Contemporary Treatment of Pulmonary Arterial Hypertension: A U.S. Perspective.

Pulmonary arterial hypertension (PAH) is a complex fatal condition that requires aggressive treatment with close monitoring. Significant progress has been made over the last three decades in the treatment of PAH, but, despite this progress, survival has remained unacceptably low. In the quest to improve survival, therapeutic interventions play a central role. In the last few years, there have been remarkable attempts to identify novel treatments. Finally, we have had a breakthrough with the discovery of the fourth treatment pathway in PAH. Activin signaling inhibition distinguishes itself as a potential antiproliferative intervention as opposed to the traditional therapies, which mediate their effect primarily by vasodilatation. With this novel treatment pathway, we stand at an important milestone with an exciting future ahead and the natural question of when to use an activin signaling inhibitor for the treatment of PAH. In this state-of-the-art review, we focus on the placement of this novel agent in the PAH treatment paradigm, based on the available evidence, with special focus on the U.S. patient population. This review also provides an expert opinion of the current treatment algorithm in important subgroups of patients with comorbidities from the U.S. perspective.

Improved Survival for Patients with Systemic Sclerosis-associated Pulmonary Arterial Hypertension: The Johns Hopkins Registry.

Rationale: To date, it remains unclear whether recent changes in the management of patients with systemic sclerosis-associated pulmonary hypertension (SSc-PH) have improved survival. Objectives: To describe a cohort of patients with SSc-PH and compare their characteristics and survival between the last two decades. Methods: Patients with SSc-PH prospectively enrolled in the Johns Hopkins Pulmonary Hypertension Center Registry were grouped into two cohorts based on the date of diagnostic right heart catheterization: cohort A included patients whose disease was diagnosed between 1999 and 2010, and cohort B included those whose disease was diagnosed between 2010 and 2021. Patients' characteristics were compared between the two cohorts. Measurements and Main Results: Of 504 patients with SSc-PH distributed almost equally between the two cohorts, 308 (61%) had World Symposium on Pulmonary Hypertension group 1, 43 (9%) had group 2, and 151 (30%) had group 3 disease. Patients with group 1 disease in cohort B had significantly better clinical and hemodynamic characteristics at diagnosis, were more likely to receive upfront combination pulmonary arterial hypertension therapy, and had a nearly 4-year increase in median transplant-free survival in univariable analysis than those in cohort A (P < 0.01). Improved transplant-free survival was still observed after adjusting for patients' baseline characteristics. In contrast, for group 2 or 3 patients with SSc-PH, there were no differences in baseline clinical, hemodynamic, or survival characteristics between the two cohorts. Conclusions: This is the largest single-center study that compares clinical characteristics of patients with SSc-PH between the last two decades. Transplant-free survival has improved significantly for those with group 1 disease over the last decade, possibly secondary to earlier detection and better therapeutic management. Conversely, those with group 2 or 3 disease continue to have dismal prognosis.

Management of the peri-intubation period in patients with pulmonary arterial hypertension and respiratory failure.

PURPOSE OF REVIEW: The endotracheal intubation of patients with pulmonary arterial hypertension (PAH) in respiratory distress is a highly morbid procedure that can precipitate hemodynamic collapse. Here we review our strategy for confronting this difficult clinical situation. RECENT FINDINGS: There are no clinical trials that explore best practices in the management of patients with PAH and respiratory failure. Here we provide a practical approach to respiratory support, inopressor and pulmonary vasodilator selection, hemodynamic considerations, point-of-care ultrasound monitoring, and endotracheal intubation in patients with PAH in respiratory failure.

Pathophysiology and Treatment of Pulmonary Arterial Hypertension.

Pulmonary hypertension (PH) is recognized as a pathophysiological disorder encompassing a wide spectrum of clinical conditions related to various cardiovascular and respiratory diseases [...].

Immunotherapy for Pulmonary Arterial Hypertension: From the Pathogenesis to Clinical Management.

