cardiac preconditioning: myths and mysteries
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Cardiac preconditioning: myths and mysteries. Enjarn Lin May 2011. Introduction. Perioperative myocardial infarction is associated with prolonged hospital stay & increased mortality Identify at risk patients Institute therapeutic strategies coronary revascularisation β-blockade - PowerPoint PPT PresentationTRANSCRIPT
Cardiac preconditioning: myths and mysteries
Enjarn LinMay 2011
Introduction Perioperative myocardial infarction is
associated with prolonged hospital stay & increased mortality
Identify at risk patients Institute therapeutic strategies
coronary revascularisation β-blockade α2-adrenoceptor agonists aspirin & statins prayer
US Multicentre RCT 1802 patients undergoing CABG Randomised to 3 groups:
Uncertain but received prayer Uncertain & did not receive prayer Certain & received prayer
Intercessory prayer
No effect on complication-free recovery from CABG
Intercessory prayer had a higher incidence of complications.
Ischaemia-reperfusion injury
ATP depletion Accumulation of H+
Na+ & Ca2+ influx
Ischaemia-reperfusion injury
Rapid normalisation of pH
Ca2+/ROS Opening of
mitochondrial permeabilitytransition pore (mPTP)
Uncoupling of oxidative phosphorylation
Goals of myocardial protection
1. Limit the duration and extent of ischaemia
2. Ensure the adequacy of timely reperfusion
3. Modify the cellular responses to ischaemia-reperfusion injury
4. Cardiac conditioning
Ischaemic Preconditioning
4 cycles of 5 minute ischaemia with intermittent reperfusion prior to coronary occlusion
Subsequent infarct size 75% smaller than controls
22 RCT’s 933 patients On pump patients received cardioplegia or ICCF Variable IPC protocols Pooled analysis:
No difference in mortality or perioperative MI Significant reductions in ventricular arrhythmias,
inotrope use & ICU length of stay
Ischaemic PostConditioning Conditioning stimulus applied after onset of
myocardial ischaemia during reperfusion period
Similar ability to attenuate the detrimental effects of IRI as IPC.
Strategy to improve outcome from evolving myocardial infarction
Ischaemic postconditioning in cardiac surgery
Study Patient group Stimulus Outcomes Number
Luo 2007 Repair Tetralogy of Fallot Aortic clamping (2 cycles of 5 min)
Less troponin I release 24
Luo 2008 Valve surgery(cold-blood cardioplegia)
Aortic clamping (3 cycles of 5 min)
Reduced CK-MBNo change to troponin ILess inotropic support
50
Luo 2008 Congenital heart disease(cold-blood cardioplegia)
Aortic clamping (2 cycles of 5 min)
Less troponin I releaseLess inotropic support
40
6 RCTs, 244 patients presenting with STEMI undergoing primary PCI
Significant reduction in peak CK & improved LV performance
Intervention benefit over standard care
Clinical Applicability Clinical benefits limited :
Cardiology & cardiothoracic surgery Transplantation
Inducing ischaemia in an already diseased target organ
‘Preconditioning at a distance’
Brief episodes of ischaemia & reperfusion in LCx territory reduced size of a subsequent infarct due to occlusion of LAD coronary artery
Magnitude of ischaemic protection similar to direct ischaemic preconditioning
Extended to non cardiac organs: kidney, small intestine, brain & skeletal muscle
Remote ischaemic preconditioning or ischaemic preconditioning at a distance
Conditioning the myocardium
Ischaemia Reperfusion PostCon
ReperfusionIschaemia PreConBrief ischaemia remotely or locally
ReperfusionIschaemia PerConRemote ischaemia
Activation via G-protein
couple receptor
Mitogen-activated protein kinases
Pro-survival protein kinases
Mitochondrial KATP channel
Mitochondrial permeabilityTransition pore (mPTP)
The end effectors?mitochondrial KATP
channel:
