Frequency of Thrombotic Risk Factors in Patients with Chronic Thromboembolic Pulmonary Hypertension and Acute Pulmonary Embolism: A Case-Control Study.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious complication of acute pulmonary embolism (PE) which remains underdiagnosed. A better understanding of risk factors for CTEPH would improve our ability to predict which PE survivors are at risk. Several medical conditions-including malignancy, splenectomy, thyroid hormone supplementation, the presence of an intravascular device, inflammatory bowel disease, osteomyelitis, and non-O blood group-have been associated with increased risk of CTEPH, primarily in studies comparing patients with CTEPH to individuals with non-thrombotic conditions. Because many of these conditions increase thrombosis risk, it remains unclear whether their association with CTEPH reflects a general effect on thrombosis risk, or a specific effect on the risk of developing CTEPH as an outcome of thrombosis. We performed a case-control study comparing the frequencies of these conditions in patients with CTEPH versus patients with acute PE who did not develop CTEPH. The conditions studied were equally frequent in the CTEPH and PE cohorts, although there was a trend towards an increased frequency of splenectomy and non-O blood group among the CTEPH cohort. Thus, other than the possible exceptions of splenectomy and non-O blood group, the investigated medical conditions do not appear likely to increase the risk of CTEPH as an outcome of acute PE, and thus are unlikely to be useful in predicting CTEPH risk among PE survivors.

Chronic Thromboembolic Pulmonary Hypertension Cases Cluster in Families.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious sequela of pulmonary embolism (PE) and occurs in about 3% of acute PE survivors. Common inherited thrombophilias, including the Factor V Leiden mutation, are not associated with increased risk of CTEPH, even though they increase the risk for VTE. Whether other inherited genetic factors contribute to the risk of developing CTEPH remains unknown. Familial clustering of a disease can indicate inherited genetic risk for that disease. In this study, the Utah Population Database (UPDB), a unique genealogy resource, was used to assess whether CTEPH cases cluster in families. METHODS: Prevalent CTEPH patients in Utah were identified and were then matched to control subjects. Using the UPDB, the Genealogical Index of Familiality (a statistical measure of relatedness of individuals with a given phenotype) was calculated. The UPDB was also used to calculate the relative risk of CTEPH and VTE in the family members of patients with CTEPH. RESULTS: This study found that Utah patients with CTEPH are significantly more related than would be expected by chance, with both close and distant relationships identified. We also found that the relative risk of VTE was significantly increased among first-degree relatives of CTEPH probands. CONCLUSIONS: The study data suggest that heritable genetic factors influence an individual's risk of developing CTEPH, providing the strongest evidence to date for a genetic contribution to CTEPH risk. Although our data suggest that these inherited genetic factors likely also increase the risk for VTE, they are likely to be distinct from the common inherited thrombophilias.

Pulmonary Arterial Hypertension.

This article provides an overview of pulmonary arterial hypertension (PAH), beginning with the initial pathologic recognition of pulmonary hypertension more than 100 years ago and progressing to the current diagnostic categorization of PAH. It reviews the epidemiology, pathophysiology, genetics, and modern treatment of PAH. The article discusses several important recent studies that have highlighted the importance of new management strategies, including serial risk assessment and combination pharmacotherapy.

EIF2AK4 Mutations in Patients Diagnosed With Pulmonary Arterial Hypertension.

