NLRP3 Inflammasome: A New Promising Therapeutic Target to Treat Heart Failure

Inflammation plays a central role in the pathogenesis and progression of all heart failure (HF) phenotypes.1 Elevated levels of plasma pro-inflammatory biomarkers have been observed in HF patients and showed to correlate with disease severity2 and accurately predict cardiovascular complications independent of traditional clinical parameters [ie, left ventricular ejection fraction (LVEF), peak oxygen consumption, and New York Heart Association functional class].3 These observations opened the way for targeting inflammatory response as a new therapeutic strategy to treat HF (Fig. 1). However, until recently, all attempts to target inflammatory response in HF have yielded disappointing results when translated in large randomized clinical trials, raising the question on whether inflammation is the cause or the consequence of HF itself due their complex and bidirectional interlink.1FIGURE 1.: Sustained pro-inflammatory response in patients with HF and potential role of direct therapies targeting pro-inflammatory cytokines to blunt HF progression in humans. IL, interleukin; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; TNF-α, tumor necrosis factor-α.In this regard, the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) trial has helped to further understand the role of inflammation in cardiovascular diseases.4 Indeed, the results of a prespecified analysis of this trial reported that canakinumab, an interleukin (IL)-1β blockade, was associated with a significant reduction of HF-related hospitalization and mortality in patients with history of myocardial infarction, with or without diagnosis of HF on study entry, who responded to canakinumab [as showed by the reduction in high sensitivity C-reactive protein (CRP) to <2 mg/dL], suggesting a causative role of chronic inflammation in HF pathogenesis.4 IL-1β, the main form of circulating IL-1, and IL-18 are processed by caspase-1 in the setting of a macromolecular structure known as the “inflammasome” and act as soluble myocardial cardiodepressant factors.5 NLRP3 (ie, NOD-, LRR- and pyrin domain-containing protein 3, NALP3 or cryopyrin) is one of the intracellular sensors, part of the Nod-like receptor (NLR) family, that trigger the formation of the inflammasome and activation of caspase-1,5 and has recently emerged as a new therapeutic strategy to limit myocardial injury following ischemia-reperfusion injury in the mouse.5,6 Since IL-1 blockade in patients with HF has been shown to improve cardiorespiratory fitness and reduce HF hospitalizations,4,7,8 an upstream signaling blockade through NLRP3 inflammasome inhibition is hypothesized to be a promising new therapeutic target to treat HF. In the January 2021 issue of the Journal, Wohlford et al9 report the result of an interesting phase IB randomized trial with dapansutrile, an oral selective NLRP3 inflammasome inhibitor, to investigate its safety and tolerability in stable patients with HF and reduced ejection fraction. The authors tested 3 doses of dapansutrile (500 mg daily, 1000 mg daily, and 2000 mg daily) for consecutive 14 days in 3 cohort of patients with stable HF and reduced ejection fraction (New York Heart Association class II–III) and elevated hs-CRP levels (>2 mg/L), each of 10 patients (8 subjects under the investigational drug, 2 under placebo, randomized at a ratio of 4:1) for a total of 30 patients, comparing them with a placebo group. All patients underwent clinical evaluation, biomarker analysis, transthoracic echocardiogram, and cardiopulmonary exercise testing at baseline, day 14, and day 28. They found that dapansutrile appeared safe and well tolerated at adequate exposure to the drug as assessed by pharmacokinetics analysis, without any serious adverse events and significant changes on blood pressure, heart rate, renal function, or parameters of water or sodium retention. Furthermore, improvements in LVEF and exercise time at cardiopulmonary exercise testing were seen with the dapansutrile 2000 mg/daily cohort at 14 days. No significant changes in quality of life measures nor in CRP levels were seen in the dapansutrile-pooled cohort or the 3 individual cohorts. Although the results of the study were reassuring, it may be surprising to see that dapanusutrile had no meaningful effect on the levels of CRP, which is the preferred inflammatory biomarker for cardiovascular risk stratification, being established for IL-1 activity,5 itself downstream of NLRP3 inflammasome activation. The potential explanations behind these findings are multiple and not mutually exclusive: (1) the study was specifically designed to evaluate the safety and tolerability of this new drug and not powered to detect the effect on CRP levels; (2) there is the possibility that the exposure to treatment in drug dose or time was insufficient to fully inhibit the NLRP3 inflammasome, IL-1β, the secondary IL-6 production, and hepatic production of CRP in 14 days, and therefore a higher dose or longer duration would have reduced CRP levels; (3) it is possible that in spite of the NLRP3 inflammasome inhibition, a residual IL-6 signaling may be still present independent of NLRP3 inhibition through additional pathways. The positive results coming from this study should be therefore interpreted with caution and only as hypothesis-generating and future powered studies are however needed to give a better understanding of the effect of dapansutrile on inflammatory markers, clinical variables (ie, LVEF, cardiac remodeling, natriuretic peptide reduction), quality of life measures, and cardiovascular outcomes. Based on this preliminary data, a dapansutrile dose of 2000 mg/d seems to be the promising dose to be tested in the future studies. Of course, some limitations apply. First, the study size and duration limit the scope and external validity of the efficacy results. Second, no claim of clinical effectiveness (ie, impact on clinically relevant outcomes, including fatal events) can be made based on this small early phase trial. Third, the scope of HF management is becoming more and more complex, with several multiple pharmacologic agents and classes being potentially beneficial, bringing forward the issue of appropriate choice, timing, titration, and combination, with preliminary thorough appraisal of diagnostic and prognostic detail, with a personalized scope.10,11 In conclusion, the Virginia Commonwealth University research group should be again congratulated for providing promising data on a new class of drug in HF patients, in this case for enabling hypothesis generation for possible future applications of selective NLRP3 inflammasome inhibitors for cardiovascular disease indications. Growing evidence suggests the role NLRP3 inflammasome and the IL-1 cytokines in the pathogenesis and progression of cardiovascular diseases.4,12 The future will likely include cytokine target therapies and possibly oral NLRP3 inflammasome inhibitors, to counteract the harmful sustained pro-inflammatory activation in patients with HF and hopefully improve HF-associated morbidity and mortality.