REVIEWS

The NLRP3 inflammasome in acute

myocardial infarction
Stefano Toldo1–3 and Antonio Abbate1,2
Abstract | 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.

Acute myocardial infarction (AMI) remains one of the the resorption of the wound and the formation of the
common causes of hospitalization and death world- scar, whereas tissue regeneration, while present, seems
wide1. The sudden reduction in coronary artery flow not to be particularly effective3,4. Before the introduc-
secondary to coronary artery atherothrombosis results tion of reperfusion strategies to treat AMI, the disease
in an abrupt reduction in cellular energy, leading to often led to transmural myocardial necrosis, which
subsequent cell necrosis. Current treatment strategies exposes the patient to increased risk of wall rupture.
for AMI are centred on restoring flow in the coronary In such cases, inflammation was considered a neces-
artery (reperfusion) by dissolving the thrombus with sary consequence of AMI, as it allows the infarct to
medications and/or implantation of an intravascular heal and the scar to form; anti-inflammatory therapies
stent 1. Although reperfusion strategies are successful in were thus thought to increase the risk of wall rupture3.
limiting injury to the heart, reducing infarct size, and However, researchers have since discovered that exces-
improving overall prognosis, patients with AMI remain sive or unopposed inflammation can equally impair
at short-term and long-term increased risk of heart the formation of a solid scar and pose a similar risk
failure1–2. Therefore, improved treatment strategies for of rupture3,5–7.
1
Pauley Heart Center, AMI are urgently needed for the prevention of adverse With the advent of reperfusion therapy, the inflam-
Sanger Hall, 1201 East
cardiac remodelling and eventual heart failure. In this matory response to ischaemia and reperfusion has
Marshall Street, Richmond,
Virginia 23298, USA. Review, we describe the data from experimental stud- proven also to be more complex than previously
2
VCU Johnson Center for ies in small and large animals showing that NACHT, thought3. This extended paradigm proposes that inflam-
Critical Care and Pulmonary LRR, and PYD domains-containing protein 3 (NLRP3) mation has a role not only in removal of cellular debris
Research, Molecular Medicine inflammasome-targeted therapies might be a viable and repair of injured tissue, but that it also contributes to
Research Building, 1220 East
Broad Street, Richmond,
strategy for the reduction of infarct size and prevention further injury. The inflammation-­mediated worsening
Virginia 23298, USA. of heart failure following AMI. Additional studies with of the injury occurs in a paracrine manner to the myo-
3
Division of Cardiothoracic selective NLRP3 inhibitors are eagerly awaited. cardial tissue that was initially salvaged by reperfusion
Surgery, Sanger Hall, in the infarct border zone. In addition, inflam­mation
1201 East Marshall Street,
Acute inflammatory response in AMI can further induce a systemic response that favours
Richmond, Virginia 23298,
USA. The paradigm of inflammation following injury adverse remodelling, similar to the ­neurohormonal
Correspondence to A.A.
involves the elimination of the offending agent (in case ­activation seen after AMI3.
[Link]@ of an infection), removal of cell debris, repair of the
[Link] injured tissue, and promotion of tissue regeneration NLRP3 as a sensor of injury
doi:10.1038/nrcardio.2017.161 (if applicable). As the injury to the heart during AMI As an integral part of the innate immune system, the
Published online 16 Nov 2017 is sterile, the resulting inflammation is responsible for inflammasome is a macromolecular protein complex

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Key points of the inflammasome. Although caspase 1 has several

functions unrelated to the inflammasome, its main
• The inflammasome is a macromolecular structure in the cell responsible for sensing role in the inflammasome is to cleave pro‑IL‑1β into
danger and triggering a local or systemic inflammatory response its active form, and as such, caspase 1 is also known as
• Upon activation, the inflammasome produces large amounts of active cytokines the IL‑1β‑converting enzyme12,13.
(primarily IL‑1β) for extracellular secretion, and those cytokines mediate the acute IL‑1α and IL‑18 are other members of the IL‑1 f­ amily
phase of an inflammatory response, such as fever of cytokines8,12. Caspase 1 can also activate IL‑18 by
• The most widely characterized inflammasome sensor in the heart is NACHT, LRR, cleavage of the inactive pro‑IL‑18 (REFS 8,12). Contrary
and PYD domains-containing protein 3 (NLRP3), which is activated in response to pro‑IL‑1β and pro‑IL‑18, pro‑IL‑1α lacks a cleavage
to noninfectious stimuli such as cell debris during acute myocardial infarction
site for caspase 1, but is already active in this form14.
• Activation of the NLRP3 inflammasome triggers further myocardial damage indirectly Nevertheless, cleavage of pro‑IL‑1α seems to increase
through the release of IL‑1β and directly through promotion of inflammatory cell
the affinity of IL‑1α for the IL‑1 receptor 14. In rare
death via pyroptosis
instances, pro‑IL‑1α is cleaved by the Ca2+-dependent
• Experimental studies have shown that strategies inhibiting the activation of the
enzyme calpain14. Other extracellular enzymes (such
NLRP3 inflammasome in the early reperfusion period after acute myocardial
infarction reduce the overall size of the infarct and preserve normal cardiac function
as neutrophil elastase, granzyme B, and chymase) can
also cleave pro‑IL‑1α14. Furthermore, caspase 1 activity
• IL‑1 blockade can prevent the recurrence of acute myocardial infarction in patients
can regulate the secretion of pro‑IL‑1α15. Activation of
who have experienced a previous event and might improve exercise capacity and
cardiac function in patients with heart failure caspase 1 within the inflammasome results in a form
of inflammatory cell death known as pyroptosis8,12.
In contrast to apoptosis (typical programmed cell
death), death by pyroptosis is associated with cell swell-
that finely regulates the activation of caspase 1 and the ing, increased membrane permeability, and cell rupture,
production and secretion of powerful pro-­inflammatory leading to the extracellular release of pro-inflammatory
cytokines such as IL‑1β and IL‑18 (REF. 8). The sensing mediators such pro‑IL‑1α8,10,12,14. The loss of cell mem-
component of the inflammasome is a member of the brane integrity is mediated by gasdermin D, a substrate
nucleotide-binding oligomerization domain-­containing of caspase 1 that forms N‑terminal fragment oligomers
protein (NOD)-like receptor (NLR) proteins8,9. The within the cell membrane after its cleavage, followed by
classic structure of an NLR is tripartite with leucine-rich the formation of pores16. Gasdermin D pores are perme­
repeats domain at the C‑terminal, a central NOD, and able to macromolecules and mediate the unconven­
an effector domain at the N‑terminal, which interacts tional extracellular release of mature IL‑1β, IL‑18, and
with downstream signalling molecules8,9. active caspase 1. Whether gasdermin D mediates the
NLRP3 senses ‘danger’ in the form of lysosomal caspase 1‑dependent release of IL‑1α has not been
destabilization or a decline in intracellular K+ concen­ determined. In addition, caspase 1 cleaves several pro-
tration8. The presence of any microbial or nonmicro- teins involved in the Krebs cycle, resulting in a dramatic
bial pathogen that cannot be digested by the lysosomal decrease in cell energy production that eventually leads
machinery leads to the activation of a secondary to cell swelling and rupture17.
defence mechanism that involves the leakage of cathep-
sin B into the cytoplasm and K+ efflux from the cell, to NLRP3 inflammasome in the heart
induce conformational changes to the NLRP3 (REF. 8). The activation of the NLRP3 inflammasome in the
Such changes lead to oligomerization and recruit- heart involves two independent steps18. NLRP3 and
ment of a macromolecular assembly with a central other important components of the inflammasome
scaffold protein known as the apoptosis-associated are not constitutively expressed in cardiomyocytes,
speck-like protein containing a caspase recruitment and their expression is regulated by nuclear factor
domain (ASC), so-called because of its character­istic (NF)‑κB8,18 (FIG. 1). Pro-inflammatory stimuli such as
formation of a large perinuclear speck under light cellular debris or microbial products that bind to Toll-
microscopy when the inflammasome is formed in like receptors or cytokines can induce the expression
leukocytes8,10. A model for the formation of the ASC of NLRP3 and the other inflammasome components in
specks has been proposed based on findings from cardiomyocytes, leukocytes, and other noncardiomyo­
electron microscopy 11. The initial oligomerization of cyte resident cells such as fibroblasts and endothelial
NLRP3 that occurs in a ring-like conformation forms a cells10,19. The cellular debris and microbial products are
platform for the polymerization of ASC into filaments. collectively referred to as damage-associated m ­ olecular
Given that these filaments are insoluble in common patterns (DAMPs) or pathogen-associated molecu-
detergents used in cell biology, the structure is very lar ­patterns (PAMPS)8. When priming is completed and
stable. In addition to NLRP3 and ASC, another impor- the inflammasome components are expressed, a trigger
tant component of the inflammasome is caspase 1, is required for the activation of the NLRP3, which is
an enzymatic effector. During the formation of the largely, but not exclusively, dependent on intracellular
inflammasome, a large number of caspase 1 filaments K+ concentration. Lysosomal destabilization activates
branch out from the central core of polymerized ASC, a signalling pathway that indirectly leads to increased
generating a star-like structure. This high concentra- membrane permeability for K+ and increased intra­
tion of caspase 1 might favour contact with substrates11. cellular efflux. Extracellular ATP triggers K+ efflux bind-
Activation of caspase 1 is required for the formation ing to the P2X purino­receptor 7 (P2X7). The change

