The role of cardiometabolic risk factors and endothelial dysfunction in serum albumin levels and capillary leak syndrome of patients with COVID-19

Background: Growing evidence focuses on the role of hypoalbuminemia in the COVID-19 course and the role of vascular inflammation in the progression to Capillary Leak Syndrome (CLS). CLS may be mediated by a derangement of endothelial barrier following vascular endothelial dysfunction. We investigated the role of cardiometabolic risk factors in the association of hypoalbuminemia with endothelial dysfunction of hospitalized COVID-19 patients. Method(s): In this cross-sectional study, patients hospitalized for COVID- 19 at the medical ward or Intensive Care Unit (ICU) were enrolled. Medical history and laboratory examinations were collected while the endothelial function was assessed by brachial artery flow-mediated dilation (FMD) between the first 24-72 hours of their admission to the hospital. According to the body mass index, history of hypertension, dyslipidemia, and diabetes mellitus, COVID-19 patients were categorized in those with Cardiometabolic Risk Factors (CRFact) or without CRFact (no-CRFact). From the study population, we excluded subjects with established cardiovascular disease. Result(s): Sixty-six patients with COVID-19 (37% admitted in ICU) were recruited. From the study population, 41 were in the group of CRFact and 25 in the no-CRFact. Patients with CFRact were older (65+/-9 years vs. 53+/-14 years, p<0.001), had more impaired FMD (1.16+/-2.13% vs. 2.60+/-2.44%, p=0.01), and lower serum albumin levels (3.10+/-0.68 g/dL vs. 3.52+/-0.26 g/dL, p=0.006) compared to the no-CRFact group. Between CRFact and no-CRFact, there was no difference in CRP and IL-6 levels. Interestingly, serum albumin in patients with CRFact was significantly lower than the lower reference limit (LRL) (=3.5 g/dl) of albumin (p=0.001), while no such finding was noted in subjects with no CRFact (p=0.64). Furthermore, regression analysis revealed that, even after adjustment for age, the presence of CRFact was associated with decreased serum albumin levels by 0.31mg/dl (95% CI 0.08 to 0.63, p=0.04). In the CRFact population, there was a correlation of albumin with FMD (R=0.29, p=0.05) and an inverse correlation with CRP (rho=-0.48, p=0.02) and IL-6 (rho=-0.66, p<0.001), while in the no-CRFact group no such correlation were observed (p=NS for all). Conclusion(s): COVID-19 patients with cardiometabolic risk factors present with low serum albumin levels early at the course of the disease, which may be driven by endothelial dysfunction and vascular inflammation. This data gives insights into the potential association of a dysfunctional endothelial layer and the progression to capillary leak syndrome. (Figure Presented).

Impaired endothelial glycocalyx, vascular dysfunction and myocardial deformation four months after COVID-19 infection are partially improved at twelve months

Introduction: COVID-19 patients present impaired subclinical markers of cardiovascular and endothelial function. Subclinical myocardial and vascular dysfunction during COVID-19 disease have been associated with worse outcomes and higher mortality risk. Purpose: We investigated the effect of COVID-19 infection on markers of endothelial, vascular and myocardial function at four and twelve months after the infection Methods: We recruited 70 patients who were examined in a dedicated post-COVID-19 outpatient clinic during a scheduled follow-up visit at four and twelve months after a confirmed COVID-19 infection and 70 healthy individuals with similar clinical characteristics. At four and twelve months we measured (i) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced endothelial glycocalyx thickness), (ii) flow-mediated dilatation (FMD), (iii) coronary flow reserve (CFR) by Doppler echocardiography, (iv) pulse wave velocity (PWV) and central systolic blood pressure (cSBP), (v) global left and right ventricular longitudinal strain (GLS), (vi) myocardial global work index (GWI) global constructive work (GCW), global wasted work (GWW) and the myocardial global work efficiency (GWE) and v) malondialdehyde (MDA), an oxidative stress marker. Results: At four months, COVID-19 patients displayed higher values of PBR5–25 compared to control group (p<0.001) which increased at twelve months (p<0.001). FMD, PWV and cSBP values were similar between 4 and 12 months (p>0.05 for all the comparisons) and higher than those in controls (p<0.001, p=0.057, p=0.003 respectively). At four months, COVID-19 patients presented impaired CFR and LVGLS values which were improved at twelve months (p=0.002, p=0.069 respectively), though remained impaired compared to controls (p=0.003 for all the comparisons). At four months, COVID-19 patients had impaired RVGLS values which were significantly improved at twelve months (p=0.001,) and showed no statistically significant difference compared to controls (p>0.05). COVID-19 patients at four months display higher myocardial wasted work and decreased myocardial efficiency compared to controls (p=0.01, p=0.006 respectively). There was a modest improvement in GWW and GWE at twelve months,(p=0.043, p=0.001, respectively);however, these markers remained impaired compared to controls (p>0.05). At four months, MDA was higher in COVID-19 patients compared to control group and significantly decreased at twelve months (p<0.001);however, these values remain higher than in controls (p=0.002) (Table 1). Conclusions: SARS-CoV-2 causes endothelial and cardiovascular dysfunction which are partially restored at twelve months after the infection. Funding Acknowledgement: Type of funding sources: None.Table 1

