Exosomal miR-145 and miR-885 regulate thrombosis in COVID-19.

We hypothesized that exosomal microRNAs (miRNAs) could be implied in the pathogenesis of thromboembolic complications in COVID-19. We isolated circulating exosomes from COVID-19 patients and then we divided our population in two arms based on the D-dimer level on hospital admission. We observed that exosomal miR-145 and miR-885 significantly correlate with D-Dimer levels. Moreover, we demonstrate that human endothelial cells express the main cofactors needed for SARS-CoV-2 internalization, including ACE2, TMPRSS2, and CD-147. Interestingly, human endothelial cells treated with serum from COVID-19 patients release significantly less miR-145 and miR-885, exhibit increased apoptosis, and display significantly impaired angiogenetic properties compared to cells treated with non-COVID-19 serum. Taken together, our data indicate that exosomal miR-145 and miR-885 are essential in modulating thromboembolic events in COVID-19. Significance Statement In this work, we demonstrate for the first time that two specific microRNA (namely miR-145 and miR-885) contained in circulating exosomes are functionally involved in thromboembolic events in COVID-19. Our findings are especially relevant to the general audience when considering the emerging prominence of post-acute sequelae of COVID-19 systemic manifestations known as Long-COVID.

COVID-19 and atrial fibrillation: Intercepting lines.

Almost 20% of COVID-19 patients have a history of atrial fibrillation (AF), but also a new-onset AF represents a frequent complication in COVID-19. Clinical evidence demonstrates that COVID-19, by promoting the evolution of a prothrombotic state, increases the susceptibility to arrhythmic events during the infective stages and presumably during post-recovery. AF itself is the most frequent form of arrhythmia and is associated with substantial morbidity and mortality. One of the molecular factors involved in COVID-19-related AF episodes is the angiotensin-converting enzyme (ACE) 2 availability. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 to enter and infect multiple cells. Atrial ACE2 internalization after binding to SARS-CoV-2 results in a raise of angiotensin (Ang) II, and in a suppression of cardioprotective Ang(1-7) formation, and thereby promoting cardiac hypertrophy, fibrosis and oxidative stress. Furthermore, several pharmacological agents used in COVID-19 patients may have a higher risk of inducing electrophysiological changes and cardiac dysfunction. Azithromycin, lopinavir/ritonavir, ibrutinib, and remdesivir, used in the treatment of COVID-19, may predispose to an increased risk of cardiac arrhythmia. In this review, putative mechanisms involved in COVID-19-related AF episodes and the cardiovascular safety profile of drugs used for the treatment of COVID-19 are summarized.

Glycaemic control is associated with SARS-CoV-2 breakthrough infections in vaccinated patients with type 2 diabetes.

Patients with type 2 diabetes (T2D) are characterized by blunted immune responses, which are affected by glycaemic control. Whether glycaemic control influences the response to COVID-19 vaccines and the incidence of SARS-CoV-2 breakthrough infections is unknown. Here we show that poor glycaemic control, assessed as mean HbA1c in the post-vaccination period, is associated with lower immune responses and an increased incidence of SARS-CoV-2 breakthrough infections in T2D patients vaccinated with mRNA-BNT162b2. We report data from a prospective observational study enroling healthcare and educator workers with T2D receiving the mRNA-BNT162b2 vaccine in Campania (Italy) and followed for one year (5 visits, follow-up 346 ± 49 days) after one full vaccination cycle. Considering the 494 subjects completing the study, patients with good glycaemic control (HbA1c one-year mean < 7%) show a higher virus-neutralizing antibody capacity and a better CD4 + T/cytokine response, compared with those with poor control (HbA1c one-year mean ≥ 7%). The one-year mean of HbA1c is linearly associated with the incidence of breakthrough infections (Beta = 0.068; 95% confidence interval [CI], 0.032-0.103; p < 0.001). The comparison of patients with poor and good glycaemic control through Cox regression also show an increased risk for patients with poor control (adjusted hazard ratio [HR], 0.261; 95% CI, 0.097-0.700; p = 0.008). Among other factors, only smoking (HR = 0.290, CI 0.146-0.576 for non-smokers; p < 0.001) and sex (HR = 0.105, CI 0.035-0.317 for females; p < 0.001) are significantly associated with the incidence of breakthrough infections.

