Right ventricular plasticity in a porcine model of chronic pressure overload

doi:10.1016/j.healun.2013.10.026

The Journal of Heart and Lung Transplantation

Volume 33, Issue 2, February 2014, Pages 194-202

https://doi.org/10.1016/j.healun.2013.10.026 Get rights and content

Background

Ventricular–arterial coupling is a measure of the relationship between ventricular contractility and afterload. We sought to determine the relationship between ventricular–arterial coupling and right ventricular (RV) remodeling in a novel porcine model of progressive pulmonary hypertension (PH).

Methods

Chronic PH was induced in pigs by ligation of the left pulmonary artery (PA) followed by 5 weekly injections of cyanoacrylate to progressively obstruct the right lower lobe arteries (PH group, n = 10). At 6 weeks, 5 PH animals underwent reperfusion of the left lung through conduit anastomosis to decrease RV afterload, whereas 5 other animals received no treatment. Five sham-operated piglets were used as controls. RV function was assessed using echocardiography and conductance catheterization. RV gene expression of beta-myosin heavy chain (β-MHC) and B-type natriuretic peptide (BNP) were quantified by polymerase chain reaction.

Results

At 6 weeks, compared with controls, the PH group had higher mean PA pressure (32 ± 6 vs 14 ± 2 mm Hg, p < 0.01). The increase in RV elastance was insufficient to compensate for the increase in pulmonary arterial elastance in the PH group and altered ventricular–arterial coupling occurred (0.65 ± 0.16 vs 1.28 ± 0.14, p < 0.01). The degree of ventricular–arterial uncoupling was related to RV enlargement and systolic dysfunction. Ventricular–arterial uncoupling and increased RV mass index were associated with up-regulation of β-MHC and BNP expression.

Conclusions

Ventricular–arterial coupling is closely associated with ventricular remodeling and systolic function as well as contractile and BNP gene expression. Dynamic changes in myosin expression may determine RV work efficiency in PH.

Section snippets

Animals and experimental design

Twenty-one 2-month-old Large White piglets with a mean weight of 25.1 ± 5.7 kg were used in these experiments. Piglets were randomized to a sham operation (control group) or to PH induction (PH group), followed after 6 weeks by either PH surgical treatment (REP group) or observation (NO-REP group). All animals were euthanized using a lethal intravenous potassium infusion at 12 weeks (Figure 1). The research protocol was approved by our institutional committee on animal welfare and all animals

Part I: Induction of experimental PH in piglets

Changes in pulmonary hemodynamics and RV remodeling. Table 1 summarizes the characteristics of the piglets at 6 weeks. Compared with controls, the PH group had higher MPAP and TPR at 6 weeks, as well as higher RVEDAI (6.2 ± 1.3 vs 10.6 ± 2.4 cm²/m², p < 0.001) (Figure 2). RV systolic dysfunction also developed as reflected by significant decrease in both RVFAC and TAPSE over the same period (44.8 ± 9.1% vs 27.8 ± 6.2%, p < 0.001; and 1.89 ± 0.17 vs 1.41 ± 0.27 cm, p < 0.001, respectively) (

Discussion

The main finding of our study is that ventricular–arterial coupling is strongly related to RV remodeling and to β-MHC and BNP gene expression in chronic PH. Our results also suggest that altered ventricular–arterial coupling occurs early with the development of PH. For this study, we utilized a novel large-animal model of chronic RV pressure overload that allows us to generate PH of varying severity. In addition, the pulmonary conduit anastomosis provides an opportunity to study reverse

Disclosure statement

The authors have no conflicts of interest to disclose.

We thank the team at the Laboratory of Surgical Research, Marie Lannelongue Hospital, for technical assistance and animal care. This study was supported by the Association chirurgicale pour le développement et l'amélioration des techniques de dépistage et de traitement des maladies cardio-vasculaires (ADETEC, Suresnes, France). The Vivid E9 cardiac ultrasound system (General Electric Medical System) was financed by a grant from the

