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Background: Glucagon-like peptide-1 (GLP-1) agonists are an existing treatment option for patients with insulin-resistant states, which elicit further pleiotropic effects related to immune cell recruitment and vascular inflammation. GLP-1 agonists downregulate the cluster of differentiation 147 (CD147) receptor, one of several receptors for the SARS-CoV-2 spike protein that mediate viral infection of host cells. Methods: We conducted an open-label prospective safety and tolerability study including biomarker responses of the GLP-1 agonist Liraglutide, administered for 5 days as an add-on therapy to the standard of care within 48 h of presentation in a cohort of 13 patients hospitalized with COVID-19 pneumonia. Biomarker responses were compared in patients admitted to critical care and those not requiring critical care admission (non-critical group). Results: Liraglutide (0.6 mg, subcutaneously) was well tolerated by all patients and all patients were alive 30 days after diagnosis. Plasma soluble CD147 levels were reduced in the non-critical patient group at day 5 in contrast to critical care-treated patients, who demonstrated an increase in soluble CD147 levels between day 0 and day 5. Patients with milder COVID-19 pneumonia severity also demonstrated improvement in echocardiographic parameters of right and left ventricular function, reduction in plasma Troponin levels, increased CD147 expression on T lymphocytes, and reduction in plasma IL-8. Conclusions: This first-in-disease use of the GLP-1 agonist Liraglutide demonstrates its safety and tolerability in an unselected cohort of patients hospitalized with COVID-19 pneumonia across a range of clinical severities.

BackgroundData on right ventricular (RV) exercise adaptation following acute intermediate and high-risk pulmonary embolism (PE) remain limited. This study aimed to evaluate the symptom burden, RV functional recovery during exercise and cardiopulmonary exercise parameters in survivors of intermediate and high-risk acute PE.MethodsWe prospectively recruited patients following acute intermediate and high-risk PE at four sites in Australia and UK. Study assessments included stress echocardiography, cardiopulmonary exercise testing (CPET) and ventilation–perfusion (VQ) scan at 3 months follow-up.ResultsThirty patients were recruited and 24 (median age: 55 years, IQR: 22) completed follow-up. Reduced peak oxygen consumption (VO2) and workload was seen in 75.0% (n=18), with a persistent high symptom burden (mean PEmb-QoL Questionnaire 48.4±21.5 and emPHasis-10 score 22.4±8.8) reported at follow-up. All had improvement in RV-focused resting echocardiographic parameters. RV systolic dysfunction and RV to pulmonary artery (PA) uncoupling assessed by stress echocardiography was seen in 29.2% (n=7) patients and associated with increased ventilatory inefficiency (V̇E/V̇CO2 slope 47.6 vs 32.4, p=0.03), peak exercise oxygen desaturation (93.2% vs 98.4%, p=0.01) and reduced peak oxygen pulse (p=0.036) compared with controls. Five out of seven patients with RV–PA uncoupling demonstrated persistent bilateral perfusion defects on VQ scintigraphy consistent with chronic thromboembolic pulmonary vascular disease.ConclusionIn our cohort, impaired RV adaptation on exercise was seen in almost one-third of patients. Combined stress echocardiography and CPET may enable more accurate phenotyping of patients with persistent symptoms following acute PE to allow timely detection of long-term complications.

Myocardial failure has a central role in the complex pathophysiology of septic shock and contributes to organ failure and death. During the sepsis-induced inflammatory process, specific factors are released that depress myocardial contractile function. We aimed to identify these mediators of myocardial depression in meningococcal septic shock. We combined gene-expression profiling with protein and cellular methods to identify a serum factor causing cardiac dysfunction in meningococcal septic shock. We identified genes that were significantly upregulated in blood after exposure to meningococci. We then selected for further analysis those genes whose protein products had properties of a myocardial depressant factor—specifically a 12–25 kDa heat-stable protein that is released into serum shortly after onset of meningococcal infection. We identified 174 significantly upregulated genes in meningococcus-infected blood: six encoded proteins that were of the predicted size and had characteristics of a myocardial depressant factor. Of these, interleukin 6 caused significant myocardial depression in vitro. Removal of interleukin 6 from serum samples of patients with meningococcaemia and from supernatants of inflammatory cells stimulated by meningococci in vitro abolished the negative inotropic activity. Furthermore, concentrations in serum of interleukin 6 strongly predicted degree of myocardial dysfunction and severity of disease in children with meningococcal septic shock. Interleukin 6 is a mediator of myocardial depression in meningococcal disease. This cytokine and its downstream mediators could be a target for future treatment strategies.

