The heart is extremely sensitive to ischaemic injury. During an acute myocardial infarction (AMI) event, the injury is initially caused by reduced blood supply to the tissues, which is then further ...exacerbated by an intense and highly specific inflammatory response that occurs during reperfusion. Numerous studies have highlighted the central role of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in this process. The inflammasome, an integral part of the innate immune system, is a macromolecular protein complex that finely regulates the activation of caspase 1 and the production and secretion of powerful pro-inflammatory cytokines such as IL-1β and IL-18. In this Review, we summarize evidence supporting the therapeutic value of NLRP3 inflammasome-targeted strategies in experimental models, and the data supporting the role of the NLRP3 inflammasome in AMI and its consequences on adverse cardiac remodelling, cytokine-mediated systolic dysfunction, and heart failure.
Myocardial ischemia-reperfusion injury induces a sterile inflammatory response, leading to further injury that contributes to the final infarct size. Locally released danger-associated molecular ...patterns lead to priming and triggering of the NOD-like receptor protein 3 inflammasome and amplification of the inflammatory response and cell death by activation of caspase-1. We review strategies inhibiting priming, triggering, or caspase-1 activity or blockade of the inflammasome-related cytokines interleukin-1β and interleukin-18, focusing on the beneficial effects in experimental models of acute myocardial infarction in animals and the initial results of clinical translational research trials.
The intracellular sensing protein termed NLRP3 (for NACHT, LRR, and PYD domains-containing protein 3) forms a macromolecular structure called the NLRP3 inflammasome. The NLRP3 inflammasome plays a ...major role in inflammation, particularly in the production of IL (interleukin)-1β. IL-1β is the most studied of the IL-1 family of cytokines, including 11 members, among which are IL-1α and IL-18. Here, we summarize preclinical and clinical findings supporting the key pathogenetic role of the NLRP3 inflammasome and IL-1 cytokines in the formation, progression, and complications of atherosclerosis, in ischemic (acute myocardial infarction), and nonischemic injury to the myocardium (myocarditis) and the progression to heart failure. We also review the clinically available IL-1 inhibitors, although not currently approved for cardiovascular indications, and discuss other IL-1 inhibitors, not currently approved, as well as oral NLRP3 inflammasome inhibitors currently in clinical development. Canakinumab, IL-1β antibody, prevented the recurrence of ischemic events in patients with prior acute myocardial infarction in a large phase III clinical trial, including 10 061 patients world-wide. Phase II clinical trials show promising data with anakinra, recombinant IL-1 receptor antagonist, in patients with ST-segment–elevation acute myocardial infarction or heart failure with reduced ejection fraction. Anakinra also improved outcomes in patients with pericarditis, and it is now considered standard of care as second-line treatment for patients with recurrent/refractory pericarditis. Rilonacept, a soluble IL-1 receptor chimeric fusion protein neutralizing IL-1α and IL-1β, has also shown promising results in a phase II study in recurrent/refractory pericarditis. In conclusion, there is overwhelming evidence linking the NLRP3 inflammasome and the IL-1 cytokines with the pathogenesis of cardiovascular diseases. The future will likely include targeted inhibitors to block the IL-1 isoforms, and possibly oral NLRP3 inflammasome inhibitors, across a wide spectrum of cardiovascular diseases.
Acute myocardial infarction (AMI) leads to molecular, structural, geometric, and functional changes in the heart in a process known as ventricular remodeling. An intense organized inflammatory ...response is triggered after myocardial ischemia and necrosis and involves all components of the innate immunity, affecting both cardiomyocytes and noncardiomyocyte cells. Inflammation is triggered by tissue injury; it mediates wound healing and scar formation and affects ventricular remodeling. Many therapeutic attempts aimed at reducing inflammation in AMI during the past 3 decades presented issues of impaired healing or increased risk of cardiac rupture or failed to show any additional benefit in addition to standard therapies. More recent strategies aimed at selectively blocking one of the key factors upstream rather than globally suppressing the response downstream have shown some promising results in pilot trials. We herein review the pathophysiological mechanisms of inflammation and ventricular remodeling after AMI and the results of clinical trials with anti-inflammatory strategies.
Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with severe disease show hyperactivation of ...the immune system, which can affect multiple organs besides the lungs. Here, we propose that SARS-CoV-2 infection induces a process known as immunothrombosis, in which activated neutrophils and monocytes interact with platelets and the coagulation cascade, leading to intravascular clot formation in small and larger vessels. Microthrombotic complications may contribute to acute respiratory distress syndrome (ARDS) and other organ dysfunctions. Therapeutic strategies aimed at reducing immunothrombosis may therefore be useful. Several antithrombotic and immunomodulating drugs have been proposed as candidates to treat patients with SARS-CoV-2 infection. The growing understanding of SARS-CoV-2 infection pathogenesis and how it contributes to critical illness and its complications may help to improve risk stratification and develop targeted therapies to reduce the acute and long-term consequences of this disease.
