scholarly journals Relative Contributions of Matrix and Myocytes to Biaxial Mechanics of the Right Ventricle in Pulmonary Arterial Hypertension

2019 ◽  
Vol 141 (9) ◽  
Author(s):  
Daniela Vélez-Rendón ◽  
Erica R. Pursell ◽  
Justin Shieh ◽  
Daniela Valdez-Jasso
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Full Range ◽  
Biological Tissues ◽  
Outflow Tract ◽  
Control Group ◽  
Biaxial Test ◽  
Ecm Remodeling ◽  
Before And After ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) commonly leads to right ventricular (RV) hypertrophy and fibrosis that affect the mechanical properties of the RV myocardium (MYO). To investigate the effects of PAH on the mechanics of the RV MYO and extracellular matrix (ECM), we compared RV wall samples, isolated from rats in which PAH was induced using the SuHx protocol, with samples from control animals before and after the tissues were decellularized. Planar biaxial mechanical testing, a technique first adapted to living soft biological tissues by Fung, was performed on intact and decellularized samples. Fung's anisotropic exponential strain energy function fitted the full range of biaxial test results with high fidelity in control and PAH samples both before and after they were decellularized. Mean RV myocardial apex-to-outflow tract and circumferential stresses during equibiaxial strain were significantly greater in PAH than control samples. Mean RV ECM circumferential but not apex-to-outflow tract stresses during equibiaxial strain were significantly greater in the PAH than control group. The ratio of ECM to myocardial stresses at matched strains did not change significantly between groups. Circumferential stresses were significantly higher than apex-to-outflow tract stresses for all groups. These findings confirm the predictions of a mathematical model based on changes in RV hemodynamics and morphology in rat PAH, and may provide a foundation for a new constitutive analysis of the contributions of ECM remodeling to changes in RV filling properties during PAH.

Treatment of pulmonary arterial hypertension with circulating angiogenic cells

2011 ◽  
Vol 301 (1) ◽  
pp. L12-L19 ◽  
Author(s):  
Rachel Mirsky ◽  
Sarah Jahn ◽  
Juha W. Koskenvuo ◽  
Richard E. Sievers ◽  
Sarah M. Yim ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Study Endpoint ◽  
Control Group ◽  
Multiple Time ◽  
Late Time ◽  
Cell Transplant ◽  
Circulating Angiogenic Cells ◽  
Time Points ◽  
Pulmonary Arterial

Despite advances in the treatment of pulmonary arterial hypertension, a truly restorative therapy has not been achieved. Attention has been given to circulating angiogenic cells (CACs, also termed early endothelial progenitor cells) because of their ability to home to sites of vascular injury and regenerate blood vessels. We studied the efficacy of human CAC therapy in the treatment of pulmonary arterial hypertension at two different stages of disease severity. Cells were isolated from peripheral blood and administered to nude rats on day 14 (“early”) or day 21 (“late”) after monocrotaline injection. The control group received monocrotaline but no cell treatment. Disease progression was assessed using right heart catheterization and echocardiography at multiple time points. Survival differences, right ventricular hypertrophy (RVH), and vascular hypertrophy were analyzed at the study endpoint. Quantitative PCR was performed to evaluate cell engraftment. Treatment with human CACs either at the early or late time points did not result in increased survival, and therapy did not prevent or reduce the severity of disease compared with control. Histological analysis of RVH and vascular muscularization showed no benefit with therapy compared with control . No detectable signal was seen of human transcript in transplanted lungs at 14 or 21 days after cell transplant. In conclusion, CAC therapy was not associated with increased survival and did not result in either clinical or histological benefits. Future studies should be geared toward either earlier therapeutic time points with varying doses of unmodified CACs or genetically modified cells as a means of delivery of factors to the pulmonary arterial circulation.

scholarly journals Directing Therapy in Pulmonary Arterial Hypertension Using a Target 6 Min Walk Distance

2013 ◽  
Vol 20 (2) ◽  
pp. 111-115
Author(s):  
Nancy Rose Porhownik ◽  
Renelle Myers ◽  
Zoheir Bshouty
Keyword(s):  
Survival Rate ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Survival Rates ◽  
Registry Data ◽  
Walk Distance ◽  
Treatment Groups ◽  
Advanced Therapies ◽  
Before And After ◽  
Pulmonary Arterial

