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.

[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.

Partitioning of pulmonary vascular resistance in primary pulmonary hypertension.

OBJECTIVES: This study sought to determine the site of increased pulmonary vascular resistance (PVR) in primary pulmonary hypertension by standard bedside hemodynamic evaluation. BACKGROUND: The measurement of pulmonary vascular pressures at several levels of flow (Q) allows the discrimination between active and passive, flow-dependent changes in mean pulmonary artery pressure (Ppa), and may detect the presence of an increased pulmonary vascular closing pressure. The determination of a capillary pressure (Pc') from the analysis of a Ppa decay curve after balloon occlusion allows the partitioning of PVR in an arterial and a (capillary + venous) segment. These approaches have not been reported in primary pulmonary hypertension. METHODS: Ppa and Pc' were measured at baseline and after an increase in Q induced either by exercise or by an infusion of dobutamine, at a dosage up to 8 microg/kg body weight per min, in 11 patients with primary pulmonary hypertension. Reversibility of pulmonary hypertension was assessed by the inhalation of 20 ppm nitric oxide (NO), and, in 6 patients, by an infusion of prostacyclin. RESULTS: At baseline, Ppa was 52+/-3 mm Hg (mean value+/-SE), Q 2.2+/-0.2 liters/min per m2, and Pc' 29+/-3 mm Hg. Dobutamine did not affect Pc' and allowed the calculation of an averaged extrapolated pressure intercept of Ppa/Q plots of 34 mm Hg. Inhaled NO had no effect. Prostacyclin decreased Pc' and PVR. Exercise increased Pc' to 40+/-3 mm Hg but did not affect PVR. CONCLUSIONS: ns. These findings are compatible with a major increase of resistance and reactivity at the periphery of the pulmonary arterial tree.

Sympathetic modulation of hypoxic pulmonary vasoconstriction in intact dogs.

BACKGROUND: The effects of the sympathetic nervous system on hypoxic pulmonary vasoconstriction (HPV) have been reported variably. We studied the effects of adrenergic receptor blockade and epidural blockade on HPV in 32 pentobarbital-anaesthetised intact dogs. METHODS: Pulmonary arterial flow-pressure relationships were determined in hyperoxia and hypoxia, at baseline and after alpha-blockade (phentolamine 2 mg/kg + 50 micrograms.kg-1.-1), beta-blockade (propranolol 2 mg/kg), alpha beta-blockade, epidural blockade (lignocaine 20 mg/kg), and alpha beta-plus epidural blockade. RESULTS: At reference flow of 3.5 1.min-1.m-2, the mean hypoxic response (hypoxia-induced increase in transpulmonary pressure gradient, each n = 8) changed from 6.0 +/- 0.9 to 3.5 +/- 1.0 mmHg after alpha-blockade, from 5.8 +/- 0.9 to 0.7 mmHg after beta-blockade, from 4.1 +/- 0.8 to 0.9 +/- 1.4 mmHg after alpha beta-blockade from 3.4 +/- 1.0 to 4.3 +/- 0.9 mmHg after epidural blockade (all P < 0.05), and was not affected by epidural blockade after alpha beta-blockade. CONCLUSIONS: In pentobarbital-anaesthetised dogs, (1) HPV is attenuated by alpha- and enhanced by beta-, alpha beta- and epidural blockade, and (2) epidural blockade has no significant adrenergic-unrelated effect on the pulmonary vasculature.

Atrial natriuretic peptides in canine hypoxic pulmonary vasoconstriction.

STUDY OBJECTIVE: The aim of the study was to investigate whether atrial natriuretic peptides have a physiological role in regulation of the pulmonary circulation. DESIGN: Plasma concentrations of immunoreactive atrial natriuretic peptide and guanosine-3',5'-cyclic monophosphate (cGMP) were measured during evaluation of pulmonary vascular tone by multipoint pulmonary arterial pressure-cardiac index (Ppa/Q) relationships. SUBJECTS: Experimental animals were 17 mongrel dogs of either sex, 21-35 kg weight, anaesthetised with pentobarbitone. MEASUREMENTS AND MAIN RESULTS: Measurements of Ppa/Q relationships and atrial natriuretic peptide/cGMP were made during hyperoxia (Fio2 0.4) and hypoxia (Fio2 0.1). Hypoxic pulmonary vasoconstriction, defined as hypoxia induced increase in pulmonary artery pressure over the entire range of Q studied from 2-5 litre.min-1.m-2, was elicited in nine dogs ("responders"). In the other eight dogs, hypoxia did not change pulmonary artery pressure over the entire range of Q studied ("non-responders"). At neither the highest nor the lowest Q in hyperoxia did atrial natriuretic peptide and cGMP concentrations differ between these two groups, nor did acute reduction in Q affect the concentrations in either group. At the highest Q, plasma atrial natriuretic peptide increased in hypoxia from 11(SEM 2) to 15(3) pmol.litre-1 in the responders (p less than 0.05), and from 15(2) to 20(2) pmol.litre-1 in the non-responders (p less than 0.05). However at the lowest Q, atrial natriuretic peptide was increased in non-responders only, from 17(3) to 23(4) pmol.litre-1 (p less than 0.05). CGMP did not vary significantly in any experimental condition. CONCLUSIONS: Hypoxia slightly increased plasma atrial natriuretic peptides without any relationship with associated pulmonary haemodynamic changes. These data do not support the hypothesis that atrial natriuretic peptides play a physiological role in the regulation of the pulmonary circulation in dogs.

