Co-PI: Sachin Yende, MD
Funding: BaCCoR (CTSI Basic to Clinical Collaborative Research Pilot Program) (Completed)
Cardiovascular disease (CVD) and sepsis are two of the biggest public health problems in America. Increasing evidence suggests they are linked. Studies of sepsis find that those who survive to hospital discharge are at increased risk of death in the following months and a third of these deaths are due to CVD. Similarly, studies of acute coronary events and stroke found a higher than expected frequency of recent respiratory infection.
The ‘infection’ hypothesis suggested that this epidemiologic link is due to persistent infection in vascular tissue, but recent studies have raised doubts about this hypothesis. We propose an alternate hypothesis. Unresolved immune response after an infection, despite eradication of the pathogen, may increase risk of acute deterioration of CVD. Pathways activated during infection, including inflammation, coagulation-fibrinolysis, endothelium activation, and oxidative stress, may convert stable atherosclerotic plaques to activated and vulnerable plaques, and lead to plaque rupture and thrombosis; thereby leading to acute deterioration of CVD. Our hypothesis is based on clinical observations in patients hospitalized for pneumonia. Inflammatory and coagulation-fibrinolysis markers activated during the acute infection remained elevated at hospital discharge, despite clinical recovery. Higher circulating concentrations of these markers were associated with higher one-year mortality, particularly due to CVD. Our results are important in light of results of the JUPITER trial suggested that persistent inflammation can be targeted with statins to prevent CVD.
Before embarking on additional studies, two key issues should be addressed. First, developing an animal model of sepsis in the presence of atherosclerosis is crucial. Such a model could improve understanding of mechanisms. Furthermore, animal models offer a distinct advantage over epidemiologic studies that are limited by the inability to account for differences in pre-infection status. For example, animals with similar burden of atherosclerosis could be exposed to infection and compared to controls to understand long-term consequences of infection. Although there are well described animal models of atherosclerosis, such as apolipoprotein E knockout (ApoE-/-) mice fed with high fat diet, and there are well described animal models of sepsis, including cecal-ligation and puncture (CLP) model, a single composite model to examine effects of infection and sepsis on atherosclerosis has not been developed. Second, a limitation of our preliminary work was that immune response was only assessed at hospital discharge. Understanding the natural history of immune response resolution in the outpatient setting and its relationship with acute cardiovascular events are necessary.
We therefore propose two parallel aims for this translational project: to develop an animal model to understand the effect of infection and sepsis on atherosclerosis progression and to conduct a pilot study to assess the natural history of immune response resolution in survivors of pneumonia hospitalization.