Role of Angiotensin II in Cardiovascular Diseases: Introducing Bisartans as a Novel Therapy for Coronavirus 2019.

Cardiovascular diseases (CVDs) are the main contributors to global morbidity and mortality. Major pathogenic phenotypes of CVDs include the development of endothelial dysfunction, oxidative stress, and hyper-inflammatory responses. These phenotypes have been found to overlap with the pathophysiological complications of coronavirus disease 2019 (COVID-19). CVDs have been identified as major risk factors for severe and fatal COVID-19 states. The renin-angiotensin system (RAS) is an important regulatory system in cardiovascular homeostasis. However, its dysregulation is observed in CVDs, where upregulation of angiotensin type 1 receptor (AT1R) signaling via angiotensin II (AngII) leads to the AngII-dependent pathogenic development of CVDs. Additionally, the interaction between the spike protein of severe acute respiratory syndrome coronavirus 2 with angiotensin-converting enzyme 2 leads to the downregulation of the latter, resulting in the dysregulation of the RAS. This dysregulation favors AngII/AT1R toxic signaling pathways, providing a mechanical link between cardiovascular pathology and COVID-19. Therefore, inhibiting AngII/AT1R signaling through angiotensin receptor blockers (ARBs) has been indicated as a promising therapeutic approach to the treatment of COVID-19. Herein, we review the role of AngII in CVDs and its upregulation in COVID-19. We also provide a future direction for the potential implication of a novel class of ARBs called bisartans, which are speculated to contain multifunctional targeting towards COVID-19.

Cardiovascular Complications of Coronavirus Disease-2019.

Cardiovascular complications associated with the severe acute respiratory syndrome coronavirus 2 infection are common and lead to high mortality in the acute phase and high morbidity in the chronic phase impacting an individual's quality of life and health outcomes. Patients afflicted with coronavirus disease-2019 (COVID-19) infection display an increased risk for myocarditis, dysrhythmia, pericarditis, ischemic heart disease, heart failure, and thromboembolism. Although cardiovascular complications are reported across all patients with COVID-19, hospitalized patients with severe infection are most vulnerable. The underline pathobiology remains poorly defined albeit complex. Following current guidelines in decision-making for evaluation and management in addition to the beginning or returning exercise is recommended.

Circulating Plasma Concentrations of ACE2 in Primary Aldosteronism and Cardiovascular Outcomes.

CONTEXT: The plasma concentrations of angiotensin-converting enzyme 2 (pACE2) has been independently associated with cardiovascular diseases. OBJECTIVE: Higher pACE2 concentrations may be found in patients with primary aldosteronism (PA) and might lead to increased cardiovascular events. METHODS: Using an inception observational cohort, we examined pACE2 among 168 incident patients with PA. The expression of ACE2, serine protease 2 (TMPRSS2), and metalloprotease 17 (ADAM17) were assessed in peripheral blood mononuclear cells. RESULTS: Incident PA and essential hypertension (EH) patients had similarly elevated pACE2 (47.04 ± 22.06 vs 46.73 ± 21.06 ng/mL; P = .937). Age was negatively (ß = -2.15; P = .033) and higher serum potassium level (ß = 2.29; P = .024) was positively correlated with higher pACE2 in PA patients. Clinical complete hypertension remission after adrenalectomy (Primary Aldosteronism Surgery Outcome criteria) was achieved in 36 (50%) of 72 surgically treated unilateral PA (uPA) patients. At follow-up, pACE2 decreased in surgically treated patients who had (P < .001) or had no (P = .006) hypertension remission, but the pACE2 attenuation was not statistically significant in uPA (P = .085) and bilateral PA (P = .409) administered with mineralocorticoid receptor antagonist (MRA). Persistently elevated pACE2 (> 23 ng/mL) after targeted treatments was related to all-cause mortality and cardiovascular events among PA patients (hazard ratio = 8.8; P = .04); with a mean follow-up of 3.29 years. TMPRSS2 messenger RNA (mRNA) expression was higher in uPA (P = .018) and EH (P = .038) patients than in normotensive controls; it was also decreased after adrenalectomy (P < .001). CONCLUSION: PA and EH patients had elevated pACE2 and higher expression of TMPRSS2 mRNA compared to those of normotensive population. Persistently elevated pACE2 (> 23 ng/mL) after targeted treatments was associated risk of mortality and incident cardiovascular events.