BACKGROUND: Differentiating pulmonary venoocclusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) from idiopathic pulmonary arterial hypertension (IPAH) or heritable pulmonary arterial hypertension (HPAH) is important clinically. Mutations in eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) cause heritable PVOD and PCH, whereas mutations in other genes cause HPAH. The aim of this study was to describe the frequency of pathogenic EIF2AK4 mutations in patients diagnosed clinically with IPAH or HPAH. METHODS: Sanger sequencing and deletion/duplication analysis were performed to detect mutations in the bone morphogenetic protein receptor type II (BMPR2) gene in 81 patients diagnosed at 30 North American medical centers with IPAH (n = 72) or HPAH (n = 9). BMPR2 mutation-negative patients (n = 67) were sequenced for mutations in four other genes (ACVRL1, ENG, CAV1, and KCNK3) known to cause HPAH. Patients negative for mutations in all known PAH genes (n = 66) were then sequenced for mutations in EIF2AK4. We assessed the pathogenicity of EIF2AK4 mutations and reviewed clinical characteristics of patients with pathogenic EIF2AK4 mutations. RESULTS: Pathogenic BMPR2 mutations were identified in 8 of 72 (11.1%) patients with IPAH and 6 of 9 (66.7%) patients with HPAH. A novel homozygous EIF2AK4 mutation (c.257+4A>C) was identified in 1 of 9 (11.1%) patients diagnosed with HPAH. The novel EIF2AK4 mutation (c.257+4A>C) was homozygous in two sisters with severe pulmonary hypertension. None of the 72 patients with IPAH had biallelic EIF2AK4 mutations. CONCLUSIONS: Pathogenic biallelic EIF2AK4 mutations are rarely identified in patients diagnosed with HPAH. Identification of pathogenic biallelic EIF2AK4 mutations can aid clinicians in differentiating HPAH from heritable PVOD or PCH.

When to offer genetic testing for pulmonary arterial hypertension.

Genetic testing is poised to play a greater role in the diagnosis and management of pulmonary arterial hypertension (PAH). Physicians who manage PAH should know the heritable PAH phenotypes, inheritance patterns, and responsible genes. They also should know indications, potential risks and benefits, and the issues surrounding genetic counselling and testing for patients with PAH.

EIF2AK4 mutations in pulmonary capillary hemangiomatosis.

BACKGROUND: Pulmonary capillary hemangiomatosis (PCH) is a rare disease of capillary proliferation of unknown cause and with a high mortality. Families with multiple affected individuals with PCH suggest a heritable cause although the genetic etiology remains unknown. METHODS: We used exome sequencing to identify a candidate gene for PCH in a family with two affected brothers. We then screened 11 unrelated patients with familial (n = 1) or sporadic (n = 10) PCH for mutations. RESULTS: Using exome sequencing, we identified compound mutations in eukaryotic translation initiation factor 2 α kinase 4 (EIF2AK4) (formerly known as GCN2) in both affected brothers. Both parents and an unaffected sister were heterozygous carriers. In addition, we identified two EIF2AK4 mutations in each of two of 10 unrelated individuals with sporadic PCH. EIF2AK4 belongs to a family of kinases that regulate angiogenesis in response to cellular stress. CONCLUSIONS: Mutations in EIF2AK4 are likely to cause autosomal-recessive PCH in familial and some nonfamilial cases.

Adherence to PIOPED II investigators' recommendations for computed tomography pulmonary angiography.

BACKGROUND: Computed tomography (CT) pulmonary angiography use has increased dramatically, raising concerns for patient safety. Adherence to recommendations and guidelines may protect patients. We measured adherence to the recommendations of Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED II) investigators for evaluation of suspected pulmonary embolism and the rate of potential false-positive pulmonary embolism diagnoses when recommendations of PIOPED II investigators were not followed. METHODS: We used a structured record review to identify 3500 consecutive CT pulmonary angiograms performed to investigate suspected pulmonary embolism in 2 urban emergency departments, calculating the revised Geneva score (RGS) to classify patients as "pulmonary embolism unlikely" (RGS≤10) or "pulmonary embolism likely" (RGS>10). CT pulmonary angiograms were concordant with PIOPED II investigator recommendations if pulmonary embolism was likely or pulmonary embolism was unlikely and a highly sensitive D-dimer test result was positive. We independently reviewed 482 CT pulmonary angiograms to measure the rate of potential false-positive pulmonary embolism diagnoses. RESULTS: A total of 1592 of 3500 CT pulmonary angiograms (45.5%) followed the recommendations of PIOPED II investigators. The remaining 1908 CT pulmonary angiograms were performed on patients with an RGS≤10 without a D-dimer test (n=1588) or after a negative D-dimer test result (n=320). The overall rate of pulmonary embolism was 9.7%. Potential false-positive diagnoses of pulmonary embolism occurred in 2 of 3 patients with an RGS≤10 and a negative D-dimer test result. CONCLUSIONS: Nonadherence to recommendations for CT pulmonary angiography is common and exposes patients to increased risks, including potential false-positive diagnoses of pulmonary embolism.

