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Pulmonary hypertension is a condition with high morbidity and mortality. Resting transthoracic echocardiography is a pivotal diagnostic and screening test for pulmonary hypertension. The role of exercise stress echocardiography in the diagnosis of pulmonary hypertension is not well-established. We studied right ventricular size changes during exercise using exercise stress echocardiography to assess differences between normal and pulmonary hypertension patients and evaluate test safety, feasibility, and reproducibility. Healthy control and pulmonary hypertension patients performed recumbent exercise using a bicycle ergometer. Experienced echocardiography sonographers recorded the following resting and peak exercise right ventricular parameters using the apical four chamber view: end-diastolic area; end-systolic area; mid-diameter; basal diameter; and longitudinal diameter. Two cardiologists masked to clinical information subsequently analyzed the recordings. Parameters with acceptable inter-rater reliability were analyzed for statistical differences between the normal and pulmonary hypertension patient groups and their association with pulmonary hypertension. We enrolled 38 healthy controls and 40 pulmonary hypertension patients. Exercise stress echocardiography testing was found to be safe and feasible. Right ventricular size parameters were all readily obtainable and all had acceptable inter-observer reliability except for right ventricular longitudinal diameter. During exercise, healthy controls demonstrated a decrease in right ventricular end-systolic area, end-diastolic area, mid-diameter, and basal diameter ( P

World Health Organization (WHO) Group 1 pulmonary hypertension (PH) (PAH, pulmonary arterial hypertension) and WHO Group 4 PH (CTEPH, chronic thromboembolic pulmonary hypertension) are rare diseases of the pulmonary vascular system characterized by elevated pulmonary artery pressure and pulmonary vascular resistance in the absence of elevated left ventricular filling pressures, which may progress to right heart failure and death.1 Left untreated, the median survival for idiopathic (IPAH) and heritable (HPAH) disease is about 2.8 years from diagnosis.2 Adherence to expert consensus guidelines on PH diagnosis and management is of critical importance to correctly target therapy and improve patient outcomes.

Pulmonary arterial hypertension (PAH) is a progressive potentially fatal disease. Multiple pharmacologic options are now available, which facilitated transitions between different therapeutic options, although the evidence for such transitions has not been well described. We sought to review the evidence supporting the safety and/or efficacy of transitioning between PAH-specific medications. We performed a systematic review of all published studies in the Medline database between 1 January 2000 and 30 June 2016 reporting on any transition between the currently Food and Drug Administration (FDA)-approved PAH-specific medications. Studies reporting on three or more adult patients published in the English language reporting on transitions between FDA-approved PAH medications were extracted and tabulated. Forty-one studies met the selection criteria, nine of which included less than eight patients (and thus were reported separately in the supplement), for a total of 32 studies. Transitioning from parenteral epoprostenol to parenteral treprostinil appears to be safe and efficacious in patients who have less severe disease and more favorable hemodynamics. Transitioning from a prostacyclin analogue to an oral medication may be successful in patients who have favorable hemodynamics and stable disease. There is conflicting evidence supporting the transition from a parenteral to an inhaled prostacyclin analogue, even in patients who are on background oral therapy. Currently, the only evidence in support of transitioning between oral PDE5 inhibitors is from sildenafil to tadalafil. Patients on higher doses of sildenafil are more likely to fail. In patients with liver abnormalities due to bosentan or sitaxentan, the transition to ambrisentan appears to be safe and can result in clinical improvement. Studies regarding PAH medication transitions are limited. Patients who have less severe disease, better functional status, and are on lower medications doses may be more successful at transitioning.

Pulmonary hypertension remains a challenging condition to diagnose and manage. Decentralized care for pulmonary arterial hypertension (PAH) has led to shortcomings in the diagnosis and management of PAH. The Pulmonary Hypertension Association-sponsored Pulmonary Hypertension Care Center program is designed to recognize specialty centers capable of providing multidisciplinary and comprehensive care of PAH. Ideally, Pulmonary Hypertension Care Centers will comanage PAH patients with community-based practitioners and address the growing needs of this emerging population of long-term PAH patients.

The field of pulmonary arterial hypertension (PAH) has significantly evolved in recent years through greater understanding of pulmonary vascular pathophysiology and pathobiology with associated development of multiple PAH-specific medications. This article reviews the updated 2013 clinical classification of pulmonary hypertension (PH) along with our current understanding of the epidemiology and genetics of PAH. An approach to the diagnosis of PH and an overview of concepts in the contemporary medical management of PAH are discussed. Surgical interventions for medically refractory PAH, emerging PAH therapies, and new approaches to PAH management are briefly examined.

