NLRP3-mediated inflammation in cardio-oncology: sterile yet harmful

Abstract

Despite significant advances and the continuous development of novel, effective therapies to treat a variety of malignancies, cancer therapy-induced cardiotoxicity has been identified as a prominent cause of morbidity and mortality, closely competing with secondary malignancies. This unfortunate limitation has prompted the inception of the field of cardio-oncology with its purpose to provide the necessary knowledge and key information on mechanisms that support the use of the most efficacious cancer therapy with minimal or no interruption while paying close attention to preventing cardiovascular related morbidity and mortality. Several mechanisms that contribute to cancer therapy-induced cardiotoxicity have been proposed and studied. These mainly involve mitochondrial dysfunction and reactive oxygen species-induced oxidative stress, lysosomal damage, impaired autophagy, cell senescence, DNA damage, and sterile inflammation with the formation and activation of the NLRP3 inflammasome. In this review, we focus on describing the principal mechanisms for different classes of cancer therapies that lead to cardiotoxicity involving the NLRP3 inflammasome. We also summarize current evidence of cardio-protection with inflammasome inhibitors in the context of heart disease in general, and further highlight the potential application of this evidence for clinical translation in at risk patients for the purpose of preventing cancer therapy associated cardiovascular morbidity and mortality. (Translational Research 2022; 000:1-19)

INTRODUCTION

Cancer remains a prominent cause of mortality worldwide, and the incidence of various cancers, including breast, liver, and myeloma among others, continues to increase.¹ The oncology field has always strived to advance research and develop new anticancer therapies that combined with early screening and lifestyle intervention (ie, smoking cessation), have significantly extended longevity and improved prognosis and quality of life for many cancer survivors.¹ Although cancer management has improved dramatically over the last few decades, serious side effects of cancer therapy have been reported, including the risk of cardiotoxicity.² Cardiotoxicity secondary to chemotherapy is the most significant adverse reaction of many cancer treatments, with a devastating impact on overall morbidity and mortality for cancer survivors.³ Additionally, pre-existing cardiovascular risk, specific antineoplastic agent usage, or the combination of different antineoplastic therapies, can ultimately increase the probability for cancer patients to experience cardiac-related side effects.^3,4

Anti-cancer therapies have been developed and tailored for the treatment of diverse types of cancer, targeting distinct pathways or having different effects on the target cells.⁴ However, cell injury, including that of tumor cells, can promote the activation of cellular pathways linked to damage response and healing. One such pathway is the NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD) domains-containing protein 3 (Nod-like receptor protein 3), NLRP3 inflammasome, a stereotyped, gene-coded, response to cell and tissue damage, which can promote unintended cell dysfunction and perpetuate myocellular injury (Fig 1).^5,6 The NLRP3 pathway activation has been observed in several pre-clinical and clinical settings as a potential driver of cardiotoxicity. This review focuses on the NLRP3 inflammasome biology, its role in the development of cardiovascular disease, and the experimental evidence that links the mechanism of action of anticancer therapies to the activation of the NLRP3 inflammasome in the myocardium.

Fig 1.

Proposed mechanism of the activation of NLRP3 inflammasome following the administration of cancer therapies. Cancer treatment induces cardiomyocyte injury, which mediates the priming signaling of the NLRP3 inflammasome. NF-KB is activated, migrates to the nucleus, and begins the synthesis of the inactive NLRP3 components. Mitochondrial dysfunction in the heart consequently results in oxidative stress. Coupled with impaired autophagy, this then leads to the triggering of the NLRP3. The NLRP3 then oligomerizes and induces an auto-proteolytical activation of caspase-1. Active caspase-1 processes pro-IL1β and pro-IL18 into their mature forms, and triggers pyroptotic myocardial cell death. This NLRP3-mediated cardiac injury can induce long-term consequences on the heart, leading to the onset of heart failure.

DEFINITION OF CHEMOTHERAPY-INDUCED CARDIOTOXICITY

The manifestations of cardiotoxicity related to antineoplastic agents vary from asymptomatic myocardial injury, revealed by a moderate increase in plasmatic levels of cardiac damage biomarkers (ie, cardiac troponin and brain natriuretic peptide),⁷ to a more severe decline in left ventricular ejection fraction (LVEF).^8–10 While the asymptomatic form may usually predict a benign progression after treatment discontinuation, critical LVEF decline is often characterized by progressive and irreversible structural myocardial impairment over time.^8,11

Cardiotoxicity signs vary considerably. Acute symptoms include epicardial coronary arterial related syndromes, myopericarditis, and disturbances in the heart conduction system leading to both atrial and conduction defects and ventricular arrhythmias.^2,8 In contrast, long-term cancer survivors may remain asymptomatic for lengthy periods of time and experience left or right ventricular systolic and/or diastolic dysfunction long after the remission phase.⁴ This observation, unfortunately, supports the premise regarding the possible progression to a more severe phenotype of cardiotoxicity manifesting in congestive heart failure (CHF) ⁴.

NLRP3 INFLAMMASOME, STERILE INFLAMMATION, AND CARDIAC INJURY

The inflammasomes are a large family of macromolecular complexes that form upon the activation of intra-and extracellular receptors designated to recognize a host of dangerous stimuli.¹² The inflammasomes are conserved among different species and involve highly regulated pathways.¹³ They are part of the innate immunity and link the sensing of both extracellular and intracellular danger stimuli associated with pathogen infection or tissue damage with the inflammatory response.¹⁴ The danger signals identified by the inflammasome include microbic-and viral-associated molecules, intracellular proteins, nucleic acids, lipids, mitochondrial content, and organic and inorganic compounds. The recognition of danger- or pathogen-associated molecular patterns (DAMPs or PAMPs) is initiated by specific extracellular receptors,^12,15 as well as the engagement of the nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), the retinoic acid-inducible gene (RIG-) I-like receptors (RLRs),¹⁵ and the AIM2-like receptor (ALR), which take part in the inflammasome formation.^15,16

NLRP3, is a pattern recognition receptor (PRR) recognizing bacterial and viral PAMPs, but also numerous DAMPs involved in tissue and cell injury. To date, NLRP3 is the most studied and well-characterized inflammasome.^15,17,18 The involvement of NLRP3 in response to the disruption of cell homeostasis makes this protein a crucial contributor to the inflammatory response to tissue damage.¹⁵ (Fig 1)

