Fatty acid metabolism promotes TRPV4 activity in lung microvascular endothelial cells in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a morbid disease characterized by significant lung endothelial cell (EC) dysfunction. Prior work has shown that microvascular endothelial cells (MVECs) isolated from animals with experimental PAH and patients with PAH exhibit significant abnormalities in metabolism and calcium signaling. With regards to metabolism, we and others have shown evidence of increased aerobic glycolysis and evidence of increased utilization of alternate fuel sources (such as fatty acids) in PAH EC. In the realm of calcium signaling, our prior work linked increased activity of the transient receptor potential vanilloid-4 (TRPV4) channel to increased proliferation of MVECs isolated from the Sugen/Hypoxia rat model of PAH (SuHx-MVECs). However, the relationship between metabolic shifts and calcium abnormalities was not clear. Specifically, whether shifts in metabolism were responsible for increasing TRPV4 channel activity in SuHx-MVECs was not known. In this study, using human data, serum samples from SuHx rats, and SuHx-MVECs, we describe the consequences of increased MVEC fatty acid oxidation in PAH. In human samples, we observed an increase in long-chain fatty acid levels that was associated with PAH severity. Next, using SuHx rats and SuHx-MVECs, we observed increased intracellular levels of lipids. We also show that increasing intracellular lipid content increases TRPV4 activity, whereas inhibiting fatty acid oxidation normalizes basal calcium levels in SuHx-MVECs. By exploring the fate of fatty acid-derived carbons, we observed that the metabolite linking increased intracellular lipids to TRPV4 activity was ß-hydroxybutyrate (BOHB), a product of fatty acid oxidation. Finally, we show that BOHB supplementation alone is sufficient to sensitize the TRPV4 channel in rat and mouse MVECs. Returning to humans, we observe a transpulmonary BOHB gradient in human patients with PAH. Thus, we establish a link between fatty acid oxidation, BOHB production, and TRPV4 activity in MVECs in PAH. These data provide new insight into metabolic regulation of calcium signaling in lung MVECs in PAH.NEW & NOTEWORTHY In this paper, we explore the link between metabolism and intracellular calcium levels in microvascular endothelial cells (MVECs) in pulmonary arterial hypertension (PAH). We show that fatty acid oxidation promotes sensitivity of the transient receptor potential vanilloid-4 (TRPV4) calcium channel in MVECs isolated from a rodent model of PAH.

Severe Pulmonary Arterial Hypertension in Healthy Young Infants: Single Center Experience.

OBJECTIVE: We studied the clinical presentation and management of acute pulmonary arterial hypertension (PAH) in healthy young infants, and the effect of thiamine therapy. METHODS: Review of hospital records was conducted for 56 healthy infants (aged below 6 month) who developed sudden onset of pulmonary arterial hypertension as diagnosed on 2D echocardiography, and were admitted at our institution. RESULTS: All patients received supportive care and pulmonary vasodilator therapy, whereas those admitted after Sep-tember, 2019 (n=28) received thiamine in addition, as per the institute's protocol. Overall, complete recovery was seen in 80% (n=45). Infants who died had significantly lower mean pH (7.05 vs 7.27; P=0.001) and serum bicarbonate (9.1 vs 14.9; P=0.007), higher arterial lactate (72.7 vs 61.5; P=0.92), ventricular dysfunction (16 vs 10; P=0.01) and shock (7 vs 9; P=0.008) when compared to those who survived. Baseline characteristics, severity of acidosis and pulmonary hypertension, time taken to recover from PAH, presence of ventricular dysfunction were comparable among those who received thiamine and those who did not receive it. Similarly, recovery (89% vs 71%; P=0.17) and mortality (11% vs 29%) were also comparable between the two groups. CONCLUSIONS: A significant proportion of infants with PAH improve with supportive treatment and pulmonary vasodilator therapy. Thiamine supplementation may not give any additional benefit in these patients.

Scurvy-induced pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature that results in precapillary pulmonary hypertension. PAH is caused by a group of clinical conditions involving multiple organ systems. Several cases have been reported in the literature demonstrating an association between vitamin C deficiency and PAH. Low endothelial nitric oxide levels in the pulmonary vasculature, combined with the inappropriate activation of hypoxia-inducible transcription factors, seen in patients with ascorbic acid deficiency, are believed to be the main contributors to the pathogenesis of pulmonary vasculopathy and the exaggerated pulmonary vasoconstrictive response seen in patients with scurvy-induced PAH. Vitamin C supplementation is considered the definitive treatment.

