SARS-CoV-2 infection aggravates chronic comorbidities of cardiovascular diseases and diabetes in mice.

Background: Cardiovascular diseases (CVDs) and diabetes mellitus (DM) are top two chronic comorbidities that increase the severity and mortality of COVID-19. However, how SARS-CoV-2 alters the progression of chronic diseases remain unclear. Methods: We used adenovirus to deliver h-ACE2 to lung to enable SARS-CoV-2 infection in mice. SARS-CoV-2's impacts on pathogenesis of chronic diseases were studied through histopathological, virologic and molecular biology analysis. Results: Pre-existing CVDs resulted in viral invasion, ROS elevation and activation of apoptosis pathways contribute myocardial injury during SARS-CoV-2 infection. Viral infection increased fasting blood glucose and reduced insulin response in DM model. Bone mineral density decreased shortly after infection, which associated with impaired PI3K/AKT/mTOR signaling. Conclusion: We established mouse models mimicked the complex pathological symptoms of COVID-19 patients with chronic diseases. Pre-existing diseases could impair the inflammatory responses to SARS-CoV-2 infection, which further aggravated the pre-existing diseases. This work provided valuable information to better understand the interplay between the primary diseases and SARS-CoV-2 infection.

Cardiovascular aspects of COVID-19.

Coronavirus disease 2019 (COVID-19) is primarily a pulmonary disease, but also affects the cardiovascular system in multiple ways. In this review, we will summarise and put into perspective findings and debates relating to the diverse aspects of cardiovascular involvement of COVID-19. We will review evidence for the role of the renin-angiotensin-aldosterone system (RAAS), the risk of pre-existing cardiovascular disease in COVID-19 susceptibility and course, and the mechanism of acute and long-term myocardial injury. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) uses membrane-bound angiotensin converting-enzyme-2 (ACE2) as a receptor for cell entry. ACE2 is part of an important counter-regulatory circuit antagonising the harmful effects of angiotensin II on lung and heart. Modulation of ACE2 may therefore affect disease susceptibility and disease course. However, observational clinical studies and one randomised trial have so far not yielded evidence for harmful or beneficial effects of blockers of the RAAS during COVID-19. Age, gender, and multi-morbidity all increase susceptibility to SARS-CoV-2. In contrast, pre-existing cardiovascular diseases do so only minimally, but they may aggravate the disease course. Direct SARS-CoV-2 infection of the heart tissue and myocytes is rare. Nevertheless, COVID-19 may lead to myocarditis-like acute cardiac injury, characterised by myocardial oedema, but lacking extensive myocyte loss and lymphocytic infiltration. Independent of this, increases in cardiac biomarkers (troponin, N-terminal pro-brain natriuretic peptide, D-dimer) are frequent, especially in the phase of severe systemic inflammation and acute respiratory distress syndrome, and quantitatively associated with poor outcome. The pulmonary infection may result initially in right ventricular dysfunction, but in cases with severe systemic infection hypoxia, hyperinflammation and cytokine storm heart failure may eventually ensue. Unlike other infections and inflammatory states, COVID-19 does not appear to trigger acute coronary syndromes. In children, even mild COVID-19 can induce a multisystem inflammatory syndrome with Kawasaki-like symptoms frequently accompanied by cardiogenic shock.

Mechanisms contributing to adverse outcomes of COVID-19 in obesity.

A growing amount of epidemiological data from multiple countries indicate an increased prevalence of obesity, more importantly central obesity, among hospitalized subjects with COVID-19. This suggests that obesity is a major factor contributing to adverse outcome of the disease. As it is a metabolic disorder with dysregulated immune and endocrine function, it is logical that dysfunctional metabolism contributes to the mechanisms behind obesity being a risk factor for adverse outcome in COVID-19. Emerging data suggest that in obese subjects, (a) the molecular mechanisms of viral entry and spread mediated through ACE2 receptor, a multifunctional host cell protein which links to cellular homeostasis mechanisms, are affected. This includes perturbation of the physiological renin-angiotensin system pathway causing pro-inflammatory and pro-thrombotic challenges (b) existent metabolic overload and ER stress-induced UPR pathway make obese subjects vulnerable to severe COVID-19, (c) host cell response is altered involving reprogramming of metabolism and epigenetic mechanisms involving microRNAs in line with changes in obesity, and (d) adiposopathy with altered endocrine, adipokine, and cytokine profile contributes to altered immune cell metabolism, systemic inflammation, and vascular endothelial dysfunction, exacerbating COVID-19 pathology. In this review, we have examined the available literature on the underlying mechanisms contributing to obesity being a risk for adverse outcome in COVID-19.