Upon activation, the NLRP3 oligomerizes and binds (through a PYD-PYD interlinkage) with the adaptor protein apoptosis-associated speck-like protein containing a carboxy-terminal caspase recruitment domain (CARD), or simply ASC.^15,19 ASC subsequently polymerizes into insoluble filamentous structures that constitute the scaffold required to recruit the effector enzyme, pro-caspase-1, into the NLRP3 inflammasome through a CARD-CARD interaction.^15,16 This induces a proteolytical activation of zymogen pro-caspase-1 into caspase-1, which in turn mediates the release of pro-inflammatory Interleukin-1β (IL-1β) and Interleukin-18 (IL-18).^15,16,20 Caspase-1 is also responsible for a controlled form of cell death known as pyroptosis.²¹ Pyroptotic cell death features a plasma-membrane disruption with the release of intracellular content, which serves as a pro-inflammatory mediator, propagating the signaling to bystander cells.²¹

As part of the innate immune response, every cell type constituting the heart can induce the expression of NLRP3. Eventually, however, each cell type produces a different response. In endothelial cells, leukocyte and fibroblast activation of NLRP3 induce the processing of IL-1β.^22–24 In cardiomyocytes, the IL-1β production may be scarce, favoring a pyroptotic cell death. Pyroptosis is often the culprit behind cardiomyocyte loss following the activation of the NLRP3 pathway in the heart.^5,25,26 It becomes evident that a sustained inflammatory risk can diminish the cardiomyocyte number over time, limiting the contractile capacity of the heart.

Priming and triggering of NLRP3 inflammasome.

As stated above, the inflammasome pathway is highly regulated.¹³ The priming and triggering of the NLRP3 inflammasome are the two distinct yet essential steps orchestrating the activation of the NLRP3 inflammasome (Fig 1).^6,15 The priming is mediated by the presence of DAMPs and alarmins signaling through toll-like receptors (TLR) and NOD2.⁶ Additionally, the activation of the receptor for advanced glycation end-products (RAGE) or the release of other pro-inflammatory cytokines can ultimately constitute a priming signal.^6,15,27 The intracellular signaling cascade following activation of the above-mentioned receptors culminates with the release of the inducing nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB)^28–30. NF-kB is responsible for the transcription of hundreds of pro-inflammatory genes, including those required to synthesize all NLRP3 inflammasome components.^6,15 Following successful priming, the cell needs an additional signal to complete the NLRP3 inflammasome assembly.^6,26,31 This second signal, named triggering, functions as a safety mechanism to prevent excessive activation of the NLRP3 inflammatory process. The triggering phase culminates with the activation of caspase-1, which proteolytically cleaves IL-1β and IL-18 and mediates their release by inducing the formation of pores on the cytoplasmic membrane generated by the oligomerization of the N-terminal domain of the cell-membrane-pore-forming protein gasdermin D (GSDMD).^5,32,33

The activation of the purinergic receptor channel P2 × 7 is one of the signals leading to NLRP3 triggering. Upon binding with extracellular ATP, the opening of the channel mediates the extracellular release of potassium (K⁺). The efflux of K⁺ ions activates the mitotic serine and/or threonine kinase NEK7, a member of the NIMA-related kinases proteins (NEK), that binds NLRP3 and mediates its activation by inducing oligomerization and consequent interaction with the other inflammasome components.^34,35

In addition to K⁺ efflux, the mobilization of calcium (Ca²⁺) from the endoplasmic reticulum (ER) into the cytoplasm (or leaks within the interstitial space) has been proven to be a trigger signal for the NLRP3 inflammasome.³⁶ Furthermore, lysosomal damage, and interrupted autophagic processes that may occur during cellular injury or stress can activate the inflammasome as well. The first process depicts the pathogenesis of gouty arthritis, in which uric acid precipitates in the joints due to the destabilization of lysosomes in pro-inflammatory cells upon clearing.³⁷ The phagocytosis of tiny crystals such as monosodium urate or calcium phosphate crystals and silicates, in general, can induce a lysosomal engulfment and consequent leak of lysosomal enzymes into the cytoplasm.³⁸ Cell homeostasis relies on autophagy, a lysosome-dependent regulated mechanism, to degrade and recycle many cellular components, including cytoplasmic organelles such as mitochondria.³⁹ Experimental inhibition of several components in the autophagic process has been linked with triggering the NLRP3 inflammasome.^15,26 Conversely, in cardiac cells, the experimental induction of autophagy through the administration of an activator, such as rapamycin or cell starvation, can reduce the NLRP3 response once already activated.⁴⁰

Mitochondria are the primary energy source of the cells and cardiomyocytes, due to their high metabolic demands, contain a significantly higher number of mitochondria compared to any other cell type.⁴¹ Following myocardial damage, mitochondria can contribute to increase the oxidative stress.⁴² The altered mitochondrial metabolism has been experimentally proven to trigger the signaling cascade of many pro-inflammatory pathways, including the NLRP3.³⁶ Mitochondrial dysfunction and electron chain transport impairment are the primary determinants in producing reactive oxygen species (ROS) in cells,^43,44 although ROS may be generated through other non-mitochondrial sources.⁴⁵ ROS generation and mitochondrial DNA (mtDNA), cardiolipin, and thioredoxin-interacting protein (TXNIP) can all activate a robust NLRP3-mediated response.^46,47 This is particularly important in the context of cardiotoxicity or any other cardiac injury given that mitochondria occupy ~ 30% by volume of the cardiomyocyte.⁴⁸

ROLE OF NLRP3 INFLAMMASOME IN CARDIOVASCULAR DISEASE

In recent years, overwhelming scientific evidence has established the important role of the NLRP3 inflammasome in the pathogenesis of several cardiovascular disorders, including those with ischemic and non-ischemic etiologies.^5,49,50

Atherosclerosis, acute myocardial infarction and hypertrophic cardiomyopathy.

Atherosclerosis is a chronic condition that can affect many significant arteries in the human body.^51,52 Atherosclerotic plaques occur as a consequence of cholesterol lipid accumulation in the intima layer of the arteries.⁵¹ In the attempt to clear the lesion, macrophages become foam cells, a lipid-laden cell capable to trigger a detrimental pro-inflammatory reaction mediated by NLRP3.^53,54 In the context of the coronary arteries, the destabilization of the atherosclerotic plaque and its consequent rupture is the culprit of the pathogenesis of acute myocardial infarction (AMI).⁵² To confirm the contributions of the NLRP3 inflammasome and its related signals in exacerbating atherogenesis, several animal mechanistic studies have been performed. Low-density lipoprotein receptor (LDLR) knock-out mice transplanted with bone marrow cells derived from mice with genetic deletion of NLRP3, ASC, and IL-1β, displayed lower atherogenesis following a high-cholesterol diet.⁵⁵

