Pulmonary Hypertension Association Research Articles

The Scientific Leadership Council of the Pulmonary Hypertension Association

The Scientific Leadership Council of the Pulmonary Hypertension Association

The Scientific Leadership Council of the Pulmonary Hypertension Association

The Scientific Leadership Council of the Pulmonary Hypertension Association

The Scientific Leadership Council of the Pulmonary Hypertension Association

The Scientific Leadership Council of the Pulmonary Hypertension Association

The Scientific Leadership Council of the Pulmonary Hypertension Association

The Scientific Leadership Council of the Pulmonary Hypertension Association

The Prostacyclin Story: From Discovery to Future Directions

Until recent years, the concept of treating pulmonary arterial hypertension through a variety of mediators and mechanisms seemed beyond our grasp. As much as it is routinely done in other illnesses, the possibility of applying this concept in pulmonary hypertension was remote. This picture has radically changed, however, with the introduction of new agents that may be used in conjunction with prostacyclin and its analogs. The revolution in therapy started with the man profiled in this issue, Sir John Vane, a Nobel Prize winner recognized for his work in prostaglandin research.Perhaps the theme of this issue should be that the revolution continues. After paying a debt of gratitude to Dr Vane, our story about prostacyclin continues throughout this issue. We explore the need to develop prostacyclin analogs to overcome the limitations of the epoprostenol delivery system, elaborate on the intriguing work with inhaled iloprost, and round it up with a roundtable discussion ranging across the spectrum of issues involving prostacyclin. We are also grateful to Bruce Brundage, MD, president of the Pulmonary Hypertension Association, who provided the images for this issue's cover.Slowly, but with encouraging progress, we are getting to the point where we will better understand how to treat pulmonary arterial hypertension through a variety of mediators and mechanisms. There is still much to be discovered about prostacyclin—for example, how precisely does the medication work? When we discover its true mechanisms and determine how it can be used in combination with other treatments, perhaps the revolution in therapy will have achieved its goals.

Hipertensão Portopulmonar e Gravidez

The severity of the association of pulmonary hypertension with pregnancy is well known. Pulmonary arterial hypertension constitutes one of the highest risk conditions for maternal mortality in late pregnancy and postpartum. Patients with portal hypertension of varying etiology may develop pulmonary arterial hypertension (portopulmonary hypertension) and most cases present cirrhosis as the underlying disease; however, a few cases of noncirrhotic etiology have been described. Clinical and pathological findings in two cases of portopulmonary hypertension and pregnancy are presented here. The two patients (30 and 24 years old) developed severe right heart failure and shock just after the delivery and the disease progressed rapidly to death. Autopsy demonstrated fibrosis in hepatic portal tracts, as has been described in cases of idiopathic portal hypertension. Also, pulmonary hypertension classified as plexogenic was reported.

Bridging the Gap Between Specialists With Insights From an Expert Panel

Often unsuspected and underappreciated, pulmonary arterial hypertension in some forms of scleroderma is much like primary pulmonary hypertension; the cause of the dyspnea and associated symptoms frequently eludes diagnosis until very late in the disease.Unfortunately, by that time, pulmonary hypertension may have reached an advanced stage less amenable to treatment. Although many patients with collagen vascular disease are considered at high risk for inflammatory pulmonary involvement, the disease process is often insidious and appropriate evaluation, including pulmonary function tests, echocardiography, and right-heart catheterization, may not be ordered when the benefit of treatment might be more substantial. One of the key issues concerns separating the potential causes of pulmonary hypertension that may occur in these patients and recognizing why they may require more aggressive follow-up to identify an evolving inflammatory component and potential progressive vasculopathy.For these reasons, the Pulmonary Hypertension Roundtable discussion in this issue will have broad appeal to our readership, which includes cardiologists, pulmonologists, and rheumatologists. Clearly, this is a disease that is likely to present to each of these groups, and by transcending the boundaries of these specialties, our discussion offers insights about its incidence, evolution, and appropriate evaluation. From the diverse backgrounds of our experts, you will find clinical pearls relevant to your practice regardless of your specialty. One of the goals of Advances in Pulmonary Hypertension is to bring you this kind of distilled knowledge, based on contributions from the Scientific Leadership Council of the Pulmonary Hypertension Association (PHA). These physicians are listed on page 2 and provide a tremendous breadth of experience gathered at leading institutions throughout the world. Their continued involvement with the journal gives us one of the clearest perspectives on the latest information in diagnosis and treatment.We appreciate the warm welcome Advances in Pulmonary Hypertension has received in the medical community and look forward to fulfilling the commitment PHA has made toward expanding your awareness of managing this disease. We also welcome your comments and suggestions regarding articles that appear in this issue by contacting PHA.

