The global view.

PURPOSE OF REVIEW: To understand the global distribution of different forms of pulmonary hypertension. RECENT FINDINGS: Different registries have explored the epidemiological characteristics of pulmonary hypertension. Interestingly, there is a clear difference in the prevalence of different forms of pulmonary hypertension in developed regions in comparison with less developed countries. This finding suggests not only that extrapolation of data should be avoided but also that the known prevalence of pulmonary hypertension might be underestimated. SUMMARY: Pulmonary hypertension might be more prevalent than what is currently believed. Specific forms of pulmonary hypertension distributed worldwide might characterize an unrecognized burden that still have to be properly approached. This highlights the heterogeneity of pulmonary hypertension around the world. It is clear that more epidemiological data are still needed as well as studies addressing management alternatives in these specific regions.

Pulmonary Embolism and Gas Exchange.

Acute pulmonary embolism (PE) impairs hemodynamics, gas exchange, and lung mechanical capacity. Considering PE pathophysiology, most attention has been paid to hemodynamic impairment. However, the most prevalent symptoms in PE patients come from gas exchange alterations, which have not been in the spotlight for many years. Pulmonary physiology and consequent gas exchange impairment play a pivotal role in the high risk of death from PE. In this review, we will look at the pathophysiology of PE, from the vascular occlusion to the resultant heterogeneity in pulmonary perfusion and gas exchange impairment, discussing in detail its causes and consequences.

Biomarkers and prognostic indicators in pulmonary arterial hypertension.

Our understanding of the pathophysiology of pulmonary arterial hypertension (PAH) has increased substantially in the past decades. More accurate diagnosis and increased options for treatment have given researchers the opportunity to better explore the response to medical therapy and prognosis. As a result, the use of biomarkers and prognostic indicators for this devastating disease has been widely investigated. Biomarkers and prognostic indicators have also been more frequently incorporated into the design of new clinical trials. This approach has helped the pulmonary hypertension (PH) community step forward in the search for effective treatments for PAH. However, no single biomarker has shown significant superiority in predicting prognosis or patient response and an integrative approach is necessary to understand which combination of markers should be used in each of the clinical scenarios that characterize the management of PAH.

Pulmonary artery enlargement in schistosomiasis associated pulmonary arterial hypertension.

BACKGROUND: Schistosomiasis associated pulmonary arterial hypertension (Sch-PAH) might represent the most prevalent form of PAH worldwide. In Sch-PAH, the presence of aneurismal dilation of the pulmonary artery has been described, although it is still a matter of debate whether on average the pulmonary artery is more enlarged in Sc-PAH than IPAH. METHODS: We retrospectively evaluated patients with IPAH (n = 25) and Sch-PAH (n = 22) who underwent computed tomography pulmonary angiogram and right heart catheterization. RESULTS: Sch-PAH patients were older and presented less severe hemodynamic profiles. Main pulmonary artery diameter (MPAD) was greater in Sch-PAH than IPAH (4.5 ± 1.8 vs 3.7 ± 1.1 cm, p = 0.018). For the same level of mean pulmonary artery pressure, the MPAD in Sch-PAH was 0.89 cm larger than in IPAH (Covariance model p = 0.02). CONCLUSION: This study demonstrated that pulmonary artery enlargement is more pronounced in Sch-PAH than IPAH, independently of mean pulmonary artery pressure level, suggesting that this is more likely a feature of Sch-PAH.

Goal-oriented treatment of pulmonary arterial hypertension.

PURPOSE OF REVIEW: To understand the rational of establishing a goal-oriented therapy for pulmonary arterial hypertension management. RECENT FINDINGS: During the last decades, the development of targeted therapies and the recognition of prognostic markers represented a major step for improving pulmonary arterial hypertension survival. Now, changing the strategy on using these compounds therapies might represent the best way to optimize treatment response. SUMMARY: Prespecified goals with regular reassessment should be incorporated as the routine practice for pulmonary arterial hypertension management to provide the best available treatment, aiming to improve or maintain every patient in a clinical and functional status that reflects better long-term survival.

Quality of life as a prognostic marker in pulmonary arterial hypertension.