Prostacyclin pathway medications have been shown to be highly efficacious in the treatment of pulmonary arterial hypertension (PAH) through multiple prospective clinical trials and more than two decades of clinical experience. The strongest support for prostacyclin use in PAH management is with parenteral administration. Numerous risks and limitations of parenteral delivery systems as well as significant patient burdens restrict widespread parenteral use. Highly effective and tolerable oral prostacyclin preparations to manage PAH have long been sought. We review the development of the oral prostacyclin agents beraprost, treprostinil, and selexipag and including current indications and limitations. Research into new approaches to the management of PAH, expanding indications for existing agents, and development of novel agents are also discussed. Two oral prostacyclin pathway medications, oral treprostinil and selexipag, were FDA approved in December 2013 and 2015, respectively. Current guidelines recommend use of selexipag in WHO-FC II and III (class 1, level B recommendation) and oral treprostinil in WHO-FC III (class 2b, level B recommendation). The use of these medications is challenging due to complexity in dosing and their side effect profiles which limit patient tolerability and acceptance. There is a promising role for oral prostacyclin pathway medications in patients with PAH. Future investigations are underway of alternative dose regimens and transitioning from parenteral therapies in order to improve efficacy and tolerability.

Pulmonary arterial hypertension (PAH) associated with portal hypertension [portopulmonary hypertension (PPHTN)] occurs in 2% to 10% of patients with advanced liver disease and carries a very poor prognosis without treatment. Most hepatic transplantation centers consider moderate to severe PPHTN to be a contraindication to liver transplantation because of the high rate of perioperative complications. We present 3 patients with PPHTN who were managed with intravenous prostacyclin therapy followed by living donor liver transplantation (LDLT). These individuals demonstrated subsequent resolution of their pulmonary hypertension and were weaned off all PAH-specific medical therapy. We present their demographics, clinical courses, and hemodynamics. We discuss the potential indications for LDLT and risks with respect to this patient population. Limitations of the Model for End-Stage Liver Disease scoring system and outcome data for this patient population are reviewed. Future studies should be directed toward better defining indications for LDLT in patients with PPHTN, improving medicosurgical management, and assessing long-term outcomes.

Study objectives: To compare the relative numbers andhospital course of men vs women admitted at least twice with asthma orstatus asthmaticus to Yale-New Haven Hospital (YNHH) during the periodfrom 1985 to 1994. Design: A retrospective chartreview. Setting: YNHH. Patients: High-risk men and women (age range, 18 to 50 years) admitted at leasttwice during the study period with the discharge diagnosis of asthma orstatus asthmaticus. Results: Of 561 adult asthmapatients admitted during the study period, 188 were admitted at leasttwice and accounted for 68% of the total asthma admissions. Onehundred three of the 188 patients were randomly selected, and all oftheir asthma admissions were retrospectively reviewed. The 103 patientsaccounted for 382 admissions. Seventy-two percent of these patients and68.6% of the admissions were women. The proportions of each genderrequiring admission to the medical ICU (15.65% women vs 11.67% men)or intubation (8.00% women vs 5.80% men) were not significantlydifferent. Women did exhibit a definite trend toward longer admissions(4.92 days vs 4.04 days; p co 2 levels (p co 2 levels than women (48.73 mm Hg vs41.04 mm Hg; p co 2 levels than their respective femalecounterparts (p Conclusions: At YNHH, 68% of all admissions for asthma in this age group are attributable tohigh-risk patients. High-risk female patients are admitted twice asoften as high-risk male patients and tend to have longer admissions. Once admitted, however, the proportion of men and women requiring themedical MICU or intubation were similar. High-risk male patients onpresentation are consistently more hypercapneic than high-risk femalepatients. Therefore, the mechanisms contributing to the genderdifferences in asthma admissions may include differences in theventilatory response to hypercapnea or in the tolerance to airwayobstruction.