The Scientific Leadership Council of the Pulmonary Hypertension Association

The Scientific Leadership Council of the Pulmonary Hypertension Association

Pulmonary arteriovenous malformations. A state of the art review.

Pulmonary arteriovenous malformations represent a direct communication between one or more pulmonary arteries and one or more pulmonary veins. Common anatomic forms include single sacs ranging from 1 to >10 cm in diameter, macroscopic tangles, and microscopic telangiectases. The main complications of pulmonary arteriovenous malformations are believed to relate to right-to-left shunting of blood through the pulmonary arteriovenous malformations and include stroke and brain abscess, which together occur in up to one half of patients if untreated. However, the association of pulmonary hypertension is not common. In this case, a young woman with a pulmonary arteriovenous fistula localized to the left lower lobe coexisting with pulmonary hypertension is described. A 42-year-old woman was evaluated for progressively worsening exertional dyspnea. Her past medical history was unremarkable. The electrocardiogram revealed sinus rhythm with right ventricular hypertrophy with strain. Transthoracic echocardiography showed enlarged right atrium and ventricle with elevated right ventricular systolic pressure (tricuspid regurgitant jet velocity 4.8 m/s). There was no evidence of pulmonic stenosis. Chest computed tomography was performed to rule out chronic pulmonary embolism and revealed multiple pulmonary arteriovenous fistulas on the left lung, the largest (17mm) on left lower lobe-posterior basal segment, middle on the left lower lobe-medial basal segment, and the smallest on anterior segment of left upper lobe (Fig. 1). Contrast echocardiography was performed by intravenous injection of hand-agitated saline while visualizing the atria. Contrast appears in the left atrium 3 to 5 seconds after it is seen in the right atrium, suggestive of pulmonary arteriovenous fistula (Fig. 2). On cardiac catheterization, peak systolic and diastolic pressures of main pulmonary artery were 90 and 35 mmHg, respectively. Mean pulmonary artery wedge pressure was 11 mmHg. Angiography revealed a huge pulmonary arteriovenous fistula in the middle and lower lobes of the left lung (Fig. 3). The patient decided to be treated conservatively and discharged.

CONTINUOUS INTRAVENOUS INFUSION OF EPOPROSTENOL FOR THE TREATMENT OF PORTOPULMONARY HYPERTENSION1

The association of pulmonary hypertension with portal hypertension, also called portopulmonary hypertension (PPHTN), is a known complication of chronic liver disease. Previously, the presence of PPHTN was considered to be a contraindication to orthotopic liver transplantation (OLT). Although there are selected case reports of successful OLT in the setting of PPHTN, an excessive mortality rate is associated with OLT and PPHTN. Heretofore, therapy for chronic management of PPHTN was lacking. Recently, continuous intravenous infusion of epoprostenol has been demonstrated to improve symptomatology and survival in the general population of patients with primary pulmonary hypertension. We now report the use of epoprostenol in the more specific instance of PPHTN. Over a period of 6-14 months, epoprostenol (10-28 ng/kg/min) therapy was associated with a 29-46% decrease in mean pulmonary artery pressure, a 22-71% decrease in pulmonary vascular resistance, and a 25-75% increase in cardiac output in a group of four patients. These results suggest that effective chronic therapy for PPHTN is available. In conjunction with inhaled nitric oxide as acute intraoperative therapy, epoprostenol infusion represents an additional therapeutic option for treatment of PPHTN in the liver transplant candidate.

TOP STORIES OF 1997.

The Top Medical Stories of 1997 Each year, the Editors of Journal Watch choose the past year's top medical stories. Typically, stories emerge from a group of papers on a similar topic, rather than a single study. All citations are from 1997 unless otherwise stated. --AS Brett. A TURBULENT YEAR FOR DIET PILLS 1997 was a turbulent year for diet pills, beginning with carryover from the late-1996 concerns about the association of dexfenfluramine (dexfenfluramine) use and primary pulmonary hypertension ( JW Accession Number 960913001, or N Engl J Med 1996 Aug 29:335;609; also JW Accession Number 961115005). By mid-1997, dexfenfluramine and the combination of fenfluramine and phentermine, known as fen-phen, were in still bigger trouble. A case series and several additional cases reported in the New England Journal of Medicine ( JW Accession Number 970718001, or N Engl J Med Aug 28; 337:581; also JW Accession Number 970905001, or N Engl J Med Aug 28: 337;602, 629, 635, 636) found significant mitral, aortic, or tricuspid valve disease in 53 patients who had been taking fen-phen for an average of 10 months. By September, the FDA had received a total of 144 case reports of valvular disease associated with fen-phen or dexfenfluramine, of which 77 percent were symptomatic. The FDA also reported that 33 percent of 284 asymptomatic fen-phen and dexfenfluramine users had abnormal cardiac valves on echocardiography. Accordingly, the makers of dexfenfluramine and fenfluramine pulled them from the market, and the U.S. Department of Health and Human Services recommended that all dexfenfluramine or fen-phen users have a cardiac evaluation, with echocardiography for patients with positive physical findings or at risk for bacterial endocarditis ( MMWR Nov 14; 46:1061). In late November, the FDA did approve another serotonergic agent, sibutramine, after having rejected it in 1996 because of an association with risk for hypertension, …

