Cases Of Primary Pulmonary Hypertension Research Articles

Progress in the understanding and management of pulmonary arterial hypertension.

In 1981 the “Patient Registry for the Characterization of Primary Pulmonary Hypertension” was set up, supported by the National Heart, Lung and Blood Institute, and recruited 194 patients across 32 clinical centres over 4 years in the United States1,2. The estimated median survival of these incident cases of primary pulmonary hypertension (which approximates to what we would now term idiopathic pulmonary arterial hypertension, IPAH) was 2.8 years, with a 68% survival rate at 1 year, 48% at 3 years and 35% at 5 years1. Since 2000 a number of national registries have been set-up across the world to study the developing epidemiology of pulmonary arterial hypertension (PAH)3. The largest of these is the REVEAL (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) Registry in the United States4. Between 2006 and 2009, 2635 prevalent and incident cases were included in survival analysis across 55 centres. For IPAH, there was a 91% survival rate at 1 year, 74% at 3 years and 65% at 5 years4. The Spanish registry also recruited 866 prevalent and incident cases of IPAH between 2007 and 2008 and calculated 1-, 3- and 5-year survival rates of 87%, 75% and 65% respectively5. In the French registry, which also analysed prevalent and incident cases, for a sub-population of 190 patients with IPAH, hereditary PAH (HPAH) and anorexigen-associated PAH cases (which all have similar baseline characteristics and outcomes) between 2002 and 2003, a 1-year survival rate of 83% and 3-year of 58% was calculated6,7. In the UK there was a focus on incident cases, and 482 patients with IPAH, HPAH, and anorexigen-associated PAH were included between 2001 and 2009 and had 1-, 3- and 5-year survival rates of 93%, 73% and 61% respectively8. Although there is debate about the inclusion of both prevalent and incident cases in these registries (owing to survivor bias), there is broad agreement over current survival rates across these registries. Measurable progress has been made in the management of pulmonary arterial hypertension over the last 33 years – now, at 5 years, a larger proportion of people are living with the disease, rather than dying from it. In this review article we take a historical approach to reflect on the journey that has brought us to where we are today, focussing on the key milestones in the management of pulmonary arterial hypertension, signposted by the World Health Organisation (WHO) “World Symposia in Pulmonary Hypertension”. It will become apparent that this mirrors the developments and movements in medicine over the last 150 years: from pathology to physiology, from physiology to pharmacology, from pharmacology to cell biology, from cell biology to genetics9.

Pulmonary Veno-Occlusive Disease: A Rare Cause of Pulmonary Hypertension

Supported by CVPath Institute, Inc. (Gaithersburg, MD). Accepted for publication November 25, 2014. Disclosures: R.V. receives research support from Abbott Vascular, BioSensors International, Biotronik, Boston Scientific, Medtronic, MicroPort Medical, OrbusNeich Medical, SINO Medical Technology, and Terumo Corporation; has speaking engagements with Merck; receives honoraria from Abbott Vascular, Boston Scientific, Lutonix, Medtronic, and Terumo Corporation; and is a consultant for 480 Biomedical, Abbott Vascular, Medtronic, and W.L. Gore. K.Y. reports no conflicts of interest relevant to the topic of this manuscript. Address correspondence to Renu Virmani, M.D., CVPath Institute, Inc., 19 Firstfield Rd., Gaithersburg, MD 20878. E-mail: rvirmani@cvpath.org. Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension (PH), characterized by increased pulmonary artery pressure contributing to right heart failure and death. Historically, PVOD has been described by diverse terms, such as isolated pulmonary venous sclerosis, obstructive disease of the pulmonary veins, or venous form of primary pulmonary hypertension (PPH). The true incidence of PVOD is uncertain, considering that a large number of PPH cases are misclassified. The estimated frequency of PVOD is between 5% to 25%; however, 10% incidence of PVOD in a pooled analysis of seven studies totaling 465 PPH cases examined between 1970 and 1991 has also been reported. The noninvasive diagnosis of PVOD in cases confirmed by histology-identified clinical features of pulmonary arterial hypertension (PAH) include: >10 pack per year smoking history, high-resolution CT showing nodular ground glass opacities, septal lines, lymph node enlargement, and pleural effusion with occult alveolar hemorrhage confirmed by bronchoalveolar lavage. In 1975, the World Health Organization (WHO) further classified pulmonary hypertension (PH) into primary or secondary PH. In 1998, the WHO established a clinical classification of PH to include five groups, which share similar pathological and hemodynamic etiologies and therapeutic approaches to treatment. The clinical classification of PH includes i) PAH, ii) PH due to left heart disease, iii) PH due to lung disease and/or hypoxia, iv) chronic thromboembolic pulmonary hypertension, and v) PH with unclear multifactorial mechanism. This consensus has remained the same with some modifications published in 2009 and during the 2013 meeting of the Fifth World Symposium. Major categories of PAH include sporadic or idiopathic PAH, heritable PAH, and PAH attributed to drugs and toxins, congenital heart disease, and others. The PAH classification also includes PVOD classified as Group 1, which is