Effects of continuous positive airway pressure (CPAP) on right ventricular (RV) function in patients with untreated mild‐to‐moderate obstructive sleep apnea (OSA) are unclear. In this exploratory analysis of cardiac magnetic resonance (CMR)‐derived indices of RV function in patients with minimally symptomatic OSA from the MOSAIC randomized control trial we found no effect of CPAP on RV CMR parameters. In those with lower RV ejection fraction and higher RV end‐diastolic volume (EDV) at baseline, CPAP treatment appeared to improve RV function with a significant reduction in both RV EDV and RV end‐systolic volume although between‐group effects were not observed. These data suggest potential merit in a larger randomized study of CPAP in patients with mild‐to‐moderate OSA and a greater breadth of RV dysfunction.

IntroductionParticipating in singing is considered to have a range of social and psychological benefits. However, the physiological demands of singing and its intensity as a physical activity are not well understood.MethodsWe compared cardiorespiratory parameters while completing components of Singing for Lung Health sessions, with treadmill walking at differing speeds (2, 4 and 6 km/hour).ResultsEight healthy adults were included, none of whom reported regular participation in formal singing activities. Singing induced acute physiological responses that were consistent with moderate intensity activity (metabolic equivalents: median 4.12, IQR 2.72–4.78), with oxygen consumption, heart rate and volume per breath above those seen walking at 4 km/hour. Minute ventilation was higher during singing (median 22.42 L/min, IQR 16.83–30.54) than at rest (11 L/min, 9–13), lower than 6 km/hour walking (30.35 L/min, 26.94–41.11), but not statistically different from 2 km/hour (18.77 L/min, 16.89–21.35) or 4 km/hour (23.27 L/min, 20.09–26.37) walking.ConclusionsOur findings suggest the acute metabolic demands of singing are comparable with walking at a moderately brisk pace, hence, physical effects may contribute to the health and well-being benefits attributed to singing participation. However, if physical training benefits result remains uncertain. Further research including different singing styles, singers and physical performance impacts when used as a training modality is encouraged.Trial registration numberClinicalTrials.gov registry (NCT04121351).

Approved therapies for the treatment of patients with pulmonary arterial hypertension (PAH) mediate pulmonary vascular vasodilatation by targeting distinct biological pathways. International guidelines recommend that patients with an inadequate response to dual therapy with a phosphodiesterase type‐5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), are recommended to either intensify oral therapy by adding a selective prostacyclin receptor (IP) agonist (selexipag), or switching from PDE5i to a soluble guanylate‐cyclase stimulator (sGCS; riociguat). The clinical equipoise between these therapeutic choices provides the opportunity for evaluation of individualized therapeutic effects. Traditionally, invasive/hospital‐based investigations are required to comprehensively assess disease severity and demonstrate treatment benefits. Regulatory‐approved, minimally invasive monitors enable equivalent measurements to be obtained while patients are at home. In this 2 × 2 randomized crossover trial, patients with PAH established on guideline‐recommended dual therapy and implanted with CardioMEMS™ (a wireless pulmonary artery sensor) and ConfirmRx™ (an insertable cardiac rhythm monitor), will receive ERA + sGCS, or PDEi + ERA + IP agonist. The study will evaluate clinical efficacy via established clinical investigations and remote monitoring technologies, with remote data relayed through regulatory‐approved online clinical portals. The primary aim will be the change in right ventricular systolic volume measured by magnetic resonance imaging (MRI) from baseline to maximal tolerated dose with each therapy. Using data from MRI and other outcomes, including hemodynamics, physical activity, physiological measurements, quality of life, and side effect reporting, we will determine whether remote technology facilitates early evaluation of clinical efficacy, and investigate intra‐patient efficacy of the two treatment approaches.

