Hypertensive Pulmonary Vascular Disease Research Articles

Pediatric Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) can cause morbidity and mortality in children. Although adult and pediatric PAH share many similarities, many differences have been found in children. Thus, a new classification for pediatric pulmonary hypertensive vascular disease has been proposed. Both child and adult gene mutation carriers with PAH tend to have worse prognoses. Pediatric patients present with better preserved functional class, and parents should pay high attention to any children with unexplained shortness of breath, fatigue or syncope, as symptoms of PAH in children are often misleading. Right heart catheterization is necessary for diagnosis. Although there are few medications approved for pediatric PAH and evidence-based treatment algorithms for children are still lacking, the survival of pediatric patients has been improved significantly since targeted therapies approved for adults were introduced to pediatric patients. PAH in children is unique, and further studies are needed to have a better understanding of it.

An Unusual Cause of Congestive Heart Failure in a Young Woman

BackgroundCongestive heart failure (CHF) is a common Emergency Department (ED) disorder that accounts for >5 million ED visits annually. Although quite rare, patent ductus arteriosus (PDA) is a serious cause of CHF that if left untreated can lead to life-threatening sequelae, such as hypertensive pulmonary vascular disease, endarteritis, and aneurysms of the ductus. ObjectiveTo discuss a case of PDA leading to CHF that illustrates one of the common complications of untreated PDA. Case ReportA 35-year-old woman presented to the ED with a 2-month history of shortness of breath, dyspnea on exertion, decreased exercise tolerance, and orthopnea. The physical examination revealed a 4/6 continuous machine-like murmur. In the presence of new CHF and an atypical murmur, a transthoracic echocardiogram was performed that confirmed the diagnosis of PDA. She underwent an uncomplicated percutaneous closure of the ductus with significant improvement in her symptoms. ConclusionsPersistent PDA in adulthood is a rare but important cause of CHF with significant morbidity and mortality if not appropriately diagnosed and treated.

Hemodynamic Improvement of Pulmonary Arterial Hypertension After Bariatric Surgery: Potential Role for Metabolic Regulation

Insulin resistance, metabolic syndrome, and adipokine dysregulation are now implicated in hypertensive pulmonary vascular disease (1–3). Even in nonobese humans with idiopathic pulmonary arterial hypertension (IPAH), the prevalence of insulin resistance is nearly 50% (1,2), suggesting a link between glucose dysregulation and IPAH. Additionally, IPAH develops spontaneously in animal models of obesity and adipokine alterations (4). The underlying mechanisms by which metabolic mediators exacerbate or cause pulmonary vascular disease are unknown. We tested the hypothesis that improvements in metabolic hormones are associated with amelioration of pulmonary hemodynamics in a 48-year-old morbidly obese female IPAH patient who underwent bariatric surgery. Despite no change in IPAH therapy, she had dramatic hemodynamic improvement coupled with reduced insulin resistance, plasma lipids, and cholesterol levels. The IPAH patient was New York Heart Association functional class III and desired bariatric surgery. After counseling about elevated …

Dehydroepiandrosterone, Over-studied but Under-used in the Treatment of Vascular Remodeling Diseases

Vascular remodeling is characterized by a narrowing of the lumen of the vessels, resulting in decreased blood flow, increased pressure and heart failure. This process is found in diseases like atherosclerosis, restenosis after angioplasty, transplants coronary disease, systemic and pulmonary hypertensive vascular disease, and is stimulated by elevated levels of cholesterol, inflammation, oxidative stress, excess of vasodilating molecules and growth factors. Efficient treatments able to fix or prevent the progression of this process are still missing. The hormone dehydroepiandrosterone (DHEA), which levels decrease with aging while cardiovascular risks increase, was hypothesized to have a role in the pathophysiology of vascular diseases. Despite the fact that numerous properties such as fat-reducing, anti-oxidant, vasodilating, anti-inflammatory and anti-proliferative have emerged from two decade of studies, DHEA remain clinically underused in the treatment of vascular remodeling diseases. The lack of understanding of the exact mechanism of action and some controversial epidemiological studies are not foreign to the fact that DHEA is shunned. Nonetheless, we believe that DHEA cannot be ignored since promising results were obtained pre-clinically and clinically in the treatment of vascular remodeling diseases. We are probably close to understand the function of this molecule, especially by its action as a peroxisome proliferator, and it will be a shame to deprive patient of a way to improve their quality of life, or worst a way to extend their survival.

