New opportunity for targeting systemic inflammation in patients with heart failure through leucocyte immunomodulation
Authors: Bertram Pitt, Sai Prasad N. Iyer, H. David Humes
Journal: European Journal of Heart Failure (2024)

Despite current therapy of patients hospitalized with acute (AHF) or worsening (WHF) heart failure, both heart failure with a reduced ejection fraction (HFrEF) and a preserved ejection fraction (HFpEF), there remains a relatively high incidence of cardiovascular (CV) mortality and hospitalizations for HF (HHF) at 30 and 90 days post-admission and/or discharge.1 The administration of sodium–glucose cotransporter inhibitors prior to and or shortly after discharge for AHF or WHF is effective in reducing CV outcomes 30 and 90 days post-discharge.2 However, there is little if any effect on reducing CV outcomes when agents are administered on or shortly after admission for AHF or WHF, a vulnerable period with high CV risk.3 The increasing evidence of the role of inflammation in patients with HF and the effect of anti-inflammatory agents such as colchicine and canakinumab on CV outcomes has spurred interest in further strategies to reduce inflammation as a means of further reducing CV outcomes in patients hospitalized with AHF or WHF as well as those currently with HF but ineligible for a left ventricular assist device (LVAD) due to severe renal disease and/or right HF.4, 5 Systemic inflammation has long been identified as a key driver of disease, and this association has been demonstrated across of the spectrum of ejection fraction, and particularly more pronounced in HFpEF, which has a strong association with inflammatory biomarkers.6, 7 In HFrEF, myocardial injury instigates the inflammatory response, which is mediated by both innate and adaptive immune systems, and is characterized by an initial surge in proinflammatory cytokines and chemokines, and the infiltration of neutrophils and monocytes into the injured myocardium. Furthermore once HF occurs, especially right HF, there is an increase in intestinal permeability with a consequent increase in lipopolysaccharides, trimethylamine N-oxide and a decrease in short chain fatty acids associated with an increase in inflammation, fibrosis, and thrombosis.8 Once through the resolution of the initial inflammatory event, chronic inflammation can persist through sustained myocardial injury and continued activation of proinflammatory cascades.6 This can be further exacerbated and maintained (in a process known as para-inflammation), through activation of the neurohormonal pathways involving the renin–angiotensin–aldosterone system and excess haemodynamic load, even without tissue injury. Finally, attenuated or impaired resolution of inflammatory processes (e.g. through decreases in plasma and urinary lipoxins and plasma resolvin D1 and a shift in activated leucocyte and T-lymphocyte profiles towards immunoquiescence) can further result in persistence of systemic inflammation. In HFpEF, the presence of underlying comorbidities such as obesity, chronic kidney disease or diabetes may initiate the inflammatory trigger, resulting in microvascular endothelial cell inflammation, increased reactive oxygen species production, myocardial infiltration by monocytes and subsequent differentiation into proinflammatory M1 macrophages, all of which are thought to culminate into structural aberrances with left ventricular remodelling and relaxation.6 Finally, while the above examples describe the involvement of systemic inflammation across ejection fractions and mainly in the chronic setting, activation of a systemic inflammatory process may be even more pronounced in AHF, and may persist well beyond the index acute event and potentially contribute to high hospital readmissions and mortality.6 However, despite the evidence of a strong correlation of inflammatory biomarkers, the exact mechanisms through which inflammation contributes to pathogenesis and progression of HF remain uncertain. While a detailed description of all the proinflammatory factors involved across these processes is beyond the scope of this article, it is worth noting that cytokines such as interleukin (IL)-1 (IL-1β), IL-6, tumour necrosis factor-α, and other biomarkers such as C-reactive protein (CRP) may play pivotal roles in perpetuating systemic inflammatory pathophysiology.6 Another biomarker that has demonstrated evidence as a measure of systemic inflammation and dysregulated leucocyte activation is neutrophil:lymphocyte ratio (NLR). A recent analysis of the BIOSTAT-CHF patient cohort including those with new-onset or WHF across a spectrum of ejection fractions revealed that an elevated NLR was significantly associated with the primary outcomes of time to all-cause mortality or HHF (p < 0.001), irrespective of left ventricular ejection fraction.9 Patients with NLR in the highest tertile had significantly worse outcomes than those in the lowest, independent of left ventricular ejection fraction. Inpatients were found to have higher NLRs than outpatients suggesting that inflammation may factor in HF decompensations. Furthermore, when applied to a validation cohort from the GoDARTS study, an elevated NLR demonstrated similar correlations with the primary outcome. More importantly, a