The Role of Rehabilitation in Arterial Function Properties of Convalescent COVID-19 Patients.

Coronavirus disease (COVID-19) is a respiratory disease, although arterial function involvement has been documented. We assess the impact of a post-acute COVID-19 rehabilitation program on endothelium-dependent vasodilation and arterial wall properties. We enrolled 60 convalescent patients from COVID-19 and one-month post-acute disease, who were randomized at a 1:1 ratio in a 3-month cardiopulmonary rehabilitation program (study group) or not (control group). Endothelium-dependent vasodilation was evaluated by flow-mediated dilation (FMD), and arterial wall properties were evaluated by carotid-femoral pulse wave velocity (cf-PWV) and augmentation index (AIx) at 1 month and at 4 months post-acute disease. FMD was significantly improved in both the study (6.2 ± 1.8% vs. 8.6 ± 2.4%, p < 0.001) and control groups (5.9 ± 2.2% vs. 6.6 ± 1.8%, p = 0.009), but the improvement was significantly higher in the study group (rehabilitation) (p < 0.001). PWV was improved in the study group (8.2 ± 1.3 m/s vs. 6.6 ± 1.0 m/s, p < 0.001) but not in the control group (8.9 ± 1.8 m/s vs. 8.8 ± 1.9 m/s, p = 0.74). Similarly, AIx was improved in the study group (25.9 ± 9.8% vs. 21.1 ± 9.3%, p < 0.001) but not in the control group (27.6 ± 9.2% vs. 26.2 ± 9.8 m/s, p = 0.15). Convalescent COVID-19 subjects of the study group (rehabilitation) with increased serum levels of circulating IL-6 had a greater reduction in FMD. Conclusively, a 3-month cardiopulmonary post-acute COVID-19 rehabilitation program improves recovery of endothelium-dependent vasodilation and arteriosclerosis.

Cardiovascular and cerebral vascular health in females with postacute sequelae of COVID-19.

Many individuals who had coronavirus disease 2019 (COVID-19) develop detrimental persistent symptoms, a condition known as postacute sequelae of COVID-19 (PASC). Despite the elevated risk of cardiovascular disease following COVID-19, limited studies have examined vascular function in PASC with equivocal results reported. Moreover, the role of PASC symptom burden on vascular health has not been examined. We tested the hypothesis that peripheral and cerebral vascular function would be blunted and central arterial stiffness would be elevated in patients with PASC compared with age-matched controls. Furthermore, we hypothesized that impairments in vascular health would be greater in those with higher PASC symptom burden. Resting blood pressure (BP; brachial and central), brachial artery flow-mediated dilation (FMD), forearm reactive hyperemia, carotid-femoral pulse wave velocity (PWV), and cerebral vasodilator function were measured in 12 females with PASC and 11 age-matched female controls without PASC. The severity of persistent symptoms in those with PASC was reported on a scale of 1-10 (higher score: greater severity). Brachial BP (e.g., systolic BP, 126 ± 19 vs.109 ± 8 mmHg; P = 0.010), central BP (P < 0.050), and PWV (7.1 ± 1.2 vs. 6.0 ± 0.8 m/s; P = 0.015) were higher in PASC group compared with controls. However, FMD, reactive hyperemia, and cerebral vasodilator function were not different between groups (P > 0.050 for all). Total symptom burden was not correlated with any measure of cardiovascular health (P > 0.050 for all). Collectively, these findings indicate that BP and central arterial stiffness are elevated in females with PASC, whereas peripheral and cerebral vascular function appear to be unaffected, effects that appear independent of symptom burden.NEW & NOTEWORTHY We demonstrate for the first time that resting blood pressure (BP) and central arterial stiffness are higher in females with PASC compared with controls. In contrast, peripheral and cerebral vascular functions appear unaffected. Moreover, there was no relationship between total PASC symptom burden and measures of BP, arterial stiffness, or vascular function. Collectively, these findings suggest that females with PASC could be at greater risk of developing hypertension, which appears independent of symptom burden.

Effects of l-Arginine Plus Vitamin C Supplementation on l-Arginine Metabolism in Adults with Long COVID: Secondary Analysis of a Randomized Clinical Trial.

