Table 2.

Drugs targeting NLRP3 inflammasome or proteostasis pathway with potential benefit in AF.

Key modulators	Drug	Action	Clinical Phase	Indication	Ref/identifier (clinicaltrails.gov)
Targeting NLRP3 inflammasome
IL-1β	Canakinumab (Ilaris®)	Neutralizing anti-IL-1β antibody	Phase III Phase III Phase III Phase III Phase III Phase III Phase II	CAPS Atherosclerosis & MI115 schizophrenia Gout Systemic Juvenile Idiopathic Arthritis Non-Small-Cell Lung Cancer Atrial fibrillation	NCT01576367 NCT01327846 NCT01390350 NCT01431638 NCT02396212 NCT03626545 NCT01805960*
IL-1R	Rilonacept (Arcalyst®)	Soluble IL-1 decoy receptor	Phase II Phase III Phase II Phase IV	CAPS Gout Recurrent Pericarditis Vascular dysfunction in CKD	NCT00288704 NCT00855920 NCT03737110 NCT01663103
IL-1R	Anakinra (Kineret®)	IL-1R antagonist	Phase III Phase II Phase II/III Phase II Phase III	Rheumatoid arthritis Multiple Myeloma Myocarditis Heart failure, acute MI ST segment elevation during acute MI	NCT00117091 NCT03233776 NCT03018834 NCT01175018 NCT00789724
Caspase-1	VX-765 (Belnacasan)	Caspase-1 inhibitor	Phase II Phase II	Epilepsy Psoriasis	NCT01048255 NCT00205465
NLRP3	MCC950 (CRID3, CP456773)116	Specific NLRP3 inhibitor upstream of ASC oligomerization	Preclinical	AF Atherosclerotic lesion Type-2 diabetes	59 179 180
KATP	Glibenclamide (Glyburide)	Prevent intracellular K+ depletion	Phase IV	Type-2 diabetes	181
Microtubule polymerization	Colchicine	Prevent microtubule polymerization	Phase IV Phase II Phase III Phase IV	Gout Behcet’s disease POAF Arrhythmia recurrence after acute pericardial effusion	NCT02500641 NCT03888846 NCT03015831 NCT02260206
TNFα	Etanercept (Enbrel®)	Decoy receptor can bind to TNFα, thereby preventing its binding with the endogenous TNFR.	Phase III Phase IV	Rheumatoid arthritis Plaque psoriasis	NCT04079374 NCT02274792
P2X7R	AZD9056 182	P2X7 receptor antagonist	Phase II	Rheumatoid Arthritis	NCT00520572
P2X7R	16673-34-0	Prevent the P2X7R mediated K+-efflux	Preclinical	Ischemic cardiomyopathy	118
II. Targeting proteostasis derailment
ER stess	4PBA (Buphenyl® & Ammonaps®)	Chemical chaperone	Phase II Phase II Phase II Phase II Phase III Phase IV Phase III Preclinical	Cystic fibrosis Amyotrophic lateral sclerosis Huntington’s disease Pulmonary tuberculosis Maple syrup urine disease Diabetes Urea cycle disorder AF	NCT00590538 NCT00107770 NCT00212316 NCT01580007 NCT01529060 NCT00533559 NCT00947544 81
HDAC6	tubastatin A	HDAC6 inhibitor	Preclinical	AF	183
HDAC6	ACY-1215 (ricolinostat)	HDAC6 inhibitor	Phase II	Lymphoma	NCT02091063
DNA damage	ABT888	PARP inhibitor	Phase II Phase II Phase I Phase II Phase II Preclinical	Metastatic breast cancer Hepatocellular carcinoma Adult solid neoplasm Ovarian cancer Colorectal cancer AF	NCT01009788 NCT01205828 NCT01154426 NCT01113957 NCT01051596 86
Mitochondrial dysfunction	Nicotinamide (niagen®)	PARP inhibitor Sirt inhibitor NAD-precursor	Phase III Phase III Phase II Phase II Preclinical	Lung carcinoma Chronic kidney disease Neurodegenerative disease Alzheimer’s disease AF	NCT02416739 NCT02258074 NCT01589809 NCT00580931 183
HSP	GGA (teprenone)	HSP induction	Phase IV Preclinical Phase II	Gastric ulcers Gastritis Gastric lesion AF Cardiac bypass surgery	NCT01190657 NCT015475559 NCT01397448 75 77
HSP	GGA derivatives	HSP induction	Preclinical	AF	76

AF, atrial fibrillation; CAPS, cryopyrin-associated periodic syndromes; CKD, chronic kidney disease; MI, myocardial infarction.

^*prematurely ended