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.

gp120 Envelope Glycoproteins of HIV-1 Group M Subtype A and Subtype B Differentially Affect Gene Expression in Human Vascular Endothelial Cells.

Cardiovascular complications are seen among human immunodeficiency virus (HIV)-positive individuals, who now survive longer due to successful antiretroviral therapies. Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased blood pressure in the lung circulation. The prevalence of PAH in the HIV-positive population is dramatically higher than that in the general population. While HIV-1 Group M Subtype B is the most prevalent subtype in western countries, the majority of HIV-1 infections in eastern Africa and former Soviet Union countries are caused by Subtype A. Research on vascular complications in the HIV-positive population in the context of subtype differences, however, has not been rigorous. Much of the research on HIV has focused on Subtype B, and information on the mechanisms of Subtype A is nonexistent. The lack of such knowledge results in health disparities in the development of therapeutic strategies to prevent/treat HIV complications. The present study examined the effects of HIV-1 gp120 of Subtypes A and B on human pulmonary artery endothelial cells by performing protein arrays. We found that the gene expression changes caused by gp120s of Subtypes A and B are different. Subtype A is a more potent downregulator of perostasin, matrix metalloproteinase-2, and ErbB than Subtype B, while Subtype B is more effective in downregulating monocyte chemotactic protein-2 (MCP-2), MCP-3, and thymus- and activation-regulated chemokine proteins. This is the first report of gp120 proteins affecting host cells in an HIV subtype-specific manner, opening up the possibility that complications occur differently in HIV patients throughout the world.

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.

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.

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.

Novel Mechanisms Targeted by Drug Trials in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a rare disease associated with abnormally elevated pulmonary pressures and right heart failure resulting in high morbidity and mortality. Although the prognosis for patients with PAH has improved with the introduction of pulmonary vasodilators, disease progression remains a major problem. Given that available therapies are inadequate for preventing small-vessel loss and obstruction, there is active interest in identifying drugs capable of targeting angiogenesis and mechanisms involved in the regulation of cell growth and fibrosis. Among the mechanisms linked to PAH pathogenesis, preclinical studies have identified promising compounds that are currently being tested in clinical trials. These drugs target seven of the major mechanisms associated with PAH pathogenesis: bone morphogenetic protein signaling, tyrosine kinase receptors, estrogen metabolism, extracellular matrix, angiogenesis, epigenetics, and serotonin metabolism. In this review, we discuss the preclinical studies that led to prioritization of these mechanisms, and discuss completed and ongoing phase 2/3 trials using novel interventions such as sotatercept, anastrozole, rodatristat ethyl, tyrosine kinase inhibitors, and endothelial progenitor cells, among others. We anticipate that the next generation of compounds will build on the success of the current standard of care and improve clinical outcomes and quality of life for patients with PAH.

[Pulmonary arterial hypertension: achievements and realities of modern treatment, a look into the future].

The paper summarizes the most important aspects of modern treatment of patients with pulmonary arterial hypertension (PAH): the goals of therapy are indicated, the issues of risk stratification of PAH progression/mortality, the place of combination specific therapy and switching strategies are considered, as well as new promising approaches to therapy; features of the course of the new coronavirus infection COVID-19 in this category of patients are discussed.

Dysbalance of ACE2 levels - a possible cause for severe COVID-19 outcome in COPD.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to healthcare systems worldwide. Binding of the virus to angiotensin-converting enzyme 2 (ACE2) is an important step in the infection mechanism. However, it is unknown if ACE2 expression in patients with chronic lung diseases (CLDs), such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary arterial hypertension (IPAH), or pulmonary fibrosis (PF), is changed as compared to controls. We used lung samples from patients with COPD (n = 28), IPAH (n = 10), and PF (n = 10) as well as healthy control donor (n = 10) tissue samples to investigate the expression of ACE2 and related cofactors that might influence the course of SARS-CoV-2 infection. Expression levels of the ACE2 receptor, the putative receptor CD147/BSG, and the viral entry cofactors TMPRSS2 (transmembrane serine protease 2), EZR, and FURIN were determined by quantitative PCR and in open-access RNA sequencing datasets. Immunohistochemical and single-cell RNA sequencing (scRNAseq) analyses were used for localization and coexpression, respectively. Soluble ACE2 (sACE2) plasma levels were analyzed by enzyme-linked immunosorbent assay. In COPD as compared to donor, IPAH, and PF lung tissue, gene expression of ACE2, TMPRSS2, and EZR was significantly elevated, but circulating sACE2 levels were significantly reduced in COPD and PF plasma compared to healthy control and IPAH plasma samples. Lung tissue expressions of FURIN and CD147/BSG were downregulated in COPD. None of these changes were associated with changes in pulmonary hemodynamics. Histological analysis revealed coexpression of ACE2, TMPRSS2, and Ezrin in bronchial regions and epithelial cells. This was confirmed by scRNAseq analysis. There were no significant expression changes of the analyzed molecules in the lung tissue of IPAH and idiopathic PF as compared to control. In conclusion, we reveal increased ACE2 and TMPRSS2 expression in lung tissue with a concomitant decrease of protective sACE2 in COPD patients. These changes represent the possible risk factors for an increased susceptibility of COPD patients to SARS-CoV-2 infection.

Pulmonary Hemodynamics and Ventilation in Patients With COVID-19-related Respiratory Failure and ARDS (preprint)

Background: It has been suggested that COVID-19-associated severe respiratory failure (CARDS) might differ from usual acute respiratory distress syndrome (ARDS) due to failing auto-regulation of pulmonary vessels and higher shunt. We sought to investigate pulmonary hemodynamics and ventilation properties in patients with CARDS compared to patients with ARDS of pulmonary origin. Methods: Retrospective analysis of prospectively collected data of consecutive adults with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 patients treated on our ICU in 04/2020 and comparison of the data to matched controls with ARDS due to respiratory infections treated on our ICU from 01/2014 to 08/2019 and for whom pulmonary artery catheter data were available. Results: CARDS patients (n = 10) had similar ventilation characteristics as compared to ARDS (n = 10) patients. Still, mechanical power applied by ventilation was significantly higher in CARDS patients (23.4 ± 8.9 J/min) than in ARDS (15.9 ± 4.3 J/min; p<0.05). COVID-19 patients had similar pulmonary artery pressure but significantly lower pulmonary vascular resistance, as cardiac output was higher in CARDS vs. ARDS patients (p<0.05). Shunt fraction and dead space were similar in CARDS compared to ARDS (p>0.05) and was in both groups correlated with hypoxemia. The arterio-venous pCO2 difference (DpCO2) was elevated (CARDS 5.5±2.8 mmHg vs. ARDS 4.7±1.1 mmHg; p>0.05) as was P(v-a)CO2/C(a-v)O2 ratio (CARDS mean 2.2±1.5 vs. ARDS 1.7±0.8; p>0.05). Conclusions: Respiratory failure in COVID-19 patients seems to differ only slightly from ARDS regarding ventilation characteristics and pulmonary hemodynamics. Differences are mainly due to increased CO2 production in CARDS patients. Our data indicate microcirculatory dysfunction. More data needs to be collected to assure these findings and gain more pathophysiological insights in COVID-19 and respiratory failure.