In addition to atherosclerosis, NLRP3 activity is detrimental for cardiomyocytes as well. Following an AMI, activation of NLRP3 in cardiomyocytes induces pyroptotic cell death, which, in addition to the ischemia-reperfusion-mediated injury, contributes significantly to the extent of the infarcted area secondary to AMI.¹⁴ A genetic deletion strategy or pharmacological inhibition of NLRP3 and its products has been beneficial in reperfused and non-reperfused myocardial infarction models.²⁶ Inhibiting NLRP3 has been demonstrated (in pre-clinical settings) to help lower the extent of infarct and prevent cardiac dysfunction following AMI.^15,26,14 A genetic deletion strategy or pharmacological inhibition of NLRP3 and its products has been beneficial in reperfused and non-reperfused myocardial infarction models.²⁶ Inhibiting NLRP3 has been demonstrated (in pre-clinical settings) to help lower the extent of infarct and prevent cardiac dysfunction following AMI.^14,15,26

NLRP3 activity has also been linked to hypertrophic cardiomyopathy.⁵⁶ In several models of induced volume overload, possibly in response to the activity of Ca²⁺/calmodulin-dependent protein kinase II δ (CaMKIIδ), the genetic deletion or pharmacological inhibition of NLRP3 lowered the inflammatory risk and the consequent fibrotic response.⁵⁶ NLRP3 inhibition was able to prevent cardiac remodeling and heart failure onset following hypertrophic/hypertensive cardiomyopathy.⁵⁶

Metabolic syndrome.

A long-term diagnosis with metabolic syndrome is one of the main determinants of insulin resistance and type II diabetes, which may result in diabetic cardiomyopathy. Dysregulation of glucose metabolism and liver disease are crucial components responsible for increasing oxidative stress, which function as priming signals for an NLRP3-mediated response. Several pre-clinical investigations have connected sustained cardiac damage by NLRP3 activation to the structural cardiac abnormalities occurring secondary to diabetes.^57–60

The presence of comorbidities at the time of cancer diagnosis, including metabolic disorders, can indeed influence cancer treatment decision due to the overall increased cardiovascular risk.⁶¹

Moreover, future studies are needed to better understand the metabolic interaction between cancer and cardiovascular disease and how they affect one another. Metabolic abnormalities and inflammation often coexist and negatively impact both cancer progression and cardiovascular health. As pointed out in an elegant review by Karlstaedt et al., the metabolic reprogramming in cardiovascular disease and cancer can be quite complex, especially when attempting to elucidate how cancer cells affect other organs and potentially impair their function.⁶²

Atrial fibrillation.

Atrial fibrillation (AF) commonly occurs in patients with HF and is associated with the cardiotoxic effects of anti-cancer therapy.⁴ IL-1ß and IL-18 are increased in patients with AF and molecular analysis shows that NLRP3 protein is increased in atrial samples of patients with AF.^63–65 To further strengthen this association, experimental studies using mice expressing an active mutant NLRP3 in cardiomyocytes demonstrated the development of spontaneous premature atrial contractions and inducible AF. Moreover, the use of AAV9-mediated silencing of NLRP3 in cardiomyocytes abolished the effects of the mutant NLRP3.⁶⁴

Inflammatory cardiomyopathy.

The effect of NLRP3 activation has also been investigated in relation to acute myocarditis, an inflammatory disease of the myocardium characterized by devastating effects with an uncertain prognosis.^66,67 Although the etiology is not fully understood, it appears to be viral in most patients. Unfortunately, myocarditis is more often reported as a consequence of cancer therapies that target the immune system.⁶⁸

The presence of NLRP3 increased in patients who suffer from a more severe heart failure symptomatology.⁶⁶ In the pre-clinical model of Coxsackievirus B3 (CVB3)-mediated myocarditis in mice, NLRP3 activity, as well as IL-1β expression, were found to increase a week after the onset of the disease.⁶⁷ Interestingly, caspase-1 inhibition or IL-1 blockade both ameliorated the progression of the disease in mice following CVB3 myocarditis.⁶⁷ In a recent study, the NLRP3 inflammasome activation has also been linked to the pathogenesis of myocarditis following mRNA vaccination (mRNA-1273 COVID-19 vaccine).⁶⁹ This information will likely become more relevant with the rapid advancement of mRNA vaccines for cancer immunotherapy in the near future.^69,70

Pericardial inflammation.

The NLRP3 has been linked with the pathogenesis of pericardial inflammation.⁷¹ Pericarditis is an injury due to an acute inflammatory reaction to the pericardium, a mesothelial layer surrounding and protecting the heart.^71,72 The etiology of the disease is predominantly linked to viral infection, although pericarditis can arise due to cancer therapies, particularly following radiation therapy.⁷³ Additionally, pericarditis may occur as part of the paraneoplastic syndrome.⁷⁴ A recent study has revealed that the NLRP3 inflammasome is central in the pathogenesis of acute pericarditis.⁷⁵ NLRP3, ASC, and caspase 1 activity were measured in pericardial samples of patients with chronic pericarditis experiencing an acute flare.⁷⁵ In the same study, a murine model of pericarditis was developed by intra-pericardial instillation of zymosan A, from Saccharomyces cerevisiae, to elicit an inflammatory response mimicking an acute pericarditis phenotype in mice.⁷⁵ Pharmacological inhibition of NLRP3 or the blockade of IL-1α and IL-1β were able to inhibit pericardial effusion, thickening, and inflammation in mice with acute pericarditis. These findings are in agreement with a phase 3 clinical study testing rilonacept, an inhibitor of both IL-1α and IL-1β, in patients with recurrent pericarditis.^71,76 Rilonacept use was associated with a staggering 96% reduction in recurrences compared to placebo.⁷⁶ Similar results were seen in the smaller AIRTRIP trial using anakinra, a recombinant IL-1 receptor antagonist (IL-1Ra) in patients with recurrent pericarditis resistant to colchicine.⁷⁷

NLRP3 AND CANCER THERAPY-INDUCED CARDIOTOXICITY

Anthracyclines.

