Casadei Group: Translational approaches in chronic cardiac disease
Our programme of work aims to understand nitric oxide (NO) and redox signalling in healthy and diseased myocardium, with a particular focus on atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF). Building on the resources and original discoveries that we have made recently, we plan to test novel interventions that aim to correct the myocardial substrate that promotes the new onset of AF, or HFpEF, or prevent the adverse atrial remodelling that is induced by AF.
Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) are rapidly growing public health problems worldwide. However, so far, no intervention – with the exception of anticoagulation for stroke prevention in AF – has been shown to change the natural history of these diseases or improve patient survival.
Perturbations in the nitric oxide (NO)-redox balance have been strongly linked to both of these chronic cardiac diseases, and have been shown to directly promote adverse electrical remodelling, functional impairment and alter metabolism in the heart leading to disease progression. Given this, our research efforts have focused on:
- understanding why the NO-redox balance is shifted
- how this modifies the disease
- whether this information can be used to develop new treatments for AF and HFpEF.
To address these questions we preform investigations in human cardiac tissue and animal models, with a strong focus on patient-based research comprising mechanistic in vivo and in vitro studies, prospective investigations in cohorts of patients and, more recently, clinical trials. We have a broad range of methods for mechanistic studies in tissue samples or cells isolated from either human atrial tissue or the myocardium of our mouse models. These include patch-clamping and various live-cell imaging techniques (eg calcium transient measurements, FRET, FRAP and oxygen consumption rate), biochemical analyses (including genomics, proteomics, metabolomics) and molecular biology approaches. To complement these studies we have developed, in collaboration with the University of Maastricht, techniques for evaluating the cardiac electrophysiological and phenotype of murine models of human disease (eg in vivo programmed electrical stimulation, and optical mapping in isolated hearts). In addition, our experimental patch-clamping data has been used to inform in silico modelling in the context of human atrial fibrillation, developed in collaboration with Dr Blanca Rodriguez (Department of Computer Science, Oxford) and used as a hypothesis-generating tool to dissect the ion channels and transporters involved in the changes in action potential duration and calcium handling that are evoked by the activity of oxidase systems in atrial myocytes isolated from patients with atrial fibrillation.
More recently, our research has been directed to the identification of biomarkers and therapeutic targets for the prediction and prevention of atrial fibrillation and other in-hospital complications in patients undergoing cardiac surgery. We have already tested some of our ideas in rigorous clinical trials that have impacted on international guidelines on the management of patients with AF. We are currently testing novel interventions intended to either correct the abnormalities in cardiac tissue that promote the new onset of AF or to prevent the adverse changes in the atria that are induced by AF. Taking advantage of the biobank of human atrial tissue from our Statins In Cardiac Surgery (STICS) trial, we will also apply high-throughput technologies to analyse the changes in gene expression in patients in normal sinus rhythm who develop AF after cardiac surgery. This approach should reveal, for the first time, molecular signatures that promote the new onset of AF.
Nuffield Department of Population Health (Oxford)
Oxford Centre for Magnetic Resonance (Oxford)
University of Maastricht (Department of Physiology)
Department of Computer Science (Oxford)