Benjamin Sztrymf

Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation.

RATIONALE Germline mutations in the gene encoding for bone morphogenetic protein receptor 2 (BMPR2) are a cause of pulmonary arterial hypertension (PAH). OBJECTIVES We conducted a study to determine the influence, if any, of a BMPR2 mutation on clinical outcome. METHODS The French Network of Pulmonary Hypertension obtained data for 223 consecutive patients displaying idiopathic or familial PAH in whom point mutation and large size rearrangements of BMPR2 were screened for. Clinical, functional, and hemodynamic characteristics, as well as outcomes, were compared in BMPR2 mutation carriers and noncarriers. MEASUREMENTS AND MAIN RESULTS Sixty-eight BMPR2 mutation carriers (28 familial and 40 idiopathic PAH) were compared with 155 noncarriers (all displaying idiopathic PAH). As compared with noncarriers, BMPR2 mutation carriers were younger at diagnosis of PAH (36.5 +/- 14.5 vs. 46.0 +/- 16.1 yr, P < 0.0001), had higher mean pulmonary artery pressure (64 +/- 13 vs. 56 +/- 13 mm Hg, P < 0.0001), lower cardiac index (2.13 +/- 0.68 vs. 2.50 +/- 0.73 L/min/m(2), P = 0.0005), higher pulmonary vascular resistance (17.4 +/- 6.1 vs. 12.7 +/- 6.6 mm Hg/L/min/m(2), P < 0.0001), lower mixed venous oxygen saturation (59 +/- 9% vs. 63 +/- 9%, P = 0.02), shorter time to death or lung transplantation (P = 0.044), and younger age at death (P = 0.002), but similar overall survival (P = 0.51). CONCLUSIONS BMPR2 mutation carriers with PAH present approximately 10 years earlier than noncarriers, with a more severe hemodynamic compromise at diagnosis.

Pulmonary Veno-Occlusive Disease Clinical, Functional, Radiologic, and Hemodynamic Characteristics and Outcome of 24 Cases Confirmed by Histology

Pulmonary veno-occlusive disease (PVOD) is defined by specific pathologic changes of the pulmonary veins. A definite diagnosis of PVOD thus requires a lung biopsy or pathologic examination of pulmonary explants or postmortem lung samples. However, lung biopsy is hazardous in patients with severe pulmonary hypertension, and there is a need for noninvasive diagnostic tools in this patient population. Patients with PVOD may be refractory to pulmonary arterial hypertension (PAH)-specific therapy and may even deteriorate with it. It is important to identify such patients as soon as possible, because they should be treated cautiously and considered for lung transplantation if eligible. High-resolution computed tomography of the chest can suggest PVOD in the setting of pulmonary hypertension when it shows nodular ground-glass opacities, septal lines, lymph node enlargement, and pleural effusion. Similarly, occult alveolar hemorrhage found on bronchoalveolar lavage in patients with pulmonary hypertension is associated with PVOD. We conducted the current study to identify additional clinical, functional, and hemodynamic characteristics of PVOD. We retrospectively reviewed 48 cases of severe pulmonary hypertension: 24 patients with histologic evidence of PVOD and 24 randomly selected patients with idiopathic, familial, or anorexigen-associated PAH and no evidence of PVOD after meticulous lung pathologic evaluation. We compared clinical and radiologic findings, pulmonary function, and hemodynamics at presentation, as well as outcomes after the initiation of PAH therapy in both groups. Compared to PAH, PVOD was characterized by a higher male:female ratio and higher tobacco exposure (p < 0.01). Clinical presentation was similar except for a lower body mass index (p < 0.02) in patients with PVOD. At baseline, PVOD patients had significantly lower partial pressure of arterial oxygen (PaO2), diffusing lung capacity of carbon monoxide/alveolar volume (DLCO/VA), and oxygen saturation nadir during the 6-minute walk test (all p < 0.01). Hemodynamic parameters showed a lower mean systemic arterial pressure (p < 0.01) and right atrial pressure (p < 0.05), but no difference in pulmonary capillary wedge pressure. Four bone morphogenetic protein receptor II (BMPR2) mutations have been previously described in PVOD patients; in the current study we describe 2 additional cases of BMPR2 mutation in PVOD. Computed tomography of the chest revealed nodular and ground-glass opacities, septal lines, and lymph node enlargement more frequently in patients with PVOD compared with patients with PAH (all p < 0.05). Among the 16 PVOD patients who received PAH-specific therapy, 7 (43.8%) developed pulmonary edema (mostly with continuous intravenous epoprostenol, but also with oral bosentan and oral calcium channel blockers) at a median of 9 days after treatment initiation. Acute vasodilator testing with nitric oxide and clinical, functional, or hemodynamic characteristics were not predictive of the subsequent occurrence of pulmonary edema on treatment. Clinical outcomes of PVOD patients were worse than those of PAH patients. Abbreviations: BMPR2 = bone morphogenetic protein receptor II, CI = cardiac index, CT = computed tomography, DLCO = diffusing lung capacity of carbon monoxide, DLCO/VA = diffusing lung capacity of carbon monoxide/alveolar volume, FEV1 = forced expiratory volume in 1 second, HIV = human immunodeficiency virus, mPAP = mean pulmonary arterial pressure, mSAP = mean systolic arterial pressure, NO = nitric oxide, NYHA = New York Heart Association, PaCO2 = partial pressure of arterial carbon dioxide, PAH = pulmonary arterial hypertension, PaO2 = partial pressure of arterial oxygen, PCWP = pulmonary capillary wedge pressure, PVOD = pulmonary venoocclusive disease, PVRi = indexed pulmonary vascular resistance, SpO2 = pulse arterial oxygen saturation, TLC = total lung capacity, TPRi = indexed total pulmonary resistance, VC = vital capacity.