Altered l-arginine metabolism has been described in patients with COVID-19 and has been associated with immune and vascular dysfunction. In the present investigation, we determined the serum concentrations of l-arginine, citrulline, ornithine, monomethyl-l-arginine (MMA), and symmetric and asymmetric dimethylarginine (SDMA, ADMA) in adults with long COVID at baseline and after 28-days of l-arginine plus vitamin C or placebo supplementation enrolled in a randomized clinical trial, compared with a group of adults without previous history of SARS-CoV-2-infection. l-arginine-derived markers of nitric oxide (NO) bioavailability (i.e., l-arginine/ADMA, l-arginine/citrulline+ornithine, and l-arginine/ornithine) were also assayed. Partial least squares discriminant analysis (PLS-DA) models were built to characterize systemic l-arginine metabolism and assess the effects of the supplementation. PLS-DA allowed discrimination of participants with long COVID from healthy controls with 80.2 ± 3.0% accuracy. Lower markers of NO bioavailability were found in participants with long COVID. After 28 days of l-arginine plus vitamin C supplementation, serum l-arginine concentrations and l-arginine/ADMA increased significantly compared with placebo. This supplement may therefore be proposed as a remedy to increase NO bioavailability in people with long COVID.

Impaired Endothelial Function in Convalescent Phase of COVID-19: A 3 Month Follow Up Observational Prospective Study.

BACKGROUND: Endothelial dysfunction has a role in acute COVID-19, contributing to systemic inflammatory syndrome, acute respiratory distress syndrome, and vascular events. Evidence regarding COVID-19 middle- and long-term consequences on endothelium are still lacking. Our study aimed to evaluate if COVID-19 severity could significantly affect the endothelial function after three months from the acute phase. METHODS: We assessed endothelial function in outpatients with previous COVID-19 three months after negative SARS-CoV-2 molecular test by measuring flow-mediated dilation (FMD) in patients categorized according to a four-variable COVID-19 severity scale ("home care"; "hospital, no oxygen"; "hospital, oxygen"; "hospital requiring high-flow nasal canula, non-invasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation"). FMD difference among COVID-19 severity categories was assessed with analysis of variance; we further clarified the relationship between FMD and previous COVID-19 severity with multivariate logistic models. RESULTS: Among 658 consecutive COVID-19 subjects, we observed a significant linear trend of FMD reduction with the increase of the COVID-19 category (p < 0.0001). The presence of endothelial dysfunction was more frequent among hospitalized patients (78.3%) with respect to home-care patients (21.7%; p < 0.0001). COVID-19 severity was associated with increased endothelial dysfunction risk (OR: 1.354; 95% CI: 1.06-1.71; p = 0.011) at multivariate binary logistic analysis. FMD showed a significant direct correlation with PaO2 (p = 0.004), P/F ratio (p = 0.004), FEV1 (p = 0.008), and 6MWT (p = 0.0001). CONCLUSIONS: Hospitalized COVID-19 subjects showed an impaired endothelial function three months after the acute phase that correlated with pulmonary function impairment. Further studies are needed to evaluate if these subjects are at higher risk of developing pulmonary disease or future cardiovascular events.

Endothelial dysfunction in acute and long standing COVID-19: A prospective cohort study.

BACKGROUND: Coronavirus disease-19 (COVID-19) is implicated by active endotheliitis, and cardiovascular morbidity. The long-COVID-19 syndrome implications in atherosclerosis have not been elucidated yet. We assessed the immediate, intermediate, and long-term effects of COVID-19 on endothelial function. METHODS: In this prospective cohort study, patients hospitalized for COVID-19 at the medical ward or Intensive Care Unit (ICU) were enrolled and followed up to 6 months post-hospital discharge. Medical history and laboratory examinations were performed while the endothelial function was assessed by brachial artery flow-mediated dilation (FMD). Comparison with propensity score-matched cohort (control group) was performed at the acute (upon hospital admission) and follow-up (1 and 6 months) stages. RESULTS: Seventy-three patients diagnosed with COVID-19 (37% admitted in ICU) were recruited. FMD was significantly (p < 0.001) impaired in the COVID-19 group (1.65 ± 2.31%) compared to the control (6.51 ± 2.91%). ICU-treated subjects presented significantly impaired (p = 0.001) FMD (0.48 ± 1.01%) compared to those treated in the medical ward (2.33 ± 2.57%). During hospitalization, FMD was inversely associated with Interleukin-6 and Troponin I (p < 0.05 for all). Although, a significant improvement in FMD was noted during the follow-up (acute: 1.75 ± 2.19% vs. 1 month: 4.23 ± 2.02%, vs. 6 months: 5.24 ± 1.62%; p = 0.001), FMD remained impaired compared to control (6.48 ± 3.08%) at 1 month (p < 0.001) and 6 months (p = 0.01) post-hospital discharge. CONCLUSION: COVID-19 patients develop a notable endothelial dysfunction, which is progressively improved over a 6-month follow-up but remains impaired compared to healthy controls subjects. Whether chronic dysregulation of endothelial function following COVID-19 could be accompanied by a residual risk for cardiovascular and thrombotic events merits further research.