症例 経口PGI2が著効したが,肺動静脈瘻,脊髄部動静脈瘻を合併した原発性肺高血圧症の1例

症例 経口PGI2が著効したが,肺動静脈瘻,脊髄部動静脈瘻を合併した原発性肺高血圧症の1例

Primary Pulmonary Hypertension: A Case Report

Primary pulmonary hypertension (PPH) is a rare disease which usually presents with shortness of breath. We report a case of a female patient who presented with dyspnoea. We diagnosed her as a case of PPH on the basis of detailed history, careful physical examination and common investigations like electrocardiogram (ECG), chest radiography and Doppler echocardiograhy. DOI: http://dx.doi.org/10.3329/jemc.v1i2.11468 J Enam Med Col 2011; 1(2): 81-84

A case of primary pulmonary hypertension diagnosed at postpartum

원발성 폐동맥고혈압은 아주 드문 질환으로 임신부에게 잘 나타나지 않으나, 이러한 환자가 임신하게 되면 높은 사망률과 유병률을 보 이므로 임신은 금기이다. 또한 원발성 폐동맥고혈압을 잠재적으로 가지고 있어 평소 증상이 없는 여성이 임신을 한 경우에도 임신 시의 생리적 혈액량의 증가만으로도 폐동맥고혈압을 더욱 악화시킴으로써 심장에 부담을 가중시켜 심부전을 일으키게 되어 사망까지 이를 수 있다. 저자들은 임신 22주에 자궁경부무력증으로 입원하여 봉축수술 후 절대 안정 가료 치료로 임신 중 특이 증상을 보이지 않다가, 임신 30주 6일에 조기질식 분만 후 퇴원하였다가 분만 후 7일째 갑자기 발생한 호흡곤란 주소로 내원한 환자에서 다른 검사에서 이상이 없어 원발성 폐동맥고혈압으로 최종 진단한 1예를 경험하였기에 문헌고찰과 함께 보고하는 바이다.

GDF5 and BMP2 inhibit apoptosis via activation of BMPR2 and subsequent stabilization of XIAP

GDF5 and BMP2, members of the TGF-β superfamily of growth factors, are known to regulate apoptosis in different cell types either positively or negatively. We wanted to investigate the effects of GDF5 and BMP2 on vascular smooth muscle cells and mouse embryonic fibroblasts and disclose the mechanism by which GDF5 and BMP2 might exert anti-apoptotic effects. The effect of GDF5 and BMP2 on proliferation and/or programmed cells death was assessed in isolated human vascular smooth muscle cells and mouse embryonic fibroblasts. We demonstrate that GDF5 and BMP2 prevent apoptosis induced by serum starvation in mouse embryonic fibroblasts but not in smooth muscle cells via the BMP receptor 2 (BMPR2), which is often mutated in hereditary cases of primary pulmonary hypertension. GDF5 and BMP2 stimulate the interaction of BMPR-2 with XIAP thereby reducing the ubiquitination of XIAP, which results in enhanced protein stability. The increased concentration of XIAP counteracts apoptosis by binding and inactivating activated caspases. We conclude that the inhibition of apoptosis in mouse embryonic fibroblasts by BMP2 and GDF5 does not depend on more complex signal transduction pathways such as smad and MAPK signaling but on direct stabilization of XIAP by BMPR2.