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in K+ concentration leads to a conformational change Activation by kinases and oxidative stress

of the NLRP3 that allows recruitment of ASC8 (FIG. 1). Several intermediate steps dependent on additional cyto-
Furthermore, cathepsin B leakage from lysosomal and plasmic adaptor proteins or kinases are also involved in
autophagic vesicles contributes to NLRP3 activation the activation process. The serine/threonine–­protein
and post-AMI myocardial injury 20. kinase Nek7, a member of the never in mitosis A

DAMPs
↑eATP
K+ Cellular stress
TLR/ Plasma or injury
IL-1R P2X7 membrane
K+
NOD2 MyD88
K+ efflux Mitochondrion
IRAK1/4 Lysosome Autophagy or
Nek7 ROS
destabilization mitophagy
• Oxidative stress
Cathepsin B • Unfolded protein response

NLRP3 TXN TXN

TXNIP TXNIP
Inflammasome Inflammasome IL-1β
priming trigger NLRP3 IL-18
activation NLRP3
oligomerization
GSDMD
NF-κB oligomerization
BTK
mRNAs for inflammasome
components
• NLRP3
• ASC
• Pro-caspase-1 ASC polymerization
• Pro-IL-1β
• Pro-IL-18
ASC

Pro-caspase-1
recruitment and
activation
NF-κB
Pro-caspase-1

Nucleus Cytoplasm
Pro-IL-1β Pro-IL-18 GSDMD
Figure 1 | NLRP3 inflammasome formation pathways. The formation of the inflammasome inNature the heart requires
Reviews two
| Cardiology
independent steps: priming and triggering. The priming signal is dependent on the activity of nuclear factor (NF)‑κB through
stimulation of the membrane Toll-like receptors (TLRs) and the downstream signalling mediated by myeloid differentiation
primary response protein MyD88 and interleukin‑1 receptor-associated kinases (IRAKs). The TLRs sense extracellular threats
through damage-associated molecular patterns (DAMPs) and prime the cells to respond to the potential injurious conditions
by increasing the transcription and translation of inflammasome components and the associated cytokines (IL‑1β and IL‑18).
These cytokines function in a paracrine fashion on the membrane cytokine receptor and converge on the same pathways to
amplify the signal. A similar priming effect is mediated by nucleotide-binding oligomerization domain-containing protein 2
(NOD2). The primary signal is necessary but insufficient to form the inflammasome in cardiomyocytes in the absence of the
trigger signal. The activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) is mediated by extracellular
and/or intracellular pathways. The increase in extracellular ATP (eATP) activates the P2X purinoreceptor 7 (P2X7) and leads
to K+ efflux, a step that triggers NLRP3 activation. Lysosomal destabilization by indigestible material is another mechanism
that leads to NLRP3 activation by leakage of the lysosomal enzyme cathepsin B and by induction of K+ efflux. The serine/
threonine–protein kinase Nek7 senses the K+ efflux and binds NLRP3, allowing its activation. Thioredoxin-interacting protein
(TXNIP) links oxidative stress and the unfolded protein response to NLRP3 activation. TXNIP is freed from thioredoxin (TRX)
and binds NLRP3. The mitochondria also have an important role in producing reactive oxygen species (ROS). Furthermore,
ineffective clearance of mitochondrial debris by mitophagy contributes to lysosomal destabilization. By contrast, effective
mitophagy and autophagy suppress the activation of NLRP3. The tyrosine–protein kinase BTK also binds NLRP3 and
apoptosis-associated speck-like protein containing a CARD (ASC), leading to inflammasome activation after ischaemia.
The active NLRP3 oligomerizes, forming a circular structure that functions as a platform for the polymerization of ASC into
filaments, which in turn work as a central core from which caspase 1 filaments branch, forming a star-like structure. Active
caspase 1 cleaves the inactive pro‑IL‑1β and pro‑IL‑18 into the active forms, IL‑1β and IL‑18. Gasdermin D (GSDMD) is an
additional substrate of caspase 1 that oligomerizes upon cleavage and forms pores in the cell membrane with the N‑terminal
fragments, which allow the extracellular release of active IL‑1β and IL‑18.

