Forms Of Pulmonary Hypertension Research Articles

Safety and efficacy of exercise training in various forms of pulmonary hypertension

The objective of this prospective study was to assess safety and efficacy of exercise training in a large cohort of patients with different forms and World Health Organization (WHO) functional classes of chronic pulmonary hypertension (PH). 183 patients with PH (pulmonary arterial hypertension (PAH), chronic thromboembolic PH and PH due to respiratory or left heart diseases received exercise training in hospital for 3 weeks and continued at home. Adverse events have been monitored during the in-hospital training programme. Efficacy parameters were evaluated at baseline, and after 3 and 15 weeks. After 3 and 15 weeks, patients significantly improved the distance walked in 6 min (6MWD) compared to baseline, scores of quality of life, WHO functional class, peak oxygen consumption, oxygen pulse, heart rate and systolic pulmonary artery pressure at rest and maximal workload. The improvement in 6MWD was similar in patients with different PH forms and functional classes. Even in severely affected patients (WHO functional class IV), exercise training was highly effective. Adverse events, such as respiratory infections, syncope or presyncope, occurred in 13% of patients. Exercise training in PH is an effective but not a completely harmless add-on therapy, even in severely diseased patients, and should be closely monitored.

Role of FPR1 Formyl Peptide Receptors in the Cardioprotective Actions of Annexin-A1 Against Ischaemia–Reperfusion (I–R) Injury

M. Imran ∗, A. Keogh, E. Kotylar, C. Hayward, P. Macdonald, R. Prichard Heart Transplant Unit, St. Vincent’s Hospital, NSW, Australia Introduction: A high transpulmonary gradient (i.e. >10mmHg) secondary to severe left heart failure is associatedwith increasedmortality after heart transplantation and left ventricular assist device implantation. Endothelin receptor antagonists are useful in certain forms of pulmonary hypertension (PAH), but avoided in PAH due to LHF. In this small studywe assessed the effect of bosentan on right heart haemodynamics in LHF with high TPG. Methods: Four patients with advanced LHF and high TPG-unresponsive to vasodilator challenge with nitroglycerine infusion or inhaled nitric oxide (precluding transplant or LVAD) received bosentan (62.5mg or 125mg BD) supplied on compassionate usage by Actelion Pharmaceuticals Australia. Serial right heart catheterisations were performed. Results: One of four patients had no fall in TPG after six weeks therapy and bosentan was discontinued. Three of four patients showed a good response to bosentan. Patient #1: was on LVAD support, developed a TPG of 16mmHg, falling to <10 on bosentan allowing successful heart transplant at 2 months. Patient #2: three months bosentan therapy resulted in improvement inTPG from20 to 12mmHg, PVR from 421 to 218 dyne s cm−5 and cardiac 2 of the actions of full-length ANX-A1 and activates both formyl peptide receptor (FPR)1 and FPR2. Although their anti-inflammatory effects are largely mediated by FPR2, receptors responsible for ANX-A1-based cardioprotection have not been resolved. In this study, rat isolated hearts were Langendorff-perfused with physiological buffer at constant flow (10mL/min), subjected to global, no-flow 30-min ischaemia followed by 30-min reperfusion. Hearts (n= 6–8 per group) were randomly allocated to treatment during reperfusion with Ac-ANX-A12–26 (0.3 M) in absence or presence of either non-selective FPR1/FPR2 antagonist Boc-2 (10 M), FPR2-selective antagonist Quinc-7 (10 M) or FPR1-selective antagonist Cyclosporin-H (1 M). Upon reperfusion, LV developed pressure (LVDP) was significantly reduced compared to pre-ischaemic baseline, and remained depressed during reperfusion. Lactate dehydrogenase (LDH) release was significantly elevated during reperfusion compared to sham (p= 0.001). In comparison, Ac-ANX-A12–26 treated hearts elicited complete recovery of LVDP by 10min reperfusion (p< 0.01), and LDH release was significantly attenuated (p= 0.005). Interestingly, preservation of LV function and cell viability mediated by Ac-ANXA12–26 were prevented by Boc-2, partially attenuated by Cyclosporin-H, but were unaffected by Quinc-7. Our findings suggest administration of Ac-ANX-A12–26 on reperfusion rescues LV function likely via activation of index from 1.7 to 2.0 l/min/m . He remains under consideration for heart transplant. Patient #3: bosentan for six months resulted inTPGfall from27 to18mmHg,PVRfrom 424 to 300 dyne s cm−5 with improvement in symptoms. Conclusion: Bosentan therapy can diminish disproportionately elevated TPG, secondary to left heart failure, facilitating definitive therapy (LVAD implant or transplant). http://dx.doi.org/10.1016/j.hlc.2012.05.232