SARS-CoV-2 is associated withabnormal biomarkers of oxidative stress,and endothelial function linked with cardiovascular dysfunction four months after the infection

Introduction: COVID-19 infection has been associated with increase arterial stiffness, endothelialdysfunction, and impairment in coronary and cardiac performance. Inflammation and oxidative stress have beensuggested as possible pathophysiological mechanisms leading to vascular and endothelial deregulation afterCOVID-19 infection. Purpose: The objective of our study is to evaluate premature alterations in arterial stiffness, endothelial,coronary, and myocardial function markers four months after SARS-CoV-2 infection. Methods: In a case-control prospective study, we included 70 patients 4 months after COVID-19 infection, 70 age- and sex-matched untreated hypertensive patients (positive control) and 70 healthy individuals. We measured (i) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced endothelial glycocalyx thickness), (ii) flow-mediated dilatation (FMD), (iii) coronary flow reserve (CFR) by Doppler echocardiography, (iv) pulse wave velocity (PWV) and central systolic blood pressure (cSBP), (v) global left and right ventricular longitudinal strain (GLS), (vi) malondialdehyde (MDA), an oxidative stress marker, thrombomodulin and von Willebrand factor as endothelial biomarkers. Results: COVID-19 patients had similar CFR and FMD with hypertensives (2.48±0.41 vs 2.58±0.88, p=0.562, 5.86±2.82% vs 5.80±2.07%, p=0.872 respectively) but lower values than controls (3.42±0.65, p=0.0135, 9.06±2.11%, p=0.002 respectively). Compared to controls, both COVID-19 and hypertensives had greater PBR5–25 (2.07±0.15μm and 2.07±0.26μm p=0.8 vs 1.89±0.17μm, p=0.001), higher PWV, (12.09±2.50 vs 11.92±2.94, p=0.7 vs 10.04±1.80m/sec, p=0.036) increased cSBP (128.43±17.39 vs 135.17±16.83 vs 117.89±18.85) and impaired LV and RV GLS (−19.50±2.56% vs −19.23±2.67%, p=0.864 vs −21.98±1.51%, p=0.020 and −16.99±3.17% vs −18.63±3.20%, p=0.002 vs −20.51±2.28%, p<0.001). MDA and thrombomodulin were higher in COVID-19 patients than both hypertensives and controls (10.67±2.75 vs 1.76±0.30, p=0.003 vs 1.01±0.50nmole/L, p=0.001 and 3716.63±188.36 vs 3114.46±179.18, p=0.017 vs 2590.02±156.51pg/ml, p<0.001). COVID-19 patients displayed similar vWF values with hypertensives but higher compared with healthy controls (4018.03±474.31 vs 3756.65±293.28 vs 2079.33±855.10 ng/ml, p=0.718 and p=0.016 respectively). Conclusions: SARS-CoV-2 infection is associated with oxidative stress, endothelial and vascular dysfunction, which are linked to impaired longitudinal myocardial deformation 4 months after COVID-19 infection. Funding Acknowledgement: Type of funding sources: None.