Hypertension artérielle pulmonaire primitive familiale révélée par l’association bilatérale chémosis, myopisation et exophtalmie

To report a rare case of primary pulmonary hypertension (PPH) revealed by a relapsing chemosis, exophthalmos, and subacute myopia. A 46-year-old woman presented with recurrent bouts of chemosis, exophthalmos, and subacute myopia. Her visual troubles were triggered by physical effort. She had a history of a longstanding high blood pressure that was noncompliant to all conventional hypotensive therapy. Automated refraction under cycloplegia showed recent myopia. At observation she had a bilateral, moderate chemosis. Hertel exophthalmometer measured a symmetric exophthalmos of 23 mm. Intraocular pressure was 20 mmHg OD and 24 mmHg OS. Eye fundus was strictly normal. Laboratory analysis showed no thyroid or inflammatory disease. HIV serology was negative as were antinuclear antibodies. Orbital CT confirmed the axial, symmetric exophthalmos. Echocardiogram brought out the diagnosis of PPH. Genetic studies by PCR localized the BMPR2 mutation that is characteristic of the familial type of PPH. Symptoms decreased under treatment. PPH is a rare disease caused by thickening of the arteriolar walls in the pulmonary bed, which results in a right-heart hypertension with venous stasis. Many authors have reported different posterior segment diseases secondary to PPH. However, anterior segment manifestations are extremely rare. These may be caused by a ciliary body congestion and retrobulbar vasodilatation. The association of chemosis, exophthalmos, and subacute myopia is unusual in PPH. We recommend keeping in mind the PPH as a differential diagnosis in those cases, especially in patients who suffer from high blood pressure.

Prostacyclin Synthase Promoter Regulation and Familial Pulmonary Arterial Hypertension

Primary pulmonary hypertension (PPH) is a rare disease of unknown etiology characterized by sustained elevations in pulmonary artery pressure. Familial PPH accounts for approximately 6% of cases of PPH and has an autosomal-dominant mode of inheritance. Studies over the last 15 years have identified that both familial and sporadic cases of PPH have an association with mutations in the bone morphogenic protein receptor (BMPR) type II gene. Prostacyclin (PGI2) is currently the standard of care for most patients with severe PPH. Prostacyclin synthase (PGIS) catalyzes the production of PGI2 from prostaglandin H2 and is a critical regulatory step in PGI2 production. Decreased or absent expression of PGIS in the pulmonary microvasculature has been reported in patients with PPH, raising the potential for PGIS as a disease modifying gene. We hypothesize that functional mutations in the PGIS promoter affect transcription regulation of PGI2 production and play a pivotal role in PPH pathogenesis.

Severe Left Ventricular Dysfunction Secondary to Primary Pulmonary Hypertension: Bridging Therapy With Bosentan Before Lung Transplantation

When right ventricular failure develops secondary to primary pulmonary hypertension, right-left ventricular interaction may lead to severe impairment of left ventricular function. In such cases, many experts favor combined heart-lung transplantation by fear that the left ventricle may not recover after transplantation of the lungs alone. We report a case of primary pulmonary hypertension with severely diminished right and left ventricular function. The patient was rendered amenable to isolated pulmonary transplantation with the endothelin-receptor antagonist bosentan. The medication improved right and left ventricular function to the point that heart transplantation no longer appeared necessary. After double-lung transplantation the patient's cardiac function made a full recovery. This approach might be particularly welcome considering both the current donor organ shortage and the limited number of surgical teams with expertise in heart-lung transplantation.