Effect of Hyperglycemia on COVID-19 Outcomes: Vaccination Efficacy, Disease Severity, and Molecular Mechanisms.

BACKGROUND/AIMS: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-stranded single-stranded RNA virus, a member of the subgenus Sarbecovirus (beta-CoV lineage B) and responsible for the coronavirus disease 2019 (COVID-19). COVID-19 encompasses a large range of disease severity, from mild symptoms to severe forms with Intensive Care Unit admission and eventually death. The severe forms of COVID-19 are usually observed in high-risk patients, such as those with type two diabetes mellitus. Here, we review the available evidence linking acute and chronic hyperglycemia to COVID-19 outcomes, describing also the putative mediators of such interactions. FINDINGS/CONCLUSIONS: Acute hyperglycemia at hospital admission represents a risk factor for poor COVID-19 prognosis in patients with and without diabetes. Acute and chronic glycemic control are both emerging as major determinants of vaccination efficacy, disease severity and mortality rate in COVID-19 patients. Mechanistically, it has been proposed that hyperglycemia might be a disease-modifier for COVID-19 through multiple mechanisms: (a) induction of glycation and oligomerization of ACE2, the main receptor of SARS-CoV-2; (b) increased expression of the serine protease TMPRSS2, responsible for S protein priming; (c) impairment of the function of innate and adaptive immunity despite the induction of higher pro-inflammatory responses, both local and systemic. Consistently, managing acute hyperglycemia through insulin infusion has been suggested to improve clinical outcomes, while implementing chronic glycemic control positively affects immune response following vaccination. Although more research is warranted to better disentangle the relationship between hyperglycemia and COVID-19, it might be worth considering glycemic control as a potential route to optimize disease prevention and management.

SARS-COV-2 colonizes coronary thrombus and impairs heart microcirculation bed in asymptomatic SARS-CoV-2 positive subjects with acute myocardial infarction.

BACKGROUND: The viral load of asymptomatic SAR-COV-2 positive (ASAP) persons has been equal to that of symptomatic patients. On the other hand, there are no reports of ST-elevation myocardial infarction (STEMI) outcomes in ASAP patients. Therefore, we evaluated thrombus burden and thrombus viral load and their impact on microvascular bed perfusion in the infarct area (myocardial blush grade, MBG) in ASAP compared to SARS-COV-2 negative (SANE) STEMI patients. METHODS: This was an observational study of 46 ASAP, and 130 SANE patients admitted with confirmed STEMI treated with primary percutaneous coronary intervention and thrombus aspiration. The primary endpoints were thrombus dimension + thrombus viral load effects on MBG after PPCI. The secondary endpoints during hospitalization were major adverse cardiovascular events (MACEs). MACEs are defined as a composite of cardiovascular death, nonfatal acute AMI, and heart failure during hospitalization. RESULTS: In the study population, ASAP vs. SANE showed a significant greater use of GP IIb/IIIa inhibitors and of heparin (p < 0.05), and a higher thrombus grade 5 and thrombus dimensions (p < 0.05). Interestingly, ASAP vs. SANE patients had lower MBG and left ventricular function (p < 0.001), and 39 (84.9%) of ASAP patients had thrombus specimens positive for SARS-COV-2. After PPCI, a MBG 2-3 was present in only 26.1% of ASAP vs. 97.7% of SANE STEMI patients (p < 0.001). Notably, death and nonfatal AMI were higher in ASAP vs. SANE patients (p < 0.05). Finally, in ASAP STEMI patients the thrombus viral load was a significant determinant of thrombus dimension independently of risk factors (p < 0.005). Thus, multiple logistic regression analyses evidenced that thrombus SARS-CoV-2 infection and dimension were significant predictors of poorer MBG in STEMI patients. Intriguingly, in ASAP patients the female vs. male had higher thrombus viral load (15.53 ± 4.5 vs. 30.25 ± 5.51 CT; p < 0.001), and thrombus dimension (4.62 ± 0.44 vs 4.00 ± 1.28 mm2; p < 0.001). ASAP vs. SANE patients had a significantly lower in-hospital survival for MACE following PPCI (p < 0.001). CONCLUSIONS: In ASAP patients presenting with STEMI, there is strong evidence towards higher thrombus viral load, dimension, and poorer MBG. These data support the need to reconsider ASAP status as a risk factor that may worsen STEMI outcomes.