decrease in NLR at 6 months after the index event was associated with reductions in the primary outcome (p = 0.036), indicating that a reduction in inflammation was beneficial, and provides a target that can be modified and potentially improve HHF and mortality.9 The concept of targeted anti-inflammatory strategies to address systemic inflammation is not novel and has been attempted before, albeit with suboptimal and often conflicting results, likely contributing to some of the lack of clarity around the role of inflammation in HF.6 For example, while there is substantial evidence of the role of IL-1/IL-1β as major mediators of the inflammatory process in HF pathophysiology, blockade of either the IL-1 receptor through anakinra or direct targeting of IL-1β through canakinumab have resulted in suboptimal results. In the REDHART study, despite improvements in CRP and peak aerobic capacity at 12 weeks, there were no differences in mortality or HHF in AHF patients treated for 2 weeks with anakinra versus placebo (although the trial was not sufficiently powered to detect such outcomes due to low event rates).10 Exploratory analysis of the CANTOS trial demonstrated that treatment with canakinumab reduced HHF in high-risk patients with prior myocardial infarction and persisting systemic inflammation and while encouraging, these results need to be validated in a randomized controlled trial specifically in HF patients.5 Furthermore colchicine has recently been shown to be effective in reducing inflammation and HF outcomes.4 While many efforts continue along this front, targeting of singular proinflammatory factors, no matter how focal or central to HF pathophysiology, may underestimate the incredible redundancy of the immune system to overcome such inhibitions. Attempts to systemically immunosuppress with glucocorticoids in AHF have also not yielded clear results, albeit a non-statistically significant trend of benefit correlating with increasing CRP levels was observed in a recent study.11, 12 An alternative strategy may be to target cellular sources of proinflammatory molecules, i.e. activated leucocytes. The above-mentioned correlation of NLR with outcomes from BIOSTAT-CHF implicates activated neutrophils as a potential target. A novel extracorporeal device known as the selective cytopheretic device (SCD) has shown significant promise in targeting of proinflammatory leucocytes, namely activated neutrophils and monocytes, resulting in quelling of systemic inflammation and improved outcomes in various hyperinflammatory acute conditions including acute kidney injury (AKI), acute respiratory distress syndrome, and cardiorenal syndrome.13-15 As part of a continuous kidney replacement therapy circuit, the SCD achieves its immunomodulatory properties using regional citrate anticoagulation to lower ionized calcium levels to <0.4 mmol/L, under which the most highly activated neutrophils undergo apoptosis and proinflammatory monocytes are shifted to a less inflammatory phenotype (Figure 1).15 A recent safety summary of SCD trials in AKI demonstrated a favourable safety profile for the SCD, with no serious adverse events, device-related infections, or any observations of immunodepletion or immunosuppression across over 19 000 cumulative hours of continuous exposure in over 150 critically ill patients (including paediatric) with AKI and multi-organ failure.13 The effect of the SCD on cardiac function was recently demonstrated in a first-in-human case report of a 71-year-old male patient with cardiorenal syndrome who was treated with the device and effectively bridged to LVAD.14 This patient had severe HFrEF and was deemed ineligible for cardiac transplantation or LVAD due to worsening renal function (WRF) and right ventricular dysfunction. Despite prior aggressive decongestion and inotropic therapy, the patient remained refractory with WRF and a significant inflammatory burden. Treatment with the SCD for 6 h daily over 6 consecutive days resulted in dramatic and durable improvements across multiple parameters, including cardiac output, cardiac index, and inflammatory burden, with no serious adverse events. With his improved cardiac and stable renal function, the patient received LVAD 3 days after discontinuing SCD treatment and was subsequently discharged without further complications. This approach is now being evaluated in a multicentre trial utilizing SCD treatment as a bridge to LVAD implantation in patients ineligible for this procedure due to right ventricular dysfunction or WRF (NCT03836482). While the above patient case is only a single example, it does propose a novel approach of how to address the systemic inflammatory component in the multi-factorial pathophysiology of HF, which will need to be evaluated in adequately powered randomized trials. Further studies will be required to determine whether the use of the SCD alone or in conjunction with subsequent oral anti-inflammatory strategies, such as colchicine, are required to reduce CV mortality and HHFs in patients with AHF or WHF. While further studies are warranted, availability of the SCD has the potential to improve HHF and mortality following hospitalization for AHF or WHF, a major unmet medical need. Conflict of interest: none declared.