Tracking peripheral vascular function for six months in young adults following SARS-CoV-2 infection.

SARS-CoV-2 infection is known to instigate a range of physiologic perturbations, including vascular dysfunction. However, little work has concluded how long these effects may last, especially among young adults with mild symptoms. To determine potential recovery from acute vascular dysfunction in young adults (8 M/8F, 21 ± 1 yr, 23.5 ± 3.1 kg⋅m-2 ), we longitudinally tracked brachial artery flow-mediated dilation (FMD) and reactive hyperemia (RH) in the arm and hyperemic response to passive limb movement (PLM) in the leg, with Doppler ultrasound, as well as circulating biomarkers of inflammation (interleukin-6, C-reactive protein), oxidative stress (thiobarbituric acid reactive substances, protein carbonyl), antioxidant capacity (superoxide dismutase), and nitric oxide bioavailability (nitrite) monthly for a 6-month period post-SARS-CoV-2 infection. FMD, as a marker of macrovascular function, improved from month 1 (3.06 ± 1.39%) to month 6 (6.60 ± 2.07%; p < 0.001). FMD/Shear improved from month one (0.10 ± 0.06 AU) to month six (0.18 ± 0.70 AU; p = 0.002). RH in the arm and PLM in the leg, as markers of microvascular function, did not change during the 6 months (p > 0.05). Circulating markers of inflammation, oxidative stress, antioxidant capacity, and nitric oxide bioavailability did not change during the 6 months (p > 0.05). Together, these results suggest some improvements in macrovascular, but not microvascular function, over 6 months following SARS-CoV-2 infection. The data also suggest persistent ramifications for cardiovascular health among those recovering from mild illness and among young, otherwise healthy adults with SARS-CoV-2.

Effects of l-Arginine Plus Vitamin C Supplementation on Physical Performance, Endothelial Function, and Persistent Fatigue in Adults with Long COVID: A Single-Blind Randomized Controlled Trial.

Long COVID, a condition characterized by symptom and/or sign persistence following an acute COVID-19 episode, is associated with reduced physical performance and endothelial dysfunction. Supplementation of l-arginine may improve endothelial and muscle function by stimulating nitric oxide synthesis. A single-blind randomized, placebo-controlled trial was conducted in adults aged between 20 and 60 years with persistent fatigue attending a post-acute COVID-19 outpatient clinic. Participants were randomized 1:1 to receive twice-daily orally either a combination of 1.66 g l-arginine plus 500 mg liposomal vitamin C or a placebo for 28 days. The primary outcome was the distance walked on the 6 min walk test. Secondary outcomes were handgrip strength, flow-mediated dilation, and fatigue persistence. Fifty participants were randomized to receive either l-arginine plus vitamin C or a placebo. Forty-six participants (median (interquartile range) age 51 (14), 30 [65%] women), 23 per group, received the intervention to which they were allocated and completed the study. At 28 days, l-arginine plus vitamin C increased the 6 min walk distance (+30 (40.5) m; placebo: +0 (75) m, p = 0.001) and induced a greater improvement in handgrip strength (+3.4 (7.5) kg) compared with the placebo (+1 (6.6) kg, p = 0.03). The flow-mediated dilation was greater in the active group than in the placebo (14.3% (7.3) vs. 9.4% (5.8), p = 0.03). At 28 days, fatigue was reported by two participants in the active group (8.7%) and 21 in the placebo group (80.1%; p < 0.0001). l-arginine plus vitamin C supplementation improved walking performance, muscle strength, endothelial function, and fatigue in adults with long COVID. This supplement may, therefore, be considered to restore physical performance and relieve persistent symptoms in this patient population.

Vaccination Against SARS-CoV-2 Protects from COVID-19-induced Endothelial Dysfunction.

