Pediatric pulmonary arterial hypertension due to a novel homozygous GDF2 missense variant affecting BMP9 processing and activity.

Pulmonary arterial hypertension (PAH) is a rare and severe disorder characterized by progressive pulmonary vasculopathy. Growth differentiation factor (GDF)2 encodes the pro-protein bone morphogenetic protein (BMP) 9, activated after cleavage by endoproteases into an active mature form. BMP9, together with BMP10, are high-affinity ligands of activin receptor-like kinase 1 (ALK1) and BMP receptor type II (BMPR2). GDF2 mutations have been reported in idiopathic PAH with most patients being heterozygous carriers although rare homozygous cases have been described. The link between PAH occurrence and BMP9 or 10 expression level is still unclear. In this study, we describe a pediatric case of PAH also presenting with telangiectasias and epistaxis. The patient carries the novel homozygous GDF2 c.946A > G mutation, replacing the first arginine of BMP9's cleavage site (R316) by a glycine. We show that this mutation leads to an absence of circulating mature BMP9 and mature BMP9-10 heterodimers in the patient's plasma although pro-BMP9 is still detected at a similar level as controls. In vitro functional studies further demonstrated that the mutation R316G hampers the correct processing of BMP9, leading to the secretion of inactive pro-BMP9. The heterozygous carriers of the variant were asymptomatic, similarly to previous reports, reinforcing the hypothesis of modifiers preventing/driving PAH development in heterozygous carriers.

[Pulmonary arterial hypertension]. / L'hypertension artérielle pulmonaire.

Pulmonary arterial hypertension (PAH) is a rare vascular lung disease with a complex etiopathogeny characterized by an increased pulmonary arterial pressure of 25 mmHg or above assessed by right heart catheterization. The diagnosis is difficult due to the atypical presentation with shortness of breath requiring a sequential approach bringing at the end the clinician to perform a right heart catheterization. Nowadays, several therapies have proven to be efficient for treating PAH. Recently, international recommendations have moved to an initial combination therapy reducing the overall morbi-mortality of the patients. Therefore, early therapy appears to be a priority in PAH underlying the need for increasing the global knowledge around PAH.

L'hypertension artérielle pulmonaire (HTAP) est une maladie rare, rapidement évolutive et associée à une morbi-mortalité élevée. D'étiopathogénie pléomorphe, elle est définie par une majoration de la pression artérielle pulmonaire moyenne (PAPm) à une valeur supérieure ou égale à 25 mmHg, mesurée par cathétérisme cardiaque droit, sans majoration de la pression capillaire pulmonaire (PCP) ou pression artérielle pulmonaire occluse (PAPo), en l'absence de causes cardiaques et/ou respiratoires. Le diagnostic est rendu difficile par la présentation insidieuse et le caractère aspécifique des symptômes de la maladie. L'approche diagnostique est basée sur une suspicion échocardiographique et clinique, puis une approche séquentielle nécessitant, in fine, une mesure hémodynamique invasive. Au fil des dernières années, de nouvelles thérapeutiques ont été développées pour traiter l'HTAP. La stratégie actuelle recommande l'utilisation de combinaisons médicamenteuses dès que le diagnostic est établi. Dans ce contexte et au vu de l'impact significatif sur la morbi-mortalité des patients souffrant d'HTAP, il apparaît primordial d'instaurer au plus vite une thérapeutique spécifique dès la réalisation du diagnostic.

[Pulmonary hypertension in left heart disease: how to define it and how to manage it in 2013?]. / Hypertension pulmonaire associée aux maladies du coeur gauche: quelle définition et quelle prise en charge en 2013?

Pulmonary hypertension is a frequent complication of left heart disease arising from a wide range of cardiac disorders and is associated with poor prognosis. Its pathophysiology is complex with both passive mechanisms of elevated filling pressures in left cavities and occasionally reactive mechanisms of arterial vasoconstriction and remodelling to interplay. This stage, called <> pulmonary hypertension, further worsens the heart failure patients' prognosis but is still a matter of debate concerning the criteria to apply for its diagnosis and concerning the best way to manage it. This article gives an overview of the importance and pathophysiology of pulmonary hypertension associated with left heart disease, and discusses the challenges associated with its diagnosis and treatment.

[Pulmonary hypertension: a rare cause of unexplained dyspnea]. / L'hypertension pulmonaire: une cause rare de dyspnée inexpliquée.