Impact of metabolic and cardiovascular disease on COVID-19 mortality: A systematic review and meta-analysis.

BACKGROUND AND AIMS: This meta-analysis aims to highlight the impact of cardio-metabolic comorbidities on COVID-19 severity and mortality. METHODS: A thorough search on major online databases was done for studies describing the clinical outcomes of COVID-19 patients. We used random-effects model to compute pooled estimates for critical or fatal disease. RESULTS: A total of 20,475 patients from 33 eligible studies were included. Maximum risk of development of critical or fatal COVID-19 disease was seen in patients with underlying cardiovascular disease [OR: 3.44, 95% CI: 2.65-4.48] followed by chronic lung disease, hypertension and diabetes mellitus. Of the total cases, 64% had one of the four comorbidities with the most prevalent being hypertension with a pooled prevalence of 27%. CONCLUSIONS: Presence of comorbidities like cardiovascular disease, chronic lung disease, hypertension and diabetes mellitus led to a higher risk of development of critical or fatal COVID-19 disease, with maximum risk seen with underlying cardiovascular disease.

The Role of Thromboxane in the Course and Treatment of Ischemic Stroke: Review.

Cardiovascular diseases are currently among the leading causes of morbidity and mortality in many developed countries. They are distinguished by chronic and latent development, a course with stages of worsening of symptoms and a period of improvement, and a constant potential threat to life. One of the most important disorders in cardiovascular disease is ischemic stroke. The causes of ischemic stroke can be divided into non-modifiable and modifiable causes. One treatment modality from a neurological point of view is acetylsalicylic acid (ASA), which blocks cyclooxygenase and, thus, thromboxane synthesis. The legitimacy of its administration does not raise any doubts in the case of the acute phase of stroke in patients in whom thrombolytic treatment cannot be initiated. The measurement of thromboxane B2 (TxB2) in serum (a stable metabolic product of TxA2) is the only test that measures the effect of aspirin on the activity of COX-1 in platelets. Measurement of thromboxane B2 may be a potential biomarker of vascular disease risk in patients treated with aspirin. The aim of this study is to present the role of thromboxane B2 in ischemic stroke and to present effective therapies for the treatment of ischemic stroke. Scientific articles from the PubMed database were used for the work, which were selected on the basis of a search for "thromboxane and stroke". Subsequently, a restriction was introduced for works older than 10 years, those concerning animals, and those without full text access. Ultimately, 58 articles were selected. It was shown that a high concentration of TXB2 may be a risk factor for ischemic stroke or ischemic heart disease. However, there is insufficient evidence to suggest that thromboxane could be used in clinical practice as a marker of ischemic stroke. The inclusion of ASA in the prevention of stroke has a beneficial effect that is associated with the effect on thromboxane. However, its insufficient power in 25% or even 50% of the population should be taken into account. An alternative and/or additional therapy could be a selective antagonist of the thromboxane receptor. Thromboxane A2 production is inhibited by estrogen; therefore, the risk of CVD after the menopause and among men is higher. More research is needed in this area.

Increased complications of COVID-19 in people with cardiovascular disease: Role of the renin-angiotensin-aldosterone system (RAAS) dysregulation.

