Evidence Of Pulmonary Arterial Hypertension Research Articles

Echocardiographic Assessment of Pulmonary Arterial Hypertension Following Inhaled Nitric Oxide in Infants with Severe Bronchopulmonary Dysplasia

Objectives: Inhaled nitric oxide (iNO) is an effective pulmonary vasodilator. However, the efficacy of iNO in former premature infants with established bronchopulmonary dysplasia (BPD) has not been studied. This study aimed to determine the efficacy of iNO in reducing pulmonary artery pressure in infants with severe BPD as measured by echocardiography. Study Design: Prospective, observational study enrolling infants born at less than 32 weeks gestation and in whom (1) iNO therapy was initiated after admission to our institution, or (2) at the outside institution less than 48 h before transfer and received an echocardiogram prior to iNO initiation, and (3) had severe BPD. Data were collected at three time-points: (1) before iNO; (2) 12–48 h after initiation of iNO; and (3) 48–168 h after initiation of iNO. The primary outcome was the effect of iNO on pulmonary artery pressure measured by echocardiography in patients with severe BPD between 48 and 168 h after initiating iNO therapy. Results: Of 37 enrolled, 81% had echocardiographic evidence of pulmonary arterial hypertension (PAH) before iNO and 56% after 48 h of iNO (p = 0.04). FiO2 requirements were significantly different between time-points (1) and (3) (p = 0.05). There were no significant differences between Tricuspid Annular Plane Systolic Excursion (TAPSE) Z-Scores, time to peak velocity: right ventricular ejection time (TPV:RVET), and ventilator changes. Conclusions: Although we found a statistically significant reduction of PAH between time-point (1) and (3), future trials are needed to further guide clinical care.

Prevalence and Risk Factors of Pulmonary Arterial Hypertension in Interstitial Lung Diseases: A Cross-sectional Study

Introduction: Interstitial Lung Diseases (ILD) is associated with inflammatory and/or fibrotic changes in the lungs. Pulmonary Arterial Hypertension (PAH) is a complication of many end-stage lung diseases due to the re-modelling of pulmonary vasculature associated with hypoxia leading to pulmonary vascular resistance. The Association of PAH in ILD contributes significantly to high morbidity and mortality. ILD being a progressive disease it is difficult to predict when the PAH will set in. Aim: To assess the clinical and radiological profiles of patients with ILD and to associate these with the severity of PAH. Materials and Methods: The present cross-sectional study was conducted in the Department of Respiratory Medicine at GSL Medical College on 23 patients with ILD from 1st October 2019 to 31st august 2021, in GSL medical college and hospital, Andhra Pradesh. Each patient was subjected to chest X-ray (CXR), Electrocardiogram (ECG), and 2-Dimensional Echocardiogram (2D ECHO). Evidence of PAH in any one investigation was considered. In ECG reports evidence of right ventricular enlargement (R>S in V1/V2 and right axis deviation >110 degrees, R=11 mm) was considered as PAH. CXR showing dilatation of the pulmonary artery with an increased cardiothoracic ratio was considered as PAH. A 2-D ECHO was performed to estimate the right arterial pressure and evidence of pulmonary arterial systemic pressure of >40 mmHg was considered as PAH. All the data were statistically analysed by using IBM Statistical Package for Social Sciences (SPSS) version 20.0. Results: Fifty-two percent of the population constituted females, and the mean age of the whole population was 59.7±14.4 years and the majority of them (65%) belonged to upper lower socioeconomic class. Usual Interstitial Pneumonia (UIP) was the most common pattern observed accounting for 57%. Prevalence of PAH was 65% and a longer duration of symptoms, 57% of the population had grade 3 of Modified Medical Research Council (MMRC) and 52.17% covered less than 200 meters in the 6-Minute Walk Test (6MWT). Oxygen desaturation after 6MWT was observed to be the contributing factor for the development of severe pulmonary hypertension in ILD patients. Conclusion: Factors like delayed seeking of medical care, co-morbidity like hypertension, higher grades of dyspnoea at the time of presentation, shorter 6MWD, and post-walk oxygen saturation were found to be predictors of pulmonary artery hypertension in patients with ILD. Early recognition of these risk factors in patients with ILD and the prompt treatment of the disease can reduce the development of severe PAH.

Heterozygous premature termination in zinc-finger domain of Krüppel-like factor 2 gene associates with dysregulated immunity.

Krüppel-like factor 2 (KLF2) is a transcription factor with significant roles in development, maturation, differentiation, and proliferation of several cell types. In immune cells, KLF2 regulates maturation and trafficking of lymphocytes and monocytes. KLF2 participates in regulation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Although pulmonary arterial hypertension (PAH) related to KLF2 genetic variant has been suggested, genetic role of KLF2 associated with immune dysregulation has not been described. We identified a family whose members suffered from lymphopenia, autoimmunity, and malignancy. Whole exome sequencing revealed a KLF2 p.(Glu318Argfs*87) mutation disrupting the highly conserved zinc finger domain. We show a reduced amount of KLF2 protein, defective nuclear localization and altered protein-protein interactome. The phenotypically variable positive cases presented with B and T cell lymphopenia and abnormalities in B and T cell maturation including low naive T cell counts and low CD27+IgD-IgM- switched memory B cells. KLF2 target gene (CD62L) expression was affected. Although the percentage of (CD25+FOXP3+, CD25+CD127-) regulatory T cells (Treg) was high, the naive Treg cells (CD45RA+) were absent. Serum IgG1 levels were low and findings in one case were consistent with common variable immunodeficiency (CVID). Transcription of NF-κβ pathway genes and p65/RelA phosphorylation were not significantly affected. Inflammasome activity, transcription of genes related with JAK/STAT pathway and interferon signature were also comparable to controls. Evidence of PAH was not found. In conclusion, KLF2 variant may be associated with familial immune dysregulation. Although the KLF2 deficient family members in our study suffered from lymphopenia, autoimmunity or malignancy, additional study cohorts are required to confirm our observations.