BACKGROUND: Improvement in quality of life together with better survival are the ultimate goals in the treatment of pulmonary arterial hypertension (PAH) patients. The objective of this study was to evaluate the health-related quality of life (HRQL) of pulmonary arterial hypertension (PAH) patients with the SF-36 generic questionnaire and to identify the prognostic implication of this assessment. METHODS: Fifty-four consecutive newly diagnosed PAH patients (WHO classification group I) in a single PAH reference center were included. Patients were evaluated at baseline for clinical and hemodynamic parameters, and they subsequently received first-line therapy with either an endothelin receptor antagonist or a phosphodiesterase-5 inhibitor. After 16 weeks of specific PAH therapy, all patients were re-evaluated using a 6MWT and a SF 36 questionnaire, and then they were followed up for at least 36 months. RESULTS: After treatment, the patients demonstrated an improved 6MWT (414 ± 124 m vs. 440 ± 113 m, p = 0.001). Specific PAH therapy also improved the HRQL scores.Patients with a baseline Physical Component Score (PCS) higher than 32 had a better survival rate than those who had a score under 32 (p = 0.04). Similarly, patients with a PCS of at least a 38 after the 16 week therapy period had a better survival rate when compared with those who did not achieve this value (p = 0.016). Unlike the absolute PCS values, the post-treatment PCS variability was unable to predict better survival rates (p = 0.58). CONCLUSIONS: Our findings suggest that HRQL is associated with prognosis in PAH. Furthermore, achieving pre-determined PCS scores might represent a specific goal to be reached in treatment-to-target strategies.

Selectins and platelet-derived growth factor (PDGF) in schistosomiasis-associated pulmonary hypertension.

PURPOSE: The aim of this study was to evaluate the expression profiles of the relevant selectins and PDGF in schistosomiasis-associated pulmonary hypertension. METHODOLOGY: Patients with three distinct clinical profiles were enrolled in the study: IPAH(n = 11), schistosomiasis-associated PH (Sch-PH))(n = 13), and schistosomiasis without PH (Sch) (n = 13). Healthy volunteers, were recruited as a control group(n = 13). Echocardiography was performed in all groups, and the PH patients underwent right heart catheterization. Plasma soluble adhesion molecules E- and P-Selectin, PDGF-AB, PDGF-BB were determined by ELISA. RESULTS: E-selectin was significantly increased in the IPAH group compared with the other groups [the control, Sch + PH and Sch groups) (p < 0.001) (Fig. 2)]. P-selectin was lower in Sch (20.2 + 8.9 × 103 pg/mL) as compared to the control, (43 16.8 × 103 pg/mL), IPAH (35.8 7.8 × 103 pg/mL), and Sch + PH (36.8 ± 15.7 × 103 pg/mL) (p = 0.005) groups. Serum PDGF-BB levels were higher in the control group (8.9 ± 4.8 × 103 pg/mL) compared with the IPAH (3.7 ± 2.17 × 103 pg/mL), Sch + PH (5.2 ± 3.7 × 103 pg/mL) and Sch (2.4 ± 1.7 × 103 pg/mL) groups (p < 0.05). PDGF-AB levels were also higher in the control group (25.6 ± 8.6 × 103 pg/mL), compared with the other three groups, being the Sch group the one with lower serum levels of this marker (11.4 ± 8.6 × 103 pg/mL) (p = 0.006). CONCLUSIONS: In conclusion, vascular inflammation in schistosomiasis, with or without PH, is different from IPAH suggesting distinct pathophysiological mechanisms associated with the development of pulmonary hypertension.

Idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (IPAH), formerly called primary pulmonary hypertension, is a rare disease (incidence and prevalence rates of approximately one and six cases per million inhabitants, respectively) with different clinical phenotypes. A group of diverse conditions manifest pulmonary arterial hypertension (PAH) and share similar pathological and/or clinical findings with IPAH. By definition, IPAH is diagnosed only after alternative diagnoses have been ruled out. Extensive investigation is needed to determine if PAH is associated with thyroid diseases, infectious diseases, autoimmune conditions, exposure to certain drugs (particularly anorexigens), certain genetic mutations, and so on. The presence of genetic abnormalities and risk factors (such as specific drug exposures) reinforces the "multiple hit" concept for the development of pulmonary hypertension. Fortunately, within the past two decades, therapeutic options have become available for IPAH, resulting in improved survival and clinical outcomes. At least seven different compounds have been registered for PAH treatment. However, even with aggressive PAH-specific therapy, mortality rates remain high (∼40% at 5 years). Given the high mortality rates, the use of combinations of agents that work by different pathways has been advocated (either as "add-on" therapy or initial "up front" therapy). Further, new therapeutic agents and treatment strategies are on the near horizon, aiming to further improve survival from the remarkable progress already seen.