Pulmonary hypertension due to chronic lung disease: Updated Recommendations of the Cologne Consensus Conference 2011

The 2009 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) in chronic lung disease. These guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors) have not been sufficiently investigated in other forms of PH. Therefore, the use of these drugs in patients with chronic lung disease and PH is not recommended. This recommendation, however, is not always in agreement with medical needs as physicians feel sometimes inclined to also treat other forms of pulmonary hypertension which may affect the quality of life and survival of these patients in a similar manner as in PAH. In June 2010, a consensus conference was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. The conference was sponsored by the German Society of Cardiology, the German Society of Respiratory Medicine and the German Society of Pediatric Cardiology (DGK, DGP and DGPK). To this end, a number of working groups were initiated, one of which was specifically dedicated to the diagnosis and treatment of PH due to chronic lung disease. This manuscript describes in detail the results and recommendations of this working group which were last updated in October 2011.

Cologne Consensus Conference on pulmonary hypertension

The updated European Guidelines on the diagnosis and treatment of pulmonary hypertension that were jointly developed by the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) have recently been published [1,2]. Based on board decisions of the German Society of Cardiology (Deutsche Gesellschaft fur Kardiologie, DGK) and the German Society of Respiratory Medicine (Deutsche Gesellschaft fur Pneumologie, DGP), no new national guidelines have been issued so that the European Guidelines were adopted for Germany. A short version of the ESC/ERS guidelines has recently been published in German [3]. However, with regard to the practical implementation of the European Guidelines in Germany, several country-specific issues as well as relevant novel developments could not be sufficiently addressed in the European Guidelines. The ESC/ERS Guidelines focus in detail on the diagnosis and treatment of pulmonary arterial hypertension (PAH), representing group 1 of the Dana Point Classification [4] (Table 1), but also address other forms of pulmonary hypertension (PH), particularly PH associated with left heart disease and chronic lung disease as well as chronic thromboembolic pulmonary hypertension (CTEPH).

Perioperative Management of Pulmonary Hypertension in Children with Critical Heart Disease

Pulmonary hypertension (PHTN) is common to a variety of conditions occurring in infants and children presenting to the intensive care unit. A fundamental understanding of the response of the right ventricle to an increase in afterload and the clinical syndromes responsible for PHTN is essential for managing patients with PHTN and critical heart disease. There are important distinguishing features between PHTN syndromes, and although one form of PHTN may predominate, often more than one mechanism of PHTN is contributing to the pathophysiologic state. Thus, it is imperative to tailor therapies accordingly in order to optimize outcomes.

International Classification of Diseases Coding Changes Lead to Profound Declines in Reported Idiopathic Pulmonary Arterial Hypertension Mortality and Hospitalizations: Implications for Database Studies

Database studies have reported several associations between the diagnosis of idiopathic pulmonary arterial hypertension (IPAH) and mortality attributable to IPAH, including older age, black race, and diabetes. We investigated reported deaths and hospital discharges coded as IPAH and compared these with other forms of pulmonary hypertension. Three databases were used: the US National Center for Health Statistics database (1979-2006), queried for mortality data; the Nationwide Inpatient Sample database (1993-2007), queried for hospital discharge data; and the University of Texas Southwestern Hospital-Zale Lipshy discharge database (1999, 2002). Marked increases in mortality attributable to IPAH and to pulmonary hypertension (all codes combined) generally were reported from 1979 until 2002 in the National Center for Health Statistics database. In 2003, reported IPAH mortality fell sharply while total pulmonary hypertension deaths increased. The Nationwide Inpatient Sample database showed a similar pattern of changes beginning approximately 2 years earlier. In both cases, the timing of these observations corresponded with changes made to the International Classification of Diseases (ICD) coding system in use for pulmonary hypertension in that particular database. Review of pulmonary hypertension discharge data from the University of Texas Southwestern Hospital-Zale Lipshy showed similar changes in diagnosis code use. Sudden shifts in reported IPAH mortality and hospital discharges were seen in all databases, likely related to coding changes. These findings raise questions about the accuracy of pulmonary hypertension diagnosis codes. Studies based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, 10th Revision codes may have inadvertently included patients with other forms of pulmonary hypertension and should be reevaluated in this context. Validation studies of the IPAH diagnosis code are needed, and changes to the ICD coding system should be considered.