Delay in recognition of pulmonary arterial hypertension: factors identified from the REVEAL Registry.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive and fatal disorder. Despite the emergence of effective therapy, PAH is commonly at an advanced stage when recognized. Factors associated with a prolonged symptomatic period before the recognition of PAH have not been fully evaluated. METHODS: The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry) enrolled 2,967 US adult patients with PAH from March 2006 to September 2007. Patients were considered to have delayed disease recognition if > 2 years elapsed between symptom onset and the patient receiving a PAH diagnosis, starting on PAH-specific therapy, or receiving a diagnosis by right-sided heart catheterization. RESULTS: In 21.1% of patients, symptoms were experienced for > 2 years before PAH was recognized. Patients with onset of PAH symptoms before age 36 years showed the highest likelihood of delayed disease recognition (OR, 3.07; 95% CI, 2.03-4.66). History of obstructive airways disease (OR, 1.93; 95% CI, 1.5-2.47) and sleep apnea (OR, 1.72; 95% CI, 1.33-2.22) were independently associated with delayed PAH recognition. Six-minute walk distance < 250 m (OR, 1.91; 95% CI, 1.16-3.13), right atrial pressure < 10 mm Hg (OR, 1.77; 95% CI, 1.26-2.48), and pulmonary vascular resistance < 10 Wood units (OR, 1.28; 95% CI, 1.02-1.60) were also associated with delayed disease recognition, but sex, race/ethnicity, and geographic region showed no association. CONCLUSIONS: One in five patients in the REVEAL Registry who were diagnosed with PAH reported symptoms for > 2 years before their disease was recognized. Younger individuals and patients with histories of common respiratory disorders were most likely to experience delayed PAH recognition. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

Diagnosis: imaging techniques.

The diagnosis of venous thromboembolism (VTE) cannot be confirmed or excluded by the medical history and physical examination alone. Objective testing is required in all cases of clinically suspected VTE; for most patients, this includes imaging modalities such as compression ultrasonography, ventilation-perfusion lung scintigraphy, or computed tomography pulmonary angiography (CTPA). Conventional pulmonary arteriography remains useful when CTPA is nondiagnostic or when an intervention such as catheter embolectomy is planned. Although CTPA is important in the evaluation of suspected VTE, ultimately the clinician must balance the risks against the benefits of CTPA for individual patients. Bedside echocardiography may be most appropriate for patients with hypotension or shock and suspected pulmonary embolism.

Worldwide physician education and training in pulmonary hypertension: pulmonary vascular disease: the global perspective.

Pulmonary hypertension (PH) affects > 25 million individuals worldwide and causes premature disability and death for many. The diagnosis and treatment of PH have advanced dramatically through the development of a clearly defined diagnostic classification, an evidence-based treatment algorithm for adults with pulmonary arterial hypertension using life-saving medications, and life-saving surgical procedures. However, worldwide education and training of physicians has lagged behind advances in the management of PH. Expertise in the diagnosis and management of PH is uncommon, even though physicians receive training on PH during their graduate and postgraduate education. Advances in worldwide physician education and training in PH will require substantial organization and work. Organizations working in this field will need to work collaboratively to maximize funding for education and to optimize the achievement of educational goals. Political, economic, and cultural barriers must be identified and overcome as part of any strategic plan. Global education should include training objectives for generalist, non-PH specialist, and PH specialist physicians.

Alum application to improve water quality in a municipal wastewater treatment wetland: effects on macrophyte growth and nutrient uptake.