The rapid spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19), has had a dramatic negative impact on public health and economies worldwide. Recent studies on COVID-19 complications and mortality rates suggest that there is a higher prevalence in cardiovascular diseases (CVD) patients. Past investigations on the associations between pre-existing CVDs and susceptibility to coronavirus infections including SARS-CoV and the Middle East Respiratory Syndrome coronavirus (MERS-CoV), have demonstrated similar results. However, the underlying mechanisms are poorly understood. This has impeded adequate risk stratification and treatment strategies for CVD patients with SARS-CoV-2 infections. Generally, dysregulation of the expression of angiotensin-converting enzyme (ACE) and the counter regulator, angiotensin-converting enzyme 2 (ACE2) is a hallmark of cardiovascular risk and CVD. ACE2 is the main host receptor for SARS-CoV-2. Although further studies are required, dysfunction of ACE2 after virus binding and dysregulation of the renin-angiotensin-aldosterone system (RAAS) signaling may worsen the outcomes of people affected by COVID-19 and with preexisting CVD. Here, we review the current knowledge and outline the gaps related to the relationship between CVD and COVID-19 with a focus on the RAAS. Improved understanding of the mechanisms regulating viral entry and the role of RAAS may direct future research with the potential to improve the prevention and management of COVID-19.

Circadian disruption and human health.

Circadian disruption is pervasive and can occur at multiple organizational levels, contributing to poor health outcomes at individual and population levels. Evidence points to a bidirectional relationship, in that circadian disruption increases disease severity and many diseases can disrupt circadian rhythms. Importantly, circadian disruption can increase the risk for the expression and development of neurologic, psychiatric, cardiometabolic, and immune disorders. Thus, harnessing the rich findings from preclinical and translational research in circadian biology to enhance health via circadian-based approaches represents a unique opportunity for personalized/precision medicine and overall societal well-being. In this Review, we discuss the implications of circadian disruption for human health using a bench-to-bedside approach. Evidence from preclinical and translational science is applied to a clinical and population-based approach. Given the broad implications of circadian regulation for human health, this Review focuses its discussion on selected examples in neurologic, psychiatric, metabolic, cardiovascular, allergic, and immunologic disorders that highlight the interrelatedness between circadian disruption and human disease and the potential of circadian-based interventions, such as bright light therapy and exogenous melatonin, as well as chronotherapy to improve and/or modify disease outcomes.

COVID-19: Cardio-pulmonary and Vascular Manifestations.

The COVID-19 pandemic is still threatening us, our patients, and the global health care system. Since the first outbreak at the end of 2019 in China, it became rapidly clear that a new variant of a SARS virus, SARS-CoV-2, is threatening our human society worldwide. Since then, the scientific community has accumulated an incredibly large amount of knowledge about the pathophysiology of this virus, primarily affecting the respiratory tract and, in severe cases, subsequently resulting in acute respiratory distress syndrome and multiple organ failure due to uncontrolled systemic inflammatory response syndrome.1 2.

Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies.

The endothelium, a cellular monolayer lining the blood vessel wall, plays a critical role in maintaining multiorgan health and homeostasis. Endothelial functions in health include dynamic maintenance of vascular tone, angiogenesis, hemostasis, and the provision of an antioxidant, anti-inflammatory, and antithrombotic interface. Dysfunction of the vascular endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion and hyperpermeability, and endothelial cell senescence. Recent studies have implicated altered endothelial cell metabolism and endothelial-to-mesenchymal transition as new features of endothelial dysfunction. Endothelial dysfunction is regarded as a hallmark of many diverse human panvascular diseases, including atherosclerosis, hypertension, and diabetes. Endothelial dysfunction has also been implicated in severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive drugs, and antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors and interleukin 1ß monoclonal antibodies, counter endothelial dysfunction as part of their clinical benefits. The regulation of endothelial dysfunction by noncoding RNAs has provided novel insights into these newly described regulators of endothelial dysfunction, thus yielding potential new therapeutic approaches. Altogether, a better understanding of the versatile (dys)functions of endothelial cells will not only deepen our comprehension of human diseases but also accelerate effective therapeutic drug discovery. In this review, we provide a timely overview of the multiple layers of endothelial function, describe the consequences and mechanisms of endothelial dysfunction, and identify pathways to effective targeted therapies. SIGNIFICANCE STATEMENT: The endothelium was initially considered to be a semipermeable biomechanical barrier and gatekeeper of vascular health. In recent decades, a deepened understanding of the biological functions of the endothelium has led to its recognition as a ubiquitous tissue regulating vascular tone, cell behavior, innate immunity, cell-cell interactions, and cell metabolism in the vessel wall. Endothelial dysfunction is the hallmark of cardiovascular, metabolic, and emerging infectious diseases. Pharmacotherapies targeting endothelial dysfunction have potential for treatment of cardiovascular and many other diseases.