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(NIMA)-related kinase family, acts downstream of NLRP3 inflammasome formation, whereas activation of
P2X7 and K+ efflux. Nek7 binds to NLRP3 and regulates autophagy limits the secretion of active IL‑1β32. During
NLRP3 oligomerization and activation21. Nek7 is highly myocardial ischaemia–­reperfusion injury, autophagy
expressed in heart muscle and might be a target for limits myocardial damage; conversely, inhibition of
intervention to inhibit inflammasome formation in the autophagy exacerbates c­ ardiac remodelling 33. However,
heart 21. Oxidative stress can also activate the inflamma­ whether autophagy regu­lates inflammasome activity
some in a process mediated by thioredoxin-interacting during myocardial ischaemia–reperfusion needs to
protein (TXNIP)22. The production of reactive oxygen be determined.
species (ROS) and the induction of the unfolded pro-
tein response together cause the detachment of TXNIP Differential roles of the inflammasome
from thioredoxin, which functions as an antioxidant Although every cell type in the heart might be capable
by reducing oxidized sulfhydryl groups. Free TXNIP of triggering the NLRP3 inflammasome if appropriately
then participates in NLRP3 activation and subsequent stimulated, the stimuli needed to activate the inflamma­
inflammasome formation. The inhibition of TXNIP some and the effects of the active inflammasome might
using small interfering RNA in the heart has been be different. Circulating monocytes constitutively
shown to reduce inflammasome activation and infarct express many components of the inflammasome and
size after ischaemia–reperfusion injury 22. This process require minimal priming to produce large amounts of
couples the response to oxidative stress to initiation of IL‑1β34. Cardiomyocytes have low expression of NLRP3
the i­ nflammatory response (FIG. 1). and caspase 1 and do not express and secrete high
The tyrosine–protein kinase BTK interacts with ­levels of IL‑1β even when stimulated with high doses of
both NLRP3 and ASC and is also required for the activ­ pro-inflammatory mediators. However, both monocytes
ation of NLRP3 in vivo23. Furthermore, the inhibition and cardiomyocytes can express and activate IL‑18, and
of BTK with ibrutinib has been shown to suppress cardiomyocytes die of pyroptosis following caspase 1
inflammasome activation and reduce infarct size after activation8,34,35. The difference between the secretion of
cerebral ischaemia23. IL‑1β and secretion of IL‑18 might involve differences
in how they are transcriptionally regulated. Indeed,
Role of mitochondria IL‑1β mRNA levels in cardiomyocytes are very low,
Mitochondria are one of the major sources of ROS and often undetectable, and unaffected by treatment such as
have an important role in determining cell fate under lipopolysaccharide incubation34.
conditions of stress24. In addition, mitochondria are
involved in necrotic and apoptotic cell death25. In the NLRP3 inflammasome in AMI
past 6 years, the role of the mitochondria in the regu­ NLRP3 inflammasome formation
lation of the inflammasome and their association In patients, evidence of NLRP3 inflammasome activ­
with pyroptosis have become well understood 26,27. ation in the context of AMI is limited to several autopsy
Mitochondrial dysfunction directly activates the NLRP3 cases19 and to measurement of plasma levels of NLRP3
inflammasome by producing ROS and by inducing and caspase 1 (REF. 36). However, the time-dependent
K+ efflux 26,27. Mitophagy, the clearance of damaged and activation of the NLRP3 inflammasome in the heart
dysfunctional mitochondria through the autophagic has been investigated in preclinical studies using a­ nimal
pathway, has also been shown to regulate inflamma­ models. The expression of NLRP3 and the activity of
some activity 28,29. Ineffective mitophagy perpetuates the the inflammasome in the heart were low when meas-
cellular surge in ROS, but also promotes the cytoplasmic ured within 3 h after AMI37,38 in a mouse model of
accumulation of mitochondrial DNA, which enhances ischaemia–­reperfusion injury. In this model, the NLRP3
caspase 1 activation and IL‑1β production28. In addition, inflamma­some was formed in the myocardium within
mitochondrial fission (division) and fusion also contrib- 3–24 h of the AMI37 and contributed to both the inflam-
ute to the regulation of mitochondrial homeostasis and matory response and the exacerbation of the ischaemia–­
inflammasome activation29,30. Impairment of mitochon- reperfusion injury 8,10,37–40. Increased expression and
drial fission, caused by the deletion of dynamin 1‑like activity of the inflammasome was found to peak after
protein, leads to an increase in NLRP3‑dependent 1 and 3 days in mice with reperfused and nonreperfused
caspase 1 activation and IL‑1β secretion29. Finally, AMI, respectively. During the early phases of formation,
cardio­lipin, a mitochondrial lipid, can bind to and activ­ the inflammasome specks can be seen in the endothelial
ate the NLRP3 inflammasome31. Conversely, inhibition cells, cardiomyocytes, and fibroblasts. As the leukocytes
of cardiolipin production suppresses the activation of infiltrate the heart, the majority of specks can be seen
the inflammasome. within the granulocytes and macrophages. During the
postinjury healing phase, as the infiltrate resolves,
Role of autophagy the aggregates are seen more commonly in isolated
The autophagic pathway is another regulator of inflam- ­cardiomyocytes or fibroblasts8,10.
masome function28,32. Autophagy is a proteolytic process Experimental data suggest that the effects of NLRP3
that involves the removal of misfolded and damaged pro- activation in the heart are cell-type-specific41,42. The
teins and organelles and is important for the maintenance induction of inflammasome formation in fibroblasts,
of the cellular homeostasis28. In primary human mono- endothelial cells, or leukocytes results in the secretion
cytes and macrophages, inhibition of autophagy enhances of IL‑1β. However, cardiomyocytes do not consistently

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However, in the context of sterile inflammation, this

