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European Journal of Heart Failure 2008 10(12):1158-1165; doi:10.1016/j.ejheart.2008.09.016
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© 2008 European Society of Cardiology

Effects of phosphodiesterase-5 inhibition by sildenafil in the pressure overloaded right heart

Asger Andersena,*, Jan Møller Nielsena, Christian Daugaard Petersb, Uffe Kjær Schoub, Erik Slothc and Jens Erik Nielsen-Kudska

a Department of Cardiology, Aarhus University Hospital Skejby, Denmark
b The Water and Salt Research Centre, Institute of Anatomy, Aarhus University Denmark
c Department of Anaesthesiology and Intensive Care, Aarhus University Hospital Skejby, Denmark

* Corresponding author. Department of Cardiology, B-research, Aarhus University Hospital, Skejby, Brendstrupgaardsvej 100, Aarhus, Denmark. Tel.: +45 89496229; fax: +45 26363226. E-mail address: asgerandersen{at}gmail.com (A. Anderson).


   Abstract
Top
 Abstract
1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 References
 
Background: Sustained pressure overload of the right ventricle (RV) causes RV hypertrophy and failure. Cyclic-GMP has previously been shown to modulate left ventricular hypertrophy.

Aim: To evaluate the effects of sildenafil, a phosphodiesterase-5 (PDE5) inhibitor elevating c-GMP, on myocardial hypertrophy and function in rats with RV hypertrophy.

Methods: Rats were pulmonary trunk banded (PTB) and randomized to receive sildenafil (SIL) or vehicle (VEC) for three (n = 14) and nine weeks (n = 18). In addition, rats with established RV hypertrophy were randomized to SIL or VEC (n = 17) three weeks after PTB. Right ventricular function was evaluated by echocardiography and RV hypertrophy by histology and RV weight.

Results: Sildenafil failed to inhibit the development of RV hypertrophy when given for both 3 and 9 weeks. On the contrary, sildenafil increased RV hypertrophy after 3 weeks (RV/bodyweight: SIL 0.099±0.016 vs. VEC 0.081±0.011; p<0.05) and total heart weight after 9 weeks (SIL 1.05±0.10 vs. VEC 0.93±0.08g; p<0.05). Sildenafil also failed to reverse established RV hypertrophy, but significantly improved RV myocardial function as measured by Tricuspid Annular Plane Systolic Excursion (TAPSE: SIL 1.8±0.027 vs. VEC 1.39±0.037 mm; p<0.05).

Conclusion: PDE5 inhibition by sildenafil failed to prevent or reverse RV hypertrophy in rats operated by pulmonary trunk banding. It actually increased RV hypertrophy and improved RV contractile function when given to rats with established RV hypertrophy.

Key Words: Pulmonary hypertension • Right ventricular hypertrophy • Sildenafil • Pulmonary trunk banding • Echocardiography • Right ventricular failure

Received March 7, 2008; Revised June 27, 2008; Accepted September 30, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 References
 
Sustained pressure overload of the right ventricle (RV) is a significant pathophysiological factor in several cardiovascular disorders. They include pulmonary artery hypertension (PAH) and various forms of congenital heart disease with anatomically obstructed RV outflow or a RV supporting the systemic circulation [1,2].

Right ventricle hypertrophy may be a consequence of sustained pressure overload. At first, this can be considered a beneficial adaptive response. However, sustained pressure overload may lead to dilatation, fibrosis and dysfunction of the RV, and eventually right-sided heart failure [3]. The RV function has a major impact on morbidity and mortality in patients with a pressure overloaded right side of the heart. In pulmonary arterial hypertension (PAH), patients with reduced cardiac index and elevated right atrial pressure due to RV dysfunction have a poor prognosis [4]. In congenital heart diseases and systemic RV, the progressive deterioration of RV function over time is critical to the clinical outcome [5,6]. However, the mechanisms involved in the development of RV hypertrophy, remodelling and failing of the RV and the potential of pharmacological intervention are only sparsely understood.

Much more is known about the cellular mechanisms involved in the development of hypertrophy and remodelling of the left ventricle (LV). The cGMP cascade is one of the pathways that seem to play an important role. It was recently demonstrated that genetically increased synthesis of cGMP inhibits pressure-induced pathological LV remodelling [7]. Moreover, pharmacologically-induced elevation of cGMP by the phosphodiesterase-5 (PDE5) inhibitor sildenafil, prevented and reversed LV hypertrophy in mice exposed to chronic pressure overload induced by transverse aortic constriction [8]. Sildenafil also improved the in vivo heart function in these mice with LV hypertrophy [8].