Cardiovascular disease and COVID-19: a consensus paper from the ESC Working Group on Coronary Pathophysiology & Microcirculation, ESC Working Group on Thrombosis and the Association for Acute CardioVascular Care (ACVC), in collaboration with the European Heart Rhythm Association (EHRA).

The cardiovascular system is significantly affected in coronavirus disease-19 (COVID-19). Microvascular injury, endothelial dysfunction, and thrombosis resulting from viral infection or indirectly related to the intense systemic inflammatory and immune responses are characteristic features of severe COVID-19. Pre-existing cardiovascular disease and viral load are linked to myocardial injury and worse outcomes. The vascular response to cytokine production and the interaction between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and angiotensin-converting enzyme 2 receptor may lead to a significant reduction in cardiac contractility and subsequent myocardial dysfunction. In addition, a considerable proportion of patients who have been infected with SARS-CoV-2 do not fully recover and continue to experience a large number of symptoms and post-acute complications in the absence of a detectable viral infection. This conditions often referred to as 'post-acute COVID-19' may have multiple causes. Viral reservoirs or lingering fragments of viral RNA or proteins contribute to the condition. Systemic inflammatory response to COVID-19 has the potential to increase myocardial fibrosis which in turn may impair cardiac remodelling. Here, we summarize the current knowledge of cardiovascular injury and post-acute sequelae of COVID-19. As the pandemic continues and new variants emerge, we can advance our knowledge of the underlying mechanisms only by integrating our understanding of the pathophysiology with the corresponding clinical findings. Identification of new biomarkers of cardiovascular complications, and development of effective treatments for COVID-19 infection are of crucial importance.

The Controversial Role of Glucose-6-Phosphate Dehydrogenase Deficiency on Cardiovascular Disease: A Narrative Review.

Cardiovascular disorders (CVD) are highly prevalent and the leading cause of death worldwide. Atherosclerosis is responsible for most cases of CVD. The plaque formation and subsequent thrombosis in atherosclerosis constitute an ongoing process that is influenced by numerous risk factors such as hypertension, diabetes, dyslipidemia, obesity, smoking, inflammation, and sedentary lifestyle. Among the various risk and protective factors, the role of glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common inborn enzyme disorder across populations, is still debated. For decades, it has been considered a protective factor against the development of CVD. However, in the recent years, growing scientific evidence has suggested that this inherited condition may act as a CVD risk factor. The role of G6PD deficiency in the atherogenic process has been investigated using in vitro or ex vivo cellular models, animal models, and epidemiological studies in human cohorts of variable size and across different ethnic groups, with conflicting results. In this review, the impact of G6PD deficiency on CVD was critically reconsidered, taking into account the most recent acquisitions on molecular and biochemical mechanisms, namely, antioxidative mechanisms, glutathione recycling, and nitric oxide production, as well as their mutual interactions, which may be impaired by the enzyme defect in the context of the pentose phosphate pathway. Overall, current evidence supports the notion that G6PD downregulation may favor the onset and evolution of atheroma in subjects at risk of CVD. Given the relatively high frequency of this enzyme deficiency in several regions of the world, this finding might be of practical importance to tailor surveillance guidelines and facilitate risk stratification.

An organ systems-based review of outcomes associated with sleep apnea in hospitalized patients.

ABSTRACT: The current global health crisis due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has prompted the medical community to investigate the effects of underlying medical conditions, including sleep-disordered breathing, on inpatient care. Obstructive sleep apnea (OSA) is a common form of sleep-disordered breathing that may complicate numerous acquired conditions, particularly in inpatient and critical care settings. Viral pneumonia is a major contributor to intensive care unit (ICU) admissions and often presents more severely in patients with underlying pulmonary disease, especially those with obesity and OSA. This review summarizes the most recent data regarding complications of both OSA and obesity and highlights their impact on clinical outcomes in hospitalized patients. Additionally, it will highlight pertinent evidence for the complications of OSA in an organ-systems approach. Finally, this review will also discuss impatient treatment approaches for OSA, particularly in relation to the SARS-CoV-2 pandemic.

Autonomic innervation of the carotid body as a determinant of its sensitivity: implications for cardiovascular physiology and pathology.

