Chronic overcirculation-induced pulmonary arterial hypertension in aorto-caval shunt.

Pulmonary arterial hypertension is a common complication of congenital heart defects with left-to-right shunts. Current preclinical models do not reproduce clinical characteristics of shunt-related pulmonary hypertension. Aorto-caval shunt was firstly described as a model of right ventricle volume overload. The pathophysiology and the possible determination of pulmonary arterial hypertension of different periods of shunt exposure are still undefined. A method to create standardized, reproducible aorto-caval shunt was developed in growing rats (260±40 g). Three groups of animals were considered: shunt exposure for 10 weeks, shunt exposure for 20 weeks and control (sham laparotomy). Echocardiography and magnetic resonance revealed increased right ventricular end diastolic area in shunt at 10 weeks compared to control. Hemodynamic analysis demonstrated increased right ventricular afterload and increased effective pulmonary arterial elastance (Ea) in shunt at 20 weeks compared to control (1.29±0.20 vs. 0.14±0.06 mmHg/μl, p=0.004). At the same time point, the maximal slope of end-systolic pressure-volume relationship (Ees) decreased (0.5±0.2 mmHg/ml vs. 1.2±0.3, p<0.001). Consequently, right ventricular-arterial coupling was markedly deteriorated with a ≈50% decrease in the ratio of end-systolic to pulmonary artery elastance (Ees/Ea). Finally, left ventricular preload diminished (≈30% decrease in left ventricular end-diastolic volume). Histology demonstrated medial hypertrophy and small artery luminal narrowing. Chronic exposure to aorto-caval shunt is a reliable model to produce right ventricular volume overload and secondary pulmonary arterial hypertension. This model could be an alternative with low mortality and high reproducibility for investigators on the underlying mechanisms of shunt-related pulmonary hypertension.

Rungatscher A ，Linardi D ，Milani E ，Ucci G ，Nicolato E ，Merigo F ，Salvetti B ，Mazzucco A ，Luciani GB ，Faggian G ... -  《-》

Ventricular and pulmonary vascular remodeling induced by pulmonary overflow in a chronic model of pretricuspid shunt.

Current preclinical models of pulmonary arterial hypertension do not reproduce the clinical characteristics of congenital heart anomalies. Aortocaval shunt is relevant to a variety of clinical conditions. The pathophysiology and possible determination of pulmonary hypertension in this model are still undefined. A method to create a standardized and reproducible aortocaval shunt was developed in rats. After creation of the shunt, the animals were followed up for 20 weeks and a sham laparotomy was used as a control. The chronic effects of volume overload on the right and left ventricles and pulmonary hemodynamic modifications were evaluated by biventricular catheterization, echocardiography, and magnetic resonance. Pulmonary vascular changes were defined by histology. An increased right ventricular end-diastolic area was confirmed by echocardiography. Left ventricular overload and decreased biventricular ejection fraction were demonstrated by magnetic resonance after 20 weeks in the shunt group compared with the controls (left ventricle, 50% ± 5% vs 62% ± 3%, P = .029; right ventricle, 53% ± 2% vs 65% ± 2%, P = .036). Preload recruitable stroke work of left and right ventricles decreased after 20 weeks in shunt rats (left ventricle: 36 ± 7 vs 98 ± 5, P = .004; right ventricle: 19 ± 2 vs 32 ± 9, P = .047). At the same time point, catheterization showed that effective pulmonary arterial elastance was increased only in the shunt group (1.29 ± 0.20 vs 0.14 ± 0.06 mm Hg/μL; P = .004). Histology showed medial hypertrophy, small artery luminal narrowing, and occlusion. The aortocaval shunt model reliably produces right ventricular volume overload and secondary pulmonary hypertension. Due to a combination of left ventricular dysfunction and pulmonary overflow, the pulmonary hypertension produced shows features similar to those found in patients with chronic atrial-level shunt.

Linardi D ，Rungatscher A ，Morjan M ，Marino P ，Luciani GB ，Mazzucco A ，Faggian G ... -  《-》

S-nitroso human serum albumin attenuates pulmonary hypertension, improves right ventricular-arterial coupling, and reduces oxidative stress in a chronic right ventricle volume overload model.

