Disclosures Department of Cardiac Sciences and Libin Cardiovascular - - PowerPoint PPT Presentation

Ischemic Conditioning

Todd Anderson Libin Cardiovascular Institute University of Calgary

Disclosures

• Department of Cardiac Sciences and Libin

Cardiovascular Institute – U of Calgary

• Grant support by Alberta Innovates

– Merck, Amgen, Abbott

Ischemic Conditioning

• Ischemia-reperfusion injury
• Ischemic conditioning
• Endothelial function
• PCI
• CABG
• Myocardial infarction
• Others
• Remote ischemic conditioning

Ischemic Conditioning

• Ischemia-reperfusion injury

– Kloner JCI 1974:54:1496 – No reflow in dogs – Reimer et al. Circulation 1977; 56:786 – wavefront of ischemic death – Braunwald and Kloner. JCI 1985;76:1713 – double edged sword and concept of stunned myocardium Circulation 1982

• Ischemic conditioning

– Murry et al. Circulation 1986; 74:1174 – IPC – Series of 3-4 cycles of reperfusion and occlusion (minimum of 30 s in duration) – Longer cycles have been used for remote conditioning

Ischemia-reperfusion injury

Mozaffari et al. Am J CV Disease 2013;3:180

Endothelial Dysfunction No reflow Myocardial stunning

Ischemic Conditioning

Mozaffari et al. Am J CV Disease 2013;3:180

Ischemic Conditioning

Vinten-Johansen JAP 2007;103:1441

Significant parallelism between pre and post- conditioning End effector is closing

• f the mitochondrial

permeability transfer pore

Ischemic Conditioning

Murry et al. Circ 1986;74:1124

Canine studies with either 40 minutes or 3 hours of ischemia 4x5min cycles prior

Ischemic Conditioning

Hausenloy Nature Reviews Cardiology 2011;8:619

Ischemic Conditioning

Kharbanda Circ 2001; 103:1624

BASELINE (3.65 mm) REACTIVE HYPEREMIA (4.08 mm)

Flow-Mediated Vasodilation

FMD = 10.5 %

Ischemic Conditioning

Kharbanda Circ 2001; 103:1624

Attenuation of NO dependent increases in FBF post IR injury with activation of neutrophils as well Attenuation of FMD with pre-conditioning attenuating this abnormality

Remote Ischemic Conditioning

Kharbanda Circ 2002; 106:2881

20 minutes of ischemia with and without 3 cycles of 5 minutes of IPC on the contra-lateral arm

Ischemic Conditioning in PCI

Crisp et al. Circ 2009;188:820

242 elective PCI patients Normal TnI pre Remote IPC with 3 5 min cycles upper arm Primary EP was TnI at 24 h as was lower in IPC group (p=0.04)

Remote Ischemic Conditioning in PCI

Yetgin Circ J 2012;76:2392

Meta-analysis 4 PCI (2 STEMI) 13 CABG Remote IPC Biomarkers EP

Ischemic Post-Conditioning in STEMI

Frohlich EHJ 2013;34:1714

No reflow, microvascular dysfunction and hemorrhage, stunning, arrhythmias

Ischemic Post-Conditioning

Staat et al. Circ 2005;112:2143

30 patients with primary PCI Randomized to 4 cycles of 1 min inflation/deflation prior to PCI AUC CK rise post MI

Ischemic Conditioning in STEMI

Schevchuck Circ CV Interventions 2013, 6:484

Ischemic Conditioning in STEMI

Schevchuck Circ CV Interventions 2013, 6:484

Biomarker reduction

Ischemic Conditioning in STEMI

Schevchuck Circ CV Interventions 2013, 6:484

Infarct size by CMR

Ischemic Conditioning in STEMI – time effect?

Schevchuck Circ CV Interventions 2013, 6:484

Ischemic Post-Conditioning

Dwyer et al. J Interventional Cardiol; 2013;26:482.

102 patients with primary PCI Randomized to 4 cycles of 1 min inflation/deflation prior to PCI CMR EP of Area at Risk No change in EF or microvascular

• bstruction

Remote Ischemic Conditioning in STEMI

• 1st STEMI n=242 pts , Upper limb RIPC
• 4 x 5 min cycles
• Primary – LV function by echo and perfusion
• Overall no change in EF but there was improvement in large MI

Munk et al. Circ CV Imaging 2010;3:656

Remote Ischemic Conditioning in STEMI

• Anterior STEMI
• Lower limb RIPC
• 3 x 5 min cycles
• 100 pts
• Primary – CK-MB
• Secondary – CMR no

difference in infarct size at 3-5 days or 4 months

Crimi et al. JACC CV Inter 2013; 6:1055

P=0.043

Ischemic Conditioning and renal function

• 225 pts with NSTEMI

and PCI

• 3 cycles of coronary

IPC

• AKI endpoint
• Baseline creat 88 µM
• Trend for decrease in

30 day outcomes as well

• Previous trial by Er

Circ 2012

Defteros JACC 2013;61:1949

Ischemic Conditioning

• Other possible indications
• Blood pressure reduction
• Exercise capacity improvement
• Neurosurgery
• Bowel surgery

Ischemic Conditioning - Summary

• Attractive, safe and inexpensive approach with rich

basic science rationale

• Significant heterogeneity in the result so far for

IPC in PCI, CABG and STEMI

• Similar ambiguity exists for remote IPC
• Several large randomized trials are underway
• Large definitive trial needed with clinical end-

points to determine utility of the approach