Acute respiratory distress syndrome in patients with Coronavirus disease 19 is associated with an unusually high incidence of pulmonary embolism and microthrombotic disease, with evidence for reduced fibrinolysis. We describe seven patients requiring invasive ventilation for COVID-19-associated acute respiratory distress syndrome with pulmonary thromboembolic disease, pulmonary hypertension ± severe right ventricular dysfunction on echocardiography, who were treated with alteplase as fibrinolytic therapy. All patients were non-smokers, six (86%) were male and median age was 56.7 (50–64) years. They had failed approaches including therapeutic anticoagulation, prone ventilation (n = 4), inhaled nitric oxide (n = 5) and nebulised epoprostenol (n = 2). The median duration of mechanical ventilation prior to thrombolysis was seven (5–11) days. Systemic alteplase was administered to six patients (50 mg or 90 mg bolus over 120 min) at 16 (10–22) days after symptom onset. All received therapeutic heparin pre- and post-thrombolysis, without intracranial haemorrhage or other major bleeding. Alteplase improved PaO2/FiO2 ratio (from 97.0 (86.3–118.6) to 135.6 (100.7–171.4), p = 0.03) and ventilatory ratio (from 2.76 (2.09–3.49) to 2.36 (1.82–3.05), p = 0.011) at 24 h. Echocardiographic parameters at two (1–3) days (n = 6) showed right ventricular systolic pressure (RVSP) was 63 (50.3–75) then 57 (49–66) mmHg post-thrombolysis (p = 0.26), tricuspid annular planar systolic excursion (TAPSE) was unchanged (from 18.3 (11.9–24.5) to 20.5 (15.4–24.2) mm, p = 0.56) and right ventricular fractional area change (from 15.4 (11.1–35.6) to 31.2 (16.4–33.1)%, p = 0.09). At seven (1–13) days after thrombolysis, using dual energy computed tomography imaging (n = 3), average relative peripheral lung enhancement increased from 12.6 to 21.6% (p = 0.06). In conclusion, thrombolysis improved PaO2/FiO2 ratio and ventilatory ratio at 24 h as rescue therapy in patients with right ventricular dysfunction due to COVID-19-associated ARDS despite maximum therapy, as part of a multimodal approach, and warrants further study.