Loss of response to calcium channel blockers after long-term follow-up treatment in patients with idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (PAH) patients with a positive response to acute vasodilator challenge and a clinical response to calcium channel blockers (CCBs) for at least one year are traditionally designated true responders. Nevertheless, little is known about a sustained response to CCBs over longer periods of time. We evaluated the loss of response to CCBs after long-term treatment in a cohort of idiopathic PAH patients previously classified as being true responders. Our data suggest that idiopathic PAH patients can lose clinical response to CCBs even after one year of clinical stability, reinforcing the need for constant multidimensional reevaluation to assess the need for targeted PAH therapies and to classify these patients correctly.

Safety and efficacy of sitaxsentan 50 and 100 mg in patients with pulmonary arterial hypertension.

OBJECTIVE: To assess safety and efficacy of sitaxsentan 50 and 100 mg in patients with pulmonary arterial hypertension (PAH). BACKGROUND: Sitaxsentan is a highly selective endothelin-A receptor antagonist that was recently withdrawn by the manufacturer because of a pattern of idiosyncratic liver injury. METHODS: Before sitaxsentan withdrawal, this 18-week double-blind, placebo-controlled study randomized patients with PAH to receive placebo or sitaxsentan 50 or 100 mg once daily. The primary efficacy endpoint was change from baseline in 6-min walk distance (6MWD) at week 18. Changes in World Health Organization (WHO) functional class and time to clinical worsening (TTCW) were secondary endpoints. The primary efficacy analysis was powered for sitaxsentan 100 mg versus placebo. RESULTS: Of 98 randomized patients, 61% were WHO functional class II at baseline. Improvement from baseline to week 18 in 6MWD occurred with sitaxsentan 100 but not 50 mg; a strong placebo effect was observed. At week 18, WHO functional class was improved or maintained in more patients receiving sitaxsentan 100 mg than placebo (P = 0.038); 0% versus 12% of patients deteriorated, respectively. TTCW was not significantly different for 100-mg sitaxsentan patients than placebo (P = 0.090). Adverse events (AEs) occurring more frequently with sitaxsentan (50 or 100 mg) included headache, peripheral edema, dizziness, nausea, extremity pain, and fatigue; most AEs were of mild or moderate severity. CONCLUSION: Sitaxsentan 100 mg improved functional class but not 6MWD in PAH patients who were mostly WHO functional class II at baseline. No patient receiving sitaxsentan 100 mg experienced clinical worsening; sitaxsentan was well tolerated.

Stent-armed kyphoplasty in osteoporotic thoracolumbar fractures-clinical and functional results and a center experience over 10 years.

Background: The optimal treatment of osteoporotic vertebral fractures is still a controversial and under discussion topic. Armed kyphoplasty with expansive intravertebral implants is an emerging procedure, which, in theory, it not only makes it possible to achieve instant analgesia, and to get stabilization gains of benefits of kyphoplasty and vertebroplasty, but also, allows for a more effective maintenance of the restored vertebral height. Methods: A retrospective observational study is presented, in which 30 patients participated, including a total of 33 osteoporotic thoracolumbar compression burst vertebral fractures with involvement of one or both vertebral platforms and of more than one fifth of the posterior wall. These individuals underwent armed kyphoplasty with VBS® stents (or stentoplasty) filled with bone cement over 10 years (between 2012 and 2022) at the same center. Clinical (visual analogue scale, Oswestry Disability Index and Patient Global Impression of Change) and imaging results (restoration and maintenance of vertebral body heights) achieved were investigated. The mean follow-up time was 4.5 years (range, 1-10 years). Results: There was a statistically significant improvement in all clinical and functional parameters evaluated, as well as a statistically significant difference in the various vertebral body heights between preoperative and end of follow-up time [increase of 10.7-15.2-5.0 mm (anterior-median-posterior) in the sagittal plane and 6.7-11.6-9.7 mm (right-median-left) in the coronal plane]. There was a statistically significant direct correlation between vertebral heights in the coronal plane, and between the Beck index assessed at the end of the follow-up period and the improvement in functional disability. Conclusions: The percutaneous transpedicular posterior approach, the ability to anatomically restore the fractured vertebra and to maintain it in the medium-long term, as well as the reduced risk of adverse effects, make stent-armed kyphoplasty a very attractive treatment option for osteoporotic compressive thoracolumbar fractures. A clinical-morphological correlation was demonstrated regarding the surgical treatment of these fractures, it was found that a more effective morphological restoration of vertebral heights in both the sagittal and coronal planes is associated with superior satisfactory clinical functional parameters.

Differences in health policies for drug availability in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension across Latin America.