Anthracyclines are a class of anticancer drugs used to treat a variety of cancers, including forms of leukemia, lymphomas, bladder cancer, breast cancer, small cell lung cancer, and other solid tumors.⁷⁸ The first anthracycline, daunorubicin, was extracted from Streptomyces peucetius in the 1960s. Doxorubicin (DOX) was later identified in a mutant strain of Streptomyces peucetius and showed higher potency. More anthracyclines (Epirubicin, Idarubicin, Mitoxantrone, and Valrubicin) and anthracycline formulations have been developed.^78,79 There are different mechanisms of action attributed to anthracyclines that prove effective against cancer cells.^80,81 One of the main mechanisms is the inhibition of topoisomerase-II, leading to increased DNA breaks, arrest of the cell cycle, and cell death. In addition, anthracyclines can intercalate within the DNA double helix and inhibit the synthesis of DNA and RNA or can react with DNA and initiate apoptosis. Furthermore, DOX induces the generation of ROS in the presence of specific enzymes (NADH dehydrogenase, xanthine oxidase, cytochrome P450 reductase).²

Anthracyclines display many side effects, that vary between the different types and formulations.⁷⁸ DOX is the most investigated anthracycline due to its ample use and the frequent development of adverse side effects, the most common of which is anthracycline-induced cardiomyopathy (AICM).⁸² The administration protocols and dosages of anthracyclines have been adjusted to lower the occurrence and the severity of these side effects.⁸² However, AICM remains a serious complication of anthracycline-based anti-cancer treatment that may occur acutely (a few days after administration) or late (a month to several years) and is refractory to common therapies used to treat cardiovascular disease.⁸³ Common side effects are myopericarditis, tachycardia, electrocardiographic changes (eg, nonspecific ST-T alterations), premature atrial and ventricular beats, and left ventricular (LV) dysfunction and failure in the most severe cases.^82,84,85

Cardiomyocytes are terminally differentiated cells, therefore the mechanism of damage to the cardiomyocytes may differ from the mechanism that damages cancer cells. Several mechanisms of action have been identified in the search for the cause of AICM.⁸⁶ One emerging mechanism is the DOX-induced NLRP3 inflammasome pathway activation, leading to the new paradigm that the NLRP3 inflammasome inhibition may reduce AICM. Initial experimental studies showed that DOX induces elevation of circulating IL-1β in mice, and treatment of mice with IL-1Ra reduced the mortality, cardiac fibrosis, dysfunction, and cardiomyocyte apoptosis following DOX treatment.⁸⁷ These were evidence of the potential involvement of the NLRP3 pathway after DOX treatment. However, the proof that DOX led to the NLRP3 inflammasome activation came from the study by Sauter et al., which showed that bone marrow-derived macrophages (BMDMs) production of IL-1β, following DOX treatment, was inhibited in BMDMs from ASC^−/−, Caspase^−/−, and NLRP3^−/− mice.⁸⁸ Furthermore, NLRP3^−/− mice failed to promote pro-caspase-1 and pro-IL-1β cleavage, further indicating the necessity of NLRP3 protein to promote inflammasome activation in these cells. Moreover, ROS inhibitors could reduce the release of IL-1β in BMDMs treated with DOX. These data were replicated a few years after in wild type and NLRP3^−/− BMDMs.⁸⁹ It has been reported that the specific NLRP3 inhibitor 16673-34-0, given 30 minutes before DOX, and then once a day for 10 days, reduced DOX induced cardiac dysfunction in wild-type mice.⁹⁰ The effects of DOX on the inflammasome activation became evident also in cardiomyocytes. DOX induces NLRP3-dependent cell death in cultured H9c2 cardiomyocytes.⁹¹. In a different study, Caspase-1^−/−, and NLRP3^−/− mice displayed preserved function and remodeling, and no activation of the inflammasome pathway, when treated with DOX, further proving the detrimental effects of NLRP3 activation on cardiac structure and function following DOX treatment.⁸⁸ Recently, it has been demonstrated that ROS scavenging reduces ROS generation and NLRP3 inflammasome activation in primary cardiomyocytes.⁹² Despite this compelling evidence suggesting a cardioprotective effect of NLRP3 inflammasome inhibition in DOX-treated mice, an inflammasome-independent NLRP3 activity may also be responsible for protective effects against DOX. Kobayashi et al. have shown that 15 mg/kg cumulative dose of DOX did not induce cardiac dysfunction in wild type mice, but NLRP3 deletion caused a drop in LV fractional shortening. This protective effect of NLRP3 was linked to a NLRP3-dependent IL-10 production from macrophages.⁹³ This discrepancy is difficult to reconcile because similar animal strain and dose of DOX used (15mg/kg) were previously reported in other studies. However, in this study, the effect of DOX on cardiac function in wild type mice was negligible, which needs further exploration. Other protective inflammasome effects have been reported in the past. ⁹⁴

Other anti-inflammatory drugs linked to NLRP3 activity have been investigated. One example is resveratrol, a polyphenolic compound naturally produced by plants, which was shown to reduce DOX cardiomyopathy in mice with late-onset of hypertension-induced cardiomyopathy.⁹⁵ Resveratrol, like many other drugs linked to NLRP3 activity is not a direct inhibitor of NLRP3.⁹⁶ However, it was found capable of inhibiting the activation step of the NLRP3 inflammasome by suppressing mitochondrial damage.⁹⁷

Radiation Therapy.

Radiation therapy (RT) directed to the chest is part of the treatment of several tumors (Hodgkin’s Lymphoma, breast, neck, and lung cancer), that can result in irradiation of the heart as an involuntary target. High doses of radiation, from single or fractionated doses, can lead to a complexity of cardiovascular events as arrhythmia, atherosclerosis, pericarditis, constrictive cardiomyopathies, and valvular abnormalities.⁴ Recent improvements in RT aimed to reduce radiation dose and injury to healthy tissues mitigated but did not eliminate the occurrence of asymptomatic cardiovascular abnormalities that are difficult to detect. Low dose radiation exposure has been associated with an increased risk of developing heart failure with preserved ejection fraction (HFpEF) in older women after breast cancer therapy,⁹⁸ and contribute to impair peak oxygen consumption (VO₂ peak), reduced diastolic functional reserve index and elevation in NTproBNP in patients receiving thoracic radiation for lung and breast cancer.^99,100

Radiation drives oxidative stress leading to DNA damage that can accelerate senescence and cell death in tumor cells. However, the specific mechanisms by which radiation can impact healthy tissues (directly or indirectly) have not been completely elucidated yet. Several signals induced by radiation can lead to mitochondrial instability with ROS production leading to NLRP3 inflammasome activation.¹⁰¹ Radiation therapy has been reported to induce local and systemic inflammatory increased levels of IL-1β and IL-18 have in animal models.¹⁰² Human arteries with chronic radiation injury expressed high levels of IL-1α, IL-1β, caspase-1 and NLRP3.¹⁰³ Gamma radiation induces death of microvascular endothelial cells associated with the activation of inflammasome signaling.¹⁰⁴ The successful use of IL-1β blockers supports the idea that the NLRP3 inflammasome can be involved in radiation-induced cardiovascular injury. In mice receiving chest radiation, anakinra treatment was able to prevent the decrease in cardiac contractile reserve observed in control irradiated mice.¹⁰⁵ Interleukin-1 receptor type I (IL-1RI) deletion reproduces similar data and improved survival of mice six months after irradiation.¹⁰⁵ Furthermore, the use of anakinra in irradiated ApoE^−/− mice was able to attenuate radiation-induced arterial inflammation.¹⁰³ Even though cardiomyocytes have been shown to be quite resistant to direct damage from radiation,¹⁰⁶ other cardiac cell types can contribute to the complexity of the cardiovascular inflammation and damage, leaving this broad field to be further explored.