Evidence for reduced SMAD signalling in diverse forms of pulmonary arterial hypertension (PAH)

Mutations in BMPR2, the gene encoding the type II bone morphogenetic protein receptor (BMPR-II), underlie many cases of primary pulmonary hypertension (PPH). PAH is characterised by an increased pulmonary vascular resistance in response to obliteration of small arteries by myofibroblast and endothelial cell proliferations (lesions). Mutant BMPR2 may disrupt downstream signalling leading to disordered vascular cell differentiation and proliferation. We explored BMPR-II, phosphorylated Smad (pSmad1) and Smad ubiquitination regulatory factor-1 (SMURF1; a Smad inhibitor), expression in PPH and in PAH due to other causes.

高齢男性に発症した原発性肺高血圧症の１例

A rare case of primary pulmonary hypertension was observed in a 73-year-old man. Angina pectoris was diagnosed at the age of 67 and he received several percutaneous coronary interventions because of refractory restenosis. He also had coronary artery bypass surgery at the age of 69. After 4 years, he again suffered from dyspnea and chest pain upon physical exertion. On admission to our hospital, a chest radiograph showed dilatation of bilateral pulmonary arteries. Moreover, echocardiography showed right ventricular dilatation and tricuspid regurgitation. Continuous wave Doppler imaging revealed a pressure gradient of 82.1 mmHg. Pulmonary capillary wedge pressure was normal, but pulmonary artery pressure was elevated upon cardiac catheterization. Because there was no apparent etiology of pulmonary hypertension, primary pulmonary hypertension was diagnosed and appropriate conventional therapy was started.

Descriptive patterns of severe chronic pulmonary hypertension by chest radiography

To find chest roentgenographic (CXR) features to help differentiate two representative diseases with severe chronic pulmonary hypertension (PH). Thirty-six consecutive patients with chronic thromboembolic PH (CTEPH), 38 with primary PH (PPH), and 37 with left heart disease and PH. CXRs were reviewed about 6 features (left 2nd arc protrusion, right descending pulmonary artery diameter (rPAD), cardiothoracic ratio (CTR), right 2nd arc width, avascular area and pleural abnormality). Hemodynamic data and the degree of tricuspid regurgitation (TR) on echocardiography were compared with CXR findings. The diagnostic pattern of CTEPH was the presence of one of two findings, an avascular area or marked rPAD (>20mm) together with pleuritic change. The diagnostic pattern of PPH was one of the two features; without pleuritic abnormality, marked left 2nd arc protrusion (>10mm) or moderate left 2nd arc protrusion (5-10mm) with marked rPAD (<20mm). The sensitivity for the diagnosis of CTEPH among the three diseases was 78% and specificity was 92%. The sensitivity for the diagnosis of PPH was 45% and specificity was 88%. CTR and right 2nd arc width were related to the degree of TR in CTEPH and PPH. Characteristic roentgenographic findings can help differentiate two frequent diseases associated with chronic pulmonary hypertension and reflect the severity of disease.

Peripartum Heart Failure due to Primary Pulmonary Hypertension: Two Case Reports

Primary pulmonary hypertension (PPH) with pregnancy can result in peripartum heart failure and a high mortality rate. We report two cases of fatal PPH in pregnant women. From July 1992 to July 2002, two pregnant women with PPH were treated in our hospital. Case 1 was a 24-year-old primigravida, referred to our institution at 33 weeks of gestation because of signs of heart failure. She delivered a male baby by emergency cesarean section under general anesthesia. Five hours later, she developed severe systemic hypotension and died of cardiovascular collapse despite aggressive treatment and intensive care. Case 2 was a 29-year-old para 0 gravida 1 woman. She had been transferred to our hospital at 34 weeks of gestation, when fatigue, increasing dyspnea, orthopnea, tachycardia, chest pain, and peripheral cyanosis were found in our emergency department. She delivered a male baby by cesarean section under general anesthesia. Four hours later, she suddenly developed cyanosis and tachycardia, followed by electromechanical dissociation. All attempts at resuscitation were unsuccessful, and cardiac arrest ensued. We suggest that cesarean section be carried out with the help of the intensive care unit since transportation of the patient from the operating theatre to the intensive care unit is time-consuming and may result in deterioration of the patient's condition. A multidisciplinary team approach to management in the second trimester may reduce the high mortality rate.

