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.

Pulmonary Arterial Hypertension After Hematopoeitic Stem Cell Transplant

CHEST Journal ◽  
2012 ◽  
Vol 142 (4) ◽  
pp. 118A
Author(s):  
Hala Moukhachen ◽  
Prabalini Rajendram ◽  
Sanjay Chawla ◽  
Nina Raoof ◽  
Kaye Hale ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Stem Cell Transplant ◽  
Cell Transplant ◽  
Pulmonary Arterial

scholarly journals Organ-level right ventricular dysfunction with preserved Frank-Starling mechanism in a mouse model of pulmonary arterial hypertension

2018 ◽  
Vol 124 (5) ◽  
pp. 1244-1253 ◽  
Author(s):  
Zhijie Wang ◽  
Jitandrakumar R. Patel ◽  
David A. Schreier ◽  
Timothy A. Hacker ◽  
Richard L. Moss ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Pressure Overload ◽  
Multiple Time ◽  
Functional Changes ◽  
Pulmonary Arterial ◽  
Organ Level ◽  
Subcellular Level ◽  
Insight Into

Pulmonary arterial hypertension (PAH) is a rapidly fatal disease in which mortality is due to right ventricular (RV) failure. It is unclear whether RV dysfunction initiates at the organ level or the subcellular level or both. We hypothesized that chronic pressure overload-induced RV dysfunction begins at the organ level with preserved Frank-Starling mechanism in myocytes. To test this hypothesis, we induced PAH with Sugen + hypoxia (HySu) in mice and measured RV whole organ and subcellular functional changes by in vivo pressure-volume measurements and in vitro trabeculae length-tension measurements, respectively, at multiple time points for up to 56 days. We observed progressive changes in RV function at the organ level: in contrast to early PAH (14-day HySu), in late PAH (56-day HySu) ejection fraction and ventricular-vascular coupling were decreased. At the subcellular level, direct measurements of myofilament contraction showed that RV contractile force was similarly increased at any stage of PAH development. Moreover, cross-bridge kinetics were not changed and length dependence of force development (Frank-Starling relation) were not different from baseline in any PAH group. Histological examinations confirmed increased cardiomyocyte cross-sectional area and decreased von Willebrand factor expression in RVs with PAH. In summary, RV dysfunction developed at the organ level with preserved Frank-Starling mechanism in myofilaments, and these results provide novel insight into the development of RV dysfunction, which is critical to understanding the mechanisms of RV failure. NEW & NOTEWORTHY A multiscale investigation of pulmonary artery pressure overload in mice showed time-dependent organ-level right ventricular (RV) dysfunction with preserved Frank-Starling relations in myofilaments. Our findings provide novel insight into the development of RV dysfunction, which is critical to understanding mechanisms of RV failure.

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.

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 < 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 < 0.001. Mean SUV RV/LV ratio was 1.03 ± 0.68 in PAH group and 0.19 ± 0.08 in controls, p < 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

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 Temporal hemodynamic and histological progression in Sugen5416/hypoxia/normoxia-exposed pulmonary arterial hypertensive rats

2014 ◽  
Vol 306 (2) ◽  
pp. H243-H250 ◽  
Author(s):  
Michie Toba ◽  
Abdallah Alzoubi ◽  
Kealan D. O'Neill ◽  
Salina Gairhe ◽  
Yuri Matsumoto ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Male Rats ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Time Points ◽  
Pulmonary Arterial ◽  
Time Point

We have investigated the temporal relationship between the hemodynamic and histological/morphological progression in a rat model of pulmonary arterial hypertension that develops pulmonary arterial lesions morphologically indistinguishable from those in human pulmonary arterial hypertension. Adult male rats were injected with Sugen5416 and exposed to hypoxia for 3 wk followed by a return to normoxia for various additional weeks. At 1, 3, 5, 8, and 13 wk after the Sugen5416 injection, hemodynamic and histological examinations were performed. Right ventricular systolic pressure reached its maximum 5 wk after Sugen5416 injection and plateaued thereafter. Cardiac index decreased at the 3∼5-wk time point, and tended to further decline at later time points. Reflecting these changes, calculated total pulmonary resistance showed a pattern of progressive worsening. Acute intravenous fasudil markedly reduced the elevated pressure and resistance at all time points tested. The percentage of severely occluded small pulmonary arteries showed a similar pattern of progression to that of right ventricular systolic pressure. These small vessels were occluded predominantly with nonplexiform-type neointimal formation except for the 13-wk time point. There was no severe occlusion in larger arteries until the 13-wk time point, when significant numbers of vessels were occluded with plexiform-type neointima. The Sugen5416/hypoxia/normoxia-exposed rat shows a pattern of chronic hemodynamic progression similar to that observed in pulmonary arterial hypertension patients. In addition to vasoconstriction, nonplexiform-type neointimal occlusion of small arteries appears to contribute significantly to the early phase of pulmonary arterial hypertension development, and plexiform-type larger vessel occlusion may play a role in the late deterioration.