Virtually all types of cardiovascular diseases are associated with pathological activation of the innate immune system. The NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein ...3 (NLRP3) inflammasome is a protein complex that functions as a platform for rapid induction of the inflammatory response to infection or sterile injury. NLRP3 is an intracellular sensor that is sensitive to danger signals, such as ischemia and extracellular or intracellular alarmins during tissue injury. The NLRP3 inflammasome is regulated by the presence of damage-associated molecular patterns and initiates or amplifies inflammatory response through the production of interleukin-1β (IL-1β) and/or IL-18. NLRP3 activation regulates cell survival through the activity of caspase-1 and gasdermin-D. The development of NLRP3 inflammasome inhibitors has opened the possibility to targeting the deleterious effects of NLRP3. Here, we examine the scientific evidence supporting a role for NLRP3 and the effects of inhibitors in cardiovascular diseases.
The incidence of acute complications and mortality associated with COVID-19 remains poorly characterized. The aims of this systematic review and meta-analysis were to summarize the evidence on ...clinically relevant outcomes in hospitalized patients with COVID-19.
MEDLINE, EMBASE, PubMed, and medRxiv were searched up to April 20, 2020, for studies including hospitalized symptomatic adult patients with laboratory-confirmed COVID-19. The primary outcomes were all-cause mortality and acute respiratory distress syndrome (ARDS). The secondary outcomes included acute cardiac or kidney injury, shock, coagulopathy, and venous thromboembolism. The main analysis was based on data from peer-reviewed studies. Summary estimates and the corresponding 95% prediction intervals (PIs) were obtained through meta-analyses.
A total of 44 peer-reviewed studies with 14,866 COVID-19 patients were included. In general, risk of bias was high. All-cause mortality was 10% overall (95% PI, 2 to 39%; 1687/14203 patients; 43 studies), 34% in patients admitted to intensive care units (95% PI, 8 to 76%; 659/2368 patients; 10 studies), 83% in patients requiring invasive ventilation (95% PI, 1 to 100%; 180/220 patients; 6 studies), and 75% in patients who developed ARDS (95% PI, 35 to 94%; 339/455 patients; 11 studies). On average, ARDS occurred in 14% of patients (95% PI, 2 to 59%; 999/6322 patients; 23 studies), acute cardiac injury in 15% (95% PI, 5 to 38%; 452/2389 patients; 10 studies), venous thromboembolism in 15% (95% PI, 0 to 100%; patients; 3 studies), acute kidney injury in 6% (95% PI, 1 to 41%; 318/4682 patients; 15 studies), coagulopathy in 6% (95% PI, 1 to 39%; 223/3370 patients; 9 studies), and shock in 3% (95% PI, 0 to 61%; 203/4309 patients; 13 studies).
Mortality was very high in critically ill patients based on very low-quality evidence due to striking heterogeneity and risk of bias. The incidence of clinically relevant outcomes was substantial, although reported by only one third of the studies suggesting considerable underreporting.
PROSPERO registration ID for this study is CRD42020177243 ( https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=177243 ).
The management of individual patients requiring anthracyclines remains challenging because uncertainty persists on predictors of cardiotoxicity. We aimed to perform a systematic review and ...meta-analysis on incidence and predictors of anthracycline chemotherapy in patients with cancer. Databases were searched for pertinent studies. Meta-analytic pooling with random-effects methods was performed for incidence estimates, while relying on descriptive statistics for prevalence and strength of association of predictors. From 16,054 retrieved citations, 18 studies reporting on 49,017 patients with cancer were included, with 22,815 treated with anthracyclines. After a median follow-up of 9 years, clinically overt cardiotoxicity occurred in 6% (95% confidence interval 3% to 9%), whereas subclinical cardiotoxicity developed in 18% (95% confidence interval 12% to 24%). Appraisal of independent risk factors of cardiotoxicity showed that cumulative anthracycline dose was most consistently reported as an accurate and robust predictor of cardiotoxicity, with an acceptable prognostic role also for chest radiotherapy, African-American ethnicity, very young or very old age, diabetes, hypertension, very high or very low body weight, or severe co-morbidities. In conclusion, despite ongoing refinements in chemotherapy regimens, anthracyclines still pose a significant risk of cardiotoxicity, especially in those requiring a high cumulative dose or chest radiotherapy.
Patients with recurrent pericarditis were treated with the interleukin-1 trap rilonacept. Those who had a response were randomly assigned to receive continued rilonacept or placebo. Rilonacept led to ...a significantly lower risk of pericarditis recurrence than placebo.
Neutrophil extracellular traps (NETs) are formed by decondensed chromatin, histones, and neutrophil granular proteins and have a role in entrapping microbial pathogens. NETs, however, have ...pro-thrombotic properties by stimulating fibrin deposition, and increased NET levels correlate with larger infarct size and predict major adverse cardiovascular (CV) events. NETs have been involved also in the pathogenesis of diabetes, as high glucose levels were found to induce NETosis. Accordingly, NETs have been described as drivers of diabetic complications, such as diabetic wound and diabetic retinopathy. Inflammasomes are macromolecular structures involved in the release of pro-inflammatory mediators, such as interleukin-1, which is a key mediator in CV diseases. A crosstalk between the inflammasome and NETs is known for some rheumatologic diseases, while this link is still under investigation and not completely understood in CV diseases. In this review, we summarized the most recent updates about the role of NETs in acute myocardial infarction and metabolic diseases and provided an overview on the relationship between NET and inflammasome activities in rheumatologic diseases, speculating a possible link between these two entities also in CV diseases.
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