Pulmonary hypertension (PH) is an increasingly recognized cause of morbidity and mortality, and in the past 20 years, there has been a rapid expansion in research and available therapies. Although it is defined quite simply as a mean pulmonary arterial pressure of ≥ 25 mm Hg, PH encompasses a heterogeneous group of disease processes. In the past, PH was classified as primary or secondary, but as understanding of the various contributing diseases has increased, classification systems have attempted to group these diseases by clinical features and disease mechanism. The evaluation of patients with suspected PH can be cumbersome, and a careful and methodical approach is needed to ensure timely and accurate diagnosis, correct physiological classification, and appropriate treatment. In this review, we discuss the classification and diagnostic evaluation of PH in adults as well as some of the billing and coding considerations involved in this evaluation.
Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertenslon (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development.
Pulmonary hypertension (PH) is a chronic, progressive, life-threatening disease that requires expert multidisciplinary care. To facilitate this level of care, the Pulmonary Hypertension Association established across the United States a network of pulmonary hypertension care centers (PHCCs) with special expertise in PH, particularly pulmonary arterial hypertension, to raise the overall quality of care and outcomes for patients with this life-threatening disease. Since the inception of PHCCs in September 2014, to date 35 centers have been accredited in the United States. This model of care brings together physicians and specialists from other disciplines to provide care, facilitate basic and clinical research, and educate the next generation of providers. PHCCs also offer additional opportunities for improvements in PH care. The patient registry offered through the PHCCs is an organized system by which data are collected to evaluate the outcomes of patients with PH. This registry helps in detecting variations in outcomes across centers, thus identifying opportunities for improvement. Multiple tactics were undertaken to implement the strategic plan, training, and tools throughout the PHCC network. In addition, strategies to foster collaboration between care center staff and individuals with PH and their families are the cornerstone of the PHCCs. The Pulmonary Vascular Network of the American College of Chest Physicians believes this to be a positive step that will improve the quality of care delivered in the United States to patients with PH.
Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon disease that is the most serious complication associated with unresolved pulmonary embolism. This disease has several risk factors, but no familial pattern has been described. Few thrombophilic conditions have been reported to increase risk of CTEPH, and none of the hereditary thrombophilias causes this disease. The reason CTEPH develops in some patients after pulmonary embolism remains unknown. We describe a 54-year-old woman and her maternal aunt who both underwent pulmonary thromboendarterectomy for CTEPH. This represents the first description of familial CTEPH.
Extracellular vesicles (EVs) from mice with monocrotaline (MCT)-induced pulmonary hypertension (PH) induce PH in healthy mice, and the exosomes (EXO) fraction of EVs from mesenchymal stem cells (MSCs) can blunt the development of hypoxic PH. We sought to determine whether the EXO fraction of EVs is responsible for modulating pulmonary vascular responses and whether differences in EXO-miR content explains the differential effects of EXOs from MSCs and mice with MCT-PH. Plasma, lung EVs from MCT-PH, and control mice were divided into EXO (exosome), microvesicle (MV) fractions and injected into healthy mice. EVs from MSCs were divided into EXO, MV fractions and injected into MCT-treated mice. PH was assessed by right ventricle-to-left ventricle + septum (RV/LV + S) ratio and pulmonary arterial wall thickness-to-diameter (WT/D) ratio. miR microarray analyses were also performed on all EXO populations. EXOs but not MVs from MCT-injured mice increased RV/LV + S, WT/D ratios in healthy mice. MSC-EXOs prevented any increase in RV/LV + S, WT/D ratios when given at the time of MCT injection and reversed the increase in these ratios when given after MCT administration. EXOs from MCT-injured mice and patients with idiopathic pulmonary arterial hypertension (IPAH) contained increased levels of miRs-19b,-20a,-20b, and -145, whereas miRs isolated from MSC-EXOs had increased levels of anti-inflammatory, anti-proliferative miRs including miRs-34a,-122,-124, and -127. These findings suggest that circulating or MSC-EXOs may modulate pulmonary hypertensive effects based on their miR cargo. The ability of MSC-EXOs to reverse MCT-PH offers a promising potential target for new PAH therapies.