Impact of COVID-19 on the cardiovascular health of women: a review by the Italian Society of Cardiology Working Group on 'gender cardiovascular diseases'.

The coronavirus disease 19 (COVID-19), due to coronavirus 2 (SARS-CoV-2) infection, presents with an extremely heterogeneous spectrum of symptoms and signs. COVID-19 susceptibility and mortality show a significant sex imbalance, with men being more prone to infection and showing a higher rate of hospitalization and mortality than women. In particular, cardiovascular diseases (preexistent or arising upon infection) play a central role in COVID-19 outcomes, differently in men and women. This review will discuss the potential mechanisms accounting for sex/gender influence in vulnerability to COVID-19. Such variability can be ascribed to both sex-related biological factors and sex-related behavioural traits. Sex differences in cardiovascular disease and COVID-19 involve the endothelial dysfunction, the innate immune system and the renin-angiotensin system (RAS). Furthermore, the angiotensin-converting enzyme 2 (ACE2) is involved in disease pathogenesis in cardiovascular disease and COVID-19 and it shows hormone-dependent actions. The incidence of myocardial injury during COVID-19 is sex-dependent, predominantly in association with a greater degree of inflammation and coagulation disorders among men. Its pathogenesis is not fully elucidated, but the main theories foresee a direct role for the ACE2 receptor, the hyperimmune response and the RAS imbalance, which may also lead to isolated presentation of COVID-19-mediated myopericarditis. Moreover, the latest evidence on cardiovascular diseases and their relationship with COVID-19 during pregnancy will be discussed. Finally, authors will analyse the prevalence of the long-covid syndrome between the two sexes and its impact on the quality of life and cardiovascular health.

Nonalcoholic fatty liver disease and non-liver comorbidities.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by excess fat accumulation in the liver. It is closely associated with metabolic syndrome, and patients with NAFLD often have comorbidities such as obesity, type 2 diabetes mellitus, and dyslipidemia. In addition to liver-related complications, NAFLD has been associated with a range of non-liver comorbidities, including cardiovascular disease, chronic kidney disease, and sleep apnea. Cardiovascular disease is the most common cause of mortality in patients with NAFLD, and patients with NAFLD have a higher risk of developing cardiovascular disease than the general population. Chronic kidney disease is also more common in patients with NAFLD, and the severity of NAFLD is associated with a higher risk of developing chronic kidney disease. Sleep apnea, a disorder characterized by breathing interruptions during sleep, is also more common in patients with NAFLD and is associated with the severity of NAFLD. The presence of non-liver comorbidities in patients with NAFLD has important implications for the management of this disease. Treatment of comorbidities such as obesity, type 2 diabetes mellitus, and dyslipidemia may improve liver-related outcomes in patients with NAFLD. Moreover, treatment of non-liver comorbidities may also improve overall health outcomes in patients with NAFLD. Therefore, clinicians should be aware of the potential for non-liver comorbidities in patients with NAFLD and should consider the management of these comorbidities as part of the overall management of this disease.

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.

Association between periodontal diseases and cardiovascular diseases, diabetes and respiratory diseases: Consensus report of the Joint Workshop by the European Federation of Periodontology (EFP) and the European arm of the World Organization of Family Doctors (WONCA Europe).