Pulmonary hypertension (PH) is a progressive cardiovascular disease, which may lead to severe cardiopulmonary dysfunction. As one of the main PH disease groups, pulmonary artery hypertension (PAH) is characterized by pulmonary vascular remodeling and right ventricular dysfunction. Increased pulmonary artery resistance consequently causes right heart failure, which is the major reason for morbidity and mortality in this disease. Although various treatment strategies have been available, the poor clinical prognosis of patients with PAH reminds us that further studies of the pathological mechanism of PAH are still needed. Inflammation has been elucidated as relevant to the initiation and progression of PAH, and plays a crucial and functional role in vascular remodeling. Many immune cells and cytokines have been demonstrated to be involved in the pulmonary vascular lesions in PAH patients, with the activation of downstream signaling pathways related to inflammation. Consistently, this influence has been found to correlate with the progression and clinical outcome of PAH, indicating that immunity and inflammation may have significant potential in PAH therapy. Therefore, we reviewed the pathogenesis of inflammation and immunity in PAH development, focusing on the potential targets and clinical application of anti-inflammatory and immunosuppressive therapy.

Pulmonary arterial hypertension in pregnancy.

PURPOSE OF REVIEW: Although pregnancy in pulmonary arterial hypertension (PAH) is considered high risk and contraindicated, the incidence is rising. It is paramount to understand the pathophysiology and effective management strategies to ensure optimal outcomes for maternal and fetal survival. RECENT FINDINGS: In this review, we highlight the outcomes of recent case series of PAH patients in pregnancy, with a focus on proper risk assessment and target goals of PAH therapy. These findings support the notion that the pillars of PAH management, including pulmonary vascular resistance reduction resulting in right heart functional improvement, and widening of the cardiopulmonary reserve, should serve as a blueprint for PAH management in pregnancy. SUMMARY: Multidisciplinary and tailored management of PAH in pregnancy, with emphasis on optimizing right heart function prior to delivery, can result in excellent clinical outcomes in a referral pulmonary hypertension center.

Approach to the hospitalized patient with pulmonary arterial hypertension.

PURPOSE OF REVIEW: Hospitalization in pulmonary arterial hypertension (PAH) patients is an important clinical worsening event significantly associated with subsequent mortality. Furthermore, irrespective of the cause of hospitalization, the overall outcome is closely related to the severity of the right ventricular (RV) dysfunction. Therefore, understanding the pathophysiology of pulmonary hypertension and RV failure is paramount in successfully managing PAH patients requiring hospitalization. This review highlights diagnostic and therapeutic approaches in various clinical scenarios that might be encountered during hospitalization of the World Health Organization group I PAH patient. RECENT FINDINGS: This article covers recent literature describing risk factors, predictors of outcome and state-of the art management approach to a hospitalized PAH patients with a special focus on management of RV failure and common complications in PAH requiring hospitalization. SUMMARY: The review highlights the importance of multidisciplinary approach to a hospitalized PAH patient and highlight important implications in clinical practice and knowledge gaps for potential future research.

End-of-Life and Palliative Care Issues for Patients Living with Pulmonary Arterial Hypertension: Barriers and Opportunities.

Pulmonary arterial hypertension (PAH) is a progressive, incurable disease that results in significant symptom burden, health care utilization, and eventually premature death. Despite the advancements made in treatment and management strategies, survival has remained poor. End-of-life care is a challenging issue in management of PAH, especially when patients are in younger age group. End-of-life care revolves around symptom palliation and reducing psychosocial disease burden for a dying patient and entails advanced care planning that are often challenging. Thus, support from palliative care specialist becomes extremely important in these patients. Early introduction to palliative care in patients with high symptom burden and psychosocial suffering is suggested. Despite of the benefits of an early intervention, palliative care remains underutilized in patients with PAH, and this significantly raises issues around end-of-life care in PAH. In this review, we will discuss the opportunities offered and the existing barriers in addressing high symptom burden and end-of-life care issues. We will focus on the current evidence, identify areas for future research, and provide a call-to-action for better guidance to PAH specialists in making timely, appropriate interventions that can help mitigate end-of-life care issues.

Acute Vasoreactivity Testing and Outcomes in Pulmonary Arterial Hypertension: A Call for Increased Testing.

