Evolving nonvasodilator treatment options for pulmonary arterial hypertension.

PURPOSE OF REVIEW: With the establishment of vasodilator therapy as a mainstay of treatment for pulmonary arterial hypertension (PAH), new therapeutic approaches are needed to prevent the development of the vasculopathy associated with this disease. Many studies are currently underway to investigate nonvasodilator treatment options. RECENT FINDINGS: Modulation of bone morphogenic protein receptor type 2 (BMPR2) signaling with sotatercept showed promising results in phase 2 studies. Rituximab, an anti-CD20 monoclonal antibody, showed some signal for beneficial effect in patients with scleroderma-associated PAH. Studies evaluating agents including tocilizumab, selonsertib, bardoxolone, 10-nitro-9(E)-enoic acid (CXA-10) and intravenous iron have not shown acceptable efficacy in treating PAH. SUMMARY: Pharmacologic approaches for the treatment of PAH include altering of transforming growth factor ß/BMPR2 signaling, proliferation via growth factors, immune response, oxidative stress, estrogen signaling, metabolism, and neurohormonal modulation. Other treatment modalities including pulmonary artery nerve denervation, stem cell therapy, and inter-atrial shunt formation are also being explored.

Impact of race on survival in pulmonary arterial hypertension: Results from the REVEAL registry.

BACKGROUND: Prior research has suggested that the prevalence and outcomes of pulmonary arterial hypertension (PAH) may vary by race or ethnicity. However, these studies have been limited by small sample size or methodological techniques relying on epidemiologic data. The purpose of this study is to evaluate the relationship between race/ethnicity and survival in a large U.S.-based prospective multicenter registry. METHODS: Patients in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a 5-year observational study of Group 1 PAH, were categorized by race/ethnicity. Baseline hemodynamic characteristics, clinical characteristics, and medication use was described. The relationship between race/ethnicity and outcome was evaluated by Kaplan-Meier and Cox proportional hazards modeling techniques. Left-truncation analysis, which adjusted for time from diagnosis to study enrollment, was used to minimize the effect of survivor bias. RESULTS: This analysis included 3,046 patients; 2,202 identified as white, 393 as black, 263 as Hispanic, 100 as Asian or Pacific Islander, and 88 as other. Unadjusted Kaplan-Meier survival analysis indicated that white patients had the lowest survival rates. After adjusting for variables of prognostic impact, race/ethnicity was no longer significantly associated with survival. Other results showed that black patients were more likely to have connective tissue disease-associated PAH, Hispanic patients were more likely to have portopulmonary hypertension, and Asian patients were more likely to have congenital heart disease-associated PAH. CONCLUSIONS: Analysis of the REVEAL registry did not find race/ethnicity to be a significant predictor of mortality. This is the largest analysis to date evaluating the role of race/ethnicity on outcomes in PAH.

Ethnicity in Pulmonary Arterial Hypertension: Possibilities for Novel Phenotypes in the Age of Personalized Medicine.

In the past decade and a half, the introduction of new therapeutic agents has revolutionized the management of pulmonary arterial hypertension (PAH). These new treatment options have improved the quality of life and survival in PAH. With an armamentarium of options available, the identification of unique phenotypes can help practitioners choose tailored treatment regimens. Experts in other cardiovascular diseases, such as congestive heart failure and hypertension, have recommended race-specific treatments in their fields based on data highlighting variations in response to therapies. With this perspective, we review evidence supporting the hypothesis that ethnicity or race plays an important role in the management of PAH. Preliminary research suggests that races/ethnicities have differences in the presentation and outcome of PAH and could respond to PAH-specific medications with varying efficacy. Genetic, physiological, and anatomic differences exist between races, particularly regarding the structure and function of the right ventricle. Unfortunately, clinical trials have not adequately included minorities, and registry data often omit inclusion of this demographic information. Further studies are needed to characterize the role that ethnicity plays in the prevalence, presentation, outcomes, and optimal treatment of PAH.

Predictive Biomarkers for Asthma Therapy.

PURPOSE OF REVIEW: Asthma is a heterogeneous disease characterized by multiple phenotypes. Treatment of patients with severe disease can be challenging. Predictive biomarkers are measurable characteristics that reflect the underlying pathophysiology of asthma and can identify patients that are likely to respond to a given therapy. This review discusses current knowledge regarding predictive biomarkers in asthma. RECENT FINDINGS: Recent trials evaluating biologic therapies targeting IgE, IL-5, IL-13, and IL-4 have utilized predictive biomarkers to identify patients who might benefit from treatment. Other work has suggested that using composite biomarkers may offer enhanced predictive capabilities in tailoring asthma therapy. Multiple biomarkers including sputum eosinophil count, blood eosinophil count, fractional concentration of nitric oxide in exhaled breath (FeNO), and serum periostin have been used to identify which patients will respond to targeted asthma medications. Further work is needed to integrate predictive biomarkers into clinical practice.