Sildenafil is used in the treatment of patients with PAH [9]. PDE5 is abundant in the pulmonary circulation and sildenafil is a potent pulmonary vasodilator that also inhibits cell proliferation in pulmonary arteries [10]. In a double-blind randomised trial, PDE5 inhibition by sildenafil decreased RV hypertrophy [11]. Whether this effect was due to decreased resistance in the pulmonary vasculature alone or additional to a direct antihypertrophic effect on RV cardiomyocytes is unknown.

The purpose of this study was to evaluate the direct effects of PDE5 inhibition by sildenafil on RV myocardial function and hypertrophy in a rat model of right heart pressure overload.


   2. Material and methods
Top
 Abstract
 1. Introduction
 2. Material and methods
3. Results
 4. Discussion
 References
 
2.1. Study design
Wistar rats (n=60) with an initial weight of 150-200 g were used. The rats were given free access to tap water and standard rat chow (Altromin #1324, Altromin, Lage, Germany) and housed in a room with a 12:12-h light cycle and a temperature of 21 °C.

The effects of sildenafil treatment were evaluated in three different groups of rats (Fig. 1).


Figure 01
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  		Fig. 1 Study design, a schematic illustration. TTE: transthoracic echocardiography. In the Short term group, rats were randomised to three weeks of sildenafil or vehicle treatment immediately after pulmonary trunk banding (PTB). In the Long term group, rats were randomised to nine weeks of sildenafil or vehicle treatment immediately after PTB. In the Reversal group, rats with established right ventricular hypertrophy were randomised to three weeks of sildenafil treatment, three weeks after PTB. A small number of SHAM operated rats were included in all groups. Collection of blood and tissue samples and measurements of RV and LV+septum weights were performed at sacrifice.

 
In a short term group and in a long term group, it was evaluated if sildenafil could prevent the development of RV hypertrophy and dysfunction during three and nine weeks of sildenafil treatment, respectively. In a reversal group the effects of sildenafil on established hypertrophy and cardiac dysfunction was evaluated. The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1985).

2.2. Pulmonary artery trunk banding
There are three widely used experimental models to evaluate the anatomy, function, biochemical and cellular mechanisms of the hypertrophied right ventricle: The isolated heart (Langendorff), the pulmonary artery trunk banding (PTB) model and a model of increased resistance in the pulmonary vascular tree (the monocrotaline or hypoxia model). We wanted to investigate the in vivo and direct effects of sildenafil in the hypertrophied right ventricle without any influence from the pulmonary vasodilatory action of the drug. As sildenafil is known to lower pulmonary artery pressure in hypoxia and monocrotaline induced pulmonary hypertension [12,13], we found the PTB model to be the most useful.

Rats were intubated and mechanically ventilated with 2% isoflurane (Forene-isoflurane, Abbot Scandinavia AB, Solona, Sweden) in a mixture of 50% O2 and 50% N2O at 75 breaths/min and a tidal volume of 3 ml. Body temperature was maintained at 37 °C by placing the rats on a heating pad during the procedure. A lateral thoracotomy was performed on the left side of the sternum and the pericardium was opened. Using a dual view surgical microscope, the pulmonary artery (PA) was separated from the aorta. The banding was performed with a horizon applier (Horizon Applier, small, cat. nr. HZ137081, Weck Closure Systems, USA) pre-modified to compress a titanium-clip (Horizon Ligating Clips ref. 001200, Weck Closure Systems, USA) to allow an outer diameter of 1.08 mm of the PA. The thorax wall was closed in three separate layers. Postoperatively, the rats were given a 4 ml subcutaneous injection of isotonic saline and buprenorphine (Anorfin, GEA, Frederiksberg, Denmark) 0.12 mg/kg s.c. 3 times a day for 3 days [14]. The SHAM animals underwent the same procedures except for banding of the PA.

2.3. PDE5 inhibitor treatment
To ensure therapeutically relevant plasma concentrations, an oral dose of 100 mg/kg/day sildenafil (Viagra, Pfizer, Sandwich, UK) was provided in the drinking water [13,15,16]. Twice a week the intake was calculated and adjusted if necessary. The p-sildenafil concentration was measured in ten randomly selected rats.

