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Title: Combination of pharmacotherapy and mechanical unloading for the treatment of chronic heart failure
Author: Navaratnarajah, Manoraj
ISNI:       0000 0004 2743 6699
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Background: Left ventricular assist devices (LVAD) mechanically unload the failing left ventricle, and reverse heart failure-induced remodelling. However, achievement of clinical functional recovery remains rare (4-10%, “Bridge-to-recovery” (BTR)). Reasons for this disparity are unknown, but are likely due to detrimental changes caused by prolonged unloading. Pharmacological prevention of these changes has attracted considerable interest. This thesis aimed to test the central broad hypothesis that “mechanical unloading-induced reverse remodelling of whole heart / cellular structure and function in failing hearts, is improved by combination pharmacotherapy” and was tested using an animal model. Methods: Heart failure was induced by left coronary artery ligation (12 weeks) in male Lewis rats. Mechanical unloading was achieved by heterotopic abdominal heart transplantation (4 weeks). An array of techniques to study in vivo whole heart function, and structural and functional effects at the myocardial, cellular and molecular levels was used. The thesis firstly investigates the effects of clenbuterol, a drug used as part of the “Harefield Protocol” which enhanced functional recovery in patients with dilated cardiomyopathy, and then other novel pharmacological strategies: A) clenbuterol enantiomers (D / L) B) combined β2-AR agonism (clenbuterol) + β1-AR blockade (metoprolol) and C) If blockade (ivabradine), during prolonged mechanical unloading in the treatment of heart failure. Results: Treatment with clenbuterol or either of its enantiomers improves whole heart function of non-transplanted failing hearts. During mechanical unloading clenbuterol and its D-enantiomer enhance mechanical unloading-induced recovery of deranged cellular excitation-contraction coupling, but do not prevent myocardial atrophy. Chronic combined clenbuterol and metoprolol therapy, improves whole heart function of non-transplanted failing hearts in a synergistic manner. During mechanical unloading either clenbuterol, or metoprolol enhances mechanical unloading-induced recovery of deranged excitation-contraction coupling, but this enhancement is lost during combined drug therapy. Metoprolol alone prevented mechanical unloading-induced myocardial atrophy. Ivabradine therapy improves whole heart function and reverses myocardial fibrosis in non-transplanted failing hearts. During mechanical unloading ivabradine reverses myocardial fibrosis and enhances recovery of deranged excitation-contraction coupling. Conclusions: Manipulation of mechanical unloading-induced remodelling can be achieved by specific pharmacological therapy. The results presented here are relevant for the use of LVADs as treatment of heart failure and deserve to be tested in clinical trials.
Supervisor: Terracciano, Cesare ; Marczin, Nandor Sponsor: Qatar Foundation ; Wellcome Trust ; Magdi Yacoub Institute
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available