Grant: Operating Grant

Severe infections strike young and old alike with an incidence of ~75,000 per year in Canada requiring an average hospital stay of 18 days at a cost of $40,000 per patient. In 40% of these patients severe infection is complicated by low blood pressure and heart dysfunction leading to cardiovascular collapse with a mortality rate of 20-60%. The number of deaths due to severe infection is greater than the number of deaths due to heart attack, and continues to increase. Bacterial toxins trigger these adverse consequences and these toxins are cleared by the liver. We have recently discovered that decreased activity of a molecule known to regulate liver clearance pathways, PCSK9, results in improved survival in mice and in humans from severe infections. We now propose to investigate this finding to understand the mechanisms whereby decreased PCSK9 activity ultimately improves cardiovascular function and survival. We will study clearance of bacterial toxins by mice and humans where we will measure the clinically relevant consequences of decreased blood pressure, impaired heart function, and survival.