Prospective Evaluation of Clinico-Pathological Predictors of Postoperative Atrial Fibrillation: An Ancillary Study From the OPERA Trial.

BACKGROUND: Postoperative atrial fibrillation (POAF) occurs in 30% to 50% of patients undergoing cardiac surgery and is associated with increased morbidity and mortality. Prospective identification of structural/molecular changes in atrial myocardium that correlate with myocardial injury and precede and predict risk of POAF may identify new molecular pathways and targets for prevention of this common morbid complication. METHODS: Right atrial appendage samples were prospectively collected during cardiac surgery from 239 patients enrolled in the OPERA trial (Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation), fixed in 10% buffered formalin, and embedded in paraffin for histology. We assessed general tissue morphology, cardiomyocyte diameters, myocytolysis (perinuclear myofibril loss), accumulation of perinuclear glycogen, interstitial fibrosis, and myocardial gap junction distribution. We also assayed NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-cTnT, CRP (C-reactive protein), and circulating oxidative stress biomarkers (F2-isoprostanes, F3-isoprostanes, isofurans) in plasma collected before, during, and 48 hours after surgery. POAF was defined as occurrence of postcardiac surgery atrial fibrillation or flutter of at least 30 seconds duration confirmed by rhythm strip or 12-lead ECG. The follow-up period for all arrhythmias was from surgery until hospital discharge or postoperative day 10. RESULTS: Thirty-five percent of patients experienced POAF. Compared with the non-POAF group, they were slightly older and more likely to have chronic obstructive pulmonary disease or heart failure. They also had a higher European System for Cardiac Operative Risk Evaluation and more often underwent valve surgery. No differences in left atrial size were observed between patients with POAF and patients without POAF. The extent of atrial interstitial fibrosis, cardiomyocyte myocytolysis, cardiomyocyte diameter, glycogen score or Cx43 distribution at the time of surgery was not significantly associated with incidence of POAF. None of these histopathologic abnormalities were correlated with levels of NT-proBNP, hs-cTnT, CRP, or oxidative stress biomarkers. CONCLUSIONS: In sinus rhythm patients undergoing cardiac surgery, histopathologic changes in the right atrial appendage do not predict POAF. They also do not correlate with biomarkers of cardiac function, inflammation, and oxidative stress. Graphic Abstract: A graphic abstract is available for this article.

Therapeutic Modulation of the Immune Response in Arrhythmogenic Cardiomyopathy.

BACKGROUND: Inflammation is a prominent feature of arrhythmogenic cardiomyopathy (ACM), but whether it contributes to the disease phenotype is not known. METHODS: To define the role of inflammation in the pathogenesis of ACM, we characterized nuclear factor-κB signaling in ACM models in vitro and in vivo and in cardiac myocytes from patient induced pluripotent stem cells. RESULTS: Activation of nuclear factor-κB signaling, indicated by increased expression and nuclear accumulation of phospho-RelA/p65, occurred in both an in vitro model of ACM (expression of JUP2157del2 in neonatal rat ventricular myocytes) and a robust murine model of ACM (homozygous knock-in of mutant desmoglein-2 [Dsg2mut/mut]) that recapitulates the cardiac manifestations seen in patients with ACM. Bay 11-7082, a small-molecule inhibitor of nuclear factor-κB signaling, prevented the development of ACM disease features in vitro (abnormal redistribution of intercalated disk proteins, myocyte apoptosis, release of inflammatory cytokines) and in vivo (myocardial necrosis and fibrosis, left ventricular contractile dysfunction, electrocardiographic abnormalities). Hearts of Dsg2mut/mut mice expressed markedly increased levels of inflammatory cytokines and chemotactic molecules that were attenuated by Bay 11-7082. Salutary effects of Bay 11-7082 correlated with the extent to which production of selected cytokines had been blocked. Nuclear factor-κB signaling was also activated in cardiac myocytes derived from a patient with ACM. These cells produced and secreted abundant inflammatory cytokines under basal conditions, and this was also greatly reduced by Bay 11-7082. CONCLUSIONS: Inflammatory signaling is activated in ACM and drives key features of the disease. Targeting inflammatory pathways may be an effective new mechanism-based therapy for ACM.

Prolonged RV endocardial activation duration: a novel marker of arrhythmogenic right ventricular dysplasia/cardiomyopathy.

BACKGROUND: Parietal block, defined as intra right ventricular (RV) conduction slowing, is a major diagnostic criterion for arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). OBJECTIVE: We evaluated the utility of total RV endocardial activation duration (EAD) measured by 3-dimensional electroanatomic mapping during sinus rhythm in the diagnosis of ARVD/C. METHODS: Twenty-five consecutive patients with frequent left bundle branch block morphology premature ventricular complexes who underwent electroanatomic mapping as a part of the evaluation for ARVD/C were included in the study. All patients were evaluated using standard protocol that included electrocardiogram (ECG), signal-averaged ECG, Holter monitoring, echocardiography, and magnetic resonance imaging. Invasive testing was performed as indicated. Total RV EAD was measured as the time interval between the onset of RV activation to the latest activated region in the RV. RESULTS: The mean age of the study subjects was 38 +/- 11 years, and 32% were men. Fourteen subjects were diagnosed with ARVD/C using task force criteria, and the remainder had idiopathic ventricular tachycardia. Although the surface QRS durations were similar, the total RV EAD was significantly prolonged in ARVD/C compared with idiopathic VT (83.9 +/- 10 ms vs. 50.8 +/- 7 ms, P <.001). None of the idiopathic VT subjects had RV EAD of >65 ms. RV EAD also showed significant negative correlation with RV ejection fraction. CONCLUSION: Total RV EAD obtained by 3-dimensional electroanatomic mapping is a sensitive marker of intra-RV conduction delay in ARVD/C, and a total RV EAD of >65 ms accurately differentiates ARVD/C from idiopathic VT.