No abstract

The intracellular sensing protein termed NLRP3 (for NACHT, LRR, and PYD domains-containing protein 3) forms a macromolecular structure called the NLRP3 inflammasome. The NLRP3 inflammasome plays a major role in inflammation, particularly in the production of IL (interleukin)-1β. IL-1β is the most studied of the IL-1 family of cytokines, including 11 members, among which are IL-1α and IL-18. Here, we summarize preclinical and clinical findings supporting the key pathogenetic role of the NLRP3 inflammasome and IL-1 cytokines in the formation, progression, and complications of atherosclerosis, in ischemic (acute myocardial infarction), and nonischemic injury to the myocardium (myocarditis) and the progression to heart failure. We also review the clinically available IL-1 inhibitors, although not currently approved for cardiovascular indications, and discuss other IL-1 inhibitors, not currently approved, as well as oral NLRP3 inflammasome inhibitors currently in clinical development. Canakinumab, IL-1β antibody, prevented the recurrence of ischemic events in patients with prior acute myocardial infarction in a large phase III clinical trial, including 10 061 patients world-wide. Phase II clinical trials show promising data with anakinra, recombinant IL-1 receptor antagonist, in patients with ST-segment–elevation acute myocardial infarction or heart failure with reduced ejection fraction. Anakinra also improved outcomes in patients with pericarditis, and it is now considered standard of care as second-line treatment for patients with recurrent/refractory pericarditis. Rilonacept, a soluble IL-1 receptor chimeric fusion protein neutralizing IL-1α and IL-1β, has also shown promising results in a phase II study in recurrent/refractory pericarditis. In conclusion, there is overwhelming evidence linking the NLRP3 inflammasome and the IL-1 cytokines with the pathogenesis of cardiovascular diseases. The future will likely include targeted inhibitors to block the IL-1 isoforms, and possibly oral NLRP3 inflammasome inhibitors, across a wide spectrum of cardiovascular diseases.

No abstract

A multicenter registry for the purpose of research collaboration of this rare disease was established, with the University of Michigan serving as the coordinating center for this study. This registry was © 2014 American Heart Association, Inc. Original Article Circ Arrhythm ElectrophysiolBackground-The purpose of this study was to assess whether delayed enhancement (DE) on MRI is associated with ventricular tachycardia (VT)/ventricular fibrillation or death in patients with cardiac sarcoidosis and left ventricular ejection fraction >35%. Methods and Results-Fifty-one patients with cardiac sarcoidosis and left ventricular ejection fraction >35% underwent DE-MRI. DE was assessed by visual scoring and quantified with the full-width at half-maximum method. The patients were followed for 48.0±20.2 months. Twenty-two of 51 patients (63%) had DE. Forty patients had no prior history of VT (primary prevention cohort). Among those, 3 patients developed VT and 2 patients died. DE was associated with risk of VT/ventricular fibrillation or death (P=0.0032 for any DE and P<0.0001 for right ventricular DE). The positive predictive values of the presence of any DE, multifocal DE, and right ventricular DE for death or VT/ventricular fibrillation at mean follow-up of 48 months were 22%, 48%, and 100%, respectively. Among the 11 patients with a history of VT before the MRI, 10 patients had subsequent VTs, 1 of whom died. approved by all institutional review boards with data use agreements in place. Using previously published criteria, 5,6 patients who met diagnostic criteria for CS were identified. Patients from the University of Michigan, Henry Ford Hospital, University of Colorado, Johns Hopkins University, and Virginia Commonwealth University were included. Medical records were reviewed to identify patients who had cardiac MRIs, a left ventricular (LV) ejection fraction >35%, and ≥6 months of follow-up. Stored electrograms documenting arrhythmia episodes were reviewed to confirm appropriateness of ICD therapies (antitachycardia pacing or ICD discharge). Electrocardiograms and stored electrograms were analyzed, and ventricular arrhythmias were classified as monomorphic ventricular tachycardia (VT), polymorphic VT, or ventricular fibrillation (VF). Ventricular arrhythmia in the non-ICD group was defined as cardiac arrest, VT lasting ≥30 seconds or requiring defibrillation. VT/VF storm was defined as ≥3 episodes of VT/VF in a 24-hour period. Conclusions-RV DE in patients with cardiac sarcoidosis is associated with a risk of adverse events in patients with Cardiac MRIAll patients underwent cardiac MRI, including cine imaging of cardiac morphology and function and DE-MRI. All studies were performed on 1.5 Tesla scanners (Signa Excite CV/i; General Electric; Milwaukee, Wisconsin; Magnetom Sonata; Siemens Medical Solutions; Erlangen, Germany, Philips Healthcare, Best, The Netherlands). Cine imaging was performed in ventricular short-and long-axis planes using a segmented 2D steady-statefree-precession pulse sequence (repetition time,...