Translation of Immunomodulatory Therapy to Treat Chronic Heart Failure: Preclinical Studies to First in Human

ABSTRACT The objective of this study was to evaluate the use of an extracorporeal immunomodulatory device on the immune dysregulated state of chronic heart failure (CHF). Inflammation has been associated with progression and complications of CHF but no effective therapy has yet been identified to treat this dysregulated immunologic state. The selective cytopheretic device (SCD) provides extracorporeal autologous cell processing to lessen the inflammatory activity of circulating leukocytes of the innate immunologic system. SCD treatment in a canine model of systolic CHF diminished leukocyte inflammatory activity and enhanced cardiac performance as measured by left ventricular (LV) ejection fraction and myocardial contractility by stroke volume (SV) up to 4 weeks after treatment initiation. Translation of these observations in first in human, proof of concept clinical study was evaluated in a patient with severe systolic CHF ineligible for cardiac transplantation or left ventricular assist device (LVAD) due to renal insufficiency and right ventricular dysfunction. Six hour SCD treatments over 6 consecutive days resulted in selective removal of inflammatory neutrophils and monocytes and reduction in key plasma cytokines, including tumor necrosis factor (TNF)-a, interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1. These immunologic changes were associated with significant improvements in cardiac power output, right ventricular stroke work index, cardiac index and LVSV index, stabilization of renal function with progressive volume removal permitted successful LVAD implantation. This translational research study demonstrates a promising immunomodulatory approach to improve cardiac performance in systolic CHF and supports the important role of inflammation in the progression of CHF.