COMMON VARIABLE IMMUNODEFICIENCY WITH GROUP 1 PULMONARY HYPERTENSION TREATED WITH INHALED PROSTACYCLINS

TOPIC: Pulmonary Vascular Disease TYPE: Fellow Case Reports INTRODUCTION: Common Variable Immunodeficiency (CVID) is a disorder that is occasionally complicated by a rare form of interstitial lung disease: granulomatous lymphocytic interstitial lung disease (GLILD). Progression of GLILD may result in Group 3 pulmonary hypertension (PH). Group 1 PH is rare in CVID. We present a patient with CVID with group 1 PH treated with inhaled prostacyclin. CASE PRESENTATION: A 39-year-old woman with medical history of CVID treated with long-term intravenous immunoglobulin (IVIg) therapy, immune mediated thrombocytopenia (ITP) and chronic respiratory failure on 2 liters of supplemental oxygen presented with acute right ventricular (RV) failure and for evaluation of heart and lung transplant. She had worsening dyspnea. She was treated for pneumonia with sepsis. Computed Tomography Angiography (CTA) chest showed pulmonary artery dilation, septal thickening, bilateral reticulation and mild bilateral lower lobe traction bronchiectasis, with scattered pulmonary nodules. This was suggestive of GLILD. Echocardiogram showed a left ventricular ejection fraction of 60%, pulmonary arterial pressure of 78 mmHg, with trivial pericardial effusion and severe RV dysfunction. Right heart catheterization demonstrated, in mmHg, right atrial pressure of 2, mean pulmonary arterial pressure of 42, pulmonary capillary wedge pressure of 2, cardiac output and index of 2.83 and 1.71 respectively with pulmonary vascular resistance of 14 wood units, consistent with severe PAH. Pulmonary function tests showed severe restrictive disease. The degree of PVR elevation was higher than what was expected in the setting of diffuse parenchymal lung disease, suggesting a vasculopathic component beyond that attributable to group 3 disease. There was concern of potentially worsening ventilation perfusion (VQ) mismatch if treated with pulmonary vasodilators. The patient was deemed a poor transplant candidate due to ITP and was started on inhaled Treprostinil, and discharged home on tapering dose of steroids and supplemental oxygen. She was seen in PH clinic where she is was showing improved New York Heart Association functional class and was tolerating inhaled treprostinil with no worsening in hypoxia. DISCUSSION: CVID is a severe immunodeficiency that is caused by failure of antibody production. GLILD is the usual primary pulmonary parenchymal disease associated with CVID. Progression of GLILD can be further complicated by the development of PH which is usually classified as Group 3. Until recently, these patients did poorly. CONCLUSIONS: Group 3 PH is not treated with pulmonary vasodilator therapy. Our patient did well on inhaled prostacyclin, in the setting of parenchymal lung disease. This is attributed to a pulmonary vascular phenotype, similar to those with PAH. Treatment of Group 1 PH in this setting with inhaled prostacyclin could represent a novel frontier in the treatment of pulmonary vascular phenotype. REFERENCE #1: Huston J, Johnson J, Hemnes A, Pugh M. Evidence of pulmonary arterial hypertension in two patients with common variable immunodeficiency. Pulm Circ. 2020 May 1;10(2):2045894020922792. doi: 10.1177/2045894020922792. PMID: 32426112; PMCID: PMC7218961. REFERENCE #2: P501 Pulmonary hypertension rates in common variable immunodeficiency J. Farmer M, Ong S, Barmettler, J. WalterDOI:https://doi.org/10.1016/j.anai.2017.09.067 REFERENCE #3: Pulmonary hypertension in interstitial lung diseaseJ. Behr, J. H. RyuEuropean Respiratory Journal Jun 2008, 31 (6) 1357-1367; DOI: 10.1183/09031936.00171307 DISCLOSURES: No relevant relationships by ALAA ABU SAYF, source=Web Response No relevant relationships by Sara Hegab, source=Web Response Speaker/Speaker's Bureau relationship with Bayer Please note: 11/20/20-4/2021 Added 04/29/2021 by Reem Ismail, source=Web Response, value=Consulting fee No relevant relationships by Rajaninder Sharma, source=Web Response

Clinical characteristics and therapeutic outcomes of pulmonary arterial hypertension secondary to congenital portosystemic shunts.