Wild-type mice Downregulation or inhibition
in vivo or ex vivo of inflammasome components inflammatory response results in further injury and very
little benefit 8. When exposed to ischaemia–reperfusion
injury, mice that lack the Nlrp3 gene or have under­going
• Nlrp3–/– ex vivo siRNA silencing to suppress Nlrp3 expression have a
• Asc–/– in vivo
• Casp1–/– smaller infarct size and better cardiac function than
• siRNA against Nlrp3 wild-type mice19,22,44 (FIG. 2). Accordingly, mice deficient
• NLRP3 inhibitors in ASC or caspase 1 are protected against ischaemia–
reperfusion injury and have reduced myocardial levels
↓ Infarct size
of active IL‑1β, suggestive of reduced inflammasome
activity 19 (FIG. 2). Consistent with the time course of the
expression of NLRP3 and the activity of the inflamma­
some in the heart, which are both low at the onset of
Figure 2 | Strategies to reduce infarct size by inhibiting the NLRP3 inflammasome
Nature Reviews | Cardiology ischaemia37,38,45, the NLRP3 knockout mouse was not
in experimental animal models of myocardial ischaemia–reperfusion injury. The left
and right ventricular cavities and the infarct areas of the hearts of untreated wild-type protected against injury within the first few hours after
mice and genetically modified or treated mice are shown. The formation of the ischaemia was induced38,45.
inflammasome is a critical step following ischaemia–reperfusion injury. Preventing the
formation of the inflammasome by genetically deleting any of the inflammasome Novel inhibitors of the inflammasome
components (NACHT, LRR, and PYD domains-containing protein 3 [NLRP3], apoptosis- Although the molecular structure of NLRP3 is known,
associated speck-like protein containing a CARD [ASC], or caspase 1), using small the exact mechanism by which K + concentration
interfering RNA (siRNA) specific for NLRP3, or administering selective NLRP3 inhibitors induces the conformational change and aggregation of
has been shown to reduce infarct size. the inflammasome is not well understood. The sulfonyl­
urea glyburide was shown to inhibit IL‑1β release from
secrete high levels of IL‑1β. Nevertheless, NLRP3 leukocytes independently of its capacity to induce
inflammasome formation in cardiomyocytes activates insulin release from the pancreatic β cells, and it also
caspase 1 and induces pyroptosis41,42. inhibited the NLRP3 inflammasome in vitro without
NLRP3 is not the only inflammasome sensor that suppressing its ATPase activity 46. However, when used at
can trigger caspase 1 to release IL‑1β and IL‑18. Other the doses required to inhibit the inflammasome in vivo,
well-characterized NLRs include NLRP1, NLR family glyburide caused lethal hypoglycaemia in mice39.
CARD domain-containing protein 4 (NLRC4), and FIGURE 3 and TABLE 1 show the characteristics and the
the interferon-inducible protein AIM2, but the role of proposed sites of action of the different experimental
these receptors in the context of cardiovascular diseases NLRP3 inflammasome inhibitors that have been tested
is less clear 8. Another important member of this family in models of AMI. Marchetti and colleagues designed a
of innate immune receptors, NOD2, has been shown novel inhibitor derived from glyburide, but lacking the
to exacerbate myocardial injury in a mouse model of cycloexylurea moiety group, which is responsible for
permanent coronary occlusion43. NOD2 expression was insulin secretion39. Therefore, this molecule could not
increased in the myocardium of wild-type mice, whereas induce insulin release, and after modification of side
its deletion reduced myocardial damage and the expres- residues, could selectively inhibit the NLRP3 (REF. 39).
sion of pro-inflammatory markers, including IL‑1β43. When given in a single dose or in repeated doses before
NOD2 induces NF‑κB activation and thus contributes ischaemia or after reperfusion, this NLRP3 inhibitor
to inflammasome priming 9,43. significantly reduced infarct size and preserved cardiac
function, thus demonstrating the critical role of early
The inflammasome in disease progression activation of the NLRP3 inflammasome for downstream
The role of the NLRP3 inflammasome in AMI pro- inflammatory signalling 39,47. The inhibitor is specific
gression should not come as a surprise, considering for NLRP3 and prevents NLRP3 oligomerization after
that inflammasome activity is involved in the typical its activation. Marchetti and colleagues also obtained
response to injury. Given that AMI is a proto­typical similar results using a different NLRP3 inhibitor
example of sterile inflammation, the response to injury (OLT1177)48. In a mouse model, OLT1177 administra-
and the recruitment of inflammatory cells are expected tion resulted in a 60% reduction in infarct size compared
to be at least partly dependent on the NLRP3 inflamma­ with vehicle-treated controls (A. A., unpublished data).
some8. Whether the formation of the inflammasome in OLT1177 was initially developed as a topical treatment
the injured cardiomyocytes is a beneficial and protective for degenerative arthritis, but is now being tested in a
mechanism or a mechanism of further injury remains phase II clinical trial for the treatment of acute gouty
unclear. Since 2011, numerous experi­mental studies arthritis after successful phase I clinical testing 49.
have investigated this question 10,19. Inflammasome In 2010, Juliana and colleagues reported that
formation is an energy-requiring process that occurs Bay 11–7082, a compound known to inhibit NF‑κB,
in injured cells to rapidly induce an inflammatory could also inhibit the ATPase activity of NLRP3, pre-
response to the area. This inflammatory cascade of venting the formation of the inflammasome in response
events ­resembles the ‘defensive’ process, which, from to NLRP3‑specific stimuli50. In a separate mouse study,
an evolutionary standpoint, results from a microbial Bay 11–7082 administered intraperitoneally 10 min
invasion at the cost of sacrificing those ‘sentinel’ cells. before reperfusion in an ischaemia–reperfusion AMI

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Extracellular
ATP

K+
P2X7
K+

K+ efflux
Lysosome
destabilization

NLRP3
oligomerization
Intracellular
ATP NLRP3
activation

ATPase
ASC
polymerization

BAY 11-7082 INF4E OLT1177 16673-34-0 MCC950 Colchicine

(dapansutrile)

Figure 3 | Mechanism of action of NLRP3 inhibitors tested in experimental models of acute myocardial
Nature Reviewsinfarction.
| Cardiology
Several chemical compounds have been developed with inhibitory effects on inflammasome activity, some of which have
been tested in animal models of acute myocardial infarction and in clinical trials. BAY‑11‑7072, INF4E, and OLT1177 can
inhibit the ATPase activity of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3). OLT1177, 16673‑34‑0, and
MCC950 are compounds that inhibit NLRP3 and prevent its oligomerization. Colchicine has multiple mechanisms of
inhibition, acting upstream of NLRP3 to prevent the opening of the P2X purinoreceptor 7 (P2X7) channel, to destabilize
the lysosome, and to inhibit NLRP3 activation. Colchicine can also act downstream of NLRP3 by inhibiting the
polymerization of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC).

model significantly reduced inflammasome formation suppress the transport of mitochondria and the subse-
in the heart and decreased infarct size22. When given quent colocalization of ASC to NLRP3, which suggests
30 min before induction of ischaemia in a rat model of that microtubules create the sites for the inflamma­
ischaemia–reperfusion, the Bay 11–7082 compound some components to interact, which eventually leads
also significantly reduced infarct size and preserved to NLRP3 inflammasome activation57. In a non­reper­
cardiac function51. Cocco and colleagues developed fused AMI mouse model, a high dose of colchicine
acrylamide derivatives that covalently bind to NLRP3 (0.1 mg/kg) administered daily for 7 days signifi­cantly
to inhibit its ATPase activity 52. A dose of 50 μmol/l of reduced inflammasome activation after 24 h, decreased
the compound administered ex vivo to a mouse model infarct size and ventricular remodelling, and prolonged
of AMI 20 min before induction of ischaemia resulted in 7‑day survival58 (FIG. 3).
a reduction in inflammasome activity and infarct size52. Although the pharmacological inhibitors discussed
Furthermore, MCC950, a small molecule known for its have inherent limitations in specificity, they are impor-
anti-­inflammatory properties, was shown to selectively tant tools for the validation of genetic mouse models and
inhibit the binding of NLRP3 to ASC in mice in vivo, are therefore essential for clinical translation. Additional
independently of NLRP3 ATPase activity 53. MCC950 validation and comparative studies between different
also reduced infarct size in a porcine model of ischae- experimental models are needed59.
mia induced by balloon occlusion of the left anterior
descending c­ oronary artery 54. NLRP3 inflammasome inhibition: beyond infarct size
Colchicine is a nonspecific inhibitor of the NLRP3 reduction. In agreement with the timeline of the expres-
inflammasome55. Originally thought to function only as sion and the activation of the NLRP3 inflamma­some,
an inhibitor of microtubule polymerization and leuko­ Toldo and colleagues have shown that delaying treatment
cyte diapedesis, a large part of the efficacy of colchicine with an NLRP3 inhibitor (16673‑34‑0) by 60 min after
as an anti-inflammatory drug is related to its the inhib­ the beginning of reperfusion did not limit its cardio­
ition of the NLRP3 inflammasome56. Colchicine pre- protective benefits37. However, the benefit of NLRP3
vents inflammasome activity at two levels: it inhibits the inflammasome inhibition was lost if treatment was
activation of the P2X7 receptor, and the poly­merization given >3 h after the beginning of reperfusion, suggest­
of ASC by interfering with the interaction between the ing that the formation of the NLRP3 inflamma­some
pyrin domains56 (FIG. 3). Colchicine has been shown to in the heart occurs between 1 and 3 h after reperfusion