AIM: To explore the implications for dentists and family doctors of the association between periodontal and systemic diseases and the role of dentists and family doctors in managing non-communicable diseases (NCDs) and promoting healthy lifestyles. MATERIALS AND METHODS: The consensus reports of the previous Focused Workshops on the associations between periodontitis and diabetes (2017) and periodontitis and cardiovascular diseases (2019) formed the technical reviews to underpin discussions on both topics. For the association with respiratory diseases, a systematic review was specifically commissioned for the Workshop discussions. Working groups prepared proposals independently, and then the proposals were discussed and approved at plenary meetings. RESULTS: Periodontitis is independently associated with cardiovascular diseases, diabetes, chronic obstructive pulmonary disease (COPD), obstructive sleep apnea and COVID-19 complications. Dentists and family doctors should collaborate in managing NCDs, implementing strategies for early detection of periodontitis in primary care centres and of cardiovascular diseases or diabetes in dental settings. Family doctors should be informed about periodontal diseases and their consequences, and oral health professionals (OHPs) should be informed about the relevance of NCDs and the associated risk factors. CONCLUSIONS: Closer collaboration between OHPs and family doctors is important in the early detection and management of NCDs and in promoting healthy lifestyles. Pathways for early case detection of periodontitis in family medicine practices and of NCDs in dental practices should be developed and evaluated.

Hypotheses on Atherogenesis Triggering: Does the Infectious Nature of Atherosclerosis Development Have a Substruction?

Since the end of the 20th century, it has been clear that atherosclerosis is an inflammatory disease. However, the main triggering mechanism of the inflammatory process in the vascular walls is still unclear. To date, many different hypotheses have been put forward to explain the causes of atherogenesis, and all of them are supported by strong evidence. Among the main causes of atherosclerosis, which underlies these hypotheses, the following can be mentioned: lipoprotein modification, oxidative transformation, shear stress, endothelial dysfunction, free radicals' action, homocysteinemia, diabetes mellitus, and decreased nitric oxide level. One of the latest hypotheses concerns the infectious nature of atherogenesis. The currently available data indicate that pathogen-associated molecular patterns from bacteria or viruses may be an etiological factor in atherosclerosis. This paper is devoted to the analysis of existing hypotheses for atherogenesis triggering, and special attention is paid to the contribution of bacterial and viral infections to the pathogenesis of atherosclerosis and cardiovascular disease.

The effect of SGLT2 inhibitors, GLP1 agonists, and their sequential combination on cardiometabolic parameters: A randomized, prospective, intervention study.

BACKGROUND: Pulse wave velocity (PWV) and augmentation index (AIx) are indices used to assess arterial stiffness. We aim to compare the effect of empagliflozin, liraglutide and their sequential combination on arterial stiffness indices in patients with type 2 diabetes (T2D). METHODS: This was a randomized single blind study evaluating the effect of empagliflozin vs liraglutide in adult patients with T2D. Patients were randomized to liraglutide titrated gradually to 1.8 mg or empagliflozin 25 mg in 1:1 ratio. Three months later empagliflozin was added to the liraglutide group, and liraglutide was added to the empagliflozin group. Patients were assessed with non-invasive tests for arterial stiffness (i.e., carotid-femoral PWV and AIx of aortic pressure) at baseline, 3-month and 9-month visits (final visit was extended for 3 months from the initial design due to Covid 19 pandemic). The primary outcome was the between-group difference of PWV change (ΔPWV) and ΔAIx at 3 months. Secondary outcomes included the between-group difference of ΔPWV and ΔAIx at 9 months, as well as the ΔPWV and ΔAIx between baseline and 9-month visit when total study population was assessed. RESULTS: A total of 62 patients with T2D (30 started liraglutide; 32 empagliflozin, mean age 63 years, 25 % with established cardiovascular disease) participated in the study. We failed to show any significant between-group differences of ΔPWV and ΔΑΙx at 3 and 9 months, as well as between-group difference of ΔPWV and ΔAIx for the total study population between baseline and 9-month visit. In contrast, systemic vascular resistance and lipoprotein(a) levels improved, showing better results with liraglutide than empagliflozin. Favorable effects were also observed on body weight, body mass index, body and visceral fat, blood pressure, HbA1c, and uric acid levels. CONCLUSION: No evidence of a favorable change in arterial stiffness indices was seen with empagliflozin or liraglutide or their combination in this study. Well-designed powerful studies are needed to address any potential effects on arterial stiffness in selected populations.