Characterization of the bone morphogenetic protein (BMP) system in human pulmonary arterial smooth muscle cells isolated from a sporadic case of primary pulmonary hypertension: roles of BMP type IB receptor (activin receptor-like kinase-6) in the mitotic action.

The functional involvement of bone morphogenetic protein (BMP) system in primary pulmonary hypertension (PPH) remains unclear. Here we demonstrate a crucial role of the BMP type IB receptor, activin receptor-like kinase (ALK)-6 for pulmonary arterial smooth muscle cell (pphPASMC) mitosis isolated from a sporadic PPH patient bearing no mutations in BMPR2 gene. A striking increase in the levels of ALK-6 mRNA was revealed in pphPASMC compared with control PASMCs, in which ALK-6 transcripts were hardly detectable. BMP-2 and -7 stimulated the mitosis of pphPASMCs, which was opposite to their suppressive effects on the mitosis of the control PASMCs. BMP-4 and -6 and activin inhibited pphPASMC mitosis, whereas these did not affect control PASMCs. The presence of BMP signaling machinery in pphPASMCs was elucidated based on the analysis on Id-1 transcription and Smad-reporter genes. Overexpression of a dominant-negative ALK-6 construct revealed that ALK-6 plays a key role in the mitosis as well as intracellular BMP signaling of pphPASMCs. Gene silencing of ALK-6 using small interfering RNA also reduced DNA synthesis as well as Id-1 transcription in pphPASMCs regardless of BMP-2 stimulation. Although Id-1 response was not stimulated by BMP-2 in control PASMCs, the gene delivery of wild-type ALK-6 caused significant increase in the Id-1 transcripts in response to BMP-2. Additionally, inhibitors of ERK and p38 MAPK pathways suppressed pphPASMC mitosis induced by BMP-2, implying that the mitotic action is in part MAPK dependent. Thus, the BMP system is strongly involved in pphPASMC mitosis through ALK-6, which possibly leads to activation of Smad and MAPK, resulting in the progression of vascular remodeling of pulmonary arteries in PPH.

Advances in Prostacyclin Therapy for Pulmonary Arterial Hypertension

Advances in Prostacyclin Therapy for Pulmonary Arterial Hypertension

A Case of Primary Pulmonary Hypertension in Pregnancy Presented as Massive Hemoptysis

Primary pulmonary hypertension (PPH) is a rare, progressive and incurable disease, which is characterized by an increase in the pulmonary artery pressure without a demonstrable cause. The most common presenting symptom is dyspnea on exertion, with other symptoms comprising of chest pain, syncope and hemoptysis. The diagnosis is one of exclusion of any of the known causes of pulmonary hypertension. When associated with pregnancy, the maternal mortality ranges from 30 to 50%. Because pregnancy and labor are very serious problems for patients with PPH, the available evidence suggests that pregnancy when afflicted with PPH should be avoided. In account the case of a 33- year old patient, reporting with massive hemoptysis, and diagnosed with PPH during her twenty seventh week of gestation, is presented. She was treated with conservative management, including oxygen and a vasodilator, and underwent a pregnancy termination. However, due to aggravation of right heart failure, she presented with severe systemic hypotension and hypoxemia, and eventually died. This case is reported, with brief review of the literature. (Tuberc Respir Dis 2004; 57:66-67)

BMPR2 mutations found in Japanese patients with familial and sporadic primary pulmonary hypertension.