BACKGROUND: Pulmonary arterial hypertension (PAH) has a progressive, unremitting clinical course. Vasoreactivity testing (VdT) during right heart catheterisation (RHC) identifies a subgroup with excellent long-term response to calcium channel blockade (CCB). Reporting on these patients is limited. Established in 2011, the Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) registry offers the opportunity to assess the frequency of VdT during RHC, treatment and follow up of PAH patients. METHODS: Registry data from 3,972 PAH patients with index RHC revealed 1,194 VdT appropriate patients. Data was analysed in three groups: 1) VdT+CCB+: VdT positive, CCB treated; 2) VdT+CCB-: VdT positive, no CCB prescribed, 3) VdT-/noVdT: VdT negative, or VdT not tested. Data was reviewed for adherence to guidelines, clinical response (World Health Organization functional class [WHO FC], 6-minute-walk-distance [6MWD], RHC), and outcomes (survival or lung transplantation). RESULTS: Patients included had idiopathic (IPAH=1,087), heritable (HPAH=67) and drug or toxin-induced PAH (DPAH=40). A VdT was performed in 22% (268/1,194), with incomplete data in 26% (70/268); 28% (55/198) were VdT+. Analysis group allocation was: VdT+CCB+ (33/55), VdT+CCB- (22/55), VdT- (143)/noVdT (996). From patients with 1-year data VdT+CCB+ and VdT-/noVdT patients improved WHO FC, 6MWD and cardiac index (CI); VdT+CCB- data remained similar. Within the VdT+CCB+ group, 30% (10/33) were long-term CCB responders with a 100% 5-year survival; non-responders had a 61% survival at 5.4 years. Long-term responders were younger at diagnosis (40 yrs vs 54 yrs). CONCLUSION: Use of VdT testing and documentation is poor in this contemporary patient cohort. Nonetheless, survival in VdT+CCB+ patients from the PHSANZ registry is excellent, supporting guidelines promoting VdT testing. Strategies to promote the use of VdT are warranted.

Pulmonary Arterial Hypertension in Connective Tissue Diseases Beyond Systemic Sclerosis.

Pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD) (CTD-PAH) is a devastating condition that may progress rapidly to cause right ventricular dysfunction, resulting in significant morbidity and mortality. The pathobiology, epidemiology, natural history, early diagnosis, and treatment response of PAH associated with scleroderma (SSc-PAH) have been the subjects of intense research efforts over the previous decade. The success of these efforts has resulted in increased awareness and earlier detection of SSc-PAH. Practitioners are less aware of the risk of PAH associated with other CTDs; the aim of this article is to discuss the broader scope of CTD-PAH.

Management of COVID-19 in Patients with Pulmonary Arterial Hypertension.

In this review, we discuss the evidence regarding the course and management of COVID-19 in patients with pulmonary arterial hypertension (PAH), the challenges in PAH management during the pandemic and, lastly, the long-term complications of COVID-19 in relation to pulmonary vascular disease. The inherent PAH disease characteristics, as well as age, comorbidities, and the patient's functional status act synergistically to define the prognosis of COVID-19 in patients with PAH. Management of COVID-19 should follow the general guidelines, while PAH-targeted therapies should be continued. The pandemic has caused a shift toward telemedicine in the chronic care of patients with PAH. Whether COVID-19 could predispose to the development of chronic pulmonary hypertension is a subject of future investigation.

Regulation of the Methylation and Expression Levels of the BMPR2 Gene by SIN3a as a Novel Therapeutic Mechanism in Pulmonary Arterial Hypertension.

BACKGROUND: Epigenetic mechanisms are critical in the pathogenesis of pulmonary arterial hypertension (PAH). Previous studies have suggested that hypermethylation of the BMPR2 (bone morphogenetic protein receptor type 2) promoter is associated with BMPR2 downregulation and progression of PAH. Here, we investigated for the first time the role of SIN3a (switch-independent 3a), a transcriptional regulator, in the epigenetic mechanisms underlying hypermethylation of BMPR2 in the pathogenesis of PAH. METHODS: We used lung samples from PAH patients and non-PAH controls, preclinical mouse and rat PAH models, and human pulmonary arterial smooth muscle cells. Expression of SIN3a was modulated using a lentiviral vector or a siRNA in vitro and a specific adeno-associated virus serotype 1 or a lentivirus encoding for human SIN3a in vivo. RESULTS: SIN3a is a known transcriptional regulator; however, its role in cardiovascular diseases, especially PAH, is unknown. It is interesting that we detected a dysregulation of SIN3 expression in patients and in rodent models, which is strongly associated with decreased BMPR2 expression. SIN3a is known to regulate epigenetic changes. Therefore, we tested its role in the regulation of BMPR2 and found that BMPR2 is regulated by SIN3a. It is interesting that SIN3a overexpression inhibited human pulmonary arterial smooth muscle cells proliferation and upregulated BMPR2 expression by preventing the methylation of the BMPR2 promoter region. RNA-sequencing analysis suggested that SIN3a downregulated the expression of DNA and histone methyltransferases such as DNMT1 (DNA methyltransferase 1) and EZH2 (enhancer of zeste 2 polycomb repressive complex 2) while promoting the expression of the DNA demethylase TET1 (ten-eleven translocation methylcytosine dioxygenase 1). Mechanistically, SIN3a promoted BMPR2 expression by decreasing CTCF (CCCTC-binding factor) binding to the BMPR2 promoter. Last, we identified intratracheal delivery of adeno-associated virus serotype human SIN3a to be a beneficial therapeutic approach in PAH by attenuating pulmonary vascular and right ventricle remodeling, decreasing right ventricle systolic pressure and mean pulmonary arterial pressure, and restoring BMPR2 expression in rodent models of PAH. CONCLUSIONS: All together, our study unveiled the protective and beneficial role of SIN3a in pulmonary hypertension. We also identified a novel and distinct molecular mechanism by which SIN3a regulates BMPR2 in human pulmonary arterial smooth muscle cells. Our study also identified lung-targeted SIN3a gene therapy using adeno-associated virus serotype 1 as a new promising therapeutic strategy for treating patients with PAH.