Clinical Trials in Neonates and Children: Report of the Pulmonary Hypertension Academic Research Consortium Pediatric Advisory Committee

Drug trials in neonates and children with pulmonary hypertensive vascular disease pose unique but not insurmountable challenges. Childhood is defined by growth and development. Both may influence disease and outcomes of drug trials. The developing pulmonary vascular bed and airways may be subjected to maldevelopment, maladaptation, growth arrest, or dysregulation that influence the disease phenotype. Drug therapy is influenced by developmental changes in renal and hepatic blood flow, as well as in metabolic systems such as cytochrome P450. Drugs may affect children differently from adults, with different clearance, therapeutic levels and toxicities. Toxicity may not be manifested until the child reaches physical, endocrine and neurodevelopmental maturity. Adverse effects may be revealed in the next generation, should the development of ova or spermatozoa be affected. Consideration of safe, age-appropriate tablets and liquid formulations is an obvious but often neglected prerequisite to any pediatric drug trial. In designing a clinical trial, precise phenotyping and genotyping of disease is required to ensure appropriate and accurate inclusion and exclusion criteria. We need to explore physiologically based pharmacokinetic modeling and simulations together with statistical techniques to reduce sample size requirements. Clinical endpoints such as exercise capacity, using traditional classifications and testing cannot be applied routinely to children. Many lack the necessary neurodevelopmental skills and equipment may not be appropriate for use in children. Selection of endpoints appropriate to encompass the developmental spectrum from neonate to adolescent is particularly challenging. One possible solution is the development of composite outcome scores that include age and a developmentally specific functional classification, growth and development scores, exercise data, biomarkers and hemodynamics with repeated evaluation throughout the period of growth and development. In addition, although potentially costly, we recommend long-term continuation of blinded dose ranging after completion of the short-term, double-blind, placebo-controlled trial for side-effect surveillance, which should include neurodevelopmental and peripubertal monitoring. The search for robust evidence to guide safe therapy of children and neonates with pulmonary hypertensive vascular disease is a crucial and necessary goal.

041 Non-Invasive Assessment of Right Heart and Pulmonary Vascular Coupling in Children With Pulmonary Hypertensive Vascular Disease: A Simultaneous Echocardiographic and Catheterization Study

Cardiac catheterization is the gold standard for assessment of hemodynamics in children with pulmonary hypertensive vascular disease (PHVD). There is a need for accurate, non-invasive correlates of these hemodynamics. We aimed to identify correlations between echocardiographic and catheter parameters in children undergoing cardiac catheterization to investigate PHVD.

Nonketotic Hyperglycinemia Presenting as Pulmonary Hypertensive Vascular Disease and Fatal Pulmonary Edema in Response to Pulmonary Vasodilator Therapy

The association of pulmonary hypertensive vascular disease with nonketotic hyperglycinemia is rare. We describe 5infants diagnosed with nonketotic hyperglycinemia, in whom pulmonary hypertensive vascular disease was themain presenting feature, and who developed severe pulmonary edema in response to pulmonary vasodilators.

Advances in pediatric pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is an important cause of morbidity and mortality in children. Approved medications for the treatment of adult PAH have been used to treat children, but evidence-based treatment algorithms for children are lacking. Pediatric PAH registries have begun to define the incidence and prevalence of idiopathic PAH and PAH associated with congenital heart disease. A pediatric-specific classification of pulmonary hypertensive vascular disease has been proposed. Furthermore, the first randomized placebo-controlled trial of type-5 phosphodiesterase therapy in treatment-naïve children with PAH has been completed and reported. This trial highlights the importance of the difficulties of performing clinical trials in children with targeted PAH therapy as well as the importance of long-term follow-up of adverse events. Classification, clinical trials, and therapy for children with PAH must take into account the unique aspects of PAH in children.