Pulmonary hypertension (PH) is defined by an increase in mean pulmonary artery pressure above 25 mmHg, measured at right heart catheterization. The various conditions (up to 37) leading to PH are described in a clinical classification identifying 5 groups, including pulmonary arterial hypertension (PAH). With an incidence of 2-4 cases/million/year, PAH is a rare, rapidly progressive and incurable form or PH. The differential diagnosis of PH relies on a decision tree, which is typically triggered by the presence of unexplained dyspnea and followed by a non invasive approach that includes simple tests such as EKG, chest radiography, pulmonary function tests and echocardiography. Other tests have some value to exclude chronic thromboembolic pulmonary hypertension, such as ventilation/perfusion scintigraphy, angio CT scanner and pulmonary angiogram. Finally, right heart catheterization is mandatory to establish the diagnosis of PH.

How to detect disease progression in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rapidly progressive disease, ultimately leading to right heart failure and death. Accumulating evidence indicates that intervention early in disease progression results in better outcomes than delaying treatment. In this review we will discuss the assessments and strategies that can be used to monitor disease progression and guide clinical management. Many tools, such as symptoms, functional classification, exercise capacity, haemodynamic measures, findings on cardiac imaging and levels of biomarkers, have shown to be prognostic for survival both at diagnosis and during treatment. However, attempts to define goal thresholds have produced a variety of results. Several groups have developed risk calculators to estimate individual patients' mortality risk, but the accuracy of these tools across different patient populations remains unknown. What is clear is the importance of regularly assessing a range of parameters and then tailoring treatment goals to each patient. In addition, the use of a multidisciplinary team approach is crucial in order to support patients through all aspects of managing their condition. There is still an urgent need for prospective collaborative initiatives to assess novel goals and improve treatment strategies that would allow physicians to personalise and optimise clinical management for their patients with PAH.

Management of severe pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a severe, progressive condition of the small pulmonary vessels that leads to increased pulmonary vascular resistance, right ventricular failure and death. Patients in World Health Organization functional class (WHO FC) IV are the most severely affected in terms of disease severity, symptomatic impairment, exercise capacity and haemodynamics, with a very poor prognosis and low survival rate. Recent developments in PAH-specific therapies have conferred significant prognostic improvements upon PAH patients, especially when coupled with management strategies such as goal-oriented therapy and combination treatment. Despite these important developments, the outlook for WHO FC IV PAH patients remains poor. This article examines the recommendations for WHO FC IV patients that appear in current PAH treatment guidelines and the research underpinning this guidance, and discusses possible future directions for treatment of this severely unwell patient population.

Screening for pulmonary arterial hypertension in systemic sclerosis.

The onset and progression of pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc) can be particularly aggressive; however, effective treatments are available. Therefore, early identification of patients with suspected PAH, confirmation of diagnosis, and intervention is essential. PAH may be challenging to diagnose in its earliest stages, particularly in populations that have multiple causes of breathlessness, and, therefore, screening is required. The optimal screening tools and methodology are, as yet, unknown, and this is confounded by a lack of consensus over which patients to screen. Current practice favours annual screening of all SSc patients using Doppler echocardiography to detect elevated right heart pressures. This will typically identify most patients with the various forms of pulmonary hypertension found in SSc. The optimum thresholds for Doppler echocardiography are still subject to investigation, especially for patients with mild pulmonary hypertension, and this technique may, therefore, yield a significant number of false-positives and a currently unknown number of false-negatives. Confirmatory right heart catheterisation remains necessary in all suspected cases. Further research is needed to identify the optimal tools and the screening approach with greatest specificity and selectivity.

The endothelin system in pulmonary and renal vasculopathy: les liaisons dangereuses.

Endothelial cells regulate vascular tone largely by the actions of endothelin-1. Endothelin-1 is a potent vasoconstrictor, with effects that are dependent on the receptors to which it binds as well as their location. Endothelin-1 dysregulation is implicated in pathological conditions, including those of the pulmonary vasculature and the kidney. In this review, we describe the physiology and actions of endothelin-1 in lung and renal tissues and discuss therapies that disrupt these interactions in disease states. We provide an overview of the current clinical progress of these targeted agents and provide perspectives on the treatment of pulmonary and renal diseases with endothelin receptor antagonists.

Isolated right ventricular dysfunction in systemic sclerosis: latent pulmonary hypertension?