2.4. Transthoracic echocardiography (TTE)
Echocardiography was performed on spontaneously breathing rats placed on their left side on a heating pad. The lowest possible dose of isoflurane (Forene-isoflurane, Abbot Scandinavia AB, Solona, Sweden) for adequate anaesthesia was used (approximately 2%). A vivid 7 echocardiographic system (GE Healthcare, USA) with an 11-MHz phased array paediatric transducer operating at a frame rate of about 350 Hz was used to evaluate cardiac function and structure. 2D and M-mode images were recorded in both apical four chamber view and short axis view at mid-papillary level. As an index of the RV systolic function, the Tricuspid Annular Plane Systolic Excursion (TAPSE) was measured as the fractional shortening in M-mode, between the apex and the lateral tricuspid annulus in the apical four chamber view. In rats, a significant change in TAPSE is detectable as early as seven days before developing clinical signs of heart failure. In a clinical setting it correlates closely to RV ejection fraction and has prognostic value in humans correlating to long- and short-term mortality [17-20]. The end diastolic RV-cavity area compared to LV-cavity area (RVa/LVa) in apical four chamber view was used as an estimate of diastolic function and RV pressure. RV end-diastolic cavity area compared to RV end-systolic cavity area (RVed/RVes) was measured at a cross sectional mid papillary level to evaluate the radial contractility of the RV. Image analysis was performed using Echo-Pac software by a clinician blinded to the clinical source of the sample.

2.5. Right ventricular hypertrophy
At sacrifice, the right ventricular weight (RVW), left ventricular plus septum weight (LV+SW) and body weight (BW) were measured (Sartorius, AG Göttingen, Germany). The ratio RVW/BW was used as an index of RV hypertrophy.

2.6. Histology
The RV was immersion fixated by placing it in 4% formaldehyde buffer (pH 7) for 24 h. The tissue was dehydrated in graded ethanol. After tissue embedding in paraffin, 2 µm sections were cut on a rotary microtome (Microm HM 360, Brock and Michelsen, Denmark). The sections were stained with both Haematoxylin-Eosin; Masson-Trichrome-Elastine and Collagen specific Sirius Red. The Sirius Red staining was used to visualize fibrosis in a polarized light microscope. The mean area of fibrosis was evaluated by capturing digital RGB colour images of the RV (ColorViewII, Soft Imaging System, Germany) using the 4x objective (BX50F4, Olympus, Japan). Three images of each section were randomly selected for analysis which was performed using ImageJ software (Rasband, W.S., ImageJ, U. S. National Institutes of Health, Bethesda, Maryland, USA, http://rsb.info.nih.gov/ij/, 1997-2007.). The images were converted to 8 bit greyscale and automated thresholded using the entropy threshold algorithm. Particle analysis was used to determine the area fraction of fibrosis. The mean area of fibrosis was calculated as an average percentage of the three randomly selected images. Image analysis was performed by a clinician blinded to the clinical source of the sample.

2.7. Biochemical signals
We measured levels of aldosterone and angiotensin II, which are associated with the development of cardiac hypertrophy, fibrosis and failure [21,22]. The blood samples, collected at the end of the study from the abdominal aorta, were centrifuged and the serum was stored at –20 °C until further analysis. For plasma angiotensin II (p-AngII) measurements, a rabbit anti-AngII antibody (G225, provided by Prof. Jan Danser, Rotterdam, Holland) was used for radioimmunoassay on a residue from serum prepared by extraction with ethanol [23]. The minimum detectable level was 0.9 pg/ml. The coefficient of variation was 13.8% (inter-assay) and 10.0% (intra-assay).

For plasma aldosterone measurements, a commercial radioimmunoassay kit (Diagnostics Systems laboratories, inc., DSL-8600 ACTIVE® RIA-Kit) was used on a residue from serum [24]. The minimum detectable level was 7.64 pg/ml. The coefficient of variation was 5.8% (inter-assay) and 3.9% (intra-assay). Plasma concentrations of sildenafil were kindly measured by Pfizer (Sandwich, UK).

2.8. Data analysis and statistics
Unless otherwise stated, quantitative data are expressed as mean±standard deviation (SD). Significance of differences was evaluated with one-way ANOVA, followed by post hoc Bonferroni analysis. p<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
4. Discussion
 References
 
3.1. Right ventricular hypertrophy
The PTB procedure caused significant hypertrophy of the RV compared to the SHAM operated animals. RVW/BW, RV/LV+S and total heart weight were markedly increased after three, six and nine weeks (Table 1A).


