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According to current guidelines, pulmonary arterial hypertension (PAH) is diagnosed when mean pulmonary arterial pressure (Ppa) exceeds 25 mmHg at rest or 30 mmHg during exercise. Issues that remain unclear are the classification of Ppa values ,25mmHg and whether Ppa .30 mmHg during exercise is always pathological.We performed a comprehensive literature review and analysed all accessible data obtained by right heart catheter studies from healthy individuals to determine normal Ppa at rest and during exercise. Data on 1,187 individuals from 47 studies in 13 countries were included. Data were stratified for sex, age, geographical origin, body position and exercise level.Ppa at rest was 14.0¡3.3 mmHg and this value was independent of sex and ethnicity. Resting Ppa was slightly influenced by posture (supine 14.0¡3.3 mmHg, upright 13.6¡3.1 mmHg) and age (,30 yrs: 12.8¡ 3.1mmHg; 30-50 yrs: 12.9¡3.0 mmHg; o50 yrs: 14.7¡4.0 mmHg). Ppa during exercise was dependent on exercise level and age. During mild exercise, Ppa was 19.4¡4.8 mmHg in subjects aged ,50 yrs compared with 29.4¡8.4 mmHg in subjects o50 yrs (p,0.001).In conclusion, while Ppa at rest is virtually independent of age and rarely exceeds 20 mmHg, exercise Ppa is age-related and frequently exceeds 30 mmHg, especially in elderly individuals, which makes it difficult to define normal Ppa values during exercise.

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C hronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism with uncertain prevalence, ranging from 0.4% to 9.1%. 1 Diagnosis is strongly associated with a history of acute venous thromboembolism (VTE). 2,3 It is caused by nonresolving fibrothrombotic obstructions of large pulmonary arteries, combined Background-Chronic thromboembolic pulmonary hypertension, a rare complication of acute pulmonary embolism, is characterized by fibrothrombotic obstructions of large pulmonary arteries combined with small-vessel arteriopathy. It can be cured by pulmonary endarterectomy, and can be clinically improved by medical therapy in inoperable patients. A European registry was set up in 27 centers to evaluate long-term outcome and outcome correlates in 2 distinct populations of operated and not-operated patients who have chronic thromboembolic pulmonary hypertension. Methods and Results-A total of 679 patients newly diagnosed with chronic thromboembolic pulmonary hypertension were prospectively included over a 24-month period. Estimated survival at 1, 2, and 3 years was 93% (95% confidence interval [CI], 90-95), 91% (95% CI, 87-93), and 89% (95% CI, 86-92) in operated patients (n=404), and only 88% (95% CI, 83-91), 79% (95% CI, 74-83), and 70% (95% CI, 64-76) in not-operated patients (n=275). In both operated and not-operated patients, pulmonary arterial hypertension-targeted therapy did not affect survival estimates significantly. Mortality was associated with New York Heart Association functional class IV (hazard ratio [HR], 4.16; 95% CI, 1. P=0.0065 and HR, 4.76; 95% CI, P=0.0021), increased right atrial pressure (HR, 1.34; 95% CI, 0.95-1.90; P=0.0992 and HR, 1.50; 95% CI, 1.20-1.88; P=0.0004), and a history of cancer (HR, 3.02; 95% CI, 1.36-6.69; P=0.0065 and HR, 2.15; 95% CI, 1.18-3.94; P=0.0129) in operated and not-operated patients, respectively. Additional correlates of mortality were bridging therapy with pulmonary arterial hypertension-targeted drugs, postoperative pulmonary hypertension, surgical complications, and additional cardiac procedures in operated patients, and comorbidities such as coronary disease, left heart failure, and chronic obstructive pulmonary disease in not-operated patients. Conclusions-The long-term prognosis of operated patients currently is excellent and better than the outcome of notoperated patients. with small-vessel arteriopathy in some patients. Both proximal and small-vessel obstruction increase pulmonary vascular resistance (PVR), leading to progressive pulmonary hypertension, right heart failure, and ultimately death. CTEPH can be cured by pulmonary endarterectomy (PEA) 4 and clinically improved by medical therapy. 5,6 Therefore, current guidelines recommend PEA as first-choice therapy, whereas the use of pulmonary arterial hypertension (PAH)-targeted drugs is restricted to inoperable patients or patients with persistent/recurrent pulmonary hypertension after PEA.7 Balloon pulmonary angioplasty, a new and promising treatment method for ...

Key Points• Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL.• Updated results on safety and efficacy of the CLL8 trial.Despite promising results with targeted drugs, chemoimmunotherapy with fludarabine, cyclophosphamide (FC), and rituximab (R) remains the standard therapy for fit patients with untreated chronic lymphocytic leukemia (CLL). Herein, we present the long-term follow-up of the randomized CLL8 trial reporting safety and efficacy of FC and FCR treatment of 817 treatment-naïve patients with CLL. The primary end point was progressionfree survival (PFS). With a median follow-up of 5.9 years, median PFS were 56.8 and 32.9 months for the FCR and FC group (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.50-0.69, P < .001). Median overall survival (OS) was not reached for the FCR group and was 86.0 months for the FC group (HR, 0.68; 95% CI, 0.54-0.89, P 5 .001). In patients with mutated IGHV (IGHV MUT), FCR improved PFS and OS compared with FC (PFS: HR, 0.47; 95% CI, 0.33-0.68, P < .001; OS: HR, 0.62; 95% CI, 0.34-1.11, P 5 .1). This improvement remained applicable for all cytogenetic subgroups other than del(17p). Long-term safety analyses showed that FCR had a higher rate of prolonged neutropenia during the first year after treatment (16.6% vs 8.8%; P 5 .007). Secondary malignancies including Richter's transformation occurred in 13.1% in the FCR group and in 17.4% in the FC group (P 5 .1). First-line chemoimmunotherapy with FCR induces long-term remissions and highly relevant improvement in OS in specific genetic subgroups of fit patients with CLL, in particular those with IGHV MUT. This trial was registered at www.clinicaltrials.gov as #NCT00281918. (Blood. 2016;127(2):208-215)

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Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

Background-Chronic thromboembolic pulmonary hypertension (CTEPH) is often a sequel of venous thromboembolism with fatal natural history; however, many cases can be cured by pulmonary endarterectomy.