Myocardial Infarction and Reperfusion (Goldhaber) Flashcards
Ischemia vs. Infarction
Ischemia: O2 supply doesn’t meet demand
Infarction: when ischemia causes necrosis
Using PET to look for MI
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)
Sequence of failure during MI
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
Creatine phosphate
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+)
How do you get decreased ATP during MI?
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
How does reduced ATP cause impaired relaxation?
1) SERCA pump can’t sequester Ca2+
2) Inhibition of cross-bridge release
What causes impaired active force development?
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)
Coronary perfusion pressure
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
Hemodynamic consequences of ischemia
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
What does increased Na+ in the cell after ischemia do?
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)
Why is elevated intracellular Ca2+ bad?
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
What happens after continued depletion of high energy phosphates (ATP)
Crossbridges cannot relax (rigor)
Na/K pump inhibition leads to elimination of all electrical excitability
Akinetic, hypokinetic, dyskinetic
Akinetic: absence of wall motion (irreversibly injured)
Hypokinetic: reduced systolic motion (potentially recoverable)
Dyskinetic: wall movement in opposite direction from normal
Where does infarct start?
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)
Different locations of MI based on location of thrombosis
RCA: inferior MI (II, III, aVF)
LAD: anterior MI (V1-V6)
LCx: lateral MI (I, aVL, V5, V6)
Hemopericardium
External rupture of the heart most common 4-7 days after occlusion of artery
Nowadays this is rare
Clinical features of MI
Angina
Dyspnea
Diaphoresis
Nausea
Sense of doom
Lab evaluation of infarction
Troponin I high
Creatine kinase (CK-MB) high
Myoglobin high
ST segment elevation (but can also have NSTEMI)
Treatment
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)
Why does reperfusion cause injury?
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)
Preventing irreversible injury by increasing supply and decreasing demand
Reperfuse early
Decrease demand before increasing supply (in surgery this works)
Low Ca2+ reperfusate (in surgery this works)
Beta blockers
Free radical scavengers
Stunning
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
Hibernating myocardium
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
(Maladaptive) Remodeling
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
Prevention of remodeling
Beta blockers
ACE inhibitors
Aldosterone antagonists
Preconditioning
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)
When should you use inotropic agents in reperfusion injury or MI in general?
Only if absolutely necessary to prevent hypotension because this icreases myocardial oxygen demand (MvO2)