Neonatal and Childhood Pulmonary Hypertension - An Update (2012)

Although substantial advances have been made in our understanding of pulmonary hypertensive vascular disease there remain important challenges to overcome in designing pediatric drug trials and improving long term survival. We address the current classifications and review the current knowledge on epidemiology, pathogenesis and therapy of pulmonary hypertension.

Classification of Pediatric Pulmonary Hypertensive Vascular Disease: Does it Need to Be Different from the Adult Classification?

Classification of Pediatric Pulmonary Hypertensive Vascular Disease: Does it Need to Be Different from the Adult Classification?

A Consensus Approach to the Classification of Pediatric Pulmonary Hypertensive Vascular Disease: Report from the PVRI Pediatric Taskforce, Panama 2011

Current classifications of pulmonary hypertension have contributed a great deal to our understanding of pulmonary vascular disease, facilitated drug trials, and improved our understanding of congenital heart disease in adult survivors. However, these classifications are not applicable readily to pediatric disease. The classification system that we propose is based firmly in clinical practice. The specific aims of this new system are to improve diagnostic strategies, to promote appropriate clinical investigation, to improve our understanding of disease pathogenesis, physiology and epidemiology, and to guide the development of human disease models in laboratory and animal studies. It should be also an educational resource. We emphasize the concepts of perinatal maladaptation, maldevelopment and pulmonary hypoplasia as causative factors in pediatric pulmonary hypertension. We highlight the importance of genetic, chromosomal and multiple congenital malformation syndromes in the presentation of pediatric pulmonary hypertension. We divide pediatric pulmonary hypertensive vascular disease into 10 broad categories.

Sildenafil therapy for neonatal and childhood pulmonary hypertensive vascular disease

We hypothesised that sildenafil would improve hemodynamics in children with pulmonary hypertension and attenuate rebound pulmonary hypertension after inhaled nitric oxide withdrawal. We undertook an open-label, single-drug study of sildenafil in patients under 5 years of age with either symptomatic or rebound pulmonary hypertension following inhaled nitric oxide withdrawal. We recruited 25 patients (median age 180 days, 10-1790) to receive sildenafil. The median right ventricular to systemic systolic blood pressure ratio before sildenafil therapy was 1.0 (0.5-1.4) and decreased to 0.5 (with a range from 0.3 to 1.3; p = 0.0002). In five patients the baseline pulmonary vascular resistance index was 10 (7.1-13.6) Wood units metre square and decreased to 5.8 (2.7-15.6) Wood units metre square (p = 0.04) at 6 months. Ten patients were treated with sildenafil for a median of 34 days (9-499) until resolution of pulmonary artery hypertension and continue to do well. Six patients continued sildenafil therapy for a median of 1002 days (384-1574) with improvement but without resolution of pulmonary hypertension. There was no change in serum creatinine, urea, liver function tests, or platelet count. In 15 patients sildenafil abolished rebound pulmonary artery hypertension following withdrawal of inhaled nitric oxide. Median right ventricular pressure to systemic systolic pressure ratio decreased from 1.0 (0.8-1.4) during nitric oxide withdrawal to 0.4 (0.3-0.8) p = 0.006 after pre-treatment with sildenafil. In children under 5 years of age with severe pulmonary hypertension, sildenafil therapy resulted in prolonged hemodynamic improvements without adverse effects. Sildenafil attenuated rebound pulmonary hypertension after withdrawal of inhaled nitric oxide.