The aim of this retrospective study was to investigate the clinical characteristics and therapeutic outcomes of pulmonary arterial hypertension (PAH) secondary to congenital portosystemic shunts (CPSS). Thirty-three pediatric patients diagnosed in our institution with CPSS between 2012 and 2019 were enrolled in this study. The patients were divided into PAH and non-PAH groups. The PAH group included 15 patients who presented with unexplained PAH when CPSS was diagnosed. Two patients with microangiopathic hemolytic anemia died of right heart failure shortly after diagnosis. One patient received a liver transplant at the age of 4.3 years and showed a mild decrease in pulmonary artery pressure (PAP) 4 years after the operation. Seven patients underwent one-stage shunt closure at a median age of 2.8 years (1.4-13 years). Follow-up examinations, from 1.6 to 4.1 years after intervention, showed marked reduction of PAP in one patient and stabilization of PAH in six others. However, in one patient who underwent two-stage shunt closure, a marked increase in PAP was noted after partial ligation of the shunt. The remaining four patients received only pulmonary vasodilator therapy, and one of them died of right heart failure 12 years after the PAH diagnosis. The non-PAH group included 18 patients without evidence of PAH upon CPSS diagnosis. Shunt closure was carried out in eight of these patients, but one patient subsequently developed PAH after the resolution of hepatopulmonary syndrome.Conclusion: CPSS may be a more likely cause of unexplained PAH in pediatric patients than previously thought. Shunt closure or liver transplantation may prevent the progression of PAH, or even improve it for the majority of CPSS patients.

P834 Pulmonary arterial hypertension in patients with direct-acting antiviral medications for hepatitis C virus infection - a prospective observational cohort study

Abstract Funding Acknowledgements Kantonsspital Olten, Switzerland Background In patients with chronic hepatitis C virus (HCV) infection, a higher risk for pulmonary artery hypertension (PAH) has been described after interferon (IFN) therapy. With the development of direct-acting antiviral (DAA) agents, vast improvements have been made in tolerance and less complications of HCV treatment. However, except of a few case reports, to date no clinical study about the evidence of PAH in patients with DAA medication for HCV infection has been published. We hypothesized that in patients, who receive DAA medication for HCV-infection, the systolic pulmonary artery pressure (sPAP) will not change significantly during and after competition of the therapy and there may be a lower post treatment risk for PAH within the population. Methods We prospectively enrolled patients who underwent treatment with DAA for chronic HCV infection. The patients received a transthoracic echocardiography (TTE) for the measurement of the pulmonary artery pressure before, during (8 weeks after starting the medication) and 8 weeks after completion of the HCV medication for evaluation of sPAP (figure 1). The whole treatment period took 8-12 weeks. Results Between June 2016 and October 2018, 33 patients completed the study protocol. In mean, the patient’s age was 50.1 ± 1.4 years and 30% of the population were female. Three patients (9 %) were HCV and human immunodeficiency virus (HIV) coinfected. The patients received different treatment regimens, according to hepatitis C genotype and co-medication. The left ventricular systolic and diastolic function were normal in all patients before treatment was started (left ventricular ejection fraction 60.7% [59.7 – 61.7%], E/A 1.18 [1.0 – 1.37]). The following table depicts the right ventricular parameter before the DAA therapy was started, 8 weeks after therapy start, and 8 weeks after therapy was completed. The analysis showed no significant difference between the sPAP in all three groups (25.9 ± 1.2 mmHg vs. 26.0 ± 1.3 mmHg vs.26.9 ± 1.1 mmHg, p-value 0.37, see figure). Conclusion DAA-therapy in chronic HCV infected patients is not associated with PAH in a follow-up of 2 months after the treatment was completed. Echocardiography Data Echocardiography data Before DAA medication was started 8 weeks after DAA-therapy 8 weeks after completion of DAA-therapy p-Value Right ventricular fractional area change (FAC), % 49.1 ± 1.4 51.7 ± 1.0 51.8 ± 1.1 0.09 Tricuspid Annular Plane Systolic Excursion (TAPSE), mm 25.2 ± 1.1 25.8 ± 0.7 24.3 ± 0.5 0.4 Right ventricular/right atrial gradient, mmHg 19.9 ± 1.0 20.5 ± 0.9 21.0 ± 0.8 0.24 Systolic pulmonary artery pressure (sPAP), mmHg 25.9 ± 1.2 26.0 ± 1.3 26.9 ± 1.1 0.37 Abstract P834 Figure. Multiple variable graph of sPAP

P235 A happy ending for a dancing thrombus on the right atrium

Abstract A 62-year-old male, was admitted in the emergency department with chest discomfort and dyspnea for the last 2 days; he also referred pain on the right leg. He had been submitted to prostatic surgery 1 month before and since then he reduced is usual physical activity. At admission he was normotensive, with sinus tachycardia, with elevated D-Dimers and hypoxemia and hypocapnia on arterial blood gas analysis. Transthoracic echocardiogram (TTE) was performed and it showed dilation of right ventricle with diastolic left ventricular "D-shape" compatible with right ventricle pressure overload. Furthermore, it was visible a large and filiform thrombus on the right atrium, causing procidency into the right ventricle through the tricuspid valve during diastole (image top-left and top-right). Patient was hemodynamically stable at that time, and the case was promptly discussed with cardiothoracic surgery. The decision was to adopt a conservative strategy, and non-fractioned heparin (NFH) perfusion was initiated accordingly to local protocol. Patient remained hemodynamically stable, and, after 24h of treatment with NFH echocardiographic re-evaluation showed disappearance of the thrombus previously seen of the right chambers (image bottom-left). Angio-TC scan of thorax performed at that time showed extensive bilateral pulmonary thromboembolism, but with normal perfusion of the pulmonary artery trunk and both right and left pulmonary arteries. After 48h of NFH the patient started oral anticoagulation. The rest of the admission was unremarkable apart from a respiratory tract infection successfully treated with piperacillin-tazobactam. Pre-discharge TTE performed 12 days after admission showed no dilation of the right ventricle, with normal systolic function (image bottom-right), as well as no evidence of pulmonary arterial hypertension. Discussion Large right atrial thrombus in the setting of PTE is a clinical situation in which there is no consensus regarding clinical management. In most cases, management is dictated by haemodynamic status of the patient. In the setting of a hemodynamically stable patient, systemic anticoagulation can be an option. Surgery, fibrinolysis and percutaneous aspiration have also been advocated. Successful treatment of right heart thrombus with anticoagulation alone has been reported, but there are also reports of unsuccess with that strategy. This is a case of a successful treatment with anticoagulation alone and so, we currently consider that the choice of treatment strategy based on hemodynamic status continues to be the wisest strategy to adopt. Abstract P235 Figure. Thrombus before and after