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in the mouse (FIG. 4). Similarly, in the model of non­ inflammasome inhibition seems to affect only the
reperfused AMI, in which the infarct size is dictated by ­portion of the myocardium that was temporarily rescued
the area of ischaemia and reperfusion-induced inflam- by reperfusion, but eventually dies by pyroptosis follow­
matory cell death is absent, the NLRP3 inhibitor did ing inflammasome formation as part of reperfusion
not reduce infarct size47. The mechanism by which the injury. Finally, whereas inhib­ition of the components
NLRP3 inflammasome inhibitors reduce infarct size is of the inflammasome prevents ­pyroptosis, inhibition of
likely not to be attributable to reduced release of mature IL‑1β activity did not have any effect 8.
IL‑1β for several reasons. First, IL‑1β might not remain Regardless of whether the ischaemic myocardium
elevated for several hours after AMI. Furthermore, undergoes reperfusion, the NLRP3 inflammasome
IL‑1β blockers were unable to reduce infarct size when remains active for several days after AMI. The ASC specks
administered during reperfusion60. In addition, NLRP3 can be seen in individual cardiomyocytes, fibroblasts,

Table 1 | NLRP3 inflammasome inhibitors in experimental AMI

Name (chemical name) Chemical structure Doses/route/animal Experimental findings in the Refs
context of AMI
16673‑34‑0 NH2 5–100 mg/kg given before • Reduction in infarct size at 37,39,47
5‑Chloro‑2‑methoxy‑N-[2-(4‑ O S O
or up to 60 min after 24 h (measured by pathology,
sulfamoylphenyl)ethyl]benzamide reperfusion in a mouse echocardiography, and
coronary artery ligation troponin I plasma levels)
model • Improvement in cardiac
remodelling and left ventricular
dysfunction in reperfused and
nonreperfused AMI
O NH • Reduction in caspase 1
activation and cardiomyocyte
O pyroptosis in the early phases
H3C
of AMI and of apoptosis and
Cl myocardial fibrosis in the later
phases of AMI
BAY 11–7082 O Pretreatment with the • Reduction in infarct size 22,50,51
3-[(4‑Methylphenyl) S
drug (dose not specified) • Reduction in inflammasome
sulfonyl]-(2E)-propenenitrile before ischaemia or activity (caspase 1 activity,
O N
before reperfusion in a IL‑1β levels)
mouse or rat model of • Preservation of cardiac function
ischaemia and reperfusion
Colchicine CH3 0.1 mg/kg given daily for • Reduced infarct size (measured 55,56,58
O
N-[(7S)-1,2,3,10‑tetramethoxy‑ O
7 days starting before by pathology)
9‑oxo‑6,7‑dihydro‑5H‑ ischaemia in a reperfused • Reduction in inflammasome
NH
benzo[a]heptalen‑7‑yl]acetamide H3C AMI mouse model activity (expression of
O inflammasome components,
O caspase 1 activity)
H3C • Prevention of adverse
O
remodelling and heart failure
O CH
3 • Prolonged survival
INF4E Cl OH O 50 μmol/l given in an • Reduction of infarct size 40,52
Ethyl 2-((2‑chlorophenyl)(hydroxy) ex vivo myocardial at 60 min (measured by
methyl)acrylate O ischaemia model pathology, cardiac markers,
20 min before induction and contractility)
of ischaemia • Reduction in caspase 1 activity,
cleaved IL‑1β levels, and
gasdermin D levels at 60 min
MCC950 3–6 mg/kg given • Reduction in infarct size 53,54
N-((1,2,3,5,6,7‑hexahydro- intravenously 15 min (measured by pathology,
s‑indacen‑4‑yl)carbamoyl)- OH
before reperfusion, then echocardiography, and
4-(2‑hydroxypropan‑2‑yl) O repeated after 24 h and troponin I plasma levels)
O NH
furan‑2‑sulfonamide; the following 5 days in a • Improvement in cardiac
N-[[(1,2,3,5,6,7‑hexahydro- S NH pig balloon angioplasty remodelling and prevention of
s‑indacen‑4‑yl)amino] O O inflation ischaemia model left ventricular dysfunction
carbonyl]-4-(1‑hydroxy‑1‑ • Reduction in local and systemic
methylethyl)-2‑furansulfonamide inflammatory response
OLT1177 (dapansutrile) O 6–600 mg/kg given before • Reduction in infarct size 48, (A. A.,
CH3
3-(methanesulfonyl)propanenitrile S or up to 30 min after (measured by pathology and unpublished
N O reperfusion in a mouse echocardiography) data)
surgical coronary artery
ligation model
AMI, acute myocardial infarction; NLRP3, NACHT, LRR and PYD domains-containing protein 3.

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Window of opportunity Iinflammasome and cardiac dysfunction

for intervention The expression of the components of the NLRP3 inflam-
inflammasome activity
NLRP3 expression/