BACKGROUND: Coronavirus Disease-19 (COVID-19) is implicated in endotheliitis, which adversely affects cardiovascular events. The impact of vaccination with COVID-19 on the clinical outcome of patients is documented. OBJECTIVE: To evaluate the impact of vaccination with COVID-19 on the severe acute respiratory syndrome, coronavirus-2 (SARS-CoV-2) infection-related endothelial impairment. METHODS: We enrolled 45 patients hospitalized for COVID-19 (either vaccinated or not against SARS-CoV-2). Clinical and laboratory data were collected, and brachial artery flow-mediated dilation (FMD) was evaluated. Subjects without COVID-19 were used as the control group. RESULTS: There was no difference in age (64.7 ± 7.5 years vs. 61.2 ± 11.1 years vs. 62.4 ± 9.5, p = 0.28), male sex (49% vs. 60% vs. 52%, p = 0.71), control subjects, vaccinated, and unvaccinated subjects with COVID-19, respectively. Of the patients with COVID-19, 44% were vaccinated against SARS-CoV-2. Unvaccinated COVID-19 patients had significantly impaired FMD compared to vaccinated COVID-19 patients and Control subjects (2.05 ± 2.41 % vs. 7.24 ± 2.52% vs. 7.36 ± 2.94 %, p <0.001). Importantly, post hoc tests revealed that unvaccinated COVID-19 patients had significantly impaired FMD from both Vaccinated COVID-19 subjects (p <0.001) and from Control subjects (p <0.001). There was no difference in FMD between the control group and the vaccinated COVID-19 group (p = 0.99). CONCLUSION: Hospitalized patients with COVID-19 present endothelial dysfunction in the acute phase of the disease. Endothelial function in unvaccinated patients with COVID-19 is impaired compared to control subjects as well compared to vaccinated patients with COVID-19. Vaccinated hospitalized subjects with COVID-19 do not show endothelial dysfunction, strengthening the protective role of vaccination against SARS-CoV-2.

Clinical implications of vascular dysfunction in acute and convalescent COVID-19: A systematic review.

BACKGROUND: Accumulating evidence suggests that endothelial dysfunction is implicated in the pathogenesis and severity of coronavirus disease 2019 (COVID-19). In this context, vascular impairment in COVID-19 might be associated with clinical manifestations and could refine risk stratification in these patients. METHODS: This systematic review aims to synthesize current evidence on the frequency and the prognostic value of vascular dysfunction during acute and post-recovery COVID-19. After systematically searching the MEDLINE, clinicaltrials.gov and the Cochrane Library from 1 December 2019 until 05 March 2022, we identified 24 eligible studies with laboratory confirmed COVID-19 and a thorough examination of vascular function. Flow-mediated dilation (FMD) was assessed in 5 and 12 studies in acute and post-recovery phase respectively; pulse wave velocity (PWV) was the marker of interest in three studies in the acute and four studies in the post-recovery phase. RESULTS: All studies except for one in the acute and in the post-recovery phase showed positive association between vascular dysfunction and COVID-19 infection. Endothelial dysfunction in two studies and increased arterial stiffness in three studies were related to inferior survival in COVID-19. DISCUSSION: Overall, a detrimental effect of COVID-19 on markers of endothelial function and arterial stiffness that could persist even for months after the resolution of the infection and provide prognostic value was congruent across published studies. Further research is warranted to elucidate clinical implications of this association.

Impact of breakthrough COVID-19 cases during the omicron wave on vascular health and cardiac autonomic function in young adults.

We and others have previously shown that COVID-19 results in vascular and autonomic impairments in young adults. However, the newest variant of COVID-19 (Omicron) appears to have less severe complications. Therefore, we investigated whether recent breakthrough infection with COVID-19 during the Omicron wave impacts cardiovascular health in young adults. We hypothesized that measures of vascular health and indices of cardiac autonomic function would be impaired in those who had the Omicron variant of COVID-19 when compared with controls who never had COVID-19. We studied 23 vaccinated adults who had COVID-19 after December 25, 2021 (Omicron; age, 23 ± 3 yr; 14 females) within 6 wk of diagnosis compared with 13 vaccinated adults who never had COVID-19 (age, 26 ± 4 yr; 7 females). Macro- and microvascular function were assessed using flow-mediated dilation (FMD) and reactive hyperemia, respectively. Arterial stiffness was determined as carotid-femoral pulse wave velocity (cfPWV) and augmentation index (AIx). Heart rate (HR) variability and cardiac baroreflex sensitivity (BRS) were assessed as indices of cardiac autonomic function. FMD was not different between control (5.9 ± 2.8%) and Omicron (6.1 ± 2.3%; P = 0.544). Similarly, reactive hyperemia (P = 0.884) and arterial stiffness were not different between groups (e.g., cfPWV; control, 5.9 ± 0.6 m/s and Omicron, 5.7 ± 0.8 m/s; P = 0.367). Finally, measures of HR variability and cardiac BRS were not different between groups (all, P > 0.05). Collectively, these data suggest preserved vascular health and cardiac autonomic function in young, otherwise healthy adults who had breakthrough cases of COVID-19 during the Omicron wave.NEW & NOTEWORTHY We show for the first time that breakthrough cases of COVID-19 during the Omicron wave does not impact vascular health and cardiac autonomic function in young adults. These are promising results considering earlier research showing impaired vascular and autonomic function following previous variants of COVID-19. Collectively, these data demonstrate that the recent Omicron variant is not detrimental to cardiovascular health in young, otherwise healthy, vaccinated adults.