Transcatheter InterAtrial Shunt Device for the treatment of heart failure: Rationale and design of the pivotal randomized trial to REDUCE Elevated Left Atrial Pressure in Patients with Heart Failure II (REDUCE LAP-HF II)

A randomized, sham-controlled trial in patients with heart failure (HF) and left ventricular ejection fraction (LVEF) ≥40% demonstrated reductions in pulmonary capillary wedge pressure (PCWP) with a novel transcatheter InterAtrial Shunt Device (IASD). Whether this hemodynamic effect will translate to an improvement in cardiovascular outcomes and symptoms requires additional study. REDUCE Elevated Left Atrial Pressure in Patients with Heart Failure II (REDUCE LAP HF-II) is a multicenter, prospective, randomized, sham-controlled, blinded trial designed to evaluate the clinical efficacy of the IASD in symptomatic HF and elevated left atrial pressures. Up to 608 HF patients age ≥ 40 years with LVEF ≥40%, PCWP ≥25 mm Hg during supine ergometer exercise, and PCWP ≥5 mm Hg higher than right atrial pressure will be randomized 1:1 to the IASD versus sham control. Key exclusion criteria include hemodynamically significant valvular disease, evidence of pulmonary arterial hypertension, and right heart dysfunction. The primary endpoint is a hierarchical composite, analyzed by the Finkelstein-Schoenfeld methodology, that includes (1) cardiovascular mortality or first nonfatal ischemic stroke through 12 months; (2) total (first plus recurrent) HF hospitalizations or healthcare facility visits for intravenous diuretics up to 24 months, analyzed when the last randomized patient completes 12 months of follow-up; and (3) change in Kansas City Cardiomyopathy Questionnaire overall summary score from baseline to 12 months. Follow-up echocardiography will be performed at 6, 12, and 24 months to evaluate shunt flow and cardiac chamber size/function. Patients will be followed for a total of 5 years after the index procedure. REDUCE LAP-HF II is designed to evaluate the clinical efficacy of the IASD device in patients with symptomatic HF with elevated left atrial pressure and LVEF ≥40%.

P591Insights from Exercise Cardiac Magnetic Resonance Imaging (ExMR) With Cardiopulmonary Testing in HIV Patients

Abstract Background Cardiac magnetic resonance imaging in conjunction with exercise (exMR) and cardiopulmonary testing (CPET) to evaluate cardiopulmonary function has the potential of uncovering poorly understood mechanisms of dyspnea in patients that cannot be otherwise discerned with a single imaging modality. Purpose We prospectively evaluated the value of this technique in dyspneic patients with HIV without obvious cardiopulmonary etiologies to comprehensively assess mechanisms of dyspnea. Methods Thirty-six HIV patients with dyspnea without obvious cardiopulmonary causes [normal chest x-ray, normal resting LVEF and resting pulmonary artery (PA) pressures <40 mm Hg on echo] and exercise limitation [Modified Medical Research Council (MMRC) dyspnea scale >2] underwent testing using a novel combined exMR/CPET platform (Figure 1). Resting and exercise magnetic resonance imaging (MRI), including flow velocities across the pulmonary artery together with CPET was evaluated at pre and post peak stress. We analyzed the correlation between CPET and MRI pre and peak exercise variables. Results The mean age was 51 years; 60% were male; and mean absolute CD4 count was 718. Ventilator efficiency at peak exercise (Peak VO2) did not correlate with exMR parameters. Peak VE/VCO2 was negatively associated with peak LV and RV stroke volume (p values 0.002 & 0.005 respectively). There was a positive relationship between peak petCO2and LV cardiac output (p=0.02), peak exercise RV stroke volume (p=0.003), peak exercise LV stroke volume (p=0.02). Absolute CD4 count was positively correlated with post exercise pulmonary artery velocity (p=0.045). We found no correlation between absolute CD8 count and CMR and CPET exercise parameters. Figure 1. MRI-CPET setting Conclusion HIV patients appear to have an impairment of ventilatory efficiency, exemplified by the association of VE/VCO2and PetCO2 with exMR parameters in the context of normal RV/LV contractile reserve and no evidence of Pulmonary arterial hypertension. A combined CPET/exMRI platform may provide new insight into cardiopulmonary function and the factors influencing exercise tolerance in symptomatic HIV patients. Acknowledgement/Funding 7R01HL125060-03

Design of the exercise MRI evaluation of HIV-pulmonary arterial hypertension longitudinal determinants (EXALTED) trial.

