Beneficial effects of mesenchymal stem cell delivery via a novel cardiac bioscaffold on right ventricles of pulmonary arterial hypertensive rats

Right ventricular failure (RVF) is a common cause of death in patients suffering from pulmonary arterial hypertension (PAH). The current treatment for PAH only moderately improves symptoms, and RVF ultimately occurs. Therefore, it is necessary to develop new treatment strategies to protect against right ventricle (RV) maladaptation despite PAH progression. In this study, we hypothesize that local mesenchymal stem cell (MSC) delivery via a novel bioscaffold can improve RV function despite persistent PAH. To test our hypothesis, we induced PAH in adult rats with SU5416 and chronic hypoxia exposure; treated with rat MSCs delivered by intravenous injection, intramyocardial injection, or epicardial placement of a bioscaffold; and then examined treatment effectiveness by in vivo pressure-volume measurement, echocardiography, histology, and immunohistochemistry. Our results showed that compared with other treatment groups, only the MSC-seeded bioscaffold group resulted in RV functional improvement, including restored stroke volume, cardiac output, and improved stroke work. Diastolic function indicated by end-diastolic pressure-volume relationship was improved by the local MSC treatments or bioscaffold alone. Cardiomyocyte hypertrophy and RV fibrosis were both reduced, and von Willebrand factor expression was restored by the MSC-seeded bioscaffold treatment. Overall, our study suggests a potential new regenerative therapy to rescue the pressure-overload failing RV with persistent pulmonary vascular disease, which may improve quality of life and/or survival of PAH patients. NEW & NOTEWORTHY We explored the effects of mesenchymal stem cell-seeded bioscaffold on right ventricles (RVs) of rats with established pulmonary arterial hypertension (PAH). Some beneficial effects were observed despite persistent PAH, suggesting that this may be a new therapy for RV to improve quality of life and/or survival of PAH patients.

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Macrophage Immunomodulation: The Gatekeeper for Mesenchymal Stem Cell Derived-Exosomes in Pulmonary Arterial Hypertension?

International Journal of Molecular Sciences ◽

10.3390/ijms19092534 ◽

2018 ◽

Vol 19 (9) ◽

pp. 2534 ◽

Cited By ~ 19

Author(s):

Gareth Willis ◽

Angeles Fernandez-Gonzalez ◽

Monica Reis ◽

S. Mitsialis ◽

Stella Kourembanas

Keyword(s):

Stem Cell ◽

Pulmonary Arterial Hypertension ◽

Mesenchymal Stem Cell ◽

Arterial Hypertension ◽

Pulmonary Inflammation ◽

Pulmonary Arteries ◽

Cross Sectional ◽

Macrophage Function ◽

Beneficial Effects ◽

Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by remodeling of the pulmonary arteries, increased pulmonary infiltrates, loss of vascular cross-sectional area, and elevated pulmonary vascular resistance. Despite recent advances in the management of PAH, there is a pressing need for the development of new tools to effectively treat and reduce the risk of further complications. Dysregulated immunity underlies the development of PAH, and macrophages orchestrate both the initiation and resolution of pulmonary inflammation, thus, manipulation of lung macrophage function represents an attractive target for emerging immunomodulatory therapies, including cell-based approaches. Indeed, mesenchymal stem cell (MSC)-based therapies have shown promise, effectively modulating the macrophage fulcrum to favor an anti-inflammatory, pro-resolving phenotype, which is associated with both histological and functional benefits in preclinical models of pulmonary hypertension (PH). The complex interplay between immune system homeostasis and MSCs remains incompletely understood. Here, we highlight the importance of macrophage function in models of PH and summarize the development of MSC-based therapies, focusing on the significance of MSC exosomes (MEx) and the immunomodulatory and homeostatic mechanisms by which such therapies may afford their beneficial effects.

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EXPRESS: Association of daily physical activity with psychosocial aspects and functional capacity in patients with Pulmonary Arterial Hypertension: a cross-sectional study

Pulmonary Circulation ◽

10.1177/2045894021999955 ◽

2021 ◽

pp. 204589402199995

Author(s):

Layse Nakazato Lima ◽

Felipe Mendes ◽

Ilma Paschoal ◽

Daniela Oliveira ◽

Marcos Mello Moreira ◽

...