masome is constitutively low in the majority of tissue-­

Progressive increase in resident cells. As mentioned above, activ­ation of the

Infarct size
NLRP3 expression and
inflammasome activation NLRP3 inflammasome requires two indepen­dent steps:
priming and triggering 18. The use of a transgenic mouse
with constitutively active NLRP3 has highlighted how
NLRP3 activation alone is insufficient to induce car-
diac dysfunction18. When priming occurs together
1 3 6 with activation of NLRP3, cardiac dysfunction, pro-
Time (h)
gression of nonischaemic cardiomyopathy, and death
ensue18. The need for priming explains why patients
with cryopyrin-­associated periodic syndromes, who
Onset of
reperfusion carry a mutation in the Nlrp3 gene that causes NLRP3
Figure 4 | Window of opportunity for intervention using NLRP3 Natureinhibitors
Reviews | Cardiology
in to be constitutively active, generally do not seem to
ischaemia–reperfusion injury. The left and right ventricular cavities and the progression have cardiac dysfunction but might be more vulnerable
of the infarct areas over time are shown. At the onset of reperfusion injury and for the to ­cardiac ­dysfunction during the clinically active phases
initial hour, NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) myocardial of the disease71.
expression and inflammasome activity are low, increasing between 1 and 3 h IL‑1β, the main product of the active inflammasome,
after reperfusion injury. The size of the infarct continues to grow after reperfusion. had already been identified as a soluble cardio­depressant
The time that precedes the activation of the inflammasome is a therapeutic window factor 21 years ago, initially in patients with sepsis72 and
for intervention with NLRP3 inhibitors. more recently in those with acute decompensated heart
failure73. The effects of IL‑1β administration on impaired
and leukocytes throughout the heart, and the inflam- contractility follow the timeline of a fever, with a peak
matory response is systemic. Inhibition of the NLRP3 inflammatory response occurring 3–4 h after adminis-
inflammasome in nonreperfused AMI results in more tration, an effect that requires new protein synthesis61.
favourable cardiac remodelling without affecting infarct IL‑1β‑induced impairment in contractility is reversible
size47. This pattern resembles those seen with IL‑1β even after repeated treatments61,73,74 and results from a
blockade strategies and is characterized by a reduction fault of the electrical–mechanical association at a cellu-
in apoptosis and preservation of cardiac contractil- lar level, whereby the expression and function of L‑type
ity 61–63. Treatment after the onset of ischaemia using calcium channels, phospholamban, and sarcoplasmic/­
anakinra, a recombinant IL‑1 receptor antagonist, or a endoplasmic reticulum calcium ATPase 2 (SERCA2)
mouse anti‑IL‑1β antibody (analogue of canakinu­ are simultaneously altered, leading to functional desen-
mab) significantly reduced cardiomyocyte apopto- sitization of the β‑adrenergic receptors61,75. Impaired
sis in the border zone of the infarcted area, and also contractility, altered expression and function of calcium-­
decreased left ventricular dilatation and dysfunction regulating proteins, and ­β ‑adrenergic desensitiza­
without reducing infarct size61–63. IL‑1β blockade has tion, as seen with IL‑1β treatment, are all hallmarks of
also been shown to improve left ventricular contractil- heart failure.
ity and β‑adrenergic receptor responsiveness in models
of ischaemic cardio­myopathy 64. FIGURE 5 summarizes Inflammasome in nonischaemic injury
the role of IL‑1β in adverse cardiac remodelling and During the process of NLRP3 inflammasome priming
cardiac dysfunction. and triggering, the membrane and cytoplasmic sensors
Compared with IL‑1β, IL‑1α has a less established are activated in a similar pattern after cell death, depend-
role in AMI. In contrast to IL‑1β, pro‑IL‑1α is constitu- ing on whether ischaemia was the cause of cell death.
tively expressed in the heart and is active in its precursor Toll-like receptors and purinergic 2X receptors on the
form65. When released during cell death, pro‑IL‑1α func- membrane recognize cell debris and extracellular ATP,
tions as a signal for tissue and cell damage. Accordingly, respectively, both byproducts of cell death, and provide
a strategy that inhibits IL‑1α might prove more useful in signals for the priming and triggering of the inflamma­
limiting the first wave of the inflammatory injury than some8. The inflammatory response to injury is, there-
one that involves IL‑1β blockade66. fore, a rather nonspecific type of response that occurs for
Similarly, the role of IL‑18 in AMI is largely both ischaemic and nonischaemic injury. Experimental
unknown67. IL‑18 activity has been shown to contribute studies have shown that the NLRP3 inflammasome has
to contractile dysfunction in human ischaemic myo­ a central pathogenic role in nonischaemic cardiomyo-
cardial strips68. In a mouse model of AMI, pretreatment pathy in a mouse model with cardiac-specific hetero­
with an IL‑18 blocking antibody reduced infarct size69. zygous overexpression of the calcineurin transgene,
Furthermore, IL‑18 blockade following reperfusion which results in cardiac hypertrophy, inflammation,
injury in a mouse model of heterotopic heart transplan- apoptosis, and ventricular dilatation76,77. Myocardial
tation reduced myocardial inflammation and improved injury owing to coxsackievirus infection also leads to
graft survival 70. Additional studies are required to NLRP3 activation and formation of the inflammasome,
determine the safety and efficacy of IL‑18 blockade in which is ultimately responsible for the progression of
­preclinical models of AMI. cardiac dysfunction78.

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In experimental models of sepsis, cardiac fibroblasts selective NLRP3 inhibitors are currently available in the
respond to pro-inflammatory stimuli by forming the clinic. Two IL‑1 blockers have been tested in phase I–III
NLRP3 inflammasome and producing IL‑1β, which clinical trials for AMI or heart failure61.
then acts in a paracrine fashion on the cardiomyocytes All members of the IL‑1 family (IL‑1β, IL‑1 receptor
to induce β‑adrenergic receptor desensitization and antagonist, soluble ST2 [interleukin‑1 receptor-like 1],
contractile dysfunction75. Myocardial injury due to and IL‑18) and surrogates (IL‑6 and C‑reactive pro-
doxoru­bicin, the most commonly used anti­neoplastic tein [CRP]) serve as very good biomarkers and pre-
chemotherapeutic agent, is also associated with activ­ dictors of unfavourable outcomes in patients with
ation of the NLRP3 inflammasome; doxorubicin-­ AMI80. NLRP3 and caspase 1 mRNA transcription in
induced cardiotoxicity can be reduced with an NLRP3 circulating monocytes are increased in patients with
inflamma­some inhibitor (16673‑34‑0)47. An increase acute coronary syndrome or stable angina compared
in NLRP3 inflammasome activity in the heart has also with healthy controls. At the protein level, NLRP3 also
been seen in animal models of pressure overload, such increased in parallel to an increase in the active forms
as those of transverse aortic constriction79. of caspase 1, IL‑1β, and IL‑18 (REF. 36). Although not
probative, the available clinical data in patients with
Indirect NLRP3 inhibition in AMI AMI, together with preclinical data in animals, create a
Data on the role of the NLRP3 inflammasome in compelling argument for further assessment of selective
patients with AMI are scarce and are mostly based on NLRP3 inhibitors.
biomarker studies and on indirect evidence resulting
from trials that used nonselective NLRP3 inhibitors or Colchicine
IL‑1 blockers. Indeed, with the exception of OLT117, Colchicine was historically used off label to treat
which is currently being investigated in a phase II clin- Mediterranean fever and was approved by the FDA in
ical trial for the treatment of acute gouty arthritis, and 2009 for the treatment of Mediterranean fever and acute
of colchicine, which is not a selective inhibitor, no other gouty arthritis, after evidence of its capacity to inhibit
the assembly and activation of NLRP3 inflamma­some
in response to monosodium urate crystals55. Consistent
Reversible with a central role of the NLRP3 inflammasome during
IL-1β cardiomyopathy
ischaemia–reperfusion injury, colchicine (1.5 mg i­ nitial
• Contractile dysfunction dose, followed by 0.5 mg given 1 h later and 0.5 mg
• ↓ β-adrenergic responsiveness
given twice daily for 5 days) significantly reduced the
size of the infarct in patients with ST-segment eleva-
Acute myocardial infarction tion myocardial infarction undergoing primary per-
cutaneous coronary intervention81 (TABLE 2). Notably,
Acute
phase
however, 26% of 77 patients assigned to colchicine
Ischaemia–reperfusion injury,
necrosis, and pyroptosis discontinued treatment before completion owing to
Inflammasome-mediated injury
poor tolerance, which is common for doses of colchi-
cine >1.0 mg daily. In another clinical trial, 532 patients
with ­stable coronary artery disease were randomly
assigned 1:1 to low-dose colchicine (0.5 mg daily)
Subacute
phase or ­placebo for a median of 2.3 years82. Colchicine signifi­
Cardiomyocyte apoptosis and cantly reduced the incidence of a combined adverse
adverse cardiac remodelling cardio­v ascular end point compared with p ­ lacebo,
• Contractile dysfunction owing to a large reduction in the incidence of acute
• Impaired β-adrenergic coronary syndromes (4.6% v­ ersus 13.6%; OR 0.33,
receptor responsiveness 95% CI 0.18–0.63, P <0.001)82.
• Heart failure

