Translation of immunomodulatory therapy to treat chronic heart failure: Preclinical studies to first in human

Abstract

Background: Inflammation has been associated with progression and complications of chronic heart failure (HF) 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 burden of inflammatory activity of circulating leukocytes of the innate immunologic system.

Aim: The objective of this study was to evaluate the effects of the SCD as an extracorporeal immunomodulatory device on the immune dysregulated state of HF. HF.

Methods and results: SCD treatment in a canine model of systolic HF or HF with reduced ejection fraction (HFrEF) diminished leukocyte inflammatory activity and enhanced cardiac performance as measured by left ventricular (LV) ejection fraction and 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 HFrEFHFrEF ineligible for cardiac transplantation or LV LV 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-alpha (TNF-α),), interleukin (IL)-6, IL-8, and 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.

Conclusion: This translational research study demonstrates a promising immunomodulatory approach to improve cardiac performance in HFrEFHFrEF and supports the important role of inflammation in the progression of HFHF.

Fig 1. Schematic of extracorporeal blood circuits integrating SCD in canine and human studies.

Left panel displays the extracorporeal circuit for SCD treatment in the canine model of HF/HFrEF. Blood flow rate was 100ml/min, citrate (ACD-A) was administered at 180 ml/hour and 2% CaCl2 was given at 40 ml/min to maintain systemic and circuit iCa between 0.9 to 1.4 and 0.25 to 0.4 mmol/L, respectively. Right panel displays the extracorporeal circuit for SCD treatment for human subjects. Blood flow rate was 80 ml/min. Citrate (ACD-A) and CaCl₂ were administered as per protocol (S1 Appendix) to maintain systemic and circuit iCa between 0.9–1.4 and 0.25–0.4 mmol/L, respectively. The hemofilter was placed in the circuit to improve citrate removal to minimize any tendency to citrate toxicity during treatment.

Fig 2. SCD treatment effects on cardiac performance in HF/HFrEF dogs treated for 4h with SCD (n = 3) or sham (n = 2).

LVEF (Left Panel) was returned near normal levels of 50–55% under SCD treatment. No effect on EF with sham therapy with systemic heparin anticoagulation was observed. Ventriculograms of a HF dog heart (Right Panel) are shown at baseline (before therapy) and at the end of the 4h therapy session. The red line depicts the border of the diastolic silhouette overlayed on the systolic image, demonstrating improved contractility (black arrows) of the left ventricle after SCD treatment.

Fig 3. SCD treatment improves cardiac parameters compared to sham controls.

SCD treatment (HF-SCD) significantly increased cardiac output (CO), left ventricular (LE) ejection fraction (EF), LV stroke volume (SV), and decreased LV end systolic volume (ESV) compared to sham treatment (HF-Sham) by ANOVA repeated measures over a 4 week time course; p<0.02, p<0.001, p<0.01, p<0.001, respectively.

Fig 4. SCD treatments diminishes activation markers in circulating leukocytes compared to sham controls.

SCD treatment lowered the MFIs of the cell surface markers CD11b for circulating neutrophils and CD14 for circulating monocytes compared to sham treatment at various time points during the 4 week evaluation period.

Fig 5. Effect of SCD treatment on cardiac parameters in enrolled subject.

Left panel. Improvements in Cardiac Power Output (CPO) and Right Ventricle Stroke Work Index (RVSWI) from Baseline (pre-SCD treatment, Day-6 to Day-1) and during SCD treatment (Day1-6). Right panel. Improvements in Cardiac Index (CI) and Left Ventricle Stroke Volume Index from Baseline and during SCD treatment.

Fig 6. Effect of SCD treatment on leukocyte phenotypes in a patient with severe systolic HF.

Each graph displays the MFI of various cell surface markers on either circulating blood neutrophils or monocytes during the 6 day course of daily 6 hours of SCD treatment. Also displayed are the MFIs of the eluted neutrophils and monocytes from the SCD after treatments on day 1, 3, and 5. All monocyte graphs depict the MFI of the entire monocyte population except for the Monocyte HLADR graph which presents the MFI of the surface marker of HLADR in the intermediate (CD14+CD16+) monocyte subpopulation. Day 1 values were baseline measurements prior to initiation of SCD treatment. Day 2 and all subsequent Days represent values obtained during the morning after the prior day’s treatment.