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  		Table 1 Right ventricular hypertrophy, myocardial fibrosis, right ventricular function and biochemical markers

 
Sildenafil did not prevent the development of RV hypertrophy. On the contrary, the RVW/BW was increased after three weeks of sildenafil treatment compared to vehicle (0.99±0.16 g vs. 0.81±0.11 g; p<0.05) and the total heart weight increased after nine weeks of treatment (1.05±0.10 vs. 0.93±0.08 g; p<0.05) compared to vehicle (Fig. 2). The sildenafil treated animals gained more weight during the nine weeks of treatment compared to those treated with vehicle (Table 1A).


Figure 02
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  		Fig. 2 Right ventricular hypertrophy. A) RVW/BW: Right ventricular weight/Body weight ratio in the short term, long term and reversal group. B) Total heart weight (g) in the short term, long term and reversal groups. Results are geometric mean, 95% CI. *p<0.05, **p<0.001.

 
Three weeks of sildenafil treatment had no effect on established RV hypertrophy measured by RVW/BW, RV/LV+S and total heart weight (Fig. 2).

3.2. Myocardial fibrosis
The amount of myocardial fibrosis was comparable in vehicle and SHAM operated animals. However, a tendency to increased interstitial fibrosis in vehicle animals compared to SHAM at three, six and nine weeks was found (Table 1B). The RV wall diameter was increased and more trabeculated in the PTB animals compared to SHAM (Fig. 3).


Figure 03
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  		Fig. 3 Pulmonary artery trunk banding. Transthoracic echocardiographic images of four chamber view, Tricuspid Annular Plane Systolic Excursion and a Masson Trichrome and Elastin stained histological image (1.25x), of the right ventricular wall before pulmonary trunk banding and three weeks after.

 
We found no difference in the fraction of interstitial fibrosis between sildenafil and vehicle treated animals in any group.

3.3. Right ventricular function
The PTB procedure caused a decrease in TAPSE after three, six and nine weeks compared to SHAM. The RV function evaluated by RVed/RVes and RVa/LVa was decreased after six and nine weeks compared to SHAM (Table 1C).

Sildenafil had no effect on the development of RV dysfunction during three and nine weeks of treatment compared to vehicle as no differences were found in TAPSE, RVa/LVa and RVed/RVes (Table 1C).

In the reversal group, the RV systolic function evaluated by TAPSE was significantly improved in the sildenafil treated animals compared to vehicle treated animals (1.85±0.27 vs. 1.39±0.37 mm, p<0.05) (Fig. 4). TAPSE was similar in the two groups when the treatment was initiated (1.71±0.35 vs.1.70±0.44 mm; p=0.96). RVed/RVes and RVa/LVa was not significantly improved after three weeks of sildenafil treatment compared to vehicle (Table 1C).


Figure 04
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  		Fig. 4 Right ventricular function. Measured by transthoracic echocardiography using Tricuspid Annular Plane Systolic Excursion (TAPSE). Results are geometric mean, 95% CI. *p<0.05, **p<0.001.

 
The heart rate in the sildenafil treated reversal group was slightly higher than in the vehicle treated group, but this difference was not statistically significant (p=0.074). To make sure that the improvements in RV function seen in the sildenafil group was not simply due to a higher heart rate (force-frequency relation); we made a correlation analysis of TAPSE and heart rate for the total data set. We found no significant correlation (correlation coefficient=0.13).

3.4. Biochemical results
A trend towards increased p-AngII and p-aldosterone concentrations after three, six and nine weeks were found in the vehicle rats compared to SHAM operated rats (Table 1C).

The p-AngII concentration was reduced after nine weeks of sildenafil treatment compared to vehicle (78±45 vs. 205±129 pg/ml; p<0.05). There was no difference in p-aldosterone concentrations in either group (Table 1D).

In the reversal group, sildenafil caused no significant changes in p-AngII or p-aldosterone concentrations compared to vehicle.

In the ten randomly selected rats, the mean p-sildenafil concentration was 17±38.35 ng/ml.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
References
 
The PTB procedure performed in this study effectively induced RV hypertrophy and dysfunction. The RV/BW index was more than doubled in all three groups of rats and RV function was impaired when measured by RVed/RVes and RVa/LVa. The impairments in RV function measured by TAPSE were comparable to findings in humans with PAH in all three groups [25]. There was a tendency to more fibrosis in PTB compared with SHAM rats, but this was not statistically significant. We found no significant differences in AngII and aldosterone levels between animals with RV hypertrophy and SHAM. The weight gain and total weight of the SHAM rats were higher than the PTB rats (although not significant in all groups). This could be an indicator of a better well being among SHAM animals.