Tyrosine kinase inhibitors.

Genetic alterations of tyrosine kinases (TK) are often responsible for tumor development and progression.¹⁰⁷ TKs are pivotal proteins in regulating cellular functions, including cell proliferation, differentiation, and migration, making these specific proteins highly critical in the progression of mutagenesis toward a carcinogenic cell phenotype.^108,109

The activation of TK signaling involves the triggering of the mitogen-activated protein kinase (MAPK) cascade, which activates Ras, a small G protein.¹⁰⁹ Ras resides inactive on the inner layer of the plasma membrane and binds to a molecule of guanosine diphosphate. (GDP).¹⁰⁹ When active, the guanosine triphosphate bounded Ras phosphorylates the first serine-threonine kinase in the MAP kinase cascade, leading to the phosphorylation cascade downstream that MAP kinases which culminates with the activation of a targeted transcriptional factor involved in the transcription of a particular set of genes.^107,110 Tyrosine kinases are classified explicitly by their specificity for their own receptors and ligands. Extracellular domain receptor tyrosine kinases (RTKs) consist of epidermal-grow factor receptor (EGFR), platelet-derived grow factor receptor (PDGFR), fibroblast grow factor receptor (FGFR), and vascular endothelial growth factor (VEGFR), while intracellular proteins with regulatory activities include the SRC, ABL, FAK, and Janus, a member of the family of non-receptor tyrosine kinase (NRTK).¹¹¹

Pharmacological tyrosine kinase inhibitors (TKI) are molecules that bind and block the ATP site, resulting in irreversible inhibition of its activity. Alternatively, monoclonal antibodies, are human chimeric or bispecific antibodies directed against the extracellular domain of the RTKs.¹¹²

More than 50 pharmacologic TKIs have been authorized by the Food and Drug Administration (FDA), and the majority are utilized as cancer treatments.¹¹³ Unfortunately, small molecule TKIs and inhibiting antibodies frequently carry side effects, including an increased risk of cardiac toxicity, which can significantly impact the quality of life of cancer survivors.¹¹⁴

The mechanism of TKI cardiotoxicity is not yet fully elucidated; however, mitochondrial dysfunction and consequent oxidative stress seem to have a critical role in damaging cardiac cells.^44,107,115 Metastatic renal cell carcinoma and gastrointestinal stromal tumors are often treated with sunitinib and nilotinib, TKIs approved by US and European Commission regulatory agencies. Sunitinib and nilotinib have been associated with increased cardiac dysfunction in treated cancer patients. Pre-clinical evidence has also uncovered a link between the administration of sunitinib to cultured H9c2 cardiomyocytes and mitochondrial dysfunction and ROS production, which ultimately lead to an impairment of the mitochondrial electron transport chain and cardiomyocyte death.¹¹⁶ Both ROS production and ER stress are known activating stimuli for NLRP3. In fact, elevated signaling of the NLRP3 pathway was seen in both AC-16 and H9C2 cell lines following treatment with sunitinib. NLRP3 expression and IL-1β and IL-18 production were reduced by pharmacological inhibition of the oxidative stress following the exposure to sunitinib. ¹¹⁷ Sunitinib was also able to increase autophagic flux in treated H9c2 cells. Pharmacological assessment with autophagy inhibitors (3-Methyladenine, Bafilomycin A1, and Chloroquine diphosphate) confirmed that geldanamycin, a heat shock protein-90 inhibitor, attenuated the cytotoxicity of sunitinib by limiting the activity of the autophagic pathway.^118,119 Nilotinib, a Bcr-Abl kinase inhibitor, in H9c2 cells, increased ER stress markers such as ATF4 and CHOP and mediated cytotoxicity in cultured cardiomyocytes.^118,119 Other TKIs, including imatinib and masitinib, activated NLRP3 inflammasome by causing lysosomal swelling and damage in BMDMs.¹²⁰ Lysosomal destabilization following TKI leads to cathepsin-mediated destabilization of myeloid cell membranes and K⁺ efflux, which triggers the NLRP3 activity.¹²⁰ Although there is no strong correlation between the use of TKIs and NLRP3, these results argue in favor of an association between TKIs and NLRP3 inflammasome activity as a conceivable explanation for the cardiotoxicity of this modality of cancer therapy. Further studies using either pharmacologic inhibition or genetic deletion of NLRP3 components are needed to shed more light on this plausible association.

Immune Checkpoint inhibitor-associated cardiotoxicities.

Although rare, the adverse cardiac manifestations following immune checkpoint inhibitor (ICI) therapy can be life-threatening.¹²¹ Approximately 70% to 90% of cancer patients treated with ICI suffer side effects following treatment. These side effects can range from encephalitis and hepatitis to a devastating episode of myocarditis.^9,122 Typically, these side effects occur within 12 weeks from therapy initiation, with 15% of the patients experiencing severe manifestation.⁹ Myocarditis is the most severe side effect; pathologically, myocarditis is distinguished by the presence of myocyte necrosis and mononuclear infiltrates. These infiltrates are mainly CD3, CD4 and CD8 positive lymphocytes, including CD68 positive macrophages.^121,123

The higher risk of myocarditis was correlated with anti-CTLA4 and anti-PD-1 antibodies.^9,124 Unfortunately, ICI administration has been linked to other cardiovascular manifestations; including heart failure up to 2%, and ventricular arrhythmias in up to 1% of the total patients.¹²⁵ Pericarditis and pericardial effusions were reported as well, with 0.38% in patients with pericardial effusion needing surgical pericardiocentesis to relieve symptoms.^9,126

The evidence of an NLRP3 involvement in the ICI-induced cardiotoxicity is still limited. As already mentioned before, NLRP3 plays a key role in the pathogenesis of myocarditis and pericarditis,^66,75 which are the two most life-threatening manifestations of ICI-related side effects.^{68,122,127,128} In pre-clinical studies, the activity of NLRP3, MyD88, and p65/NF-kB was assessed in mice treated with Ipilimumab and Nivolumab, a CTLA-4, and PD-1 blocking agents.¹²⁹ Mice treated with Ipilimumab showed a significant decrease in cardiac function compared to untreated mice (−11% of the fractional shortening). Although no pathological investigation of myocardial inflammation was performed, the myocardial expression of NLRP3, MyD88, and several interleukins were measured.¹²⁹ Additional data linking NLRP3 and myocardial inflammation following ICI therapy were generated in a model of myocardial injury achieved by immunizing BALB/c mice with murine cardiac troponin I (cTnI) peptide concomitant with administration of PD-1 antibody.¹³⁰ Despite the limitations, these findings provide a signal of NLRP3 involvement in the pathogenesis of ICI cardiomyopathy. More studies are needed to test the effects of specific NLRP3 inhibitors and also measuring exclusive readouts of NLRP3 activity (ie, ASC aggregation and/or caspase-1 activity).

