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Auricchio A.,Fondazione Cardiocentro Ticino | Prinzen F.W.,Cardiovascular Research Institute Maastricht
Circulation Journal | Year: 2011

A variable proportion of cardiac resynchronization therapy (CRT) patients do not benefit from treatment (termed 'non-responders'). The problem of non-response to CRT might become increasingly important, because it is anticipated that larger groups of heart failure patients are indicated to the therapy. This article will discuss the definition of response to CRT, the parameters related to response to CRT, and finally whether response to CRT might be predicted. The effort to improve patient selection in order to maximize human and financial resource utilization has fallen short so far. It is, however, conceivable that rather than the identification of a 'universally' applicable cut-off value, risk strata - in which inclusion of method for determination of left ventricular volumes, etiology, QRS duration and morphology, etc - might better serve the goal of defining non-responders. Potentially simple clinical scores might help in refining outcome and by doing so, allow to more precisely measure response to CRT in daily practice in the individual patient at the time of CRT implantation. Although sophisticated cardiac imaging modalities have been intensively utilized for improving patient outcome, it seems that many mechanical dyssynchrony measures suffer from technical limitations and from difficult interpretation of the complex signals, which lack reproducibility outside highly specialized laboratories.

Prinzen F.W.,Cardiovascular Research Institute Maastricht | Auricchio A.,Fondazione Cardiocentro Ticino
Journal of Cardiovascular Translational Research | Year: 2012

The hemodynamic, mechanical and electrical effects of cardiac resynchronization therapy (CRT) occur immediate and are lasting as long as CRT is delivered. Therefore, it is reasonable to assume that acute hemodynamic effects should predict long-term outcome. However, in the literature there is more evidence against than in favour of this idea. This raises the question of what factor(s) do relate to the benefit of CRT. There is increasing evidence that dyssynchrony, presumably through the resultant abnormal local mechanical behaviour, induces extensive remodelling, comprising structure, as well as electrophysiological and contractile processes. Resynchronization has been shown to reverse these processes, even in cases of limited hemodynamic improvement. These data may indicate the need for a paradigm shift in order to achieve maximal long-term CRT response. © The Author(s) 2011.

Linz D.,Universitatsklinikum des Saarlandes | Mahfoud F.,Universitatsklinikum des Saarlandes | Schotten U.,Cardiovascular Research Institute Maastricht | Ukena C.,Universitatsklinikum des Saarlandes | And 3 more authors.
Hypertension | Year: 2012

The aim of this study was to identify the relative impact of adrenergic and cholinergic activity on atrial fibrillation (AF) inducibility and blood pressure (BP) in a model for obstructive sleep apnea. Obstructive sleep apnea is associated with sympathovagal disbalance, AF, and postapneic BP rises. Renal denervation (RDN) reduces renal efferent and possibly also afferent sympathetic activity and BP in resistant hypertension. The effects of RDN compared with β-blockade by atenolol on atrial electrophysiological changes, AF inducibility, and BP during obstructive events and on shortening of atrial effective refractory period (AERP) induced by high-frequency stimulation of ganglionated plexi were investigated in 20 anesthetized pigs. Tracheal occlusion with applied negative tracheal pressure (NTP; at -80 mbar) induced pronounced AERP shortening and increased AF inducibility in all of the pigs. RDN but not atenolol reduced NTP-induced AF-inducibility (20% versus 100% at baseline; P=0.0001) and attenuated NTP-induced AERP shortening more than atenolol (27 ±5 versus 43 ±3 ms after atenolol; P=0.0272). Administration of atropine after RDN or atenolol completely inhibited NTP-induced AERP shortening. AERP shortening induced by highfrequency stimulation of ganglionated plexi was not influenced by RDN, suggesting that changes in sensitivity of ganglionated plexi do not play a role in the antiarrhythmic effect of RDN. Postapneic BP rise was inhibited by RDN and not modified by atenolol. We showed that vagally mediated NTP-induced AERP shortening is modulated by RDN or atenolol, which emphasizes the importance of autonomic disbalance in obstructive sleep apnea-associated AF. Renal denervation displays antiarrhythmic effects by reducing NTP-induced AERP shortening and inhibits postapneic BP rises associated with obstructive events. © 2012 American Heart Association, Inc.

Wellens H.J.,Cardiovascular Research Institute Maastricht
Applied Cardiopulmonary Pathophysiology | Year: 2012

Death from heart disease has continued to diminish during the last two decades, but still half of those deaths are sudden, often occurring unexpectedly outside hospital, claiming at least 250.000 lives in Europe each year. What can we do to prevent this from happening and how can we successfully resuscitate the victim? When an arrhythmic sudden death occurs outside the hospital, the only chance for survival is recognition of the situation by a witness, the start of cardiac massage and a call to bring a defibrillator and experienced people to the scene as soon as possible. Increasing the number of people trained in resuscitation, and the density of the automatic external defibrillator in the community are important factors to increase the success rate of the resuscitation attempt. However, a real breakthrough requires the development of a device that recognizes cardiac arrest, sounds an alarm, and transmits the location of the victim, thereby shortening the time interval of the different steps in the chain of survival.

Kubben N.,Cardiovascular Research Institute Maastricht
Nucleus (Austin, Tex.) | Year: 2010

The nuclear lamina is an interconnected meshwork of intermediate filament proteins underlying the nuclear envelope. The lamina is an important regulator of nuclear structural integrity as well as nuclear processes, including transcription, DNA replication and chromatin remodeling. The major components of the lamina are A- and B-type lamins. Mutations in lamins impair lamina functions and cause a set of highly tissue-specific diseases collectively referred to as laminopathies. The phenotypic diversity amongst laminopathies is hypothesized to be caused by mutations affecting specific protein interactions, possibly in a tissue-specific manner. Current technologies to identify interaction partners of lamin A and its mutants are hampered by the insoluble nature of lamina components. To overcome the limitations of current technologies, we developed and applied a novel, unbiased approach to identify lamin A-interacting proteins. This approach involves expression of the high-affinity OneSTrEP-tag, precipitation of lamin-protein complexes after reversible protein cross-linking and subsequent protein identification by mass spectrometry. We used this approach to identify in mouse embryonic fibroblasts and cardiac myocyte NklTAg cell lines proteins that interact with lamin A and its mutant isoform progerin, which causes the premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS). We identified a total of 313 lamina-interacting proteins, including several novel lamin A interactors, and we characterize a set of 35 proteins which preferentially interact with lamin A or progerin.

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