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This review focuses on the advancements in the treatment of pulmonary hypertension (PH), especially after the Food and Drug Administration (FDA) approval of sotatercept and the advances in treatment recommendations after seven World Symposia on PH. PH, a complex and progressive condition defined hemodynamically by a mean pulmonary artery pressure >20 mmHg, encompasses multiple PH groups, each with distinct pathophysiological characteristics and treatment implications. Diagnosing PH can be challenging because symptoms like shortness of breath, fatigue, and chest pain are nonspecific. Contemporary treatment of pulmonary arterial hypertension aims to improve outcomes, symptoms, and overall quality of life, with a primary focus on preventing and treating right ventricular failure. Comprehensive risk stratification remains crucial, aiding in personalized therapy adjustments that improve patients’ outcomes. This review also touches upon the limited treatment options for other PH groups, like PH associated with left heart disease, parenchymal lung diseases, and chronic thromboembolic PH, underscoring the need for expanded therapeutic options. Despite advances, challenges remain: diagnostic delays, misdiagnosis, absence of head-to-head clinical trials, and the timing of introducing newer treatments such as sotatercept are discussed, emphasizing an integrated approach that transcends vasodilation to target underlying disease mechanisms. Future directions envision a comprehensive risk stratification incorporating right ventricular function and a mechanism-based treatment paradigm, encouraging a tailored therapeutic approach in PH management. Plain language summary Contemporary treatment of pulmonary hypertension Pulmonary hypertension is a condition characterized by high pressure in the vessels of the lung. During the last three decades, great progress has been made in the treatment of the disease. This review article describes the current treatment of pulmonary arterial hypertension, based on recommendations from the 7th World Symposium in Pulmonary Hypertension. It incorporates current knowledge on the use of a recently FDA approved medication, i.e. sotatercept, a medication with unique mechanism of action that directly acts on the disease process. It emphasizes the importance of risk stratification and early and aggressive treatment of the disease to improve outcomes. Furthermore it discusses the current treatment of different types of pulmonary hypertension, including pulmonary hypertension associated with left heart disease and parenchymal lung disease.

Background: Initial regimen selection is critical for pulmonary arterial hypertension (PAH) management and survival. Since 2015, guidelines have recommended upfront combination therapy as the standard of care in newly diagnosed patients. Objectives: To highlight real-world treatment patterns and predictors of initial combination therapy. Design: Retrospective cohort analysis of U.S. administrative claims from 01 January 2013 (Optum’s de-identified Clinformatics® Data Mart Database [CDM]) or 01 July/2015 (IQVIA PharMetrics® Plus) through 30 September 2020. Methods: Patients initiating PAH medications (phosphodiesterase-5 inhibitors (PDE5i), soluble guanylate cyclase stimulators (SGCS), endothelin receptor antagonists (ERA), or prostacyclin analogues (PCY)) were identified and indexed on the first medication date. All PAH medications identified between index and 365 days post-index were identified and classified as PDE5i/SGCS/ERA monotherapy, PDE5i/SGCS + ERA dual therapy, or PCY-containing regimen. Treatment regimens were analyzed by index year, physician specialty, and among physician specialists associated with a Pulmonary Hypertension Care Center. Multivariable regression was conducted to identify patient characteristics predictive of the first-line regimen. Results: 1754 (CDM) and 1107 (IQVIA PharMetrics Plus) met selection criteria. The most initiated first-line regimen was PDE5i/SGCS/ERA monotherapy (CDM: 61.2%; IQVIA PharMetrics Plus: 50.9%). The proportion of CDM patients initiating PDE5i/SGCS + ERA dual therapy increased from 13.1% in 2013 to 21.9% in 2019; for IQVIA PharMetrics Plus, PDE5i/SGCS + ERA dual therapy remained consistent (24.4% in 2015, 23.7% in 2019). More pulmonologists prescribed PDE5i/SGCS + ERA dual therapy (CDM: 30.2%; IQVIA PharMetrics Plus: 38.6%) than cardiologists (CDM: 18.3%; IQVIA PharMetrics Plus: 24.3%). PHCC patients were prescribed first-line dual therapy (35.7% vs 26.9%) and PCY-containing regimens (30.3% vs 21.7%) more frequently than non-PHCC patients, respectively. Females (vs males) were more likely to receive dual therapy and PCY-containing regimens; Black (vs White) patients were less likely to receive PCY-containing regimens. Conclusion: Additional research is needed to better understand barriers to optimal initial treatment regimen selection and to quantify the impacts of therapeutic delay. Plain language summary Use of combination treatment in patients with pulmonary arterial hypertension Why was the study done? Selecting the treatment approach for newly diagnosed pulmonary arterial hypertension (PAH) is critical for improving patient survival. Research has shown that patients newly diagnosed with PAH who are started on combination therapy experience less disease progression, hospitalization, and death, than those started on monotherapy. Thus, experts now recommend starting treatment in patients with newly diagnosed PAH using a combination of medications, but it is not clear if this is happening. What did the researcher do? Using two large databases, with data spanning from 2013-2020, this study explored the treatment approaches used for newly diagnosed patients with PAH and found patient factors that influenced treatment selection. What did the researchers find? In total, 1,754 and 1,107 patients were identified from each database. In both databases, more than one-half of patients started PAH treatment with one medication (61.2% and 50.9%). However, combination treatments did increase over time (from 13.1% in 2013 to 21.9% in 2019), and in the other database, dual therapy stayed at approximately 24% from 2015 to 2019. Females were more likely than males to receive dual therapy. Lung specialists and doctors at specialty care clinics were more likely to start patients on combination treatments. What do the findings mean? Even though clinical guidelines recommend starting PAH therapy using combination treatments, most patients are initiating therapy with only one medication.