Sigma-1 Receptor Signaling: In Search of New Therapeutic Alternatives for Cardiovascular and Renal Diseases.

Cardiovascular and renal diseases are among the leading causes of death worldwide, and regardless of current efforts, there is a demanding need for therapeutic alternatives to reduce their progression to advanced stages. The stress caused by diseases leads to the activation of protective mechanisms in the cell, including chaperone proteins. The Sigma-1 receptor (Sig-1R) is a ligand-operated chaperone protein that modulates signal transduction during cellular stress processes. Sig-1R interacts with various ligands and proteins to elicit distinct cellular responses, thus, making it a potential target for pharmacological modulation. Furthermore, Sig-1R ligands activate signaling pathways that promote cardioprotection, ameliorate ischemic injury, and drive myofibroblast activation and fibrosis. The role of Sig-1R in diseases has also made it a point of interest in developing clinical trials for pain, neurodegeneration, ischemic stroke, depression in patients with heart failure, and COVID-19. Sig-1R ligands in preclinical models have significantly beneficial effects associated with improved cardiac function, ventricular remodeling, hypertrophy reduction, and, in the kidney, reduced ischemic damage. These basic discoveries could inform clinical trials for heart failure (HF), myocardial hypertrophy, acute kidney injury (AKI), and chronic kidney disease (CKD). Here, we review Sig-1R signaling pathways and the evidence of Sig-1R modulation in preclinical cardiac and renal injury models to support the potential therapeutic use of Sig-1R agonists and antagonists in these diseases.

COVID-19's immuno-pathology and cardiovascular diseases.

The pandemic of COVID-19 in worldwide causes recent millions of morbidity and mortality in all countries and is the most important challenge in the world in recent years. Coronavirus is a single-stranded RNA virus and infection with COVID-19 leads to acute respiratory distress syndrome, lung inflammation, cytokine storm, and death. The other complications include endothelial dysfunction, activation of coagulation, thromboembolic events, and vascular disease. Cardiovascular complications such as myocardial and stroke ischemia, pulmonary thromboembolism, systemic arterial, and deep vein thrombosis were reported. In this review, we presented immuno-pathological mechanisms and the effects of COVID-19 on the cardiovascular system, heart, vessels, coagulation system, and molecular glance of immuno-inflammation to the COVID-19's pathology on the cardiovascular system.

Rationale and design of the Effects of intensive Systolic blood Pressure lowering treatment in reducing RIsk of vascular evenTs (ESPRIT): A multicenter open-label randomized controlled trial.

BACKGROUND: Lowering blood pressure (BP) effectively reduces the risk of cardiovascular (CV) events in high CV risk individuals. The optimal target of BP lowering among high CV risk individuals remains unclear. METHODS: The Effects of intensive Systolic blood Pressure lowering treatment in reducing RIsk of vascular evenTs (ESPRIT) trial is a multi-center, open-label, randomized controlled trial to compare the efficacy and safety of intensive BP lowering strategy (Systolic BP target <120 mm Hg) and standard BP lowering strategy (Systolic BP target <140 mm Hg). Participants aged at least 50 years old with baseline systolic BP within 130 to 180 mm Hg at high CV risk, defined by established CV diseases or 2 major CV risk factors, were enrolled. The primary outcome is a composite CV outcome of myocardial infarction, coronary or non-coronary revascularization, hospitalization or emergency department visit from new-onset heart failure or acute decompensated heart failure, stroke, or death from CV diseases. Secondary outcomes include components of the primary composite outcome, all-cause death, a composite of the primary outcome or all-cause death, kidney outcomes, as well as cognitive outcomes. RESULTS: Despite of the interruption of COVID-19 outbreak, the ESPRIT trial successfully enrolled and randomized 11,255 participants from 116 hospitals or primary health care institutions. The mean age of the participants was 64.6 (standard deviation [SD], 7.1) years, 4,650 (41.3%) were women. Among them 28.9%, 26.9% and 38.7% had coronary heart disease, prior stroke and diabetes mellitus, respectively. COVID-19 outbreak affected the BP lowering titration process of the trial, and delayed the reach of BP target. CONCLUSIONS: The ESPRIT trial will address the important question on the optimal BP lowering target for individuals with high CV risk, and generate high quality evidence for treating millions of patients from East Asian countries.