Clinical Outcomes of Pulmonary Arterial Hypertension in Patients Carrying an ACVRL1 (ALK1) Mutation

RATIONALE Activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) mutation is a cause of hereditary hemorrhagic telangiectasia (HHT) and/or heritable pulmonary arterial hypertension (PAH). OBJECTIVES To describe the characteristics of patients with PAH carrying an ACVRL1 mutation. METHODS We reviewed clinical, functional, and hemodynamic characteristics of 32 patients with PAH carrying an ACVRL1 mutation, corresponding to 9 patients from the French PAH Network and 23 from literature analysis. These cases were compared with 370 patients from the French PAH Network (93 with a bone morphogenetic protein receptor type 2 [BMPR2] mutation and 277 considered as idiopathic cases without identified mutation). Distribution of mutations in the ACVRL1 gene in patients with PAH was compared with the HHT Mutation Database. MEASUREMENTS AND MAIN RESULTS At diagnosis, ACVRL1 mutation carriers were significantly younger (21.8 +/- 16.7 yr) than BMPR2 mutation carriers and noncarriers (35.7 +/- 14.9 and 47.6 +/- 16.3 yr, respectively; P < 0.0001). In seven of the nine patients from the French PAH Network, PAH diagnosis preceded manifestations of HHT. ACVRL1 mutation carriers had better hemodynamic status at diagnosis, but none responded to acute vasodilator challenge and they had shorter survival when compared with other patients with PAH despite similar use of specific therapies. ACVRL1 mutations in exon 10 were more frequently observed in patients with PAH, as compared with what was observed in the HHT Mutation Database (33.3 vs. 5%; P < 0.0001). CONCLUSIONS ACVRL1 mutation carriers were characterized by a younger age at PAH diagnosis. Despite less severe initial hemodynamics and similar management, these patients had worse prognosis compared with other patients with PAH, suggesting more rapid disease progression.

Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases

The aim of the present study was to describe a large cohort of fenfluramine-associated pulmonary arterial hypertension (fen-PAH) and its possible prognostic markers. The records of all patients with a diagnosis of fen-PAH evaluated at the present authors’ centre from 1986–2004 were retrospectively studied. Baseline clinical and haemodynamic data were collected, as well as survival times. The median duration of fenfluramine exposure was 6 months, with a median of 4.5 yrs between exposure and onset of symptoms. Nine (22.5%) out of 40 patients evaluated resulted positive for the presence of germline bone morphogenetic protein receptor (BMPR) type 2 mutations. In these patients, the duration of exposure to fenfluramine was significantly lower than in patients without mutation. The median survival was 6.4 yrs, without significant difference between fen-PAH and a control group of idiopathic and familial pulmonary arterial hypertension patients referred to the present authors’ centre during the same time frame and treated identically. Duration of fenfluramine exposure showed no relation to survival, while cardiac index was the only independent predictor of multivariate analysis. Fenfluramine-associated pulmonary arterial hypertension shares clinical, functional, haemodynamic and genetic features with idiopathic pulmonary arterial hypertension, as well as overall survival rates. Therefore, the present authors conclude that fenfluramine exposure characterises a potent trigger for pulmonary arterial hypertension without influencing its clinical course.

