The Outcome of Patients with Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension during the COVID-19 Pandemic.

BACKGROUND: The coronavirus 2019 (COVID-19) has affected the lives of many people worldwide. Patients with chronic underlying morbidities are vulnerable to get the severe form of the infection. The goal of this study was to evaluate the outcome of patients with pulmonary arterial hypertension during the COVID-19 pandemic in Iran. METHODS: This cross-sectional study was conducted at a large tertiary center for pulmonary artery hypertension (PAH) patients. The primary end point was the prevalence of SARS-CoV-2 infection in PAH patients. The secondary end points were investigating the severity and mortality of COVID-19 infection in PAH patients during the COVID-19 pandemic. RESULTS: Totally 75 patients were enrolled in the study from December 2019 to October 2021 and 64% were female. The mean ± SD age was 49 ± 16 years. The prevalence of COVID-19 in PAH/chronic thromboembolic pulmonary hypertension patients was 44%. About 66.7% of patients had comorbidities, which was a prognostic factor for COVID-19 infection in PAH patients (P < 0.001). Fifty-six percent of infected patients were asymptomatic. The most reported symptoms in symptomatic patients were fever (28%) and malaise (29%). Twelve percent of patients were admitted with severe symptoms. The mortality rate in infected individuals was 3.7%. CONCLUSIONS: COVID-19 infection in PAH/chronic thromboembolic pulmonary hypertension patients seems to be associated with high mortality and morbidity. More scientific proof is needed to clarify different aspect of COVID-19 infection in this population.

Efficacy of Sildenafil in Patients with Severe COVID-19 and Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is common in severe coronavirus disease 2019 (COVID-19) and worsens the prognosis. Sildenafil, a phosphodiesterase-5 inhibitor, is approved for PAH treatment but little is known about its efficacy in cases of severe COVID-19 with PAH. This study aimed to investigate the clinical efficacy of sildenafil in patients with severe COVID-19 and PAH. Intensive care unit (ICU) patients were randomly assigned to receive sildenafil or a placebo, with 75 participants in each group. Sildenafil was administered orally at 0.25 mg/kg t.i.d. for one week in a placebo-controlled, double-blind manner as an add-on therapy alongside the patient's routine treatment. The primary endpoint was one-week mortality, and the secondary endpoints were the one-week intubation rate and duration of ICU stay. The mortality rate was 4% vs. 13.3% (p = 0.078), the intubation rate was 8% and 18.7% (p = 0.09), and the length of ICU stay was 15 vs. 19 days (p < 0.001) for the sildenafil and placebo groups, respectively. If adjusted for PAH, sildenafil treatment significantly reduced mortality and intubation risks: OR = 0.21 (95% CI: 0.05-0.89) and OR = 0.26 (95% CI: 0.08-0.86), respectively. Sildenafil demonstrated some clinical efficacy in patients with severe COVID-19 and PAH and should be considered as an add-on therapy in these patients.

Interaction of Biochemical Processes between Chronic Obstructive Pulmonary Disease (COPD), Pulmonary Arterial Hypertension (PAH), and Coronavirus Disease 2019 (COVID-19).

Both pulmonary arterial hypertension (PAH) and chronic obstructive pulmonary disease (COPD) are risk factors for coronavirus disease 2019 (COVID-19). Patients with lung injury and altered pulmonary vascular anatomy or function are more susceptible to infections. The purpose of the study is to ascertain whether individuals with COPD or PAH are affected synergistically by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Data sources for the construction of a protein-protein interaction (PPI) network and the identification of differentially expressed genes (DEGs) included three RNA-seq datasets from the GEO database (GSE147507, GSE106986, and GSE15197). Then, relationships between miRNAs, common DEGs, and transcription factor (TF) genes were discovered. Functional analysis using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and other databases, as well as the forecasting of antiviral medications for COPD and PAH patients infected with SARS-CoV-2, were also performed. Eleven common DEGs were found in the three datasets, and their biological functions were primarily enriched in the control of protein modification processes, particularly phosphorylation. Growth factor receptor binding reflects molecular function. KEGG analysis indicated that co-DEGs mainly activate Ras, and PI3K-Akt signaling pathways and act on focal adhesions. NFKB1 interacted with HSA-miR-942 in the TF-miRNA-DEGs synergistic regulatory network. Acetaminophen is considered an effective drug candidate. There are some connections between COPD and PAH and the development of COVID-19. This research could aid in developing COVID-19 vaccines and medication candidates that would work well as COVID-19 therapies.

