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Background: Myocarditis can lead to myocyte loss and myocardial fibrosis resulting in dilated cardiomyopathy (DCMP). Currently employed methods for assessing the risk for development of DCMP are inaccurate or rely on invasive myocardial biopsies. We hypothesized that molecular imaging of tissue inflammation with contrast enhanced ultrasound during peak inflammation in myocarditis could predict development of fibrosis and impaired left ventricular function., Methods and Results: Experimental autoimmune myocarditis (EAM) was induced in Balbc mice by injection of the α-myosin heavy chain peptide. Contrast enhanced ultrasound (CEU) using microbubbles targeted to leukocytes (MBLc), to CD4+ lymphocytes (MBCD4), and to the endothelial cell adhesion molecule P-selectin (MBPSel) was performed during the expected EAM peak inflammatory activity 21 days after induction. High resolution ultrasound, invasive hemodynamic measurements and fibrosis quantification were done 63 days after EAM assessment. All tested microbubbles correlated to fibrosis (MBLc spearman r 0.28, p 0.047, MBCD4 r 0.44, p 0.01, MBPSel r 0.73, p 0.02), however, correlations were weak overall and the spread of data was considerable. Also, targeted CEU data on day 21 did not correlate to hemodynamic and functional data on day 63., Conclusions: Ultrasound molecular imaging using targeted microbubbles during the peak inflammatory activity of myocarditis correlates weakly with later development of fibrosis but not with hemodynamic or left ventricular functional parameters., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Left atrial (LA) enlargement is an important risk factor for incident stroke and a key determinant for the success of rhythm control strategies in patients with atrial fibrillation (AF). However, factors associated with LA volume in AF patients remain poorly understood., Methods: Patients with paroxysmal or persistent AF were enrolled in this study. Real time 3-D echocardiography was performed in all participants and analyzed offline in a standardized manner. We performed stepwise backward linear regression analyses using a broad set of clinical parameters to determine independent correlates for 3-D LA volume., Results: We included 210 patients (70.9% male, mean age 61±11years). Paroxysmal and persistent AF were present in 95 (45%) and 115 (55%) patients, respectively. Overall, 115 (55%) had hypertension, 11 (5%) had diabetes, and 18 (9%) had ischemic heart disease. Mean indexed LA volume was 36±12ml/m2. In multivariable models, significant associations were found for female sex (β coefficient -10.51 (95% confidence interval (CI) -17.85;-3.16), p = 0.0053), undergoing cardioversion (β 11.95 (CI 5.15; 18.74), p = 0.0006), diabetes (β 14.23 (CI 2.36; 26.10), p = 0.019), body surface area (BSA) (β 34.21 (CI 19.30; 49.12), p<0.0001), glomerular filtration rate (β -0.21 (CI -0.36; -0.06), p = 0.0064) and plasma levels of NT-pro brain natriuretic peptide (NT-proBNP) (β 6.79 (CI 4.05; 9.52), p<0.0001), but not age (p = 0.59) or hypertension (p = 0.42). Our final model explained 52% of the LA volume variability., Conclusions: In patients with AF, the most important correlates with LA volume are sex, BSA, diabetes, renal function and NT-proBNP, but not age or hypertension. These results may help to refine rhythm control strategies in AF patients., Competing Interests: The authors have declared that no competing interests exist.

Background: Treatment to restore sinus rhythm among patients with atrial fibrillation (AF) has limited long-term success rates. Gene expression profiling may provide new insights into AF pathophysiology., Objective: To identify biomarkers and improve our understanding of AF pathophysiology by comparing whole blood gene expression before and after electrical cardioversion (ECV)., Methods: In 46 patients with persistent AF that underwent ECV, whole blood samples were collected 1-2 hours before and 4 to 6 weeks after successful cardioversion. The paired samples were sent for microarray and plasma biomarker comparison., Results: Of 13,942 genes tested, expression of SLC25A20 and PDK4 had the strongest associations with AF. Post-cardioversion, SLC25A20 and PDK4 expression decreased by 0.8 (CI 0.7-0.8, p = 2.0x10-6) and 0.7 (CI 0.6-0.8, p = 3.0x10-5) fold respectively. Median N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations decreased from 127.7 pg/mL to 44.9 pg/mL (p = 2.3x10-13) after cardioversion. AF discrimination models combining NT-proBNP and gene expression (NT-proBNP + SLC25A20 area under the curve = 0.88, NT-proBNP + PDK4 AUC = 0.86) had greater discriminative capacity as compared with NT-proBNP alone (AUC = 0.82). Moreover, a model including NT-proBNP, SLC25A20 and PDK4 significantly improved AF discrimination as compared with other models (AUC = 0.87, Net Reclassification Index >0.56, p<5.8x10-3). We validated the association between SLC25A20 and PDK4 with AF in an independent sample of 17 patients., Conclusion: This study demonstrates that SLC25A20, PDK4, and NT-proBNP have incremental utility as biomarkers discriminating AF from sinus rhythm. Elevated SLC25A20 and PDK4 expression during AF indicates an important role for energy metabolism in AF.