Familial Association of Primary Pulmonary Hypertension and a New Low-Oxygen Affinity β-Chain Hemoglobinopathy, Hb Washtenaw

A Hungarian-American kindred with familial primary pulmonary hypertension (PPH) and a new, low-oxygen affinity beta-chain variant hemoglobin, Hb Washtenaw, is described. The index case presented with severe PPH and was found to have the abnormal hemoglobin. Two siblings with the abnormal hemoglobin also demonstrated increased pulmonary artery pressures on exercise echocardiography suggestive of early PPH. The occurrence of PPH and the abnormal hemoglobin could be due to genetic or biochemical factors or simply coincidental. A previous study had described a possible association of an abnormal beta-chain variant hemoglobin, Hb Warsaw, and PPH. It was suggested that the putative gene for familial PPH may be located near the beta-globin gene on chromosome 11. The association of PPH and the beta-chain variant hemoglobin in this kindred adds further support to this hypothesis.

Hypoxemia after Blunt Chest Injury: Right-To-Left Intracardiac Shunt Managed Non-Operatively

A case of patent foramen ovale with right-to-left intracardiac shunt after blunt chest injury is presented. The association of pulmonary contusion, pulmonary hypertension, and patent foramen ovale in a previously healthy subject is discussed. In such a case reduction of the afterload on the right ventricle is the suggested modality of treatment for hypoxemia due to the right-to-left shunt.

Evidence for the association of unexplained pulmonary hypertension in children with the major histocompatibility complex.

A link between primary pulmonary hypertension (PPH) and autoimmune disorders has been postulated. To investigate this relation, we performed immunofluorescent antinuclear antibody tests (ANA) and serological human leukocyte antigen (HLA)-A, B, C, DR, and DQ typing on two groups of Caucasian children with unexplained pulmonary hypertension (PHT) and their parents. Group 1 consisted of 17 children with PPH including two patients with familial PPH and three patients with trivial congenital pulmonary to systemic communications. Group 2 consisted of 13 children with advanced PHT and anatomically large congenital pulmonary to systemic communications (PHT + shunt). Both groups had comparably severe pulmonary vascular disease documented by cardiac catheterization. The following statistically significant data (p less than 0.05) were obtained when the study groups were compared with those published for normal controls. Although positive ANAs and varying titers of autoantibodies were found in both groups of children and mothers (not fathers), +ANAs were only significant for the maternal groups. The PPH (group 1) children had increased frequencies of HLA-DR3, DRw52, and DQw2 and decreased DR5, whereas the group 2 (PHT + shunt) children (also their parents) had no statistically significant alterations in any of the DR or DQ alleles. The PPH mothers had decreased DQw3, an allele in linkage disequilibrium with DR5. These immunogenetic data suggest that childhood PPH appears to be associated with the major histocompatibility complex alleles HLA-DR3, DRw52, and DQw2. This newly found correlation of juvenile PPH with these alleles adds this disease to the DR3+ group of autoimmune diseases. Further studies are needed to determine whether there is also an immunological or autoimmune component in some children with PHT + shunt lesions because this group lacked an HLA association.

Association of elective repeat cesarean delivery and persistent pulmonary hypertension of the newborn

Seventy-one cases of persistent pulmonary hypertension of the newborn have been reviewed in an attempt to identify possibly preventable causes. Three groups of infants were identified. The first group consisted of 36 infants with evidence of perinatal asphyxia. The second group was made up of 23 infants who exhibited a variety of associated factors including pneumonia, septic shock, and congenital diaphragmatic hernia. A third group included 12 infants delivered by elective repeat cesarean section. Infants in the third group did not have evidence of perinatal asphyxia, meconium aspiration, or infection. Chest roentgenograms revealed amniotic fluid aspiration in seven cases, retained lung fluid in three cases, and normal findings in two cases. All 12 infants in the third group developed respiratory distress which eventually progressed to respiratory failure and persistent pulmonary hypertension of the newborn. These data suggest that infants of elective repeat cesarean deliveries are at risk for developing persistent pulmonary hypertension of the newborn and constitute a group of patients with a potentially preventable course of events.