Chronic Anakinra in AMI and heart failure

phase The first study of IL‑1 blockade in patients with AMI
IL-1β-driven systemic inflammatory response was a 2010 pilot feasibility study involving ten patients
maintains a state of impaired cardiac function with ST-segment elevation myocardial infarction83.
and β-adrenergic receptor responsiveness in
heart failure A second proof-of-concept study involving 30 patients
was published 3 years later 84. Administration of
anakinra (100 mg daily for 14 days) in patients with
ST-segment elevation myocardial infarction was well
Figure 5 | Role of IL‑1β in acute myocardial infarction. TheNatureleft and right ventricular
Reviews | Cardiology tolerated and blunted the acute systemic inflammatory
cavities in diastole and in systole (dotted lines) are shown. IL‑1β reduces myocardial
response. The clinical follow-up of the small number
contractility and the myocardial response to β‑adrenergic receptor agonists in the heart,
even in the absence of myocardial infarction. In the subacute phase that follows acute of patients enrolled revealed a favourable clinical pro-
myocardial infarction, IL‑1β induces cardiomyocyte apoptosis, favouring adverse file with lower CRP levels and a trend towards reduced
myocardial remodelling and heart failure. Enhanced IL‑1β activity in the subacute and incidence of adverse remodelling and heart failure at
chronic phases that follow myocardial infarction contribute to impaired myocardial 3 months and at long-term follow up with anakinra83–85
contractility and β‑adrenergic responsiveness in heart failure. (TABLE 2). Anakinra is now being further explored in a

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larger phase II trial in patients with ST-segment eleva- control patients87,88. Based on known cardiodepressive
tion myocardial infarction86. In 2014, the results of a effects of IL‑1β, small proof-of-concept pilot studies
phase II clinical trial involving 182 patients with non- have explored the beneficial effects of IL‑1 blockade
ST-segment elevation myocardial infarction showed a in heart failure. In a series of studies in patients with
similar reduction in the acute inflammatory response acute or chronic systolic or diastolic heart failure,
with anakinra (100 mg daily for 14 days)87 (TABLE 2). The anakinra (100 mg once or twice daily) reduced the
clinical events at 30 days and 3 months were unaffected systemic inflammatory response (defined by a >50%
by anakinra treatment, but by 12 months, surprisingly, reduction in plasma CRP level) and improved exer-
the anakinra-treated patients had experienced signifi- cise c­ apacity, Doppler echocardiographic parameters,
cantly more recurrent ischaemic events than untreated and/or ­quality-of-life measures73,89–92 (TABLE 2).

Table 2 | Clinical trials of colchicine and IL‑1 blockers in AMI and heart failure
Study (year) Indication (n) Study design and drug regimen Main findings Refs
Anti- ST-segment elevation Randomization 1:1 colchicine or • Reduction in infarct size (measured using cardiac 81
inflammatory AMI (151) placebo; loading dose of 2 mg (initial magnetic resonance and by area under the curve for
treatment with dose of 1.5 mg followed by 0.5 mg cardiac markers)
colchicine in after 1 h) and continuing treatment • Reduction of peak CRP level
AMI (2015) with 0.5 mg twice daily, or placebo,
for 5 days
Low-dose Stable coronary artery Randomization 1:1 colchicine or • Reduction in combined adverse cardiovascular end 82
colchicine in disease (532) placebo (0.5 mg daily for a median points, owing to a large reduction in the incidence
coronary artery of 2.4 years) of acute coronary syndrome
disease (2013)
VCU-ART ST-segment elevation Randomization 1:1 anakinra • Blunting of the inflammatory response during AMI 83–85
(2010) and AMI (n = 10 for or placebo (100 mg once daily • Trend towards reduced incidence of adverse
VCU‑ART2 VCU-ART and n = 30 for 14 days) remodelling/heart failure at 3 months and at long-term
(2013) for VCU‑ART2) follow-up with anakinra
• The larger VCU‑ART3 clinical trial (n = 99) is ongoing
and aims to evaluate two different anakinra regimens
MRC-ILA Heart Non-ST-segment Randomization 1:1 anakinra • Blunting of the inflammatory response during AMI 87
Study (2015) elevation AMI (182) or placebo (100 mg once daily • No differences in major adverse cardiac events at
for 14 days) 30 days and 3 months, but more events occurring after
6 months in the anakinra-treated group
AIR‑HF (2012) Stable NYHA class II–III Single-arm, open-label treatment • Reduction in CRP levels 73
systolic HF with CRP with anakinra (100 mg once daily • Improvement in peak aerobic exercise capacity
>2 mg/l (10) for 2 weeks) at 2 weeks
• Improvement in ventilator efficiency at 2 weeks
DHART (2014) Stable NYHA class II–III Randomized, double-blind, crossover • Reduction in CRP levels 89
diastolic HF with LVEF trial of anakinra versus placebo for • Improvement in peak aerobic exercise capacity
>50% and CRP >2 mg/l 2 weeks (100 mg given once daily at 2 weeks
(12) for 2 weeks) • Improvement in quality-of-life scores
ADHF (2016) Acute decompensated Randomized, double-blind trial • Reduction in CRP levels at 72 h and 14 days with 90
systolic HF with CRP assessing anakinra versus placebo for anakinra
>5 mg/l (30) 2 weeks (100 mg given twice daily for • Trend towards favourable effects on congestive signs
3 days, then once daily for 2 weeks) and LVEF with anakinra
REDHART Recently Randomized, double-blind trial of • Reduction in CRP levels 91
(2017) decompensated anakinra continued for 2 weeks, • Improvement in peak aerobic exercise capacity and
systolic HF with anakinra for 12 weeks, or placebo for quality-of-life questionnaires with anakinra treatment
CRP >2 mg/l (within 2 weeks (100 mg once daily) given for 12 weeks
2 weeks of hospital • Trend towards reduced heart failure readmissions at
discharge) (60) 6 months with 12‑week anakinra treatment
CANTOS Prior AMI with CRP Randomized, double-blind trial • Significant reduction in the incidence of the composite 95
(2017) >2 mg/l (at least of canakinumab 50 mg, 150 mg, end point of cardiac death, nonfatal AMI, or nonfatal
30 days after AMI) or 300 mg, or placebo for a median stroke with canakinumab 150 mg versus placebo
(10,060) of 3.5 years (1:1:1:1.5) • Significant reduction in the incidence of recurrent
AMI, unstable angina, and need for revascularization
with canakinumab 150 mg versus placebo
• Trend towards reduced cardiac and all-cause mortality
with canakinumab 150 mg versus placebo
• Small increase in the risk of fatal infections with
canakinumab (all doses combined) versus placebo
• Small reduction in cancer-related mortality with
canakinumab 150 mg or 300 mg versus placebo
AMI, acute myocardial infarction; CRP, C‑reactive protein; HF, heart failure; LVEF, left ventricular ejection fraction; NLRP3, NACHT, LRR, and PYD domains-containing
protein 3.

