Abstract P238: Effect of Zamicastat in Chronic Treatment on Right Ventricle Pressure Overload in the Rat Monocrotaline Lung Injury Model of Pulmonary Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Bruno Igreja ◽  
Nuno Pires ◽  
Paul Moser ◽  
Patrício Soares-da-Silva
Keyword(s):  
Heart Rate ◽  
Pulmonary Hypertension ◽  
Lung Injury ◽  
Right Ventricle ◽  
Oral Treatment ◽  
Systolic Pressure ◽  
Pressure Overload ◽  
Vehicle Group ◽  
Injury Model ◽  
Lung Injury Model

Pulmonary arterial hypertension (PAH) is defined, foremost, as a plexogenic arteriopathy with subtotal luminal obliteration that increases pulmonary vascular resistance and imposes a hemodynamic stress on the right ventricle (RV) leading to RV hypertrophy and failure that contributes to premature death. There is experimental and clinical evidence that supports a relation between PAH and the sympathetic nervous system (SNS), indicating that PAH can be mediated, at least partly, by SNS hyperactivation. A strategy for the modulation of sympathetic nerve function is to reduce the biosynthesis of norepinephrine (NE) by inhibiting dopamine β-hydroxylase (DβH), the enzyme that catalyzes the conversion of dopamine (DA) to NE in sympathetic nerves. Here, we evaluated the effect of 18-day oral treatment with the DβH inhibitor zamicastat on RV pressure overload in the monocrotaline (MCT)-induced pulmonary hypertension (PH) model in the rat. MCT increased RV systolic pressure (54.7±2.9 vs 32.3±1.0 mmHg, p<0.0001), mean RV pressure (23.9±1.7 vs 16.6±1.1 mmHg, p<0.001), and decreased heart rate (240.0±5.9 vs 285.8±7.6 beats/min, p<0.0001) in vehicle-treated rats, as compared to pre-MCT values. Zamicastat treatment prevented the MCT-induced increase in mean RV pressure (change from baseline: +1.9±1.5 vs +7.4±1.8 mmHg, p<0.05). Likewise, the HR decrease was significantly attenuated in the zamicastat group as compared to the vehicle group (change from baseline: -14.3±9.7 vs -45.8±8.1 beats/min, p<0.05). Chronic zamicastat treatment decreased NE levels (480.5±43.9 vs 712.1±46.5 ng/mg protein, p<0.005) and increased DA levels (533.0±49.7 vs 12.3±2.3 ng/mg protein, p<0.0001) in adrenal gland homogenates of MCT-treated rats, as compared to vehicle group demonstrating robust inhibition of DβH. In conclusion, the DβH inhibitor zamicastat reverses heart rate and RV pressure changes, two hallmarks of PAH, in the rat MCT lung injury model.

Relationship between Invasive and Non-Invasive Hemodynamic Measures in Experimental Pulmonary Hypertension

2020 ◽  
Vol 16 (1) ◽  
pp. 47-53
Author(s):  
Vicente Benavides-Córdoba ◽  
Mauricio Palacios Gómez
Keyword(s):  
Heart Rate ◽  
Pulmonary Hypertension ◽  
Ejection Fraction ◽  
Right Ventricle ◽  
Correlation Coefficient ◽  
Pearson Correlation ◽  
Systolic Pressure ◽  
Control Group ◽  
Pearson Correlation Coefficient ◽  
Non Invasive