Trastuzumab-mediated cardiotoxicity.

Trastuzumab is a humanized monoclonal antibody specifically developed to inhibit the Human epidermal growth factor receptor 2 (HER2) signaling.¹³¹ HER2 activation is implicated in the activation of mitogenic and pro-survival pathways that alter neo-transformed cell proliferation.¹³¹ HER2 signaling is indeed altered in almost 30% of breast cancers and up to 34% of gastric neoplasia.¹³¹ The efficacy in inhibiting HER2 signaling makes trastuzumab the first-line treatment option for many cancers; however, incidents of cardiotoxic effects have been reported, including QT-prolongation and myocardial dysfunction.^131,132 Cardiotoxicity induced by trastuzumab administration exhibits, in most cases, a benign prognosis. Indeed, the most common cardiac manifestations tend to resolve on their own after the discontinuation of treatment.¹³¹ Nonetheless, a few clinical reports have pointed to long-term cardiac consequences following trastuzumab treatment, including deteriorated cardiac health when co-administered with anthracyclines.¹³³ The mechanism behind trastuzumab cardiac toxicity is still not fully identified; however, oxidative stress and autophagy seem again to be implicated. HER2 signaling is necessary for the routine upkeep of cellular function in any cell type, including cardiomyocytes. The activity of MAPK, Phosphoinositide 3 Kinase (PI3K), and Protein kinase B (AKT) is also initiated by the signaling of HER2. These pathways are essential for promoting energy production and ROS scavenging in cardiomyocytes.¹³³ Thus, the inhibitory effect of trastuzumab, which is beneficial to combat cancer, becomes detrimental to the survival of cardiomyocytes, which in turn become more prone to oxidative stress.¹³⁴ Pre-clinical murine and rat models have shown that trastuzumab increases nitrosative and oxidative stress in treated animals causing myocardial ultrastructural changes while compromising cardiomyocyte survival.^135–137

An additional mechanism proposed to explain the trastuzumab-induced cardiotoxicity is the impairment of the autophagic flux in cardiomyocytes. Alteration of HER2 signaling has been detrimental by lowering LC3 I/II expression and increasing p62 levels while impairing autophagosome-associated effector peptides including Atg 5–12, Atg 7, Atg 14, and Beclin 1 in mouse cardiomyocytes treated with trastuzumab.¹³⁴ Ultimately, the impairment of autophagy leads to increased ROS production, altering the overall oxidative stress status in cardiomyocytes. ¹³⁸

Preliminary evidence linking the oxidative stress induced by trastuzumab to the activity of NLRP3 inflammasome was obtained in immortalized rat atrial HL-1 cardiomyocytes exposed to a subclinical concentration of DOX and Trastuzumab.¹³⁹ Although this study is reported in abstract format, it constitutes one of the first reports on the potential role of NLRP3 and trastuzumab-mediated cardiotoxicity. Trastuzumab mediated an increase in transcriptional levels of NLRP3 and TLR4/MyD88, as well as p65/NF-kB in treated HL-1 cells. The authors also measured the secretion of pro-inflammatory cytokines, including IL-1β, a primary product of NLRP3 activity.¹³⁹ These pieces of information are indeed partial and will benefit from additional future investigations in which targeted genetic deletion of NLRP3, or the use of specific pharmacological inhibitors will be investigated employing a more comprehensive in vivo model of trastuzumab-induced cardiotoxicity.

Sodium-glucose Cotransporter-2 (SGLT-2) inhibitors have been linked with anti-inflammatory activity against NLRP3 in diabetic cardiomyopathy in mice.¹⁴⁰ Recently, SGLT-2 inhibitors have been investigated as potential cardioprotective agents against cardiotoxicity in HL-1 cells with DOX and trastuzumab (100 nM) and treated with 50 nM dapagliflozin. Dapagliflozin improved Ca²⁺ homeostasis and inhibited the pro-inflammatory “NLRP3-NF-kB–cytokines” pathways. ¹⁴¹ Although SGLT-2 inhibitors present anti-inflammatory properties, these classes of molecules are not direct inhibitors of the NLRP3 inflammasome. Indeed, recent evidence suggests an inhibitory activity on the MyD88 and NF-kb pathway which drives the priming of the NLRP3 inflammasome.¹⁴²

Pharmacologic inhibitory strategies against NLRP3 activation.

Pharmacologic inhibition of the NLRP3 inflammasome has been tested in pre-clinical studies of cardiotoxicity induced by cancer therapies, mainly following anthracycline administration (Table I). A sulfonylurea compound named glyburide, used for the treatment of type-II diabetes, was found to inhibit NLRP3 inflammasome at high concentrations in vitro.^143,144 A derivative of this compound, named 16673-34-0, lacking the cyclohexylurea moiety responsible for lowering blood glucose levels, was tested in both ischemic and non-ischemic cardiomyopathies in mice, including an anthracycline model of cardiotoxicity. Marchetti and colleagues induced cardiac dysfunction with a single dose injection of 10mg/kg of DOX.⁹⁰ Mice were then treated with the 16673-34-0 NLRP3 inflammasome inhibitor at 100 mg/kg given 30 minutes before DOX, and then once a day for 10 days.⁹⁰ Mice treated with NLRP3 inhibitor displayed a less severe reduction in cardiac contractility, measured as LVEF, and reduced LV interstitial fibrosis deposition.⁹⁰ 16673-34-0 was found to reduce the activity of NLRP3 and caspase-1 and to consequently reduce infarct size expansion in mice.^90,145 16673-34-0 was also protective in the setting of a non-reperfused MI, which emphasized the beneficial role of NLRP3 inhibition independently from infarct size reduction.⁹⁰

Table I.