Pulmonary Aterial Hypertension in an Adolescent Treated with Methylphenidate

Journal of Child and Adolescent PsychopharmacologyVol. 20, No. 3 Letters to the EditorPulmonary Aterial Hypertension in an Adolescent Treated with MethylphenidateMehmet Goksin Karaman, Figen Atalay, Ali Evren Tufan, and Ayten ErdoganMehmet Goksin KaramanZonguldak Karaelmas University Medical Faculty, Department of Child and Adolescent Psychiatry, Zonguldak, Turkey.Search for more papers by this author, Figen AtalayZonguldak Karaelmas University Medical Faculty, Department of Child and Adolescent Psychiatry, Zonguldak, Turkey.Search for more papers by this author, Ali Evren TufanDepartment of Child and Adolescent Psychiatry, Elazig Hospital for Mental Disorders, Elazig, Turkey.Search for more papers by this author, and Ayten ErdoganZonguldak Karaelmas University Medical Faculty, Department of Child and Adolescent Psychiatry, Zonguldak, Turkey.Search for more papers by this authorPublished Online:26 Jun 2010https://doi.org/10.1089/cap.2009.0095AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited byA second hit? Pulmonary arterial hypertension, BMPR2 mutation, and exposure to prescription amphetamines14 March 2022 | Pulmonary Circulation, Vol. 12, No. 1No Good Deed Goes UnpunishedChest, Vol. 159, No. 3Use of methylphenidate and risk for valvular heart disease: A case‐control study nested in the BIFAP cohort30 January 2020 | Pharmacoepidemiology and Drug Safety, Vol. 29, No. 3Amphetamine-induced sensitization of hypertension and lamina terminalis neuroinflammationAmerican Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 318, No. 3Drug-associated pulmonary arterial hypertension6 March 2018 | Clinical Toxicology, Vol. 56, No. 9Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents - assessment of adverse events in non-randomised studies10 May 2018 | Cochrane Database of Systematic Reviews, Vol. 48Stimulants and Pulmonary Arterial Hypertension: An UpdateAdvances in Pulmonary Hypertension, Vol. 17, No. 2Anorexigen-Associated Pulmonary Arterial Hypertension and the Serotonin Hypothesis: A Story Worth TellingAdvances in Pulmonary Hypertension, Vol. 17, No. 2Methylphenidate off-label use and safety7 June 2014 | SpringerPlus, Vol. 3, No. 1Updated Clinical Classification of Pulmonary HypertensionJournal of the American College of Cardiology, Vol. 62, No. 25Possible Association with Amphetamine Usage and Development of High Altitude Pulmonary EdemaWilderness & Environmental Medicine, Vol. 23, No. 4Consenso sobre la clasificación de la enfermedad vascular pulmonar hipertensiva en niños: Reporte del task force pediátrico del Pulmonary Vascular Research Institute (PVRI) Panamá 2011Revista Colombiana de Cardiología, Vol. 19, No. 6A Consensus Approach to the Classification of Pediatric Pulmonary Hypertensive Vascular Disease: Report from the PVRI Pediatric Taskforce, Panama 20111 April 2011 | Pulmonary Circulation, Vol. 1, No. 2 Volume 20Issue 3Jun 2010 InformationCopyright 2010, Mary Ann Liebert, Inc.To cite this article:Mehmet Goksin Karaman, Figen Atalay, Ali Evren Tufan, and Ayten Erdogan.Pulmonary Aterial Hypertension in an Adolescent Treated with Methylphenidate.Journal of Child and Adolescent Psychopharmacology.Jun 2010.229-231.http://doi.org/10.1089/cap.2009.0095Published in Volume: 20 Issue 3: June 26, 2010PDF download

Postoperative pathology of congenital heart disease

The evaluation of congenitally malformed hearts that have been subjected to operative and nonoperative interventions includes not only a categorization of the underlying anomalies and various procedures but also an assessment of interventional complications, postprocedural changes in chamber, valvular, and vascular sizes, presence of ischemia or fibrosis, presence of cardiac or extracardiac infections, and evidence of regression or progression of hypertensive pulmonary vascular disease. Input from clinicians or surgeons may be helpful, but biases should be avoided. Referral of cardiopulmonary specimens to experienced pathologists may also be considered.

Histopathology of pulmonary hypertensive diseases

The spectrum of histopathological lesions of pulmonary hypertensive vascular disease is extraordinarily varied. A number of distinct patterns can be recognized, and these correlate with aetiological factors and clinical data. Recent research has yielded important new insights on the pathogenesis of pulmonary hypertension at the molecular and cellular level, and various key mechanisms are emerging. These include induction and maintenance of vasoconstriction, endothelial activation and proliferation, and thrombosis. In the light of these developments, a re-evaluation of lesions at the histopathological level is receiving a new level of significance, as histological data complement those from research based on non-morphological techniques. We review the main histopathological features of hypertensive pulmonary vascular disease in this perspective.

