The Relationship between COVID-19 and Hypothalamic-Pituitary-Adrenal Axis: A Large Spectrum from Glucocorticoid Insufficiency to Excess-The CAPISCO International Expert Panel.

Coronavirus disease 2019 (COVID-19) is a highly heterogeneous disease regarding severity, vulnerability to infection due to comorbidities, and treatment approaches. The hypothalamic-pituitary-adrenal (HPA) axis has been identified as one of the most critical endocrine targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that might significantly impact outcomes after infection. Herein we review the rationale for glucocorticoid use in the setting of COVID-19 and emphasize the need to have a low index of suspicion for glucocorticoid-induced adrenal insufficiency, adjusting for the glucocorticoid formulation used, dose, treatment duration, and underlying health problems. We also address several additional mechanisms that may cause HPA axis dysfunction, including critical illness-related corticosteroid insufficiency, the direct cytopathic impacts of SARS-CoV-2 infection on the adrenals, pituitary, and hypothalamus, immune-mediated inflammations, small vessel vasculitis, microthrombotic events, the resistance of cortisol receptors, and impaired post-receptor signaling, as well as the dissociation of ACTH and cortisol regulation. We also discuss the increased risk of infection and more severe illness in COVID-19 patients with pre-existing disorders of the HPA axis, from insufficiency to excess. These insights into the complex regulation of the HPA axis reveal how well the body performs in its adaptive survival mechanism during a severe infection, such as SARS-CoV-2, and how many parameters might disbalance the outcomes of this adaptation.

Statin intolerance: new data and further options for treatment.

PURPOSE OF REVIEW: Hypercholesterolemia is a major risk factor for cardiovascular diseases. Administration of statins represents the cornerstone of the prevention and treatment of cardiovascular disease, with demonstrated long-term safety and efficacy. This review aims to revisit statin intolerance mechanisms, as well as to discuss new data and therapeutic options. RECENT FINDINGS: Although statins are well tolerated, myopathy and other adverse effects are a challenging problem, being the main reason for poor adherence to treatment and failure in lowering cardiovascular risk. Statin intolerance is the subject of ongoing research, as these drugs are widely used. There are alternative options of treatment if statin intolerance emerges, that is, lowering the dose, intermittent dosages, and/or combining a statin with other drugs, such as ezetimibe, proprotein convertase subtilisin-kexin type 9 inhibitors, bempedoic acid, angiopoietin-like 3 protein inhibitors, and nutraceuticals. If even the lowest statin dose cannot be tolerated, a nonstatin regimen is recommended to reduce LDL cholesterol levels. SUMMARY: Treatment options in statin intolerance include combinations of a lower dose of statin with other lipid-lowering regimens or only nonstatin drugs in the presence of complete intolerance. New hypolipidemic therapies that address gene editing are emerging, and may prove useful in the future.

Post-COVID syndrome, inflammation, and diabetes.

The raging COVID-19 pandemic is in its third year of global impact. The SARS CoV 2 virus has a high rate of spread, protean manifestations, and a high morbidity and mortality in individuals with predisposing risk factors. The pathophysiologic mechanisms involve a heightened systemic inflammatory state, cardiometabolic derangements, and varying degrees of glucose intolerance. The latter can be evident as significant hyperglycemia leading to new-onset diabetes or worsening of preexisting disease. Unfortunately, the clinical course beyond the acute phase of the illness may persist in the form of a variety of symptoms that together form the so-called "Long COVID" or "Post-COVID Syndrome". It is thought that a chronic, low-grade inflammatory and immunologic state persists during this phase, which may last for weeks or months. Although numerous insights have been gained into COVID-related hyperglycemia and diabetes, its prediction, course, and management remain to be fully elucidated.

Molecular and pro-inflammatory aspects of COVID-19: The impact on cardiometabolic health.

Obesity, type 2 diabetes (T2DM), hypertension (HTN), and Cardiovascular Disease (CVD) often cluster together as "Cardiometabolic Disease" (CMD). Just under 50% of patients with CMD increased the risk of morbidity and mortality right from the beginning of the COVID-19 pandemic as it has been reported in most countries affected by the SARS-CoV2 virus. One of the pathophysiological hallmarks of COVID-19 is the overactivation of the immune system with a prominent IL-6 response, resulting in severe and systemic damage involving also cytokines such as IL2, IL4, IL8, IL10, and interferon-gamma were considered strong predictors of COVID-19 severity. Thus, in this mini-review, we try to describe the inflammatory state, the alteration of the adipokine profile, and cytokine production in the obese state of infected and not infected patients by SARS-CoV2 with the final aim to find possible influences of COVID-19 on CMD and CVD. The immunological-based discussion of the molecular processes could inspire the study of promising targets for managing CMD patients and its complications during COVID-19.

Associations between Periodontitis, COVID-19, and Cardiometabolic Complications: Molecular Mechanisms and Clinical Evidence.

Periodontitis is a microbially driven, host-mediated disease that leads to loss of periodontal attachment and resorption of bone. It is associated with the elevation of systemic inflammatory markers and with the presence of systemic comorbidities. Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the majority of patients have mild symptoms, others experience important complications that can lead to death. After the spread of the COVID-19 pandemic, several investigations demonstrating the possible relationship between periodontitis and COVID-19 have been reported. In addition, both periodontal disease and COVID-19 seem to provoke and/or impair several cardiometabolic complications such as cardiovascular disease, type 2 diabetes, metabolic syndrome, dyslipidemia, insulin resistance, obesity, non-alcoholic fatty liver disease, and neurological and neuropsychiatric complications. Therefore, due to the increasing number of investigations focusing on the periodontitis-COVID-19 relationship and considering the severe complications that such an association might cause, this review aims to summarize all existing emerging evidence regarding the link between the periodontitis-COVID-19 axis and consequent cardiometabolic impairments.