Pulmonary arterial hypertension

Clinical Case Download : Download full-size image A 27-year-old female presented with progressive shortness of breath over 1 year. She was initially treated with inhaled bronchodilators after she was diagnosed with asthma. However, she continued to have progressive dyspnea and eventually experienced chest pain and syncope with moderate exertion. She had no past medical or surgical history, and her family history was unremarkable. There was no history of substance abuse and she had no travels outside the United States. On examination her blood pressure was 105/65 mmHg and her body mass index (BMI) was normal. Her jugular venous pressure was elevated but she had no peripheral edema. Cardiac examination demonstrated a regular rhythm with a prominent P2 and a right ventricular heave. Her lungs were clear. Noninvasive testing included an electrocardiogram which showed sinus rhythm with a right axis deviation and ST depressions in V1–V3 suggestive of right ventricular strain. An echocardiogram revealed a small left ventricular cavity size with septal shift consistent with right ventricular pressure and volume overload. There was right atrial enlargement, severe right ventricular enlargement with moderate dysfunction, moderate tricuspid regurgitation, and an estimated pulmonary artery pressure of 90 mmHg. A 6-min walk test was performed, and it was reduced at 330 m. How would you manage her next? Abstract Pulmonary arterial hypertension (PAH), a form of pulmonary hypertension (PH), is a complex disorder with sexual dimorphism. The disease preferentially affects women, and female sex influences both the development of PAH and right ventricular remodeling. Large registries have demonstrated that while women are more likely to develop PAH, older men with PAH have increased mortality. Sex hormones may impact right ventricular function as well as response to PAH-specific medications. Despite advancements in therapeutics for PAH, mortality remains high for both men and women. Further investigation is necessary to fully elucidate the impact of sex on PAH pathogenesis and help guide novel therapeutics.

Pulmonary veno-occlusive disease: The bête noire of pulmonary hypertension in connective tissue diseases?

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension that may develop in patients with connective tissue diseases (CTD). Most cases have been reported in patients with systemic sclerosis, though associations with systemic lupus erythematosis and mixed connective tissue disease have also been described. PVOD is characterised by progressive obstruction of small pulmonary veins and venules that leads to increased pulmonary vascular resistance, right heart failure and premature death. Distinguishing PVOD from pulmonary arterial hypertension (PAH) is often difficult, though use of a diagnostic algorithm may improve diagnostic accuracy and preclude recourse to lung biopsy. The finding of normal left-heart filling pressures in the context of radiological studies suggestive of pulmonary oedema is an important diagnostic clue, particularly if this clinical scenario coincides with the introduction of vasodilator therapy. There are no approved treatments for the disorder, though cautious use of PAH specific therapy may improve short-term outcomes in selected idiopathic PVOD cases. This review summarises the epidemiologic, clinico-pathologic and imaging characteristics of PVOD in the setting of CTD and discusses potential management approaches.

Pulmonale Hypertonie bei chronischen Lungenerkrankungen

The 2009 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) in chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase-5 inhibitors) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of pulmonary hypertension which may affect quality of life and survival of these patients in a similar manner. In June 2010, a group of German experts met in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. The conference was sponsored by the German Society of Cardiology, the German Society of Respiratory Medicine and the German Society of Pediatric Cardiology. One of the working groups was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.