Accurate and regular risk assessment is important for evaluation and treatment of pulmonary arterial hypertension (PAH) patients, including those with functional class (FC) II symptoms, a population considered at low risk for disease progression. Risk assessment methods include subjective and objective evaluations. Multiparametric assessments include tools based on the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines (COMPERA and FPHR methods, respectively) and the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL; REVEAL 2.0 tool). To better understand risk status determination in FC II patients, we compared physician-reported risk assessments with objective multiparameter assessment tools. This retrospective chart analysis included PAH patients with FC II symptoms receiving monotherapy or dual therapy. Physicians were surveyed (via telephone) to obtain an assessment of patient risk using their typical methodology, which might have been informed by objective risk assessment. Patient risk was then calculated independently using COMPERA, FPHR and REVEAL 2.0 tools. Factors associated with incongruent risk assessment were identified. Of the 153 patients, 41%, 46%, and 13% were classified as low, intermediate, and high risk, respectively, by physicians. Concordance between physician gestalt and objective methods ranged from 43%-54%. Among patients considered as low risk by physician gestalt, 4%-28% were categorized as high risk using objective methods. The most common physician factor associated with incongruent risk assessment was less frequent echocardiography during follow-up (every 7-12 months vs. every 3 months; p = 0.01). More than half of FC II PAH patients were classified as intermediate/high risk using objective multiparameter assessments. Incorporating objective risk-assessment algorithms into clinical practice may better inform risk assessment and treatment strategies.

Portopulmonary hypertension (PoPH) is defined as pulmonary arterial hypertension (PAH) associated with portal hypertension and is a subset of Group 1 pulmonary hypertension (PH). PoPH is a cause of significant morbidity and mortality in patients with portal hypertension with or without liver disease. Significant strides in elucidating the pathogenesis, effective screening algorithms, accurate diagnoses, and treatment options have been made in past 20 years. Survival of PoPH has remained poor compared to IPAH and other forms of PAH. Recently, the first randomized controlled trial was done in this patient population and showed promising results with PAH specific therapy. Despite positive effects on hemodynamics and functional outcomes, it is unclear whether PAH specific therapy has a beneficial effect on long term survival or transplant outcomes. In this review, we will discuss the epidemiology, pathophysiology, clinical and hemodynamic characteristics of PoPH. Additionally, this review will highlight the lacunae in our current management strategy, challenges faced and will provide direction to potentially useful futuristic management strategies.

The severe pneumonia caused by the human coronavirus (hCoV)-SARS-CoV-2 has inflicted heavy casualties, especially among the elderly and those with co-morbid illnesses irrespective of their age. The high mortality in African-Americans and males, in general, raises the concern for a possible X-linked mediated process that could affect the viral pathogenesis and the immune system. We hypothesized that G6PD, the most common X-linked enzyme deficiency, associated with redox status, may have a role in severity of pneumonia. Retrospective chart review was performed in hospitalized patients with COVID19 pneumonia needing supplemental oxygen. A total of 17 patients were evaluated: six with G6PD deficiency (G6PDd) and 11 with normal levels. The two groups (normal and G6PDd) were comparable in terms of age, sex, co-morbidities, and laboratory parameters—LDH, IL-6, CRP, and ferritin, respectively. Thirteen patients needed ventilatory support ; 8 in the normal group and 5 in the G6PDd group (72% vs.83%). The main differences indicating increasing severity in normal vs. G6PDd groups included G6PD levels (12.2 vs. 5.6, P = 0.0002), PaO2/FiO2 ratio (159 vs. 108, P = 0.05), days on mechanical ventilation (10.25 vs. 21 days P = 0.04), hemoglobin level (10 vs. 8.1 P = 0.03), and hematocrit (32 vs. 26 P = 0.015). Only one patient with G6PDd died; 16 were discharged home. Our clinical series ascribes a possible biological role for G6PDd in SARS-CoV2 viral proliferation. It is imperative that further studies are performed to understand the interplay between the viral and host factors in G6PDd that may lead to disparity in outcomes.Key Points• COVID19 studies show higher mortality in men, due to severe pneumonia and ARDS, indicating possible X-linked mediated differences• G6PD, the most common X-linked enzymopathy, highly prevalent in African Americans and Italians, maintains redox homeostasis.• Preclinical studies using G6PD deficient (G6PDd) cells infected with human coronavirus (hCoV), show impaired cellular responses, viral proliferation and worsening oxidative damage.• Retrospective chart review in hospitalized patients with COVID19 pneumonia needing supplemental oxygen shows differences between the two groups (Normal and G6PDd) in hematological indices; the G6PDdgroup demonstrated prolonged PaO2/FiO2 ratio, and longer days on mechanical ventilation indicating the severity of the pneumonia.