Background Pulmonary hypertension (PH) is hemodynamically classified as pre-capillary (as seen in idiopathic pulmonary arterial hypertension [IPAH]) or post-capillary (as seen in heart failure with preserved ejection fraction [HFpEF]). Overlaps between these conditions exist. Some patients present with risk factors for left heart disease but pre-capillary PH, whereas patients with HFpEF may have combined pre- and post-capillary PH. Objectives This study sought to further characterize similarities and differences among patient populations with either PH-HFpEF or IPAH. Methods We used registry data to analyze clinical characteristics, hemodynamics, and treatment responses in patients with typical IPAH (<3 risk factors for left heart disease; n = 421), atypical IPAH (≥3 risk factors for left heart disease; n = 139), and PH-HFpEF (n = 226) receiving PH-targeted therapy. Results Compared with typical IPAH, patients with atypical IPAH and PH-HFpEF were older, had a higher body mass index, had more comorbidities, and had a lower 6-min walking distance, whereas mean pulmonary artery pressure (46.9 ± 13.3 mm Hg vs. 43.9 ± 10.7 mm Hg vs. 45.7 ± 9.4 mm Hg, respectively) and cardiac index (2.3 ± 0.8 l/min/m vs. 2.2 ± 0.8 l/min/m vs. 2.2 ± 0.7 l/min/m , respectively) were comparable among groups. After initiation of targeted PH therapies, all groups showed improvement in exercise capacity, functional class, and natriuretic peptides from baseline to 12 months, but treatment effects were less pronounced in patients with PH-HFpEF than typical IPAH; with atypical IPAH in between. Survival rates at 1, 3, and 5 years were almost identical for the 3 groups. Conclusions Patients with atypical IPAH share features of both typical IPAH and PH-HFpEF, suggesting that there may be a continuum between these conditions.
Background A subset of patients with hereditary hemorrhagic telangiectasia (HHT) develops pulmonary hypertension (PH) by mechanisms including pulmonary arterial hypertension, high flow, and elevated pulmonary arterial wedge pressure (PAWP). We aimed to describe echocardiographic and hemodynamic characteristics of patients with coexisting HHT and PH. Methods We conducted a single-center cohort study of patients with confirmed HHT who underwent right-sided heart catheterization (RHC) and transthoracic two-dimensional echocardiography for suspected PH between June 1, 2003 and September 1, 2013 at Mayo Clinic Rochester, Minnesota. Results Of 38 patients with confirmed HHT who underwent RHC and echocardiography, 28 (74%) had a mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg. Of those 28, 12 (43%) had pulmonary arterial hypertension. Two patients had normal PAWP and pulmonary vascular resistance (PVR), with PH secondary to either an atrial septal defect or high cardiac flow. Fourteen patients (50%) had elevated PAWP (≥ 15 mm Hg), nine with evidence of high flow. RHC in all 28 patients demonstrated a MPAP of 41 ± 11 mm Hg, PAWP of 17 ± 10 mm Hg, and PVR of 4.5 ± 4.2 Wood units. Echocardiography demonstrated moderate/severe right ventricular dysfunction in nine patients (32%). The presence of PH trended toward worse survival ( P = .06). Conclusions PH in patients with HHT occurs by different mechanisms, and there is a trend toward worse survival in patients who develop PH despite the mechanism. The equal predilection toward all subtypes of PH illustrates the necessity of RHC to clarify the hemodynamics.
Background Hemodynamic differentiation between pulmonary arterial hypertension (PAH) and postcapillary pulmonary hypertension (PH) is important because treatment options are strikingly different for the two disease subsets. Whereas patients with PAH can be treated effectively with targeted therapies, their use in postcapillary PH is currently not recommended. Our aim was to establish an algorithm to identify patients who are likely to experience a significant hemodynamic treatment response. Methods We determined hemodynamic cutoffs to discriminate between idiopathic PAH and postcapillary PH in a large database of 4,363 stable patients undergoing first diagnostic right and left heart catheterizations. In a second step, we performed a patient-level pooled analysis of four randomized, placebo-controlled trials including 541 patients with PAH who received treprostinil or placebo, to validate hemodynamic cutoffs with regard to treatment response. Results Receiver operating characteristic analysis identified mean pulmonary arterial wedge pressure (mPAWP) 20 mm Hg or a combination of both had a significant placebo-corrected improvement in hemodynamics. Conclusions mPAWP 20 mm Hg identify patients with PAH who are likely to have significant hemodynamic improvement with prostacyclin treatment.