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