Pulmonary arterial hypertension (PAH) is a potentially serious cause of dyspnea and exercise limitation in patients with HIV infection. In this trial, we propose using exercise MRI in conjunction with cardiopulmonary testing to delineate PAH from other causes of cardiovascular dysfunction, identify individuals with exercise-induced PAH who are at high risk of developing resting PAH, and provide longitudinal estimates of progression of PAH and right ventricular function. In this prospective observational study, HIV patients with dyspnea and exercise limitation in the absence of identifiable causes and those who meet the inclusion criteria will be enrolled based on resting pulmonary artery pressure (≤ or >40 mmHg) on a screening echocardiogram and exercise limitation on the Modified Medical Research Council dyspnea scale. Patients without evidence of resting PAH will be enrolled into both rest and exercise MRI and cardiopulmonary testing protocol, whereas patients with evidence of PAH on resting echocardiograms will undergo only resting cardiac MRI studies to evaluate right ventricular function and fibrosis. Both patient subgroups will be followed for 24 months to obtain longitudinal progression of the disease. In a sub-study, we will further analyze inflammatory variables that may predict these changes, thus allowing early identification of these patients. This trial will be the first study to provide an understanding of the mechanisms underpinning the functional deterioration of the right ventricle in patients with HIV and will impart insight into the immune mediators of PAH progression and right ventricular functional deterioration in patients with HIV-PAH.

Splenectomy‐Induced Diastolic Dysfunction With Normal Ejection Fraction

BackgroundUnderstudied and often disregarded, the spleen is perceived as redundant, non‐vital or even a vestigial organ. Conversely, epidemiological studies indicate splenectomy (or splenic injury) increase the prevalence of cardiovascular diseases and associated risk factors, suggesting the physiological function of the spleen is not yet realized. Recent investigations have examined the role of the spleen in experimental heart failure, however, the effect of long‐term splenectomy on cardiac function in healthy models remains to be determined. Thus, the aim of this study was to reconcile the observations made in the epidemiological studies by investigating cardiac function and morphology following splenectomy in healthy rodents.MethodsSplenectomized and sham male Wistar rats were assessed at 5, 9, and 18 weeks post‐surgery by echocardiography, invasive hemodynamics, cardiac histology, and thromboelastography. Serum IL‐10 was measured by ELISA and left ventricular free wall was used for the analysis of select molecular markers.ResultsSplenectomy caused progressive left ventricular diastolic dysfunction (i.e., increases in dP/dt min, Tauw, and LVEDP), with no evidence of cardiac decompensation or systolic dysfunction. Left ventricular remodeling (fibrosis, hypertrophy and decreases in capillary to myocyte cross sectional area) were associated with decreases in serum IL‐10 and ventricular BNP expression. Increases in blood coagulability following splenectomy are associated with increased risk of developing thromboembolic pulmonary hypertension. In our model however, we found no evidence of pulmonary arterial hypertension or lung remodeling despite a ~2‐fold increase in coagulability.ConclusionsSplenectomy in healthy rodents caused progressive diastolic dysfunction and significant cardiac remodeling (i.e., fibrosis, hypertrophy and decreased capillary density), demonstrating an underappreciated role of the spleen in cardiac homeostasis. Future studies need to characterize the mechanism(s) by which the spleen contributes to a healthy cardiovascular phenotype.Support or Funding InformationThis work was supported by the J.P. Bickell Foundation (to JA Simpson), the Natural Sciences and Engineering Research Council (to JA Simpson and KR Brunt), and the Ontario Veterinary College Pet Fund (to SL Blois). JA Simpson is a new investigator with the H&SF of Ontario.

Effects of Acute Intravenous Iloprost on Right Ventricular Hemodynamics in Rats with Chronic Pulmonary Hypertension

The inotropic effects of prostacyclins in chronic pulmonary arterial hypertension (PAH) are unclear and may be important in directing patient management in the acute setting. We sought to study the effects of an acute intravenous (IV) infusion of iloprost on right ventricular (RV) contractility in a rat model of chronic PAH. Rats were treated with monocrotaline, 60 mg/kg intraperitoneally, to induce PAH. Six weeks later, baseline hemodynamic assessment was performed with pressure-volume and Doppler flow measurements. In one group of animals, measurements were repeated 10-15 minutes after IV infusion of a fixed dose of iloprost (20 μg/kg). A separate group of rats underwent dose-response assessment. RV contractility and RV-pulmonary artery coupling were assessed by the end-systolic pressure-volume relationship (ESPVR) and end-systolic elastance/effective arterial elastance (Ees/Ea). RV cardiomyocytes were isolated, and intracellular cAMP (cyclic adenosine monophosphate) concentration was measured with a cAMP-specific enzyme immunoassay kit. Animals had evidence of PAH and RV hypertrophy. Right ventricle/(left ventricle + septum) weight was 0.40 ± 0.03. RV systolic pressure (RVSP) was 39.83 ± 1.62 mmHg. Administration of iloprost demonstrated an increase in the slope of the ESPVR from 0.29 ± 0.02 to 0.42 ± 0.05 (P < .05). Ees/Ea increased from 0.63 ± 0.07 to 0.82 ± 0.06 (P < .05). The RV contractility index (max dP/dt normalized for instantaneous pressure) increased from 94.11 to 114.5/s (P < .05), as did the RV ejection fraction, from 48.0% to 52.5% (P < .05). This study suggests a positive inotropic effect of iloprost on a rat model of chronic PAH.