Admission for COPD Exacerbation Is Associated with the Clinical Diagnosis of Pulmonary Hypertension: Results from a Retrospective Longitudinal Study of a Veteran Population.

Patients with chronic obstructive pulmonary disease and pulmonary hypertension (PH-COPD) have an increased risk of hospitalizations and death compared to COPD alone. Identifying PH in COPD is challenging because performing right heart catheterization, the gold standard for PH diagnosis, is invasive and not routinely performed. Clinical characterization of COPD patients at risk who are progressing toward PH will aid therapeutic development at earlier stages of progressively fatal PH-COPD. We studied the records of 5,45,086 patients in a large Veterans Affairs healthcare network (2000-2012) with a primary discharge diagnosis of COPD based on encounters' ICD-9 codes and further stratified into those who received an additional ICD-9 code for a PH diagnosis. Patients with PH-COPD were assigned to one of the four subgroups: those with (a) no history of exacerbation or hospital admissions, (b) history of exacerbations but no hospital admissions, (c) hospital admissions unrelated to COPD and (d) history of COPD exacerbation-related hospital admissions. We also examined the COPD and COPD-PH cohorts for associated comorbidities such as cardiac disease and the presence of obstructive sleep apnea (OSA). A regression analysis revealed that patients with COPD exacerbation-related hospital admissions had 7 × higher risk of having a concomitant clinical diagnosis of PH compared to non-hospitalized patients. COPD-PH patients had higher rates of cardiac comorbidities (89% vs. 66%) and OSA (34% vs. 16%) compared to COPD alone. We conclude that COPD patients hospitalized for COPD exacerbations are at a higher risk for developing PH, and hospitalized COPD patients with cardiac comorbidities and/or OSA should be screened as at-risk population for developing PH.

Longitudinal change in pulmonary arterial capacitance as an indicator of prognosis and response to therapy and in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a chronic progressive disease that leads to right heart failure and death. Pulmonary arterial capacitance (PAC), defined as stroke volume divided by the pulmonary pulse pressure, has been identified as a prognostic factor in PAH. The impact of changes in PAC over time, however, is unclear. We evaluated changes in PAC over time to determine if such changes predicted transplant-free survival. A single-center retrospective study of consecutive group 1 PAH patients who had two or more right heart catheterizations (RHC) between January 2007 and June 2016 was undertaken. Hemodynamic data, clinical data, and outcomes were collected. Univariate and multivariate Cox proportional-hazards modelling to identify the contribution of risk factors for a composite outcome of death or lung transplantation was done. Mixed-effects logistic regression was performed to investigate the association between the change in PAC value over time and the composite outcome. A P value < 0.05 was considered significant. In total, 109 consecutive patients with a total of 300 RHC data were identified. PAC correlated inversely with functional status ( P < 0.001) and inversely with pulmonary vascular resistance ( P < 0.001). PAC values increased with the addition of new PAH-specific medications. Mixed effects logistic regression modeling using longitudinal data showed that a decrease in PAC over the study period was associated with increased mortality and transplantation (adjusted P = 0.039) over the study period. Change in PAC was a better predictor of outcome over the study period than baseline PAC or changes in other hemodynamic or clinical parameters. Decreases in PAC were predictive of increased mortality or transplantation in patients with group 1 PAH. There was a trend towards increased PAC in response to the addition of a PAH-specific medication. Our data support the use of PAC as a therapeutic target in PAH.

Fatal Progressive Membranous Obliterative Bronchitis: A Sequela of Influenza?

Occlusion of the bronchial orifices by tissue-like structures is an uncommonly reported finding: it has been referred to as bronchial webs, bronchial synechiae, vanishing bronchus syndrome, or membranous obliterative bronchitis. It differs from bronchiolitis obliterans, a well-described clinical entity that involves smaller airways not visualized on bronchoscopy. Although initially only recognized as a congenital condition, later reports have described it in situations where chronic inflammation results in the irritation of the airways. Here we report a case of a woman with postinfectious bronchiectasis who developed membranous occlusion of multiple subsegmental bronchi, resulting in progressive airflow obstruction and postobstructive collapse of involved lung parenchyma. This process eventually caused her demise. It the first report of membranous occlusion of the bronchi in an adult who does not have cystic fibrosis or a history of lung transplantation. Clinicians should be aware of this entity, and further research could help illuminate its pathogenesis and management.