Application of low doses of alum to treatment wetlands to reduce elevated outflow winter phosphorus concentrations were tested in mesocosms vegetated with either Typhadomingensis, Schoenoplectus californicus, or submerged aquatic vegetation (SAV) (Najas guadalupensis-dominated). Alum was pumped to experimental units at a rate of 0.91 g Al m(-2) d(-1) and water quality monitored for 3 months. The alum application significantly improved the outflow water quality and overall the growth of the plants was unaffected by the alum application. Biomass and growth varied between species and through time, but no significant effects of alum application were detected. The concentrations of nutrients and mineral elements in the aboveground tissues differed between species and over time, but only the concentration of Al in plant tissue was increased by alum additions. The concentration of Al was 50-fold higher in alum-treated SAV as compared to the control, and in Typha and Schoenoplectus the concentrations were 4- and 2-fold, higher, respectively. The N/P ratios in the plant tissues were low (<10) suggesting that their growth and biomass was limited by nitrogen. The research suggests that a continuous or seasonal low-dosage alum application to treatment wetlands provides an effective tool to maintain discharge concentrations within permitted values during the inefficient winter treatment times. We suggest that the use of alum should be restricted to treatment wetland areas dominated by emergent vegetation as the effects of the elevated Al concentrations in SAV needs further study.

Alum application to improve water quality in a municipal wastewater treatment wetland.

Nutrient removal in treatment wetlands declines during winter months due to temperature. A 3-mo (wintertime) mesocosm study was conducted to determine the effectiveness of alum in immobilizing P as well as other nutrients during this period of reduced treatment efficiency. Eighteen mesocosms, triplicate alum, and three controls or no alum were established with either Typha spp., Schoenoplectus californicus, or SAV (Najas guadalupensis-dominated). Alum was delivered by timer at a rate of 0.81 g Al m(-2) d(-1) and parameters measured included: pH, soluble reactive phosphorus (SRP), total phosphorus (TP), dissolved organic carbon (DOC), dissolved inorganic nitrogen (DIN), total kjeldahl nitrogen (TKN), and soluble aluminum (Al). Alum-treated mesocosms had significantly lower pH values (8.1) than controls (8.8), but well within the elevated pH range for aluminum toxicity. Alum significantly reduced all measured water column nutrients with the exception of ammonium N, which remained unaffected, and particulate P, which increased. This study demonstrated that seasonal low-dosage alum application to different vegetation communities in a treatment wetland can significantly improve treatment efficiencies for SRP (87 vs. 58%) and TP (62 vs. 44%) but also increase DOC (19 vs. 0%) and TKN (12 vs. -3%) removal capacity to a lesser degree. Alum applications within close proximity of the treatment wetland effluent points should be implemented with caution due to the production of alum floc-bound P which could potentially affect discharge permit compliance for total suspended solids or total P.

Soil biogeochemical characteristics influenced by alum application in a municipal wastewater treatment wetland.

Constructed treatment wetlands are a relatively low-cost alternative used for tertiary treatment of wastewater. Phosphorus (P) removal capacity of these wetlands may decline, however, as P is released from the accrued organic soils. Little research has been done on methods to restore the treatment capacity of aging constructed wetlands. One possibility is the seasonal addition of alum during periods of low productivity and nutrient removal. Our 3-mo mesocosm study investigated the effectiveness of alum in immobilizing P during periods of reduced treatment efficiency, as well as the effects on soil biogeochemistry. Eighteen mesocosms were established, triplicate experimental and control units for Typha sp., Schoenoplectus californicus, and submerged aquatic vegetation (SAV) (Najas guadalupensis dominated). Alum was slowly dripped to the water column of the experimental units at a rate of 0.91 g Al m(-2) d(-1) and water quality parameters were monitored. Soil cores were collected at experiment initiation and completion and sectioned into 0- to 5- and 5- to 10-cm intervals for characterization. The alum floc remained in the 0- to 5-cm surface soil, however, soil pH and microbial parameters were impacted throughout the upper 10 cm with the lowest pH found in the Typha treatment. Plant type did not impact most biogeochemical parameters; however, data were more variable in the SAV mesocosms. Amorphous Al was greater in the surface soil of alum-treated mesocosms, inversely correlated with soil pH and microbial biomass P in both soil layers. Microbial activity was also suppressed in the surface soil of alum-treated mesocosms. This research suggests alum may significantly affect the biogeochemistry of treatment wetlands and needs further investigation.