BACKGROUND: The most effective approaches to escalating advanced therapies in pulmonary arterial hypertension (PAH) are controversial.OBJECTIVE: To compare outcomes before and after introducing a target 6 min walk distance (6MWD) treatment strategy in PAH using registry data.METHODS: From 2001 to 2005, WHO class II to IV patients were treated with bosentan or prostanoids. In July 2005, a target 6MWD strategy was adopted. Monotherapy continued if 6MWD remained >350 m. For patients in whom 6MWD was ≤350 m, sildenafil was added. If 6MWD remained <350 m, prostanoids were considered. Changes in 6MWD, WHO class and survival rate were compared between periods.RESULTS: Before using the 6MWD strategy, there was a statistically significant improvement in mean WHO class at six, nine and 12 months (2.5±0.8 [P<0.015]; 2.5±0.8 [P<0.005]; and 2.5±0.9 [P<0.03], respectively) compared with baseline (2.9±0.9). There was a statistically significant increase in mean 6MWD at three, six, nine and 12 months (383±113 m [P<0.005]; 401±102 m [P<0.006]; 400±109 m [P<0.001]; and 399±110 m [P<0.004], respectively) compared with baseline (321±119 m). The survival rate was 95% at one and two years. From 2005 to 2009, there was a statistically significant improvement in mean WHO class at three, six, nine and 12 months (2.6±0.8 [P<0.05]; 2.3±0.9 [P<0.0001]; 2.3±0.9 [P<0.0001]; and 2.3±1.0 [P<0.0005], respectively) compared with baseline (2.8±0.7). There was statistically significant improvement in 6MWD at six months (381±126 m [P<0.05]), followed by a decline toward baseline (354±117 m). One- and two-year survival rates in the 6MWD target era were 95% and 80%, respectively.CONCLUSION: Based on registry data, adoption of this strategy did not affect survival rates, nor cause a sustained improvement in 6MWD by 12 months. WHO class improved similarly in both treatment groups.

scholarly journals Hemodynamic effects of fluoxetine in pulmonary arterial hypertension: an open label pilot study

2020 ◽  
Vol 10 (4) ◽  
pp. 204589402097195
Author(s):  
Adetoun Sodimu ◽  
Sonja Bartolome ◽  
Oluwatosin P. Igenoza ◽  
Kelly M. Chin
Keyword(s):  
Pilot Study ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Therapeutic Potential ◽  
Hemodynamic Effects ◽  
Open Label ◽  
Before And After ◽  
Secondary Endpoints ◽  
Pulmonary Arterial ◽  
Fluoxetine Therapy

In order to evaluate the therapeutic potential of fluoxetine in pulmonary arterial hypertension, 13 patients with pulmonary arterial hypertension underwent catheterization before and after 12 (N = 5) or 24 (N = 8) weeks fluoxetine therapy. No change was seen in the primary endpoint of pulmonary vascular resistance, other hemodynamic values, or any secondary endpoints.

scholarly journals 408 The relationship between right ventricle-arterial coupling and cardiac metabolism in pulmonary arterial hypertension - multimodal study

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
R Kazimierczyk ◽  
P Szumowski ◽  
P Blaszczak ◽  
E Kazimierczyk ◽  
K Ptaszynska-Kopczynska ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Control Group ◽  
Hemodynamic Parameters ◽  
Metabolic Demand ◽  
Pulmonary Arterial ◽  
The Relationship ◽  
Rv Function ◽  
Worse Prognosis

