Cardioprotective treatment strategies

Abstract: In myocardial ischemia-reperfusion (I/R) injury, complement activation, tissue plasminogen activator (t-PA) and extracellular adenosine triphosphate (ATP) release contribute to myocardial injury. ATP is degraded into adenosine by the enzyme apyrase, and adenosine possesses cardioprotective properties. ADC-1004 is an antagonist of the receptor to the activated complement factor C5a. Hypothermia has been shown to suppress the development of I/R injury.

In this thesis, the cardioprotective effects of ADC-1004 (paper I), apyrase (paper II) and hy- pothermia (paper III) were investigated. The effects of hypothermia on coronary t-PA release (paper IV), and on systemic t-PA release in cardiogenic shock (paper V) were also studied. An experimental porcine ischemia/reperfusion model was used. Infarct size (IS), microvascular obstruction and area at risk (AAR) were measured with ex-vivo MRI and SPECT.

ADC-1004 treatment (paper I) was found to reduce infarct size (ADC-1004: 58.3±3.4 vs control: 74.1±2.9 %AAR, p=0.007) but not microvascular obstruction (ADC-1004: 2.2±1.2 vs control: 5.3±2.5 %AAR, p=NS). Treatment with apyrase (paper II) did not reduce infarct size (apyrase: 75.7±4.2 vs saline: 69.4±5.0 %AAR, p=NS) nor microvascular obstruction (apyrase: 10.7±4.8 vs saline: 11.4±4.8 %IS, p=NS). Hypothermia (paper III) reduced both infarct size (hypothermia: 60.8±4.9 vs normothermia: 73.8±4.0 %AAR, p<0.05) and microvascular obstruction (hypothermia: 0.5±0.5 vs normothermia: 21.5±5.2 %IS, p<0.001). Hypothermia also inhibited an increase in coronary net t-PA release during reperfusion (paper IV; hypothermia: 0.79±0.45 ng/ml vs normothermia: 9.44±4.34 ng/ml, p<0.05); and an increase in systemic net t-PA release in cardiogenic shock (paper V; hypothermia: 0.60 ± 0.12 ng/ml vs normothermia: 2.16 ± 1.09 ng/ml, p<0.05).

In conclusion, complement inhibition by ADC-1004 and therapeutic hypothermia reduces myocardial ischemia-reperfusion injury, and represents clinically applicable treatment strategies. Mechanistically, therapeutic hypothermia acts to reduce t-PA release in myocardial ischemia and cardiogenic shock. Treatment with apyrase does not protect the heart from ischemia/reperfusion injury.