New-Onset Diabetes in COVID-19: Time to Frame Its Fearful Symmetry.

There is increasing evidence that coronavirus disease 2019 (COVID-19) may lead to new-onset diabetes mellitus (DM). This may occur even in patients without predisposing factors for impaired glucose metabolism. Both impaired pancreatic insulin secretion and insulin resistance have been implicated as underlying mechanisms. Importantly, new-onset hyperglycaemia is associated with worse prognosis in patients with COVID-19. Indeed, its prognosis may be even more sinister than in patients with pre-existing DM. More research data and knowledge are currently being collected to improve our insights into this constellation and to guide therapies in clinical reality.

Genetic and Epigenetic Biomarkers for Diagnosis, Prognosis and Treatment of Metabolic Syndrome.

BACKGROUND: Metabolic syndrome is a clinical condition that deserves special attention because it puts the individual at high cardiovascular risk, especially heart attack and stroke. Considering precision medicine, it would be advisable to evaluate the individual cardio-metabolic risk by estimating the coexistence of risk factors (abdominal obesity, low level of High-Density Lipoprotein Cholesterol, High Triglycerides, and small dense Low-Density Lipoproteins sub-classes, hypertension, and elevated fasting glycemia), which could engrave on metabolism increasing cardiovascular mortality. OBJECTIVE: To identify genetic and epigenetic biomarkers may assist in the possibility of helping follow-up strategies and other measures of prevention and in metabolic risk. METHODS: We searched for studies that valued the combination between epigenetic biomarkers and all factors of cardio-metabolic risk. RESULTS: Numerous researches have investigated the molecular start of metabolic alterations, focusing on the epigenetic mark, as methylation of DNA, histone modifications and non.coding RNAs. It has been found that DNA methylation is the most searched epigenetic sign in the human genome concerning the control of gene expression. CONCLUSION: For the screening, diagnosis, and prognosis of metabolic syndrome and the prescription of personalized medicine, the DNA methylation biomarkers specify for subjects have been recognized as an ensuring tool. While these results are promising, further investigations are needed to unravel the complicated synergic association of the genome, epigenome and the situations related to metabolic pathology.

Promoting a Syndemic Approach for Cardiometabolic Disease Management During COVID-19: The CAPISCO International Expert Panel.

Efforts in the fight against COVID-19 are achieving success in many parts of the world, although progress remains slow in other regions. We believe that a syndemic approach needs to be adopted to address this pandemic given the strong apparent interplay between COVID-19, its related complications, and the socio-structural environment. We have assembled an international, multidisciplinary group of researchers and clinical practitioners to promote a novel syndemic approach to COVID-19: the CArdiometabolic Panel of International experts on Syndemic COvid-19 (CAPISCO). This geographically diverse group aims to facilitate collaborative-networking and scientific exchanges between researchers and clinicians facing a multitude of challenges on different continents during the pandemic. In the present article we present our "manifesto", with the intent to provide evidence-based guidance to the global medical and scientific community for better management of patients both during and after the current pandemic.

Hypoglycaemia and Cardiovascular Disease Risk in Patients with Diabetes.

Hypoglycaemia represents an important side effect of insulin therapy and insulin secretagogues. It can occur in both type 1 and type 2 diabetes mellitus patients. Also, some associations between hypoglycaemia and cardiovascular (CV) risk have been reported. Several mechanisms may be involved, including the sympathoadrenal system, hypokalaemia, endothelial dysfunction, coagulation, platelets, inflammation, atherothrombosis and impaired autonomic cardiac reflexes. This narrative review discusses the associations of hypoglycaemia with CV diseases, including coronary heart disease (CHD), cardiac arrhythmias, stroke, carotid disease and peripheral artery disease (PAD), as well as with dementia. Severe hypoglycaemia has been related to CHD, CV and all-cause mortality. Furthermore, there is evidence supporting an association between hypoglycaemia and cardiac arrhythmias, potentially predisposing to sudden death. The data linking hypoglycaemia with stroke, carotid disease and PAD is limited. Several factors may affect the hypoglycaemia-CV relationships, such as the definition of hypoglycaemia, patient characteristics, co-morbidities (including chronic kidney disease) and antidiabetic drug therapy. However, the association between hypoglycaemia and dementia is bilateral. Both the disorders are more common in the elderly; thus, glycaemic goals should be carefully selected in older patients. Further research is needed to elucidate the impact of hypoglycaemia on CV disease.

Effects of Aging and Diet on Cardioprotection and Cardiometabolic Risk Markers.

The prevalence of several diseases increases by age, including cardiovascular diseases, which are the leading cause of morbidity and mortality worldwide. Aging, as a complex process characterized by senescence, triggers various pathways, such as oxidative stress, systemic inflammation, metabolism dysfunction, telomere shortening, mitochondrial dysfunction and deregulated autophagy. A better understanding of the mechanisms underlying senescence may lead to the development of new therapeutic targets and strategies for age-related pathologies and extend the healthy lifespan. Modulating lifestyle risk factors and adopting healthy dietary patterns remain significant tools in delaying the aging process, decreasing age-associated comorbidities and mortality, increasing life expectancy and consequently, preventing the development of cardiovascular disease. Furthermore, such a strategy represents the most cost-effective approach, and the quality of life of the subjects may be significantly improved. An integrated, personalized approach targeting cardiometabolic aging and frailty is suggested in daily clinical practice. However, it should be initiated from an early age. Moreover, there is a need for further well designed and controlled studies in order to elucidate a link between the time of feeding, longevity and cardiovascular prevention. In the future, it is expected that the pharmacological treatment in cardioprotective management will be necessary, accompanied by equally important lifestyle interventions and adjunctive exercise.