Intracellular Chloride Channels Regulate Endothelial Metabolic Reprogramming in Pulmonary Arterial Hypertension.

Mitochondrial fission and a metabolic switch from oxidative phosphorylation to glycolysis are key features of vascular pathology in pulmonary arterial hypertension (PAH) and are associated with exuberant endothelial proliferation and apoptosis. The underlying mechanisms are poorly understood. We describe the contribution of two intracellular chloride channel proteins, CLIC1 and CLIC4, both highly expressed in PAH and cancer, to mitochondrial dysfunction and energy metabolism in PAH endothelium. Pathological overexpression of CLIC proteins induces mitochondrial fragmentation, inhibits mitochondrial cristae formation, and induces metabolic shift toward glycolysis in human pulmonary artery endothelial cells, consistent with changes observed in patient-derived cells. Interactions of CLIC proteins with structural components of the inner mitochondrial membrane offer mechanistic insights. Endothelial CLIC4 excision and mitofusin 2 supplementation have protective effects in human PAH cells and preclinical PAH. This study is the first to demonstrate the key role of endothelial intracellular chloride channels in the regulation of mitochondrial structure, biogenesis, and metabolic reprogramming in expression of the PAH phenotype.

Potential of the TRPM7 channel as a novel therapeutic target for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is an intractable vascular disease characterized by a progressive increase in pulmonary vascular resistance caused by pulmonary vascular remodeling, which ultimately leads to right-sided heart failure. PAH remains incurable, despite the development of PAH-targeted therapeutics centered on pulmonary artery relaxants. It is necessary to identify the target molecules that contribute to pulmonary artery remodeling. Transient receptor potential (TRP) channels have been suggested to modulate pulmonary artery remodeling. Our study focused on the transient receptor potential ion channel subfamily M, member 7, or the TRPM7 channel, which modulates endothelial-to-mesenchymal transition and smooth muscle proliferation in the pulmonary artery. In this review, we summarize the role and expression profile of TRPM7 channels in PAH progression and discuss TRPM7 channels as possible therapeutic targets. In addition, we discuss the therapeutic effect of a Chinese herbal medicine, Ophiocordyceps sinensis (OCS), on PAH progression, which partly involves TRPM7 inhibition.

Supplementation with Iron in Pulmonary Arterial Hypertension. Two Randomized Crossover Trials.

Rationale: Iron deficiency, in the absence of anemia, is common in patients with idiopathic and heritable pulmonary arterial hypertension (PAH) and is associated with a worse clinical outcome. Oral iron absorption may be impeded by elevated circulating hepcidin concentrations. The safety and benefit of parenteral iron replacement in this patient population is unclear. Objectives: To evaluate the safety and efficacy of parenteral iron replacement in PAH. Methods: In two randomized, double-blind, placebo-controlled 12-week crossover studies, 39 patients in Europe received a single infusion of ferric carboxymaltose (Ferinject) (1,000 mg or 15 mg/kg if weight <66.7 kg) or saline as placebo, and 17 patients in China received iron dextran (Cosmofer) (20 mg iron/kg body weight) or saline placebo. All patients had idiopathic or heritable PAH and iron deficiency at entry as defined by a serum ferritin <37 µg/L or iron <10.3 µmol/L or transferrin saturations <16.4%. Results: Both iron treatments were well tolerated and improved iron status. Analyzed separately and combined, there was no effect on any measure of exercise capacity (using cardiopulmonary exercise testing or 6-minute walk test) or cardiopulmonary hemodynamics, as assessed by right heart catheterization, cardiac magnetic resonance, or plasma NT-proBNP (N-terminal-pro hormone brain natriuretic peptide) at 12 weeks. Conclusions: Iron repletion by administration of a slow-release iron preparation as a single infusion to patients with PAH with iron deficiency without overt anemia was well tolerated but provided no significant clinical benefit at 12 weeks. Clinical trial registered with ClinicalTrials.gov (NCT01447628).

A machine learning cardiac magnetic resonance approach to extract disease features and automate pulmonary arterial hypertension diagnosis.