Glycated ACE2 receptor in diabetes: open door for SARS-COV-2 entry in cardiomyocyte.

RATIONALE: About 50% of hospitalized coronavirus disease 2019 (COVID-19) patients with diabetes mellitus (DM) developed myocardial damage. The mechanisms of direct SARS-CoV-2 cardiomyocyte infection include viral invasion via ACE2-Spike glycoprotein-binding. In DM patients, the impact of glycation of ACE2 on cardiomyocyte invasion by SARS-CoV-2 can be of high importance. OBJECTIVE: To evaluate the presence of SARS-CoV-2 in cardiomyocytes from heart autopsy of DM cases compared to Non-DM; to investigate the role of DM in SARS-COV-2 entry in cardiomyocytes. METHODS AND RESULTS: We evaluated consecutive autopsy cases, deceased for COVID-19, from Italy between Apr 30, 2020 and Jan 18, 2021. We evaluated SARS-CoV-2 in cardiomyocytes, expression of ACE2 (total and glycosylated form), and transmembrane protease serine protease-2 (TMPRSS2) protein. In order to study the role of diabetes on cardiomyocyte alterations, independently of COVID-19, we investigated ACE2, glycosylated ACE2, and TMPRSS2 proteins in cardiomyocytes from DM and Non-DM explanted-hearts. Finally, to investigate the effects of DM on ACE2 protein modification, an in vitro glycation study of recombinant human ACE2 (hACE2) was performed to evaluate the effects on binding to SARS-CoV-2 Spike protein. The authors included cardiac tissue from 97 autopsies. DM was diagnosed in 37 patients (38%). Fourth-seven out of 97 autopsies (48%) had SARS-CoV-2 RNA in cardiomyocytes. Thirty out of 37 DM autopsy cases (81%) and 17 out of 60 Non-DM autopsy cases (28%) had SARS-CoV-2 RNA in cardiomyocytes. Total ACE2, glycosylated ACE2, and TMPRSS2 protein expressions were higher in cardiomyocytes from autopsied and explanted hearts of DM than Non-DM. In vitro exposure of monomeric hACE2 to 120 mM glucose for 12 days led to non-enzymatic glycation of four lysine residues in the neck domain affecting the protein oligomerization. CONCLUSIONS: The upregulation of ACE2 expression (total and glycosylated forms) in DM cardiomyocytes, along with non-enzymatic glycation, could increase the susceptibility to COVID-19 infection in DM patients by favouring the cellular entry of SARS-CoV2.

SARS-CoV-2 Emergency and Long-Term Cognitive Impairment in Older People.

The SARS-CoV-2 infection has spread to all continents, affecting particularly older people. The complexity of SARS-CoV2 infection is still under study. Despite respiratory involvement is the main clinical manifestation of COVID-19, neurological manifestations are common. Although it is obvious to give priority to infectious emergency and the infectious disease itself, at present, however, data on potential long-term damages generally and on long-term cognitive functions impairment of older COVID-19 survivors have yet to be investigated. Because the hypothesis on the involvement of SARS-CoV-2 on the long-term cognitive decline pathogenesis would seem difficult to prove, we wanted to explore the brain mechanisms of SARS-CoV-2, in order to provide more in-depth analysis and to draw attention to a topic relevant to basic scientific research and, more generally, to the elderly population.Looking forward, we argue that an early clinical and instrumental cognitive assessment can help prevent and slow down this possible complication or at least improve the quality of life for older people Covid-19 survivor.

