Epicardial fat was closely related to atrial fibrillation (AF). Transthoracic echocardiography (TTE) has been proposed to be a convenient imaging tool in assessing epicardial adipose tissue (EAT). The goal of the present study was to investigate whether the EAT thickness measured on TTE was a useful parameter in predicting procedural outcomes of AF ablations. A total of 227 paroxysmal AF (PAF) and 56 non-paroxysmal AF (non-PAF) patients receiving catheter ablations from 2008-2010 were enrolled. Echocardiography-derived regional EAT thickness from parasternal long-axis view was quantified for each patient. Free of recurrence was defined as the absence of atrial arrhythmias without using antiarrhythmic agents after ablations. The mean EAT thickness of the study population was 6.1 ± 0.8 mm. Non-PAF patients had a thicker EAT than that of PAF patients (7.0 ± 0.7 mm versus 5.9 ± 0.7 mm, p value <0.001). During the follow-up of 16 ± 9 months, there were 95 patients (33.6%) suffering from recurrences of atrial arrhythmias. Non-PAF, chads₂ score, left atrial diameter and EAT thickness were independent predictors of recurrence after catheter ablations. At a cutoff value of 6 mm for PAF and 6.9 mm for non-PAF, the measurement of EAT thickness could help us to identify patients at risk of recurrences. EAT thickness may serve as a useful parameter in predicting recurrences after AF ablations. Compared to other imaging modalities, TTE can be an alternative choice with less cost and time in assessing the effects of EAT on ablation outcomes.

Fabry disease (FD) is an X-linked inherited lysosomal storage disease caused by α-galactosidase A (GLA) deficiency. Progressive intracellular accumulation of globotriaosylceramide (Gb3) is considered to be pathogenically responsible for the phenotype variability of FD that causes cardiovascular dysfunction; however, molecular mechanisms underlying the impairment of FD-associated cardiovascular tissues remain unclear. In this study, we reprogrammed human induced pluripotent stem cells (hiPSCs) from peripheral blood cells of patients with FD (FD-iPSCs); subsequently differentiated them into vascular endothelial-like cells (FD-ECs) expressing CD31, VE-cadherin, and vWF; and investigated their ability to form vascular tube-like structures. FD-ECs recapitulated the FD pathophysiological phenotype exhibiting intracellular Gb3 accumulation under a transmission electron microscope. Moreover, compared with healthy control iPSC-derived endothelial cells (NC-ECs), reactive oxygen species (ROS) production considerably increased in FD-ECs. Microarray analysis was performed to explore the possible mechanism underlying Gb3 accumulation-induced ROS production in FD-ECs. Our results revealed that superoxide dismutase 2 (SOD2), a mitochondrial antioxidant, was significantly downregulated in FD-ECs. Compared with NC-ECs, AMPK activity was significantly enhanced in FD-ECs. Furthermore, to investigate the role of Gb3 in these effects, human umbilical vein endothelial cells (HUVECs) were treated with Gb3. After Gb3 treatment, we observed that SOD2 expression was suppressed and AMPK activity was enhanced in a dose-dependent manner. Collectively, our results indicate that excess accumulation of Gb3 suppressed SOD2 expression, increased ROS production, enhanced AMPK activation, and finally caused vascular endothelial dysfunction. Our findings suggest that dysregulated mitochondrial ROS may be a potential target for treating FD.

Fabry disease (FD) is a rare inherited disorder characterized by a wide range of systemic symptoms; it is particularly associated with cardiovascular and renal problems. Enzyme replacement therapy and pharmacological chaperone migalastat are the only approved and effective treatment strategies for FD patients. It is well documented that alpha-galactosidase A (GLA) enzyme activity deficiency causes globotriaosylceramide (Gb3) accumulation, which plays a crucial role in the etiology of FD. However, the detailed mechanisms remain unclear, and the lack of a reliable and powerful disease model is an obstacle. In this study, we created such a model by using CRISPR/Cas9-mediated editing of GLA gene to knockout its expression in human embryonic stem cells (hESCs). The cardiomyocytes differentiated from these hESCs (GLA-null CMs) were characterized by the accumulation of Gb3 and significant increases of cell surface area, the landmarks of FD-associated cardiomyopathy. Furthermore, we used mass spectrometry to compare the proteomes of GLA-null CMs and parental wild type CMs and found that the Rab GTPases involved in exocytotic vesicle release were significantly downregulated. This caused impairment of autophagic flux and protein turnover, resulting in an increase of reactive oxygen species and apoptosis. To summarize, we established a FD model which can be used as a promising tool to study human hypertrophic cardiomyopathy in a physiologically and pathologically relevant manner and to develop new therapies by targeting Rab GTPases signaling-related exosomal vesicles transportation.

Aortic pulse wave velocity (PWV), which substantially increases with arterial stiffness and aging, is a major predictor of cardiovascular mortality. It is commonly estimated using applanation tonometry at carotid and femoral arterial sites (cfPWV). More recently, several cardiovascular magnetic resonance (CMR) studies have focused on the measurement of aortic arch PWV (archPWV). Although the excellent anatomical coverage of CMR offers reliable segmental measurement of arterial length, accurate transit time (TT) determination remains a challenge. Recently, it has been demonstrated that Fourier-based methods were more robust to low temporal resolution than time-based approaches. We developed a wavelet-based method, which enables temporal localization of signal frequencies, to estimate TT from ascending and descending aortic CMR flow curves. This method (archPWVWU) combines the robustness of Fourier-based methods to low temporal resolution with the possibility to restrict the analysis to the reflectionless systolic upslope. We compared this method with Fourier-based (archPWVF) and time domain upslope (archPWVTU) methods in relation to linear correlations with age, cfPWV and effects of decreasing temporal resolution by factors of 2, 3 and 4. We studied 71 healthy subjects (45 ± 15 years, 29 females) who underwent CMR velocity acquisitions and cfPWV measurements. Comparison with age resulted in the highest correlation for the wavelet-based method (archPWVWU:r = 0.84,p < 0.001; archPWVTU:r = 0.74,p < 0.001; archPWVF:r = 0.63,p < 0.001). Associations with cfPWV resulted in the highest correlations for upslope techniques whether based on wavelet (archPWVWU:r = 0.58,p < 0.001) or time (archPWVTU:r = 0.58,p < 0.001) approach. Furthermore, while decreasing temporal resolution by 4-fold induced only a minor decrease in correlation of both archPWVWU (r decreased from 0.84 to 0.80) and archPWVF (r decreased from 0.63 to 0.51) with age, it induced a major decrease for the archPWVTU age relationship (r decreased from 0.74 to 0.38). By CMR, measurement of aortic arch flow TT using systolic upslopes resulted in a better correlation with age and cfPWV, as compared to the Fourier-based approach applied on the entire cardiac cycle. Furthermore, methods based on harmonic decomposition were less affected by low temporal resolution. Since the proposed wavelet approach combines these two advantages, it might help to overcome current technical limitations related to CMR temporal resolution and evaluation of patients with highly stiff arteries.