Use of Sildenafil in Pulmonary Arterial Hypertension: Findings from a U.S. Healthcare Claims Database

Background: Pulmonary arterial hypertension (PAH) is a disease characterized by dyspnea, fatigue, chest pain and syncope. As there is no known cure for PAH, the goal of treatment is to control symptoms and slow disease progression. Sildenafil, a phosphodiesterase-5 inhibitor, has been indicated to improve exercise capacity in PAH in both the United States and the European Union since 2005; since 2009, it also has been indicated in the United States to delay clinical worsening. Patterns of sildenafil use in PAH patients have not been reported. Objectives: To describe patterns of treatment with sildenafil among commercially insured patients in the United States with PAH. Methods: Using a large U.S. healthcare claims database, we identified all patients with evidence of PAH (International Classification of Disease, 9th Revision, Clinical Modification [ICD-9-CM] diagnosis codes 416.0, 416.8) and receipt of sildenafil between January 1, 2005 and September 30, 2008. The date of each patient's earliest pharmacy claim for sildenafil was designated as his or her "index date"; patients with <6 months of data prior to this date were excluded. Post-index use of sildenafil was then examined in terms of the numbers of pharmacy claims and therapy-days, the medication possession ratio (MPR), and the incidence of therapy switching. Results: We identified a total of 855 PAH patients who began sildenafil therapy and met all other entry criteria. Mean (standard deviation [SD]) follow-up was 423.4 (313.0) days. Over this period, these patients averaged 7.1 (6.8) (median, 5) pharmacy dispensings for sildenafil, representing 273.4 (254.8) therapy-days (median, 180). Mean MPR was 71% (median, 83%). Fourteen percent of sildenafil patients switched to another agent during follow-up. Conclusions: In "real-world" clinical practice, many PAH patients beginning treatment with sildenafil remain on therapy for extended periods and are relatively compliant with treatment.

Clinical and autoantibody profile in systemic sclerosis: baseline characteristics from a West Malaysian cohort

To evaluate the clinical and antibody profile of systemic sclerosis (SSc) in a Malaysian cohort. Consecutive patients with SSc in University Malaya Medical Centre from March to November 2012 were included in this study. In addition to clinical characterization, all subjects underwent autoantibody testing using Euroline immunoblot assay. The association between clinical features and autoantibody profile was evaluated. There were 31, predominantly Chinese (45.2%), subjects. Limited cutaneous disease was the most common subtype (71%). Raynaud's phenomenon was the most commonly observed feature (83.9%). Nine (29%) had esophageal dysmotility symptoms and 23 (74.2%), including all patients with diffuse SSc, had symptoms of gastro-esophageal reflux disease (GERD). Restrictive pattern on pulmonary function test and evidence of lung fibrosis were seen in more than 70% of patients. Echocardiographic evidence of pulmonary arterial hypertension was seen in 58.1%. Telangiectasia, calcinosis, digital ulcers, digital pulp loss or pitting were seen more commonly in the diffuse subtype. The two most prevalent autoantibodies were anti-Scl-70 and anti-Ro-52. The presence of anti-Scl-70 was significantly associated with restrictive lung disease (P = 0.05). Anti-Ro-52 was associated with control subjects with other autoimmune diseases (P = 0.043). The presence of anti-PM-Scl-75 was associated with overlap syndrome (P = 0.032). Patients with anticentromere antibodies were more likely to have vasculitic rash (P = 0.012). In Malaysia, SSc most commonly affects the Chinese. Limited cutaneous is more common than diffuse subtype. Features of CREST (calcinosis, Reynaud disease, esophageal dysmotility, sclerodactyly, telangiectasia) are more commonly observed in the diffuse cutaneous subgroup. Anti-Scl-70 and anti-Ro-52 antibodies are promising biomarkers for pulmonary involvement in SSc.

Risk factors for thromboembolism and pulmonary artery hypertension following splenectomy in children with hereditary spherocytosis

The aim was to study risk-factors for vascular thrombosis and incidence of pulmonary artery hypertension (PAH) in splenectomized children with hereditary spherocytosis (HS) at a single center. Pre- and post-splenectomy hemoglobin and platelet counts were recorded. Post-splenectomy lipid-profile, fibrinogen, D-dimer, CRP and anti-coagulant-protein levels were compared to established controls. Echo-Doppler was performed for PAH. Twenty-six children with HS had undergone splenectomy; the mean age at surgery was 7.9 ± 3.7 years. Nineteen of the 26 were prospectively investigated at a median duration of 4.5 years (range: 4 months to 19 years) following splenectomy. Thrombocytosis was observed in 19 (73%), whereas no patient had erythrocytosis at the last follow-up visit. Total cholesterol, LDL-C, HDL-C, and triglyceride levels were not deranged (P ≥ 0.3). Mean CRP levels (males: 2.8 ± 0.5; females: 2.1 ± 0.5 mg/L) were significantly higher than described for normal children (P < 0.001). Six (23%) patients had a positive D-dimer assay. Protein S, anti-thrombin-III and fibrinogen were in range. A single patient had a borderline low protein C activity. Lupus anticoagulant and anti-cardiolipin antibody assays were negative. The mean tricuspid regurgitant jet velocity (TRJV) was 1.8 ± 0.55 meter per second (range: 0-2.4). None had a TRJV ≥2.5 meter per second to suggest PAH. There was no evidence of PAH, dyslipidemia, elevation of fibrinogen or a reduction in anti-coagulant proteins, at a median follow-up duration of 4.5 years following splenectomy in children with HS. However, elevated CRP level (42%), persistent thrombocytosis (73%) and elevated D-dimer levels (23%) were observed. These have been recognized as risk factors for cerebrovascular and coronary heart disease.