Renin-Angiotensin System and Coronavirus Disease 2019: A Narrative Review.

Although clinical manifestations of the 2019 novel coronavirus disease pandemic (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), are mainly respiratory symptoms, patients can also develop severe cardiovascular damage. Therefore, understanding the damage caused by SARS-COV-2 to the cardiovascular system and the underlying mechanisms is fundamental. The cardiovascular damage may be related to the imbalance of the renin-angiotensin-system (RAS) as this virus binds the Angiotensin-Converting-Enzyme 2 (ACE2), expressed on the lung alveolar epithelial cells, to enter into cells. Virus internalization may cause a downregulation of ACE2 on host cell surface that could lead to a local increased level of angiotensin II (AII) and a reduced level of angiotensin 1-7 (A1-7). An imbalance between these angiotensins may be responsible for the lung and heart damage. Pharmacological strategies that interfere with the viral attachment to ACE2 (umifenovir and hydroxychloroquine/chloroquine) or that modulate the RAS (analogous of A1-7 and ACE2, losartan) are in clinical development for COVID-19. The use of RAS inhibitors has also become a matter of public concern as these drugs may increase the mRNA expression and levels of ACE2 and impact the virulence and transmission of SARS-COV-2. Data on the effect of RAS inhibitors on ACE2 mRNA expression are scarce. Scientific societies expressed their opinion on continuing the therapy with RAS inhibitors in patients with COVID-19 and underlying cardiovascular diseases. In conclusion, RAS may play a role in SARS-COV-2-induced cardiac and pulmonary damage. Further studies are needed to better understand the role of RAS in COVID-19 and to guide decision on the use of RAS inhibitors.

Implications of AB0 blood group in hypertensive patients with covid-19.

BACKGROUND: Hypertension is the most frequent co-morbidity in patients with covid-19 infection, and we might speculate that a specific blood group could play a key role in the clinical outcome of hypertensive patients with covid-19. METHODS: In this prospective study, we compared 0 vs. non-0 blood group in hypertensive patients with covid-19 infection. In these patients, we evaluated inflammatory and thrombotic status, cardiac injury, and death events. RESULTS: Patients in non-0 (n = 92) vs. 0 blood group (n = 72) had significantly different values of activated pro-thrombin time, D-dimer, and thrombotic indexes as Von Willebrand factor and Factor VIII (p < 0.05). Furthermore, patients in non-0 vs. 0 blood group had higher rate of cardiac injury (10 (13.9%) vs. 27 (29.3%)) and death, (6 (8.3%) vs. 18 (19.6%)), (p < 0.05). At the multivariate analysis, Interleukin-6 (1.118, CI 95% 1.067-1.171) and non-0 blood group (2.574, CI 95% 1.207-5.490) were independent predictors of cardiac injury in hypertensive patients with covid-19. D-dimer (1.082, CI 95% 1.027-1.140), Interleukin-6 (1.216, CI 95% 1.082-1.367) and non-0 blood group (3.706, CI 95% 1.223-11.235) were independent predictors of deaths events in hypertensive patients with covid-19. CONCLUSIONS: Taken together, our data indicate that non-0 covid-19 hypertensive patients have significantly higher values of pro-thrombotic indexes, as well as higher rate of cardiac injury and deaths compared to 0 patients. Moreover, AB0 blood type influences worse prognosis in hypertensive patients with covid-19 infection.

Covid-19 Kills More Men Than Women: An Overview of Possible Reasons.