Radial Peripapillary Capillary Plexus Perfusion and Endothelial Dysfunction in Early Post-SARS-CoV-2 Infection.

BACKGROUND: Endothelial cells damage and thromboinflammation are considered key elements in the generation of organ impairment in patients with COVID-19 disease. The endothelial function is evaluated by measuring flow-mediated dilation (FMD). We aimed to analyze the association between FMD impairment and retinal vascular parameters in early post-COVID-19 patients. 00118-00199Tomography (OCT), OCT Angiography (OCTA) and slit lamp examination were performed. FMD ≤ 7% was considered as pathological. Our primary outcome was to assess potential differences in the radial peripapillary capillary plexus flow index (RPCP-FI) and RPCP density (RPCP-D) values between post-COVID-19 patients with and without FMD impairment. The associations of other retinal vascular parameters with FMD impairment were assessed as secondary endpoints. RESULTS: FMD impairment was detected in 31 patients (37.8%). RPCP-FI (p = 0.047), age (p = 0.048) and prevalence of diabetes (p = 0.046) significantly differed in patients with FMD ≤ 7% in regression analysis. RPCP-FI was linearly correlated with FMD values (R = 0.244, p =0.027). SCT was found to be lower in patients with impaired FMD (p = 0.004), although this difference was only a trend in binary logistic regression output (p = 0.07). CONCLUSIONS: Early post-COVID-19 patients showed a higher prevalence of FMD impairment compared to the general population. Age, diabetes and RPCP-FI were independently correlated with the presence of endothelial impairment in the early post-infective period.

Persistent Endothelial Dysfunction in Coronavirus Disease-2019 Survivors Late After Recovery.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can result in an endothelial dysfunction in acute phase. However, information on the late vascular consequences of COVID-19 is limited. METHODS: Brachial artery flow-mediated dilation (FMD) examination were performed, and inflammatory biomarkers were assessed in 86 survivors of COVID-19 for 327 days (IQR 318-337 days) after recovery. Comparisons were made with 28 age-matched and sex-matched healthy controls and 30 risk factor-matched patients. RESULTS: Brachial artery FMD was significantly lower in the survivors of COVID-19 than in the healthy controls and risk factor-matched controls [median (IQR) 7.7 (5.1-10.7)% for healthy controls, 6.9 (5.5-9.4)% for risk factor-matched controls, and 3.5(2.2-4.6)% for COVID-19, respectively, p < 0.001]. The FMD was lower in 25 patients with elevated tumor necrosis factor (TNF)-α [2.7(1.2-3.9)] than in 61 patients without elevated TNF-α [3.8(2.6-5.3), p = 0.012]. Furthermore, FMD was inversely correlated with serum concentration of TNF-α (r = -0.237, p = 0.007). CONCLUSION: Survivors of COVID-19 have a reduced brachial artery FMD, which is inversely correlated with increased serum concentration of TNF-α. Prospective studies on the association of endothelial dysfunction with long-term cardiovascular outcomes, especially the early onset of atherosclerosis, are warranted in survivors of COVID-19.

Is endothelial dysfunction a driving force of COVID-19 induced coagulopathy?