Right ventricular function is frequently abnormal in patients with systemic sclerosis, but whether this is related to pulmonary vascular complications of the disease is unclear. Standard echocardiography with tissue Doppler imaging was performed at rest and during exercise for the study of right ventricular function and pulmonary circulation in 25 consecutive systemic sclerosis patients and in 13 age-matched healthy controls. When compared with the controls, the patients had no difference in systolic right ventricular pressure gradient, but a decreased pulmonary flow acceleration time, and increased right ventricular free wall thickness and end-diastolic dimensions. At the tricuspid annulus, the E maximal velocity was decreased (8.9 +/- 4 versus 11.7 +/- 2.3 cm.s(-1)) and the isovolumic relaxation time corrected to RR interval was increased (6.5 +/- 2.9 versus 4.5 +/- 2.5%). The tissue Doppler imaging profile at the mitral annulus was similar in both groups. At exercise, 18 patients had a decreased maximum workload and cardiac output, no change in systolic right ventricular pressure gradient, but an increase in the slope of pulmonary artery pressure/flow relationships. These results suggest that patients with systemic sclerosis may present with latent pulmonary hypertension as a likely cause of right ventricular diastolic dysfunction, as revealed by stress echocardiography and tissue Doppler imaging.

[Spontaneous coronary artery dissection on the 10th post-partum day: a case report]. / Dissection spontanée d'une artère coronaire au 10e jour post-partum: observation clinique.

Spontaneous coronary artery dissection is a rare cause of myocardial infarction. It most commonly occurs in young women in the peri-partum period. The aetiology remains obscure. The authors describe the case of a 38 year old woman who suffered an inferior wall myocardial infarction on the 10th post-partum day. After failure of thrombolysis, coronary angiography showed dissection of the right coronary artery. An attempted angioplasty was unsuccessful and the patient was treated medically with a favourable clinical outcome. Spontaneous coronary artery dissection should be considered in all young patients without coronary risk factors presenting with acute myocardial ischaemia, especially young women in the peri-partum period. Emergency coronary angiography should be undertaken to establish the diagnosis and orientate appropriate treatment which may be medical, interventional or surgical.

Physiological response to the six-minute walk test in pulmonary arterial hypertension.

The 6-min walk test (6MWT) is commonly used to evaluate exercise capacity in patients with pulmonary arterial hypertension (PAH). However, little is known about the corresponding metabolic stress as measured by cardiopulmonary exercise testing. The present study, therefore, measured ventilatory variables and heart rate during the 6MWT and symptom-limited incremental maximal exercise testing in 20 patients with PAH. The distance walked in 6 min was 450+/-22 m (mean+/-se). During the 6MWT, ventilation, O2 consumption, CO2 production and heart rate increased during the first 3-4 min, and then remained stable. As compared with the maximum values measured during the cardiopulmonary exercise test, O2 consumption tended to be higher (14.2+/-0.6 versus 12.9+/-0.7 mL.kg-1.min-1), while maximum ventilation (46+/-3 versus 57+/-4 L.min-1), respiratory quotient (0.90+/-0.02 versus 1.15+/-0.02) and heart rate (119+/-4 versus 135+/-4 beats.min-1) remained lower. In conclusion, patients with pulmonary arterial hypertension exercise at higher aerobic capacity and lower metabolic stress during the 6MWT than during a cardiopulmonary exercise test.

Exercise testing in pulmonary arterial hypertension and in chronic heart failure.

Exercise capacity is reduced in pulmonary arterial hypertension and in chronic left heart failure, but it is not known whether the cardiopulmonary exercise testing profile is different in the two conditions at the same severity of functional limitation. Nineteen patients with pulmonary arterial hypertension and 19 with chronic heart failure underwent a 6-min walk test and symptom-limited maximal incremental cycle ergometry. The patients with pulmonary arterial hypertension and chronic heart failure did not differ in New York Heart Association Functional Class (mean +/- SEM 2.8 +/- 0.1 versus 2.8 +/- 0.2), 6-min walking distance (395 +/- 30 versus 419 +/- 20 m), peak work-rate, oxygen consumption, ventilation and cardiac frequency. However, patients with pulmonary arterial hypertension exhibited higher dyspnoea scores (5.8 +/- 0.6 versus 3.8 +/- 0.5) higher ventilatory equivalents for carbon dioxide (58 +/- 3 versus 44 +/- 3 at the anaerobic threshold) and lower peak oxygen pulse (5.9 +/- 0.4 versus 8.7 +/- 0.5 mL x beat(-1), or 53 +/- 4 versus 64 +/- 4% of the predicted value). It is concluded that the cardiopulmonary exercise testing profile in pulmonary arterial hypertension differs from that in chronic heart failure by showing more dyspnoea at comparable work-rates, related to greater reductions in ventilatory efficiency and stroke volume.

[ACE inhibitors and/or sartans in heart failure: is there a difference?]. / IECA et/ou sartans dans l'insuffisance cardiaque: y a-t-il une différence?