AIMS: Pulmonary arterial hypertension (PAH) is a progressive condition with high mortality. Quantitative cardiovascular magnetic resonance (CMR) imaging metrics in PAH target individual cardiac structures and have diagnostic and prognostic utility but are challenging to acquire. The primary aim of this study was to develop and test a tensor-based machine learning approach to holistically identify diagnostic features in PAH using CMR, and secondarily, visualize and interpret key discriminative features associated with PAH. METHODS AND RESULTS: Consecutive treatment naive patients with PAH or no evidence of pulmonary hypertension (PH), undergoing CMR and right heart catheterization within 48 h, were identified from the ASPIRE registry. A tensor-based machine learning approach, multilinear subspace learning, was developed and the diagnostic accuracy of this approach was compared with standard CMR measurements. Two hundred and twenty patients were identified: 150 with PAH and 70 with no PH. The diagnostic accuracy of the approach was high as assessed by area under the curve at receiver operating characteristic analysis (P < 0.001): 0.92 for PAH, slightly higher than standard CMR metrics. Moreover, establishing the diagnosis using the approach was less time-consuming, being achieved within 10 s. Learnt features were visualized in feature maps with correspondence to cardiac phases, confirming known and also identifying potentially new diagnostic features in PAH. CONCLUSION: A tensor-based machine learning approach has been developed and applied to CMR. High diagnostic accuracy has been shown for PAH diagnosis and new learnt features were visualized with diagnostic potential.

Electrical Stimulation-Guided Approach to Pulmonary Artery Catheter Ablation in Patients with Idiopathic Pulmonary Arterial Hypertension: A Pilot Feasibility Study with a 12-Month Follow-Up.

BACKGROUND: Recently, transcatheter pulmonary artery (PA) ablation aiming at sympathetic denervation has been proposed in pulmonary arterial hypertension (PAH). This pilot feasibility study aimed to assess the feasibility of selective radiofrequency PA ablation based on response to high-frequency stimulation mapping. METHODS: The study comprised 3 female patients with idiopathic PAH (IPAH). The following reactions to PA stimulation were noted and marked by color points on the three-dimensional map: sinus bradycardia (heart rate decrease ≥15%), tachycardia (heart rate increase ≥15%), phrenic nerve capture, and cough. Since the most appropriate ablation strategy was unknown, two approaches were suggested, according to stimulation results: ablation at points with any heart rate response (either bradycardia or tachycardia)-this approach was applied in patient #1 (IPAH long-term responder to calcium channel blockers); segmental ablation at points with no response and with tachycardia response (one IPAH long-term responder to calcium channel blockers patient and one-IPAH with negative vasoreactive testing). Hemodynamic measurements were performed before and after denervation. Follow-up visits were scheduled at 6 and 12 months. RESULTS: Six-months follow-up was uneventful for patients #1 and 3; patient #2 had one syncope and reduced 6-minute walk test distance and peak VO2 consumption. At 12 months, there was a normalization of mean PA pressure and pulmonary vascular resistance (PVR) in patient #1. Patient #2 had no change in PA pressure and PVR at 12 months. Patient #3 remained in II functional class; however, there was an increase in mean PA pressure and loss of vasoreactivity. CONCLUSIONS: Electrical high-frequency stimulation of the PA identifies several types of evoked reactions: heart rate slowing, acceleration, phrenic nerve capture, and cough. The improvement in clinical and hemodynamic parameters following targeted PA ablation in the IPAH patient with positive vasoreactive testing should be confirmed in larger studies.

[Evolution of pathogenetic therapy of pulmonary arterial hypertension].

