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Gorelik J.,Imperial College London | Wright P.T.,Imperial College London | Lyon A.R.,Imperial College London | Lyon A.R.,Cardiovascular Biomedical Research Unit | Harding S.E.,Imperial College London
Cardiovascular Research | Year: 2013

The beta1-adrenoceptors (β1AR) and beta-2 (β2AR) adrenoceptors represent the predominant pathway for sympathetic control of myocardial function. Diverse mechanisms have evolved to translate signalling via these two molecules into differential effects on physiology. In this review, we discuss how the functions of the βAR are organized from the level of secondary messengers to the whole heart to achieve this. Using novel microscopy and bio-imaging methods researchers have uncovered subtle organization of the control of cyclic adenosine monophosphate (cAMP), the predominant positively inotropic pathway for the βAR. The β2AR in particular is demonstrated to give rise to highly compartmentalized, spatially confined cAMP signals. Organization of β2AR within the T-tubule and caveolae of cardiomyocytes concentrates this receptor with molecules which buffer and shape its cAMP signal to give fine control. This situation is undermined in various forms of heart failure. Human and animal models of heart failure demonstrate disruption of cellular micro-architecture which contributes to the change in response to cardiac βARs. Loss of cellular structure has proved key to the observed loss of confined β2AR signalling. Some pharmacological and genetic treatments have been successful in returning failing cells to a more structured phenotype. Within these cells it has been possible to observe the partial restoration of normal β2AR signalling. At the level of the organ, the expression of the two βAR subtypes varies between regions with the β2AR forming a greater proportion of the βAR population at the apex. This distribution may contribute to regional wall motion abnormalities in Takotsubo cardiomyopathy, a syndrome of high sympathetic activity, where the phosphorylated β2AR can signal via G i protein to produce negatively inotropic effects. © 2012 The Author.

Tranter M.H.,Imperial College London | Wright P.T.,Imperial College London | Sikkel M.B.,Imperial College London | Lyon A.R.,Imperial College London | Lyon A.R.,Cardiovascular Biomedical Research Unit
Heart Failure Clinics | Year: 2013

Takotsubo cardiomyopathy (TTC) is an acute heart failure syndrome classically characterized by hypocontractile apical and midventricular regions of the left ventricle, with a compensatory hypercontractile base. Available data support the hypothesis that TTC and atypical TTC-like disorders are primarily induced by catecholaminergic overstimulation, with epinephrine playing a crucial role. Knowledge from the available preclinical models should be used to guide the development of potential clinical trials in the most severe cases, where rates of acute morbidity and mortality are highest, and also to prevent recurrence in susceptible individuals. © 2013 Elsevier Inc.

Ware J.S.,Imperial College London | Roberts A.M.,Imperial College London | Cook S.A.,Imperial College London | Cook S.A.,Cardiovascular Biomedical Research Unit
Heart | Year: 2012

The fast moving field of genomic medicine is already impacting on clinical care and cardiologists are fortunate to be in a position to benefit early from the transformative advances in genomics. However, the challenges associated with genomics in the clinic in general, and with next generation sequencing technologies in particular, are significant and cardiologists need to be prepared if they wish to surf the wave of genomic opportunity. This paper presents an overview of the implications of next generation sequencing for clinical diagnostics and personalised medicine in the cardiology clinic.

Keegan J.,Cardiovascular Biomedical Research Unit
Journal of Magnetic Resonance Imaging | Year: 2015

Like X-Ray contrast angiography, MR coronary angiograms show the vessel lumens rather than the vessels themselves. Consequently, outward remodeling of the vessel wall, which occurs in subclinical coronary disease before luminal narrowing, cannot be seen. The current gold standard for assessing the coronary vessel wall is intravascular ultrasound, and more recently, optical coherence tomography, both of which are invasive and use ionizing radiation. A noninvasive, low-risk technique for assessing the vessel wall would be beneficial to cardiologists interested in the early detection of preclinical disease and for the safe monitoring of the progression or regression of disease in longitudinal studies. In this review article, the current state of the art in MR coronary vessel wall imaging is discussed, together with validation studies and recent developments. J. Magn. Reson. Imaging 2015;41:1190-1202. © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.

Ludman P.F.,Queen Elizabeth Hospital | Moat N.,Royal Brompton and Harefield Hospital | De Belder M.A.,James Cook University | Blackman D.J.,Leeds Teaching Hospitals | And 14 more authors.
Circulation | Year: 2015

Background - We assessed trends in the performance of transcatheter aortic valve implantation in the United Kingdom from the first case in 2007 to the end of 2012. We analyzed changes in case mix, complications, outcomes to 6 years, and predictors of mortality. Methods and Results - Annual cohorts were examined. Mortality outcomes were analyzed in the 92% of patients from England and Wales for whom independent mortality tracking was available. A total of 3980 transcatheter aortic valve implantation procedures were performed. In successive years, there was an increase in frequency of impaired left ventricular function, but there was no change in Logistic EuroSCORE. Overall 30-day mortality was 6.3%; it was highest in the first cohort (2007-2008), after which there were no further significant changes. One-year survival was 81.7%, falling to 37.3% at 6 years. Discharge by day 5 rose from 16.7% in 2007 and 2008 to 28% in 2012. The only multivariate preprocedural predictor of 30-day mortality was Logistic EuroSCORE ≥40. During long-term follow-up, multivariate predictors of mortality were preprocedural atrial fibrillation, chronic obstructive pulmonary disease, creatinine >200 μmol/L, diabetes mellitus, and coronary artery disease. The strongest independent procedural predictor of long-term mortality was periprocedural stroke (hazard ratio=3.00; P<0.0001). Nonfemoral access and postprocedural aortic regurgitation were also significant predictors of adverse outcome. Conclusions - We analyzed transcatheter aortic valve implantation in an entire country, with follow-up over 6 years. Although clinical profiles of enrolled patients remained unchanged, longer-term outcomes improved, and patients were discharged earlier. Periprocedural stroke, nonfemoral access, and postprocedural aortic regurgitation are predictors of adverse outcome, along with intrinsic patient risk factors. © 2015 American Heart Association, Inc.

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