Background/Introduction: There are numerous reports regarding the direct endothelial damage by the SARS-CoV-2 that can lead to activation of both plasma hemostasis and platelet aggregation. However, the mechanism of interaction between endothelium and haemostasis in COVID-19 remains unclear. Purpose: The aim of our study was to assess the relationship between each link of clot formation process (endothelial function, plasma coagulation, platelet aggregation) with the severity of the disease. Methods: 58 COVID-19 patients were included in our study. Patients were divided into moderate (n=39) and severe (n=18) subgroups. All patients underwent a flow-mediated dilation (FMD) test, impedance aggregation, rotational thromboelastometry, thrombodynamics and von Willebrand factor antigen (vWF: Ag) quantification. All measurements were repeated on days 3 (point 2) and 9 (point 3) of hospitalization. Results: COVID-19 patients demonstrated the enhanced plasma coagulation (clotting time, s 613,0 [480;820], clot growth rate, μm/min 32,75 [29,3;38,7]). At point 1 no significant difference in parameters of plasma coagulation between patients' subgroups was noted. At point 2 a significant decrease in the size (CS, μm 1278.0 [1216.5;1356.5] vs 965.0 [659.8;1098.0], p<0,01) and clot growth rate (μm/min 32,4 [29,2;35,0] vs 17,7 [10,3;24,4], p<0,01) under the influence of anticoagulants in the moderate subgroup compared with point 1 was observed. We didn't observe such phenomenon in severe subgroup. There was no significant difference in platelet aggregation between subgroups at point 1. During the course of the disease the patients in the moderate and severe subgroups demonstrated a significant increase in platelet aggregation induced by arachidonic acid and ADP (severe: AUC ARA 48,0 [25,0;59,0] vs 77,5 [55,8;92,7], p=0,04;AUC ADP 44,0 [41,0;56,0] vs 58,0 [45,5;69,0], p=0,04;moderate: AUC ARA 31,5 [19,8;50,7] vs 56,0 [39,0;76,0], p=0,01;AUC ADP 43,0 [20,0;59,0] vs 56,6 [50,3;70,5], p=0,04;), in moderate subgroup the significant increase in TRAP-induced aggregation was also noted (AUC TRAP 58,0 [41,0;69,5] vs 76,0 [58,3;81,5], p=0,048). There were no significant differences in the FMD-test results between the patient subgroups. FMD-test results were predominantly within the reference ranges (7,1 [4,0;8,8]). Patients in the severe subgroup had significantly higher levels of vWF: Ag (228,0 [205,3;240,7] vs 232,0 [226,0;423,0], p=0,03). Conclusion: SARS-CoV-2 infection was characterized by increased levels of vWF:Ag, that could represent the local endothelial damage, meanwhile there was no generalized endothelial dysfunction assessed via FMD-test in moderate to severe patients. At the same time the enhanced plasma coagulation in COVID-19 patients was observed.

Long-term post-discharge coagulation abnormalities in patients with moderate to severe COVID-19

Introduction: Coagulopathy plays a significant role in COVID-19 pathogenesis. Benefit from anticoagulation is well established in hospitalized patients. But since there is a lack of data on coagulopathy resolution: there is no consensus in guidelines if extended anticoagulation is required. Purpose: The purpose of our work was to analyze coagulation abnormalities at 2 to 5 months after moderate to severe COVID-19. Methods: COVID-19 reconvalescents (CR), discharged from our hospital, were called for follow-up at 2-3 (CR1 group, 21 patients) or 5-6 (CR2 group, 26 patients) months after discharge. All CR were not on the anticoagulation therapy by that time. In addition to clinical examination and standard lab tests, we performed an FMD-test to analyze endothelial function, impedance aggregometry to analyze platelet aggregation, and a thrombodynamics test to assess thrombogenesis and fibrinolysis. The control group was recruited before the pandemic started. Results: All CR were free from thrombotic complications after discharge from the hospital. Endothelial function was not significantly impaired in CR compared with control, and was still in the normal range (7,07, IQR (3,36;11,56) vs. 7,87 (5,42;13,45)). Platelet aggregation was significantly lower in CR1 than in the control group in ADP-induced mode (37, IQR (19;47) vs. 46, IQR (41;50), p=0,02) and didn't differ in other groups and other modes (Asa, TRAP-induced). Thrombodynamics tests revealed suppression of the clot formation process in both CR1 and CR2 compared with control. There were decreased clot growth rates (μm/min) (CR1/CR2: 27,1, IQR (26,1;29,2)/27,6, IQR (26,4;30,0) vs. 32,2, IQR (30,0;35,1), both p<0,001);decreased clot size (μm) (CR1/CR2: 1099, IQR (1069;1194)/1199, IQR (1058;1221) vs. 1304, IQR (1164;1380), both p<0,001), and decreased optical density (arb units) (CR1/CR2: 21'607, IQR (20'363;24'545)/22'741, IQR (21'344;25'961) vs. 26'556, IQR (24'672;29'387, p<0,001 and p=0,09 respectively. Fibrinolysis was enhanced in CR groups compared with control (lysis progression was significantly higher for CR2 only, CR1/CR2: 2,9, IQR (2,5;3,8)/3,8, IQR (2,6;5,4) vs. 2,5, IQR (1,1;3,4) %/min, p=0,087 and p=0,007 respectively;expected clot lysis time was shorter in both CR1 and CR2: 36,5, IQR (29,8;44,2)/31,7, IQR (24,3;42,7) vs. 65,9. IQR (36,3;95,5) min, p=0,019 and p=0,016 respectively). There was no statistical difference in clot formation and in fibrinolysis between CR1 and CR2. Conclusion: In the deferred period (2-5 months) of COVID-19 the fibrinolysis process remains still active whereas the process of clot formation is mostly suppressed. Endothelial function assessed via the FMD test is within the normal range in the post COVID period.

Delivery of Nitric Oxide in the Cardiovascular System: Implications for Clinical Diagnosis and Therapy.