Invited commentary

The present article by Sachweh and colleagues [1Sachweh J.S. Daebritz S.H. Hermanns B. et al.Hypertensive pulmonary vascular disease in adults with secundum or sinus venosus atrial septal defect.Ann Thorac Surg. 2006; 81: 207-213Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar] is important because it is a rare series of adult atrial septal defect (ASD) patients that were worked up and studied in a systematic manner at a single institution using preoperative catheterization and lung biopsy at the time of repair in all patients. This allowed the authors to perform some valid, albeit retrospective, analysis of a problem that is not hugely prevalent, but is nevertheless encountered with some frequency by most heart surgeons. When confronted with an adult ASD patient with an elevated pulmonary artery (PA) pressure, the following questions arise: is surgery safe and at what level of PA pressure and pulmonary vascular resistance? Such a patient should be evaluated for device closure, given that one can temporarily balloon occlude the ASD and observe hemodynamics and the effect of cardiopulmonary bypass on hypertensive lungs is avoided. Assuming the patient is not a candidate for device closure, there are no clear-cut current guidelines that can guide surgical decision-making. Unfortunately, although the present study is very instructive, it still leaves the clinician with no definitive answer to the previously posed question. An important statement of this article is the sentence that states: “Preoperative hemodynamic data do not predict the degree of hypertensive pulmonary vascular disease (HPVD) in lung biopsy specimens.” Other criteria that did not influence development of HPVD were defect size and age of the patient. Indeed, the mean Qp/Qs in group III (those with histologic changes considered irreversible) was 2.9. Of course, as acknowledged by the authors, a major limitation is that lesions may be irregularly distributed among the lung segments; thus a lung biopsy will not be representative of the entire lung. Nevertheless this suggests that we have much to learn yet about what causes HPVD and why certain patients have HPVD develop at a younger age and why others do not.

Hypertensive Pulmonary Vascular Disease in Adults with Secundum or Sinus Venosus Atrial Septal Defect

The development of hypertensive pulmonary vascular disease (HPVD) is considered a risk factor in the long-term course of patients with secundum atrial septal defects (ASD). The aim of this study was to assess the prevalence and histologic degree of HPVD and pulmonary hypertension in relation to preoperative clinical and hemodynamic data, intraoperative findings, and operative outcome in adults. Lung biopsies of 75 patients, mean age 44 +/- 14 years (18-71 years), with secundum ASD or sinus venosus defect including ten patients with partial anomalous pulmonary venous return were analyzed in accordance with preoperative and intraoperative findings as well as operative outcome. Lung biopsy was performed at the time of defect closure and was classified according to Heath and Edwards. Structural changes of the pulmonary vasculature were found in 59% of patients; grade 3 and higher changes were present in 19%. There were no statistically significant relations between histologic findings and preoperative clinical and hemodynamic data, intraoperative findings, and operative outcome. The prevalence of moderate (32-50 mm Hg) and severe (> 50 mm Hg) systolic pulmonary hypertension was 27% and 17%, respectively. Increased systolic pulmonary arterial pressure was associated with increased pulmonary vascular resistance (p < 0.000) and patients' age (p = 0.001). Patients with a lower functional capacity had a higher prevalence of pulmonary hypertension (p = 0.011). The prevalence of HPVD and pulmonary hypertension in adult patients with secundum ASD or sinus venosus defect is considerable. Preoperative hemodynamic data do not predict the degree of HPVD in lung biopsy. Closure is generally advised to prevent increasing pulmonary arterial pressure and decreasing functional capacity over time.