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.

scholarly journals Clinical Value of Asymmetrical Dimethylarginine Detection in Patients with Connective Tissue Disease-Associated Pulmonary Arterial Hypertension

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Juan Liu ◽  
Qiang Fu ◽  
Lili Jiang ◽  
Youlian Wang
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Connective Tissue ◽  
Pulmonary Function ◽  
Arterial Hypertension ◽  
Connective Tissue Disease ◽  
Control Group ◽  
Clinical Value ◽  
Asymmetrical Dimethylarginine ◽  
Healthy Control ◽  
Pulmonary Arterial

Objective. To evaluate the clinical value of serum asymmetrical dimethylarginine (ADMA) in patients with connective tissue disease- (CTD-) associated pulmonary arterial hypertension (PAH). Methods. 88 patients with CTD were recruited between December 2017 and August 2018 in Jiangxi Provincial People’s Hospital. Patients were further divided into two groups: CTD-without PAH (n = 45 cases) and CTD-with PAH (n = 43 cases), according to the pulmonary systolic blood pressure measured by echocardiography. 40 healthy controls were also included (n = 40 cases). The clinical data, including laboratory examinations, echocardiographic measurements, pulmonary function, and serum ADMA levels determined by enzyme-linked immunosorbent assay, (ELISA) were collected. The correlation between ADMA levels and the occurrence of PAH, pulmonary function, and other laboratory indexes in CTD patients were analyzed. Statistical analyses were performed by SPSS (version 23); P<0.05 was considered statistically significant. Results. The serum levels of ADMA in the CTD-PAH group were significantly higher than those of the CTD-without PAH group and healthy control group (P<0.05); the serum ADMA levels were (0.706 ± 0.153 μmol/L), (1.015 ± 0.122 μmol/L), and (0.661 ± 0.113 μmol/L), respectively. There was no significant difference between the CTD-without PAH group and healthy control group (P<0.05). Correlation analysis showed that serum ADMA levels were positively correlated with sPAP and NT-proBNP and negatively correlated with DLCO% (r = 0.802, 0.475, −0.585, P<0.001). Multivariate analysis indicated that elevated serum ADMA levels increased the risk for the appearance of PAH in CTD patients (OR = 57.460, P<0.001). Using the receiver operating characteristic (ROC) curve analysis, at the cutoff level of 0.810 μmol/L, ADMA showed good diagnostic efficacy as follows: sensitivity was 97.7%, specificity was 75.6%, and the area under the curve (AUC) was 0.947 (P<0.001). Conclusion. Increased ADMA levels are independently associated with the presence and severity of PAH in CTD patients. The levels of ADMA in the serum may contribute to be a noninvasive indicator for early diagnosis of CTD-with PAH patients.

Safety and effect of sildenafil on treating paediatric pulmonary arterial hypertension: a meta-analysis on the randomised controlled trials

2020 ◽  
Vol 30 (12) ◽  
pp. 1882-1889
Author(s):  
Qingyou Zhang ◽  
Bowen Xu ◽  
Jichen Lv ◽  
Zhijian Wang ◽  
Junbao Du
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Randomised Controlled Trials ◽  
Meta Analysis ◽  
Statistical Significance ◽  
Hypertensive Crisis ◽  
Control Group ◽  
Controlled Trials ◽  
Pulmonary Arterial ◽  
Randomised Controlled

AbstractBackground:Efficacy of sildenafil in treating paediatric pulmonary arterial hypertension is controversial. This systematic review aimed to explore the safety and effect of sildenafil on treating paediatric pulmonary arterial hypertension (PAH) through meta-analysis.Methods and results:In this study, the electronic databases, including the Cochran Library database, EMBASE, and MEDLINE were systemically retrieved to identify the related randomised controlled trials (RCTs). Two reviewers had independently completed study selection, data collection, and assessment of the bias risk. Amongst 938 articles researched according to our retrieval strategy, 15 papers that involved 673 cases had been screened. Relative to control group, the sildenafil group had markedly reduced mortality (RR = 0.25, 95% CI: 0.12–0.51; p < 0.0001), but difference within the mortality was not statistically significant between high- and low-dose sildenafil groups (p = 0.152). Nonetheless, difference of the mean pulmonary arterial pressure between sildenafil as well as control group was of no statistical significance. Differences in the length of hospital stay and the incidences of pulmonary hypertensive crisis between children with PAH and controls were of no statistical significance. However, the summary estimate favoured that sildenafil reduced the duration of mechanical ventilation time, as well as the length of ICU stay and inotropic support.Conclusions:Sildenafil therapy reduces the mortality of PAH patients, but its effects on the haemodynamic outcomes and other clinical outcomes are still unclear.

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