Objective: To study the clinical characteristics and prognosis of patients with diffuse pulmonary arteriovenous malformations (AVMs). Design: Retrospective chart review of all patients (n 5 16) with diffuse pulmonary AVMs seen at Yale New Haven Hospital, Johns Hopkins Hospital, and St. Michael’s Hospital. Up-to-date follow-up information was obtained in all living patients. Results: All patients were severely hypoxic. Neurologic complications (stroke or brain abscess) had occurred in 70% of patients by the time of diagnosis. During the follow-up period (mean, 6 years), three patients died and two others developed new neurologic complications. One of the deaths occurred perioperatively during lung transplantation. All patients underwent transcatheter embolotherapy of any large pulmonary AVMs. A selected group underwent pulmonary flow redistribution, a novel technique. Oxygenation did not improve significantly with embolotherapy of the larger AVMs, but there was a small significant improvement in those patients who underwent pulmonary flow redistribution. The majority (85%) of the living patients are currently working or studying full-time. Conclusions: Patients with diffuse pulmonary AVMs are at increased risk of neurologic complications. Transcatheter embolotherapy does not significantly improve the profound hypoxia, but it may reduce the risk of neurologic complications. Antibiotic prophylaxis is recommended for bacteremic procedures to prevent brain abscess. These patients can live for many years and lead productive lives. We do not recommend lung transplantation because survival with disease is difficult to predict and we have observed a perioperative transplant death. (CHEST 2000; 117:31‐38)

Summary of PHPN Symposium Session by Joel Wirth, MD, and Traci Stewart, RN, MSN

Background . The purpose of this study was to document the long-term results of transcatheter embolotherapy of large pulmonary arteriovenous malformations (PAVMs). Methods . From a data base of 221 consecutive patients with PAVMs treated by embolotherapy between 1978 and 1995, 45 patients with 52 PAVMs, supplied by feeding arteries 8 mm in diameter or larger, were selected for a retrospective investigation. Results . Of 45 patients with 52 large PAVMs, 38 patients (84%) with 44 PAVMs (85%) were cured by the first embolotherapy (mean follow-up, 4.7 years). Acute periprocedural complications included self-limited pleurisy (31%), angina secondary to air embolus (2%), and paradoxical embolization of a device during deployment (4%). None of these events led to short- or long-term sequelae. Seven patients (16%) had persistence of the PAVM attributable to either recanalization (n = 4) or interim accessory artery growth (n = 3). Two of these patients presented with ischemic stroke several years after the initial treatment. Persistent PAVMs (n = 8) were retreated successfully by a second procedure (n = 7), or a third procedure (n = 1) (mean follow-up, 5.9 and 5.3 years, respectively). Conclusions . Embolotherapy of large PAVMs results in permanent occlusion in an overwhelming majority of patients. Continued patency due to recanalization or accessory artery growth is easily detected and treated.

The recent long-term studies from England, France, and the Netherlands, as well as our own, indicate that transcatheter embolotherapy is definitive treatment for PAVM. More recently, Puskas et al have questioned transcatheter embolotherapy as a primary treatment for patients with PAVM (4,56). Their opinion was based on two recurrences among five patients treated with transcatheter embolotherapy. It is not clear why one of the late recurrences in the series by Puskas et al happened, and the other recurrence could have been dut to early deflation of the balloon. Nevertheless, we believe that the collective experience in the larger series reporting on transcatheter embolotherapy of PAVM supports the use of embolotherapy as a primary modality of treatment. Because many patients have bilateral pulmonary malformations and many pulmonary malformations will grow with time, repeated surgical intervention is not ideal therapy. The recurrence rate of 8% reported by Remy et al using coils, and 2% reported by Pollak et al using balloons and coils supports our contention that transcatheter embolotherapy is durable and should be the initial treatment. Also, recurrences are easily retreated by transcatheter embolotherapy with durable results (54). We favor detachable balloons over coils for occluding PAVMs because immediate cross-sectional occlusion of the segmental artery is obtained in a position that preserves the most normal branches. The necessity for repeated introduction of coils, when using the coil method, contributes to longer procedure times with an increased risk of air introduction and, in our experience, a greater risk of postprocedure pleurisy. At the same time, we appreciate that approximately 70% of PAVMs can be occluded equally well with balloons or coils. We also believe that coils have unique advantages over balloons in specific anatomic situations including oversized arteries (where coils are the only option) and for occlusion of the aneurysm of a PAVM. As with all forms of embolotherapy, the interventionalist is best served by having more than one option of treatment, which for PAVM includes both balloons and coils. In summary, PAVMs are effectively managed by means of transcatheter embolotherapy. This therapy has been demonstrated to be safe and durable. Careful technique with modifications depending on the angioarchitecture of the PAVM is required. Patients with PAVMs require follow-up at 1 month and 1 year. While observations documenting serial growth of small PAVMs are somewhat limited, there is published evidence to support their growth with time (35,36). Because of these reports and our unpublished observations, we believe that patients with treated PAVM need long-term follow-up every 5 years to detect growth of small PAVMs that will ultimately reach a size where they may cause paradoxical embolization and stroke (1).