Idiopathic Pulmonary Hypertension Associated with Nodular Pulmonary Infiltrates and Portal Venous Thrombosis

A case of idiopathic pulmonary hypertension is associated with portal venous thrombosis. The patient's chest roentgenogram revealed numerous nodular densities which at necropsy were found to have been caused by an exuberant fibroblastic reaction around small pulmonary arterioles. This is an example of the unusual association of idiopathic pulmonary hypertension and portal venous thrombosis, and to our knowledge, the first report of roentgenographically visible pulmonary nodules secondary to the pathologic alterations of idiopathic pulmonary hypertension.

Laennec's cirrhosis and primary pulmonary hypertension

The association of cirrhosis and primary pulmonary hypertension has been rarely reported. This case report adds to the literature a case documented by liver biopsy and cardiac catheterization. The literature on this subject and potential pathophysiologic mechanisms of association are reviewed.

Cardiovascular Diseases: An Annotated Bibliography of Recent Literature

Cardiovascular Diseases: An Annotated Bibliography of Recent Literature

Tetralogy of fallot: Underdevelopment of the pulmonary infundibulum and its sequelae

It is proposed that the tetralogy of Fallot basically is a “monology”, just 1 anomaly, namely, underdevelopment of the subpulmonary infundibulum and its sequelae. The parietal band (crista supraventricularis) and the adjacent infundibular free wall together form an abnormally small cone (conus) of muscle beneath the pulmonary artery, whereas the septal band is normally formed. The hypothesis that the essence of tetralogy is an abnormally small subpulmonary conus is illustrated by angiocardiographic and anatomic findings in typical tetralogy compared with the normal. This unifying concept, which needs experimental embryologic assessment, facilitates angiocardiographic diagnosis of “masked” tetralogy in which the presence of this anomaly may be obscured by associated malformations. To demonstrate this, a rare case is presented, the fourth known patient with coexisting tetralogy and cor triatriatum. This 20 year old man also had a patent ductus arteriosus and a right pulmonary sequestration. The resulting systemic level of pulmonary hypertension “masked” the coexistence of tetralogy, which angiocardiography made evident. Despite the absence of a pulmonary outflow tract gradient due to the association of severe pulmonary hypertension, autopsy confirmed that this patient displayed the angiocardiographic hallmark of tetralogy: an abnormally small subpulmonary infundibulum.

Pulmonary hypertension due to pulmonary arterial coarctation.

With improved diagnostic methods many diseases which were previously grouped together as idiopathic can now be separated into etiologic categories. Essential pulmonary hypertension may succumb to reclassification, since several types are now found to be distinguishable on the basis of definite radiological and pathological changes (1, 27, 54). It is not only our duty to refine these idiopathic categories, but it is our privilege as physiologically oriented radiologists to try and understand the basic changes which make this refinement possible (49). There have been many recent reports (2, 6, 11, 14, 20, 41, 45, 48, 51, 53, 55, 58, 60) on supravalvular or postvalvular constriction, coarctation, or stenosis of the pulmonary arteries. Four mention the association of pulmonary hypertension with this condition (2, 11, 14, 41). It is our observation that the two are always associated. Four reports have appeared in the radiologic literature. This is apropos, since coarctation of the pulmonary artery can be diagnosed radiographically. Despite the manifest recent interest in the radiological anatomy of the pulmonary arteries and in the physiology of the lesser circulation, coarctation of the pulmonary artery was not even discussed in the recent International Symposium on the Pulmonary Circulation sponsored by the Chicago Heart Association in March 1958. It seems that up to the present the relationship between pulmonary hypertension and pulmonary coarctation has not been firmly established or generally recognized. Method of Study Three general methods of study are presented: first, an analysis and review of our own cases; second, an attempt to produce pulmonary arterial coarctation anatomically and to observe the effects, if any, upon the pulmonary blood pressure; third, a review of the world literature on the pulmonary artery coarctation made in an attempt to detect patterns, similarities, or syndromes which would prove helpful in the diagnosis. From clinical and angiocardiographic observations it appeared to us that such a relationship was a very likely probability. The intermediary between the anatomical malformation and its physiologic manifestation could be a hypothetical humoral material, a neurogenic response or a hydrostatic reaction to the mechanical constriction observed. This problem seemed to invite a combined radiological and physiological experimental attack. The major premise, however, is the only one which we have tested. The secondary hypotheses are in the process of exploration. Clinical Observations Seven children who were seen in the cardiac clinics of the University of California (Los Angeles) were found to have pulmonary arterial coarctation. All of these children had pulmonary hypertension. During this same three-year period 68 other children with pulmonary hypertension were observed among 330 who had had diagnostic heart catheterization and/or angiocardiography.