Bosentan for the Treatment of Adult Pulmonary Hypertension

Pulmonary hypertension is a severe progressive disease with a marked morbidity and a high mortality attributed to right heart failure. Bosentan, a dual endothelin receptor antagonist, is an effective and well-tolerated oral therapy for the management of pulmonary arterial hypertension (PAH; WHO group 1 pulmonary hypertension). Bosentan improves cardiopulmonary hemodynamics, exercise capacity, WHO functional class and quality of life, as well as delaying time to clinical worsening in patients with PAH. This article reviews the role of endothelin-1 in the pathogenesis and progression of PAH, the diagnosis of PAH and the pharmacology of bosentan, and summarizes the current available evidence for the safety and efficacy of bosentan for the treatment of PAH as a monotherapy and combination therapy, as well as its role in the management of other forms of pulmonary hypertension.

Diagnóstico e tratamento da hipertensão pulmonar: uma atualização

Ao longo dos últimos cinco anos, o conhecimento na área de hipertensão pulmonar evoluiu de forma consistente e significativa. Novos algoritmos diagnósticos e de tratamento foram desenvolvidos com base no resultado de diversos estudos clínicos que evidenciaram a utilidade de novas ferramentas, assim como a eficácia de novos medicamentos e de combinações. Da mesma forma, a classificação da hipertensão pulmonar evoluiu, na tentativa de agrupar as diferentes formas de hipertensão pulmonar que apresentam abordagens diagnósticas e terapêuticas semelhantes a fim de facilitar a condução clínica dos pacientes. Esta revisão visa discutir cada uma dessas modificações, tendo por base as diretrizes brasileiras para manejo da hipertensão pulmonar de 2005, ressaltando aquilo que foi acrescentado às diretrizes internacionais.

Perivascular T-Cell Infiltration Leads to Sustained Pulmonary Artery Remodeling after Endothelial Cell Damage

Pulmonary hypertension is a vascular proliferative disease characterized by pulmonary artery remodeling because of dysregulated endothelial and smooth muscle cell proliferation. Although the role of inflammation in the development of the disease is not well-defined, plexogenic lesions in human disease are characterized by perivascular inflammation composed, in part, of T cells. We explored the role of T-cell infiltration on pulmonary vascular remodeling after endothelial cell damage. We induced endothelial cell damage using monocrotaline and isolated the role of T cells by using Rag1(tm1Mom) mice and performing adoptive T-cell transfer. We found that monocrotaline causes pulmonary vascular endothelial cell injury followed by a perivascular inflammatory response. The infiltration of inflammatory cells primarily involves CD4(+) T cells and leads to the progressive muscularization of small (<30 μm) arterioles. Pulmonary vascular proliferative changes were accompanied by progressive and persistent elevations in right ventricular pressure and right ventricular hypertrophy. Supporting the central role of CD4(+) T cells in the inflammatory response, Rag1(tm1Mom) (Rag1(-/-)) mice, which are devoid of T and B cells, were protected from the development of vascular injury when exposed to monocrotaline. The introduction of T cells from control mice into Rag1(-/-) mice reproduced the vascular injury phenotype. These data indicate that after endothelial cell damage, CD4(+) T-cell infiltration participates in pulmonary vascular remodeling. This finding suggests that a CD4(+) T-cell immune response may contribute to the pathogenesis of inflammatory vascular lesions seen in some forms of pulmonary hypertension.

TISSUE DOPPLER IMAGING IN DETECTION OF RIGHT VENTRICULAR SYSTOLIC AND DIASTOLIC FUNCTION IN VARIOUS FORMS OF PULMONARY HYPERTENSION: PP.8.342

