Sanjay Mehta

PH is most commonly due to underlying diseases of the left side of the heart (WHO group 2 PH) and respiratory conditions characterised by hypoxaemia (WHO group 3 PH), cumulatively comprising about 90% of PH cases globally. WHO group 1 pulmonary arterial hypertension (PAH) and group 4 PH due to pulmonary arterial obstruction are uncommon, each being diagnosed in less than 5% of all patients with PH. However, they are a major focus of clinical PH diagnostic assessment as there are specific treatment approaches for patients in both groups. In WHO group 4, the most common and important condition chronic thromboembolic PH (CTEPH) is often curable; thus, all patients with significant PH should be rigorously assessed for possible CTEPH through pulmonary vascular imaging. WHO group 1 PAH is a disease specifically of the pulmonary circulation, sometimes related to underlying conditions and exposures (eg, connective …

Sepsis is a life-threatening disease characterized by excessive inflammation leading to organ dysfunction. During sepsis, pulmonary microvascular endothelial cells (PMVEC) lose barrier function associated with inter-PMVEC junction disruption. Matrix metalloproteinases (MMP) and a disintegrin and metalloproteinases (ADAM), which are regulated by tissue inhibitors of metalloproteinases (TIMPs), can cleave cell–cell junctional proteins, suggesting a role in PMVEC barrier dysfunction. We hypothesize that septic PMVEC barrier dysfunction is due to a disruption in the balance between PMVEC-specific metalloproteinases and TIMPs leading to increased metalloproteinase activity. The effects of sepsis on TIMPs and metalloproteinases were assessed ex vivo in PMVEC from healthy (sham) and septic (cecal ligation and perforation) mice, as well as in vitro in isolated PMVEC stimulated with cytomix, lipopolysaccharide (LPS), and cytomix + LPS vs. PBS. PMVEC had high basal Timp expression and lower metalloproteinase expression, and septic stimulation shifted expression in favour of metalloproteinases. Septic stimulation increased MMP13 and ADAM17 activity associated with a loss of inter-PMVEC junctional proteins and barrier dysfunction, which was rescued by treatment with metalloproteinase inhibitors. Collectively, our studies support a role for metalloproteinase–TIMP imbalance in septic PMVEC barrier dysfunction, and suggest that inhibition of specific metalloproteinases may be a therapeutic avenue for septic patients.

Background: There is no consensus on the most effective treatments of pulmonary arterial hypertension (PAH). Our objective was to compare effects of medications for PAH.Methods: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials andClinicaltrials.govfrom inception to December 2021. We performed a frequentist random-effects network meta-analysis on all included trials. We rated the certainty of the evidence using the Grades of Recommendation, Assessment, Development, and Evaluation approach.Results: We included 53 randomised controlled trials with 10 670 patients. Combination therapy with endothelin receptor antagonist (ERA) plus phosphodiesterase-5 inhibitors (PDE5i) reduced clinical worsening (120.7 fewer events per 1000, 95% CI 136.8–93.4 fewer; high certainty) and was superior to either ERA or PDE5i alone, both of which reduced clinical worsening, as did riociguat monotherapy (all high certainty). PDE5i (24.9 fewer deaths per 1000, 95% CI 35.2 fewer to 2.1 more); intravenous/subcutaneous prostanoids (18.3 fewer deaths per 1000, 95% CI 28.6 fewer deaths to 0) and riociguat (29.1 fewer deaths per 1000, 95% CI 38.6 fewer to 8.7 more) probably reduce mortality as compared to placebo (all moderate certainty). Combination therapy with ERA+PDE5i (49.9 m, 95% CI 25.9–73.8 m) and riociguat (49.5 m, 95% CI 17.3–81.7 m) probably increase 6-min walk distance as compared to placebo (moderate certainty).Conclusion: Current PAH treatments improve clinically important outcomes, although the degree and certainty of benefit vary between treatments.