The full-length primary structure and expression profile of a novel unconventional myosin heavy chain, human myosin-IXb, is described. The primary structure of this myosin predicts a 229 kDa protein that together with its recently described rat homolog, myr 5, is the ninth class of myosins to be identified. In comparison to skeletal muscle myosin-II, the myosin-IXb ‘head’ has two unusual features: a novel N-terminal domain of 140 amino acids, which includes a 60 amino acid extension, and a large insertion of 126 amino acids in the putative actin-binding site. The ‘neck’ contains four tandemly repeated IQ motifs, suggesting that this myosin may have four associated light chains. The ‘tail’ contains a region similar to regions found in the chimerins, with a putative zinc and diacylglycerol binding domain, homologous to the regulatory domain of protein kinase C and a putative GTPase-activating protein (GAP) domain of the rho/rac family of ras-like G-proteins. Northern blot analysis of 16 different human tissues revealed an approximately 8 kb transcript that is most highly expressed in peripheral blood leukocytes, with somewhat lower levels of expression in thymus and spleen, suggesting that myosin-IXb is most abundant in cells of myeloid origin. Myosin-IXb was also expressed in a number of other tissues at significantly lower levels. Analysis of myosin-IXb protein expression, using a tail-domain directed antibody, was performed in HL-60 cells, a human leukocyte cell. Myosin-IXb expression increases by 4- to 5-fold upon induced differentiation of these cells into macrophage-like cells. The localization of myosin-IXb is also altered upon differentiation. In undifferentiated HL-60 cells, myosin-IXb colocalizes with F-actin in the cell periphery, while in differentiated cells its localization becomes more cytoplasmic, with the highest levels in the perinuclear region.

The complete deduced amino acid sequence and MRNA expression of human unconventional myosin-IC (HuncM-IC) are described. Sequencing of overlapping cDNA clones reveals a message of 4666 nucleotides with a single open reading frame predicted to encode a 127 Kda protein of 1109 amino acids. HuncM-IC is composed of three discrete regions: a characteristic N-terminal myosin head with predicted actin and ATP-binding sites; a neck domain with an "IQ motif", predicted to bind a single light chain; and a C-terminal tail with a putative membrane-binding site. In addition, the tail contains an src-homology 3 domain. The presence of a single IQ motif and an src-homology 3 domain is reminiscent of "long-tailed" myosins-I from amoeboid organisms, a supposition confirmed by multiple sequence alignment. Northern blot analysis of human tissues shows that HuncM-IC is ubiquitously expressed, with the highest levels in kidney prostate, colon, liver and ovary. The results show that "amoeboid" myosins-I are not restricted to amoeboid organisms, rather they are expressed in the metazoa as well.

Pulmonary arterial hypertension (PAH) associated with portal hypertension [portopulmonary hypertension (PPHTN)] occurs in 2% to 10% of patients with advanced liver disease and carries a very poor prognosis without treatment. Most hepatic transplantation centers consider moderate to severe PPHTN to be a contraindication to liver transplantation because of the high rate of perioperative complications. We present 3 patients with PPHTN who were managed with intravenous prostacyclin therapy followed by living donor liver transplantation (LDLT). These individuals demonstrated subsequent resolution of their pulmonary hypertension and were weaned off all PAH-specific medical therapy. We present their demographics, clinical courses, and hemodynamics. We discuss the potential indications for LDLT and risks with respect to this patient population. Limitations of the Model for End-Stage Liver Disease scoring system and outcome data for this patient population are reviewed. Future studies should be directed toward better defining indications for LDLT in patients with PPHTN, improving medicosurgical management, and assessing long-term outcomes.

We describe a case of pulmonary hypertension, initially thought to be idiopathic, which resolved after treatment of Graves' hyperthyroidism. Results of pulmonary artery catheterization before and after treatment are reported, and the effects of thyrotoxicosis on hemodynamics and pulmonary function are briefly reviewed. Possible mechanisms for development of pulmonary hypertension caused by hyperthyroidism include pulmonary vascular endothelial dysfunction or damage because of autoimmunity or the high cardiac output state, or increased metabolism of intrinsic pulmonary vasodilators.