Patients with portal hypertension may develop pulmonary hypertension. The economic implications of these comorbidities have not been systematically assessed. We compared healthcare resource utilization and costs in the United States between patients with co-existing portal hypertension and pulmonary hypertension (pulmonary hypertension cohort) and a matched cohort of portal hypertension patients without pulmonary hypertension (control cohort). In this retrospective analysis, adult pulmonary hypertension and control patients were identified from the Optum® Clinformatics® Data Mart database between 1 July 2014 and 30 June 2018. All patients had ≥2 claims with diagnosis codes for portal hypertension; pulmonary hypertension patients had ≥2 claims with diagnosis codes for pulmonary hypertension; controls could not have pulmonary hypertension diagnoses or any claims for pulmonary arterial hypertension-specific medications. Controls were matched to pulmonary hypertension patients by age, sex, Charlson comorbidity index score, and liver diseases. We assessed 12-month healthcare resource utilization and costs. Each cohort included 146 patients. During follow-up, pulmonary hypertension cohort patients were more likely than controls to experience a hospitalization (51% vs. 32%, P = 0.0014) and an emergency room visit (55% vs. 41%, P = 0.026). The average annual total cost was higher in pulmonary hypertension patients than for matched controls ($119,912 vs. $81,839, P < 0.0001). After covariate adjustment, costs for pulmonary hypertension cohort patients were 1.47 times higher than those for controls (P = 0.0197). These findings suggest that patients with portal hypertension and co-existing pulmonary hypertension are at a greater risk for hospitalization and incur higher mean annual total costs than portal hypertension patients without pulmonary hypertension.

Energy metabolism pathways and their association with cell proliferation and growth have been related to PAH, in particular the insulin-like growth factor (IGF) axis pathways. High-throughput plasma proteome analysis in PAH patients has identified proteins that correlate to survival, identifying the insulin-growth factor binding protein-1 (IGFBP-1) as one of them. Subgroup analysis revealed that regardless of PAH subtype, above median IGFBP-4 levels were associated with worsening survival rates. Sandeep Sahay: Grants/Research Support: Research grant from United Therapeutics; Consultant: United Therapeutics, J&J, Bayer, Gossamer Bio, Liquidia technologies, Keros; Speaker's Bureau: Janssen, United Therapeutics (honorarium received by Houston Methodist Hospital Foundation); Clinical trial support from United Therapeutics, Janssen, Gossamer Bio, Altavant Sciences, Liquidia technologies, Novartis, Keros.

Pulmonary arterial hypertension is a progressive disease that can lead to right-sided ventricular failure and premature death. Tailoring therapy to individual patient’s needs, along with regular risk assessment, is integral for optimal outcomes in patients with pulmonary arterial hypertension. Results from the AMBITION trial support the use of upfront combination of tadalafil and ambrisentan. In a recent analysis of risk assessment in pulmonary arterial hypertension, abridged versions of the REVEAL 2.0 risk score were shown to be comparable to the full tools. In this report, we present a case series of the use of riociguat in upfront combination or sequentially, and the impact on risk scores as determined by the abridged REVEAL Lite 2.0 approach.

Relative to healthy subjects, patients with pulmonary arterial hypertension often present with decreased respiratory muscle strength, resulting in decreased maximum inspiratory pressure. Little is known about the impact of reduced respiratory muscle strength on the ability to achieve the peak inspiratory pressures needed for effective drug delivery when using portable dry powder inhalers (≥1.0 kPa). The objective of this study was to assess the impact of inhaler resistance and patient instruction on the inspiratory flow profiles of pulmonary arterial hypertension patients when using breath-actuated dry powder inhalers. The inspiratory flow profiles of 35 patients with pulmonary arterial hypertension were measured with variants of the RS01 dry powder inhaler. Profiles were determined with a custom inspiratory flow profile recorder. Results showed that going from the low resistance RS01 dry powder inhaler to the high resistance AOS® dry powder inhaler led to increases in mean peak inspiratory pressures for pulmonary arterial hypertension subjects from 3.7 kPa to 6.5 kPa. Instructions that ask pulmonary arterial hypertension subjects to inhale with maximal effort until their lungs are full led to a mean peak inspiratory pressures of 6.0 kPa versus 2.1 kPa when the same subjects are asked to inhale comfortably. Significant decreases in mean peak inspiratory pressures are also observed with decreases in lung function, with a mean peak inspiratory pressures of 7.2 kPa for subjects with FEV1 > 60% predicted, versus 3.3 kPa for those subjects with FEV1 < 50% predicted. In conclusion, despite having reduced respiratory muscle strength, subjects with pulmonary arterial hypertension can effectively use a breath-actuated dry powder inhaler. The probability of achieving effective dose delivery may be increased by using dry powder inhalers with increased device resistance, particularly when subjects do not follow the prescribed instructions and inhale comfortably.