Chronic obstructive pulmonary disease-associated pulmonary hypertension (COPD-PH) is an increasingly recognised condition which contributes to worsening dyspnea and poor survival in COPD. It is uncertain whether specific treatment of COPD-PH, including use of medications approved for pulmonary arterial hypertension (PAH), improves clinical outcomes. This systematic review and meta-analysis assesses potential benefits and risks of therapeutic options COPD-PH. We searched Medline and Embase for relevant publications until Sep 2020. Articles were screened for studies on treatment of COPD-PH for at least 4 weeks in 10 or more patients. Screening, data extraction, and risk of bias assessment were performed independently in duplicate. When possible, relevant results were pooled using the random effects model. Supplemental long-term O₂ therapy (LTOT) mildly reduced mean pulmonary artery pressure (PAP), slowed progression of PH, and reduced mortality, but other clinical or functional benefits were not assessed. Phosphodiesterase type-5 inhibitors significantly improved systolic PAP (pooled treatment effect −5.9 mmHg; 95%CI −10.3, −1.6), but had inconsistent clinical benefits. Calcium-channel blockers and endothelin receptor antagonists had limited hemodynamic, clinical, or survival benefits. Statins had limited clinical benefits despite significantly lowering systolic PAP (pooled treatment effect −4.6 mmHg; 95% CI: −6.3, −2.9). This review supports guideline recommendations for LTOT in hypoxemic COPD-PH patients as well as recommendations against treatment with PAH-targeted medications, Effective treatment of COPD-PH depends upon research into the pathobiology, and future high-quality studies comprehensively assessing clinically relevant outcomes are needed.

Acute respiratory distress syndrome (ARDS) remains a serious illness with significant morbidity and mortality, characterized by hypoxemic respiratory failure most commonly due to pneumonia, sepsis, and aspiration. Early and accurate diagnosis of ARDS depends upon clinical suspicion and chest imaging. Coronavirus disease 2019 (COVID-19) is an important novel cause of ARDS with a distinct time course, imaging and laboratory features from the time of SARS-CoV-2 infection to hypoxemic respiratory failure, which may allow diagnosis and management prior to or at earlier stages of ARDS. Treatment of ARDS remains largely supportive, and consists of incremental respiratory support (high flow nasal oxygen, non-invasive respiratory support, and invasive mechanical ventilation), and avoidance of iatrogenic complications, all of which improve clinical outcomes. COVID-19-associated ARDS is largely similar to other causes of ARDS with respect to pathology and respiratory physiology, and as such, COVID-19 patients with hypoxemic respiratory failure should typically be managed as other patients with ARDS. Non-invasive respiratory support may be beneficial in avoiding intubation in COVID-19 respiratory failure including mild ARDS, especially under conditions of resource constraints or to avoid overwhelming critical care resources. Compared to other causes of ARDS, medical therapies may improve outcomes in COVID-19-associated ARDS, such as dexamethasone and remdesivir. Future improved clinical outcomes in ARDS of all causes depends upon individual patient physiological and biological endotyping in order to improve accuracy and timeliness of diagnosis as well as optimal targeting of future therapies in the right patient at the right time in their disease.

Objective: Sepsis is associated with dysfunction of MVEC resulting in organ edema and inflammation. VE‐cadherin, a component of MVEC adherens junctions, may be disrupted in sepsis. However, the direct connection between individual MVEC VE‐cadherin disruption and increased paracellular permeability is uncertain.Methods: Human pulmonary MVEC were cultured on a biotin matrix and treated with cytomix, as a model of sepsis, vs PBS. MVEC permeability was assessed by trans‐MVEC monolayer leak of Oregon green 488‐conjugated avidin, which bound subcellular biotin to localize sites of paracellular leak. Leak was correlated with individual cell‐specific MVEC surface VE‐cadherin continuity by fluorescence microscopy.Results: Cytomix treatment reduced total MVEC VE‐cadherin density, disrupted surface VE‐cadherin continuity, was associated with intercellular gap formation, and enhanced paracellular avidin leak. Cytomix‐induced MVEC paracellular avidin leak was strongly correlated temporally and was highly contiguous with focal MVEC surface VE‐cadherin disruption. Total cellular VE‐cadherin density was less strongly correlated with MVEC paracellular avidin leak and individual cell‐specific focal surface VE‐cadherin discontinuity.Conclusions: These data support a mechanistic link between septic human lung MVEC VE‐cadherin disruption and contiguous paracellular protein leak, and will permit more detailed assessment of individual cell‐specific mechanisms of septic MVEC barrier dysfunction.