Inflammasome inhibitors in cancer therapy-induced cardiotoxicity

Drug	Mechanisms of action	Model of Cardiotoxicity	Finding(s)	References
Anakinra (rhIL-1Ra)	IL-1RI antagonist	AICM	Anakinra (1 mg/Kg/day) given for 4 days after DOX injection (18 mg/kg), reduced mortality, cardiac fibrosis, cardiac dysfunction, and cardiomyocyte apoptosis at 14 days after DOX treatment.	87
16673-34-0	NLRP3 inhibitor	AICM	16673-34-0 (100 mg/kg) given 30 minutes before DOX (10 mg/kg), and then once a day for 10 days, preserved cardiac function and reduced interstitial fibrosis deposition.	90
Resveratrol	Non-specific NLRP3 inhibitor	AICM	Resveratrol added in the chow of juvenile mice treated with DOX reduced NLRP3 inflammasome activity and systemic inflammation. It also prevented the detrimental effects of Ang II in a late phase.	95
Anakinra (rhIL-1Ra)	IL-1RI antagonist	Radiation-induced cardiotoxicity	Anakinra (100 mg/kg/day for 2 weeks) in irradiated ApoE−/− mice was able to attenuate radiation-induced arterial inflammation.	103
Dapagliflozin (SGLT-2 Inhibitor)	Non-specific NLRP3 inflammasome inhibitor	AICM +Trastuzumab	In HL-1 cells treated with DOX and trastuzumab (100 nM) dapagliflozin (50 nM) improved Ca2+ homeostasis and inhibited the pro-inflammatory “NLRP3-NF-κB–cytokines” pathways.	141
Anakinra (rhIL-1Ra)	IL-1RI antagonist	Radiation-induced cardiotoxicity	Anakinra (10 mg/kg twice a day for 7 days) treatment was able to prevent the decrease in cardiac contractile reserve observed in control irradiated mice.	105
MCC950	NLRP3 ATP-ase activity inhibitor	AICM	In rats, MCC950 (10mg/kg) treatment before DOX chemotherapy prevented the decline of cardiac contractility and reduced NLRP3 and IL-1β expression in the heart while reducing myocardial apoptotic cell death.	157
MCC950	NLRP3 ATP-ase activity inhibitor	AICM	MCC950 pretreated H9c2 cardiomyocytes (10 μM) 1h prior to incubation with 1 μM DOX reduced cardiomyocyte cell death and reduced the protein levels of NLRP3, caspase-1, and IL-1β.	158
NaHS	Non-specific NLRP3 inflammasome inhibitor	AICM	In H9c2 cardiomyocytes treated with DOX (5 μM), 400 μmol/l of NaHS reduced phosphorylation of p38 MAPK kinase while preserving cell viability. NaHS administration reduced also apoptotic cell death and oxidative stress following DOX.	161
NaHS	Non-specific NLRP3 inflammasome inhibitor	AICM	H2S protected H9c2 cells against DOX administration through inhibition of ER stress. Doxorubicin was administered in a range from 2 – 10 mmol/l for 24 h. NaHS given 30 min before exposure to DOX at the concentration of 400 mmol/l, following doxorubicin preserved cardiomyocyte death while reducing the oxidative stress.	162
SG1002 (H2S donor)	Non-specific NLRP3 inflammasome inhibitor	AICM	In mice, oral administration of SG1002, an H2S donor prodrug prevented early decline in cardiac function following DOX measured by global longitudinal strain and contractile reserve assessment following isoproterenol challenge.	163

AICM, anthracycline induced cardiomyopathy; DOX, Doxorubicin; IL-1Ra, Interleukin-1 receptor antagonist; IL-1RI, Interleukin-1 receptor type I; NLRP3, Nucleotide-binding and oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3

MCC950 is a small molecule that inhibits NLRP3 ATPase activity.^146–151 The use of MCC950 in several models of myocardial infarction, including pig and murine models, reduced infarct size, cardiac dysfunction, and IL-1β expression.^152,153 MCC950 also reduced myocardial fibrosis and IL-1β production in a hypertensive murine model induced by angiotensin II infusion.¹⁵⁴ MCC950 reduced hypertrophic remodeling preserving cardiac function in a model of post-menopausal heart disease.¹⁵⁵ Furthermore, the use of MCC950 (20 mg/kg/daily) for 15 weeks improved autophagy flux while reducing myocardial cell death.¹⁵⁶Importangtly, MCC950 has been tested successfully following DOX administration. Meng and colleagues have induced cardiac dysfunction in rats by administering 3 mg/kg of DOX every two days for 2 weeks, for a total cumulative dose of 21mg/kg. MCC950 at the dosage of 10 mg/kg was injected intraperitoneally 30 minutes before DOX treatment and once a day for the duration of DOX treatment.¹⁵⁷ MCC950 co-administered with DOX prevented the decline of LV contractility and reduced NLRP3 and IL-1β expression in the heart while reducing myocardial apoptotic cell death.¹⁵⁷ Corroborating results were obtained using in vitro H9c2 cardiomyocytes pretreated with the NLRP3 inhibitor MCC950 at a concentration of 10 μM for 1 hour prior to incubation with 1 μM Dox for 48 hour. MCC950 reduced the cardiomyocyte death and reduced the protein levels of NLRP3, caspase-1, and IL-1β.¹⁵⁸

Endogenous hydrogen sulfide (H₂S) is a colorless and odorless gas that is produced endogenously by the human body and exerts essential physiological functions.¹⁵⁹ Administration of H₂S has been shown to be protective against several cardiovascular diseases.¹⁶⁰ Sodium sulfide (Na₂S), an H₂S donor, reduced the NLRP3- dependent caspase-1 activation and pyroptotic cell death in treated primary cardiomyocytes following a canonical activation of NLRP3. Na₂S additionally reduced caspase-1 activity, and infarct size in mice subjected to experimental AMI.¹⁶¹ H₂S appears to reduce both the priming and triggering signals activating the NLRP3 inflammasome.¹⁶² Notably, H₂S has also been tested in reducing DOX-induced cardiomyopathy. In vitro, H9c2 cells were treated with 5 μM DOX to model the anthracycline-induced cardiotoxicity; 30 minute prior to DOX administration, a group of cells received 400 μmol/l of the H₂S donor, sodium hydrosulfide (NaHS).¹⁶³ Exogenous H₂S attenuated DOX-induced cytotoxicity in H9c2 cells by reducing phosphorylation of p38 MAPK. NaHS preserved cell viability, reduced apoptotic cell death, and reduced ROS production.¹⁶³ Similar results were obtained by another group using a similar in vitro model of cardiotoxicity. H₂S protected H9c2 cells against DOX administration through inhibition of ER stress. DOX was administered in a range from 2 to 10 mmol/l for 24 hour.¹⁶³ NaHS was then administered for 30 minute before exposure to DOX at the concentration of 400 mmol/l. NaHS preserved cardiomyocyte death while reducing the oxidative stress following DOX administration.¹⁶³An orally active, slow-releasing H₂S-donor, SG1002, was tested in mice following DOX administration. Mice were randomized to either regular chow or SG1002 enriched chow a week prior to the DOX regimen (5 weekly doses of Doxorubicin hydrochloride at 5 mg/kg). SG1002 prevented early decline in cardiac function following DOX measured by global longitudinal strain and contractile reserve assessment following isoproterenol challenge.¹⁶⁴