Cardiovascular Complications in Coronavirus Disease 2019-Pathogenesis and Management.

The coronavirus disease 2019 (COVID-19) pandemic has caused a devastating impact on morbidity and mortality around the world. Severe acute respiratory syndrome-coronavirus-2 has a characteristic tropism for the cardiovascular system by entering the host cells and binding to angiotensin-converting enzyme 2 receptors, which are expressed in different cells, particularly endothelial cells. This endothelial injury is linked by a direct intracellular viral invasion leading to inflammation, microthrombosis, and angiogenesis. COVID-19 has been associated with acute myocarditis, cardiac arrhythmias, new onset or worsening heart failure, ischemic heart disease, stroke, and thromboembolic disease. This review summarizes key relevant literature regarding the epidemiology, diagnosis, treatment, and preventive measures related to cardiovascular complications in the setting of COVID-19.

Effects of mobile health interventions on health-related outcomes in older adults with type 2 diabetes: A systematic review and meta-analysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic metabolic condition that is associated with multiple comorbidities. Apart from pharmacological approaches, patient self-management remains the gold standard of care for diabetes. Improving patients' self-management among the elderly with mobile health (mHealth) interventions is critical, especially in times of the COVID-19 pandemic. However, the extent of mHealth efficacy in managing T2DM in the older population remains unknown. Hence, the present review examined the effectiveness of mHealth interventions on cardiometabolic outcomes in older adults with T2DM. METHODS: A systematic search from the inception till May 31, 2021, in the MEDLINE, Embase, and PubMed databases was conducted, and 16 randomized controlled trials were included in the analysis. RESULTS: The results showed significant benefits on glycosylated hemoglobin (HbA1c) (mean difference -0.24%; 95% confidence interval [CI]: -0.44, -0.05; p = 0.01), postprandial blood glucose (-2.91 mmol/L; 95% CI: -4.78, -1.03; p = 0.002), and triglycerides (-0.09 mmol/L; 95% CI: -0.17, -0.02; p = 0.010), but not on low-density lipoprotein cholesterol (-0.06 mmol/L; 95% CI: -0.14, 0.02; p = 0.170), high-density lipoprotein cholesterol (0.05 mmol/L; 95% CI: -0.03, 0.13; p = 0.220), and blood pressure (systolic blood pressure -0.82 mm Hg; 95% CI: -4.65, 3.00; p = 0.670; diastolic blood pressure -1.71 mmHg; 95% CI: -3.71, 0.29; p = 0.090). CONCLUSIONS: Among older adults with T2DM, mHealth interventions were associated with improved cardiometabolic outcomes versus usual care. Its efficacy can be improved in the future as the current stage of mHealth development is at its infancy. Addressing barriers such as technological frustrations may help strategize approaches to further increase the uptake and efficacy of mHealth interventions among older adults with T2DM.

Pathomechanisms of SARS-CoV-2 infection and development of atherosclerosis in patients with COVID-19: A review.

