Sildenafil enhances systolic adaptation, but does not prevent diastolic dysfunction, in the pressure-loaded right ventricle

Marinus A. J. Borgdorff*, Beatrijs Bartelds, Michael G. Dickinson, Michel Weij, Andre Zandvoort, Herman H. W. Sillje, Paul Steendijk, Maartje de Vroomen, Rolf M. F. Berger, B. Boersma

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Right ventricular (RV) failure due to pressure or volume overload is a major risk factor for early mortality in congenital heart disease and pulmonary hypertension, but currently treatments are lacking. We aimed to demonstrate that the phosphodiesterase 5A inhibitor sildenafil can prevent adverse remodelling and improve function in chronic abnormal RV overload, independent from effects on the pulmonary vasculature.

In rat models of either pressure or volume overload, we performed pressurevolume studies to measure haemodynamic effects and voluntary exercise testing as clinical outcome after 4 weeks of sildenafil (or vehicle) administration. In the pressure-loaded right ventricle, sildenafil enhanced contractility [end-systolic elastance (mmHg/mL) 247 68 vs.155 71, sildenafil vs. vehicle, P 0.05], prevented RV dilatation [end-diastolic volume (L) 733 50 vs. 874 39, P 0.05], reduced wall stress [peak wall stress (mmHg) 323 46 vs. 492 62, P 0.05], and partially preserved exercise tolerance [running distance () 33 15 vs. 62 12, P 0.05]. Protein kinase A was not activated by sildenafil and thus did not mediate the observed effects. In contrast, protein kinase G-1 was activated by sildenafil, but hypertrophy was not inhibited. Importantly, sildenafil did not prevent diastolic dysfunction, whereas RV fibrosis appeared to be increased in sildenafil-treated rats. In the volume-loaded right ventricle, sildenafil treatment did not show any beneficial effects.

We demonstrate sildenafil to have beneficial, afterload-independent effects on the pressure-loaded right ventricle, but not on the volume-loaded right ventricle. These results indicate that sildenafil may offer a specific treatment for the pressure-loaded right ventricle, although persistent diastolic dysfunction and RV fibrosis could be of concern.

Original languageEnglish
Pages (from-to)1067-1074
Number of pages8
JournalEuropean Journal of Heart Failure
Volume14
Issue number9
DOIs
Publication statusPublished - Sep-2012

Keywords

  • Right ventricular failure
  • Congenital heart disease
  • Pressure load
  • Contractility
  • Sildenafil
  • Exercise testing
  • CONGENITAL HEART-DISEASE
  • PULMONARY-HYPERTENSION
  • CARDIAC-HYPERTROPHY
  • MOLECULAR-MECHANISMS
  • CHRONIC INHIBITION
  • FAILURE
  • RAT
  • ISOPROTERENOL
  • FIBROSIS
  • VOLUME

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