Association of COVID-19 with impaired endothelial glycocalyx, vascular function and myocardial efficiency four months after infection

Aims: SARS-CoV-2 infection may lead to endothelial and vascular dysfunction. We investigated alterations of arterial stiffness, endothelial coronary and myocardial function markers four months after COVID-19 infection. Methods: In a case-control prospective study, we included 100 patients four months after COVID-19 infection, 50 age- and sex-matched healthy individuals. We measured a) pulse wave velocity (PWV), b) flow-mediated dilation (FMD) of brachial artery, c) coronary Flow Reserve (CFR) by Doppler echocardiography d) left ventricular (LV) global longitudinal strain (GLS), e) left ventricular myocardial work index, constructive work, wasted work and work efficiency and e) von-Willenbrand factor and thrombomodulin as endothelial biomarkers. Results: COVID-19 patients had lower CFR and FMD values than controls (2.39 ± 0.39 vs 3.31 ± 0.59, p = 0.0122, 5.12 ± 2.95% vs 8.12 ± 2.23%, p = 0.006 respectively). Compared to controls, COVID-19 patients had higher PWV (PWVc-f 12.32 ± 2.44 vs 10.11 ± 1.85 m/sec, p = 0.033) and impaired LV GLS (-19.11 ± 2.14% vs -20.41 ± 1.61%, p = 0.001). Compared to controls, COVID-19 patients had higher myocardial work index, and wasted work (2067.7 ± 325.9 mmHg% vs 1929.4 ± 312.7 mmHg%, p = 0.026, 104.6 ± 58.9 mmHg% vs 75.1 ± 52.6 mmHg%, p = 0.008, respectively), while myocardial efficiency was lower (94.8 ± 2.5% vs 96.06 ± 2.3%, p = 0.008). and thrombomodulin were higher in COVID-19 patients than controls (3716.63 ± 188.36 vs 2590.02 ± 156.51pg/ml, p < 0.001). MDA was higher in COVID-19 patients than controls (10.55 ± 2.45 vs 1.01 ± 0.50 nmole/L, p = 0.001). Residual cardiovascular symptoms at 4 months were associated with oxidative stress markers. Myocardial work efficiency was related with PWV (F=-0.309, p = 0.016) and vWillenbrand (F=-0.541, p = 0.037). Myocardial wasted work was related with PWV (F = 0.255, p = 0.047) and vWillenbrand (F = 0.610, p = 0.016). Conclusions: SARS-CoV-2 may cause vascular dysfunction, followed by a waste of cardiac work, in order to compensate for increased arterial stiffness 4 months after infection.

Association of COVID-19 with impaired endothelial glycocalyx, coronary flow and longitudinal strain four months after infection

Aims: SARS-CoV-2 infection may lead to endothelial and vascular dysfunction. We investigated alterations of arterial stiffness, endothelial coronary and myocardial function markers four months after COVID-19 infection. Methods: In a case-control prospective study, we included 100 patients four months after COVID-19 infection, 50 age- and sex-matched healthy individuals. We measured a) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced endothelial glycocalyx thickness), b) flow-mediated dilation (FMD), c) coronary Flow Reserve (CFR) by Doppler echocardiography d) pulse wave velocity (PWV) e) global left (LV) and right (RV) ventricular longitudinal strain (GLS), f) malondialdehyde (MDA), an oxidative stress marker, von-Willenbrand factor and thrombomodulin as endothelial biomarkers. Results: COVID-19 patients had lower CFR and FMD values than controls (2.39 ± 0.39 vs 3.31 ± 0.59, p = 0.0122, 5.12 ± 2.95% vs 8.12 ± 2.23%, p = 0.006 respectively). Compared to controls, COVID-19 had greater PBR5-25 (2.11 ± 0.14μm vs 1.87 ± 0.16μm, p = 0.002), higher PWV (PWVc-f 12.32 ± 2.44 vs 10.11 ± 1.85 m/sec, p = 0.033) and impaired LV and RV GLS (-19.11 ± 2.14% vs -20.41 ± 1.61%, p = 0.001 and -16.45 ± 3.33% vs -20.11 ± 2.48%, p < 0.001). MDA and thrombomodulin were higher in COVID-19 patients than controls (10.55 ± 2.45 vs 1.01 ± 0.50 nmole/L, p = 0.001 and 3716.63 ± 188.36 vs 2590.02 ± 156.51pg/ml, p < 0.001). Residual cardiovascular symptoms at 4 months were associated with oxidative stress and endothelial dysfunction markers. Conclusions: SARS-CoV-2 may cause endothelial and vascular dysfunction linked to.