Introduction: The advent of electroanatomical mapping (EAM) systems for pulmonary vein isolation (PVI) has dramatically decreased radiation exposure. However, the need for some fluoroscopy remains for obtaining left atrial (LA) access. The aim was to test the feasibility of fluoroscopy-free PVI in patients with atrial fibrillation (AF) and a patent foramen ovale (PFO) guided solely by an EAM system., Methods: Consecutive patients with AF undergoing PVI and documented PFO were studied. An EAM-guided approach without fluoroscopy and ultrasound was used. After completing the map of the right atrium, the superior vena cava and the coronary sinus, a catheter pull-down to the PFO was performed allowing LA access. The map of the LA and subsequent PVI was also performed without fluoroscopy., Results: 30 patients [age 61±12 years, 73% male, ejection fraction 0.64 (0.53-0.65), LA size in parasternal long axis 38±7 mm] undergoing PVI were included. The time required for right atrial mapping including transseptal crossing was 9±4 minutes. Total procedure time was 127±37 minutes. Fluoroscopy-free PVI was feasible in 26/30 (87%) patients. In four patients, fluoroscopy was needed to access (n = 3) or to re-access (n = 1) the LA. In these four patients, total fluoroscopy time was 5±3 min and the DAP was 14.9±13.4 Gy*cm2. Single-procedure success rate was 80% (24/30) after a median follow-up of 12 months., Conclusion: In patients with a documented PFO, completely fluoroscopy-free PVI is feasible in the vast majority of cases.

Background/objectives: Inflammatory changes on the endothelium are responsible for leukocyte recruitment to plaques in atherosclerosis. Noninvasive assessment of treatment-effects on endothelial inflammation may be of use for managing medical therapy and developing novel therapies. We hypothesized that molecular imaging of vascular cell adhesion molecule-1 (VCAM-1) with contrast enhanced ultrasound (CEU) could assess treatment effects on endothelial phenotype in early atherosclerosis., Methods: Mice with atherosclerosis produced by gene deletion of the LDL-receptor and Apobec-1-editing protein were studied. At 12 weeks of age, mice received 8 weeks of regular chow or atorvastatin-enriched chow (10 mg/kg/day). At 20 weeks, CEU molecular imaging for aortic endothelial VCAM-1 expression was performed with VCAM-1-targeted (MB(VCAM)) and control microbubbles (MB(Ctr)). Aortic wall thickness was assessed with high frequency ultrasound. Histology, immunohistology and Western blot were used to assess plaque burden and VCAM-1 expression., Results: Plaque burden was reduced on histology, and VCAM-1 was reduced on Western blot by atorvastatin, which corresponded to less endothelial expression of VCAM-1 on immunohistology. High frequency ultrasound did not detect differences in aortic wall thickness between groups. In contrast, CEU molecular imaging demonstrated selective signal enhancement for MB(VCAM) in non-treated animals (MB(VCAM) 2±0.3 vs MB(Ctr) 0.7±0.2, p<0.01), but not in statin-treated animals (MB(VCAM) 0.8±0.2 vs MB(Ctr) 1.0±0.2, p = ns; p<0.01 for the effect of statin on MB(VCAM) signal)., Conclusions: Non-invasive CEU molecular imaging detects the effects of anti-inflammatory treatment on endothelial inflammation in early atherosclerosis. This easily accessible, low-cost technique may be useful in assessing treatment effects in preclinical research and in patients.