Gastric perforation due to mucormycosis after heart-lung and heart transplantation.

BACKGROUND: Gastrointestinal complications are a well-documented source of morbidity and mortality after heart and lung transplantation. METHODS: We report on two patients who presented with gastric perforation caused by mucormycosis during the first 2 months after heart-lung and heart transplantation. RESULTS: In the first patient, the clinical presentation was insidious and the diagnosis was made at an advanced stage of the disease. Despite surgery and aggressive antifungal treatment, the patient died. In the second patient, the diagnosis was made promptly, but despite antifungal treatment, he presented with gastric perforation within a week. CONCLUSIONS: These cases illustrate that fungal invasive disease may be a cause of early gastrointestinal perforation after solid organ transplantation.

Safety, tolerability and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil based formulation of cyclosporine--results at six months after transplantation.

BACKGROUND: The introduction of cyclosporine has resulted in significant improvement in the survival of cardiac allograft recipients due to decreased mortality from infection and rejection. The original oil-based cyclosporine formulation exhibits variable and unpredictable bioavailability that correlates with an increased incidence of acute and chronic rejection in those patients in whom this is most pronounced. The primary objectives of this prospective, multicenter, randomized, double-blind study in cardiac transplant patients were: to compare the efficacy of cyclosporine microemulsion (CsA-NL) with oil-based cyclosporine (CsA-SM) as measured by cardiac allograft and recipient survival and the incidence and severity of acute rejection episodes; and to assess the safety and tolerability of CsA-NL compared with CsA-SM in this population. This report represents the analysis of results 6 months after transplantation. METHODS: A total of 380 patients undergoing their first cardiac transplant at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial examining the safety and efficacy of CsA-NL versus CsA-SM. Rejection was diagnosed using endomyocardial biopsy and were graded according to standardized criteria of the International Society of Heart and Lung Transplantation (ISHLT). Clinical parameters were monitored during the study. Survival and freedom from were used for analysis as was Fisher's exact test for comparisons between groups. RESULTS: At 6 months after transplantation, allograft and patient survival were the same for both groups. The frequency of ISHLT grade 3A or greater episodes in the two groups was identical. Fewer CsA-NL patients (5.9%) required antilymphocyte antibody (ATG or OKT-3) therapy for rejection compared with the CsA-SM-treated patients (14.1%, P=0.01). Females with ISHLT rejection grade > or = 3A treated with CsA-NL had a 46% lower incidence of rejection compared with the CsA-SM-treated group (31.3% vs. 57.6%, P=0.032). Fewer infections were seen in the CsA-NL. With the exception of baseline and 1 week posttransplant creatinines which were higher in the CsA-NL group, the overall creatinine was not significantly different between the two groups. CONCLUSIONS: This multicenter, randomized study of cardiac transplant recipients documented less severe rejection (in particular those requiring antibody therapy) and a lower incidence of infection in CsA-NL-treated patients. Results from the female subgroup analysis suggest that the improved bioavailability of CsA-NL might reduce the frequency of rejection episodes in female patients. The use of CsA-NL was not associated with an increased risk of adverse events.

Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine--results at 24 months after transplantation.