Nitric oxide (NO) is a key molecule in cardiovascular homeostasis and its abnormal delivery is highly associated with the occurrence and development of cardiovascular disease (CVD). The assessment and manipulation of NO delivery is crucial to the diagnosis and therapy of CVD, such as endothelial dysfunction, atherosclerotic progression, pulmonary hypertension, and cardiovascular manifestations of coronavirus (COVID-19). However, due to the low concentration and fast reaction characteristics of NO in the cardiovascular system, clinical applications centered on NO delivery are challenging. In this tutorial review, we first summarized the methods to estimate the in vivo NO delivery process, based on computational modeling and flow-mediated dilation, to assess endothelial function and vulnerability of atherosclerotic plaque. Then, emerging bioimaging technologies that have the potential to experimentally measure arterial NO concentration were discussed, including Raman spectroscopy and electrochemical sensors. In addition to diagnostic methods, therapies aimed at controlling NO delivery to regulate CVD were reviewed, including the NO release platform to treat endothelial dysfunction and atherosclerosis and inhaled NO therapy to treat pulmonary hypertension and COVID-19. Two potential methods to improve the effectiveness of existing NO therapy were also discussed, including the combination of NO release platform and computational modeling, and stem cell therapy, which currently remains at the laboratory stage but has clinical potential for the treatment of CVD.

Vascular alterations among young adults with SARS-CoV-2.

While SARS-CoV-2 primarily affects the lungs, the virus may be inflicting detriments to the cardiovascular system, both directly through angiotensin-converting enzyme 2 receptor and initiating systemic inflammation. Persistent systemic inflammation may be provoking vascular dysfunction, an early indication of cardiovascular disease risk. To establish the potential effects of SARS-CoV-2 on the systemic vasculature in the arms and legs, we performed a cross-sectional analysis of young healthy adults (control: 5 M/15 F, 23.0 ± 1.3 y, 167 ± 9 cm, 63.0 ± 7.4 kg) and young adults who, 3-4 wk prior to testing, had tested positive for SARS-CoV-2 (SARS-CoV-2: 4 M/7 F, 20.2 ± 1.1 y, 172 ± 12 cm, 69.5 ± 12.4 kg) (means ± SD). Using Doppler ultrasound, brachial artery flow-mediated dilation (FMD) in the arm and single passive limb movement (sPLM) in the leg were assessed as markers of vascular function. Carotid-femoral pulse wave velocity (PWVcf) was asvsessed as a marker of arterial stiffness. FMD was lower in the SARS-CoV-2 group (2.71 ± 1.21%) compared with the control group (8.81 ± 2.96%) (P < 0.01) and when made relative to the shear stimulus (SARS-CoV-2: 0.04 ± 0.02 AU, control: 0.13 ± 0.06 AU, P < 0.01). The femoral artery blood flow response, as evidenced by the area under the curve, from the sPLM was lower in the SARS-CoV-2 group (-3 ± 91 mL) compared with the control group (118 ± 114 mL) (P < 0.01). PWVcf was higher in the SARS-CoV-2 group (5.83 ± 0.62 m/s) compared with the control group (5.17 ± 0.66 m/s) (P < 0.01). Significantly lower systemic vascular function and higher arterial stiffness are evident weeks after testing positive for SARS-CoV-2 among young adults compared with controls.NEW & NOTEWORTHY This study was the first to investigate the vascular implications of contracting SARS-CoV-2 among young, otherwise healthy adults. Using a cross-sectional design, this study assessed vascular function 3-4 wk after young adults tested positive for SARS-CoV-2. The main findings from this study were a strikingly lower vascular function and a higher arterial stiffness compared with healthy controls. Together, these results suggest rampant vascular effects seen weeks after contracting SARS-CoV-2 in young adults.

Blunted peripheral but not cerebral vasodilator function in young otherwise healthy adults with persistent symptoms following COVID-19.