Introduction: Animal models have been used to understand the pathophysiology of pulmonary hypertension, to describe the mechanisms of action and to evaluate promising active ingredients. The monocrotaline-induced pulmonary hypertension model is the most used animal model. In this model, invasive and non-invasive hemodynamic variables that resemble human measurements have been used. Aim: To define if non-invasive variables can predict hemodynamic measures in the monocrotaline-induced pulmonary hypertension model. Materials and Methods: Twenty 6-week old male Wistar rats weighing between 250-300g from the bioterium of the Universidad del Valle (Cali - Colombia) were used in order to establish that the relationships between invasive and non-invasive variables are sustained in different conditions (healthy, hypertrophy and treated). The animals were organized into three groups, a control group who was given 0.9% saline solution subcutaneously (sc), a group with pulmonary hypertension induced with a single subcutaneous dose of Monocrotaline 30 mg/kg, and a group with pulmonary hypertension with 30 mg/kg of monocrotaline treated with Sildenafil. Right ventricle ejection fraction, heart rate, right ventricle systolic pressure and the extent of hypertrophy were measured. The functional relation between any two variables was evaluated by the Pearson correlation coefficient. Results: It was found that all correlations were statistically significant (p <0.01). The strongest correlation was the inverse one between the RVEF and the Fulton index (r = -0.82). The Fulton index also had a strong correlation with the RVSP (r = 0.79). The Pearson correlation coefficient between the RVEF and the RVSP was -0.81, meaning that the higher the systolic pressure in the right ventricle, the lower the ejection fraction value. Heart rate was significantly correlated to the other three variables studied, although with relatively low correlation. Conclusion: The correlations obtained in this study indicate that the parameters evaluated in the research related to experimental pulmonary hypertension correlate adequately and that the measurements that are currently made are adequate and consistent with each other, that is, they have good predictive capacity.

scholarly journals 2-Methoxyestradiol Attenuates the Development and Retards the Progression of Hypoxia-And Alpha-Naphthylthiourea-Induced Pulmonary Hypertension

PRILOZI ◽  
2021 ◽  
Vol 42 (1) ◽  
pp. 41-51
Author(s):  
Stevan P. Tofovic ◽  
Xinchen Zhang ◽  
Tom J. Jones ◽  
Gordana Petruševska
Keyword(s):  
Pulmonary Hypertension ◽  
Acute Lung Injury ◽  
Pleural Effusion ◽  
Lung Injury ◽  
Right Ventricle ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Biological Effects ◽  
Systolic Pressure ◽  
Pulmonary Vascular Remodeling

Abstract Pulmonary arterial hypertension (PH), a progressive, incurable, and deadly disease, predominantly develops in women. Growing body of evidence suggest that dysregulated estradiol (E2) metabolism influences the development of PH and that some of the biological effects of E2 are mediated by its major non-estrogenic metabolite, 2-metyhoxyestradiol (2ME). The objective of this study was to examine effects of 2ME in chronic hypoxia (CH)-induced PH and alpha-naphthylthiourea (ANTU)-induced acute lung injury and PH. In addition, we investigated the effects of exposure to different levels of CH on development of PH. Chronic exposure to 15% or 10% oxygen produced similar increases in right ventricle peak systolic pressure (RVPSP) and pulmonary vascular remodeling, but oxygen concentration-dependent increase in hematocrit. Notably, right ventricle (RV) hypertrophy correlated with level of hypoxia and hematocrit, rather than with magnitude of RVPSP. The latter suggests that, in addition to increased afterload, hypoxia (via increased hematocrit) significantly contributes to RV hypertrophy in CH model of PH. In CH-PH rats, preventive and curative 2ME treatments reduced both elevated RVPSP and pulmonary vascular remodeling. Curative treatment with 2ME was more effective in reducing hematocrit and right ventricular hypertrophy, as compared to preventive treatment. Single ANTU injection produced lung injury, i.e., increased lungs weight and induced pleural effusion. Treatment with 2ME significantly reduced pleural effusion and, more importantly, eliminated acute mortality induced by ANTU (33% vs 0%, ANTU vs. ANTU+2ME group). Chronic treatment with ANTU induced PH and RV hypertrophy and increased lungs weight. 2-ME significantly attenuated severity of disease (i.e., reduced RVPSP, RV hypertrophy and pulmonary vascular injury). This study demonstrates that 2ME has beneficial effects in chronic hypoxia- and acute lung injury-induced PH and provides preclinical justification for clinical evaluation of 2ME in pulmonary hypertension.