Human Endogenous Retrovirus, SARS-CoV-2, and HIV Promote PAH via Inflammation and Growth Stimulation.

Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease characterized by the progressive elevation of pulmonary arterial pressures. It is becoming increasingly apparent that inflammation contributes to the pathogenesis and progression of PAH. Several viruses are known to cause PAH, such as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), human endogenous retrovirus K(HERV-K), and human immunodeficiency virus (HIV), in part due to acute and chronic inflammation. In this review, we discuss the connections between HERV-K, HIV, SARS-CoV-2, and PAH, to stimulate research regarding new therapeutic options and provide new targets for the treatment of the disease.

Postcardiac injury syndrome caused by radiofrequency catheter ablation of persistent atrial fibrillation: severe pulmonary arterial hypertension with severe tricuspid regurgitation: a rare case report and literature review.

BACKGROUND: Postcardiac injury syndrome (PCIS) is an easy-to-miss diagnosis, but it is not an uncommon complication. The phenomenon of echocardiography (ECHO) showing both severe pulmonary arterial hypertension (PAH) and severe tricuspid regurgitation (TR) is indeed rare in PCIS after extensive radiofrequency ablation. CASE PRESENTATION: A 70-year-old male was diagnosed with persistent atrial fibrillation. The patient received radiofrequency catheter ablation due to his atrial fibrillation being refractory to antiarrhythmic drugs. After the anatomical three-dimensional models were created, ablations were performed on the left and right pulmonary veins, roof linear and bottom linear of the left atrium, and the cavo-tricuspid isthmus. The patient was discharged in sinus rhythm (SR). After 3 days, he was admitted to the hospital for gradually worsening dyspnea. Laboratory examination showed a normal leukocyte count with an increased percentage of neutrophils. The erythrocyte sedimentation rate, C-reactive protein concentration, interleukin-6, and N-terminal pro-B-type natriuretic peptide were elevated. ECG exhibited SR, V1-V4 of precordial lead P-wave amplitude which was increased but not prolonged, PR segment depression, and ST-segment elevation. Computed tomography angiography of the pulmonary artery revealed that the lung had scattered high-density flocculent flakes and a small amount of pleural and pericardial effusion. Local pericardial thickening was seen. ECHO showed severe PAH with severe TR. Diuretics and vasodilators did not relieve the symptoms. Tumors, tuberculosis, and immune system diseases were all excluded. Considering the patient's diagnosis of PCIS, the patient was treated with steroids. The patient recovered on the 19th day post ablation. The patient's condition was maintained until 2 years of follow-up. CONCLUSIONS: The phenomenon of ECHO showing severe PAH with severe TR is indeed rare in PCIS. Due to the lack of diagnostic criteria, such patients are easily misdiagnosed, leading to a poor prognosis.

Outcomes of COVID-19 in patients vaccinated and unvaccinated against SARS-CoV-2 and suffering from pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

INTRODUCTION: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) lead to progressive right heart failure. The mortality rates in PAH and CTEPH patients due to COVID­19 are high, and vaccination against COVID­19 is recommended in this group. OBJECTIVES: We analyzed the incidence and outcomes of COVID­19in the PAH/CTEPH patients for 2 years of the pandemic, as well as the predictors of worse outcomes of COVID­19 in this group. PATIENTS AND METHODS: PAH/CTEPH patient data for this observational, cohort study were obtained from 3 pulmonary hypertension centers between March 11, 2020 and March 11, 2022. RESULTS: A total of 364 consecutive patients with PAH/CTEPH (248/122; 232 women [64%]; median [interquartile range] age, 61 years [18-92]) were included in the study. All the patients had advanced pulmonary hypertension at baseline. Eighty­five patients (23%) suffered from COVID­19. Seven of them (8%), all of whom were unvaccinated, died of COVID­19. The unvaccinated patients suffered from COVID­19 more often than the vaccinated ones (46% vs 9%; P <0.001). As many as 31% of the PAH/CTEPH patients with COVID­19 needed hospitalization, in 8% of cases in the intensive care unit. Age equal to or above 65 years and severe pulmonary hypertension defined as a World Health Organization functional class 3 or 4 were associated with severe COVID­19 in the PAH/CTEPH patients. CONCLUSIONS: The vaccinated PAH/CTEPH patients suffered from COVID­19 less frequently than the unvaccinated ones. The mortality rate and hospitalization due to COVID­19 were higher in the PAH/CTEPH patients than in the general population. All efforts should be made to convince the PAH/CTEPH patients to vaccinate against COVID­19.

