Showing papers by "Barbara Casadei published in 2015"

Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: the regulatory role of perivascular adipose tissue.

Abstract: Oxidative stress plays a critical role in the vascular complications of type 2 diabetes. We examined the effect of type 2 diabetes on NADPH oxidase in human vessels and explored the mechanisms of this interaction. Segments of internal mammary arteries (IMAs) with their perivascular adipose tissue (PVAT) and thoracic adipose tissue were obtained from 386 patients undergoing coronary bypass surgery (127 with type 2 diabetes). Type 2 diabetes was strongly correlated with hypoadiponectinemia and increased vascular NADPH oxidase-derived superoxide anions (O2˙(-)). The genetic variability of the ADIPOQ gene and circulating adiponectin (but not interleukin-6) were independent predictors of NADPH oxidase-derived O2˙(-). However, adiponectin expression in PVAT was positively correlated with vascular NADPH oxidase-derived O2˙(-). Recombinant adiponectin directly inhibited NADPH oxidase in human arteries ex vivo by preventing the activation/membrane translocation of Rac1 and downregulating p22(phox) through a phosphoinositide 3-kinase/Akt-mediated mechanism. In ex vivo coincubation models of IMA/PVAT, the activation of arterial NADPH oxidase triggered a peroxisome proliferator-activated receptor-γ-mediated upregulation of the adiponectin gene in the neighboring PVAT via the release of vascular oxidation products. We demonstrate for the first time in humans that reduced adiponectin levels in individuals with type 2 diabetes stimulates vascular NADPH oxidase, while PVAT "senses" the increased NADPH oxidase activity in the underlying vessel and responds by upregulating adiponectin gene expression. This PVAT-vessel interaction is identified as a novel therapeutic target for the prevention of vascular complications of type 2 diabetes.

Atrial fibrillation: effects beyond the atrium?

Abstract: Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is associated with significant morbidity, mostly secondary to heart failure and stroke, and an estimated two-fold increase in premature death. Efforts to increase our understanding of AF and its complications have focused on unravelling the mechanisms of electrical and structural remodelling of the atrial myocardium. Yet, it is increasingly recognized that AF is more than an atrial disease, being associated with systemic inflammation, endothelial dysfunction, and adverse effects on the structure and function of the left ventricular myocardium that may be prognostically important. Here, we review the molecular and in vivo evidence that underpins current knowledge regarding the effects of human or experimental AF on the ventricular myocardium. Potential mechanisms are explored including diffuse ventricular fibrosis, focal myocardial scarring, and impaired myocardial perfusion and perfusion reserve. The complex relationship between AF, systemic inflammation, as well as endothelial/microvascular dysfunction and the effects of AF on ventricular calcium handling and oxidative stress are also addressed. Finally, consideration is given to the clinical implications of these observations and concepts, with particular reference to rate vs. rhythm control.

Catheter-Based Renal Denervation Reduces Atrial Nerve Sprouting and Complexity of Atrial Fibrillation in Goats

Abstract: Background— Atrial fibrillation (AF) leads to structural and neural remodeling in the atrium, which enhances AF complexity and perpetuation. Renal denervation (RDN) can reduce renal and whole-body sympathetic activity. Aim of this study was to determine the effect of sympathetic nervous system modulation by RDN on atrial arrhythmogenesis. Methods and Result— Eighteen goats were instrumented with an atrial endocardial pacemaker lead and a burst pacemaker. Percutaneous catheter-based RDN was performed in 8 goats (RDN-AF). Ten goats undergoing a sham procedure served as control (SHAM-AF). AF was induced and maintained by burst pacing for 6 weeks. High-resolution mapping was used to record epicardial conduction patterns of the right and left atrium. RDN reduced tyrosine hydroxylase-positive sympathetic nerve staining and resulted in lower transcardiac norepinephrine levels. This was associated with reduced expression of nerve growth factor-β, indicating less atrial nerve sprouting. Atrial endomysial fibrosis content was lower and myocyte diameter was smaller in RDN-AF. Median conduction velocity was higher (75±9 versus 65±10 cm/s, P =0.02), and AF cycle length was shorter in RDN-AF compared with SHAM-AF. Left atrial AF complexity (4.8±0.8 fibrillation waves/AF cycle length versus 8.5±0.8 waves/AF cycle length, P =0.001) and incidence of breakthroughs (2.0±0.3 versus 4.3±0.5 waves/AF cycle length, P =0.059) were lower in RDN-AF compared with SHAM-AF. Blood pressure was normal and not significantly different between the groups. Conclusions— RDN reduces atrial sympathetic nerve sprouting, structural alterations, and AF complexity in goats with persistent AF, independent of changes in blood pressure.

A porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction.

Abstract: We present a large-animal model of hypertensive heart disease that mimics the cardiac phenotype of heart failure with preserved ejection fraction (HFPEF) in vivo and shows molecular alterations com...

Systolic ShMOLLI myocardial T1-mapping for improved robustness to partial-volume effects and applications in tachyarrhythmias

Abstract: Background T1-mapping using the Shortened Modified Look-Locker Inversion Recovery (ShMOLLI) technique enables non-invasive assessment of important myocardial tissue characteristics. However, tachyarrhythmia may cause mistriggering and inaccurate T1 estimation. We set out to test whether systolic T1-mapping might overcome this, and whether T1 values or data quality would be significantly different compared to conventional diastolic T1-mapping.

The European Network for Translational Research in Atrial Fibrillation (EUTRAF): objectives and initial results.

Abstract: Atrial fibrillation (AF) is the most common sustained arrhythmia in the general population. As an age-related arrhythmia AF is becoming a huge socio-economic burden for European healthcare systems. Despite significant progress in our understanding of the pathophysiology of AF, therapeutic strategies for AF have not changed substantially and the major challenges in the management of AF are still unmet. This lack of progress may be related to the multifactorial pathogenesis of atrial remodelling and AF that hampers the identification of causative pathophysiological alterations in individual patients. Also, again new mechanisms have been identified and the relative contribution of these mechanisms still has to be established. In November 2010, the European Union launched the large collaborative project EUTRAF (European Network of Translational Research in Atrial Fibrillation) to address these challenges. The main aims of EUTRAF are to study the main mechanisms of initiation and perpetuation of AF, to identify the molecular alterations underlying atrial remodelling, to develop markers allowing to monitor this processes, and suggest strategies to treat AF based on insights in newly defined disease mechanisms. This article reports on the objectives, the structure, and initial results of this network.

Hypertension in the military patient

Abstract: Hypertension and hypertension-related diseases are a leading cause of morbidity and mortality worldwide. A diagnosis of hypertension can have serious occupational implications for military personnel. This article examines the diagnosis and management of hypertension in military personnel, in the context of current international standards. We consider the consequences of hypertension in the military environment and potential military-specific issues relating to hypertension.

Systolic ShMOLLI T1-mapping is feasible in tachyarrhythmia, with improved image quality compared to diastolic readout

Abstract: Background T1-mapping using the Shortened Modified Look-Locker Inversion Recovery (ShMOLLI) technique [1] enables assessment of myocardial characteristics, such as oedema, scar and diffuse fibrosis. However, cardiac pathology is often accompanied by tachyarrhythmia, which may cause mistriggering and inaccurate T1 estimation. We hypothesised that systolic T1-mapping may overcome this issue without significantly affecting T1 values or data quality compared to conventional diastolic T1-mapping.