Efficacy and safety of sequential combination therapy for pulmonary arterial hypertension: A meta-analysis of Randomized-Controlled Trials.

BACKGROUND: Previous meta-analyses of pulmonary arterial hypertension (PAH) combination therapy pooled sequential and initial combination together, which might threaten their authenticity and clinical significance for the difference between two strategies. METHODS: PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) that compared sequential combination therapy (SCT) with background therapy (BT) in PAH patients. Raw data were extracted to calculate risk ratio (RR) or weighted mean difference (WMD) for predefined efficacy and safety outcomes. Mantel-Haenszel fixed or random effects model was used based on heterogeneity. RESULTS: 17 RCTs involving 4343 patients (97.2% of patients with WHO-FC II-III) were included. SCT decreased clinical worsening (RR 0.66, 95% CI 0.58 to 0.76), nonfatal clinical worsening (RR 0.61, 95% CI 0.52 to 0.71), functional class (decrease of 28% in the portion of patients with WHO-FC worsening and increase of 33% in the portion of patients with WHO-FC improvement), and increased 6-min walk distance (WMD 17.68 m, 95% CI 10.16 to 25.20), but didn't reduce mortality, lung transplantation, admission to hospital, and treatment escalation compared with BT. Although any adverse event and serious adverse event were similar between SCT and BT, SCT increased all-cause treatment discontinuation (RR 1.49, 95% CI 1.30 to 1.71) and drug-related treatment discontinuation (RR 2.30, 95% CI 1.86 to 2.84) with higher incidence of headache, flushing, nausea, diarrhoea and jaw pain. CONCLUSIONS: For WHO-FC II-III PAH patients who have established BT, our study reinforced the recommendation of SCT to improve clinical worsening, functional status, and exercise capacity, although with higher incidence of side-effects and withdrawal.

Pulmonary Arterial Hypertension: Diagnosis, Treatment, and Novel Advances.

The diagnosis and management of pulmonary arterial hypertension (PAH) includes several advances, such as a broader recognition of extrapulmonary vascular organ system involvement, validated point-of-care clinical assessment tools, and focus on the early initiation of multiple pharmacotherapeutics in appropriate patients. Indeed, a principal goal in PAH today is an early diagnosis for prompt initiation of treatment to achieve a minimal symptom burden; optimize the patient's biochemical, hemodynamic, and functional profile; and limit adverse events. To accomplish this end, clinicians must be familiar with novel risk factors and the revised hemodynamic definition for PAH. Fresh insights into the role of developmental biology (i.e., perinatal health) may also be useful for predicting incident PAH in early adulthood. Emergent or underused approaches to PAH management include a novel TGF-ß ligand trap pharmacotherapy, remote pulmonary arterial pressure monitoring, next-generation imaging using inert gas-based magnetic resonance and other technologies, right atrial pacing, and pulmonary arterial denervation. These and other PAH state of the art advances are summarized here for the wider pulmonary medicine community.

Pulmonary hypertension in connective tissue diseases, new evidence and challenges.

