Updated Clinical Classification of Pulmonary Hypertension Simonneau, Gerald, MD; Gatzoulis, Michael A., MD, PhD; Adatia, Ian, MD ...
Journal of the American College of Cardiology,
12/2013, Letnik:
62, Številka:
25
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
In 1998, a clinical classification of pulmonary hypertension (PH) was established, categorizing PH into groups which share similar pathological and hemodynamic characteristics and therapeutic ...approaches. During the 5th World Symposium held in Nice, France, in 2013, the consensus was reached to maintain the general scheme of previous clinical classifications. However, modifications and updates especially for Group 1 patients (pulmonary arterial hypertension PAH) were proposed. The main change was to withdraw persistent pulmonary hypertension of the newborn (PPHN) from Group 1 because this entity carries more differences than similarities with other PAH subgroups. In the current classification, PPHN is now designated number 1. Pulmonary hypertension associated with chronic hemolytic anemia has been moved from Group 1 PAH to Group 5, unclear/multifactorial mechanism. In addition, it was decided to add specific items related to pediatric pulmonary hypertension in order to create a comprehensive, common classification for both adults and children. Therefore, congenital or acquired left-heart inflow/outflow obstructive lesions and congenital cardiomyopathies have been added to Group 2, and segmental pulmonary hypertension has been added to Group 5. Last, there were no changes for Groups 2, 3, and 4.
The 4th World Symposium on Pulmonary Hypertension was the first international meeting to focus not only on pulmonary arterial hypertension (PAH) but also on the so-called non-PAH forms of pulmonary ...hypertension (PH). The term “non-PAH PH” summarizes those forms of PH that are found in groups 2 to 5 of the current classification of PH, that is, those forms associated with left heart disease, chronic lung disease, recurrent venous thromboembolism, and other diseases. Many of these forms of PH are much more common than PAH, but all of them have been less well studied, especially in terms of medical therapy. The working group on non-PAH PH focused mainly on 4 conditions: chronic obstructive lung disease, interstitial lung disease, chronic thromboembolic PH, and left heart disease. The medical literature regarding the role of PH in these diseases was reviewed, and recommendations regarding diagnosis and treatment of PH in these conditions are provided. Given the lack of robust clinical trials addressing PH in any of these conditions, it is important to conduct further studies to establish the role of medical therapy in non-PAH PH.
The aim of a clinical classification of pulmonary hypertension (PH) is to group together different manifestations of disease sharing similarities in pathophysiologic mechanisms, clinical ...presentation, and therapeutic approaches. In 2003, during the 3rd World Symposium on Pulmonary Hypertension, the clinical classification of PH initially adopted in 1998 during the 2nd World Symposium was slightly modified. During the 4th World Symposium held in 2008, it was decided to maintain the general architecture and philosophy of the previous clinical classifications. The modifications adopted during this meeting principally concern Group 1, pulmonary arterial hypertension (PAH). This subgroup includes patients with PAH with a family history or patients with idiopathic PAH with germline mutations (e.g., bone morphogenetic protein receptor-2, activin receptor-like kinase type 1, and endoglin). In the new classification, schistosomiasis and chronic hemolytic anemia appear as separate entities in the subgroup of PAH associated with identified diseases. Finally, it was decided to place pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis in a separate group, distinct from but very close to Group 1 (now called Group 1′). Thus, Group 1 of PAH is now more homogeneous.
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.
BACKGROUND Pulmonary hypertension (PH) is common in elderly patients, but a detailed analysis of the causes of PH in the elderly has not been performed. We hypothesized that pulmonary arterial ...hypertension (PAH) is rare in elderly patients and sought to describe the characteristics of these patients at a large referral center. METHODS Clinical and hemodynamic data were collected on consecutive patients ≥ 65 years of age referred for evaluation of PH. The subtype of PH was determined after standard evaluation using the World Health Organization (WHO) classification. Patients with PH not meeting criteria for PAH with “out-of-proportion” PH related to group 2 or group 3 disease were classified as “other/mixed PH.” A model using age, presence of connective tissue disease, and left atrial size was developed to predict the probability of PAH diagnosis. RESULTS Two hundred forty-six elderly patients were evaluated (mean age, 72.9 ± 5.5 years, 78% women); 36 had PAH (15%). Idiopathic PAH was rare (four patients, 1.6%). WHO group 2 PH was the most frequent diagnosis (n = 70, 28% of cohort); mixed/other PH (n = 43, 17%) and WHO group 3 PH (n = 34, 14%) were also common diagnoses. Connective tissue disease strongly predicted PAH diagnosis (OR, 27.2; 95% CI, 9.5-77.6). CONCLUSIONS PAH is an uncommon cause of PH in elderly patients, most frequently associated with connective tissue disease. WHO group 2 PH and mixed disease are common, highlighting a need for careful phenotyping of elderly patients with PH prior to initiating PAH therapy.