scholarly journals Dynamic single-slice CT estimates whole-lung dual-energy CT variables in pigs with and without experimental lung injury

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
John N. Cronin ◽  
João Batista Borges ◽  
Douglas C. Crockett ◽  
Andrew D. Farmery ◽  
Göran Hedenstierna ◽  
...  
Keyword(s):  
Lung Injury ◽  
Dual Energy ◽  
Dual Energy Ct ◽  
Lung Density ◽  
Density Distributions ◽  
Single Slice ◽  
Injury Model ◽  
Lung Injury Model ◽  
Ct Density ◽  
Surfactant Depletion

Abstract Background Dynamic single-slice CT (dCT) is increasingly used to examine the intra-tidal, physiological variation in aeration and lung density in experimental lung injury. The ability of dCT to predict whole-lung values is unclear, especially for dual-energy CT (DECT) variables. Additionally, the effect of inspiration-related lung movement on CT variables has not yet been quantified. Methods Eight domestic pigs were studied under general anaesthesia, including four following saline-lavage surfactant depletion (lung injury model). DECT, dCT and whole-lung images were collected at 12 ventilatory settings. Whole-lung single energy scans images were collected during expiratory and inspiratory apnoeas at positive end-expiratory pressures from 0 to 20 cmH2O. Means and distributions of CT variables were calculated for both dCT and whole-lung images. The cranio-caudal displacement of the anatomical slice was measured from whole-lung images. Results Mean CT density and volume fractions of soft tissue, gas, iodinated blood, atelectasis, poor aeration, normal aeration and overdistension correlated between dCT and the whole lung (r2 0.75–0.94) with agreement between CT density distributions (r 0.89–0.97). Inspiration increased the matching between dCT and whole-lung values and was associated with a movement of 32% (SD 15%) of the imaged slice out of the scanner field-of-view. This effect introduced an artefactual increase in dCT mean CT density during inspiration, opposite to that caused by the underlying physiology. Conclusions Overall, dCT closely approximates whole-lung aeration and density. This approximation is improved by inspiration where a decrease in CT density and atelectasis can be interpreted as physiological rather than artefactual.

PULMONARY FIBROBLAST FUNCTION IN AN ACUTE LUNG INJURY MODEL

1994 ◽  
Vol 37 (1) ◽  
pp. 156
Author(s):  
Andrew Mikulaschek ◽  
Stantey Z Trooskin ◽  
Allen Nonn ◽  
Jason Winfield
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Injury Model ◽  
Lung Injury Model ◽  
Pulmonary Fibroblast

Derivation of recruitment function from the pressure–volume curve in an acute lung injury model

2015 ◽  
Vol 205 ◽  
pp. 16-20 ◽  
Author(s):  
Yoshihiro Uzawa ◽  
Mikiya Otsuji ◽  
Koichi Nakazawa ◽  
Wei Fan ◽  
Yoshitsugu Yamada
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Volume Curve ◽  
Pressure Volume Curve ◽  
Injury Model ◽  
Lung Injury Model

scholarly journals Intratracheal Pulmonary Ventilation vs. Conventional Ventilation in an Oleic Acid Lung Injury Model in the Young Lamb 197

1998 ◽  
Vol 43 ◽  
pp. 36-36
Author(s):  
Allyson M Goodman ◽  
L Kyle Walker ◽  
Oswaldo Rivera ◽  
Winslow R Seale ◽  
Billie L Short
Keyword(s):  
Oleic Acid ◽  
Lung Injury ◽  
Pulmonary Ventilation ◽  
Conventional Ventilation ◽  
Injury Model ◽  
Lung Injury Model

Pulmonary hypertension in patients with a subaortic right ventricle: prevalence, impact and management

