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

Ewan D. Fowler*, Mark J. Drinkhill, Rachel Stones, Ed White

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

6 Citations (Scopus)
219 Downloads (Pure)

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.

Original languageEnglish
JournalClinical and Experimental Pharmacology and Physiology
Early online date10 Jan 2018
DOIs
Publication statusE-pub ahead of print - 10 Jan 2018

Keywords

  • Beta-blockers
  • Creatine kinase
  • Diastolic dysfunction
  • Heart failure
  • Pulmonary artery hypertension

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