Sildenafil failed to prevent the development of RV hypertrophy and associated myocardial dysfunction when given for both three weeks and nine weeks following PTB. We did not observe any significant differences in the pattern of myocardial fibrosis in sildenafil compared with vehicle treated animals. The plasma levels of aldosterone, a hormone associated with the development of myocardial fibrosis was not significantly different in rats treated with sildenafil compared to vehicle. We observed a significant increase in the RV/BW index after three weeks and an increase in total heart weight after nine weeks, possibly due to an enhancement of the development of RV hypertrophy by sildenafil. The sildenafil dose and administration form used in the present study has previously been proven to produce effective pulmonary vasodilatation in rats with pulmonary hypertension [13,15] and give plasma concentrations comparable to those achieved during therapy in humans [16,26,27] The plasma concentrations of sildenafil are known to vary a lot [16,27]. This and the short elimination half-life of sildenafil can explain the relatively low p-sildenafil concentrations despite careful administration of the drug. Sildenafil not only failed to prevent the development of RV hypertrophy, it also failed to revert RV hypertrophy when given for three weeks to rats with established RV hypertrophy that had undergone PTB three weeks prior to drug treatment.

Previous studies have shown that PDE5 inhibition by sildenafil prevents RV hypertrophy in rats with pulmonary hypertension induced by monocrotaline [15] and reduces RV hypertrophy in patients with pulmonary arterial hypertension (PAH)[11]. However, in these studies, the relative importance of changes in preload and afterload vs. a direct antihypertrophic effect on the RV myocardium are difficult to determine. It is well known that sildenafil is a potent pulmonary artery vasodilator, thereby lowering pulmonary artery resistance, pressure and RV afterload in both rats and humans [9,10,12].

The PTB model used in this study allowed an evaluation of the direct myocardial effect of sildenafil independently of pulmonary arterial vasodilator and afterload changes produced by the drug.

We found that sildenafil failed to inhibit RV hypertrophy in PTB animals. This is in contrast to the recently published study on mice with LV hypertrophy (surgical aortic constriction) in which sildenafil effectively prevented and reverted LV hypertrophy [8].

This difference could possibly indicate different mechanisms involved in the development of hypertrophy in the RV and LV. There seem to be important differences in gene expression, shape, physiology and embryology between the left and right ventricles [6,28,29]. The biochemical pathways involved in the development of myocardial hypertrophy are complex and most likely species-dependent. Different cellular pathways may be active at different times and at different ventricular work loads and seem to determine whether compensated adaptive hypertrophy and/or maladaptive hypertrophy will develop. At first, the right ventricular hypertrophy is a physiological response to cope with the increased work load due to the increase in RV pressure. In a later phase, interstitial fibrosis, apoptosis of the myocytes and dilatation develops leading to RV failure. This response should be considered a maladaptive/pathological process which forms a target for pharmacological therapy [3,30]. The rise in cGMP caused by sildenafil treatment only interferes with a few of the multiple pathways causing pathologic hypertrophy.

When sildenafil treatment in the present study was given to PTB banded rats with established RV hypertrophy, it improved RV myocardial function compared to vehicle as evaluated by TAPSE. TAPSE was the most robust parameter for RV contractile function used in this study. These findings suggest that sildenafil improves RV contractile function by a direct myocardial effect.

This is in agreement with the recent demonstration of a positive inotropic effect of sildenafil in RV hypertrophic hearts from monocrotaline rats suspended in a modified Langendorff preparation [31]. The authors suggested that the effect could possibly be due to a cAMP increase triggered by inhibition of the cGMP-sensitive PDE3. In the same study it was found that PDE5 is highly expressed in the hypertrophied RV but not in the normal RV. These observations suggest that sildenafil is a drug with a potential to selectively enhance the contractility of the hypertrophied right heart and can also explain the improvement in contractility despite the lack of changes in the degree of myocardial fibrosis.

The primary aim of this study was to evaluate the anatomical and functional effects of sildenafil in the pressure overloaded right heart. The biochemical and cellular responses to cardiac hypertrophy and failure are yet to be fully explored. Elucidating the functional and anatomical effects of pharmaceutical interventions on the development of cardiac hypertrophy and failure can help us understand the underlying mechanisms and promote further studies investigating the underlying biochemical and cellular mechanisms.

In conclusion, PDE5 inhibition by sildenafil failed to prevent and revert RV hypertrophy induced by pulmonary arterial banding. It actually increased RV hypertrophy and improved RV contractile function when given to animals with established RV hypertrophy.


   References
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 References
 

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