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ISCHAEMIC PRE-CONDITIONING. Prof. Mehdi Hasan Mumtaz. MYOCARDIAL ISCHAEMIC PRE-CONDITIONING. “Phenomenon by which a brief episod (s) of myocardial ischaemia increases the ability of te heart to tolerate a sbsequent prolonged period of ischaemia” ‘Murry et al’. HISTORY.
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ISCHAEMICPRE-CONDITIONING Prof. Mehdi Hasan Mumtaz
MYOCARDIAL ISCHAEMIC PRE-CONDITIONING “Phenomenon by which a brief episod (s) of myocardial ischaemia increases the ability of te heart to tolerate a sbsequent prolonged period of ischaemia” ‘Murry et al’
HISTORY • 1986 – Murry & colleagues. • 1993 – Marber & colleagues. • 1997 – Cason & colleagues. Kersten & colleagues. • 1983-89 – Davis & colleagues.
ENDPOINTS • Reperfusion arrythmias. • Slow energy metabolism. • Improve post-ischaemic function. • Protect coronary endothelium. • Post-ischaemic tension in atrial trabeculae muscle. • Resistance to hypoxic injury.
TIME COURSE OF ISCHAEMIC PRECONDITIONING • Important factors. • Duration of ischaemia. • Number of cycles. • Duration of reperfusion. • Types. • Eary, classic. • Lte, second window of protection. Delayed.
EARLY Immediate Lasts 2-3h. LATE 12-24h. Lasts 72h. Dpendent on: Cardioprotective proteins. Protects against stunning TYPES
ADDITIONAL STRESSFUL STIMULIIN ADDITION TO ISCHAEMIC • Oxidative (hyperoxia). • Mecanical (stretch). • Electrical (rapid pacing). • Thermal. • Chemical (harmonal). • Ionic (calcium). • Pharmacological.
CLASSIC/EARLY PRECONDITIONINGPutative Mecanisms • Opening of coronary colleterals. • Induction of oxidants. • Synthesis of protective proteins. • Changes in mitochondrial ATPases. • Not supported.
PRECONDITIONING “Protection is receptor mediated” • Objective Identification. • Triggers. • Tranducers. • End effectors in myocytes.
RECEPTOR DEPENDENT Adenosine. Opoid receptors. Bradykinin. Bristaglandins. Adrenergic, angiotension, endothelin receptors. Purine. Ach. RECEPTOR INDEPENDENT Nitric oxide. Free radicals. Calcium. A. TRIGGERS – ISCHAEMIC PRECONTITIONG
B-1 ATP sensitive K+ channels (K+ ATPS) B-2 Protein Kinase C (PKC) ISCHAEMIC PRE-CONDITIONINGB. MEDIATORS
Sarcolemal “Blocked by” Salfonylurea S-hydroxydecanoate Mitochondrial “Opened by” Diazoxide. “Blocked by” 5HD ISCHAEMIC PRECONTITIONGB. MdiatorsB-1 K+ ATP Channels
ISCHAEMIC PRECONTITIONG B – Mediators. B-2 Protein Kinase C (PKC). 1. “Activator” Phorbol esters. 2. “Inhibitor” Polymyxin. Stanrosporin
Sodium proton exchange. Cytoskeleton changes. TNF down regulation Energy demand. Catbolite acumulation. Lactate accumulation. Glycogen store. Intrcellular acidification. ISCHAEMIC PRECONTITIONGC. END EFFECTORS
DELAYED PRE-CONDITIONING Complex polygemic phenomenon involving activation of several genes necessary for the synthesis of severe proteins and channels (K+ATD).
DELAYED PRECONDITIONING • Latent period 12-24h. • Duration 72h. • Cardioprotective proteins. • Protects MI. • Protects M. Stunning.
Parmacological Endotoxins. Adenosine agonists Opioid agonists. TNF Non-Parmacological Ischaemia. Stress. Rapid ventricular pacing. Exercise STIMULI FOR DELAYED PRE-CONDITIONING • Infarction. • Stunning. • Arrythmias. • Endothelial dysfunction
DELAYED PRE-CONDITIONING “MEDIATORS & END EFFECTORS” Related to changes in protein activity Heat stress proteins. HSP – 72. Antioxidant enzymes. (MnSod) NOS (cox – 2) Cytokine.
DELAYED PRE-CONDITIONING • Requires. • Myocardial protein synthesis. • Phosphorylation of transcription factors. • NOS. • SOD. • Heat shock protein. • Role of ROS. • Role of NO.
CLINICAL IMPLICATIONSUse of Nicorandil • K+ATD. • No donors. • Sulfonylurea. • COX-2. • Cogeners of adenosine. • Adenosis agonists. • PKC agonists.
ANAESTHETIC INDUCEDPRECONDITIONINGVolatile Anaesthetics • Characteristics of preconditioning similar to those of ischaemic preconditioning” • A1 adenosin receptor activation. • KATP chanel activation. • Reduce Ca++ loading. • Augment post ischaemic contrctile responsiveness to Ca++. • infarct size. • Delayed preconditioning.