BACKGROUND: The widespread use of cyclosporine has improved the survival of cardiac transplant patients as a result of reduced morbidity and mortality from rejection and infection. The original oil-based form of cyclosporine demonstrated unpredictable absorption resulting in an increased frequency of acute and chronic rejection in patients with poor bioavailability. The primary end. points of the present, prospective, randomized multicenter, double-blind trial were to compare the efficacy of the micro-emulsion form of cycolsporine (CsA-NL) with the oil-based formulation as determined by cardiac allograft and recipient survival and the incidence and severity of the acute rejection episodes and to determine the safety and tolerability of CsA-NL compared with Sandimmune CsA-(SM) in the study population. The 6-month analysis of the study showed reduced number of CsA-NL patients requiring antilymphocyte antibody therapy for rejection, fewer International Society of Heart and Lung Transplantation grade > or =3A rejections in female patients and fewer infections. Our report represents the final analysis of the results 24 months after transplantation. METHODS: A total of 380 patients undergoing de novo cardiac transplants at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial evaluating the efficacy and safety of CsA-NL versus CsA-SM. Acute allograft rejection was diagnosed by endomyocardial biopsy and graded according to the International Society of Heart and Lung Transplantation nomenclature. Kaplan-Meier analysis and Fisher's exact test were used for comparisons between groups. RESULTS: After 24 months, allograft and recipient survival were identical in both groups. There were fewer CsA-NL patients (6.9%) requiring antilymphocyte antibody therapy for rejection than in the CsA-SM-treated patient group (17.7%, P=0.002). There were fewer discontinuations of study drug for treatment failures in the CsA-NL groups (7; 3.7%) compared with the CsA-SM group (18; 9.4%, P=0.037). The average corticosteroid dose was lower in the CsA-NL group (0.37 mg/kg/day) compared with the CsA-SM group (0.48 mg/kg/day, P=0.034) over the 24-month study period. Overall, there was no difference in blood pressure or creatinine between the two study groups. CONCLUSIONS: The final results of this multi-center, randomized study of two forms of cyclosporine confirmed that there were fewer episodes of rejection requiring antilymphocyte antibodies and fewer study discontinuations for treatment failures in CsA-NL-treated patients compared to those treated with CsA-SM. The use of CsA-NL did not predispose these patients to a higher risk of adverse events.

Absence of L-arginine effect on coronary hypersensitivity to serotonin in cardiac transplant recipients.

Coronary hypersensitivity to serotonin promotes platelet aggregation and, therefore, the progression of the atherosclerotic process. This abnormality occurs in the early stages of coronary atherosclerosis when the responses to bradykinin are still preserved. To determine whether such changes also occur early after cardiac transplantation, intracoronary injections of bradykinin and serotonin were performed in 7 control patients, in 19 patients with dyslipidemia, and in 15 cardiac transplant recipients (1 year after operation). Coronary angiography was normal in the 3 groups. In the segments where serotonin effects were the most pronounced, the diameter changes were measured by quantitative angiography. Bradykinin (60, 200, and 600 ng) increased in the same way as the coronary diameters in the 3 groups; in contrast, serotonin elicited vasodilation only in the control group (7+/-3%, percentage of baseline) and vasoconstriction in the hyperlipidemic group (-9+/-2%) and in transplant recipients (-15+/-3%). After intracoronary infusion of L-arginine (40 mg/min for 14 minutes), serotonin-induced constriction was attenuated in the hyperlipidemic group but not in transplant recipients. Thus, the response to bradykinin is preserved in the early stages of graft vasculopathy. However, in contrast to patients with hyperlipidemia, the absence of an L-arginine effect on the responses to serotonin suggests the involvement of mechanisms other than a decrease in endothelium-derived nitric oxide availability. Immune processes promoting the release of endothelium-derived contracting factors such as endothelin and/or superoxide anion may play a role.

Coronary vasomotility and myocardial blood flow early after heart transplantation.

Serotonin constricts coronary arteries with endothelial dysfunction, a common abnormality in cardiac transplant recipients. To assess whether endothelial dysfunction is associated with myocardial blood flow (MBF) abnormalities, 24 patients were studied 1 to 12 months after transplantation. Serotonin in increasing doses (1, 10, and 20 micrograms/min for 2.5 min each) was infused into the coronary circulation. Diameters were measured by quantitative angiography. Fourteen patients (group A) had a pronounced artery constriction (diameter reduction > 40%), while in 10 other patients (group B), such a constriction was never reached. No patient had evidence of rejection and all had angiographically normal coronary arteries. MBF was measured at rest and after intravenous dipyridamole with dynamic nitrogen-13 ammonia positron emission tomography (PET). The resting MBF was higher in group A than in group B (94 +/- 12 vs 74 +/- 15 ml/min/100 g of tissue; p < 0.05). During dipyridamole, MBF was not significantly different (191 +/- 53 vs 184 +/- 64 ml/min/100 g; p = NS). Coronary flow reserve (the ratio of perfusion after dipyridamole to perfusion at rest) was significantly lower in group A than in group B (2.08 +/- 0.54 vs 2.66 +/- 0.57; p < 0.05). Thus, coronary hypersensitivity to serotonin in cardiac transplant recipients is associated with elevated resting MBF and reduced coronary flow reserve. Immune mechanisms inducing endothelial injuries and inflammation-related hyperemia may account for these abnormalities.

