Inflammatory Cytokines Are Upregulated in Patients with Implanted Ventricular Assist Devices

Introduction: Since the implantation of left ventricular assist devices (LVAD) has become more frequent in patients with heart failure, the need to prevent, predict, and treat the associated pathologies has become paramount. The most common complications, which include thrombosis, gastrointestinal bleeds, anemia, and hemolysis, are also the adverse events that carry a less than favorable prognosis. The rate of thrombosis has been steadily increasing to as much as 6%. Pump thrombosis is a complex adverse event in terms of pathophysiology, patient presentation and management. Patients with chronic heart failure exhibit signs of systemic inflammation and the use of LVADs may increase levels of inflammatory cytokines as a result of blood contact with foreign surfaces or prolonged exposure to non-pulsatile flow. Inflammation can promote thrombosis by increasing levels of procoagulant factors, inhibiting natural anticoagulant pathways or damaging endothelium. Our study sought to determine whether alterations in levels of markers of inflammation are observed in patients with implanted LVADs to determine their potential clinical usefulness as biomarkers predictive of thrombosis.

Methods: Blood samples were collected peri-operatively and long-term post-operatively (until transplant or expiration) during normal clinic visits from 16 consented patients who were implanted with a HeartMate II LVAD (Thoratec Inc, Pleasanton, CA). Fresh whole blood specimens collected in 3.2% sodium citrate were centrifuged for platelet poor plasma and stored frozen until analysis. Using the Evidence Investigator High Sensitivity Biochip Array from Randox (Crumlin, County Antrim, UK) levels of 12 inflammatory cytokines and growth factors (interleukins 1α,1β, 2, 4, 6, 8, 10, VEGF, INFγ, EGF, MCP-1, TNFα) were quantitated. Blood samples collected from 48 healthy individuals were processed and analyzed in the same manner to establish normal levels. A database of clinical events in the consented patients was created from medical chart reviews by the Heart Failure Clinic.

Results: In pre-surgical samples, most patients exhibited IL-6 and IL-8 levels that were above the range observed in healthy individuals. Following implantation of the LVAD, the levels of IL-6 and IL-8, as well as additional acute-phase cytokines such as TNFα and IL-1β, further increased. The systemic inflammatory response was present for approximately two months post-surgery. Up to six months following implantation of the LVAD, in some patients levels of inflammatory cytokines (IL-6 and IL-8 in particular) were at times several hundred-fold higher than in healthy normals. The peak expression of the cytokine gradually reduced, sometimes to normal, over a period of weeks. Levels of cytokines whose function is more closely tied to antigen-mediated immunity were not significantly impacted by LVAD implantation.

Conclusions: An elevated inflammatory response is not surprising pre-operatively and immediately post-operatively in these heart failure patients implanted with an LVAD. The variability among patients in absolute levels of cytokines and the exceedingly high peak levels of IL-6 and IL-8 that occur at various time points in the months following implant suggest isolated pathologic activation, unique to each patient. These data will be analyzed in conjunction with ROTEM (thromboelastography), platelet activation, and cellular microparticle data already collected on these patients, at the same time points, to identify relationships between parameters that associate with clinical events. These data combined will support evidence for mechanism(s) of thrombosis and identify clinically useful biomarkers. As new patients emerge they will be enrolled in this study, and we continue to follow all patients long-term.