Pulmonary arterial hypertension (PAH) is a severe, disabling disease characterized by an increase pressure in the pulmonary artery (PA), an increase pressure in the right atrium, and a decrease of the cardiac output. It combines several diseases: idiopathic pulmonary hypertension, inherited pulmonary hypertension, PAH induced by medication and toxins, PAH associated with systemic diseases of connective tissue, HIV infection, portal hypertension, congenital heart defects, schistosomiasis. In the absence of treatment, PAH quickly leads to insufficiency of the right heart and premature death. An effective PAH therapy did not exist for a long time. However, in 1987 there was established a positive effect of taking large doses of calcium channel blockers in patients, who "responded" to their prescription in the short term, and in recently several groups of specific drugs have been developed and approved for the treatment of this pathology: prostacyclin analogues and prostacyclin receptors agonists, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors and soluble guanylate cyclase stimulators. Modern studies of treatment of PAH are based on the latest data of the molecular transmission mechanisms of intracellular and intercellular signals, the action of hormones and tissue enzymes. The available results of these studies allow to suggest the inclusion to clinical guidelines several new drugs for the pathogenetic treatment of PAH in the near future: receptor tyrosine kinase inhibitors, Rho - kinase inhibitors, immunosuppressants and type 2 activin receptor agonists, protein kinase C inhibitors, aromatase inhibitors and estrogen receptor antagonists, poly-(ADP-ribose)-polymerase inhibitors and bromodomain protein 4, elastase inhibitors. Some of the drugs have already passed the III phase of clinical trials (imatinib), others are at the preclinical stage or at the I-II phase tests (olaparib, enzastaurin, elafin).

Plasma proteome analysis in patients with pulmonary arterial hypertension: an observational cohort study.

BACKGROUND: Idiopathic and heritable pulmonary arterial hypertension form a rare but molecularly heterogeneous disease group. We aimed to measure and validate differences in plasma concentrations of proteins that are associated with survival in patients with idiopathic or heritable pulmonary arterial hypertension to improve risk stratification. METHODS: In this observational cohort study, we enrolled patients with idiopathic or heritable pulmonary arterial hypertension from London (UK; cohorts 1 and 2), Giessen (Germany; cohort 3), and Paris (France; cohort 4). Blood samples were collected at routine clinical appointment visits, clinical data were collected within 30 days of blood sampling, and biochemical data were collected within 7 days of blood sampling. We used an aptamer-based assay of 1129 plasma proteins, and patient clinical details were concealed to the technicians. We identified a panel of prognostic proteins, confirmed with alternative targeted assays, which we evaluated against the established prognostic risk equation for pulmonary arterial hypertension derived from the REVEAL registry. All-cause mortality was the primary endpoint. FINDINGS: 20 proteins differentiated survivors and non-survivors in 143 consecutive patients with idiopathic or heritable pulmonary arterial hypertension with 2 years' follow-up (cohort 1) and in a further 75 patients with 2·5 years' follow-up (cohort 2). Nine proteins were both prognostic independent of plasma NT-proBNP concentrations and confirmed by targeted assays. The functions of these proteins relate to myocardial stress, inflammation, pulmonary vascular cellular dysfunction and structural dysregulation, iron status, and coagulation. A cutoff-based score using the panel of nine proteins provided prognostic information independent of the REVEAL equation, improving the C statistic from area under the curve 0·83 (for REVEAL risk score, 95% CI 0·77-0·89; p<0·0001) to 0·91 (for panel and REVEAL 0·87-0·96; p<0·0001) and improving reclassification indices without detriment to calibration. Poor survival was preceded by an adverse change in panel score in paired samples from 43 incident patients with pulmonary arterial hypertension in cohort 3 (p=0·0133). The protein panel was validated in 93 patients with idiopathic or heritable pulmonary arterial hypertension in cohort 4, with 4·4 years' follow-up and improved risk estimates, providing complementary information to the clinical risk equation. INTERPRETATION: A combination of nine circulating proteins identifies patients with pulmonary arterial hypertension with a high risk of mortality, independent of existing clinical assessments, and might have a use in clinical management and the evaluation of new therapies. FUNDING: National Institute for Health Research, Wellcome Trust, British Heart Foundation, Assistance Publique-Hôpitaux de Paris, Inserm, Université Paris-Sud, and Agence Nationale de la Recherche.

Effect of calcium channel blockers evaluated by cardiopulmonary exercise testing in idiopathic pulmonary arterial hypertension responding to acute pulmonary vasoreactivity testing.

