Sean Gaine

Primary pulmonary hypertension

Summary Primary pulmonary hypertension (PPH) is a progressive disease characterised by raised pulmonary vascular resistance, which results in diminished right-heart function due to increased right ventricular afterload. PPH occurs most commonly in young and middle-aged women; mean survival from onset of symptoms is 2–3 years. The aetiology of PPH is unknown, although familial disease accounts for roughly 10% of cases, which suggests a genetic predisposition. Current theories on pathogenesis focus on abnormalities in interaction between endothelial and smooth-muscle cells. Endothelial-cell injury may result in an imbalance in endothelium-derived mediators, favouring vasoconstriction. Defects in ion-channel activity in smooth-muscle cells in the pulmonary artery may contribute to vasoconstriction and vascular proliferation. Diagnostic testing primarily excludes secondary causes. Catheterisation is necessary to assess haemodynamics and to evaluate vasoreactivity during acute drug challenge. Decrease in pulmonary vascular resistance in response to acute vasodilator challenge occurs in about 30% of patients, and predicts a good response to chronic therapy with oral calcium-channel blockers. For patients unresponsive during acute testing, continuous intravenous epoprostenol (prostacyclin, PGI 2 ) improves haemodynamics and exercise tolerance, and prolongs survival in severe PPH (NYHA functional class III–IV). Thoracic transplantation is reserved for patients who fail medical therapy. We review the progress made in diagnosis and treatment of PPH over the past 20 years.

Dysfunctional Voltage-Gated K+ Channels in Pulmonary Artery Smooth Muscle Cells of Patients With Primary Pulmonary Hypertension

BACKGROUND Primary pulmonary hypertension (PPH) is a rare disease of unknown cause. Although PPH and secondary pulmonary hypertension (SPH) share many clinical and pathological characteristics, their origins may be disparate. In pulmonary artery smooth muscle cells (PASMCs), the activity of voltage-gated K+ (KV) channels governs membrane potential (Em) and regulates cytosolic free Ca2+ concentration ([Ca2+]cyt). A rise in [Ca2+]cyt is a trigger of vasoconstriction and a stimulus of smooth muscle proliferation. METHODS AND RESULTS Fluorescence microscopy and patch clamp techniques were used to measure [Ca2+]cyt, Em, and KV currents in PASMCs. Mean pulmonary arterial pressures were comparable (46+/-4 and 53+/-4 mm Hg; P=0.30) in SPH and PPH patients. However, PPH-PASMCs had a higher resting [Ca2+]cyt than cells from patients with SPH and nonpulmonary hypertension disease. Consistently, PPH-PASMCs had a more depolarized Em than SPH-PASMCs. Furthermore, KV currents were significantly diminished in PPH-PASMCs. Because of the dysfunctional KV channels, the response of [Ca2+]cyt to the KV channel blocker 4-aminopyridine was significantly attenuated in PPH-PASMCs, whereas the response to 60 mmol/L K+ was comparable to that in SPH-PASMCs. CONCLUSIONS These results indicate that KV channel function in PPH-PASMCs is inhibited compared with SPH-PASMCs. The resulting membrane depolarization and increase in [Ca2+]cyt lead to pulmonary vasoconstriction and PASMC proliferation. Our data suggest that defects in PASMC KV channels in PPH patients may be a unique mechanism involved in initiating and maintaining pulmonary vasoconstriction and appear to play a role in the pathogenesis of PPH.

Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Results From an International Prospective Registry

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. The clinical characteristics and current management of patients enrolled in an international CTEPH registry was investigated. Methods and Results— The international registry included 679 newly diagnosed (≤6 months) consecutive patients with CTEPH, from February 2007 until January 2009. Diagnosis was confirmed by right heart catheterization, ventilation-perfusion lung scintigraphy, computerized tomography, and/or pulmonary angiography. At diagnosis, a median of 14.1 months had passed since first symptoms; 427 patients (62.9%) were considered operable, 247 (36.4%) nonoperable, and 5 (0.7%) had no operability data; 386 patients (56.8%, ranging from 12.0%– 60.9% across countries) underwent surgery. Operable patients did not differ from nonoperable patients relative to symptoms, New York Heart Association class, and hemodynamics. A history of acute pulmonary embolism was reported for 74.8% of patients (77.5% operable, 70.0% nonoperable). Associated conditions included thrombophilic disorder in 31.9% (37.1% operable, 23.5% nonoperable) and splenectomy in 3.4% of patients (1.9% operable, 5.7% nonoperable). At the time of CTEPH diagnosis, 37.7% of patients initiated at least 1 pulmonary arterial hypertension–targeted therapy (28.3% operable, 53.8% nonoperable). Pulmonary endarterectomy was performed with a 4.7% documented mortality rate. Conclusions— Despite similarities in clinical presentation, operable and nonoperable CTEPH patients may have distinct associated medical conditions. Operability rates vary considerably across countries, and a substantial number of patients (operable and nonoperable) receive off-label pulmonary arterial hypertension–targeted treatments. # Clinical Perspective {#article-title-40}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. The clinical characteristics and current management of patients enrolled in an international CTEPH registry was investigated. Methods and Results— The international registry included 679 newly diagnosed (⩽6 months) consecutive patients with CTEPH, from February 2007 until January 2009. Diagnosis was confirmed by right heart catheterization, ventilation-perfusion lung scintigraphy, computerized tomography, and/or pulmonary angiography. At diagnosis, a median of 14.1 months had passed since first symptoms; 427 patients (62.9%) were considered operable, 247 (36.4%) nonoperable, and 5 (0.7%) had no operability data; 386 patients (56.8%, ranging from 12.0%– 60.9% across countries) underwent surgery. Operable patients did not differ from nonoperable patients relative to symptoms, New York Heart Association class, and hemodynamics. A history of acute pulmonary embolism was reported for 74.8% of patients (77.5% operable, 70.0% nonoperable). Associated conditions included thrombophilic disorder in 31.9% (37.1% operable, 23.5% nonoperable) and splenectomy in 3.4% of patients (1.9% operable, 5.7% nonoperable). At the time of CTEPH diagnosis, 37.7% of patients initiated at least 1 pulmonary arterial hypertension–targeted therapy (28.3% operable, 53.8% nonoperable). Pulmonary endarterectomy was performed with a 4.7% documented mortality rate. Conclusions— Despite similarities in clinical presentation, operable and nonoperable CTEPH patients may have distinct associated medical conditions. Operability rates vary considerably across countries, and a substantial number of patients (operable and nonoperable) receive off-label pulmonary arterial hypertension–targeted treatments.

Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland.

RATIONALE Incident pulmonary arterial hypertension was underrepresented in most pulmonary hypertension registries and may have a different disease profile to prevalent disease. OBJECTIVES To determine the characteristics and outcome of a purely incident, treatment-naive cohort of idiopathic, heritable, and anorexigen-associated pulmonary arterial hypertension and to determine the changes in presentations and survival over the past decade in the United Kingdom and Ireland. METHODS All consecutive newly diagnosed patients from 2001 to 2009 were identified prospectively. MEASUREMENTS AND MAIN RESULTS A total of 482 patients (93% idiopathic, 5% heritable, and 2% anorexigen-associated pulmonary arterial hypertension) were diagnosed, giving rise to an estimated incidence of 1.1 cases per million per year and prevalence of 6.6 cases per million in 2009. Younger patients (age ≤ 50 yrs) had shorter duration of symptoms, fewer comorbidities, better functional and exercise capacity, higher percent diffusing capacity of carbon monoxide, more severe hemodynamic impairment, but better survival compared with older patients. In comparison with the earlier cohorts, patients diagnosed in 2007-2009 were older, more obese, had lower percent diffusing capacity of carbon monoxide,(,) and more comorbidities, but better survival. Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) equation, REVEAL risk score, and Pulmonary Hypertension Connection Registry survival equation accurately predicted survival of our incident cohort at 1 year. CONCLUSIONS This study highlights the influence of age on phenotypes of incident pulmonary arterial hypertension and has shown the changes in demographics and epidemiology over the past decade in a national setting. The results suggest that there may be two subtypes of patients: the younger subtype with more severe hemodynamic impairment but better survival, compared with the older subtype who has more comorbidities.

Selexipag for the treatment of pulmonary arterial hypertension

BACKGROUND In a phase 2 trial, selexipag, an oral selective IP prostacyclin-receptor agonist, was shown to be beneficial in the treatment of pulmonary arterial hypertension. METHODS In this event-driven, phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned 1156 patients with pulmonary arterial hypertension to receive placebo or selexipag in individualized doses (maximum dose, 1600 μg twice daily). Patients were eligible for enrollment if they were not receiving treatment for pulmonary arterial hypertension or if they were receiving a stable dose of an endothelin-receptor antagonist, a phosphodiesterase type 5 inhibitor, or both. The primary end point was a composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period (defined for each patient as 7 days after the date of the last intake of selexipag or placebo). RESULTS A primary end-point event occurred in 397 patients--41.6% of those in the placebo group and 27.0% of those in the selexipag group (hazard ratio in the selexipag group as compared with the placebo group, 0.60; 99% confidence interval, 0.46 to 0.78; P<0.001). Disease progression and hospitalization accounted for 81.9% of the events. The effect of selexipag with respect to the primary end point was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline (including those who were receiving a combination of two therapies). By the end of the study, 105 patients in the placebo group and 100 patients in the selexipag group had died from any cause. Overall, 7.1% of patients in the placebo group and 14.3% of patients in the selexipag group discontinued their assigned regimen prematurely because of adverse events. The most common adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, diarrhea, nausea, and jaw pain. CONCLUSIONS Among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower with selexipag than with placebo. There was no significant difference in mortality between the two study groups. (Funded by Actelion Pharmaceuticals; GRIPHON ClinicalTrials.gov number, NCT01106014.).

Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension.

