• connective tissue disease (CTD)
• endothelin receptor antagonists (ERA)
• phosphodiesterase type 5 inhibitor (PDE5i)
• pulmonary arterial hypertension
• systemic sclerosis (SSc)

• Humans
• Pulmonary Arterial Hypertension/etiology
• Pulmonary Arterial Hypertension/complications
• Mixed Connective Tissue Disease/complications
• Mixed Connective Tissue Disease/drug therapy
• Connective Tissue Diseases/complications
• Connective Tissue Diseases/drug therapy
• Connective Tissue Diseases/diagnosis
• Hypertension, Pulmonary/drug therapy
• Hypertension, Pulmonary/etiology
• Familial Primary Pulmonary Hypertension/complications
• Lupus Erythematosus, Systemic/complications
• Lupus Erythematosus, Systemic/drug therapy
• Scleroderma, Systemic/complications

• Acceleron
• Bayer
• GlaxoSmithKline
• Janssen and OMT

• Pulmonary hypertension
• Scleroderma
• Screening
• Systemic sclerosis
• Treatment

Iloprost has been proposed as a potential biomaterial owing to angiogenic and odontogenic properties. However, the liquid form can limit its use during clinical applications. Mineral trioxide aggregate (MTA) has been used for various dental applications in which cell–material interaction is essential. This study aimed to investigate additive effects of iloprost on the biological properties of MTA on the viability, attachment, migration and differentiation of human mesenchymal stem cells (hMSCs).

Standardized human dentin disks were prepared. MTA was prepared by mixing distilled water or iloprost solution, and the lumen of the disks was filled with MTA or MTA-iloprost. hMSCs on disk alone and hMSCs on culture plates were used as controls. Cell viability and attachment were measured after 1, 7 and 14 days using AlamarBlue assay and scanning electron microscopy (SEM). Cell migration in MTA or MTA-iloprost extracts was determined using a wound-healing model.

Osteogenic differentiation was evaluated by real-time reverse transcriptase polymerase chain reaction for alkaline phosphatase (ALP), bone sialoprotein (BSP), osteocalcin (OCN), and osteopontin (OSP) gene expressions after 7 and 14 days of osteogenic induction.

Cells on MTA-iloprost surface showed similar viability with MTA at 1 and 14 days but enhanced cellular viability and cell spreading compared to MTA at 7 days (p < 0.05). Cell migration was similar by MTA-iloprost and MTA extracts (p > 0.05). MTAiloprost significantly upregulated BSP, OCN and OSP expressions compared to MTA (p < 0.05).

The addition of iloprost to MTA improved the initial cell viability and osteogenic potential of hMSCs.

• Cell differentiation
• Iloprost
• MTA
• Mesenchymal stem cells

• Adult
• Atrial Fibrillation/diagnosis
• Atrial Fibrillation/epidemiology
• Atrial Fibrillation/therapy
• Hospital Mortality
• Hospitalization
• Humans
• Inpatients
• Scleroderma, Systemic/complications
• Scleroderma, Systemic/diagnosis
• Scleroderma, Systemic/epidemiology

• Mortality
• autoimmune diseases
• morbidity
• scleroderma renal crisis
• systemic sclerosis

• Mortality
• Saudi Arabia
• pulmonary arterial hypertension
• systemic sclerosis

• Angiogenesis
• dental pulp
• iloprost
• revascularization
• tooth-slice

• Adolescent
• Adult
• Collagen/metabolism
• Dental Pulp/blood supply
• Dental Pulp/drug effects
• Dental Pulp/growth & development
• Fluorescent Antibody Technique
• Humans
• Iloprost/pharmacology
• Microscopy, Confocal
• Neovascularization, Physiologic/drug effects
• Organ Culture Techniques/methods
• Vasodilator Agents/pharmacology
• Young Adult

• Diagnosis
• Monitoring
• Pulmonary arterial hypertension
• Systemic sclerosis

Although rare in its idiopathic form, pulmonary arterial hypertension (PAH) is not uncommon in association with various associated medical conditions, most notably connective tissue disease (CTD). In particular, it develops in approximately 10% of patients with systemic sclerosis and so these patients are increasingly screened to enable early detection. The response of patients with systemic sclerosis to PAH-specific therapy appears to be worse than in other forms of PAH. Survival in systemic sclerosis-associated PAH is inferior to that observed in idiopathic PAH. Potential reasons for this include differences in age, the nature of the underlying pulmonary vasculopathy and the ability of the right ventricle to cope with increased afterload between patients with systemic sclerosis-associated PAH and idiopathic PAH, while coexisting cardiac and pulmonary disease is common in systemic sclerosis-associated PAH. Other forms of connective tissue-associated PAH have been less well studied, however PAH associated with systemic lupus erythematosus (SLE) has a better prognosis than systemic sclerosis-associated PAH and likely responds to immunosuppression.