Pulmonary arterial hypertension (PAH) includes various forms of pulmonary hypertension of different etiology but similar clinical presentation and functional derangement. Histopathological vascular ...changes in all forms of PAH are qualitatively similar but with quantitative differences in the distribution and prevalence of pathological changes in various portions of the pulmonary vascular bed. The documentation of these topographic variations in the response of the pulmonary vasculature to injury may be important to understand the pathogenesis of the various subsets of PAH. To standardize the precise histopathological documentation of the pulmonary vasculopathy in PAH we propose a histopathological classification that includes both the predominant segment of the pulmonary vasculature affected and the possible coexistence of pathological changes in other vascular segments.
Idiopathic pulmonary arterial hypertension (IPAH) is usually without an identified genetic cause, despite clinical and molecular similarity to bone morphogenetic protein receptor type 2 ...mutation-associated heritable pulmonary arterial hypertension (PAH). There is phenotypic heterogeneity in IPAH, with a minority of patients showing long-term improvement with calcium channel-blocker therapy.
We sought to identify gene variants (GVs) underlying IPAH and determine whether GVs differ in vasodilator-responsive IPAH (VR-PAH) versus vasodilator-nonresponsive IPAH (VN-PAH).
We performed whole-exome sequencing (WES) on 36 patients with IPAH: 17 with VR-PAH and 19 with VN-PAH. Wnt pathway differences were explored in human lung fibroblasts.
We identified 1,369 genes with 1,580 variants unique to IPAH. We used a gene ontology approach to analyze variants and identified overrepresentation of several pathways, including cytoskeletal function and ion binding. By mapping WES data to prior genome-wide association study data, Wnt pathway genes were highlighted. Using the connectivity map to define genetic differences between VR-PAH and VN-PAH, we found enrichment in vascular smooth muscle cell contraction pathways and greater genetic variation in VR-PAH versus VN-PAH. Using human lung fibroblasts, we found increased stimulated Wnt activity in IPAH versus controls.
A pathway-based analysis of WES data in IPAH demonstrated multiple rare GVs that converge on key biological pathways, such as cytoskeletal function and Wnt signaling pathway. Vascular smooth muscle contraction-related genes were enriched in VR-PAH, suggesting a potentially different genetic predisposition for VR-PAH. This pathway-based approach may be applied to next-generation sequencing data in other diseases to uncover the contribution of unexpected or multiple GVs to a phenotype.
Background The 6-min walk test, commonly used to assess exercise capacity and response to therapy in pulmonary arterial hypertension (PAH), has many well-described limitations. Sedentary time is ...associated with adverse cardiovascular outcomes and reduced quality of life, and measuring sedentary time and physical activity using accelerometry is another potential way to quantify exercise capacity in PAH. Whether sedentary time is different in patients with PAH vs control subjects is unknown. Methods Physical activity was measured in 20 patients with PAH and 30 matched healthy control subjects using accelerometry for 7 consecutive days. Patients with PAH completed standard 6-min walk testing, and baseline demographics were recorded for all study participants. Total daily activity counts, sedentary time, and proportion of time at various activity levels were compared between groups. Results Sedentary time was significantly higher in patients with PAH (mean, 92.1% daily activity; 95% CI, 89.5-94.8%) than in control subjects (mean, 79.9% daily activity; 95% CI, 76.4%–83.5%; P < .001), and all levels of physical activity were reduced in the PAH group compared with the control group ( P < .01 for all). Daily moderate to vigorous physical activity was reduced in the PAH group (7.5 min; 95% CI; 0.8-15.6 min) compared with the control group (mean, 64.7 min; 95% CI, 51.1-78.2 min; P < .001). Activity counts correlated with 6-min walk distance in the PAH group (Spearman rank correlation = 0.72, P < .001). Conclusions Sedentary time is increased in patients with PAH and may lead to increased risk for metabolic and cardiovascular morbidity. Quantitation of daily activity and sedentary time using accelerometry may be a novel end point for PAH management and clinical trials.
Abstract Chronic, unresolved thromboemboli are an important cause of pulmonary hypertension (PH) with specific treatment strategies differing from other types of PH. Chronic thromboembolic pulmonary ...hypertension (CTEPH) is classified as Group 4 PH by the World Health Organization. It is a rare, but underdiagnosed, complication of acute pulmonary embolism that does not resolve and results in occlusion of large pulmonary arteries with a fibro-thrombotic material. The etiology of CTEPH remains uncertain, and it is unknown why certain patients with acute pulmonary embolism develop this disorder. The evaluation for CTEPH is an important part of the evaluation for PH in general, and it is crucial not to overlook this diagnosis as it is the only form of PH that is potentially curable. Patients diagnosed with CTEPH should be referred to an expert center for consideration of pulmonary endarterectomy, surgical removal of the chronic thromboembolic material. Not all patients with CTEPH are surgical candidates, however, and there are emerging treatments -medical therapy and balloon pulmonary angioplasty- that have shown benefit in this patient population. Without treatment, CTEPH can lead to progressive pulmonary vascular obstruction, right heart failure, and death. Thus, it is important for clinicians to recognize this subtype of PH. In this review, we providing overview of current understanding of the pathogenesis of CTEPH and highlight recommendations and recent advances in the evaluation and treatment of CTEPH.
PDF