The recent years have witnessed tremendous advances in the understanding of the pathophysiology of chronic heart failure (CHF), leading to significant improvement in therapy. Recognition of the deleterious effects of angiotensin II is an major therapeutic target. By blocking the transformation of angiotensin I to angiotensin II, angiotensin-converting enzyme inhibitors (ACEI) improve symptoms, exercise tolerance and survival at all stages of CHF. Angiotensin II-receptors blockers (ARB) have several theoretical advantages over ACEI, including a better tolerance profile, that may lead to a more favourable effect. In CHF with systolic dysfunction, randomised-controlled trials comparing losartan to captopril (ELITE 1 and ELITE 2) or valsartan versus placebo on top of conventional therapy (Val-HeFT) failed to demonstrate a superiority of ARB's compared to ACEI in terms of mortality. However, ARB's appeared better tolerated in this indication. The treatment of CHF with preserved systolic function remains unclear and may be defined in a near future by two studies addressing the role of on candesartan (CHARM study) or irbesartan (I-Preserve study) in this form of CHF. ACEI and beta-blockers remain on first line for treating CHF due to systolic dysfunction. Losartan or valsartan can be considered as an alternative if ACEI are not tolerated or contraindicated.

Single arterial occlusion to locate resistance in patients with pulmonary hypertension.

The purpose of this study was to determine the site of increased resistance using the arterial occlusion technique in patients with severe pulmonary hypertension. Pulmonary vascular resistance was partitioned in arterial and venous components based on double exponential fitting analysis of the pulmonary artery pressure decay curve: after balloon occlusion in 36 patients with pulmonary arterial hypertension (PAH); at baseline and during the inhalation of 20 parts per million of nitric oxide (NO); in four patients with chronic thromboembolic pulmonary hypertension; and in two patients with pulmonary veno-occlusive disease. In the patients with PAH, at baseline, mean pulmonary artery pressure was 56+/-2 mmHg (mean+/-SE), with an arterial component of resistance of 63+/-1%. Inhaled NO did not change the partition of resistance. The arterial component of resistance amounted on average to 42% and 77% in the patients with veno-occlusive disease and the patients with thromboembolic pulmonary hypertension, respectively. However, the partitioning of resistance did not discriminate between these three diagnostic categories. The occlusion technique may help to locate the predominant site of increased resistance in patients with severe pulmonary hypertension, but does not allow for a satisfactory differential diagnosis on an individual basis.

[The cardiology department]. / Le Service de Cardiologie.

Cardiology was present since the very beginning of the Erasme hospital. The Department of Cardiology was created in 1979. This department is made of a hospitalization unit (54 beds), a coronary care unit (12 beds) and a large technical unit. Clinical activity has increased tremendously and this had led to an important research activity in the fields of cardio-respiratory and metabolic adaptation to exercise, particularly after cardiac transplantation, of cardiovascular epidemiology, of clinical pharmacology and in pulmonary as well as systemic hypertension.

Medical therapy of pulmonary hypertension. Conventional therapies.

The 1-, 3-, and 5-year survival rates of the patients included in the National Institute of Health Registry on Primary Pulmonary Hypertension were 77%, 41%, and 27% respectively. It is unclear to what extent better applied conventional therapy contributes to improved survival rates that now are reported with calcium-channel blockers, prostacyclin, or even transplantation. To date, by far the most favorable results are reported with high-dose calcium-channel blockers combined with anticoagulant therapy, with survival rates at 3 years approximately 100%. It has to be emphasized, however, that such exceptionally favorable results are to be expected only in a small minority of patients who should not be considered to be cured because, sooner or later, their disease will continue to evolve. Further improvements obviously are needed for most patients with PAH. Interesting developments are likely in the coming years, with new multidrug approaches to control pulmonary vasoreactivity and remodeling and, hopefully, also with progress in lung transplantation. The past 2 decades have witnessed important progress in the treatment of PAH. Although significant improvements in quality of life and survival rate have been obtained with prostacyclin therapy, and better perspectives now are offered with atrial septostomy and lung transplantation, conventional therapy also has evolved. Patients now are counseled more adequately regarding how to remain physically active while avoiding exercise-induced anginal pain or syncope. Invasive and potentially risky medical procedures have been restricted in favor of noninvasive and functional evaluations whenever possible. Risk factors such as appetite suppressants, pregnancy, and hypobaric hypoxia are now better appreciated. The indications of supplemental oxygen, inotropic agents, and diuretics have been refined based on improved pathophysiologic understanding. Most patients now benefit from anticoagulant therapy with coumarin derivatives, although some uncertainty remains about the optimal international normalized ratio to be achieved. Safer acute reversibility testing now is performed with fewer and shorter-acting agents that are more specific to the pulmonary circulation to select the small proportion of patients who benefit from long-term high-dose calcium-channel blocker therapy.