The motivation for this review comes from the emerging complexity of the autonomic innervation of the carotid body (CB) and its putative role in regulating chemoreceptor sensitivity. With the carotid bodies as a potential therapeutic target for numerous cardiorespiratory and metabolic diseases, an understanding of the neural control of its circulation is most relevant. Since nerve fibres track blood vessels and receive autonomic innervation, we initiate our review by describing the origins of arterial feed to the CB and its unique vascular architecture and blood flow. Arterial feed(s) vary amongst species and, unequivocally, the arterial blood supply is relatively high to this organ. The vasculature appears to form separate circuits inside the CB with one having arterial venous anastomoses. Both sympathetic and parasympathetic nerves are present with postganglionic neurons located within the CB or close to it in the form of paraganglia. Their role in arterial vascular resistance control is described as is how CB blood flow relates to carotid sinus afferent activity. We discuss non-vascular targets of autonomic nerves, their possible role in controlling glomus cell activity, and how certain transmitters may relate to function. We propose that the autonomic nerves sub-serving the CB provide a rapid mechanism to tune the gain of peripheral chemoreflex sensitivity based on alterations in blood flow and oxygen delivery, and might provide future therapeutic targets. However, there remain a number of unknowns regarding these mechanisms that require further research that is discussed.

Cardiovascular Risk Assessment in COVID-19.

COVID-19 bezeichnet eine der schlimmsten Krisen unserer Generation und stellt (nicht nur) für das Gesundheitssystem eine schwer bewältigbare Herausforderung dar. Mortalität und Morbidität sind im Vergleich zu anderen saisonalen Erkrankungen wie der Influenza deutlich erhöht. COVID-19 bedroht allerdings nicht die gesamte Bevölkerung in gleichem Maße. Hochrisikopatienten sind älter und leiden an kardiovaskulären Erkrankungen wie Bluthochdruck, Diabetes mellitus oder einer koronaren Herzerkrankung. Um das Risiko für einen schweren Erkrankungsverlaufs zu quantifizieren bedarf es einer multimodalen Herangehensweise. Verschiedene Risikostratifizierungssysteme stehen zu Verfügung um ungünstige Verläufe wie Intensivbehandlung oder Gesamtmortalität vorauszusagen. Biomarker wie Troponin-I, D-Dimere und NT pro-BNP kombiniert mit echokardiographischen Parametern wie links- und rechtsventrikulärer Pumpfunktion sowie pulmonalarteriellem Druck können hilfreich sein um Hochrisikopatienten zu identifizieren, die ein intensiviertes Monitoring und eine stringentere Behandlung benötigen. Da kardiovaskuläre Risikofaktoren und Komorbiditäten von großer Bedeutung zur Abschätzung des Verlaufs einer SARS-CoV-2 Infektion sind, könnten alle hospitalisierten COVID-19 Patienten von einer routinemäßigen kardiologischen Betreuung durch ein COVID-19-Heart-Team profitieren. Ein frühzeitiges Erkennen von (kardiovaskulären) Hochrisikopatienten könnte das Management erleichtern sowie die Prognose einer schweren SARS-CoV-2 Infektion verbessern.

COVID-19 and cardiovascular system-a comprehensive review.

Coronavirus disease 2019 (COVID-19), a mystified cryptic virus has challenged the mankind that has brought life to a standstill. Catastrophic loss of life, perplexed healthcare system and the downfall of global economy are some of the outcomes of this pandemic. Humans are raging a war with an unknown enemy. Infections, irrespective of age and gender, and more so in comorbidities are escalating at an alarming rate. Cardiovascular diseases, are the leading cause of death globally with an estimate of 31% of deaths worldwide out of which nearly 85% are due to heart attacks and stroke. Theoretically and practically, researchers have observed that persons with pre-existing cardiovascular conditions are comparatively more vulnerable to the COVID-19 infection. Moreover, they have studied the data between less severe and more severe cases, survivors and non survivors, intensive care unit (ICU) patients and non ICU patients, to analyse the relationship and the influence of COVID-19 on cardiovascular health of an individual, further the risk of susceptibility to submit to the virus. This review aims to provide a comprehensive particular on the possible effects, either direct or indirect, of COVID-19 on the cardiovascular heath of an individual.