Fungal Sensitization Is Associated with Increased Risk of Life-Threatening Asthma.

BACKGROUND: Fungal sensitization in patients with asthma has been associated with severe asthma and worse asthma outcomes. OBJECTIVE: The purpose of this study was to determine the relationship between fungal and nonfungal sensitization, asthma severity, and clinical outcomes. METHODS: A retrospective review of patients with asthma evaluated in an urban pulmonary subspecialty clinic in the United States was performed. Patients with fungal and nonfungal allergen sensitization were identified based on serum-specific immunoglobulin E (sIgE) testing. Demographic, clinical, laboratory, and spirometric data were obtained. The relationship between fungal sensitization and asthma outcomes was examined. RESULTS: Of 390 patients with asthma identified, 307 had sIgE testing, of whom 53 (17.3%) had fungal sensitization, 117 (38.1%) had nonfungal sensitization, and 137 (44.6%) had no sensitization. Patients with fungal sensitization were more likely to be sensitized to ≥5 allergens than patients with nonfungal sensitization (66% for fungal vs 29% for nonfungal, P < .001). Serum IgE concentrations were highest in patients with fungal sensitization compared with patients with no sensitization or nonfungal sensitization (median, 825, 42, and 203 IU/mL, respectively, P < .001). Fungal sensitized patients were more likely to require intensive care unit (ICU) admission and mechanical ventilation than those with no sensitization or nonfungal sensitization (13.2%, 3.7%, and 3.4%, respectively, for ICU admission, P = .02; 11.3%, 1.5%, and 0.9%, respectively, for ventilation, P < .001). CONCLUSIONS: Fungal sensitization is common in patients with asthma in an urban setting and is associated with greater sensitization to nonfungal allergens and increased risk of life-threatening asthma.

Epidemiology and Pathophysiology of Chronic Thromboembolic Pulmonary Hypertension: Risk Factors and Mechanisms.

Chronic thromboembolic pulmonary hypertension (CTEPH) occurs when thromboemboli travel to the pulmonary vasculature, fail to resolve, and cause elevated pulmonary arterial pressure. Untreated, this disease leads to progressive right heart failure and death. It develops in approximately 1% to 5% of patients who suffer an acute pulmonary embolism (PE) and has an overall incidence of 3 to 30 per million in the general population. While it is not entirely evident why most but not all people are able to clear this clot burden, there are known risk factors for the development of CTEPH. These include signs of right heart strain at the time of incident PE, inherited coagulopathies, inflammatory conditions, hypothyroidism, and a history of splenectomy. Since CTEPH can be treated both surgically and medically, it is critical to understand the pathophysiology of the disease so affected patients can be identified and diagnosed appropriately.

Posterior circulation stroke is associated with prolonged door-to-needle time.

BACKGROUND: Lack of recognition of early symptoms of acute posterior circulation ischaemic stroke might delay timely diagnosis and treatment with tissue plasminogen activator. AIMS AND HYPOTHESIS: We hypothesized that patients with posterior circulation stroke receive delayed thrombolytic treatment in comparison to anterior circulation stroke. We investigated the differences in times to evaluation or treatment between patients with anterior circulation ischaemic stroke and posterior circulation stroke in our aim to understand the barriers that might have caused these delays. METHODS: A cross-sectional study was conducted using consecutive patients presenting to our tertiary academic centre with acute ischaemic stroke who were treated with intravenous tissue plasminogen activator within 4·5 h from symptom onset. We compared demographics, stroke severity, symptoms and signs, and time intervals among onset, emergency department arrival, emergency department physician evaluation, neurologist evaluation, brain imaging, and tissue plasminogen activator treatment in patients with anterior circulation stroke and posterior circulation stroke. RESULTS: Among 252 patients treated with intravenous tissue plasminogen activator, 12% had posterior circulation stroke. Patients with posterior circulation stroke had significantly lower median baseline the National Institutes of Health and Stroke Scale (NIHSS) score (P = 0·01), higher frequency of nausea (P < 0·01), vomiting (P < 0·01), dizziness (P < 0·01), and lower frequency of aphasia (P = 0·002) or neglect (P = 0·048). The emergency department physician evaluation-to-neurologist evaluation and door-to-needle intervals were significantly longer for posterior circulation stroke patients compared with anterior circulation stroke patients. The neurologist-to-needle time, however, was similar in the two groups. The presence of nausea and vomiting was associated with a longer time from emergency department evaluation to neurology evaluation and had a significant association with delayed treatment. CONCLUSIONS: Posterior circulation stroke patients had a delay in neurology evaluation after initial emergency department evaluation and a delay in intravenous tissue plasminogen activator administration compared with anterior circulation stroke patients. There may be difficulties in rapidly recognizing the symptoms of posterior circulation stroke, in contrast to anterior circulation stroke, in the emergency department.