The Aim: To evaluate the possibilities of Tissue Doppler Imaging (TDI) in detection of early myocardial functional changes in different forms of pulmonary hypertension (PH). Materials and Methods: 29 pts with idiopathic pulmonary hypertension (IPH), 15 pts with chronic thromboembolic disease (CTD), 18 pts with PH, associated with systemic scleroderma (SS), 13 pts with PH, associated with chronic obstructive respiratory disease (CORD),15 pts with PH, associated with congenital heart disease (CHD), 12 pts with residual PH with FC I-III (WHO) and 21 healthy volunteers in control group (CG) were included in the study. Echocardiography, complete conventional and TDI, were operated (Vivid 7, G.E.). Plasma amino-terminal pro-brain natriuretic peptide levels (NT-proBNP) were measured (Elecsys 2010, Roche). Results: IPH and CHD pts were characterized by the most marked heart remodeling accordingly to elevated SPAP (table 1). CORD and RPH pts have the least enlarged right heart chambers and SPAP. Parameters Em RV in CTD and SS pts were rather small while E/Em RV were large and comparable with E/Em RV in IPH pts. Table 1. Echocardiographic parameters and NT-proBNP levels in groups with PH and in controls.We found the higher prevalence of TDI-findings of early RV diastolic dysfunction (DD) as compared with traditional echocardiographic measurements in different forms of PH (89,7% versus 58,6% in IPH, 86,7% vs 46,7% in CTD, 77,8% vs 55,6% in SS, 100% vs 27,3% in CORD, 86,7% vs 26,7% in CHD, 41,7% vs 16,7% in RPH pts). Conclusion: Tissue Doppler Imaging can be a useful tool for detection early features of DD in different forms of PH as compared with traditional echocardiography. CTD and SS pts with moderate systolic echocardiographic parameters and SPAP but high NTpro-BNP levels have marked DD of RV by TDI measuring. Quantity of pts with DD of RV revealed by traditional Doppler measuring was significantly less than detected by TDI in all PH groups.

Bmp2 and Bmp4 exert opposing effects in hypoxic pulmonary hypertension

Patients with Familial Pulmonary Hypertension have mutations in the BMP receptor, BMPR2, but it is unknown how these mutations cause disease. These observations also raise questions as to the role of BMPR2 signaling in other forms of pulmonary hypertension (PH). To address this, we evaluated the regulation and function of Bmpr2 ligands in a mouse model of hypoxic PH. Pulmonary Bmp2 and Bmp4 are up‐regulated by hypoxia: Bmp2 is up‐regulated in the peripheral pulmonary vasculature, while Bmp4 is widely expressed in respiratory epithelia. Loss of hypoxia‐induced Bmp4 in Bmp4+/− mice is associated with reduced PH and decreased pulmonary vascular remodeling. This contrasts with Bmpr2ΔEx2/+ mice which show greater susceptibility to hypoxic PH, and suggests that an alternative ligand regulates Bmpr2‐dependent effects in the vasculature. Unlike Bmp4+/− mice, Bmp2+/− mice develop more severe hypoxic PH than wild type littermates. There is also reduced eNOS expression and activity in the pulmonary vasculature of hypoxic Bmp2+/−, but not Bmp4+/− mice. Bmp2 also up‐regulates eNOS expression and activity in intrapulmonary artery and endothelial cell preparations, indicating that eNOS is a target of Bmp2 in the pulmonary vasculature. These data indicate that Bmp2 and Bmp4 exert opposing roles in hypoxic PH, and suggest that protective effects of Bmp2 are mediated by increasing eNOS activity in the pulmonary vasculature.

Diagnostic testing to guide the management of chronic thromboembolic pulmonary hypertension: state of the art

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening and debilitating disease affecting up to 5% of survivors of pulmonary embolism. Diagnostic testing is important to distinguish it from other forms of pulmonary hypertension and to assess the feasibility of pulmonary endarterectomy. This review provides an up-to-date perspective on the diagnosis and assessment of the disease. Patients with CTEPH often have a history of pulmonary embolism, deep-vein thrombosis, thrombophilia, splenectomy, ventriculo-atrial shunt, inflammatory bowel disease or malignancy. Chest radiography may reveal pulmonary infarcts. CTEPH is often diagnosed as a wedge-shaped perfusion defect with normal ventilation scan during ventilation-perfusion scintigraphy, but multi-slice computed tomography angiography may be needed for differential diagnosis. Right heart catheterisation is required for diagnostic confirmation. Suitability for surgery is assessed by evaluating the number of obstructed vessels which could be disobliterated in the context of the pulmonary vascular resistance. Pulmonary vascular resistance that is out of proportion to evident obstructions is indicative of distal disease. Conventional pulmonary angiography, multi-slice computed tomography angiography and, potentially, magnetic resonance imaging can aid the decision to operate, but risk stratification systems are needed. In conclusion, CTEPH can be cured surgically, providing that patients are diagnosed and assessed using the appropriate techniques.