Treatment for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension in Latin America differs between countries, with regard to disease etiology, health insurance coverage, and drug availability. A group of experts from Latin America, met to share regional experiences and propose possible lines of collaboration. The available evidence, regional clinical practice data, and the global context of the proceedings of the 6th World Symposium on Pulmonary Hypertension, held in Nice, France, in February 2018, were analyzed. Here, we discuss some priority concepts identified that could guide transnational interaction and research strategies in Latin America: (1) despite being evidence-based, the 6th World Symposium on Pulmonary Hypertension proceedings may not be applicable in Latin American countries; (2) proactive identification and diagnosis of patients in Latin America is needed; (3) education of physicians and standardization of appropriate treatment for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension is vital; (4) our clinical experience for the treatment strategy for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension is based on drug availability in Argentina, Brazil, Colombia and México; (5) there are difficulties inherent to the consultation of patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension, and access to treatment; (6) the importance of data generation and research of Latin American-specific issues related to pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension is highlighted.

Brazilian Thoracic Society recommendations for the diagnosis and treatment of chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious and debilitating disease caused by occlusion of the pulmonary arterial bed by hematic emboli and by the resulting fibrous material. Such occlusion increases vascular resistance and, consequently, the pressure in the region of the pulmonary artery, which is the definition of pulmonary hypertension. The increased load imposed on the right ventricle leads to its progressive dysfunction and, finally, to death. However, CTEPH has a highly significant feature that distinguishes it from other forms of pulmonary hypertension: the fact that it can be cured through treatment with pulmonary thromboendarterectomy. Therefore, the primary objective of the management of CTEPH should be the assessment of patient fitness for surgery at a referral center, given that not all patients are good candidates. For the patients who are not good candidates for pulmonary thromboendarterectomy, the viable therapeutic alternatives include pulmonary artery angioplasty and pharmacological treatment. In these recommendations, the pathophysiological bases for the onset of CTEPH, such as acute pulmonary embolism and the clinical condition of the patient, will be discussed, as will the diagnostic algorithm to be followed and the therapeutic alternatives currently available.

Outcomes and prognostic factors of decompensated pulmonary hypertension in the intensive care unit.

BACKGROUND: Patients with acute decompensation of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) admitted to intensive care unit (ICU) have high in-hospital mortality. We hypothesized that pulmonary hypertension (PH) severity, measured by a simplified version of European Society of Cardiology/European Respiratory Society (ESC/ERS) risk assessment, and the severity of organ dysfunction upon ICU admission, measured by sequential organ failure assessment score (SOFA) were associated with in-hospital mortality in decompensated patients with PAH and CTEPH. We also described clinical and laboratory variables during ICU stay. METHODS: Observational study including adults with decompensated PAH or CTEPH with unplanned ICU admission between 2014 and 2019. Multivariate logistic regression models were used to evaluate the association of ESC/ERS risk assessment and SOFA score with in-hospital mortality. ESC/ERS risk assessment and SOFA score were included in a decision tree to predict in-hospital mortality. RESULTS: 73 patients were included. In-hospital mortality was 41.1%. ESC/ERS high-risk group (adjusted odds ratio = 95.52) and SOFA score (adjusted odds ratio = 1.80) were associated with in-hospital mortality. The decision tree identified four groups with in-hospital mortality between 8.1% and 100%. Nonsurvivors had a lower central venous oxygen saturation, higher arterial lactate and higher brain natriuretic peptide in the end of first week in the ICU. CONCLUSIONS: High-risk on a simplified version of ERS/ESC risk assessment and SOFA score upon ICU admission are associate with in-hospital mortality. A decision tree based on ESC/ERS risk assessment and SOFA score identifies four groups with in-hospital mortality between 8.1% and 100%.

Inhaled iloprost as third add-on therapy in idiopathic pulmonary arterial hypertension.

Triple combination therapy is suggested in current pulmonary arterial hypertension guidelines in case of unsatisfactory treatment with oral double combination therapy. However, there is a lack of evidence concerning some of the drug combinations currently employed. We demonstrate the clinical and hemodynamical benefits of inhaled iloprost as third add-on therapy in idiopathic pulmonary arterial hypertension.

Electrical impedance tomography in pulmonary arterial hypertension.