Keyword(s):

Quality Of Life ◽

Physical Activity ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Functional Capacity ◽

Daily Physical Activity ◽

Cross Sectional ◽

Pulmonary Arterial ◽

The Mean

Pulmonary arterial hypertension (PAH) impairs exercise tolerance and daily physical activity (PA). Aside from the hemodynamic limitations, physical, cognitive and emotional factors may play a relevant and as yet unexplored role. We investigated whether there is an association between the PA level and psychological disorders, health-related quality of life, and daily activities. We also searched for an association of the PA level with clinical factors and functional capacity. This was an analytical, cross-sectional, observational study conducted in a Brazilian University Hospital. Twenty stable PAH subjects wore an accelerometer for a week and completed an activity diary. They answered the quality of life questionnaire (SF-36), as well as the anxiety and depression scale (HADS), and the Manchester Respiratory Activities of Daily Living questionnaire (MRADL). Transthoracic echocardiography, the 6-Minute walk test (6MWT), the 1-minute sit-to-stand test (STST), and spirometry were performed. For statistical analysis we used Chi-square tests or Fisher's test as appropriate and the Mann-Whitney test to compare numerical values between two groups. The relationship between the parameters was assessed using the Spearman correlation test. The mean age was 44.3 years, 80% were women, 80% had idiopathic PAH, and 20% had connective tissue disease . The mean daily step count was 4,280 Â± 2,351, and the mean activity time was 41.6 Â± 19.3 minutes. The distance covered (6MWT) was 451.5 m, and the number of movements (1-STST) was 23.8. Thirty percent scored positive for anxiety, and 15% for depression (HADS). There was a significant correlation between accelerometer data and walking distance (6MWT), number of movements (1-STST), level of daily physical activity (MRADL), and depression symptoms. Our findings support the hypothesis that other aspects beyond physical and hemodynamic ones might impact the daily physical activity of patients with PAH.

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Effect of Pulmonary Arterial Hypertension-Specific Therapies on Health-Related Quality of Life

CHEST Journal ◽

10.1378/chest.13-2634 ◽

2014 ◽

Vol 146 (3) ◽

pp. 686-708 ◽

Cited By ~ 28

Author(s):

Gilles Rival ◽

Yves Lacasse ◽

Sylvie Martin ◽

Sébastien Bonnet ◽

Steeve Provencher

Keyword(s):

Quality Of Life ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Health Related Quality ◽

Related Quality ◽

Health Related ◽

Pulmonary Arterial

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A prescribed walking regimen plus arginine supplementation improves function and quality of life for patients with pulmonary arterial hypertension: a pilot study

Pulmonary Circulation ◽

10.1177/2045893217743966 ◽

2017 ◽

Vol 8 (1) ◽

pp. 204589321774396 ◽

Cited By ~ 5

Author(s):

Mary Beth Brown ◽

Attie Kempf ◽

Catherine M. Collins ◽

Gary M. Long ◽

Matthew Owens ◽

...

Keyword(s):

Quality Of Life ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Current Evidence ◽

Proof Of Concept ◽

Concept Study ◽

Sf 36 ◽

Pulmonary Arterial ◽

Arginine Supplementation

Current evidence suggests that exercise training is beneficial in pulmonary arterial hypertension (PAH). Unfortunately, the standard supervised, hospital-based programs limit patient accessibility to this important intervention. Our proof-of-concept study aimed to provide insight into the usefulness of a prescribed walking regimen along with arginine supplementation to improve outcomes for patients with PAH. Twelve PAH patients (all women) in New York Heart Association (NYHA) functional class (FC) II (n = 7) or III (n = 5) and in stable condition for ≥ 3 months were enrolled. Patients performed home- and fitness-center- based walking at 65–75% heart rate (HR) reserve for 45 min, six sessions/week for 12 weeks. Concomitant L-arginine supplementation (6000 mg/day) was provided to maximize beneficial endothelial training adaptations. Cardiopulmonary exercise testing, 6-min walk testing (6MWT), echocardiography, laboratory studies, and quality of life (QoL) survey (SF-36) were performed at baseline and 12 weeks. Eleven patients completed the study (72 session adherence rate = 96 ± 3%). Objective improvement was demonstrated by the 6MWT distance (increased by 40 ± 13 m, P = 0.01), VO2max (increased by 2 ± 0.7 mL/kg/min, P = 0.02), time-to-VO2max (increased by 2.5 ± 0.6 min, P = 0.001), VO2 at anaerobic threshold (increased by 1.3 ± 0.5 mL/kg/min, P = 0.04), HR recovery (reduced by 68 ± 23% in slope, P = 0.01), and SF-36 subscales of Physical Functioning and Energy/Fatigue (increased by 70 ± 34% and 74 ± 34%, respectively, P < 0.05). No adverse events occurred, and right ventricular function and brain natriuretic peptide levels remained stable, suggesting safety of the intervention. This proof-of-concept study indicates that a simple walking regimen with arginine supplementation is a safe and efficacious intervention for clinically stable PAH patients, with gains in objective function and QoL measures. Further investigation in a randomized controlled trial is warranted.

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