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A Pulmonary Trunk Banding Model of Pressure Overload Induced Right Ventricular Hypertrophy and Failure

Right ventricular (RV) failure induced by sustained pressure overload is a major contributor to morbidity and mortality in several cardiopulmonary ...

Aarhus University Hospital

We investigated if soluble guanylate cyclase stimulation either alone or in combination with phosphodiesterase-5 (PDE5) inhibition could prevent pressure overload-induced right ventricular (RV) hypertrophy and failure.

The effects of cyclic guanylate cyclase stimulation on right ventricular hypertrophy and failure alone and in combination with phosphodiesterase-5 inhibition.

Right heart function is an important predictor of morbidity and mortality in patients suffering from pulmonary arterial hypertension and congenital heart diseases. We investigated whether the prostacyclin analog iloprost has a direct inotropic effect in the pressure-overloaded hypertrophic and dysfunctional right ventricle (RV). Rats were randomized to monocrotaline injection (60 mg/kg; [Formula: see text]), pulmonary trunk banding (PTB; [Formula: see text]), or a sham operation ([Formula: see text]). RV function was evaluated with magnetic resonance imaging, echocardiography, and invasive pressure measurements at baseline, after intravenous administration of placebo, iloprost 10 ng/kg/min, or iloprost 100 ng/kg/min (Ilo100). Infusion of Ilo100 induced a [Formula: see text] ([Formula: see text]) increase in stroke volume in the sham group and a [Formula: see text] ([Formula: see text]) increase in the PTB group. RV [Formula: see text] was elevated by [Formula: see text] ([Formula: see text]) in the sham group and by [Formula: see text] ([Formula: see text]) in the PTB group. An elevation in cardiac output of [Formula: see text] ([Formula: see text]) and an [Formula: see text] ([Formula: see text]) increase in RV systolic pressure were found in the PTB group. Iloprost caused a decrease in mean arterial blood pressure (MAP) in all groups of animals. An equal reduction in MAP induced by the arterial vasodilator nitroprusside did not improve any of the measured parameters of RV function. We conclude that iloprost has inotropic properties directly improving ventricular function in the hypertrophic and dysfunctional right heart of the rat. 

Iloprost improves ventricular function in the hypertrophic and functionally impaired right heart by direct stimulation.

Sympathetic adrenergic stimulation and the renin-angiotensin-aldosterone system are highly elevated in right heart failure. We evaluated if treatment with the adrenergic receptor blocker bisoprolol or the angiotensin II receptor blocker losartan could prevent the progression of right ventricular (RV) hypertrophy and failure in rats after pulmonary trunk banding (PTB).

Effects of bisoprolol and losartan treatment in the hypertrophic and failing right heart.

Pulmonary arterial hypertension (PAH) is a fatal disease, and the ultimate cause of death is right ventricular (RV) failure. In this study, we investigated the acute hemodynamic effects of levosimendan in two rat models of RV hypertrophy and failure. Wistar rats were randomized to receive sham surgery (n = 8), pulmonary trunk banding (PTB; n = 8), or monocrotaline injection (MCT; n = 7). RV function was evaluated at baseline and after injection of placebo and two concentrations of levosimendan (12 and 60 μg/kg) using magnetic resonance imaging, echocardiography, and invasive pressure recordings. PTB and MCT injection caused hypertrophy, dilatation, and failure of the RV compared with sham surgery. Levosimendan increased RV end systolic pressure (sham surgery: 16.0% ± 3.8% [P = 0.0038]; MCT: 9.9% ± 3.1% [P = 0.018]; PTB: 24.5% ± 3.3% [P = 0.0001]; mean ± SEM) compared with placebo. Levosimendan markedly increased RV stroke volume (SV) in the MCT group (29.1% ± 8.3%; P = 0.012), did not change RV SV in the PTB group (0.4% ± 4.5%; P = 0.93), and decreased RV SV in the sham surgery group (-10.9% ± 3.7%; P = 0.020). Nitroprusside, which was used to mimic the systemic arterial vasodilator action of levosimendan, did not influence RV function. These data demonstrate that levosimendan acutely improves the failing right heart in a MCT model of PAH and that the mechanism involves a direct acute positive inotropic effect on the hypertrophic and failing RV of the rat. 

Acute effects of levosimendan in experimental models of right ventricular hypertrophy and failure.

Right heart failure occurs in various heart and pulmonary vascular diseases and may be fatal. We aimed to identify limitations in non-invasive measurements of right ventricular stroke volume in an animal model of right ventricular failure. Data from previous studies randomising rats to pulmonary trunk banding (PTB, n = 33) causing pressure-overload right ventricular failure or sham operation (n = 16) was evaluated retrospectively. We measured right ventricular stroke volume by high frequency echocardiography and magnetic resonance imaging (MRI). We found correlation between right ventricular stroke volume measured by echocardiography and MRI in the sham animals (r = 0.677, p = 0.004) but not in the PTB group. Echocardiography overestimated the stroke volume compared to MRI in both groups. Intra- and inter-observer variation did not explain the difference. Technical, physiological and anatomical issues in the pulmonary artery might explain why echocardiography over-estimates stroke volume. Flow acceleration close to the pulmonary artery banding can cause uncertainties in the PTB model and might explain the lack of correlation. In conclusion, we found a correlation in right ventricular stroke volume measured by echocardiography versus MRI in the sham group but not the PTB group. Echocardiography overestimated right ventricular stroke volume compared to MRI. 

