Factors affecting the efficacy of atenolol in treating feline hypertrophic cardiomyopathy

Khor, Kuan Hua (2012). Factors affecting the efficacy of atenolol in treating feline hypertrophic cardiomyopathy PhD Thesis, School of Veterinary Science, The University of Queensland.

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Author Khor, Kuan Hua
Thesis Title Factors affecting the efficacy of atenolol in treating feline hypertrophic cardiomyopathy
School, Centre or Institute School of Veterinary Science
Institution The University of Queensland
Publication date 2012
Thesis type PhD Thesis
Supervisor Paul C. Mills
Ian A. Shiels
Fiona E. Campbell
Thiruma Arumugam
Total pages 246
Total colour pages 25
Total black and white pages 221
Language eng
Subjects 070706 Veterinary Medicine
070710 Veterinary Pharmacology
070709 Veterinary Pathology
Formatted abstract
Hypertrophic cardiomyopathy (HCM) is a primary myocardial disease characterised by concentric left ventricular hypertrophy associated with diastolic dysfunction and arrhythmias. The disease progression of HCM is variable with congestive heart failure being an important clinical outcome. Treatment is challenging and usually focuses on attempts to delay onset or control signs of congestive heart failure and reduce the risk of systemic thromboembolism and sudden death. Atenolol, a β1-adrenoreceptor (β1-AR) antagonist is commonly used in cats with HCM based on its potential to reduce heart rate, improve diastolic function, reduce ischaemia and decrease dynamic outflow tract obstruction thereby aiming to delay congestive failure and attenuate risk of sudden arrhythmogenic death. However, the used of this drug remain controversial as there is very limited published data to support its efficacy for treating cats with HCM, particularly when atenolol has not been demonstrated to prevent disease progression of cats with HCM or reverse structural changes characteristic of the disease. Further research is therefore required to confirm the efficacy and applicability of atenolol for the treatment of HCM in cats.

This thesis outlines extrinsic and intrinsic factors that may affect the efficacy of atenolol in the treatment of cats with HCM. Extrinsic factor that may contribute to therapeutic failure includes non-compliance with medication administration from the owners and/or cats, particularly since currently available formulations are registered for human use and must be divided for feline administration. Intrinsic factors include the fact that morphological changes to the heart (e.g. myocardial fibre disarray, myocardial ischaemia and myocardial fibrosis) are unlikely to be addressed by atenolol. More importantly, pathophysiological changes during HCM may affect binding and activity of atenolol to β1-AR in the heart.

A preliminary pharmacodynamic study was performed to confirm the dose rate of atenolol in cats. An oral dose of 12.5 mg twice daily per cat provided effective negative inotropic and negative chronotropic effect in healthy cats as assessed using echocardiography. Compliance was then investigated using an extemporaneously prepared atenolol paste and suspension formulations, compared to the commercially-available tablet. The mean atenolol plasma concentration correlated with the reduced heart rate that persists for at least 12 hours following administration of all three formulations but did not significantly change the blood pressure of healthy cats. Similarly, the compliance of cat’s owner and their cat during administration of both the extemporaneously prepared formulations were comparable to the commercially available tablet. Most owners preferred the tablet, probably due to familiarity with the dosage form, but there was better compliance in term of prescribed doses actually given with the suspension formulation, which may be useful for long-term therapy, particularly in non-compliant cats.

The thesis then investigated potential intrinsic factors that may affect the efficacy of atenolol to treat cats with HCM. In addition to myocardial hypertrophy, myocardial fibre disarray and fibrosis of the left ventricle, cats diagnosed with HCM, either histopathologically (at a chronic stage) or echocardiographically (at an early stage), exhibited increased collagen deposition and inflammatory cells infiltration, compared to the healthy cats. Multifocal inflammatory infiltration was observed in 4/5 cats with HCM at the early stage of the disease. It was hypothesised that early (asymptomatic) HCM was characterised by, and possibly initiated by, inflammatory events, in addition to any increase in left ventricle wall thickness in diastole and evidence of diastolic dysfunction. Infiltration of inflammatory cells into myocardial tissue appeared to occur prior to the onset of structural and functional changes may therefore contribute to disease pathogenesis and/or efficacy of pharmacological agents used to treat HCM.

An early report had shown that a specific component of the inflammatory response, the complement pathway, may in fact affect the activity of adrenergic receptors and this same pathway had been demonstrated to contribute to the pathogenesis of HCM. The investigation of intrinsic factors was therefore focused onto the specific effects of complement fragment C5a on the efficacy of atenolol in cardiac function. A study performed in anaesthetised mice model using “normal” C57BL6/J (wild type, WT) mice and mice deficient in complement C5a receptor (C5aR, specifically CD88). The latter group had a significantly lower heart rate and increased heart rate variability at rest, while the absence of the CD88 reduced the effectiveness of β1-AR in the heart. Importantly, a C5a antagonist effectively reduced heart rate in the WT mice and significantly improved the survival rate of the WT mice subjected to an inflammatory challenge (a gut ischaemia-reperfusion model). A strong association between the β1-AR and the CD88 receptor was proposed, but further work is required to verify.

The outcome of the mouse study was applied to an anaesthetised cat model, where the administration of atenolol reduced heart rate and increased heart rate variability in healthy cats. A preliminary outcome from an asymptomatic cats diagnosed with HCM revealed a higher heart rate and reduced heart rate variability, compared to the healthy cats, which was not effectively reversed with atenolol.

Conclusions: Compounded atenolol formulation with comparable pharmacokinetic and pharmacodynamic profile to the commercially available tablet could be used interchangeably to increase both owners’ and cats’ drug compliance in a long-term treatment. However, compliance does not appear to be a factor limiting administration of atenolol to healthy cats and it would seem likely owners of cats with HCM may exhibit even higher motivation to manage disease in their pet.

There was significant evidence of early morphological changes, including increased inflammatory infiltrations and collagen depositions, in cats with early (asymptomatic) HCM. These early changes may contribute to altered autonomic activity and diastolic function in the heart. The use of atenolol in asymptomatic cats with HCM reduces heart rate and improves diastolic dysfunction and so may be beneficial in delaying or reducing the risk of adverse outcomes. However, consideration should also be given to underlying inflammatory changes, both as an adjunct to therapy and as a potential cause of reduced efficacy of atenolol in cats with HCM.
Keyword Hypertrophic cardiomyopathy
Pharmacokinetic (PK)
Pharmacodynamic (PD)
Beta 1-adrenoreceptor
C5a Receptor (c5ar)
Heart rate variability (HRV)

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Created: Wed, 15 Aug 2012, 12:55:15 EST by Kuan Hua Khor on behalf of Scholarly Communication and Digitisation Service