Ischemic Conditioning and

Endothelial Function

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

BASELINE(3.65 mm)

REACTIVE HYPEREMIA (4.08 mm)

Flow-Mediated Vasodilation

FMD = 10.5 %

Microvasculature

Philpott et al. ATVB 2007;27:2065

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

Ischemic Conditioning

Vinten-Johansen JAP 2007;103:1441

Significant parallelism between pre and post-conditioning

Ischemic Conditioning and Endothelial Function

• Ischemia-reperfusion injury causes injury and acute conduit

and NO dependent micro-vessel endothelial dysfunction

• Pre and post-conditioning with IPC bouts of transient ischemia

attenuate this abnormality

• Pharmacological conditioning prevents IR endothelial

dysfunction acutely but less reliably chronically

• IPC improves LV function during acute myocardial infarction in

some but not all studies

• Remote IPC also results in variable outcomes

• IPC may also have favorable effects on other outcomes including

blood pressure

Ischemic Conditioning

Kharbanda Circ 2001; 103:1624

Ischemic Conditioning

Kharbanda Circ 2001; 103:1624

Attenuation of NO dependent increases inFBF 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

Remote Ischemic Post-Conditioning

Loukogeorgakis et al. Circulation 2007;116:1386

19 healthy subjectsRIPC and RPostC20 minutes of ischemiaWith and without glibenclamide to assess K+ ATP channelsBoth prevented the ↓ FMD with IR (PostC in leg but not arm) and this was blocked by glibenclamide

Ischemia-Reperfusion Injury

Alhejily et al. Microcirculation 2013

45 normal subjects with 15 minutes of ischemia

Attenuation of FMD but no change in hyperemic stimulus or PAT-index

IR doesn’t impair microvascular function

Pharmacologic Conditioning - Statins

Liuni et al. Clin Hemorheol 2010;45:161

Ischemic Conditioning

Luca et al. JAHA 2013;2(1)

30 healthy subjectsIR alone vs 1 day IPC vs 7 d IPC protocol

3 cycles of 5 min of ischemia and reperfusion

Celecoxib did not change results.

Both 1 and 7 days of IPC attenuated IR decrease in FMD

Ischemic Conditioning

Luca et al. JAHA 2013;2(1)

30 healthy subjectsIR alone vs 1 day IPC vs 7 d IPC protocol

3 cycles of 5 min of ischemia and reperfusion

Celecoxib did not change results.

Both 1 and 7 days of IPC attenuated IR decrease in FMD

Ischemic Conditioning and Endothelial Function

• Effect of acute or repeated episodes of IPC in patients with

endothelial dysfunction is unknown

• Acute and 7 days of IPC can ameliorate the IR-induced

decreases in FMD with no effect on measures of microvascular

response (hyperemic velocity or PAT)

• Pre-conditioning may be more effective than post-conditioning

in the forearm acute endothelial dysfunction model (and

studies are mixed with AMI)

• Further studies are needed to assess the effects of longer term

IPC on endothelial function and cardiovascular

pathophysiology