Pulmonary arterial hypertension is a lethal complication of different connective tissue diseases such as systemic sclerosis, mixed connective tissue disease and systemic lupus erythematosus. Although the treatment possibilities for patients with pulmonary arterial hypertension have increased in the last two decades and survival of patients with idiopathic pulmonary arterial hypertension has improved, the latter is not the case for patients with pulmonary arterial hypertension associated with connective tissue disease. In this narrative review, we review recent literature and describe the improvement of early diagnostic possibilities, screening modalities and treatment options. We also point out the pitfalls in diagnosis in this patient category and describe the unmet needs and what the focus of future research should be.

Continuous Aerobic Exercise Prevents Detrimental Remodeling and Right Heart Myocyte Contraction and Calcium Cycling Dysfunction in Pulmonary Artery Hypertension.

ABSTRACT: Pulmonary artery hypertension (PAH) imposes right heart and lung detrimental remodeling which impairs cardiac contractility, physical effort tolerance, and survival. The effects of an early moderate-intensity continuous aerobic exercise training on the right ventricle and lung structure, and on contractility and the calcium (Ca2+) transient in isolated myocytes from rats with severe PAH induced by monocrotaline were analyzed. Rats were divided into control sedentary (CS), control exercise (CE), monocrotaline sedentary (MS), and monocrotaline exercise (ME) groups. Animals from control exercise and ME groups underwent a moderate-intensity aerobic exercise on a treadmill (60 min/d; 60% intensity) for 32 days, after a monocrotaline (60 mg/kg body weight i.p.) or saline injection. The pulmonary artery resistance was higher in MS than in control sedentary (1.36-fold) and was reduced by 39.39% in ME compared with MS. Compared with MS, the ME group presented reduced alveolus (17%) and blood vessel (46%) wall, fibrosis (25.37%) and type I collagen content (55.78%), and increased alveolus (52.96%) and blood vessel (146.97%) lumen. In the right ventricle, the ME group exhibited diminished hypertrophy index (25.53%) and type I collagen content (40.42%) and improved myocyte contraction [ie, reduced times to peak (29.27%) and to 50% relax (13.79%)] and intracellular Ca2+ transient [ie, decreased times to peak (16.06%) and to 50% decay (7.41%)] compared with MS. Thus, early moderate-intensity continuous aerobic exercise prevents detrimental remodeling in the right heart and lung increases in the pulmonary artery resistance and dysfunction in single myocyte contraction and Ca2+ cycling in this model.

Aerobic training-mediated DNA hypermethylation of Agtr1a and Mas1 genes ameliorate mesenteric arterial function in spontaneously hypertensive rats.

BACKGROUND: The imbalance of vasoconstrictor and vasodilator axes of the renin-angiotensin system (RAS) is observed in hypertension. Exercise regulates RAS level and improves vascular function. This study focused on the contribution of RAS axes in vascular function of mesenteric arteries and exercise-induced DNA methylation of the Agtr1a (AT1aR) and Mas1 (MasR) genes in hypertension. METHODS: Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats were randomized into exercise or sedentary group. Levels of plasma RAS components, vascular tone, and DNA methylation markers were measured. RESULTS: Blood pressure of SHR was markedly reduced after 12 weeks of aerobic exercise. RAS peptides in plasma were all increased with an imbalanced upregulation of Ang II and Ang-(1-7) in SHR, exercise revised the level of RAS and increased Ang-(1-7)/Ang II. The vasoconstriction response induced by Ang II was mainly via type 1 receptors (AT1R), while this contraction was inhibited by Mas receptor (MasR). mRNA and protein of AT1R and MasR were both upregulated in SHR, whereas exercise significantly suppressed this imbalanced increase and increased MasR/AT1R ratio. Exercise hypermethylated Agtr1a and Mas1 genes, associating with increased DNMT1 and DNMT3b and SAM/SAH. CONCLUSIONS: Aerobic exercise ameliorates vascular function via hypermethylation of the Agtr1a and Mas1 genes and restores the vasoconstrictor and vasodilator axes balance.

Emergency Use of Occlutech® Atrial Flow Regulator Device Facilitates Weaning From Veno-Arterial Extracorporeal Membrane Oxygenation in a Patient With Severe Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a severe and progressive disease. Treatment options include anti-PAH medications, continuous intravenous therapies, and diuretics. Lung transplant is required in many cases. Atrial septostomy is an under recognized option in symptomatic patients on maximal PAH therapy. However, creating a sustainable and restrictive atrial communication is challenging with existing devices. We describe emergency use of the Occlutech® Atrial Flow Regulator, a novel device, in a 35-year-old female with PAH supported on veno-arterial extracorporeal membrane oxygenation after postpartum decompensation.