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Canakinumab in AMI No data on AMI-related or heart-failure-related mor-

Canakinumab is a human monoclonal antibody devel- bidity or mortality were reported. These results from the
oped to block IL‑1β activity and is currently FDA- CANTOS trial show, for the first time, that specifically
approved for the treatment of systemic juvenile idio- targeting an inflammatory mediator can improve cardio­
pathic arthritis and some periodic fever syndromes, vascular and mortality outcomes in patients with AMI.
including cryopyrin-associated periodic syndromes and To date, these data are the strongest evidence support-
familial Mediterranean fever 93. The efficacy of canakinu­ ing the proposed role of the NLRP3 inflammasome and
mab in improving outcomes in patients with AMI was IL‑1β in the pathogenesis of heart disease.
tested in the multicentre CANTOS trial94,95. Investigators
of the CANTOS trial94,95 enrolled 10,061 patients with Conclusions
prior AMI and elevated CRP level (>2 mg/l). Patients The NLRP3 inflammasome is a ubiquitous intracellular
were randomly assigned to placebo or canakinumab pattern recognition receptor that is critically involved
(50, 150, or 300 mg every 3 months for a median in the response to injury during AMI and is responsible
of 3.5 years), with the goal of reducing the number of for the production of IL‑1β and the ensuing systemic
recurrent athero­thrombotic events94,95 (TABLE 2). Using a inflammatory response. Experimental studies in small
hierarchical statistical approach, the analysis concluded and large animals show that NLRP3 inflammasome-­
that the 150 mg canakinumab group had significantly targeted therapies might be a viable strategy for the
reduced occurrence of the primary end point of cardio- reduction of infarct size and prevention of heart failure
vascular death, AMI, and stroke (HR 0.85, 95% CI 0.74– following AMI. However, no selective NLRP3 inhibitors
0.98, P = 0.021) compared with placebo95. These patients are clinically available at present. Currently, IL‑1 block-
also had significantly fewer instances of the secondary ers are being explored in patients with AMI. In small
end point, which included unstable angina leading to phase II trials in AMI and heart failure, ­anakinra was well
revascularization (HR 0.83, P = 0.005), as well as the tolerated and effectively blunted the acute inflammatory
composite end point of death from any cause, AMI, and response. In a large, multicentre, phase III clinical trial
stroke (HR 0.85, P = 0.01). The benefit in the composite of patients with prior AMI and residual inflammatory
end point was largely driven by a reduction in nonfatal risk, canakinumab reduced the risk of recurrent acute
AMI (HR 0.76, P = 0.005). Treatment with canakinumab coronary syndromes and need for revascularization.
was associated with an overall favourable safety profile Additional studies with selective NLRP3 inhibitors are
with no significant excess in serious adverse events95. eagerly awaited.

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of inflammatory diseases. Nat. Med. 21, 248–255 myocardial dysfunction in mice with sepsis: the role The authors are grateful to Salvatore Carbone (Virginia
(2015). of NLRP3 inflammasome activation. PLoS ONE 9, Commonwealth University, Richmond, USA) for critically
54. van Hout, G. P. et al. The selective e107639 (2014). reviewing the manuscript and to Charles Dinarello (University
NLRP3‑inflammasome inhibitor MCC950 reduces 76. Bracey, N. A. et al. The Nlrp3 inflammasome of Colorado Denver, USA) for mentorship and guidance in the
infarct size and preserves cardiac function in a pig promotes myocardial dysfunction in structural field of IL‑1 over the past 10 years. S.T. is supported by a
model of myocardial infarction. Eur. Heart J. 38, cardiomyopathy through interleukin‑1β. Exp. Physiol. grant from the Virginia Commonwealth University Center for
828–836 (2017). 98, 462–472 (2013). Clinical & Translational Research, a VCU Commercialization
55. Mauro, A. G., Thurber, C. & Abbate, A. Colchicine 77. Abbate, A. The heart on fire: inflammasome and Fund Award, and a Department of Internal Medicine Pilot
in acute myocardial infarction: “teaching new tricks cardiomyopathy. Exp. Physiol. 98, 385 (2013). Study Award. A.A. is supported by grants (HL121402 and
to an old dog”. Transl Med. 5, e133 (2015). 78. Wang, Y., Gao, B. & Xiong, S. Involvement of HL136816) from the National Heart, Lung, and Blood
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— update on mechanisms of action and therapeutic myocarditis. Am. J. Physiol. Heart Circ. Physiol.
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57. Misawa, T. et al. Microtubule-driven spatial 79. Li, R. et al. Triptolide attenuates pressure overload- Both authors researched data for the article, discussed the
arrangement of mitochondria promotes activation induced myocardial remodeling in mice via the content, wrote the manuscript, and reviewed and edited
of the NLRP3 inflammasome. Nat. Immunol. 14, inhibition of NLRP3 inflammasome expression. the manuscript before submission.
454–460 (2013). Biochem. Biophys. Res. Commun. 485, 69–75
58. Fujisue, K. et al. Colchicine improves survival, left (2017). Competing interests statement
ventricular remodeling, and chronic cardiac 80. Seropian, I. M., Sonnino, C., Van Tassell, B. W., S.T. has received research grants from Olatec. A.A. has
function after acute myocardial infarction. Circ. J. Biasucci, L. M. & Abbate, A. Inflammatory markers received research grants from Novartis and Swedish Orphan
81, 1174–1182 (2017). in ST‑elevation acute myocardial infarction. Eur. Heart J. Biovitrum and has served as a scientific adviser to Olatec.
59. Toldo, S., Marchetti, C. & Abbate, A. Re. “NLRP3 Acute Cardiovasc. Care 5, 382–395 (2016).
inflammasome activation during myocardial ischemia 81. Deftereos, S. et al. Anti-inflammatory treatment with Publisher’s note
reperfusion is cardioprotective”. Biochem. Biophys. colchicine in acute myocardial infarction: a pilot study. Springer Nature remains neutral with regard to jurisdictional
Res. Commun. 470, 811–812 (2016). Circulation 132, 1395–1403 (2015). claims in published maps and institutional affiliations.

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