosphorylates ADP –> ATP in cytoplasm

(uses ATP in mitochondria to gain a phosphate then creatine phosphate attached to P goes out into cytosol and gives P to ADP to make ATP)

Creatine phosphate DECREASES in ischemia because not enough ATP in mitochondria (also get increased ADP, Pi and H+)

Question 5

How do you get decreased ATP during MI?

Answer 5

Inadequate O2 –> anaerobic metabolism with glucose instead of prefered FFA –> decreased ATP production –> decreased phosphorylation of creatine to creatine phosphate in mitochondria –> less creatine phorphate in cytoplasm to do ADP to ATP –> increased ADP, H+, P

Question 6

How does reduced ATP cause impaired relaxation?

Answer 6

1) SERCA pump can’t sequester Ca2+
2) Inhibition of cross-bridge release

Question 7

What causes impaired active force development?

Answer 7

1) Garden hose effect: loss of erectile effect of vasculature so can’t stretch and can’t develop as much force (Frank-Starling)
2) Increased H+ and P –> decreased phosphorylation of troponin by PKA –> less binding of Ca2+ to troponin
3) ATP-sensitive K+ channels open, causing shorter systole (actually causes DEPOLARIZATION by causing Non-Selective Cation channels to open and let cations in–MOSTLY Na+; arrhythmias)
4) Later on, high energy phosphate depletion causes decreased Ca2+ available (reduce Ca2+ current, reduced efficiency of RyR, so less release of Ca2+ from SR)

Question 8

Coronary perfusion pressure

Answer 8

Difference in diastolic pressure between aorta and LV

MI reduces CPP because it increases LVEDP

Aorta goes from 120/70 to 90/60; LV goes from 120/0 to 90/20

Coronary stenosis also decreases CPP

Question 9

Hemodynamic consequences of ischemia

Answer 9

Unable to relax, unable to generate force

Increased LVEDP

Decreased SV

To compensate: increase preload, increase HR, increase contractility, increase afterload

Compensation produces downward spiral of O2 supply/demand mismatch

Question 10

What does increased Na+ in the cell after ischemia do?

Answer 10

Increased Na+ causes Na/Ca exchanger to flip around and bring Na+ out of the cell and Ca2+ into the cell

Ca2+ overload

(Note: also get increased Na+ because of H+/Na+ exchange getting H+ out and bringing Na+ in)

Question 11

Why is elevated intracellular Ca2+ bad?

Answer 11

1) Activates intracellular proteases
2) Destroys key enzymes and cytoskeletal elements
3) Stimulates energy dependent Ca2+ pumps in mitochondria which increase Ca2+ uptake which arrests mitochondrial function

Question 12

What happens after continued depletion of high energy phosphates (ATP)

Answer 12

Crossbridges cannot relax (rigor)

Na/K pump inhibition leads to elimination of all electrical excitability

Question 13

Akinetic, hypokinetic, dyskinetic

Answer 13

Akinetic: absence of wall motion (irreversibly injured)

Hypokinetic: reduced systolic motion (potentially recoverable)

Dyskinetic: wall movement in opposite direction from normal

Question 14

Where does infarct start?

Answer 14

Subendocardium (most poorly perfused) and works its way out into epicardium

(endocardium protected because it’s right next to blood filling the ventricles of the heart)

Question 15

Different locations of MI based on location of thrombosis

Answer 15

RCA: inferior MI (II, III, aVF)

LAD: anterior MI (V1-V6)

LCx: lateral MI (I, aVL, V5, V6)

Question 16

Hemopericardium

Answer 16

External rupture of the heart most common 4-7 days after occlusion of artery

Nowadays this is rare

Question 17

Clinical features of MI

Answer 17

Angina

Dyspnea

Diaphoresis

Nausea

Sense of doom

Question 18

Lab evaluation of infarction

Answer 18

Troponin I high

Creatine kinase (CK-MB) high

Myoglobin high

ST segment elevation (but can also have NSTEMI)

Question 19

Treatment

Answer 19

Increase supply:

Platelet inhibitors: aspirin, clopidigrel, heparin

Thrombolytics: tenecteplase, tPA

Angioplasty/stent

Bypass (CABG)

Reduce demand: beta blockers, rest, nitrates (venodilate to reduce preload) and ACE inhibitors (vasodilate to reduce afterload)

Question 20

Why does reperfusion cause injury?

Answer 20

Restoring flow causes oxidative burst –> generation of oxygen free radicals (from leukocytes attracted to infarct zone, from myocyte itself, and from endothelium)

Free radicals arrest metabolism –> inhibit Na/K pump –> intracellular Na+ increased –> Na/Ca reverses and works even better –> Ca2+ into cell and Na+ out –> Ca2+ overload –> intracellular proteases destroy myofilaments, destroyed enzymes and cytoskeleton, mitochondria can’t function (later: lipid peroxidation disrupts sarcolemma, free radicals and Ca2+ cause apoptosis)

Question 21

Preventing irreversible injury by increasing supply and decreasing demand

Answer 21

Reperfuse early

Decrease demand before increasing supply (in surgery this works)

Low Ca2+ reperfusate (in surgery this works)

Beta blockers

Free radical scavengers

Question 22

Stunning

Answer 22

Reversible reperfusion injury

Dysfunction for hours to days (depends on extent of myofilament destruction), but then recovers

Mechanism: Ca2+ overload during reperfusion but myofilaments unable to respond normally to Ca2+ and decreased max Ca2+-activated force production

Key: contractile abnormalities can be overcome with inotropic agents because that will increase amount of Ca2+ in cells, but this increases O2 demand which you do NOT want to do. Only give inotrope if necessary to prevent severe hypotension

Question 23

Hibernating myocardium

Answer 23

Chronically ischemic, but NOT necrotic

Mechanism of decreased contractility not understood: garden hose, reduced Ca2+ so reduced contraction, reduced myocardial Ca2+ responsiveness (like stunned tissue)

Impaired contractility and relaxation

Wall motion akinetic or severely hypokinetic

Perfusion impaired but metabolism normal

Inotrope may improve function briefly but then becomes even more ischemic!

Key: can recover function with elective revascularization

Question 24

(Maladaptive) Remodeling

Answer 24

Changes in ventricle over days to months after MI, leading to enlargement, increased wall tension and deteriorating function

Instead of oval, get round basketball shape

Mechanism not well understood: angiotensin II, vasopressin, serotonin, NE involved –> hypertrophy and collagen synthesis by fibroblasts –> elongation of myocardial fibers, cells slip away and apoptose –> ventricular dilatation

Question 25

Prevention of remodeling

Answer 25

Beta blockers

ACE inhibitors

Aldosterone antagonists

Question 26

Preconditioning

Answer 26

Brief episodes (less than 10 min) of ischemia make myocardium resistant to subsequent ischemia

Reduction in infarct size, fewer arrhythmias, decreased duration of stunning

Mechanism not understood: PKC epsilon is protective by turning on “effectors” (ATP-sensitive K+ channels but unknown how)

Question 27

When should you use inotropic agents in reperfusion injury or MI in general?

Answer 27

Only if absolutely necessary to prevent hypotension because this icreases myocardial oxygen demand (MvO2)