This study examined the acute effect of intravenous S-nitroso human serum albumin (S-NO-HSA) infusion on overall hemodynamics and oxidative stress in a chronic left-to-right shunt-induced pulmonary arterial hypertension model with right ventricle (RV) failure. An aortocaval fistula (pulmonary-to-systemic blood flow ratio [Qp/Qs] > 2.0) was surgically created in 50 male Wistar rats. After 10 weeks, they were randomly treated with S-NO-HSA (n = 20) or human serum albumin (HSA; n = 25) infusion (0.5 µmol/kg/h) for 60 minutes. A sham group (n = 10) received S-NO-HSA. RV contractility, RV-vascular coupling, and ventricular interdependence were assessed in vivo at different pre-loads by biventricular conductance catheters. Heart and lung biopsy specimens were obtained for determination of high-energy phosphates, oxidative stress (oxidized glutathione/reduced glutathione), and endothelial nitric oxide synthase protein expression. S-NO-HSA, compared with HSA infusion, reduced RV afterload expressed by effective pulmonary arterial elastance (Ea; 0.49 ± 0.3 vs 1.2 ± 0.2 mm Hg/ml; p = 0.0005) and improved RV diastolic function (slope of end-diastolic pressure-volume relationship) as well as contractility indicated by slope of end-systolic pressure-volume relationship (Ees). Therefore an increase in efficiency of ventricular-vascular coupling (Ees/Ea) occurred after S-NO-HSA (0.35 ± 0.17 to 0.94 ± 0.21; p = 0.005), but not HSA infusion, leading to positive effect on ventricular interdependence with increased left ventricular stroke volume (56% ± 4% vs 19% ± 5%; p = 0.0013). S-NO-HSA, compared with HSA, treatment improved adenosine 5'-triphosphate (13.9 ± 1.1 vs 7.0 ± 1.8 µmol/g protein) and phosphocreatine (5.9 ± 3.3 vs 1.9 ± 0.6 µmol/g protein; p = 0.01) RV content and decreased the tissue oxidized glutathione/reduced glutathione ratio (p = 0.001). S-NO-HSA reduces pulmonary hypertension and improves RV systolic and diastolic function and RV-arterial coupling, with a positive effect on ventricular interdependence by increasing energetic reserve and reducing oxidative stress.

Rungatscher A ，Hallström S ，Linardi D ，Milani E ，Gasser H ，Podesser BK ，Scarabelli TM ，Luciani GB ，Faggian G ... -  《-》

Original rat model of high kinetic unilateral pulmonary hypertension surgically induced by combined surgery.

The characteristic morphologic lesions observed in the lungs of patients with congenital cardiac anomalies have not been closely modeled in rat shunt-related models, except for the reversible grade 1 changes. The present study reported an original rat model of unilateral pulmonary hypertension surgically induced by combined surgery to reproduce more advanced pulmonary vascular lesions. The right pulmonary artery was ligated through a right posterolateral thoracotomy, and a cervical shunt was established 1 week later. The immediate and chronic effects on the pulmonary hemodynamics were evaluated through right heart catheterization immediately after and at 8 and 12 weeks postoperatively. The morphologic changes in pulmonary vasculature were analyzed after staining with hematoxylin-eosin and modified Weigert's method. The right ventricular hypertrophy index was calculated and artery blood gas analysis performed. A pulmonary hypertensive status was successfully induced immediately after cervical surgery and progressively aggravated into a borderline state with disease course advancing. Pulmonary vasculopathy demonstrated a transition from reversibility (muscularization, intimal proliferation of grade 1-2) at 8 weeks to irreversibility (intimal fibrosis, entirely luminal occlusion, grade 3) at 12 weeks postoperatively. Conspicuous right ventricular hypertrophy and decreasing partial arterial pressure of oxygen were also observed. The present shunt-related model successfully simulated a hypertensive status in pulmonary circulation and reproduced the characteristic transition of pulmonary vasculopathy from reversibility to irreversibility within a relatively short period. Thus, this model could offer an alternative with low mortality and high reproducibility for investigations on the underling mechanisms of shunt-related pulmonary hypertension.

Meng L ，Liu X ，Zheng Z ，Li J ，Meng J ，Wei Y ，Hu S ... -  《-》

Non-invasive indices of right ventricular function are markers of ventricular-arterial coupling rather than ventricular contractility: insights from a porcine model of chronic pressure overload.

Guihaire J ，Haddad F ，Boulate D ，Decante B ，Denault AY ，Wu J ，Hervé P ，Humbert M ，Dartevelle P ，Verhoye JP ，Mercier O ，Fadel E ... -  《-》