Heart ◽  
2019 ◽  
Vol 105 (19) ◽  
pp. 1471-1478 ◽  
Author(s):  
Alexander Van De Bruaene ◽  
Norihisa Toh ◽  
Edward J Hickey ◽  
Lee Benson ◽  
Eric Horlick ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricle ◽  
Systolic Pressure ◽  
Area Under The Curve ◽  
Left Ventricular ◽  
Adverse Outcomes ◽  
Screening Tools ◽  
Ventricular Assist ◽  
Ventricular Systolic Pressure ◽  
Over Time

ObjectiveThis study sought to determine the prevalence, predictors, prognostic relevance and evolution of pulmonary hypertension (PH) (mean pulmonary artery pressure ≥25 mm Hg) in adult patients with a subaortic right ventricle (RV) in a biventricular circulation (2V-RV).MethodsWe analysed retrospective data from patients with 2V-RV undergoing cardiac catheterisation in our centre between 2000 and 2018. Echocardiographic assessment of subpulmonary ventricular pressures (left ventricular systolic pressure (LVSP)), age and B-type natriuretic peptide (BNP) were assessed as PH screening tools. Kaplan-Meier curves examined time to a composite outcome of death, transplant or ventricular assist device (VAD). Data from repeat catheterisations were analysed to evaluate PH changes over time, including the effects of therapy.ResultsA total of 141 patients (median age 39 (IQR 33–45) years, 68% men) underwent 191 cardiac catheterisations. At baseline, 55% had PH (isolated postcapillary 24%, combined precapillary and postcapillary 26% and precapillary 5%). BNP (area under the curve 0.80; 95% CI 0.72 to 0.88; p<0.0001), but not age at catheterisation or echocardiographic estimates of LVSP were associated with the presence of PH. The absence of PH and BNP <100 pg/mL discriminated a subgroup at very low risk during short-term (2.5 (1.3–3.9) years) follow-up (p<0.0001). Diuretics, milrinone and VAD improved haemodynamics over time.ConclusionPH is prevalent in patients with 2V-RV even when asymptomatic. It is difficult to identify by echocardiography and most importantly, is strongly associated with adverse outcomes. PH affects prognosis and transplant options for this patient group and yet is often amenable to treatment. Awareness of these results ought to lower the threshold for invasive haemodynamic assessment and may change the management of failing patients with 2V-RV.

Pressure segment length analysis of right ventricular function: influence of loading conditions

1991 ◽  
Vol 260 (4) ◽  
pp. H1087-H1097
Author(s):  
J. E. Calvin
Keyword(s):  
Right Ventricle ◽  
Right Ventricular ◽  
Ventricular Function ◽  
Systolic Pressure ◽  
Pressure Overload ◽  
Outflow Tract ◽  
Segment Length ◽  
Stroke Work ◽  
Volume Changes ◽  
The Right

The purpose of this study was to determine whether segment lengths measured from the right ventricular inflow and outflow tract regions of the right ventricle would accurately reflect true volume changes of the right ventricle and to determine the response of the right ventricle to afterload increases induced by both constricting the pulmonary artery (PAC) and embolizing the pulmonary circulation with glass beads (GBE). Three excised hearts were instrumented with segment-length crystals attached to the inflow and outflow tract regions, and saline was instilled into a balloon implanted inside the right ventricular cavity. The experiments showed a high correlation (r greater than or equal to 0.90 in all cases) between static segment lengths and volume instilled. In open chest, open pericardial canine experiments, vena caval occlusion reduced end-diastolic segments lengths and right ventricular systolic pressure consistent with a reduction in right ventricular end-diastolic volume. In a separate group of animals, volume loading with dextran increased inflow and outflow end-diastolic segment lengths and increased cardiac output. In two further groups of animals, one of which was pretreated intravenously with propranolol (Inderal), both forms of pressure overload increased end-diastolic lengths in both regions. However, GBE increased right ventricular stroke work compared with PAC. We conclude that end-diastolic segment lengths reflect true volume changes of the right ventricle. Furthermore, during acute pressure overload, the right ventricle dilates to compensate for the afterload change. However, ventricular function is better maintained after GBE.

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