Diabetes and Myocardial Ischaemia - Sensitivity of the diabetic heart to ischemic injury

Diabetes Insulin-dependent Diabetes mellitus (Type I) Non-Insulin-dependent Diabetes mellitus (Type II) Ischemia Coronary artery disease Impairment of ventricular performance

Sensitivity of the diabetic heart to ischemic injury Controversy Epidemiological and clinical studies   Susceptibility Experimental studies   or  sensitivity

Clinical studies Coronary artery disease (Atherosclerosis) Major complication Angina Acute myocardial infarctions(AMI) Congestive heart failure Cause of death in more than half of all patients

Clinical studies Long-term mortality rate after AMI 2-3 times higher

Experimental studies The sensitivity of the heart from experimental animal models of diabetes to ischemia Controversy More Less Similar

Less sensitive to ischemic injury First evidence Tani M,Neely JR. Hearts from diabetic rats are more resistant to in vitro ischemia. Possible role of altered calcium metabolism. Circ Res 1988, 62:

Less sensitive to ischemic injury Diabetic model Induced by streptozotocin (STZ) Duration: < or = 6 weeks Isolated perfused heart Global zero-flow ischemia: 5 ~ 60 min Exogenous substrates Glucose Glucose +pyruvate HR, SP,LVP,CO, arrhythmias In vivo zero-flow regional ischemia Smaller infarcts

Less sensitive to ischemic injury Mechanisms pH i control during and following ischemia Diabetic heart  Less lactate accumulation at the end of ischemia  Smaller H+ load during ischemia  SL Na+/H+ exchange 

Less sensitive to ischemic injury Mechanisms Metabolic changes in diabetic heart Energy substrate use  Glucose:   Fatty acids:  (90~99%)

Less sensitive to ischemic injury Mechanisms Metabolic changes in diabetic heart

Less sensitive to ischemic injury Mechanisms Myocardial calcium handling during ischemia Ca 2+ overload   SL Na + / Ca 2+ exchange   Na+/H+ exchange 

More sensitive to ischemic injury Duration of diabetes Longer: >6 weeks Model of diabetes More severe: high dose of STZ or alloxan

More sensitive to ischemic injury Low-flow ischemia Accumulation of lipid intermediates Arrhythmogenic  Severity of ischemic damage High levels of exogenous fatty acids  Arrhythmias  Mechanical function

More sensitive to ischemic injury Hyperglycemia ROS   excessive cell death Acutely increase circulating inflammatory cytokines in humans Levels of IL-6 and TNF-a

More sensitive to ischemic injury

No differences in the response to ischemic injury Ischemic flow rate: Low Diabetic for 10 weeks Dose of STZ: 6 weeks 55mg/kg----  recovery 60mg/kg----no difference

Other factors contributing to ischemic injury in the diabetic heart Myocardial dysfunction in diabetic patients Cardiac depression Diastolic dysfunction (first) Systolic dysfunction Cut-off point: 6 weeks mitoK ATP channels

Other factors contributing to ischemic injury in the diabetic heart Lack of blood components Platelets and neutrophils: deleterious effects Key role as mediators of cellular damage during I/R Platelet in diabetes  aggregation, secretion   Survival  Neutrophils in diabetes  Less deformable  Oxygen radicals   adhesion and emigration  by I/R

Summary Responses of the diabetic heart to ischaemia/reperfusion injury Determined by Duration and severity of the diabetic state The degree of ischemia Levels of exogenous fatty acids

Summary Less sensitive Short-duration or mild diabetes Glucose is the only metabolic substrate Zero-flow ischemia More sensitive: reflect clinical condition Longer-duration or severe diabetes Faty acids are present Low-flow ischemia