Although never tested to date in chemotherapy-induced cardiotoxicity, other pharmacological NLRP3 inhibitors are available. These molecules have been well documented, with promising results, in pre-clinical studies focused on several cardiovascular diseases.⁵

Colchicine is one of the oldest drugs in use today and was first described in Egyptian medical text. The clinical use of colchicine is not only limited to treating gout, but also for familial Mediterranean fever as well as acute and recurrent pericarditis; all diseases in which the pathogenesis is mediated by NLRP3 activity.^75,165,166 Colchicine is also under clinical investigation in several randomized trials enrolling patients with acute and chronic coronary artery disease. Colchicine treatment has been consistently found to be effective in reducing cardiovascular risk in acute settings.^167–173

An additional small synthetic inhibitor for kappa B kinase β (IKKβ) inhibitor, Bay 11-7082, was shown to inhibit the NLRP3 ATPase independently from its IKKβ inhibitory activity. This characteristic makes Bay 11-7082 capable of blocking the priming signaling by preventing NF-kB nuclear translocation while precluding the oligomerization of the NLRP3 components.¹⁷⁴

OLT1177 is a beta-sulfonyl nitrile molecule that also inhibits the ATPase activity of the NLRP3 inflammasome.^175,176 OLT1177 was able to inhibit NLRP3 activity in monocytes isolated from patients with the cryopyrin-associated periodic syndrome (CAPS); therefore, with constitutively activated NLRP3.¹⁷⁶ Phase 2 Clinical trials have been conducted to assess the safety of OLT1177 in patients with gout and with heart failure with reduced ejection fraction (HFrEF).¹⁷⁷

PERSPECTIVES AND CONCLUSION

The progress of new cancer treatments and the development of improved approaches to manage patients have dramatically increased life expectancy following a cancer diagnosis. Consequently, cardiotoxicity secondary to cancer therapy has become the non-tumor related prominent leading cause of morbidity and mortality among cancer survivors.

Although with limited success, several strategies to limit cancer therapy-related cardiotoxicity have been explored. Through improved understanding the variety of established and novel cancer therapies, opportunities exist to improve understanding of the pathophysiology of cancer treatment-induced cardiotoxicity. Refining these therapeutic strategies will meet an urgent clinical need for better cardioprotective interventions that could improve outcomes for cancer survivors.

Increasing evidence suggests that the activity of the NLRP3 inflammasome is central in the pathogenesis of several cardiovascular diseases. The most characterized mechanisms responsible for the activation of NLRP3 are mainly linked to mitochondrial dysfunction, the release of ROS, and impaired autophagy, which can foster NLRP3-mediated cell death. All the studies summarized here have explored the role of NLRP3, mostly through indirect measures. Considering the nature of this convoluted pathway and the tight regulations, it is essential to suggest the use of more complex genetically-modified animal models in order to illustrate the involvement of the NLRP3-dependent pyroptotic cell death as a mechanism of cardiac damage following cancer therapy.

The similarities shared by the involvement of NLRP3 inflammasome across many cancer treatments with existing disease processes such as atherosclerosis, acute myocardial infarction, heart failure, and myopericardial inflammatory disorders suggest the relationship between NLRP3, and cancer therapy-associated cardiotoxicity is plausible and merits additional study. Nevertheless, comorbid conditions, including atherosclerosis, hypertension and metabolic syndromes, can worsen cardiac health by triggering NLRP3 activity even before a cancer diagnosis is made and the administration of cancer therapy with potential cardiotoxic effects is initiated.

Abbreviation:

AF

Atrial fibrillation

AICM

Anthracycline-induced cardiomyopathy

AKT

Protein kinase B

ALR

AIM2-like receptor

AMI

Acute myocardial infarction

ASC

Apoptosis-associated speck-like protein containing a CARD domain

BMDM

Bone marrow-derived macrophages

Ca²⁺

Calcium

CaMKIIδ

Ca²⁺/calmodulin-dependent protein kinase II δ

CAPS

Cryopyrin-associated periodic syndrome

CARD

Carboxy-terminal caspase recruitment domain

CHF

Congestive heart failure

CVB3

Coxsackievirus B3

DAMPS

Danger-associated molecular patterns

DOX

Doxorubicin

EGFR

Epidermal-grow factor receptor

ER

Endoplasmic reticulum

FDA

Food and Drug Administration

FGFR

Fibroblast grow factor receptor

GDP

Guanosine diphosphate

GSDMD

Gasdermin D

H₂S

Hydrogen sulphide

HER2

Human epidermal growth factor receptor 2

HFpEF

Heart failure with preserved ejection fraction

HFrEF

Heart failure with reduced ejection fraction

ICI

Immune checkpoint inhibitor

IKKβ

Inhibitor for kappa B kinase β

IL-18

Interleukin-18

IL-1Ra

Recombinant IL-1 receptor antagonist

IL-1RI

Interleukin-1 receptor type I

IL-1β

Interleukin-1β

K⁺

Potassium

LDLR

Low-density lipoprotein receptor

LRR

Leucine-rich repeats

LV

Left ventricular

LVEF

Left ventricular ejection fraction

MAPK

Mitogen-activated protein kinase

mtDNA

Mitochondrial DNA

Na₂S

Sodium sulphide

NaHS

Sodium hydrosulfide

NEK

NIMA-related kinases proteins

NF-kB

Nuclear factor kappa-light-chain-enhancer of activated B cells

NLR

(NOD)-like receptors

NLRP3

Nod-like receptor protein 3

NOD

Nucleotide-binding and oligomerization domain

NRTK

Non-receptor tyrosine kinase

NTproBNP

N-terminal-pro hormone B-type natriuretic peptide

PAMPS

Pathogen-associated molecular patterns

PDGFR

Platelet-derived grow factor receptor

PI3K

Phosphoinositide 3 Kinase

PRR

Pattern recognition receptor

PYD

Pyrin domain

RAGE

Receptor for advanced glycation end-products

ROS

Reactive oxygen species

RT

Radiation therapy

RTK

Receptor tyrosine kinases

SGLT2

Sodium-glucose Cotransporter-2

TK

Tyrosine kinases

TKI

Tyrosine kinase inhibitors

TLR

Toll-like receptors

TXNIP

Thioredoxin-interacting protein

VEGFR

Vascular endothelial growth factor

VO₂

against medical advice