The high mortality observed in Covid-19 patients may be related to unrecognized pulmonary embolism, pulmonary thrombosis, or other underlying cardiovascular diseases. Recent data have highlighted that the mortality rate of Covid-19 seems to be higher in male patients compared to females. In this paper, we have analyzed possible factors that may underline this sex difference in terms of activity of the immune system and its modulation by sex hormones, coagulation pattern, and preexisting cardiovascular diseases as well as effects deriving from smoking and drinking habits. Future studies are needed to evaluate the effects of sex differences on the prevalence of infections, including Covid-19, its outcome, and the responses to antiviral treatments.

Could Anti-Hypertensive Drug Therapy Affect the Clinical Prognosis of Hypertensive Patients With COVID-19 Infection? Data From Centers of Southern Italy.

BACKGROUND Coronavirus disease 2019 (COVID-19) is the cause of a pandemic disease, with severe acute respiratory syndrome by binding target epithelial lung cells through angiotensin-converting enzyme 2 in humans. Thus, patients with hypertension with COVID-19 could have worse prognosis. Indeed, angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers may interfere with angiotensin-converting enzyme 2 expression/activity. Thus, patients with hypertension undergoing angiotensin-converting enzyme inhibitor and/or angiotensin receptor blockers drug therapy may be at a higher risk of contracting a serious COVID-19 infection and should be monitored. Moreover, in the present study we investigated the effects of angiotensin-converting enzyme inhibitor versus angiotensin receptor blockers versus calcium channel blockers on clinical outcomes as mechanical ventilation, intensive care unit admissions, heart injury, and death in 62 patients with hypertension hospitalized for COVID-19 infection. METHODS AND RESULTS The multicenter study was prospectively conducted at Department of Infectious Diseases of Sant'Anna Hospital of Caserta, and of University of Campania "Luigi Vanvitelli" of Naples, at Department of Advanced Surgical and Medical Sciences of University of Campania "Luigi Vanvitelli," Naples, and at General Medical Assistance Unit "FIMG," Naples, Italy. Lowest values of left ventricle ejection fraction predicted deaths (1.142, 1.008-1.294, P<0.05), while highest values of interleukin-6 predicted the admission to intensive care unit (1.617, 1.094-2.389), mechanical ventilation (1.149, 1.082-1.219), heart injuries (1.367, 1.054-1.772), and deaths (4.742, 1.788-8.524). CONCLUSIONS Anti-hypertensive drugs didn't affect the prognosis in patients with COVID-19. Consequently, tailored anti-inflammatory and immune therapies in addition to chronic antihypertensive therapy, could prevent a worse prognosis, as well as improve the clinical outcomes in patients with hypertension with COVID-19 infection.

Impact of diabetes mellitus on clinical outcomes in patients affected by Covid-19.

A possible association could exist between type 2 diabetes mellitus (T2DM) and Coronavirus-19 (Covid-19) infection. Indeed, patients with T2DM show high prevalence, severity of disease and mortality during Covid-19 infection. However, the rates of severe disease are significantly higher in patients with diabetes compared with non-diabetes (34.6% vs. 14.2%; p < 0.001). Similarly, T2DM patients have higher rates of need for Intensive Care Unit (ICU, 37.0% vs. 26.7%; p = 0.028). Thus, about the pneumonia of Covid-19, we might speculate that the complicated alveolar-capillary network of lungs could be targeted by T2DM micro-vascular damage. Therefore, T2DM patients frequently report respiratory symptoms and are at increased risk of several pulmonary diseases. In addition, pro-inflammatory pathways as that involving interleukin 6 (IL-6), could be a severity predictor of lung diseases. Therefore, it looks intuitive to speculate that this condition could explain the growing trend of cases, hospitalization and mortality for patients with T2DM during Covid-19 infection. To date, an ongoing experimental therapy with monoclonal antibody against the IL-6 receptor in Italy seems to have beneficial effects on severe lung disease and prognosis in patients with Covid-19 infection. Therefore, should patients with T2DM be treated with more attention to glycemic control and monoclonal antibody against the IL-6 receptor during the Covid-19 infection?