High-altitude pulmonary edema with primary pulmonary hypertension.

A 43-year-old woman had two episodes of lung edema at moderate altitudes. She had taken slimming pills containing fenfluramine hydrochloride and diethylpropion hydrochloride. At sea level, catheterization of the right side of the heart showed a mean pulmonary artery pressure of 16 mm Hg, which increased to 34 mm Hg with mild exercise in a supine position. An extensive workup failed to identify a cardiac or a pulmonary cause of pulmonary hypertension. This patient experienced mild primary pulmonary hypertension related to the intake of anorexigens, which was revealed by high-altitude pulmonary edema.

Human cytokine responses to cardiac transplantation and coronary artery bypass grafting.

Cardiac surgery with cardiopulmonary bypass triggers an inflammatory response involving proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-6, and interleukin-8. To elucidate the pathophysiology of this cytokine response, we explored the possible differences in cytokine responses between patients undergoing heart transplantation and those undergoing coronary artery bypass grafting. Plasma levels of tumor necrosis factor-alpha, interleukin-6, interleukin-8, and interleukin-10 were measured in eight patients undergoing heart transplantation (mean age 44 years) and eight patients undergoing coronary artery bypass grafting (mean age 61 years). Duration of cardiopulmonary bypass and ischemic time were both longer in the heart transplantation group than in the coronary artery bypass grafting group (133 +/- 26 min vs 100 +/- 31 min, p < 0.05, and 130 +/- 47 min vs 58 +/- 21 min, p < 0.005, respectively). Samples were collected before heparin administration, at aortic crossclamping and declamping, and at 0.5, 1, 1.5, 2, 4, 12, and 24 hours after declamping. Tumor necrosis factor-alpha levels were significantly higher 30 minutes after aortic declamping in the heart transplantation group than in the coronary artery bypass grafting group (68 +/- 30 vs 18 +/- 5 pg/ml, p < 0.05). Interleukin-6 and interleukin-8 levels were also significantly higher 90 minutes after declamping in patients undergoing heart transplantation than in those undergoing coronary artery bypass grafting (310 +/- 63 vs 169 +/- 24 pg/ml, p < 0.05, and 73 +/- 17 vs 24 +/- 5 pg/ml, p < 0.01, respectively). Furthermore, interleukin-6 and interleukin-8 values 90 minutes after declamping were significantly correlated with the ischemic time (r = 0.72 and r = 0.82, respectively, both p < 0.05). Interleukin-10 levels in both groups rose to reach a peak value of around 115 pg/ml 1 hour after declamping. Patients undergoing heart transplantation exhibited a second peak of tumor necrosis factor-alpha, interleukin-8, and interleukin-10 levels 12 hours after declamping, probably related to the administration of rabbit antihuman thymocyte immunoglobulin (Thymoglobuline) 3 hours after declamping. Interleukin-6 levels decreased more significantly 12 and 24 hours after declamping in patients undergoing heart transplantation, probably related to methylprednisolone therapy. In conclusion, cardiopulmonary bypass is associated with the production of both proinflammatory and antiinflammatory cytokines. The production of proinflammatory cytokines in patients undergoing heart transplantation is higher than that in patients undergoing coronary artery bypass grafting, and this increase could be related to the longer duration of ischemia in the former group. The later course of cytokine levels after heart transplantation may be further influenced by immunosuppressive therapy.

Oxygenation improvement with nitric oxide in right-to-left shunt without significant effects on pulmonary arterial pressure.

Following surgical closure of an interventricular communication complicating an anterior myocardial infarction, a 74-year-old woman developed severe right ventricular failure and hypoxemia due to the opening of a patent foramen ovale (PFO). Mean pulmonary artery pressure was 24 mm Hg. Treatment with inhaled nitric oxide (5 ppm) increased PaO2 from 47 to 90 mm Hg (FIo(2)1). The present observation points out that nitric oxide inhalation could be useful in the management of severe hypoxemia from a right-to-left shunt due to a PFO even when there is no significant pulmonary hypertension present.

Atrial septostomy under transesophageal guidance in a patient with primary pulmonary hypertension and absent right superior vena cava.

A patient presenting primary pulmonary hypertension and absent right superior vena cava underwent blade/balloon atrial septostomy as palliative therapy. Due to the anomaly of the venous drainage system, only transesophageal echocardiography allowed the performance of the maneuvre.