Recent findings suggest that COVID-19 causes vascular dysfunction during the acute phase of the illness in otherwise healthy young adults. To date, to our knowledge, no studies have investigated the longer-term effects of COVID-19 on vascular function. Herein, we hypothesized that young, otherwise healthy adults who are past the acute phase of COVID-19 would exhibit blunted peripheral [brachial artery flow-mediated dilation (FMD) and reactive hyperemia] and cerebral vasodilator function (cerebral vasomotor reactivity to hypercapnia; CVMR) and increased central arterial stiffness. Sixteen young adults who were at least 4 wk past a COVID-19 diagnosis and 12 controls who never had COVID-19 were studied. Eight subjects with COVID-19 were symptomatic (SYM) and eight were asymptomatic (ASYM) at the time of testing. FMD and reactive hyperemia were not different between COVID and control groups. However, FMD was lower in SYM (3.8 ± 0.6%) compared with ASYM (6.8 ± 0.9%; P = 0.007) and control (6.8 ± 0.6%; P = 0.003) with no difference between ASYM and control. Similarly, peak blood velocity following cuff release was lower in SYM (47 ± 8 cm/s) compared with ASYM (64 ± 19 cm/s; P = 0.025) and control (61 ± 14 cm/s; P = 0.036). CVMR and arterial stiffness were not different between any groups. In summary, peripheral macrovascular and microvascular function, but not cerebral vascular function or central arterial stiffness were blunted in young adults symptomatic beyond the acute phase of COVID-19. In contrast, those who were asymptomatic had similar vascular function compared with controls who never had COVID-19.NEW & NOTEWORTHY This study was the first to investigate the persistent effects of COVID-19 on vascular function in otherwise healthy young adults. We demonstrated that peripheral macrovascular and microvascular vasodilation was significantly blunted in young adults still symptomatic from COVID-19 beyond the acute phase (>4 wk from diagnosis), whereas those who become asymptomatic have similar vascular function compared with controls who never had COVID-19. In contrast, cerebral vascular function and central arterial stiffness were unaffected irrespective of COVID-19 symptomology.

Investigation of endothelial dysfunction and arterial stiffness in multisystem inflammatory syndrome in children.

Severe acute respiratory syndrome coronavirus 2 infection can result in multisystem inflammatory syndrome in children (MIS-C). MIS-C can lead to myocardial dysfunction, heart failure, and multiorgan failure; the primary finding is hyperinflammation. Endothelial dysfunction has not been evaluated in patients with MIS-C. We investigated endothelial dysfunction and arterial stiffness parameters in patients with MIS-C. The study included 38 pediatric patients (20 males and 18 females aged 4-17 years, mean age 8.89 years) with MIS-C. Thirty-eight age- and sex-matched healthy individuals were enrolled as the control group. Systolic and diastolic ventricular measurements and systolic and diastolic measurements of ascending aorta diameter were performed by M-mode echocardiography. Endothelial dysfunction was evaluated using flow-mediated dilation by measuring the brachial artery diameter with a high-resolution probe. The MIS-C group had lower flow-mediated dilation than did the controls. The MIS-C group had decreased aortic strain and aortic distensibility values and correlations between decreased flow-mediated dilation and reduced aortic strain, aortic distensibility, and reduced ejection fraction.Conclusion: The results show that patients with MIS-C had endothelial dysfunction and arterial stiffness. Furthermore, the degree of endothelial dysfunction correlated with reduced ejection fractions.What is Known:•Endothelial dysfunction and arterial stiffness are unknown in patients with MIS-C.•The effect of endothelial dysfunction and arterial stiffness on decreased cardiac function is unknown.What is New:•MIS-C patients have endothelial dysfunction and arterial stiffness.•There is a link between left ventricular dysfunction and reduced endothelial dysfunction in patients with MIS-C.

Endothelial function provides early prognostic information in patients with COVID-19: A cohort study.

BACKGROUND: The prothrombotic phenotype and diffuse intravascular coagulation observed in COVID-19 reflect endothelial dysfunction, which is linked to blood flow delivery deficiencies and cardiovascular risk. Assessments of detect vascular deficiencies among newly diagnosed and hospitalized patients due to COVID-19 have yet to be determined. OBJECTIVE: To assess endothelial function characteristics in relation to length of hospitalization and mortality in patients diagnosed with COVID-19 and compare to patients without COVID-19. METHODS: A prospective observational study involving 180 patients with confirmed COVID-19 (COVID-19 group) or suspected and ruled out COVID-19 (Non-COVID-19 group). Clinical evaluation and flow mediated vasodilation (FMD) were performed between the first 24-48 h of hospitalization. Patients were followed until death or discharge. RESULTS: We evaluated 98 patients (COVID-19 group) and 82 (Non-COVID-19 group), COVID-19 group remained hospitalized longer and more deaths occurred compared to the Non-COVID-19 group (p = 0.01; and p < 0.01). Patients in COVID-19 group also had a significantly greater reduction in both FMDmm and FMD% (p < 0.01 in both). We found that absolute FMD≤0.26 mm and relative FMD≤3.43% were the ideal cutoff point to predict mortality and longer hospital stay. In Kaplan Meyer's analysis patients had a high probability of death within a period of up to 10 days of hospitalization. CONCLUSION: Patients hospitalized for COVID-19 present endothelial vascular dysfunction early, remained hospitalized longer and had a higher number of deaths, when compared with patients without COVID-19.