Limitations and pitfalls in measurements of right ventricular stroke volume in an animal model of right heart failure.

Right heart function is an important predictor of morbidity and mortality in pulmonary arterial hypertension and many CHD. We investigated whether treatment with the prostacyclin analogue treprostinil could prevent pressure overload-induced right ventricular hypertrophy and failure.

Effects of chronic treprostinil treatment on experimental right heart hypertrophy and failure.

Prostacyclin mimetics are vasodilatory agents used in the treatment of pulmonary arterial hypertension. The direct effects of prostanoids on right-ventricular (RV) function are unknown. We aimed to investigate the direct effects of prostacyclin mimetics on RV function in hearts with and without RV hypertrophy and failure.

Inotropic Effects of Prostacyclins on the Right Ventricle Are Abolished in Isolated Rat Hearts With Right-Ventricular Hypertrophy and Failure.

Prostacyclins are vasodilatory agents used in the treatment of pulmonary arterial hypertension. The direct effects of prostacyclins on right heart function are still not clarified. The aim of this study was to investigate the possible direct inotropic properties of clinical available prostacyclin mimetics in the normal and the pressure-overloaded human right atrium. Trabeculae from the right atrium were collected during surgery from chronic thromboembolic pulmonary hypertension (CTEPH) patients with pressure-overloaded right hearts, undergoing pulmonary thromboendarterectomy (n = 10) and from patients with normal right hearts operated by valve replacement or coronary bypass surgery (n = 9). The trabeculae were placed in an organ bath, continuously paced at 1 Hz. They were subjected to increasing concentrations of iloprost, treprostinil, epoprostenol, or MRE-269, followed by isoprenaline to elicit a reference inotropic response. The force of contraction was measured continuously. The expression of prostanoid receptors was explored through quantitative polymerase chain reaction (qPCR). Iloprost, treprostinil, epoprostenol, or MRE-269 did not alter force of contraction in any of the trabeculae. Isoprenaline showed a direct inotropic response in both trabeculae from the pressure-overloaded right atrium and from the normal right atrium. Control experiments on ventricular trabeculae from the pig failed to show an inotropic response to the prostacyclin mimetics. qPCR demonstrated varying expression of the different prostanoid receptors in the human atrium. In conclusion, prostacyclin mimetics did not increase the force of contraction of human atrial trabeculae from the normal or the pressure-overloaded right heart. These data suggest that prostacyclin mimetics have no direct inotropic effects in the human right atrium.

Prostacyclins have no direct inotropic effect on isolated atrial strips from the normal and pressure-overloaded human right heart.

We investigated whether chronic levosimendan treatment can prevent and revert right ventricular (RV) failure and attenuate pulmonary vascular remodeling in a rat model of pulmonary arterial hypertension (PAH).

Article	Year
The effects of cyclic guanylate cyclase stimulation on right ventricular hypertrophy and failure alone and in combination with phosphodiesterase-5 inhibition. Journal of cardiovascular pharmacology\| PubMed ID: 23575263	2013
Iloprost improves ventricular function in the hypertrophic and functionally impaired right heart by direct stimulation. Pulmonary circulation\| PubMed ID: 25006403	2013
Effects of bisoprolol and losartan treatment in the hypertrophic and failing right heart. Journal of cardiac failure\| PubMed ID: 25135110	2014
Acute effects of levosimendan in experimental models of right ventricular hypertrophy and failure. Pulmonary circulation\| PubMed ID: 25621165	2014
Limitations and pitfalls in measurements of right ventricular stroke volume in an animal model of right heart failure. Physiological measurement\| PubMed ID: 25856199	2015
Effects of chronic treprostinil treatment on experimental right heart hypertrophy and failure. Cardiology in the young\| PubMed ID: 27087410	2017
Inotropic Effects of Prostacyclins on the Right Ventricle Are Abolished in Isolated Rat Hearts With Right-Ventricular Hypertrophy and Failure. Journal of cardiovascular pharmacology\| PubMed ID: 27652910	2017
Prostacyclins have no direct inotropic effect on isolated atrial strips from the normal and pressure-overloaded human right heart. Pulmonary circulation\| PubMed ID: 28597773	2017
Levosimendan Prevents and Reverts Right Ventricular Failure in Experimental Pulmonary Arterial Hypertension. Journal of cardiovascular pharmacology\| PubMed ID: 28640039	2017

Sarah Holmboe

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