Prevention of hepatopulmonary syndrome and hyperdynamic state by pentoxifylline in cirrhotic rats

Inhibition of tumour necrosis factor‐α (TNF‐α), levels of which are increased in the blood of cirrhotic rats, prevents hyperdynamic circulatory state, mainly by decreasing the vascular overproduction of nitric oxide. Hepatopulmonary syndrome, which is characterised by intrapulmonary vascular dilatation and increased alveolar to arterial oxygen tension difference (PA-a,O2), is mainly related to pulmonary overproduction of NO by macrophages accumulated in lung vessels. Since TNF‐α is a potent activator of macrophagic inducible nitric oxide synthase (NOS), the aim of this study was to investigate whether TNF‐α inhibition prevented hepatopulmonary syndrome and hyperdynamic circulatory state in rats with cirrhosis. TNF‐α was inhibited by 5 weeks of pentoxifylline (10 mg·kg body weight−1·day−1) in rats with cirrhosis induced by common bile duct ligation. Cardiac output, pulmonary and systemic vascular resistance, PA-a,O2 and cerebral uptake of intravenous technetium‐99m‐labelled albumin macroaggregates (which reflects intrapulmonary vascular dilatation) were similar in sham- and pentoxifylline-treated cirrhotic rats. Blood TNF‐α concentrations and pulmonary intravascular macrophage sequestration, as assessed by morphometric analysis and radioactive colloid uptake, were decreased with pentoxifylline. Pentoxifylline also prevented increases in aorta and lung NOS activities and inducible NOS expression. Thus pentoxifylline prevents development of hyperdynamic circulatory state and hepatopulmonary syndrome, probably by inhibiting the effects of tumour necrosis factor‐α on vascular nitric oxide synthase and intravascular macrophages. These results support an important role for tumour necrosis factor‐α in the genesis of hepatopulmonary syndrome.

Use of High-Flow Nasal Cannula Oxygen Therapy in Subjects With ARDS: A 1-Year Observational Study

BACKGROUND: Beneficial effects of high-flow nasal cannula (HFNC) oxygen on oxygenation and respiratory parameters have been reported in a small number of subjects with acute respiratory failure (ARF). We aimed to evaluate its effect in subjects with ARDS. METHODS: This was an observational single-center study. Prospectively obtained data were retrospectively analyzed. All patients admitted over 1 y to a university hospital medicosurgical ICU were included. Classification was according to the highest ventilatory support required. HFNC indications were reviewed, and demographics, clinical characteristics, and course of subjects with ARDS according to intubation need were compared. RESULTS: Of 607 subjects admitted, 560 required ventilatory or oxygen support, among whom 180 received noninvasive ventilatory support. HFNC was used in 87 subjects and as first-line treatment in 51 subjects (29% of first-line noninvasively treated subjects), 45 of which had ARDS (PaO2/FIO2 of 137 mm Hg; 22 men, 57.9 y of age). Pneumonia accounted for 82% of ARDS causes. The intubation rate in these subjects was 40%. Higher Simplified Acute Physiology Score II (SAPS II; 46 vs 29, P = .001), occurrence of additional organ failure (76% vs 26%, P = .002), mainly hemodynamic (50% vs 7%, P = .001) or neurological (22% vs 0, P = .01), and trends toward lower PaO2/FIO2 and higher breathing frequency after HFNC initiation were evidenced in subjects who failed HFNC. Higher SAPS II scores were associated with HFNC failure in multivariate analysis. CONCLUSIONS: In daily care, over one fourth of subjects requiring noninvasive ventilatory support were treated via HFNC, with a high success rate in subjects with severe ARDS. We conclude that HFNC may be considered as first-line therapy in ARF, including patients with ARDS.

Absence of influence of gender and BMPR2 mutation type on clinical phenotypes of pulmonary arterial hypertension