Seeking a Consensus on PH: Challenges Left by the Venice Symposium

The Venice Symposium was a unique assemblage of physicians and scientists representing a variety of disciplines ranging from pulmonary medicine to cardiology, rheumatology, pathology, genetics, molecular biology, and surgery, all with a common interest in pulmonary vascular disease. The state-of-the-art overviews provided not only a perspective of where we are and how we got there, but also glimpses into the future of new and exciting directions in basic and translational research. The opportunity for basic investigators, clinical researchers, and representatives from industry to interact and explore new avenues to pursue will undoubtedly lead to fruitful collaborations and innovative approaches to the understanding, and ultimately the cure, of hypertensive pulmonary vascular disease. It is remarkable that, despite the attendance by several hundred individuals, a consensus on major issues was reached, including the adoption of a revised nomenclature. - Lewis Rubin, MD, University of California at San Diego.

Complex Vascular Lesions at Autopsy in a Patient With Phentermine-Fenfluramin

To the Editor.—In the June 1999 issue of the Archives, Strother et al1 reported the case of a middle-aged woman who had ingested phentermine and fenfluramine for weight reduction during 8 months. The lesions of pulmonary muscular arteries shown in Figure 1, A and B, which the authors interpreted as focal organizing thrombi, are, in my opinion, plexiform lesions. The lesion in Figure 1, A, is intimal hyperplasia, and Figure 1, D, represents arterial necrosis. These lesions correspond to grades IV, II, and VI, respectively, in the grading system established by Heath and Edwards2 for the lesions of muscular arteries of 100 μm to 1000 μm diameter in pulmonary hypertensive vascular disease or to pulmonary plexogenic arteriopathy as proposed by a World Health Organization Working Group.3 My opinion is established on the morphologic study of the lungs of 37 patients who died in Switzerland after having ingested aminorex fumarate (another weight-reducing pill)4 during the so-called aminorex epidemic reviewed by Gurtner.5 Pulmonary hypertensive vascular disease affected 582 patients in Austria, former West Germany, and Switzerland during a limited period: from 1965, when the drug was introduced, until 1968, when it was withdrawn from the market. None of our cases showed arterial thromboses.In 2 cases of phentermine-related pulmonary hypertensive vascular disease submitted for assessment (unpublished data), I found similar vascular lesions. However, none of the patients (aminorex or phentermine cases) showed any correlation between the severity of the lesions and the drug intake (quantity or duration).In the absence of any serious experimental model published, the mechanism by which the lesions related to anorexigens (aminorex, phentermine, or fenfluramine hydrochloride) remains unexplained. One can only hypothesize that in some people (about 0.2% in the aminorex cases), some factors did cause an increase in the tonus of muscular pulmonary arteries, which was followed by a vasospasm, resulting in an endothelial lesion on which fibrinoid material was deposited, producing intimal proliferation. The latter, rich in myointimal cells and smooth muscular cells, might have contributed to the aggravation of the pulmonary hypertension induced by the vasospasm.I agree with the question Strother et al raised about the risk-benefit operation of the new anorexigens, which in turn leads to the more serious inquiry into unrecognized cases of pulmonary hypertensive disease in the countries where these drugs are marketed.

Pulmonary vasculopathy in idiopathic spontaneous pneumothorax in young subjects.

We have encountered instances where young subjects with idiopathic spontaneous pneumothorax have been needlessly referred for investigation of pulmonary hypertension because surgical pathologists have misinterpreted the significance of medial hypertrophy and intimal fibrosis of muscular pulmonary arteries in lung resection specimens. We reviewed 20 cases of idiopathic spontaneous pneumothorax and determined the prevalence and severity of medial and intimal lesions in the pulmonary arteries and pulmonary veins. We correlated the vascular changes with inflammation and fibrosis in the lung. Pulmonary artery medial hypertrophy was seen in 15% of cases, pulmonary artery intimal fibrosis in 90% of cases, and pulmonary vein intimal fibrosis in 80% of cases. In 95% of cases, the lung showed some fibrosis and chronic inflammation. There was a significant positive correlation between pulmonary artery medial thickness and lung fibrosis and inflammation scores. Pulmonary artery medial hypertrophy and intimal fibrosis of pulmonary arteries and pulmonary veins are commonly seen in resected lung tissue from patients with idiopathic spontaneous pneumothorax. The vascular lesions are probably secondary to chronic inflammation and fibrosis in the adjacent lung. They are not clinically significant and do not represent hypertensive pulmonary vascular disease.