IntroductionPulmonary hypertension (PH) is a rare pathophysiological disorder associated with many other medical conditions. Diagnosis of PH can be particularly complex when these associated conditions include rare infections such as Whipple’s disease. Here, we present the case of a woman initially diagnosed with sarcoidosis, who later developed severe PH and was subsequently found to have Whipple’s disease.1 2 CaseA 43-year-old woman presented with anaemia and generalised lymphadenopathy. A lymph node biopsy revealed non-necrotising granulomatous inflammation which led to an initial diagnosis of sarcoidosis. Treatment with corticosteroids was commenced. During routine cardiac evaluation, echocardiography showed severe pulmonary hypertension (pulmonary artery systolic pressure (PASP) 80 mmHg with right ventricular dysfunction). Right heart catheterisation confirmed pre-capillary PH with a mean pulmonary artery pressure (mPAP) of 29 mmHg and normal wedge pressure. She was diagnosed as having PH associated with sarcoidosis and started on sildenafil. However, the patient developed persistent diarrhoea, a known side effect of sildenafil, which prompted a switch to tadalafil. Despite this, gastrointestinal symptoms persisted. Extensive investigations, including endoscopy and duodenal biopsy, unexpectedly led to the diagnosis of Whipple’s disease. She was treated with intravenous ceftriaxone for two weeks, followed by 12 months of co-trimoxazole therapy. Following the initiation of antibiotic therapy, the patient’s gastrointestinal symptoms improved significantly. Her diarrhoea resolved, and weight gain was noted. After 12 months of co-trimoxazole, a repeat echocardiogram demonstrated a reduction in PASP to 42 mmHg, with normal function of the right ventricle. This clinical improvement supported the hypothesis that the resolution of PH was, at least partly, related to the effective treatment of Whipple’s disease.3 4 DiscussionWhipple’s disease is a rare systemic infection caused by Tropheryma whipplei, with the gastrointestinal system being most affected, patients presenting with diarrhoea, malabsorption, and weight loss. Though Whipple’s disease is primarily a gastrointestinal disease, it can involve multiple organs, including the cardiovascular system. Whipple’s disease has been rarely reported as a cause of PH.5 The exact mechanisms linking Whipple’s disease to PH remain unclear. One theory posits that the accumulation of periodic acid-Schiff (PAS)-positive macrophages within the pulmonary vasculature may increase pulmonary vascular resistance, thus contributing to the development of PH (figure 1). Moreover, the reversibility of PH upon appropriate antibiotic treatment lends support to a direct association between the two conditions.6 7 The diagnosis of PH in this patient was initially confounded by the suspicion of sarcoidosis, another cause of PH, and the side effects of sildenafil. This case demonstrates the diagnostic complexity of PH complicating many systemic diseases and the importance of considering rare infectious causes such as Whipple’s disease when gastrointestinal symptoms remain unexplained. A further learning point is that PH associated with Whipple’s disease can improve with antibiotic therapy, reinforcing the need for early correct diagnosis and treatment.Abstract 7-043 Figure 1Periodic Acid-Schiff (PAS) positive staining in macrophages[Image Omitted. See PDF.]ReferencesMcGinnis SW, Simms JR. Pulmonary hypertension associated with sarcoidosis: Clinical implications and management strategies. Chest. 2018;153(3):630–639. doi: 10.1016/j.chest.2017.11.050.Smoot JM, Alvarado LR. The role of pulmonary hypertension in systemic diseases: Review of mechanisms and management. J Clin Med. 2020;9(3):775. doi: 10.3390/jcm9030775.Dostal CL, Kollef MH. Tadalafil and ambrisentan for the treatment of pulmonary hypertension. Am J Respir Crit Care Med. 2018;198(9):1157–1168. doi: 10.1164/rccm.201804-0715OC.Soler M, González J, Díaz M, et al. Resolution of pulmonary hypertension with antibiotic therapy in Whipple's disease: A case series. Eur Respir J. 2017;50(6):1700876. doi: 10.1183/13993003.00876-2017.Desnues B, Al Moussawi K, Fenollar F. New insights into Whipple's disease and Tropheryma whipplei infections. Microbes Infect. 2010 Dec;12(14–15):1102–10. doi: 10.1016/j.micinf.2010.08.001.Villanueva R, et al. Pulmonary involvement in Whipple’s disease: Case report and review of the literature. Chest. 2015;148(4):968–974. doi: 10.1378/chest.15-0866.Cacoub P, et al. The pathophysiology of pulmonary hypertension in chronic inflammatory diseases. Curr Opin Pulm Med. 2017;23(4):305–312. doi: 10.1097/MCP.0000000000000389.

Early diagnosis of pulmonary artery hypertension (PAH) is diagnostically challenging given the extent of pulmonary vascular remodeling required to bring about clinical signs and symptoms. Exercise testing can be invaluable in this setting, as stressing the cardiopulmonary system may unmask early disease. This report describes a young patient with a positive family history of PAH in whom contemporaneous invasive cardiopulmonary exercise testing and surgical lung biopsy reveal the novel association between exercise pulmonary hypertension (ePH) and early histological changes of PAH. Exercise PH currently carries no pathological correlates which means the hemodynamic effects of early pulmonary vascular remodeling remain unknown. Following the recent proceedings from the World Symposium in Pulmonary Hypertension 2018, which broaden the hemodynamic definition of PAH, this report suggests an important association between ePH and early pulmonary vascular remodeling supporting a role for exercise hemodynamic evaluation in patients at increased familial risk of PAH.

A 36-year-old woman presented with recurrent pulmonary emboli (PE) despite oral anticoagulation. She was a type I diabetic with severe gastroparesis requiring insertion of multiple long-term peripherally inserted central catheters (PICC) over a 10-year period. Imaging at presentation demonstrated a PICC-associated mobile mass in the right atrium and signs of pulmonary hypertension (PH). She was thrombolyzed and fully anticoagulated, and diabetic management without PICC strongly recommended. PH persisted, however, and she developed chronic thromboembolic pulmonary hypertension (CTEPH), for which successful pulmonary endarterectomy (PEA) surgery led to symptomatic and hemodynamic improvement. This was the first case of CTEPH reported related to long-term PICC use outside the setting of malignant disease, and a novel observation that the PEA specimen contained multiple plastic fragments. Long-term PICC placement increases the risk of CTEPH, a life-threatening, albeit treatable, complication.