Systemic sclerosis patients with and without pulmonary arterial hypertension: a nailfold capillaroscopy study

Pulmonary arterial hypertension (PAH) is a complication of SSc due to increased vascular resistance, and abnormal vascularity is a well-known feature of the disease as shown by nailfold videocapillaroscopy (NVC). This study investigated for specific NVC changes in SSc patients with and without PAH to assess any useful difference. Twenty-four SSc patients, 12 with PAH and 12 without, entered the study. Evidence of PAH was defined as increased systolic pulmonary artery pressure (PAP) (≥35 mmHg), indirectly assessed by echocardiography and confirmed by right heart catheterization (mPAP > 25 mmHg). NVC was performed, and a semi-quantitative rating scale, a rating system for avascular areas and a specific NVC pattern evaluation, namely early, active and late, were used. An NVC score >1 was more frequently found in patients with PAH than those without, 11 cases (92%) vs 5 cases (42%) (P = 0.03); an avascular areas grade >1 was present in 10 (83%) and 2 (17%) cases, respectively (P = 0.003); and a more severe NC pattern (active/late) was described in 11 (92%) and 5 (42%) patients, respectively (P = 0.03). When we compared the mPAP with NVC parameters, we found significant correlations between mPAP values and the NVC score (P < 0.005) and with the avascular areas score (P < 0.001). Our results underline the relevance of early microvascular assessment in patients at risk of developing a severe complication such as PAH that can amplify the systemic microvascular impairment in SSc. More severe NVC abnormalities should lead to strict cardiopulmonary surveillance and a complete NVC study is indicated.

Changes in healthcare utilization and costs associated with sildenafil therapy for pulmonary arterial hypertension: a retrospective cohort study

BackgroundLittle is known concerning the degree to which initiation of sildenafil for pulmonary arterial hypertension (PAH) impacts patterns of healthcare utilization and costs.MethodsUsing a large US health insurance claims database, we identified all patients with evidence of PAH (ICD-9-CM diagnosis codes 416.0, 416.8) who received sildenafil between 1/1/2005 and 9/30/2008. Date of the first-noted prescription for sildenafil was designated the “index date,” and claims data were compiled for all study subjects for 6 months prior to their index date (“pretreatment”) and 6 months thereafter (“follow-up”); patients with incomplete data during either of these periods were excluded. Healthcare utilization and costs were then compared between pretreatment and follow-up for all study subjects.ResultsA total of 567 PAH patients were identified who began therapy with sildenafil and met all other study entry criteria. Mean (SD) age was 52 (10) years; 73% were women. Healthcare utilization was largely unchanged between pretreatment and follow-up, the only exceptions being decreases in the mean number of emergency department visits (from 0.7 to 0.5 per patient; p < 0.01) and the percentage of patients hospitalized (from 35% to 29%; p = 0.01). The mean cost of all PAH-related medication was $7139 during pretreatment and $14,095 during follow-up (sildenafil cost during follow-up = $5236); exclusive of PAH-related medications, however, total healthcare costs decreased modestly (from $30,104 to $27,605) (p < 0.01 for all comparisons).ConclusionsThe cost of sildenafil therapy may be partially offset by reductions in other healthcare costs.

