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


RESULTS
In rat models of either pressure or volume overload, we performed pressure-volume 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 (μL) 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.


CONCLUSIONS
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.
Center for Congenital Heart Diseases, Division of Pediatric Cardiology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands. m.a.j.borgdorff@umcg.nl
Marinus A J
MA
Borgdorff
Beatrijs
B
Bartelds
Michael G
MG
Dickinson
Bibiche
B
Boersma
Michel
M
Weij
Andre
A
Zandvoort
Herman H W
HH
Silljé
Paul
P
Steendijk
Maartje
M
de Vroomen
Rolf M F
RM
Berger
D000818:Animals; D003971:Diastole / Q000187:drug effects* / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage*; D011687:Purines / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage*; D013599:Systole / Q000187:drug effects* / Q000502:physiology; D018497:Ventricular Dysfunction, Right / Q000188:drug therapy* / Q000503:physiopathology; D017725:Ventricular Pressure / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate