The Fight against COVID-19 on the Multi-Protease Front and Surroundings: Could an Early Therapeutic Approach with Repositioning Drugs Prevent the Disease Severity?

The interaction between the membrane spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the transmembrane angiotensin-converting enzyme 2 (ACE2) receptor of the human epithelial host cell is the first step of infection, which has a critical role for viral pathogenesis of the current coronavirus disease-2019 (COVID-19) pandemic. Following the binding between S1 subunit and ACE2 receptor, different serine proteases, including TMPRSS2 and furin, trigger and participate in the fusion of the viral envelope with the host cell membrane. On the basis of the high virulence and pathogenicity of SARS-CoV-2, other receptors have been found involved for viral binding and invasiveness of host cells. This review comprehensively discusses the mechanisms underlying the binding of SARS-CoV2 to ACE2 and putative alternative receptors, and the role of potential co-receptors and proteases in the early stages of SARS-CoV-2 infection. Given the short therapeutic time window within which to act to avoid the devastating evolution of the disease, we focused on potential therapeutic treatments-selected mainly among repurposing drugs-able to counteract the invasive front of proteases and mild inflammatory conditions, in order to prevent severe infection. Using existing approved drugs has the advantage of rapidly proceeding to clinical trials, low cost and, consequently, immediate and worldwide availability.

Telemonitoring in the Covid-19 Era: The Tuscany Region Experience.

Covid-19 has brought many difficulties in the management of infected and high-risk patients. Telemedicine platforms can really help in this situation, since they allow remotely monitoring Covid-19 patients, reducing the risk for the doctors, without decreasing the efficiency of the therapies and while alleviating patients' mental issues. In this paper, we present the entire architecture and the experience of using the Tel.Te.Covid19 telemedicine platform. Projected for the treatment of chronic diseases, it has been technologically updated for the management of Covid-19 patients with the support of a group of doctors in the territory when the pandemic arrived, introducing new sensors and functionalities (e.g., the familiar use and video calls). In Tuscany (Central Italy), during the first wave of outbreak, a model for enrolling patients was created and tested. Because of the positive results, the latter has been then adopted in the second current wave. The Tel.Te.Covid19 platform has been used by 40 among general practitioners and doctors of continuity care and about 180 symptomatic patients since March 2020. Both patients and doctors have good opinion of the platform, and no hospitalisations or deaths occurred for the monitored patients, reducing also the impact on the National Healthcare System.

COVID-19 and cardiovascular consequences: Is the endothelial dysfunction the hardest challenge?

A Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) has become a pandemic disease named Coronavirus Disease-19 (COVID-19) of epochal dimension. The clinical spectrum of COVID-19 is wide, ranging from asymptomatic forms to severe pneumonia, sepsis and multiple organ dysfunction syndromes resulting in poor outcomes. Among the various consequences of severe COVID-19, cardiovascular (CV) collapse appears the most serious and potentially lethal. On the other hand, pre-existent CV comorbidities are also associated with higher mortality. The most reliable hypothetical pathogenetic mechanism for CV complications and cardiac injury in severe COVID-19 patients appears to be a sustained endothelial dysfunction, caused by the interplay of inflammation and coagulation. In this review, we survey papers addressing issues related to severe COVID-19, characterized by enhanced lung microvascular loss, hypercytokinemia, hypoxemia and thrombosis. We discuss about how the virus-induced downregulation of the angiotensin converting enzyme-2 (ACE2) receptor, used to enter the host cell, could affect the renin-angiotensin system, attempting to clarify the doubts about the use of ACE inhibitors and Angiotensin-II receptor blockers in COVID-19 patients. Finally, we point out how the delicate and physiological homeostatic function of the endothelium, which turns into a disastrous battlefield of the complex interaction between "cytokine and coagulative storms", can be irreparably compromised and result in systemic inflammatory complications.

[It's world war at CoViD-19. The first battle on the front of the viral invasion against the exitus for interstitial pneumonia was decisive.] / È guerra mondiale al CoViD-19. Decisiva la prima battaglia sul fronte dell'invasione virale contro l'exitus per polmonite interstiziale.

An outbreak of a new coronavirus originating from Wuhan (China), responsible for a severe acute respiratory syndrome (SARS), called SARS-CoV-2, is causing a pandemic disease called CoViD-19 (Coronavirus Disease-19), although strict containment measures and restrictions on individual travel have been taken everywhere to hinder the spread of the virus. The clinical spectrum of this infection includes, in order of lesser to greater severity, asymptomatic viremia, paucisymptomatic forms, clinical conditions characterized by respiratory failure that needs mechanical ventilation and support in an intensive care unit, systemic manifestations of infection, septic shock, and multiple organ dysfunction syndromes. There is currently no vaccine to prevent CoViD-19, but the international scientific community is intensely focused on finding a vaccine that will prevent SARS-CoV-2 transmission. In the meanwhile, to prevent hospitals from risking collapse, it is crucial to stratify patients at high risk of poor lung progression, to find effective monitoring strategies, even at home, for the positive patients and/or those highly at risk of positivity of CoViD-19. Starting from the pathogenetic mechanisms involved in the development of this infection up to the clinical characteristics of the infected patients, in this review we tried to focus on the crucial points of the infection in combination with the appropriateness of the medical intervention. We aim to offer indications of therapeutic intervention that are timely and, as far as possible, effective, targeted to the individual patient in relation to age, clinical condition and comorbidities. An early diagnosis associated with an appropriate therapeutic action in the initial stages of the disease can reduce the progression of CoViD-19 towards interstitial pneumonia, thus interfering with the number of transfers to intensive care and lethality of the pandemic in progress.

ß2-Microglobulin and TIMP1 Are Linked Together in Cardiorenal Remodeling and Failure.

BACKGROUND/AIMS: The cardiorenal syndrome is a complication in patients hospitalized with chronic heart failure (CHF). The ß2-microglobulin (b2M) level is an index of decreased glomerular filtration rate (GFR), tissue turnover and inflammation. It is an emerging new predictive marker of cardiovascular events and mortality, but its role as a biomarker of cardiorenal remodeling and failure is still unknown. TIMP1, an endogenous tissue inhibitor of activated matrix metalloproteinases, is a biomarker of heart remodeling and failure. We aimed to evaluate the circulating profile of b2M and TIMP1 in CHF patients, in sedentary controls with no tissue remodeling and in veteran athletes with physiological cardiorenal remodeling and athlete's heart (AH). METHODS: We investigated the plasma levels of b2M and TIMP1 in 24 subjects with CHF without primitive renal disease, in 25 sedentary controls and in 30 veteran marathoners with AH over 50 years. RESULTS: The b2M and TIMP1 levels were higher in CHF patients, and there was a correlation between them (r = 0.5287, p < 0.0095). The b2M level correlated with the severity of cardiorenal impairment: with proBNP (r = 0.66, p > 0.0007), percent ejection fraction (r = -0.56, p = 0.0162) and GFR (r = 0.83, p < 0.0001). b2M was also correlated with TIMP1 in AH subjects (r = 0.7548, p < 0.0001) but not in controls. This correlation was independent from GFR in both CHF patients and sedentary controls. CONCLUSIONS: In CHF patients, the plasma levels of b2M and TIMP1 were linked together and correlated with the severity of cardiorenal failure. Moreover, a strong correlation between b2M and TIMP1 characterized cardiovascular remodeling not only in CHF patients but also in AH subjects. These findings suggest that clinicians should use b2M and TIMP1 as associated biomarkers of cardiorenal remodeling and failure.

A multimarker study of degenerative aortic valve disease: stenoinsufficiency shows more indices of bad prognosis.

OBJECTIVES: It was the aim of this study to assess the pathophysiological, prognostic role of aortic regurgitation (AR) in the 'mixed pictures' of degenerative aortic valve stenoinsufficiency (ASI) by a multimarker clinical approach. METHODS: We enrolled 112 consecutive surgical PATIENTS: 19 with pure valve stenosis (PAS), 39 with mild regurgitation, 29 with severe regurgitation, and 25 controls with annulo-ectatic AR. All underwent complete echocardiography, carotid ultrasound and aortic/coronary multislice computed tomography calcium score evaluation. We determined tissue semiquantitative osteopontin, metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs) and circulating brain natriuretic peptide. We evaluated major adverse cardiac events and cardiovascular early, long-term mortality after bioprosthetic valve implantation. RESULTS: Tissue calcification, carotid and coronary atherosclerotic disease were prevalent in PAS versus ASI and AR patients. The multislice computed tomography calcium score (Agatston) was comparable between PAS and ASI (PAS 3,507.3 + 2,442.6; mild AR 4,270.7 + 2,213.5; severe AR 3,568.5 + 1,823.4), but much lower in AR (1,247.8 + 2,708.6). In ASI, a plasma/tissue 'profibrotic' MMP/TIMP balance prevailed, with circulating and echocardiographic indices of myocardial dysfunction. Percentages of major adverse cardiac events and early, long-term mortality were higher in ASI. CONCLUSIONS: In ASI, different, still unknown, genetic and dysplastic factors could work synergically with cardiovascular risk factors, determining a much more adverse myocardial and valve remodeling, resulting in worse clinical outcome.

Aortic valve disease and gamma-glutamyltransferase: accumulation in tissue and relationships with calcific degeneration.