BackgroundPrevious studies indicate that patients with pulmonary arterial hypertension (PAH) carrying a mutation in the bone morphogenetic protein receptor type 2 (BMPR2) gene, develop the disease 10 years earlier than non-carriers, and have a more severe hemodynamic compromise at diagnosis. A recent report has suggested that this may only be the case for females and that patients with missense mutations in BMPR2 gene have more severe disease than patients with truncating mutations.MethodsWe reviewed data from all patients with PAH considered as idiopathic and patients with a family history of PAH, who underwent genetic counselling in the French PAH network between January, 1st 2004 and April, 1st 2010. We compared clinical, functional, and hemodynamic characteristics between carriers and non-carriers of a BMPR2 mutation, according to gender or BMPR2 mutation type.ResultsPAH patients carrying a BMPR2 mutation (n = 115) were significantly younger at diagnosis than non-carriers (n = 267) (35.8 ± 15.4 and 47.5 ± 16.2 respectively, p < 0.0001). The presence of a BMPR2 mutation was associated with a younger age at diagnosis in females (36.4 ± 14.9 in BMPR2 mutation carriers and 47.4 ± 15.8 in non-carriers, p < 0.0001), and males (34.6 ± 16.8 in BMPR2 mutation carriers and 47.8 ± 17.1 in non-carriers, p < 0.0001). BMPR2 mutation carriers had a more severe hemodynamic compromise at diagnosis, but this was not influenced by gender. No differences in survival and time to death or lung transplantation were found in male and female PAH patients carrying a BMPR2 mutation. No differences were observed in clinical outcomes according to the type of BMPR2 mutations (missense, truncating, large rearrangement or splice defect).ConclusionWhen compared to non-carriers, BMPR2 mutation carriers from the French PAH network are younger at diagnosis and present with a more severe hemodynamic compromise, irrespective of gender. Moreover, BMPR2 mutation type had no influence on clinical phenotypes in our patient population.

Genes and Pulmonary Arterial Hypertension

Familial pulmonary arterial hypertension (FPAH) was first described more than 50 years ago. Before the availability of modern genetic tools, studies of the genealogies demonstrated that these cases segregated as an autosomic dominant trait, with an incomplete penetrance and a genetic anticipation phenomenon by which age at onset of the disease is decreasing in the subsequent generations. Germline mutations in the gene coding for the bone morphogenetic protein receptor II (BMPR2) are present in more than 70% of FPAH and up to 26% of idiopathic, apparently sporadic cases (IPAH). Incomplete penetrance (around 20%) is a major pitfall because FPAH becomes ignored when the disease skips one or several generations. Genetic counseling is complex, with a significant number of BMPR2 mutation healthy carriers screened in some families. Incomplete penetrance puts them in the anxious situation of being potentially affected in the future by this devastating condition or to transmit this risk to their offspring. Nevertheless, genetic testing and counseling is about to become a standard in the management of PAH. Recent international guidelines on PAH state that genetic testing is recommended in FPAH and that IPAH patients have to be informed about the availability of such testing.

Cirrhotic rats with bacterial translocation have higher incidence and severity of hepatopulmonary syndrome.

Background:  Bacterial translocation, that is, extra‐intestinal dissemination of gut bacteria, occurs in approximately 50% of humans and rats with cirrhosis and plays a significant role in enhanced tumor necrosis factor‐α (TNF‐α) production. The authors’ previous studies have indicated that prevention of bacterial translocation with norfloxacine or inhibition of TNF‐α with pentoxifylline treatment decreased both the incidence and severity of hepatopulmonary syndrome by attenuating the induction of pulmonary intravascular macrophages in cirrhotic rats. In the present study the hypothesis was tested that the cirrhotic rats with bacterial translocation had higher TNF‐α production, higher level of sequestration of macrophages in pulmonary vessels, and increased incidence and severity of hepatopulmonary syndrome.

Genetic counselling in a national referral centre for pulmonary hypertension

Genetic causes of pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease (PVOD) have been identified, leading to a growing need for genetic counselling. Between 2003 and 2014, genetic counselling was offered to 529 PAH and 100 PVOD patients at the French Referral Centre for Pulmonary Hypertension. Mutations in PAH-predisposing genes were identified in 72 patients presenting as sporadic PAH (17% of cases; 62 mutations in BMPR2, nine in ACVRL1 (ALK1) and one in ENG) and in 94 patients with a PAH family history (89% of cases; 89 mutations in BMPR2, three in ACVRL1 (ALK1) and two in KCNK3). Bi-allelic mutations in EIF2AK4 were identified in all patients with a family history of PVOD (n=19) and in seven patients (8.6%) presenting as sporadic PVOD. Pre-symptomatic genetic diagnosis was offered to 272 relatives of heritable PAH patients, identifying mutations in 36.4% of them. A screening programme is now offered to asymptomatic mutation carriers to detect PAH in an early phase and to identify predictors of outcomes in asymptomatic BMPR2 mutation carriers. BMPR2 screening allowed us to offer pre-implantation diagnosis to two couples with a BMPR2 mutation. Genetic counselling can be implemented in pulmonary hypertension centres. Genetic causes of PAH and PVOD have been identified; genetic counselling can be implemented in PH centres http://ow.ly/TLbee