Effects of COVID-19 pandemic on the management of pulmonary hypertension.

The coronavirus of 2019 (COVID-19) disrupted delivery of healthcare. Patients with pulmonary hypertension (PH), especially pulmonary arterial hypertension (PAH), require significant resources for both diagnosis and management and are at high risk for decompensation due to disruption in their care. A survey consisting of 47 questions related to the care of patients with PH was designed by the American College of Chest Physicians 2020-2021 Pulmonary Vascular Disease (PVD) NetWork Steering Committee and sent to all members of the PVD NetWork, as well as the multiple other professional networks for PH. Participation was voluntary and anonymous. Responses were collected from November 2020 through February 2021. Ninety-five providers responded to this survey. The majority (93%) believe that care of PH patients has been affected by the pandemic. Sixty-seven percent observed decreased referrals for PH evaluation. Prior to the pandemic, only 15% used telemedicine for management of PH patients compared to 84% during the pandemic. Telemedicine was used most for follow up of selected low-risk patients (49%). While 22% respondents were completely willing to prescribe new PAH therapy via telemedicine, 11% respondents were completely unwilling. Comfort levels differed based on type of medication being prescribed. Over 90% of providers experienced disruptions in obtaining testing and 31% experienced disruptions in renewal or approval of medications. Overall, providers perceived that the COVID-19 pandemic caused significant disruption of care for PH patients. Telemedicine utilization increased but was used mostly in low-risk patients. Some providers had a decreased level of comfort prescribing PAH therapy via telemedicine encounters.

Molecular Pathways in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension is a multifactorial, chronic disease process that leads to pulmonary arterial endothelial dysfunction and smooth muscular hypertrophy, resulting in impaired pliability and hemodynamics of the pulmonary vascular system, and consequent right ventricular dysfunction. Existing treatments target limited pathways with only modest improvement in disease morbidity, and little or no improvement in mortality. Ongoing research has focused on the molecular basis of pulmonary arterial hypertension and is going to be important in the discovery of new treatments and genetic pathways involved. This review focuses on the molecular pathogenesis of pulmonary arterial hypertension.

Chloride channels in the lung: Challenges and perspectives for viral infections, pulmonary arterial hypertension, and cystic fibrosis.

Fine control over chloride homeostasis in the lung is required to maintain membrane excitability, transepithelial transport as well as intra- and extracellular ion and water homeostasis. Over the last decades, a growing number of chloride channels and transporters have been identified in the cells of the pulmonary vasculature and the respiratory tract. The importance of these proteins is underpinned by the fact that impairment of their physiological function is associated with functional dysregulation, structural remodeling, or hereditary diseases of the lung. This paper reviews the field of chloride channels and transporters in the lung and discusses chloride channels in disease processes such as viral infections including SARS-CoV- 2, pulmonary arterial hypertension, cystic fibrosis and asthma. Although chloride channels have become a hot research topic in recent years, remarkably few of them have been targeted by pharmacological agents. As such, we complement the putative pathophysiological role of chloride channels here with a summary of their therapeutic potential.

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.

Physical Activity in Pulmonary Arterial Hypertension during Pandemic COVID-19 and the Potential Impact of Mental Factors.

One of the non-pharmacological recommendations for stable patients with pulmonary arterial hypertension (PAH) is to increase physical activity. The study aimed to analyze the degree of physical activity of PAH patients and check if mental factors may have a potential negative impact during the COVID-19 pandemic. Forty patients with stable PAH were included in the study. Physical activity was assessed by pedometer (Omron HJ-321-E) for four weeks. At baseline, in addition to the 6 min walk test (6MWT) and functional assessment, patients completed the quality-of-life questionnaire SF-36, fear of COVID-19 scale, and hospital anxiety and depression scale (HADS). The mean age of the study group was 45.5 years, 80% were women, and 62.5% had idiopathic/heritable PAH. Low physical activity defined as <5000 steps/day had 19 (47.5%), and moderate/high physical activity (≥5000 steps/day) had 21 (52.5%) patients. Patients with low physical activity less frequently worked compared with the moderate-high-activity sub-group, 42% vs. 81%, p = 0.03, and had the shorter distance in 6-6MWT, p = 0.03. There was no significant correlation between steps/day and different mental factors. Almost half of the study group had low activity during the pandemic. Mental factors did not impact physical activity in PAH patients during the pandemic.