BACKGROUND: The baseline exercise capacity evaluated by cardiopulmonary exercise testing (CPET) and the change after administration of calcium channel blockers (CCB) therapy in patients with vasodilator-responsive idiopathic pulmonary arterial hypertension (VR-IPAH)are unknown. METHODS: 25 patients with newly diagnosed VR-IPAH from 1 January 2012 to 16 November 2015 were prospectively enrolled, and 28 age, sex and pulmonary vascular resistance matched newly diagnosed patients with vasodilator-nonresponsive idiopathic pulmonary arterial hypertension (VNR-IPAH) were enrolled. CPET was performed before and after 3.5 ± 0.8 months of CCB or sildenafil therapy. RESULTS: Ventilatory efficiency at rest, anaerobic threshold (AT), and peak were significantly higher (lower in V˙E/V˙CO2@AT and higher in PETCO2@AT) in VR-IPAH group than that in VNR-IPAH group. Peak V˙O2 (13.9 ± 2.9 mL kg-1·min-1 vs 16.4 ± 4.1 mL kg-1·min-1, p = 0.001), peak O2 pulse (5.5 ± 0.8 mL min-1·beat-1 vs 6.9 ± 1.3 mL min-1·beat-1, p = 0.001), V˙E/V˙CO2@AT (34.2 ± 5.0 vs 31.6 ± 3.1, p = 0.02) and PETCO2@AT (33.1 ± 4.0 mmHg vs 35.3 ± 3.2 mmHg, p = 0.02) were significantly improved after high dose of CCB therapy, along with improvement of WHO functional class, 6-min walking distance, NT-proBNP and tricuspid regurgitation pressure gradient. CONCLUSIONS: Ventilatory efficiency in patients with VR-IPAH is better than that in patients with VNR-IPAH. CCB can improve aerobic capacity and ventilatory efficiency during exercise in patients with VR-IPAH. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov:NCT02061787.

Evaluación de efectividad y seguridad comparativas del sildenafilo para el tratamiento de pacientes con hipertensión arterial pulmonar / Comparative effectiveness and safety assessment of sildenafil for the treatment of patients with pulmonary arterial hypertension

Introducción: la hipertensión arterial pulmonar es una enfermedad grave y progresiva. Si la enfermedad no es tratada, la sobrecarga de presión del ventrículo derecho lleva a dilatación, hipertrofia, falla cardíaca en estado final entre dos a tres años y a muerte. El sildenafilo, un inhibidor de la Fosfodiesterasa tipo 5, es una alternativa para su tratamiento actualmente en uso clínico. Esta evaluación de tecnología se desarrolló para informar la toma de decisiones en el marco de la actualización integral del Plan Obligatorio de Salud para Colombia. Objetivo: examinar la efectividad y seguridad comparativas del sildenafilo para el tratamiento de pacientes con hipertensión arterial pulmonar. Metodología: se realizó una búsqueda sistemática en MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects y LILACS. La tamización de referencias se realizó por dos revisores de forma independiente y la selección de estudios fue hecha por un revisor, aplicando los criterios de elegibilidad predefinidos en el protocolo de la evaluación. La calidad de las revisiones sistemáticas se valoró con la herramienta AMSTAR. Se realizó una síntesis narrativa de las estimaciones del efecto para las comparaciones y desenlaces de interés. Resultados: los hallazgos de efectividad y seguridad de la presente evaluación se basan en cuatro revisiones sistemáticas, dos de calidad alta y dos de calidad media, y cuatro ensayos controlados aleatorizados cabeza a cabeza, en general de buena calidad, para un total aproximado de 658 pacientes. Se identificó evidencia de los efectos del sildenafilo en monoterapia comparado con bosentán, y en terapia combinada más bosentán o epoprostenol, para una variedad de desenlaces incluyendo el tiempo al primer evento de morbilidad/mortalidad, capacidad de ejercicio, mortalidad, hospitalización, cambio en la clase funcional (OMS), empeoramiento de la hipertensión, trasplante de pulmón, disnea, parámetros hemodinámicos, calidad de vida, eventos adversos globales, serios y específicos. La evidencia disponible corresponde a adultos con hipertensión arterial pulmonar, de clase funcional (OMS) I, II, III y IV. También se presentan los eventos adversos reportados en la etapa post-clínica con el uso del sildenafilo. Conclusiones: la evidencia identificada en esta evaluación de tecnología, muestra efectos mixtos en la efectividad y seguridad del sildenafilo para el tratamiento de adultos con hipertensión arterial pulmonar: en cuanto a la monoterapia con sildenafilo, los resultados de efectividad demuestran que este medicamento es similar a sus comparadores; respecto a su seguridad, hay incertidumbre. En terapia combinada, algunos hallazgos de efectividad muestran superioridad del sildenafilo frente a sus comparadores, otros datos indican que esta tecnología es similar respecto a sus alternativas y para algunos desenlaces existe incertidumbre. La seguridad comparada del sildenafilo en terapia combinada puede ser mayor, similar, menor o incierta. A juicio de los expertos clínicos y representantes de los pacientes, el sildenafilo en monoterapia y en terapia combinada, tiene una relación favorable entre los beneficios y riesgos, esto sugiere que los efectos deseables con el uso de esta tecnología superan a los efectos indeseables.(AU)

