Clinical echocardiography does not indicate cardiac dysfunction in critically ill Covid-19 patients

ObjectiveWe aimed to investigate the acute cardiac effects of severe SARS-CoV-2. MethodsThis is an observational study generated from the first 79 patients admitted to Uppsala intensive care due to respiratory failure with SARS-CoV-2 infection. 34 underwent echocardiography of which 25 were included in the study and compared to 44 non-echo patients. Exclusion was based on absence of normofrequent sinus rhythm and mechanical respiratory support. Biomarker analysis was carried out on all patients. ResultsMortality was increased in the echo compared to non-echo group (44 % vs. 16%, p<0.05). Right sided dimensions and functional parameters were not affected. Tricuspid regurgitation velocity indicated how increased pulmonary artery pressure was associated with mortality (survivors (n=5): 2.51 {+/-} 0.01 m/s vs. non-survivors (n=5): 3.06 {+/-} 0.11 m/s, p<0.05). Cardiac markers and D-dimer correlated to initiation of echocardiography (hs-TnI (ng/L): echo (n=23): 133 {+/-} 45 vs. non-echo (n=41): 81.3 {+/-} 45, p<0.01; NTproBNP (ng/L): echo (n=25): 2959 {+/-} 573 vs. non-echo (n=42): 1641 {+/-} 420, p<0.001; D-dimer (mg/L): echo (n=25): 16.1 {+/-} 3.7 vs. non-echo (n=43: 6.1 {+/-} 1.5, p<0.01) and mortality (hs-TnI (ng/L): survivors (n=48): 59.1 {+/-} 21 vs. non-survivors (n=17): 211 {+/-} 105, p<0.0001; NT-proBNP (ng/L): survivors (n=47): 1310 {+/-} 314 vs. non-survivors (n=20): 4065 {+/-} 740, p<0.0001; D-dimer (mg/L): survivors (n=50): 7.2 {+/-} 1.5 vs. non-survivors (n=18): 17.1 {+/-} 4.8, p<0.01). All intervals refer to standard error of the mean. Tricuspid regurgitation velocity was correlated with troponin I (r=0.93, r2=0.74, p<0.001, n=10). ConclusionsThese results suggest that there is no clear negative effect on cardiac function in critical SARS-CoV-2. There are indications that pulmonary pressure elevation carries a negative predictive outcome suggesting pulmonary disease as the driver of mortality. Cardiac biomarkers as well as D-dimer carry predictive value. Trial registration numberPatients were included in "Clinical trials NCT04316884" Article summaryO_ST_ABSStrength and limitations of this studyC_ST_ABS- The patient body is recruited from all patients admitted to ICU in need of mechanical respiratory support independent of background which makes it relevant to clinical practice. - The echocardiographic image acquisition was carried out by hospital assigned agents on clinical indication, which makes the results applicable in a clinical setting. - Since the image acquisition was carried out on a clinical indication, the results may be skewed towards the false positive if applied to all Covid19 patients.

Elevated Angiopoietin-2 inhibits thrombomodulin-mediated anticoagulation in critically ill COVID-19 patients

Several studies suggest that hypercoagulation and endothelial dysfunction play central roles in severe forms of COVID-19 infections. We hypothesized that the high levels of the inflammatory cytokine Angiopoietin-2 (ANGPT2) reported in hospitalized COVID-19 patients might promote hypercoagulation through ANGPT2 binding to thrombomodulin with resulting inhibition of thrombin/thrombomodulin-mediated physiological anticoagulation. Plasma was collected from critically ill COVID-19 patients treated in the intensive care unit (ICU) at Uppsala University Hospital and ANGPT2 was measured at admission (61 patients) and after ten days (40 patients). ANGPT2 levels were compared with biochemical parameters, clinical outcome, and survival. We found that ANGPT2 levels were increased in COVID-19 patients in correlation with disease severity, hypercoagulation, and mortality. To test causality, we administered ANGPT2 to wildtype mice and found that it shortened bleeding time in a tail injury model. In further support of a role for ANGPT2 in physiological coagulation, bleeding time was increased in endothelial-specific Angpt2 knockout mice. Using in vitro assays, we found that ANGPT2 inhibited thrombomodulin-mediated anticoagulation and protein C activation in human donor plasma. Our data reveal a novel mechanism for ANGPT2 in hypercoagulation and suggest that Angiopoietin-2 inhibition may be tested in the treatment of hypercoagulation in severe COVID-19 infection.

PP015. Plasma levels and placental expression of BNP/NT-proBNP in early and late onset preeclampsia.

INTRODUCTION: Women with preeclampsia (PE) have elevated plasma levels of NT-proBNP. We hypothesized that the placenta may be a source to these elevated levels. OBJECTIVES: Our objectives were to study the plasma levels of NT-proBNP and the protein and mRNA expression of placental BNP in women with early and late onset PE and controls. METHODS: Plasma levels of NT-proBNP were measured in women with early (n=18) and late (n=20) onset PE, in two groups of healthy pregnant women in gestational week 24-32 (n=22) and 36-42 (n=14), and in non-pregnant women (n=20). Placental BNP protein and mRNA was studied with immunohistochemistry and qPCR. Placental release of NT-proBNP was studied with tissue culturing. RESULTS: Women with early (365 (14-9815) pg/ml) and late (176 (33-2547) pg/ml) onset PE had higher levels of NT-proBNP in plasma than their respective controls (p<0.001). A tendency towards higher plasma levels in early compared to late onset PE was observed (p=0.057). 20 out of 25 placental tissue samples had proBNP mRNA, no differences between the study groups were found. BNP protein was found in maternal spiral arteries and syncytiotrophoblasts. NT-proBNP peptide (6-7pg/ml) was present in medium used for placenta cultures. CONCLUSIONS: Our results suggest that there may be a placental source of NT-proBNP. If this source is responsible for the elevated plasma levels of NT-proBNP in preeclamptic women and what role, if any, BNP/NT-proBNP play in PE pathophysiology remains to be elucidated.