Myocardial Ischemia Flashcards
Initial Cellular Effects of Ischemia: From aerobic to anaerobic metabolism
- Aerobic Metabolism slows
- ->decrease ATP
- 1st 15 minutes: ADP + CP supply ATP
- ATP–>ADP–>AMP–>adenosine (vasodilator) - Anaerobic metabolism–>lactic acid–>decrease pH
- H+ build-up: opens K+/ATP channels–>partial discharge of K+ gradient–>contractile dysfunction (cell self-preservation) due to hyperpolarization
- slide 37
Initial Cellular Effects of Ischemia: Irreversible Damage
- Progressive loss of ATP
- slows Na+/K+ pump - Cell dysfunction and injury
- loss of cell membrane integrity: Na+ and water–>swelling
- proteases leak across membranes–>degrade myofibrils
- inflammatory response: PMNs + further tissue degradation - Cell death and rupture cause release of measurable
- Creatinine Kinase
- Troponin
*irreversible damage can happen in 20-30 minutes
Ischemia leads to Electrical and Pump fxn changes
- Electrical
• Dysfunction of Sinus and/or AV nodes
• Changes in conduction velocity = arrhythmias - Pump
• Impaired relaxation -> increased filling pressures
(decreased compliance)
• Impaired Contraction
Reperfusion Injury
Paradox: Most of cellular injury occurs at reperfusion
• O2 = oxygen radicals injure cells, reduce NO
• Calcium: Abrupt rise in intracellular Ca++ from damage to sarcolemmal membrane and SR (oxidative stress)
– Leads to myocyte hypercontracture, increasing O2 demand
• pH: rapid return of normal pH facilitates hypercontracture
– K+/ATP channels close again, removing local ‘protection’
• Mitochondrial Permeability Transition Pore:
– opens and collapses membrane gradient
– Uncouples oxidative phosphorylation = loss of ATP production
Many possible therapeutic targets, few have helped
Types of Reperfusion Injury
- Stunning
- No Reflow
- Reperfusion Arrhythmias
- Myocyte death replaced by fibrotic scar
- Fatal Reperfusion injury
Stunning
Ventricular dysfunction even after reperfusion; no irreversible damage; return of normalish blood flow
- is a myofilament alteration
- impaired Ca2+ responsiveness to contractile machinery of myocytes
- likely result from ox. stress and Ca2+ overload from transient ischemia and reperfusion
- Prolonged Ischemia for ~20 min
- Restoration of blood flow.
- Alterations in troponin response to Ca++ drop function
- Cellular self repair over 7-14 days will recover function.
- no specific Tx
- may mean potential for improved contractility for pts w/severe ventricular dysfunction right after MI
No Reflow
micro-vascular injury (“reflow” = after opening)
Description
• Poor flow of contrast down an artery
• Seen in the cath lab after opening an occluded epicardial artery via angioplasty
Causes • Vascular occlusion due to debris • Vascular constriction in response to debris • Destruction of ischemic tissues • Tissue Edema
Impact
• Limits flow after epicardial artery is opened
• Marker of worse outcome
Reperfusion Arrhythmias
Fairly common during ischemias
- can be dangerous
- Accelerations of ventricular arrhythmias occur just at time of reperfusion
Fatal Reperfusion Injury
Reperfusion injuries can result in cell
death–>area of necrosis
*may be responsible for large percentage of myocyte death (even in reperfused tissue)
Possible Reperfusion Protection
- Not reperfusing does not work….
2. Ischemic pre-conditioning
• Clinical observation: stuttering angina = smaller MI
- Ischemic post-conditioning
• may be a way to activate same protections
- Likely involves the K+/ATP channel among others
Clinical Manifestations of Ischemia
- Chest Pain (angina)
- Impaired Ventricular relaxation (regional)
- diastolic dysfunction - Depressed myocardial contractility (regional)
- systolic dysfunction - Hibernating myocardium
- Electrical Abnormalities
- most dramatic-ventricular fibrillation–> collapse of cardiac pump–>rapid death
- majority of SCD
Impaired Ventricular relaxation (regional)
- diastolic dysfunction
- decreased compliance and increased diastolic ventricular pressure
- stiffer ventricle–increased R to filling
- LV end diastolic P increases–>pulmonary edema & decreased subendocardial blood flow
- S4 (result of reduced vent. compliance)
Depressed myocardial contractility (regional)
*systolic dysfunction
- contractile failure temporally related to intracellular acidosis and accumulation of Pi
- depress myofibrillar fxn
*H+-decrease Ca2+’s binding affinity for troponin C–>decreased myofibril sensitivity to Ca2+
- Pi-directly inhibits actin-myosin interactions
- suppresses myofibrillar force generation
- rapidly restored after brief ischemia (40% LV mass)
- ->substantial overall contractile depression
- If small, the rest of the myocardium will increase contractility to compensate
- regional LV wall motion abnormality: hypokinesis, akinesis, dyskinesis
Hibernating Myocardium
*chronically ischemic but viable w/resultant depressed regional ventricular contractility
- Chronic partial occlusion can result in “hibernation” – Reduced function but myocytes are alive.
- Will recover function if blood flow improves.
- Identifying “viability” can be clinically important
Stunning vs. Hibernation
- Stunning: transient total occlusion (myocardial dysfunction)
- Hibernation: constant partial flow
- can improve w/increased blood flow