Isorhynchophylline protects against pulmonary arterial hypertension and suppresses PASMCs proliferation.

Increased pulmonary arterial smooth muscle cells (PASMCs) proliferation is a key pathophysiological component of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). Isorhynchophylline (IRN) is a tetracyclic oxindole alkaloid isolated from the Chinese herbal medicine Uncaria rhynchophylla. It has long been used clinically for treatment of cardiovascular and cerebrovascular diseases. However, very little is known about whether IRN can influence the development of PAH. Here we examined the effect of IRN on monocrotaline (MCT) induced PAH in rats. Our data demonstrated that IRN prevented MCT induced PAH in rats, as assessed by right ventricular (RV) pressure, the weight ratio of RV to (left ventricular+septum) and RV hypertrophy. IRN significantly attenuated the percentage of fully muscularized small arterioles, the medial wall thickness, and the expression of smooth muscle α-actin (α-SMA) and proliferating cell nuclear antigen (PCNA). In vitro studies, IRN concentration-dependently inhibited the platelet-derived growth factor (PDGF)-BB-induced proliferation of PASMCs. Fluorescence-activated cell-sorting analysis showed that IRN caused G0/G1 phase cell cycle arrest. IRN-induced growth inhibition was associated with downregulation of Cyclin D1 and CDK6 as well as an increase in p27Kip1 levels in PDGF-BB-stimulated PASMCs. Moreover, IRN negatively modulated PDGF-BB-induced phosphorylation of PDGF-Rß, ERK1/2, Akt/GSK3ß, and signal transducers and activators of transcription 3 (STAT3). These results demonstrate that IRN could inhibit PASMCs proliferation and attenuate pulmonary vascular remodeling after MCT induction. These beneficial effects were at least through the inhibition of PDGF-Rß phosphorylation and its downstream signaling pathways. Therefore, IRN might be a potential candidate for the treatment of PAH.

The combination of exercise and respiratory training improves respiratory muscle function in pulmonary hypertension.

PURPOSE: Increased dyspnea and reduced exercise capacity in pulmonary arterial hypertension (PAH) can be partly attributed to impaired respiratory muscle function. This prospective study was designed to assess the impact of exercise and respiratory training on respiratory muscle strength and 6-min walking distance (6MWD) in PAH patients. METHODS: Patients with invasively confirmed PAH underwent 3 weeks of in-hospital exercise and respiratory training, which was continued at home for another 12 weeks. Medication remained constant during the study period. Blinded observers assessed efficacy parameters at baseline (I) and after 3 (II) and 15 weeks (III). Respiratory muscle function was assessed by twitch mouth pressure (TwPmo) during nonvolitional supramaximal magnetic phrenic nerve stimulation. RESULTS: Seven PAH patients (4 women; mean pulmonary artery pressure 45 ± 11 mmHg, median WHO functional class 3.1 ± 0.4, idiopathic/associated PAH n = 5/2) were included. The training program was feasible and well tolerated by all patients with excellent compliance. TwPmo was I: 0.86 ± 0.37 kPa, II: 1.04 ± 0.29 kPa, and III: 1.27 ± 0.44 kPa, respectively. 6MWD was I: 417 ± 51 m, II: 509 ± 39 m, and III: 498 ± 39 m, respectively. Both TwPmo (+0.41 ± 0.34 kPa, +56 ± 39 %) and 6MWD (+81 ± 30 m, +20 ± 9 %) increased significantly in the period between baseline and the final assessment (pairwise comparison: p = 0.012/<0.001; RM-ANOVA considering I, II, III: p = 0.037/<0.001). CONCLUSIONS: Exercise and respiratory training as an adjunct to medical therapy may be effective in patients with PAH to improve respiratory muscle strength and exercise capacity. Future, randomized, controlled trials should be carried out to further investigate these findings.