Telehealth: A winning weapon to face the COVID-19 outbreak for patients with pulmonary arterial hypertension.

BACKGROUND: COVID-19 pandemic severely affected national health systems, altering the modality and the type of care of patients with acute and chronic diseases. To minimize the risk of exposure to SARS-CoV2 for patients and health professionals, face-to-face visits were cancelled or postponed and the use of telemedicine was strongly encouraged. This reorganization involved especially patients with rare diseases needing periodic comprehensive assessment, such as pulmonary arterial hypertension (PAH). MAIN BODY: The paper reports a proposal of strategy adopted for patients followed at our PAH center in Rome, where patients management was diversified based on clinical risk according to the European Society of Cardiology/European Respiratory Society PH guidelines-derived score and the REVEAL 2.0 score. A close monitoring and support of these patients were made possible by policy changes reducing barriers to telehealth access and promoting the use of telemedicine. Synchronous/asynchronous modalities and remote monitoring were used to collect and transfer medical data in order to guide physicians in therapeutic-decision making. Conversely, the use of implantable monitors providing hemodynamic information and echocardiography-mobile devices wirelessly connecting was limited by the poor experience existing in this setting. Large surveys and clinical trials are welcome to test the potential benefit of the optimal balance between traditional PAH management and telemedicine opportunities. CONCLUSION: Italy was found unprepared to manage the dramatic effects caused by COVID-19 on healthcare systems. In this emergency situation telemedicine represented a promising tool especially in rare diseases as PAH, but was limited by its scattered availability and legal and ethical issues. Cohesive partnership of health care providers with regional public health officials is needed to prioritize PAH patients for telemedicine by dedicated tools.

COVID-19 in Patients with Pulmonary Hypertension: A National Prospective Cohort Study.

Rationale: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with pulmonary endothelial dysfunction. There are limited data available on the outcomes of coronavirus disease (COVID-19) in patients with pulmonary hypertension (PH), a disease characterized by pulmonary endothelial dysfunction. Objectives: To describe characteristics and outcomes of patients with precapillary PH and COVID-19. Methods: We prospectively collected characteristics, management, and outcomes of adult patients with precapillary PH in the French PH network who had COVID-19 between February 1, 2020, and April 30, 2021. Clinical, functional, and hemodynamic characteristics of PH before COVID-19 were collected from the French PH registry. Measurements and Main Results: A total of 211 patients with PH (including 123 with pulmonary arterial hypertension, 47 with chronic thromboembolic PH, and 41 with other types of PH) experienced COVID-19, and 40.3% of them were outpatients, 32.2% were hospitalized in a conventional ward, and 27.5% were in an ICU. Among hospitalized patients (n = 126), 54.0% received corticosteroids, 37.3% high-flow oxygen, and 11.1% invasive ventilation. Right ventricular and acute renal failure occurred in 30.2% and 19.8% of patients, respectively. Fifty-two patients (all hospitalized) died from COVID-19. Overall mortality was 24.6% (95% CI [confidence interval], 18.8-30.5) and in-hospital mortality 41.3% (95% CI, 32.7-49.9). Nonsurvivors were significantly older, more frequently male and suffering comorbidities (diabetes, chronic respiratory diseases, systemic hypertension, chronic cardiac diseases, and/or chronic renal failure), and had more severe PH at their most recent evaluation preceding COVID-19 diagnosis (in terms of functional class and 6-minute-walk distance; all P < 0.05). Use of pulmonary arterial hypertension therapy was similar between survivors and nonsurvivors. Conclusions: COVID-19 in patients with precapillary PH was associated with a high in-hospital mortality. The typical risk factors for severe COVID-19 and severity of PH were associated with mortality in this population.

The paradox of pulmonary arterial hypertension in Italy in the COVID-19 era: is risk of disease progression around the corner?