Hypertrophic pachymeningitis in systemic sclerosis sine scleroderma

Dear Editor, Hypertrophic pachymeningitis is a clinical disorder characterized by chronic refractory headache with or without neurologic manifestations, resulting from localized or diffuse thickening of the dura mater.1, 2 These meningeal changes can be found in various autoimmune, neoplastic and infective conditions.1, 3 Idiopathic hypertrophic pachymeningitis is the diagnosis of exclusion. Systemic sclerosis sine scleroderma is a condition characterized by vasculopathy, visceral manifestations and serologic findings similar to systemic sclerosis in absence of skin sclerosis. Here we describe a patient with systemic sclerosis sine scleroderma and hypertrophic pachymeningitis. To the best of our knowledge there has been no previous report of pachymeningitis in a patient with systemic sclerosis. A 45-years-old woman, a diagnosed case of systemic sclerosis sine scleroderma, presented to us with a 4-month history of severe, throbbing, holocranial headache associated with nausea. There was no other significant medical history. General physical and systemic examination was unremarkable except for basal crackles in both lungs. Hemogram and biochemical parameters were within normal limits. Antinuclear antibody titre was 1 : 320 homogenous pattern and anti-Scl-70 was positive. Tests for syphilis, hepatitis B surface antigen, anti-hepatitis C virus and human immunodeficiency virus were negative. The levels of serum angiotensin-convertase enzyme were normal. Urinalysis and 24-h urinary calcium was within normal limits. Cerebrospinal fluid (CSF) examination showed normal opening pressure, no cells, protein 18 mg/dL, blood sugar 70 mg/dL (random blood sugar 96 mg/dL). Tuberculosis polymerase chain reaction, India ink stain and malignant cytology on CSF were negative. Chest radiograph was normal. High-resolution computed tomography (HRCT) chest scan revealed features of early interstitial lung disease. Pulmonary function tests were suggestive of restrictive lung disease and echocardiography was normal with no evidence of pulmonary arterial hypertension. Gadolinium-enhanced magnetic resonance imaging (MRI) revealed diffuse pachymeningeal thickening with enhancement throughout cerebral and cerebellar hemispheres, suggestive of hypertrophic pachymeningitis (Fig. 1). Subsequently, bronchoscopy with transbronchial lung biopsy was performed. Bronchoscopic alveolar lavage revealed alveolar macrophages (82%), lymphocytes (10%) and polymorphs (8%) and lung biopsy had normal histology. The patient did not give consent for meningeal biopsy. She was started on 50 mg oral corticosteroids daily. She showed marked clinical improvement with complete resolution of headache. Follow-up gadolinium-enhanced MRI of the brain performed in September 2010 revealed marked regression in dural enhancement (Fig. 2). Hypertrophic pachymeningitis is a rare clinical disorder which commonly presents with chronic headache with or without neurological manifestations. Neuroimaging is essential in making correct diagnosis. Gadolinium-enhanced MRI is superior to contrast-enhanced computed tomography (CT) scan for diagnoses. Corticosteroid therapy has been effective in alleviating symptoms and in arrest of clinical progression. In refractory cases, immunomodulators such as azathioprine, methotrexate and cyclophosphamide can be used.3, 4 Connective tissue diseases such as Wegener's granulomatosis, rheumatoid arthritis, mixed connective tissue disease, undifferentiated connective tissue disease, sarcoidosis, Behçet's disease and Sjögren syndrome have been reported to be associated with hypertrophic cranial pachymeningitis.1, 5-8 To conclude, hypertrophic pachymeningitis is a rare association with connective tissue diseases and it should always be suspected when a patient presents with chronic refractory headache in which other etiologies have been ruled out. To the best of our knowledge this is the first case of pachymeningitis with scleroderma.

Treatment patterns and healthcare system burden of managed care patients with suspected pulmonary arterial hypertension in the United States

Objectives:To describe treatment patterns and healthcare burden among individuals with suspected pulmonary arterial hypertension (PAH), as identified through a practice guideline-based healthcare claims algorithm.Methods:Adults with evidence of PAH from 1 January 2004 (commercial and Medicaid) or 1 July 2006 (Medicare Advantage) through 30 June 2008 were identified. Given the lack of an ICD-9 code for PAH, an algorithm was developed requiring: (1) ≥1 claim for PAH medication (index date); (2) ≥1 claim with a pulmonary hypertension diagnosis code in the 6-month pre-index period (baseline) or within 90 days post-index; (3) a right heart catheterization or pulmonary hypertension-related inpatient stay during baseline or within 90 days post-index; and (4) continuous health plan enrollment for 6 months pre-index and ≥6 months post-index. Patients with PAH-specific medications during baseline were excluded. Treatment patterns, healthcare utilization, and costs were assessed during the period ending with the earlier of health plan disenrollment or 31 December 2008.Results:Among the 521 included patients, 69% were female. Most patients (94%) initiated treatment with monotherapy (most commonly sildenafil or bosentan), and 12.7% of all patients augmented their therapy by the end of the observation period. The medication possession ratio was 0.96 each for ambrisentan (SD = 0.04), bosentan (SD = 0.04), and sildenafil (SD = 0.05). Overall, 72.6% of patients discontinued therapy with a mean of 149 (SD = 170) days until discontinuation. A mean (SD) of 2.14 (1.82) all-cause office and 1.64 (1.98) outpatient visits occurred per patient per month. Mean PAH-related healthcare costs were $6617 per patient per month, comprising 71% of all-cause costs. The guideline-based algorithm may not have perfectly captured patients with PAH.Conclusions:Patients with suspected PAH were likely to initiate treatment with oral monotherapy, had high compliance rates, and received close ambulatory follow-up. PAH-related costs constituted the majority of all-cause healthcare costs.

Clinical Manifestations and Long-Term Follow-Up in Pediatric Patients Living at Altitude With Isolated Pulmonary Artery of Ductal Origin

This study's aim was to define the clinical manifestations and long-term outcome of pediatric patients living at altitude with isolated pulmonary artery (PA) of ductal origin (IPADO). This was a retrospective cohort study of 17 consecutive cases of IPADO at a single center. All patients lived at modest altitude (median 2050 m [range 1700 m to 3050 m]). Fifteen children (88%) were symptomatic at presentation. High-altitude pulmonary edema was present in 2 patients (12%) at diagnosis, and only 1 patient had episodes of hemoptysis during follow-up. Fourteen patients (82%) demonstrated evidence of pulmonary arterial hypertension (PAH). Among 14 patients with PAH, 11 patients had surgical interventions. PAH resolved in 5 of 11 patients (45%) undergoing surgical rehabilitation. One patient died during follow-up, and 7 patients are receiving oral vasodilator therapies due to residual PAH; 14 patients remained asymptomatic. Our study showed that early intervention in patients with IPADO at modest altitude can potentially rehabilitate the isolated PA and reverse PAH. Whether surgery is indicated for patients with this disorder in the absence of PAH is unknown.