Phys-ischemia & HF Flashcards
What is ischemia?
Reduced arterial blood flow, such that O2 demand is not met
*reduced washout is also a key feature of ischemia
What determines severity of ischemic damage?
- Tissue resistance to perfusion (kidney>skeletal muscle>liver, Brian, heart, intestine)
- Completeness of blockage
- Inmate resistance of tissue to ischemia (skeletal muscle>liver>kidney>brain, heart, intestine)
Global vs. Low-Flow ischemia
- Global: complete interruption of flow (ex thrombosis). Least common, but most damaging
- Low-Flow: reduction or partial interruption of flow (esp vasospasm). Most common, least damaging
Causes of flow interruption in the heart:
- Thrombosis
- Atherosclerotic plaque
- Catastrophic vascular accident
- Damaged endothelium
Intracellular anoxia generated a shift from ___ to ____ metabolism.
What happens?
Aerobic to anaerobic
- Krebs cycle decreases, less ATP is produced
- Glycolysis rates increase to cover ATP shortage
- Increased glycolysis and depressed oxidative phosphorylation cause accumulation of metabolites (lactic acid, inorganic P, free fatty acids, fatty acyl CoA)
Lack of Krebs cycle causes the rapid degradation of ___
Nucleoside triphosphates (NTPs) *5' nucleotides are degraded and exported as nucleosides, esp adenosine and inosine
endothelial cells further degrade nucleosides to ___.
____ appear in blood
Nucleobases and uric acid.
Hypoxanthine, inosine, and uric acid
___ attempts to restore energy poise by making ____ from ____
Myokinase reaction
1 ATP and 1 AMP from 2 ADP
Effects of decreased Krebs cycle activity
- Decreased ATP=increased glycolysis, decreased cell work and contraction, loss ion gradients, Na retention
- Decreased GTP=decreased protein synthesis, G-protein activity, and cytoskeletal stability
- Decreased CTP=decreased phospholipid synthesis
- Decreased UTP=decreased glycogen synthesis
Low pH , lack of high energy phosphates allow ___ to accumulate.
Cytosolic Ca
*mitochondria scavenge the extra Ca and are damaged in the process
The ___ is located in the mitochondrial inner membrane and is responsible for transporting ATP to the cytosol by exchanging ___ for ___
- Adenine nucleotide translocase protein
- Cytosolic ADP
- Matrix ATP
What happens when the mitochondria accumulate Ca?
- The AN translocase begins to dissociate
2. A large pore forms in the inner membrane (MPTP=mitochondrial permeability transition pore)
Consequences of significant numbers of MPTPs
- Swelling
- Loss of ionic gradients
- Accelerated loss of ATP
Summary of events from the onset of ischemia to cell death
⬇️flow - ⬇️O2 - ⬇️ATP - ⬆️Na - ⬆️Ca in - ⬆️MPTP - ⬆️cell death
- ⬆️ATP also leads to ⬆️glycolysis - ⬆️lactate, H+ AND ⬇️NTPs (both of these lead to ⬆️Na)
- ⬇️NTPs also leads to ⬆️membrane fragility and thus ⬆️cell death
Cell death causes certain enzymes to now be outside of the cell, which can be used as a diagnostic tool.
*which are cardiac specific?
- Myoglobin
- Myosin light chain
- Troponin I
- CK-MB (creatine kinase, MB form)
- Lactate dehydrogenase (LDH)
* 3 and 4, 5 can be evaluated in a cardiac specific way
LDH evaluation
In myocytes and RBCs LDH1»LDH2
- cell disruption releases LDH1 into the blood
- normal LDH1/LDH2 <1
- ischemia LDH1/LDH2 >1 (LDH “flip”)
Timeline of ischemic events
- Early- 5 min: metabolic shifts
* 20 min: metabolite buildup - Transition- 20 min-1 hr: cell injury
- Intermediate- 1-6 hrs: cell death
- Late- After 6 hrs: repair
Timeline of ischemic events:
Clinically observable features?
- Void areas on angiography, arrhythmia?
* ST elevation? - MRI becomes effective, loss/spreading of R wave, definite ST elevation, inverted T wave (V2-V6)
- Observable enzyme release, appearance of Q wave
- Reentrant arrhythmias, decreased plasma enzymes, spreading of QRS
Early phase contractile changes
- Shortening of AP
- ⬆️extracellular K
- ⬆️conduction velocity
- Impaired contractility
Transition phase contractile changes
- Continued loss of contractility
2. Impairment of relaxation
Intermediate phase contractile changes
- Progressive infarction
2. ventricular stiffness
Late phase contractile changes
- Ventricle is prone to reentrant arrhythmias
2. Replacement fibrosis produces collagen scar
Consequences of ischemia and it’s compensations:
CO and venous return
Initially: pump efficiency is decreased -CO decreased, RAP elevated -mostly preload overload 1st Compensation: Frank-Starling effect 2nd Compensation: increased symp tone 3rd Compensation: increased fluid retention -increased renin release due to reduced BP and increased symp tone, increases volume relative to container size, further increase in RAP 4th compensation: hypertrophy
Remodeling of tissues in the heart happens where?
“Remote zones” = non-ischemic zones
- systems involved in signal transduction are overexpressed
- huge inflammatory response
- growth factor genes are overexpressed
Tissue changes during remodeling:
Enzymatic isoform shifts
- Myosin heavy chain shifts from alpha to beta isoform (slower contraction means more efficient)
- LDH shifts from H4 to M4 isoform (more efficient)
- CPK shifts to a higher MB/MM ratio (Fetal situation)
- Increased collagen expression, more parallel elastic elements, stiffer heart
Remodeling ___ wall stress
What changes?
Reduces
*LV systolic pressure, radius, and wall thickness all increase in compensatory hypertrophy
Remodeling;
The good news
- Hemodynamics restored
- Collagen deposition results in greater contractile force
- Myosin isoform shifts cause slower, more efficient contractions
- CK and LDH shifts cause more efficient energy production in a less aerobic environment
Remodeling;
The bad news
- Hemodynamics: reduced coronary vascular reserve lessens ability to increase coronary flow on demand
- Collagen deposition results in stiffer heart which impairs relaxation and filling is energetically more costly.
- Myosin isoform shifts cause reduced contractility of the fibers themselves, makes them less responsive
- OVERALL ENERGETICALLY COSTLY AND DIFFICULT TO MAINTAIN