OBJECTIVE: Degenerative aortic valve disease is characterized by some of the histological features of atherosclerotic lesions. Gamma-glutamyltransferase (GGT) has been recently implicated in pathogenesis of atherosclerosis, as well as in modulation of cells involved in calcium metabolism. We aimed to evaluate the possible implication of this enzyme activity in aortic valve disease. METHODS: GGT immunohistochemistry was performed on valve leaflets of 64 patients with aortic valve stenosis undergoing valve replacement. Fractional GGT activity in plasma and tissue was analysed in a subgroup of cases by molecular exclusion chromatography. RESULTS: A close association was found between tissue extracellular GGT staining and lipid deposits (p<0.0001). GGT was expressed by CD68-positive cells around neovessels, as well as by MMP-9- and TRAP-positive multinucleated cells in the vicinity of bone metaplasia areas. Total plasma GGT levels were associated with low HDL-c (p=0.028) and high triglycerides (p=0.017). Total GGT activity in tissue was negatively correlated with the extent of valves calcification (p=0.03). Both serum and tissue GGT levels were negatively associated with severity of valve stenosis, as judged by peak transvalvular pressure gradients (p<0.0003 and p<0.002, respectively). CONCLUSIONS: Accumulation of GGT activity inside the lipid component of valves leaflets suggests a common mechanism of lesion shaping underlying both atherosclerosis and degenerative aortic valve disease. Moreover, the finding of GGT expression in cells with an osteoclast-like phenotype, and its negative correlation with both valves calcification and degree of valvular stenosis lend additional support to the recently envisaged involvement of GGT in the homeostasis of calcified tissues.

Circulating soluble receptor for advanced glycation end-product levels are decreased in patients with calcific aortic valve stenosis.

OBJECTIVE: It has been suggested that atherosclerotic mechanisms are involved in the pathogenesis of aortic valve stenosis (AVS). We hypothesised that low levels of the soluble receptor for advanced glycation end-products (sRAGE) might be associated with AVS due to its clinical and pathological associations with atherosclerosis. METHODS: We enrolled 75 consecutive patients with severe AVS scheduled for surgical aortic valve replacement and 39 controls without AVS matched for age and gender. Besides the traditional risk factors, we evaluated plasma levels of sRAGE, C-reactive protein (CRP) and IL-6. All patients underwent transthoracic echocardiography, carotid arteries ultrasound scan and coronary angiography. The aortic and coronary calcium by multislice computed tomography was assessed in AVS patients. RESULTS: The values of sRAGE were significantly lower (p<0.01) in AVS patients than in controls, while the CRP levels were significantly higher (p<0.05) in AVS patients than in controls. In AVS patients the sRAGE levels correlated inversely with age, cholesterol levels and coronary calcification. In all study subjects, we found an inverse correlation between circulating sRAGE and the number of echographically assessed sites of calcification (ANOVA, p<0.0001). In multivariable logistic regression analysis after adjustment for potential confounders, the sRAGE levels were significantly and independently associated with the risk of AVS (OR=0.997, 95% CI=0.994-1.000, p=0.048). CONCLUSION: Since sRAGE could exert antiatherogenic effects by preventing inflammatory responses mediated by cell surface RAGE activation, low levels in AVS patients indicate that ligand-RAGE axis could contribute to pathogenesis of AVS.

Role of matrix metalloproteinases and their tissue inhibitors as potential biomarkers of left ventricular remodelling in the athlete's heart.

The aim of the present study was to verify whether plasma MMPs (matrix metalloproteinases) and TIMPs (tissue inhibitors of MMPs) could be used as potential markers of paraphysiological remodelling in the athlete's heart, and to correlate these matrix parameters with echocardiographic signs of LV (left ventricular) remodelling. Plasma MMP-2 and MMP-9 were measured by zymography, and TIMP-1 and TIMP-2 were measured by ELISA in 42 veteran marathoners with AH (athlete's heart), and in 25 sedentary healthy subjects (CTL). All subjects were submitted to a clinical examination and two-dimensional colour Doppler echocardiography together with the measurement of circulating NT-proBNP (N-terminal pro-B-type natriuretic peptide); GGT (gamma-glutamyl transpeptidase) was evaluated as a marker of cardiovascular disease. Veteran athletes had a significant elevation in LV dimensions and calculated LV mass index. Diastolic and systolic functions were normal for both groups. MMP-9 levels were significantly lower in AH than in CTL subjects (56.9+/-4.3 compared with 119.4+/-21.5 m-units/l, P<0.01). There were significant differences in MMP-2 between the two groups, with a down-regulation in the AH subjects (182.5+/-16.8 units/ml in CTL compared with 117.1+/-9.1 units/ml in AH, P<0.01). MMP-2 and MMP-2/TIMP-2 were inversely correlated with myocardial indices of hypertrophy in AH and CTL subjects. AH and CTL subjects showed similar TIMP values. The results of the present study indicate that MMPs and TIMPs could represent potential biomarkers of adaptive heart remodelling in the athletes. In addition, the inverse correlation of the MMP-2/TIMP-2 system with echocardiographic signs of myocardial hypertrophy could represent a new diagnostic and prognostic indicator useful in the evaluation of cardiovascular risk in athletes.