Long-term therapy with inhaled iloprost in patients with pulmonary hypertension

To investigate the long-term safety of inhaled iloprost in patients with pulmonary hypertension (pH), including idiopathic PAH (IPAH group) and other forms of pulmonary hypertension (PHother). Sixty-three patients (IPAH group, n=40, PHother n=23) were enrolled to receive inhaled iloprost either from baseline or after 3 months in a prospective, open-label 2-year study. Iloprost was inhaled 6-9 times daily with a night pause employing a jet nebulizer delivering an inhaled single dose of 4microg at the mouthpiece. In the case of side effects the single dose was reduced to 2microg. Sixty patients received at least 1 dose of inhaled iloprost. Thirty-six patients completed at least 630 days of therapy (25 IPAH, 11 PHother), 19 patients dropped out prematurely and 8 patients died (3 IPAH, 5 PHother). There were no drug-induced toxicities and only mild to moderate side effects. The most common side effects were coughing and flushing. Two-year survival was estimated at 85% (IPAH group 91%, PHother 78%). A modified analysis was performed to correct for differential drop-out. It included follow-up data from the premature discontinuations and revealed a 2-year survival of 87% [95% CI, 76%-98%] in the IPAH group while the predicted survival was 63%. The iloprost dose increased by 16% over 2 years. Inhaled iloprost is well tolerated as long-term therapy and no substantial dose increase is required. Although uncontrolled, the data suggest a long-term clinical benefit from continued therapy with inhaled iloprost.

Genomewide RNA expression profiling in lung identifies distinct signatures in idiopathic pulmonary arterial hypertension and secondary pulmonary hypertension

Idiopathic pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by pulmonary arteriolar remodeling. This investigation aimed to identify genes involved specifically in the pathogenesis of PAH and not other forms of pulmonary hypertension (PH). Using genomewide microarray analysis, we generated the largest data set to date of RNA expression profiles from lung tissue specimens from 1) 18 PAH subjects and 2) 8 subjects with PH secondary to idiopathic pulmonary fibrosis (IPF) and 3) 13 normal subjects. A molecular signature of 4,734 genes discriminated among these three cohorts. We identified significant novel biological changes that were likely to contribute to the pathogenesis of PAH, including regulation of actin-based motility, protein ubiquitination, and cAMP, transforming growth factor-beta, MAPK, estrogen receptor, nitric oxide, and PDGF signaling. Bone morphogenic protein receptor type II expression was downregulated, even in subjects without a mutation in this gene. Women with PAH had higher expression levels of estrogen receptor 1 than normal women. Real-time quantitative PCR confirmed differential expression of the following genes in PAH relative to both normal controls and PH secondary to IPF: a disintegrin-like and metalloprotease with thrombospondin type 1 motif 9, cell adhesion molecule with homology to L1CAM, cytochrome b(558) and beta-polypeptide, coagulation factor II receptor-like 3, A-myb myeloblastosis viral oncogene homolog 1, nuclear receptor coactivator 2, purinergic receptor P2Y, platelet factor 4, phospholamban, and tropomodulin 3. This study shows that PAH and PH secondary to IPF are characterized by distinct gene expression signatures, implying distinct pathophysiological mechanisms.

Could uric acid be a modifiable risk factor in subjects with pulmonary hypertension?

A high serum uric acid is common in subjects with pulmonary hypertension. The increase in serum uric acid may be a consequence of the local tissue ischemia and/or hypoxia, and it may also result from other factors independent of ischemia or hypoxia that occur in various forms of pulmonary hypertension. While classically viewed as a secondary phenomenon, recent studies suggest that hyperuricemia may also have a role in mediating the local vasoconstriction and vascular remodeling in the pulmonary vasculature. If uric acid does have a contributory role in pulmonary hypertension, we may see an increasing prevalence of pulmonary hypertension as hyperuricemia is common in subjects with obesity and metabolic syndrome. We propose studies to investigate the role of uric acid in pulmonary hypertension and to determine if lowering serum uric acid may have clinical benefit in this condition.

The Right Heart and Pulmonary Circulation: Is It Really a Minor Circulation?