OBJECTIVE: The coronavirus disease 2019 (COVID-19) outbreak has led to significant restrictions on routine medical care. We conducted a multicentre nationwide survey of patients with pulmonary arterial hypertension (PAH) to determine the consequences of governance measures on PAH management and risk of poor outcome in patients with COVID-19. MATERIALS AND METHODS: The present study, which included 25 Italian centres, considered demographic data, the number of in-person visits, 6-min walk and echocardiographic test results, brain natriuretic peptide/N-terminal pro-brain natriuretic peptide test results, World Health Organization functional class assessment, presence of elective and non-elective hospitalisation, need for treatment escalation/initiation, newly diagnosed PAH, incidence of COVID-19 and mortality rates. Data were collected, double-checked and tracked by institutional records between March 1 and May 1, 2020, to coincide with the first peak of COVID-19 and compared with the same time period in 2019. RESULTS: Among 1922 PAH patients, the incidences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 were 1.0% and 0.46%, respectively, with the latter comparable to that in the overall Italian population (0.34%) but associated with 100% mortality. Less systematic activities were converted into more effective remote interfacing between clinicians and PAH patients, resulting in lower rates of hospitalisation (1.2% versus 1.9%) and related death (0.3% versus 0.5%) compared with 2019 (p<0.001). A high level of attention is needed to avoid the potential risk of disease progression related to less aggressive escalation of treatment and the reduction in new PAH diagnoses compared with 2019. CONCLUSION: A cohesive partnership between healthcare providers and regional public health officials is needed to prioritise PAH patients for remote monitoring by dedicated tools.

Oral treprostinil improves pulmonary vascular compliance in pulmonary arterial hypertension.

Oral treprostinil has been shown to improve exercise capacity and delay disease progression in patients with pulmonary arterial hypertension (PAH), but its effects on hemodynamics are not well-characterized. The FREEDOM-EV trial was a Phase III, international, placebo-controlled, double-blind, event-driven study in 690 participants with PAH who were taking a single oral PAH therapy. FREEDOM-EV demonstrated a significantly reduced risk for clinical worsening with oral treprostinil taken three times daily and did not uncover new safety signals in PAH patients. Sixty-one participants in the FREEDOM-EV trial volunteered for a hemodynamics sub-study. Pulmonary artery compliance (PAC), a ratio of stroke volume to pulmonary pulse pressure, significantly increased from Baseline to Week 24 in the oral treprostinil group compared with the placebo group (geometric mean 26.4% active vs. -6.0% placebo; ANCOVA p=0.007). There was a significant increase in cardiac output in the oral treprostinil group compared to the placebo group (geometric mean 11.3% active vs. -6.4% placebo; ANCOVA p=0.005) and a corresponding significant reduction in pulmonary vascular resistance (PVR) (geometric mean -21.5 active vs. -1.8% placebo; ANCOVA p=0.02) from Baseline to Week 24. These data suggest that increased compliance contributes to the physiological mechanism by which oral treprostinil improves exercise capacity and delays clinical worsening for patients with PAH.

Case report of mild form of a new coronavirus infection in patient with idiopathic pulmonary hypertension.

The article presents a clinical case of mild novel coronavirus infection COVID-19 complicated with bilateral interstitial pneumonia in a female patient with idiopathic pulmonary hypertension.

Potential therapeutic effect of glucagon-like peptide-1 receptor agonists on COVID-19-induced pulmonary arterial hypertension.

Coronavirus disease 2019 (COVID-19) is an infectious diseases caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Now, it is pandemic over the world. SARS-CoV-2 often causes a "cytokine storm" in people with COVID-19, causing inflammatory lung damage and pneumonia, which eventually leads to death. Glucagon like peptide-1 (GLP-1) is well known as an incretin hormone responsible for regulation of blood glucose through its receptor. Beyond glycemic control, GLP-1 receptor agonists (GLP-1RAs) have promising anti-inflammatory actions in human and rodent pathological models. Recent studies proved that GLP-1RAs attenuate pulmonary inflammation, reduce cytokine production, and preserve lung function in mice and rats with experimental lung injury. Moreover, a thickened pulmonary vascular wall, an important characteristic of pulmonary arterial hypertension (PAH) was observed in the autopsy lung tissue of a COVID-19 patient. Thus GLP-1RAs may be a novel therapeutic strategy for combating this pandemic specifically for patient characteristics of PHA after COVID-19 infection.