Diastolic dysfunction in pulmonary artery hypertension: creatine kinase and the potential therapeutic benefit of beta-blockers

Fowler, Ewan D., Drinkhill, Mark J., Stones, Rachel and White, Ed 2018. Diastolic dysfunction in pulmonary artery hypertension: creatine kinase and the potential therapeutic benefit of beta-blockers. Clinical and Experimental Pharmacology and Physiology 45 (4) , pp. 384-389. 10.1111/1440-1681.12898

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Abstract

Passive properties of the myocardium influence diastolic filling and cardiac output. In heart failure, changes in contributors to the passive properties of the ventricle, such as titin and collagen, and loss of the metabolic enzyme creatine kinase, increase resistance to filling resulting in diastolic dysfunction. Pulmonary artery hypertension (PAH) arises from interactions between the pulmonary vasculature and the right ventricle (RV) which ultimately leads to RV failure. Beta1-adrenergic receptor blockers (BB) act on the myocardium and are beneficial in left heart failure but are not used in PAH. We investigated whether BB improved survival and RV function in a rat model of PAH. Rats were injected with monocrotaline (60 mg/kg) to induce PAH and RV failure, or saline as controls (CON). When PAH was established, rats were treated with metoprolol (10 mg/kg per day) (MCT+BB) or vehicle (sucrose) (MCT); CON were treated with vehicle. In vivo measurement of RV compliance using pressure–volume catheter, indicated diastolic dysfunction in the RV of MCT rats was improved with BB treatment. Expression of creatine kinase protein and mRNA was lower in MCT rats compared to CON, with a trend for reversion by BB treatment. Isolated CON RV myocytes had a positive contraction response to faster pacing, whereas it was negative in MCT. MCT+BB cells had an intermediate response, indicating improved ability to respond to increased demand. BB improved diastolic function, partially restored metabolic enzymes and augmented contractility in PAH. These data support the hypothesis that BB may be beneficial in PAH by supporting RV function.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	Wiley
ISSN:	0305-1870
Date of First Compliant Deposit:	5 October 2021
Date of Acceptance:	16 November 2017
Last Modified:	15 Jun 2023 15:37
URI:	https://orca.cardiff.ac.uk/id/eprint/144670

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