The characterization of pulmonary arterial hypertension (PAH) relies mainly on right heart catheterization (RHC). Electrical impedance tomography (EIT) provides a non-invasive estimation of lung perfusion that could complement the hemodynamic information from RHC. To assess the association between impedance variation of lung perfusion (ΔZQ) and hemodynamic profile, severity, and prognosis, suspected of PAH or worsening PAH patients were submitted simultaneously to RHC and EIT. Measurements of ΔZQ were obtained. Based on the results of the RHC, 35 patients composed the PAH group, and eight patients, the normopressoric (NP) group. PAH patients showed a significantly reduced ΔZQ compared to the NP group. There was a significant correlation between ΔZQ and hemodynamic parameters, particularly with stroke volume (SV) (r = 0.76; P < 0.001). At 60 months, 15 patients died (43%) and 1 received lung transplantation; at baseline they had worse hemodynamics, and reduced ΔZQ when compared to survivors. Patients with low ΔZQ (≤154.6%.Kg) presented significantly worse survival (P = 0.033). ΔZQ is associated with hemodynamic status of PAH patients, with disease severity and survival, demonstrating EIT as a promising tool for monitoring patients with pulmonary vascular disease.

Update on the Treatment of Pulmonary Arterial Hypertension. / Atualização no Tratamento da Hipertensão Arterial Pulmonar.

In the last decades, important advances have been made in the treatment of pulmonary arterial hypertension (PAH), a severe, progressive, incurable, and potentially fatal disease. For an adequate therapy, correct hemodynamic diagnosis and etiology classification are fundamental. Many etiologies - rheumatic disease, portal hypertension, congenital heart diseases, schistosomiasis - require specific measures, in addition to drug therapy for PAH. The specific therapy for PAH is based on medications that act on three pathophysiological pathways - prostacyclin, endothelin, and nitric oxide pathways. These drugs have multiple presentations (oral, intravenous, subcutaneous, and inhaled) and have changed the history of PAH. This review presents an overview of drug therapy strategies and different forms and peculiarities of PAH.

Muitos avanços ocorreram nas últimas décadas na terapêutica da hipertensão arterial pulmonar (HAP), uma doença grave, progressiva, incurável e potencialmente fatal. Para seu tratamento adequado, são fundamentais o diagnóstico hemodinâmico e a classificação de sua etiologia, em que várias delas (colagenoses, hipertensão portal, cardiopatia congênitas, esquistossomose) requerem medidas específicas, além do tratamento farmacológico característico para HAP. O tratamento com fármacos-alvo para HAP baseia-se em produtos farmacêuticos que interferem em três vias fisiopatológicas moleculares: da prostaciclina, da endotelina e do óxido nítrico. Tais fármacos apresentam múltiplas apresentações (oral, endovenosa, subcutânea e inalatória) e mudaram a história da HAP. Essas medicações e suas estratégias de uso, assim como particularidades das diferentes formas de HAP, são o foco desta revisão.

[Chronic exposure to altitude. Clinical characteristics and diagnosis]. / Exposición crónica a la altura. Características clínicas y diagnóstico

Chronic exposure to altitude has been associated with hypobaric hypoxia in its inhabitants. Two entities have been associated with it, high altitude pulmonary hypertension and chronic mountain sickness. Its physiological and pulmonary circulation characteristics are described, as well as its clinical profile and diagnosis.

La exposición crónica a la altitud se ha asociado a hipoxia hipobárica en quienes la experimentan. Dos entidades se han asociado a la hipoxia hipobárica: la hipertensión pulmonar de la alta altitud y el mal de montaña crónico. Se describen sus características fisiológicas y de la circulación pulmonar, así como su perfil clínico y el diagnóstico.

Cardiopulmonary manifestations of hepatosplenic schistosomiasis.

BACKGROUND: Schistosomiasis is a highly prevalent disease with >200 million infected people. Pulmonary hypertension is one of the pulmonary manifestations in this disease, particularly in its hepatosplenic presentation. The aim of this study was to determine the prevalence of pulmonary hypertension in schistosomiasis patients with the hepatosplenic form of the disease. METHODS AND RESULTS: All patients with hepatosplenic schistosomiasis followed up at the gastroenterology department of our university hospital underwent echocardiographic evaluation to search for pulmonary hypertension. Patients presenting with systolic pulmonary artery pressure >40 mm Hg were further evaluated through right heart catheterization. Our study showed an 18.5% prevalence of patients with elevated systolic pulmonary artery pressure at echocardiography. Invasive hemodynamics confirmed the presence of pulmonary hypertension in 7.7% (95% confidence interval, 3.3 to 16.7) of patients, with a prevalence of precapillary (arterial) pulmonary hypertension of 4.6% (95% confidence interval, 1.5 to 12.7). CONCLUSIONS: Our study reinforces the role of echocardiography as a screening tool in the investigation of pulmonary hypertension, together with the need for invasive monitoring for a proper diagnosis. We conclude that hepatosplenic schistosomiasis may account for one of the most prevalent forms of pulmonary hypertension worldwide, justifying the development of further studies to evaluate the effect of specific pulmonary hypertension treatment in this particular form of the disease.