Continued education has traditionally been considered to be of great importance in Revista Espanola de Cardiologia. The “Editorial,” “Review Article,” and “Update” sections are the usual means for transmitting to readers the opinions and points of view of experts of known prestige in the different aspects of cardiovascular disease. In the case of the Update section, over the years we have attempted to select areas of obvious interest to a large part of our readers that, not being the object of attention in more classical reviews, would otherwise be overlooked. Thus, the subjects we have attempted to address in a cross-cutting manner in recent years include: “Cardiovascular disease in women” (2006),1 “Non-coronary arterial disease” (2007),2 “Cardiovascular prevention” (2008),3 and “Cardiovascular translational medicine” (2009).4 The subject selected this year for in-depth evaluation, “The right heart and pulmonary circulation,” encompasses several aspects that are undoubtedly attractive. The first is its evident implication in the practice of cardiologists of all hues, whether general or specialized, ranging from those devoted to clinical activity to basic researchers. On the other hand, after decades of highly predominant attention to the left chambers of the heart and the systemic vessels, over the last 15 years we have been witnessing a progressive awareness of the importance of right ventricle (RV) dysfunction in different heart diseases,5 both in those cases in which this chamber plays the leading role in the condition (as in arrhythmogenic right ventricular dysplasia or certain congenital heart diseases) and in those in which it accompanies conditions involving the left heart chambers and valves, significantly modifying the clinical signs and prognosis. To paraphrase the title of a recent report, we now consider that “the left heart will only be able to work as much as the right heart lets it.”6 With respect to the pulmonary circulation, the past decade has witnessed important advances based on a more complete knowledge of the pathophysiology of the different forms of pulmonary hypertension, which has been expressed in a classification that is of evident practical utility, as well as an improved diagnostic approach and, what is more important, the possibility of employing treatments that are useful for the improvement of the symptoms and the prognosis of these patients. Therefore, this Update arrives just in time to help us learn about the latest findings, incorporate the diagnostic and therapeutic advances into our clinical practice and become aware of the uncertainties and gaps left by our current knowledge. The editors of Revista Espanola de Cardiologia can state with pride that among the authors who have agreed to contribute their knowledge to this series of monographs are the major world experts in this field. Approximately half of the reports are written by authors living in the United States, and half were submitted by specialists from different European countries.

Abstract 5657: Growth Differentiation Factor-15 as a Biomarker in Pulmonary Arterial Hypertension and Hypoxia-induced Pulmonary Hypertension

Circulating growth differentiation factor (GDF)-15 is a possible biomarker in idiopathic pulmonary arterial hypertension (IPAH). We sought to verify its prognostic value and evaluate GDF-15 in other forms of pulmonary hypertension (PH). GDF-15 and N-terminal pro-brain natriuretic peptide (NT-proBNP) were assayed in 127 IPAH patients, 83 of whom received targeted therapy. GDF-15 was also measured in 16 connective tissue disease-associated PAH (CTD) patients, 64 healthy controls and 89 Kyrgyz highlanders (2500 –3600 m), 35 of whom had PH (HAPH; mean pulmonary artery pressure (mPAP) &gt;25 mmHg). GDF-15 levels were greater in IPAH (mean±SEM 987 ±81 pg/ml) and CTD (978 ±144 pg/ml) versus controls (306 ±16 pg/ml; P&lt;0.001). GDF-15 levels &gt;800 pg/ml were associated with decreased exercise capacity (p=0.002) and cardiac index (p=0.02), and increased NT-proBNP (p&lt;0.001), age (p&lt;0.001) and mean right atrial pressure (p=0.02), but did not correlate with mixed venous or arterial (SaO 2 ) oxygen saturation. 3 year mortality in IPAH was 21% (GDF-15 &lt;800 pg/ml) and 58% (GDF-15 &gt;800 pg/ml), with a hazard ratio of 5.12 (95% CI 1.89 –13.9; P&lt;0.001). GDF-15 remained an independent predictor of mortality after adjusting for clinical/haemodynamic measurements and combining NT-proBNP data improved risk stratification. SaO 2 was significantly lower in high altitude (90.4±0.4%) and HAPH subjects (87.3±0.7%) versus IPAH patients (93.3±0.6%; P&lt;0.001). GDF-15 was raised in HAPH, not high altitude residents (548±64 vs. 307±14 pg/ml; P&lt;0.001), and correlated with mPAP (p&lt;0.001). The data support the use of GDF-15 as a prognostic marker in IPAH and question whether hypoxia stimulates GDF-15 in PH.