Implicated as critical mediator
Sulphonylureas abolish IPC
Maintains Ca2+
homeostasis Interaction with
mPTP unclear
mitochondrial permeability
transition pore: Non-specific high
conductance channel
Opening uncouples oxidative phosphorylation & ATP depletion
Prevention of opening underpins IPC/RIPC
Clinical trials in RICStudy Journal Patient group Stimulus Outcomes Number
Cheung (2006) JACC Paediatric cardiac surgery
Upper-limb ischaemia (4 cycles of 5 min)
Reduced troponin; reduced inotrope score; reduced airway resistance
37
Hausenloy (2007)
Lancet CABG Upper-limb ischaemia (3 cycles of 5 min)
Reduced troponin 57
Ali (2007) Circulation AAA surgery Lower-limb ischaemia (2 cycles of 10 min)
Reduced troponin; reduced perioperative MI; preserved renal function
82
Hoole (2009) Circulation Elective coronary angioplasty
Upper-limb ischaemia (3 cycles of 5 min)
Reduced troponinI ; reduced MACCE
242
Venugopal (2009)
Heart CABG (cold-blood cardioplegia)
Upper-limb ischaemia (3 cycles of 5 min)
Reduced troponin 45
Botker (2009) Lancet Primary coronary angioplasty (STEMI)
Upper-limb ischaemia (3 cycles of 5 min)
Increased myocardial salvage; decreased infarct size at 1 month
333
Pharmacological preconditioningStudy Patient group Drug Outcomes Number
Mangano 2006 CABG Acadesine (adenosine modulator)
No difference in MI 2698
Kitakaze 2007 STEMI Atrial Natriuretic Peptide and Nicorandil
ANP: decreased infarct size & improved LV functionNicorandil: No difference
1216
Mentzer 2008 CABG Cariporide (Na+/H+ exchange inhibitor)
Decreased MIIncreased CVA
5761
Opioid preconditioning
Opioids (via δ&κ receptors) can trigger cardiac preconditioning; naloxone blocks preconditioning
Cardiomyocytes sites of endogenous opioid synthesis, storage and release
Opioids act as autocoids, released during times of stress & ischaemia
Open the KATP channel & close the mPTP.
46 patients undergoing CABG randomised to morphine or fentanyl before CPB
No difference in BNP or troponin Morphine improved LV function
40 patients randomised to receive remifentanil bolus & infusion prior to sternotomy
Primary outcome troponin I reduced Shorter mechanical ventilation time
Volatile anaesthetic preconditioning
Volatile anaesthetics can protect the myocardium Volatile anaesthetics can similarly
precondition/postcondition the myocardium Similar mechanistic pathways as ischaemic
conditioning Evidence of volatile anaesthetic late preconditioning
Clinical trials with volatile anaesthetics
Randomized 200 patients undergoing CABG to 4 anaesthetic protocols1. Propofol TIVA2. Sevoflurane from sternotomy to CPB3. Sevoflurane after coronary anastomosis4. Sevoflurane from sternotomy
Compared to TIVA, continuous Sevoflurane significantly reduced troponin I leakage for the first 48 hours
22 RCTs identified, 1922 patients undergoing cardiac surgery, all too small to report on mortality
Predominantly undergoing on-pump CABG, 6 RCTs of OPCAB, 1 of mitral surgery
Majority had volatile throughout; 6 had volatile only before or during expected period of ischaemia
Dosage: Desflurane 0.15-2.0 MAC & Sevoflurane 0.25-4.0 MAC
Landoni et al. 2007
enzyme leak inotrope requirement mechanical ventilation time ICU length of stay
hospital length of stay MI all cause mortality
PostConditioning
58 patients with STEMI IV cyclosporine (non
specific mPTP blocker) prior to PCI
Reduction in enzyme leakage
Significant reduction in infarct size assessed by cardiac MRI
RCTs in conditioning for IRI
>50 ischaemic conditioning Predominately RIC
>40 pharmacological preconditioning Predominately volatile anaesthesia
Conclusions Brief ischaemia is good/prolonged
ischaemia is bad Anaesthesia is good for you! Larger trials are required Praying for our patients doesn’t appear
to improve outcomes