The pandemic of coronavirus disease 2019 (COVID-19) has posed a major health challenge for over 2 years. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes it belongs to single-stranded ribonucleic acid viruses and causes acute respiratory distress syndrome. The initial outbreak was discovered in December 2019 in Wuhan province, where SARS-CoV-2 quickly spread to other countries. In addition to respiratory disorders, it has been shown that during and after COVID-19 infection, cardiovascular diseases are often developed or exacerbated, such as: arterial hypertension, coronary artery disease, arrhythmias, heart failure and thromboembolic complications. In view of the higher prevalence of atherosclerosis in patients with COVID-19, we described the pathomechanisms of the development of this infection and the possible correlations between SARS-CoV-2 infection and thromboembolic complications. We focused on the role of the inflammatory response, renin-angiotensin system and endothelial dysfunction in the development of atherosclerosis in patients with COVID-19. A thorough understanding of the hemodynamic mechanisms and the impact of the infection on the cardiovascular system will allow for the proper selection of appropriate therapy in patients after SARS-CoV-2 infection.

EMAS position statement: Vitamin D and menopausal health.

INTRODUCTION: There is increasing evidence that vitamin D has widespread tissue effects. In addition to osteoporosis, vitamin D deficiency has been associated with cardiovascular disease, diabetes, cancer, infections and neurodegenerative disease. However, the effect of vitamin D supplementation on non-skeletal outcomes requires clarification, especially in postmenopausal women. AIM: This position statement provides an evidence-based overview of the role of vitamin D in the health of postmenopausal women based on observational and interventional studies. MATERIALS AND METHODS: Literature review and consensus of expert opinion. RESULTS AND CONCLUSIONS: Vitamin D status is determined by measuring serum 25-hydroxyvitamin D levels. Concentrations <20 ng/ml (<50 nmol/l) and <10 ng/ml (<25 nmol/l) are considered to constitute vitamin D deficiency and severe deficiency, respectively. Observational data suggest an association between vitamin D deficiency and adverse health outcomes in postmenopausal women, although they cannot establish causality. The evidence from randomized controlled trials concerning vitamin D supplementation is not robust, since many studies did not consider whether people were deficient at baseline. Moreover, high heterogeneity exists in terms of the population studied, vitamin D dosage, calcium co-administration and duration of intervention. Concerning skeletal health, vitamin D deficiency is associated with low bone mass and an increased risk of fractures. Vitamin D supplementation at maintenance doses of 800-2000 IU/day (20-50 µg/day), after repletion of vitamin D status with higher weekly or daily doses, may be of benefit only when co-administered with calcium (1000-1200 mg/day), especially in the elderly populations and those with severe vitamin D deficiency. Concerning cardiovascular disease, vitamin D deficiency is associated with an increased prevalence of cardiovascular risk factors, mainly metabolic syndrome, type 2 diabetes mellitus and dyslipidemia. Vitamin D deficiency, especially its severe form, is associated with an increased risk of cardiovascular events (coronary heart disease, stroke, mortality), independently of traditional risk factors. Vitamin D supplementation may have a modestly beneficial effect on lipid profile and glucose homeostasis, especially in obese individuals or those ≥60 years old and at doses of ≥2000 IU/day (≥50 µg/day). However, it has no effect on the incidence of cardiovascular events. Concerning cancer, vitamin D deficiency is associated with increased incidence of and mortality from several types of cancer, such as colorectal, lung and breast cancer. However, the data on other types of gynecological cancer are inconsistent. Vitamin D supplementation has no effect on cancer incidence, although a modest reduction in cancer-related mortality has been observed. Concerning infections, vitamin D deficiency has been associated with acute respiratory tract infections, including coronavirus disease 2019 (COVID-19). Vitamin D supplementation may decrease the risk of acute respiratory tract infections and the severity of COVID-19 (not the risk of infection). Concerning menopausal symptomatology, vitamin D deficiency may have a negative impact on some aspects, such as sleep disturbances, depression, sexual function and joint pains. However, vitamin D supplementation has no effect on these, except for vulvovaginal atrophy, at relatively high doses, i.e., 40,000-60,000 IU/week (1000-1500 IU/week) orally or 1000 IU/day (25 µg/day) as a vaginal suppository.