Abstract Background Right ventricular (RV) function is a major determinant of survival in patients with pulmonary arterial hypertension (PAH). The concept of coupling mainly refers to the relationship between ventricular contractility and afterload. In advanced PAH, to maintain cardiac output, RV dilates and the uncoupling occurs with wall stress and increased metabolic demand. We previously confirmed that impaired RV function is associated with increased glucose uptake of RV myocytes estimated by PET, which marks patients with worse prognosis. Purpose Whether echocardiographic approach of coupling parameters in PAH patients has relationship with RV metabolic alterations. Methods Twenty-six stable PAH patients (mean age 49.92 ± 15.94 years) and sixteen healthy subjects (control group) were enrolled into the study. The TAPSE, reflecting RV contractility, was obtained by mono-dimensional echo in standard technique. The echo estimation of the sPAP was reflecting RV afterload. Ventricular-arterial coupling was evaluated by the ratio between those two parameters. All PAH patients had also right heart catheterization (RHC) and PET performed during baseline visit. Heart glucose metabolism was assessed with fluorodeoxyglucose (FDG) as a tracer in PET. Its uptake was quantified as mean standardized uptake value (SUV) for both left ventricle (LV) and RV. Mean follow-up time of this study was 16.6 ± 7.5 months and the clinical end-point (CEP) was defined as death or clinical deterioration. Results Most of enrolled patients were in the WHO functional Class III (61%, 16). There were significant correlations between echo-derived hemodynamic parameters and RHC-derived values e.g. emPAP vs mPAP (RHC), r = 0.86, p &lt; 0.001. Echo-estimated RV ventricular-arterial coupling parameter (TAPSE/sPAP) was 0.35 ± 0.20 in PAH group and 1.51 ± 0.22 in control group, p &lt; 0.001. Mean SUV RV/LV ratio was 1.03 ± 0.68 in PAH group and 0.19 ± 0.08 in controls, p &lt; 0.005. Echo-derived TAPSE/sPAP significantly correlated with hemodynamic parameters from RHC – cardiac output and pulmonary vascular resistance. Interestingly, we also observed significant correlations of TAPSE/sPAP with glucose uptake in PET - SUV RV as well as with SUV RV/LV (r=-0.63, p = 0.0006; r=-0.50, p = 0.0009), confirming higher metabolic demand in uncoupled heart in case of PAH. Furthermore, patients who reached CEP (n = 15, 57%) had a significantly lower TAPSE/esPAP ratio (0.29 ± 0.17 vs 0.43 ± 0.21, p = 0.04) and higher SUV RV/LV (1.39 ± 0.79 vs 0.55 ± 0.45, p = 0.01). ROC analysis revealed significant cut-off value of TAPSE/esPAP in predicting CEP (AUC 0.72 (95% CI 0.52-0.92), p = 0.03). Patients with TAPSE/esPAP lower than 0.25 mm/mmHg had worse prognosis, log-rank test, p = 0.001 (Figure 1). Conclusions Simple echocardiographic parameter reflecting RV coupling (TAPSE/esPAP) related to altered myocardium metabolism in PAH may predict outcome in patients with PAH. Abstract 408 Figure 1

scholarly journals Factors Associated with Heritable Pulmonary Arterial Hypertension Exert Convergent Actions on the miR-130/301-Vascular Matrix Feedback Loop

2018 ◽  
Vol 19 (8) ◽  
pp. 2289 ◽  
Author(s):  
Thomas Bertero ◽  
Adam Handen ◽  
Stephen Chan
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Feedback Loop ◽  
Matrix Stiffness ◽  
Ecm Remodeling ◽  
The Matrix ◽  
Vascular Stiffening ◽  
Pulmonary Arterial ◽  
Heritable Pulmonary Arterial Hypertension ◽  
Systematic Manipulation

Pulmonary arterial hypertension (PAH) is characterized by occlusion of lung arterioles, leading to marked increases in pulmonary vascular resistance. Although heritable forms of PAH are known to be driven by genetic mutations that share some commonality of function, the extent to which these effectors converge to regulate shared processes in this disease is unknown. We have causally connected extracellular matrix (ECM) remodeling and mechanotransduction to the miR-130/301 family in a feedback loop that drives vascular activation and downstream PAH. However, the molecular interconnections between factors genetically associated with PAH and this mechano-driven feedback loop remain undefined. We performed systematic manipulation of matrix stiffness, the miR-130/301 family, and factors genetically associated with PAH in primary human pulmonary arterial cells and assessed downstream and reciprocal consequences on their expression. We found that a network of factors linked to heritable PAH converges upon the matrix stiffening-miR-130/301-PPARγ-LRP8 axis in order to remodel the ECM. Furthermore, we leveraged a computational network biology approach to predict a number of additional molecular circuits functionally linking this axis to the ECM. These results demonstrate that multiple genes associated with heritable PAH converge to control the miR-130/301 circuit, triggering a self-amplifying feedback process central to pulmonary vascular stiffening and disease.

