Whole Blood Gene Expression Differentiates between Atrial Fibrillation and Sinus Rhythm after Cardioversion.

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.

Determinants of Left Atrial Volume in Patients with Atrial Fibrillation.

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 (ß coefficient -10.51 (95% confidence interval (CI) -17.85;-3.16), p = 0.0053), undergoing cardioversion (ß 11.95 (CI 5.15; 18.74), p = 0.0006), diabetes (ß 14.23 (CI 2.36; 26.10), p = 0.019), body surface area (BSA) (ß 34.21 (CI 19.30; 49.12), p<0.0001), glomerular filtration rate (ß -0.21 (CI -0.36; -0.06), p = 0.0064) and plasma levels of NT-pro brain natriuretic peptide (NT-proBNP) (ß 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.

Plasma endothelin-1 and cardiovascular risk among young and healthy adults.

OBJECTIVES: Endothelial dysfunction is a major precursor of atherosclerosis. The aim of this study was to assess the interrelationships between plasma endothelin-1 (ET-1) levels and cardiovascular risk among young and healthy individuals. METHODS: We performed a population-based study among 2160 healthy adults aged between 25 and 41 years in the Principality of Liechtenstein. Individuals with prevalent cardiovascular disease, diabetes or a body mass index >35 kg/m(2) were excluded. Plasma ET-1 was measured using a novel high-sensitive, single-molecule counting technology. The relationships between plasma levels of ET-1 and various cardiovascular risk factors were assessed by multivariable regression analyses. RESULTS: Median age of our population was 37 years. Median ET-1 levels across ET-1 quartiles were 1.86, 2.33, 2.76 and 3.48 pg/mL. After multivariable adjustment, there were significant correlations of ET-1 with systolic blood pressure (ß per 1-unit increase in log transformed ET-1 2.30 (95% confidence interval (CI) 1.03; 3.58, p = 0.0004), C-reactive protein (ß 0.19 (95% CI 0.03; 0.34, p = 0.021), glomerular filtration rate (ß -1.73 (95% CI -3.17; -0.29, p = 0.019), and current smoking (Odds ratio 1.94 (95% CI 1.39; 2.71, p < 0.0001). We also found a highly significant association between ET-1 levels and overall cardiovascular risk estimated by the "Prospective Cardiovascular Münster" (PROCAM) and the Framingham score (ß 0.18 (95% CI 0.06; 0.31, p = 0.004, and ß 0.11 (95% CI 0.05; 0.16), p < 0.0001, respectively). CONCLUSIONS: Plasma ET-1 levels are easily measurable in healthy adults and correlate with major cardiovascular risk factors and global cardiovascular risk.

Effects of sinus rhythm maintenance on left heart function after electrical cardioversion of atrial fibrillation: implications for tachycardia-induced cardiomyopathy.

BACKGROUND: The role of tachycardia-induced cardiomyopathy vs tachycardia-related short diastolic filling period and reduced atrial contraction in decline of left ventricular ejection fraction (LVEF) in atrial fibrillation (AF) is uncertain. We aimed to characterize left heart changes over time in patients with AF who undergo electrical cardioversion (ECV). METHODS: Consecutive AF patients who were to undergo ECV were enrolled. Patients with unstable or acute heart failure, severe valvular diseases, recent open-heart surgery, major disorders, or an unsuccessful ECV were excluded. Transthoracic echocardiography, including 3-dimensional left atrial and ventricular volume acquisitions, was performed 1-2 hours before and after ECV, and 4-6 weeks later. RESULTS: In 73 patients (77% male, 66 ± 11 years), ECV resulted in an immediate increase in LVEF (from 43 [interquartile range (IQR), 33-50%] to 48 [IQR, 40-53%]; P < 0.0001). Four to 6 weeks after ECV, ejection fraction increased further in patients who remained in sinus rhythm (SR) (n = 55) to 55 (IQR, 44-62)%; P < 0.001. In patients with AF relapse, LVEF returned to values comparable to pre-ECV (n = 18) (44 [IQR, 32-51]%; P = 0.03). The atrial emptying fraction did not significantly change immediately after ECV (n = 69; from 20 [IQR, 13-25]% to 20 [IQR, 15-28]%; P = 0.14). Only patients who remained in SR showed an increase in atrial emptying fraction after 4-6 weeks (n = 51; to 37 [IQR, 26-48]%; P < 0.0001 vs post-ECV). CONCLUSIONS: Immediate improvement in LVEF after ECV explains approximately 50% of total LVEF increase over time. However, in SR, LVEF, and atrial function continuously increase over 4-6 weeks after ECV. This might be attributable to recovery of tachycardia-induced cardiomyopathy.