Exploring quality of life in Italian patients with rare disease: a computer-aided content analysis of illness stories.

The present study used a narrative-based approach to identify common themes that characterized the illness experience and quality of life of patients affected by rare disease (RD). Textual data were comprised of illness stories written by 32 adult Italian patients (eight men and 24 women), with the following RD diagnoses: amyotrophic lateral sclerosis (n = 12), anorectal atresia (n = 4), Poland syndrome (n = 4), and idiopathic pulmonary hypertension (n = 12). Computer-aided content analysis was performed to detect the main themes (cluster analysis) and latent factors (correspondence analysis) emerging in patients' narratives, and to test their association with gender and diagnosis. Four thematic domains were detected in the textual corpus, which are respectively referred to as: hopelessness (12.74%), need for autonomy (38.43%), search for normalcy (11.89%), and expectations of recovery (36.94%). Three latent factors explained the overall data variance: the relationship with social and medical healthcare providers (F1), adjustment processes to disease and social limitations (F2), and self-beliefs and coping (F3). Some differences were revealed with respect to patient gender and diagnosis. Illness stories highlight the significant relationship of RD patients with healthcare services and their need for a holistic approach because of the lack of effective treatment. Physical limitation and emotional distress do not necessarily seem to overlap for adjustment and quality of life (QoL). Overall, the perception of illness chronicity is likely to affect patients' self-beliefs and coping with more than their feeling of abnormalcy, that is the less salient theme.

Standard nonspecific therapies in the management of pulmonary arterial hypertension.

Recent advances in pulmonary arterial hypertension (PAH) research have created a new era of PAH-specific therapies. Although these therapeutics have revolutionized PAH therapy, their innovation was predated by supportive but nonspecific medical therapies adapted from their use in more common cardiopulmonary diseases. These therapies include oxygen therapy, diuretics, digoxin, anticoagulation, and high-dose calcium channel blockers. Expert opinion continues to support the use of adjunct therapies based on current pathologic understandings of PAH combined with some evidence extrapolated from small studies. This article discusses why these therapies continue to play an important role in the treatment of patients with PAH.

Calcium-channel blockers in pulmonary arterial hypertension.

Voltage-activated calcium channels are a family of membrane proteins that provide the major influx pathway for calcium in many different types of cells. Calcium-channel blockers inhibit the calcium influx into vascular cells leading to relaxation of smooth muscle cells and vasodilatation. Vasoconstriction of small pulmonary arteries is recognized as a component of the pathogenesis of pulmonary arterial hypertension and treatment with calcium-channel blockers appears to be rational in this setting. No randomized controlled trial has been performed to demonstrate the beneficial effects of calcium-channel blockers in the treatment of patients with pulmonary arterial hypertension. However, uncontrolled studies have suggested that long-term administration of high-dose calcium antagonists dramatically improves survival in a small subset of patients who respond acutely to those drugs, compared with unresponsive patients. The initial response to an acute vasodilator test with inhaled nitric oxide or intravenous prostacyclin or adenosine accurately identifies patients with pulmonary arterial hypertension who are likely to respond to long-term treatment with calcium-channel blockers.

Role of curcumin in idiopathic pulmonary arterial hypertension treatment: a new therapeutic possibility.

The idiopathic pulmonary arterial hypertension is a complex disease that mainly affects pulmonary arterial circulation. This undergoes a remodeling with subsequent reduction of flow in the small pulmonary arteries. Because of this damage an increased vascular resistance gradually develops, and over time it carries out in heart failure. The inflammatory process is a key element in this condition, mediated by various cytokines. The inflammatory signal induces activation of NF-κB, and prompts TGF-ß-related signaling pathway. Clinical evolution leads to progressive debilitation, greatly affecting the patient quality of life. The actual therapeutic approaches, are few and expensive, and include systemic drugs such as prostanoids, phosphodiesterase inhibitors and antagonists of endothelin-1 (ERBs). Some researchers have long investigated the anti-inflammatory effects of curcumin. It shows a role for inactivation of NF-κB-mediated inflammation. On the basis of these findings we propose a potential role of curcumin and its pharmacologically fit derivatives for treatment of idiopathic pulmonary arterial hypertension.