Objectives The clinical features, airway histology, and detection of hexamethylene diisocyanate (HDI) protein adducts in endobronchial biopsies from a patient with HDI asthma are described. Methods Isocyanate asthma was diagnosed by history, methacholine challenge, and workplace HDI challenge. Bronchoscopy was performed 24 h after challenge and immunohistochemical staining was performed. Results Airway biopsies obtained at bronchoscopy demonstrated inflammatory changes typical for asthma, including increased airway eosinophils and T cells. Immunohistochemical staining with specific anti-HDI antibodies demonstrated the presence and localization of HDI adducts in human bronchial biopsies. Conclusion These studies confirm epithelial exposure to HDI following workplace challenge and demonstrate the feasibility of detecting and localizing isocyanate adducts in human lung tissue. Identifying and characterizing the airway macromolecules to which isocyanates bind in vivo are probably crucial to the understanding of how isocyanates cause sensitization and asthma. The ability to detect isocyanate adducts may also help characterize isocyanate exposure patterns and exposure-disease relationships.

This article describes an ongoing short-term biomarker study of Vitamin A in subjects at high risk for lung cancer. Workers exposed to asbestos and cigarettes have a markedly increased risk of developing lung cancer and parenchymal fibrosis. Epidemiologic and experimental studies have shown that dietary vitamin A has significant anticancer and immunomodulatory effects (1-6). However, whether intervention with supplemental vitamin A can reduce the mortality or morbidity from either disease and the mechanisms involved remains unclear. Airway metaplasia on bronchial biopsy and inflammation on bronchoalveolar lavage (BAL) are considered potential markers for the development of lung cancer and parenchymal fibrosis respectively. Our prior clinical studies (see below) have shown an high incidence of both of these lesions in asbestos-exposed subjects, findings consistent with the idea that the processes of inflammation and carcinogenesis are linked. We have hypothesized that 1) the vitamin A intervention may reduce both bronchial metaplasia and lung inflammation, 2) the mechanism of this effect may be through modulation of relevant pulmonary cytokines, growth factors, and/or oncogenes, and 3) local lung vitamin A status may be a key modifiable host determinant or biomarker of susceptibility. We are performing a double-blind placebo controlled 6 month trial of combination 0-carotene and retinol in 50 subjects at high risk for both lung cancer and parenchymal fibrosis to address these hypotheses. This study should provide valuable data on whether vitamin A can modify potential early markers of lung cancer and fibrosis, the mechanisms involved, and the role of local vitamin A. The findings may lead to effective preventive strategies for lung cancer.

Myosin diversity in the human epithelial cell line Caco-2BBe, the porcine epithelial cell line LLC-PK1 (CL-4), human peripheral blood leukocytes, and human liver was analyzed. PCR amplification yielded 8-11 putative myosins (depending on the cDNA source) representing six distinct myosin classes. Analysis of clones obtained by hybridization screening demonstrated that the original PCR products correspond to bona fide myosins, based on the presence of sequences highly conserved in other myosins. RNase protection analysis confirmed mRNA expression of 11 myosins in Caco-2BBe cells. Immunoblot analysis showed that at least 6 myosin immunogens are expressed in Caco-2BBe cells. The results reveal the existence of at least 11 unconventional human myosin genes, most of which are expressed in an overlapping fashion in different cell types. The abundance of myosins suggests that the myosin I vs. myosin II paradigm is inadequate to explain actin-based cellular motility.

Recent reports have suggested a possible association between HIV-1 infection and primary pulmonary hypertension (PPH), but most of the patients described to date have either had acquired immunodeficiency syndrome (AIDS) with concurrent lung infections or have administered Factor VIII intravenously for hemophilia. We report three human immunodeficiency virus type 1 (HIV-1)-positive homosexual white males with clinical and hemodynamic diagnoses of PPH. None of the patients had any opportunistic lung infections or other pulmonary pathology, nor were they hemophiliacs. They had no histories of intravenous drug use. Lung tissue from two of the patients revealed hypertensive arteriopathy consistent with PPH and no other pulmonary pathology. Attempts at localizing HIV-1 infection to the vascular endothelium with electron microscopy, immunohistochemistry, DNA in situ hybridization, and polymerase chain reaction techniques did not reveal direct pulmonary artery infection with the virus. These data and the finding of tubuloreticular structures on electron microscopy suggest that HIV-1 may play a role in the pathogenesis of these cases of PPH through mediator release associated with HIV-1 infection rather than by direct endothelial infection.