Apremilast improves endothelial glycocalyx and microvascular perfusion: A possible protective mechanism against COVID-19

Background/Introduction: The phosphodiesterase 4 inhibitor apremilast is an approved treatment option for psoriasis. Purpose: We aimed to investigate the effects of apremilast on endothelial glycocalyx, vascular and left ventricular (LV) myocardial function in psoriasis. Methods: Ninety patients with psoriasis were randomized to receive apremilast (n=30), anti-tumor necrosis factor-a (etanercept, n=30), or cyclosporine treatment (n=30). At baseline and 4 months post-treatment, we measured: (1)Perfused boundary region (PBR) of the sublingual microvessels with a diameter 5-25μm using a dedicated camera (Sidestream Dark Field imaging, Microscan, Glycocheck). Increased PBR indicates reduced glycocalyx thickness. Perfused microvascular density (PMD), an index of microvascular perfusion, was also measured. (2)Pulse wave velocity (PWV -Complior;ALAM Medical) and central systolic blood pressure (cSBP), and (3)LV global longitudinal strain (GLS) and percent difference between peak twisting and untwisting at mitral valve opening (%dpTw-UtwMVO) using speckle-tracking echocardiography. Results: Compared with baseline, PBR20-25 decreased only after apremilast treatment (-13% at 4 months, P<0.05) whereas no statistically significant changes in PBR20-25 were observed after etanercept or cyclosporine. Compared with etanercept and cyclosporine, apremilast resulted in a greater increase of PMD (+12% versus +3% versus +3%) and in a higher reduction of PWV (-10% versus -3% versus +8%) and cSBP (-8% versus -2% versus +7%) at 4 months. Apremilast showed a greater increase of GLS (+12% versus +5% versus +2%) and %dpTw-UtwMVO (+15% versus +3% versus +3%) than etanercept and cyclosporine (P<0.05 for all comparisons). Changes of PBR and PMD postapremilast treatment correlated with a concomitant reduction of PWV and cSBP (P<0.05). Conclusions: In psoriasis, apremilast confers a greater improvement of endothelial glycocalyx, microvascular perfusion and LV myocardial function compared with etanercept or cyclosporine treatment. Apremilast restores glycocalyx integrity and thus reduces vascular permeability to proinflammatory molecules. This may explain the beneficial effects of apremilast on COVID-19.

COVID-19 patients present impaired endothelial glycocalyx, vascular dysfunction and myocardial deformation resembling those observed in hypertensives four months after infection

Background/Introduction: COVID-19 infection has been associated with increase arterial stiffness, endothelial dysfunction, and impairment in coronary and cardiac performance. Inflammation and oxidative stress have been suggested as possible pathophysiological mechanisms leading to vascular and endothelial deregulation after COVID-19 infection. Purpose: The objective of our study is to evaluate premature alterations in arterial stiffness, endothelial, coronary, and myocardial function markers four months after SARS-CoV-2 infection. Methods: We conducted a case-control prospective study, including 70 patients four months after COVID-19 infection, 70 age- and sex-matched untreated hypertensive patients (positive control) and 70 healthy individuals. We measured a) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced endothelial glycocalyx thickness b) flow-mediated dilation (FMD), c) coronary Flow Reserve (CFR) by Doppler echocardiography d) pulse wave velocity (PWV) and central systolic (SBP) e) global LV longitudinal strain (GLS) by speckle tracking imaging and f) malondialdehyde (MDA) as oxidative stress marker. Results: COVID-19 patients had similar CFR and FMD with hypertensives (2.48±0.41 vs 2.58±0.88, p=0.562, 5.86±2.82% vs 5.80±2.07%, p=0.872 respectively), but lower CFR and FMD than controls (3.42±0.65, p=0.0135 9.06±2.11%, p=0.002 respectively) Both COVID-19 and hypertensive group had greater PBR than controls (PBR5-25: 2.07±0.15 μm and 2.07±0.26 μm p=0.8 vs 1.89±0.17 μm, p=0.001). COVID-19 patients and hypertensives had higher PWV and central SBP than controls (PWVcf 12.09±2.50 and 11.92±2.94, p=0.7 vs 10.04±1.80 m/sec, p=0.036). COVID-19 patients and hypertensives had impaired values of GLS compared to controls (-19.50±2.56% and -19.23±2.67%, p=0.864 vs -21.98±1.51%, p=0.020). Increased PBR5-25 was associated with increased SBP central which in turn was related with impaired GLS (p<0.05). MDA was found increased in COVID-19 patients compared to both hypertensives and controls (10.67±2.75 vs 1.76±0.30, p=0.003 vs 1.01±0.50 nmole/L, p=0.001). Conclusions: SARS-CoV-2 may cause impaired coronary microcirculatory, endothelial and vascular deregulation which remain four months after initial infection and are associated with reduced cardiac performance. The 10-fold increase of MDA compared to healthy individuals four months after COVID-19 infection indicate oxidative stress as possible pathophysiological mechanism.