Prevalence of bipolar disorder and schizophrenia in Houston Outreach Medicine, Education, and Social Services (HOMES) Clinic patients: implications for student-managed clinics for underserved populations.

PURPOSE: Psychiatric conditions require aggressive management that is challenging to provide in free clinics. The purpose of this study was to determine the prevalence of certain mental illnesses and comorbid conditions among the patients of a student-managed free clinic for the homeless. METHOD: The authors conducted a retrospective analysis of the records of patients who visited the student-run Houston Outreach Medicine, Education, and Social Services (HOMES) Clinic from May 2007 through May 2008. They assessed the prevalence of bipolar disorder and schizophrenia among patients. They compared demographics, health insurance status, comorbid medical conditions, and social habit data of patients with these mental illnesses with those of other clinic patients. RESULTS: Of 286 patients (74.5% male, mean age 45.8 years), 25 (8.7%) had a diagnosis of schizophrenia and 45 (15.7%) had bipolar disorder. Compared with other clinic patients, patients with bipolar disorder or schizophrenia were less likely to be male (P < .0001) and were more likely to have publicly funded insurance (P = .024). They were also more likely to have certain comorbid conditions, including asthma (P = .0004), seizures (P = .0007), kidney disease (P = .01), and heart disease (P = .02). CONCLUSIONS: The high prevalence of these mental illnesses combined with the increased burden of medical comorbidity among HOMES Clinic patients has implications for student-managed free clinics, which often operate on limited budgets. Strategies for providing care for these patients in this setting include integrated care, street medicine, and case management.

Autosomal dominant inheritance of a predisposition to thoracic aortic aneurysms and dissections and intracranial saccular aneurysms.

A genetic predisposition for thoracic aortic aneurysms and dissections (TAAD) can be inherited in an autosomal dominant manner with decreased penetrance and variable expression. Four genes identified to date for familial TAAD account for approximately 20% of the heritable predisposition. In a cohort of 514 families with two or more members with presumed autosomal dominant TAAD, 48 (9.3%) families have one or more members who were at 50% risk to inherit the presumptive gene causing TAAD had an intracranial vascular event. In these families, gender is significantly associated with disease presentation (P < 0.001), with intracranial events being more common in women (65.4%) while TAAD events occurred more in men (64.2%,). Twenty-nine of these families had intracranial aneurysms (ICA) that could not be designated as saccular or fusiform due to incomplete data. TGFBR1, TGFBR2, and ACTA2 mutations were found in 4 families with TAAD and predominantly fusiform ICAs. In 15 families, of which 14 tested negative for 3 known TAAD genes, 17 family members who were at risk for inheriting TAAD had saccular ICAs. In 2 families, women who harbored the genetic mutation causing TAAD had ICAs. In 2 additional families, intracranial, thoracic and abdominal aortic aneurysms were observed. This study documents the autosomal dominant inheritance of TAADs with saccular ICAs, a previously recognized association that has not been adequately characterized as heritable. In these families, routine cerebral and aortic imaging for at risk members could prevent cerebral hemorrhages and aortic dissections.

Predicting human skin absorption of chemicals: development of a novel quantitative structure activity relationship.

The objective of this study was to construct and validate a quantitative structure-activity relationship model for skin absorption. Such models are valuable tools for screening and prioritization in safety and efficacy evaluation, and risk assessment of drugs and chemicals. A database of 340 chemicals with percutaneous absorption was assembled. Two models were derived from the training set consisting 306 chemicals (90/10 random split). In addition to the experimental K(ow) values, over 300 2D and 3D atomic and molecular descriptors were analyzed using MDL's QsarIS computer program. Subsequently, the models were validated using both internal (leave-one-out) and external validation (test set) procedures. Using the stepwise regression analysis, three molecular descriptors were determined to have significant statistical correlation with K(p) (R2 = 0.8225): logK(ow), X0 (quantification of both molecular size and the degree of skeletal branching), and SsssCH (count of aromatic carbon groups). In conclusion, two models to estimate skin absorption were developed. When compared to other skin absorption QSAR models in the literature, our model incorporated more chemicals and explored a large number of descriptors. Additionally, our models are reasonably predictive and have met both internal and external statistical validations.