Primary pulmonary hypertension (PPH) is a potentially lethal disorder, in which heterozygous mutations within the bone morphogenetic protein type II receptor (BMPR2) gene (BMPR2) have been identified. We conducted a molecular study of BMPR2 mutations in 4 Japanese families with familial PPH and 30 Japanese patients with sporadic PPH, and found 13 different mutations, of which 10 were novel, including missense (n=2), nonsense (n=4), frameshift (n=3), and splice-donor site (n=1) mutations. In total, BMPR2 mutations were found in all 4 familial PPH cases and 12 (40%) of the sporadic PPH cases. Further, a majority of the mutations found were predicted to cause premature termination, as previously reported. In the 9 mutations found in the sporadic cases, 2 were shown to be de novo, 2 were shared in multiple cases, 1 was shared with an FPPH case, and 1 was the same as previously reported in Caucasian FPPH. These results indicate that a substantial portion of Japanese PPH patients carry BMPR2 mutations with considerable heterogeneity.

Fatal primary pulmonary hypertension in a 30‐yr-old female with APECED syndrome

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in the autoimmune regulator (AIRE) gene, which has a central function in maintaining immunological tolerance. A number of conditions with proven or likely autoimmune pathogenesis occur in APECED: hypoparathyroidism, adrenocortical insufficency, candidiasis, hypogonadism, type 1 diabetes, hypothyroidism, hypophysitis, hepatitis, malabsorption, nail dystrophy, enamel hypoplasia and keratopathy. It is not clear which factors are responsible for variation in clinical picture of APECED, but human leukocyte antigen (HLA) genotype may be important. The authors report the first description of a case of primary pulmonary hypertension (PPH) in patient with APECED, caused by R257X mutation in AIRE. The HLA genotype of the patient (DRB1*01/DRB1*11, DQB1*0301/DQB1*0501) has been previously reported as a predisposing factor to PPH. The findings from this study, provided that other similar cases are reported, suggest that immune deregulation plays a role in the pathogenesis of primary pulmonary hypertension.

Physiopathologie du remaniement vasculaire pulmonaire au cours de l’hypertension artérielle pulmonaire

Recent years have witnessed important advances in our understanding of the pathophysiology of primary pulmonary hypertension (PPH). Both genetic and mechanistic studies have succeeded in identifying new molecular pathways relevant to the process of pulmonary vascular remodelling which underlies PPH. Mutations in the type II bone morphogenetic protein receptor (BMPRII) are now considered to be the genetic basis for familial PPH and about 30% of cases of sporadic PPH. Identification of the BMP pathway as relevant to the aetiology of PPH now raises many questions about the link between the BMPRII mutant genotype and the PPH phenotype. That PPH does not develop in all subjects with BMPRII mutations suggests a crucial role for environmental or associated genetic factors. Simultaneously, mechanistic studies investigating the biological processes that underlie the complex vascular changes associated with PPH have identified major molecular pathways involved in constriction and proliferation of pulmonary vascular smooth muscle cells (SMCs), dysfunction of endothelial cells, and remodelling of extracellular matrix. Such mechanisms may be involved either in initiating or in perpetuating the disease. The finding that genetic polymorphism of some of the candidate genes related to these processes is closely associated with PPH suggests a causal relationship between the expression, or function, of these genes and the PPH phenotype. The association between PPH and the L allelic variant of the serotonin transporter (5-HTT) gene indicates that 5-HTT, which controls smooth muscle hyperplasia, probably contributes to susceptibility to PPH or is an important modifier of the PPH phenotype. Recognition of these molecular pathways should provide insight into the pathogenesis not only of primary PH, but also of secondary forms of PH. This should lead soon to the development of new and more selective therapeutic approaches to pulmonary hypertension.

A Case of Primary Pulmonary Hypertension Diagnosed in Puerperium

A Case of Primary Pulmonary Hypertension Diagnosed in Puerperium