Abstract 17396: RV Remodeling in Two Animal Models of Pulmonary Arterial Hypertension

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Xiaoyan Zhang ◽  
Daniela Velez-Rendon ◽  
Daniela Valdez-Jasso
Keyword(s):  
Single Dose ◽  
Pulmonary Arterial Hypertension ◽  
Animal Models ◽  
Arterial Hypertension ◽  
Isometric Tension ◽  
Model Material ◽  
Control Group ◽  
Sprague Dawley ◽  
Pulmonary Arterial

Introduction: Right-ventricular function is a good indicator of pulmonary arterial hypertension (PAH) prognosis. By relating ventricular hemodynamics to wall mechanics, we aimed to discriminate the contributions of ventricular geometric remodeling and intrinsic changes in myocardial mechanical properties in two commonly used PAH animal models at end-systole (ES) and end-diastole (ED) to the maintenance of cardiac output during the early compensated phase. Methods: PAH was induced in 13 male Sprague-Dawley rats. The MCT group (N=4) was injected with a single dose of 60mg/kg of monoctroaline and kept in normoxia for 4 weeks. The SuHx group (N=9) was injected with a single dose of 20mg/kg of sugen, a VEGF inhibitor, and was placed on a hypoxia chamber for 3 weeks followed by 3 weeks of normoxia. 7 animals were used as a control group. In-vivo measurements of RV pressure and volume with preload changes were acquired. To relate ventricular pressure-volume relations to sarcomere mechanics, a computational model of the RV was developed. Using ventricular morphology and volume measurements from PAH groups, sarcomere material mechanics were adjusted to evaluate ES and ED functions in the treated animals. Results: ED pressures rose significantly in the treated groups (31.7 vs. 70.5 and 71.1 mmHg). ED and ES volumes remained the same in SuHx and CTL group, but increased significantly in the MCT group. RV hypertrophy increased in both PAH animal models, but it was significantly higher in the SuHx group. Even though differences in pressure, volume and morphology exist between the PAH groups, SV and CO were preserved in all treated animals. Model material parameters of increased in PAH, significantly in MCT maximal isometric tension. Conclusions: The model analysis suggests compensation to ESP rises was only possible due to a significant increase in the contractility of RV myocardium in the MCT and SuHx animals. No changes in diastolic function were found in the MCT animals, but there was an increase stiffness in the SuHx animals.

scholarly journals Exhaled Nitric Oxide in Pulmonary Arterial Hypertension Associated with Systemic Sclerosis

2016 ◽  
Vol 6 (4) ◽  
pp. 545-550 ◽  
Author(s):  
Zeling Cao ◽  
Stephen C. Mathai ◽  
Laura K. Hummers ◽  
Ami A. Shah ◽  
Fredrick M. Wigley ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Involvement ◽  
Control Group ◽  
Significant Difference ◽  
Pulmonary Capillary Blood ◽  
Treatment Naïve ◽  
Pulmonary Arterial

The fractional exhaled concentration of nitric oxide (FENO) has been shown to be reduced in idiopathic pulmonary arterial hypertension (PAH) but has not been adequately studied in PAH associated with systemic sclerosis (SSc). We measured FENO at an expiratory flow rate of 50 mL/s in 21 treatment-naive patients with SSc-associated PAH (SSc-PAH), 94 subjects with SSc without pulmonary involvement, and 84 healthy volunteers. Measurements of FENO at additional flow rates of 100, 150, and 250 mL/s were obtained to derive the flow-independent nitric oxide exchange parameters of maximal airway flux (J′awNO) and steady-state alveolar concentration (CANO). FENO at 50 mL/s was similar ( P = 0.22) in the SSc-PAH group (19 ± 12 parts per billion [ppb]) compared with the SSc group (17 ± 12 ppb) and healthy control group (21 ± 11 ppb). No change was observed after 4 months of targeted PAH therapy in 14 SSc-PAH group patients ( P = 0.9). J′awNO was modestly reduced in SSc group subjects without lung disease (1.2 ± 0.5 nl/s) compared with healthy controls (1.64 ± 0.9; P < 0.05) but was similar to that in the SSc-PAH group. CANO was elevated in individuals with SSc-PAH (4.8 ± 2.6 ppb) compared with controls with SSc (3.3 ± 1.4 ppb) and healthy subjects (2.6 ± 1.5 ppb; P < 0.001 for both). However, after adjustment for the diffusing capacity of CO, there was no significant difference in CANO between individuals with SSc-PAH and controls with SSc. We conclude that FENO is not useful for the diagnosis of PAH in SSc. Increased alveolar nitric oxide in SSc-PAH likely represents impaired diffusion into pulmonary capillary blood.

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