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Right ventricular (RV) failure is the main prognostic factor in pulmonary hypertension, and ventricular capillary density (CD) has been reported to be a marker of RV maladaptive remodeling and failure. Our aim was to determine whether right intracoronary endothelial progenitor cell (EPC) infusion can improve RV function and CD in a piglet model of chronic thromboembolic pulmonary hypertension (CTEPH).
We compared 3 groups: sham (n = 5), CTEPH (n = 6), and CTEPH with EPC infusion (CTEPH+EPC; n = 5). After EPC isolation from CTEPH+EPC piglet peripheral blood samples at 3 weeks, the CTEPH and sham groups underwent right intracoronary infusion of saline, and the CTEPH+EPC group received EPCs at 6 weeks. RV function, pulmonary hemodynamics, and myocardial morphometry were investigated in the animals at 10 weeks.
After EPC administration, the RV fractional area change increased from 32.75% (interquartile range [IQR], 29.5%-36.5%) to 39% (IQR, 37.25%-46.50%; P = .030). The CTEPH+EPC piglets had reduced cardiomyocyte surface areas (from 298.3 μm² [IQR, 277.4-335.3 μm²] to 234.6 μm² (IQR, 211.1-264.7 μm²; P = .017), and increased CD31 expression (from 3.12 [IQR, 1.27-5.09] to 7.14 [IQR, 5.56-8.41; P = .017). EPCs were found in the RV free wall at 4 and 24 hours after injection but not 4 weeks later.
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Citation Excerpt :
We reported in our piglet model of chronic PH that ventricular-arterial uncoupling was strongly associated with upregulation of β-MHC expression. We suggested that dynamic changes in myosin expression over time may determine RV work efficiency [53]. Foetal β-MHC expression may be associated with a metabolic shift from fatty acid to glucose oxidation [54].
The right ventricle (RV) has to face major changes in loading conditions due to cardiovascular diseases and pulmonary vascular disorders. Clinical experience supports evidence that the RV better compensates for volume than for pressure overload, and for chronic than for acute changes. For a long time, right ventricular (RV) pathophysiology has been restricted to patterns extrapolated from left heart studies. However, the two ventricles are anatomically, haemodynamically and functionally distinct. RV metabolic properties may also result in a different behaviour in response to pathological conditions compared with the left ventricle. In this review, current knowledge of RV pathophysiology is reported in the setting of chronic pressure overload, including recent experimental findings and emerging concepts. After a time-varying compensated period with preserved cardiac output despite overload conditions, RV failure finally occurs, leading to death. The underlying mechanisms involved in the transition from compensatory hypertrophy to maladaptive remodelling are not completely understood.
Le ventricule droit (VD) fait face à d’importantes variations de ses conditions de charge en réponse aux maladies cardiovasculaires et pathologies vasculaires pulmonaires. Le VD supporte mieux une surcharge de volume qu’une surcharge de pression, de même il s’adapte mieux aux variations progressives qu’aux changements aigus. La physiopathologie du VD a pendant longtemps été résumée à des extrapolations de la physiopathologie du ventricule gauche. Cependant les deux ventricules sont différents, tant sur le plan anatomique, hémodynamique que fonctionnel. Les caractéristiques métaboliques singulières du VD peuvent également être à l’origine d’une adaptation différente aux conditions pathologiques. Après une longue période compensatrice avec préservation du débit cardiaque, la dysfonction du VD s’installe finalement face à la surcharge chronique persistante. Les mécanismes impliqués dans la transition depuis l’hypertrophie compensatrice jusqu’au remodelage inadapté sont méconnus. Dans cette revue, les connaissances actuelles de la physiopathologie du VD dans l’hypertension pulmonaire chronique sont reportées à partir des résultats récents issus de la recherche expérimentale.
Nebivolol for improving endothelial dysfunction, pulmonary vascular remodeling, and right heart function in pulmonary hypertension
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This could further explain the superiority of nebivolol over metoprolol to improve experimental PH. However, one must be aware that the MCT-induced PH is considered by some to be an acute toxic model characterized by acute/subacute damage of the peripheral vasculature of the lung and other organs (kidney, liver, and heart) (13). For this reason, we plan to test the efficacy of nebivolol in a piglet model of chronic PH, which is more relevant to the human condition (22–24). Our work demonstrates for the first time that nebivolol could be a promising option for the management of PAH, improving endothelial dysfunction, pulmonary vascular remodeling, and right heart function.
Endothelial cell (EC) dysfunction plays a central role in the pathogenesis of pulmonary arterial hypertension (PAH), promoting vasoconstriction, smooth muscle proliferation, and inflammation.
This study sought to test the hypothesis that nebivolol, a β₁-antagonist and β_2,3-agonist, may improve PAH and reverse the PAH-related phenotype of pulmonary ECs (P-EC).
We compared the effects of nebivolol with metoprolol, a first-generation β₁-selective β-blocker, on human cultured PAH and control P-EC proliferation, vasoactive and proinflammatory factor production, and crosstalk with PA smooth muscle cells. We assessed the effects of both β-blockers in precontracted PA rings. We also compared the effects of both β-blockers in experimental PAH.
PAH P-ECs overexpressed the proinflammatory mediators interleukin-6 and monocyte chemoattractant protein-1, fibroblast growth factor-2, and the potent vasoconstrictive agent endothelin-1 as compared with control cells. This pathological phenotype was corrected by nebivolol but not metoprolol in a dose-dependent fashion. We confirmed that PAH P-EC proliferate more than control cells and stimulate more PA smooth muscle cell mitosis, a growth abnormality that was normalized by nebivolol but not by metoprolol. Nebivolol but not metoprolol induced endothelium-dependent and nitric oxide–dependent relaxation of PA. Nebivolol was more potent than metoprolol in improving cardiac function, pulmonary vascular remodeling, and inflammation of rats with monocrotaline-induced pulmonary hypertension.
Nebivolol could be a promising option for the management of PAH, improving endothelial dysfunction, pulmonary vascular remodeling, and right heart function. Until clinical studies are undertaken, however, routine use of β-blockers in PAH cannot be recommended.
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View full text

Right ventricular plasticity in a porcine model of chronic pressure overload

Background

Methods

Results

Conclusions

Section snippets

Animals and experimental design

Part I: Induction of experimental PH in piglets

Discussion

Disclosure statement

Am J Cardiol

Cardiol Clin

Ann Thorac Surg

Am J Cardiol

J Heart Lung Transplant

Pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: pathophysiology

Eur Respir Rev

Chronic thromboembolic pulmonary hypertension

Circulation

Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry

Circulation

Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era

Circulation

Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL)

Circulation

Ventriculo-arterial coupling: concepts, assumptions, and applications

Ann Biomed Eng

Reliable piglet model of chronic thrombo-embolic pulmonary hypertension

Am J Respir Crit Care Med

Lung reperfusion injury after chronic or acute unilateral pulmonary artery occlusion

Am J Respir Crit Care Med

Assessment of right ventricular contractile state with the conductance catheter technique in the pig

Cardiovasc Res