Intravenous epoprostenol is currently FDA approved for management of primary pulmonary hypertension, but it requires intravenous infusion and is associated with adverse effects. The objective of this study was to evaluate the effects of an epoprostenol analog, treprostinil, for management of pulmonary hypertension. Ten tertiary care academic institutions with pulmonary hypertension programs participated in these pilot trials. In the first trial, intravenous epoprostenol and intravenous treprostinil were compared. In the second trial, intravenous treprostinil and subcutaneous treprostinil were compared. In the third trial, subcutaneous treprostinil was compared with placebo infusion during an 8-week period. Intravenous epoprostenol and intravenous treprostinil resulted in a similar reduction in pulmonary vascular resistance acutely (22% and 20%, respectively). Intravenous treprostinil and subcutaneous treprostinil also demonstrated comparable short-term decrease in pulmonary vascular resistance (23% and 28%, respectively). The placebo-controlled 8-week trial demonstrated a mean improvement of 37 ± 17 m as measured by the 6-minute walk distance in patients receiving treprostinil compared with a 6 ± 28 m reduction in those receiving placebo. There were trends toward an improvement in cardiac index and pulmonary vascular resistance index in the treprostinil group. Subcutaneous treprostinil has favorable hemodynamic effects when given acutely and in the short term. Treprostinil can be given safely to an ambulatory patient with a novel subcutaneous delivery pump system.

End points and clinical trial design in pulmonary arterial hypertension.

New and emerging therapies might provide benefit in patients with pulmonary arterial hypertension. Their efficacy and safety will be compared with existing combination therapies in randomized clinical trials. Appropriate end points for these trials need to be identified: these will include exercise testing, the composite end point of time to clinical worsening, and hemodynamic markers, including advanced imaging modalities and biomarkers. Quality-of-life questionnaires are useful and important secondary end points; pulmonary arterial hypertension-specific questionnaires are currently being developed. Advantages and disadvantages of various trial designs, including placebo-controlled monotherapy or add-on trials, noninferiority studies, and withdrawal trials are also discussed.

Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry.

BACKGROUND Originally reported to occur predominantly in younger women, idiopathic pulmonary arterial hypertension (IPAH) is increasingly diagnosed in elderly patients. We aimed to describe the characteristics of such patients and their survival under clinical practice conditions. METHODS Prospective registry in 28 centers in 6 European countries. Demographics, clinical characteristics, hemodynamics, treatment patterns and outcomes of younger (18-65 years) and elderly (>65 years) patients with newly diagnosed IPAH (incident cases only) were compared. RESULTS A total of 587 patients were eligible for analysis. The median (interquartile, [IQR]) age at diagnosis was 71 (16) years. Younger patients (n=209; median age, 54 [16] years) showed a female-to-male ratio of 2.3:1 whereas the gender ratio in elderly patients (n=378; median age, 75 [8] years) was almost even (1.2:1). Combinations of PAH drugs were widely used in both populations, albeit less frequently in older patients. Elderly patients were less likely to reach current treatment targets (6 min walking distance>400 m, functional class I or II). The survival rates 1, 2, and 3 years after the diagnosis of IPAH were lower in elderly patients, even when adjusted for age- and gender-matched survival tables of the general population (p=0.006 by log-rank analysis). CONCLUSIONS In countries with an aging population, IPAH is now frequently diagnosed in elderly patients. Compared to younger patients, elderly patients present with a balanced gender ratio and different clinical features, respond less well to medical therapy and have a higher age-adjusted mortality. Further characterization of these patients is required. CLINICAL TRIALS REGISTRATION NCT01347216.

Successful use of chronic epoprostenol as a bridge to liver transplantation in severe portopulmonary hypertension

BACKGROUND Portopulmonary hypertension, defined as mean pulmonary artery pressure >25 mmHg in the presence of a normal pulmonary capillary wedge pressure and portal hypertension, is a known complication of end-stage liver disease that has been associated with high morbidity and mortality at the time of liver transplantation. We have recently reported the successful treatment of portopulmonary hypertension with chronic intravenous epoprostenol and now report the first patient with severe portopulmonary hypertension successfully treated with epoprostenol who subsequently underwent successful liver transplantation. METHODS A patient with severe portopulmonary hypertension was treated with intravenous epoprostenol, 23 ng/kg/min, for a 4-month period, after which the portopulmonary hypertension resolved and the patient underwent successful liver transplantation. RESULTS The patient was discharged, continues to do well, and at 3 months is off epoprostenol with near normal pulmonary artery pressures. CONCLUSIONS Chronic epoprostenol, in conjunction with a multidisciplinary, well-planned perioperative evaluation and treatment plan, may be the answer to a heretofore untreatable disease.

PORTOPULMONARY HYPERTENSION AND THE LIVER TRANSPLANT CANDIDATE

The management of the liver transplant (OLT) candidate with portopulmonary hypertension (PPHTN) has dramatically changed in the past 3 years. Careful preoperative evaluation with functional characterization of right ventricular function plays a critical role. The pulmonary vascular response to epoprostenol infusion serves as a deciding factor for OLT candidacy. Careful perioperative attention to avoid right ventricular failure from acutely elevated pulmonary artery pressures or sudden increases in right ventricular preload is a key physiologic tenet of management. With increased surgical expertise, anesthetic sophistication, and availability of epoprostenol, PPHTN is no longer considered an absolute contraindication for OLT.