Primary cardiac involvement, which develops as a direct consequence of systemic sclerosis (SSc), may manifest as myocardial damage, fibrosis of the conduction system, pericardial and, less frequently, as valvular disease. In addition, cardiac complications in SSc may develop as a secondary phenomenon due to pulmonary arterial hypertension and kidney pathology. The prevalence of primary cardiac involvement in SSc is variable and difficult to determine because of the diversity of cardiac manifestations, the presence of subclinical periods, the type of diagnostic tools applied, and the diversity of patient populations. When clinically manifested, cardiac involvement is thought to be an important prognostic factor. Profound microvascular disease is a pathognomonic feature of SSc, as both vasospasm and structural alterations are present. Such alterations are thought to predict macrovascular atherosclerosis over time. There are contradictory reports regarding the prevalence of atherosclerosis in SSc. According to some authors, the prevalence of atherosclerosis of the large epicardial coronary arteries is similar to that of the general population, in contrast with other rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus. However, the level of inflammation in SSc is inferior. Thus, the atherosclerotic process may not be as aggressive and not easily detectable in smaller studies. Echocardiography (especially tissue Doppler imaging), single-photon emission computed tomography, magnetic resonance imaging and cardiac computed tomography are sensitive techniques for earlier detection of both structural and functional scleroderma-related cardiac pathologies. Screening for subclinical cardiac involvement via modern, sensitive tools provides an opportunity for early diagnosis and treatment, which is of crucial importance for a positive outcome.

• Systemic sclerosis
• Cardiac involvement

Pulmonary arterial hypertension (PAH) represents a devastating vascular complication of systemic sclerosis (SSc) and is found in 10%-15% of cases carrying a severe prognosis. PAH has a dramatic impact on the clinical course and overall survival, being the single most common cause of death in patients with this entity. The clinical course and aggressive progression of PAH has led clinicians to perform annual screening for it, since early detection and diagnosis are the cornerstone of a prompt therapeutic intervention. The diagnosis of PAH can be challenging to clinicians, particularly in its early stages, since in the context of SSc, the multiple causes of dyspnea need to be assessed. Doppler echocardiography represents the best initial screening tool, however, right heart catheterization remains the gold standard and definitive diagnostic means. Remarkable advances have been achieved in elucidating the pathogenesis of PAH in the past two decades, leading to the development of disease-specific targeted therapies: prostacyclin analogues, endothelin receptor antagonists and inhibitors of five phosphodiesterase pathways. However, the clinical response to these therapies in SSc-associated PAH has not been as great as the one seen with idiopathic PAH. This review also focuses on the diagnosis and novel therapies that are currently available for PAH, as well as potential future therapeutic developments based on newly acquired knowledge of diverse pathogenic mechanisms.

• Pulmonary arterial hypertension
• Systemic sclerosis
• Diagnosis
• Therapy
• Prognosis

Gene expression profiling of peripheral blood mononuclear cells (PBMCs) is a powerful tool for the identification of surrogate markers involved in disease processes. The hypothesis tested in this study was that chronic exposure of PBMCs to a hypertensive environment in remodeled pulmonary vessels would be reflected by specific transcriptional changes in these cells.

The transcript profiles of PBMCs from 30 idiopathic pulmonary arterial hypertension patients (IPAH), 19 patients with systemic sclerosis without pulmonary hypertension (SSc), 42 scleroderma-associated pulmonary arterial hypertensio patients (SSc-PAH), and 8 patients with SSc complicated by interstitial lung disease and pulmonary hypertension (SSc-PH-ILD) were compared to the gene expression profiles of PBMCs from 41 healthy individuals. Multiple gene expression signatures were identified which could distinguish various disease groups from controls. One of these signatures, specific for erythrocyte maturation, is enriched specifically in patients with PH. This association was validated in multiple published datasets. The erythropoiesis signature was strongly correlated with hemodynamic measures of increasing disease severity in IPAH patients. No significant correlation of the same type was noted for SSc-PAH patients, this despite a clear signature enrichment within this group overall. These findings suggest an association of the erythropoiesis signature in PBMCs from patients with PH with a variable presentation among different subtypes of disease.

In PH, the expansion of immature red blood cell precursors may constitute a response to the increasingly hypoxic conditions prevalent in this syndrome. A correlation of this erythrocyte signature with more severe hypertension cases may provide an important biomarker of disease progression.

• Adult
• Aged
• Erythroid Cells/metabolism
• Female
• Gene Expression Regulation
• Hemodynamics
• Humans
• Hypertension, Pulmonary/genetics
• Hypertension, Pulmonary/physiopathology
• Leukocytes, Mononuclear/metabolism
• Leukocytes, Mononuclear/pathology
• Lung/metabolism
• Lung/physiopathology
• Male
• Middle Aged
• Transcriptome

• P50 HL084946 NHLBI NIH HHS

• diagnosis
• pulmonary hypertension
• systemic sclerosis
• therapy

• Anticoagulants/therapeutic use
• Antihypertensive Agents/therapeutic use
• Autoantibodies/blood
• Autoimmunity
• Familial Primary Pulmonary Hypertension
• Genetic Predisposition to Disease
• Humans
• Hypertension, Pulmonary/diagnosis
• Hypertension, Pulmonary/epidemiology
• Hypertension, Pulmonary/etiology
• Hypertension, Pulmonary/physiopathology
• Hypertension, Pulmonary/therapy
• Lung Transplantation
• Predictive Value of Tests
• Risk Assessment
• Risk Factors
• Scleroderma, Systemic/complications
• Scleroderma, Systemic/diagnosis
• Scleroderma, Systemic/epidemiology
• Scleroderma, Systemic/therapy
• Treatment Outcome

• K23 HL092287 NHLBI NIH HHS
• P50 HL084946 NHLBI NIH HHS
• P50 HL084946-04 NHLBI NIH HHS

• connective tissue disease
• pulmonary arterial hypertension
• pulmonary hypertension
• systemic sclerosis

• R01 HL062000 NHLBI NIH HHS
• R01 HL062000-07S1 NHLBI NIH HHS
• R01 HL077421 NHLBI NIH HHS
• R01 HL077421-04S1 NHLBI NIH HHS