Risk Factors and Mechanisms of Cardiovascular Diseases in Posttraumatic Stress Disorder Model in Wistar Rats as Dependent on Stress Resistance and Age.

The article focuses on the pathogenetic mechanisms of posttraumatic stress disorder (PTSD), which is associated with psychological stress because of the coronavirus pandemic. The molecular mechanisms responsible for disease susceptibility in some individuals and stress resistance in others are amongst crucial research interests of experimental and clinical medicine. Priority data were obtained to indicate that distortions of synthesis and metabolism and, most significantly, a switch between two energy transport forms, glucose and lipids, underlie myocardial dysfunction in young and old stress-sensitive Wistar rats in a PTSD model. Histochemistry and polarization microscopy showed energy deficit in cardiomyocytes and signs of ischemic and hypoxic areas emerging in the myocardium as a result of an accumulation of NADH and NADPH, which initiate excessive production of reactive oxygen species.

Elevated mid-pregnancy plasma levels of angiotensin-converting enzyme 2 in women prior to the development of preeclampsia.

Preeclampsia and cardiovascular disease (CVD) share multiple features and risk factors. Circulating angiotensin-converting enzyme 2 (ACE2) is increased in CVD and mediates SARS-CoV-2 entry into host cells, causing COVID-19 infection. The role of ACE2 in preeclampsia pathophysiology is unknown. We hypothesized that circulating ACE2 is increased in mid-pregnancy in women later developing preeclampsia. We included 296 women later developing preeclampsia (cases) and 333 women with a continuous healthy pregnancy (controls). Circulating ACE2 was measured with an immunoassay based on proximity extension assay technology, with levels being expressed as relative quantification on a log2 scale. Median (interquartile range) ACE2 levels were higher in cases than in controls; 3.84 (3.50-4.24) vs. 3.72 (3.45-4.04), p = 0.002. Adjusted logistic regression models showed a 60% increased risk for later development of preeclampsia with one unit elevation of ACE2 (adjusted odds ratio (aOR) 1.60, 95% confidence intervals (CI) 1.17-2.18). Preterm preeclampsia (diagnosis before 37 gestational weeks, n = 97) seemed to have a stronger ACE2 association than term preeclampsia, n = 199 (aORs, 95% Cis 2.14, 1.15-3.96 and 1.52, 1.04-2.23, respectively). Circulating ACE2 is increased at mid-pregnancy in women later developing preeclampsia, particularly preterm preeclampsia. Thus, our finding indicates a partly shared pathophysiological pathway between preeclampsia and CVD.

Bending the Curve in Cardiovascular Disease Mortality: Bethesda + 40 and Beyond.

More than 40 years after the 1978 Bethesda Conference on the Declining Mortality from Coronary Heart Disease provided the scientific community with a blueprint for systematic analysis to understand declining rates of coronary heart disease, there are indications the decline has ended or even reversed despite advances in our knowledge about the condition and treatment. Recent data show a more complex situation, with mortality rates for overall cardiovascular disease, including coronary heart disease and stroke, decelerating, whereas those for heart failure are increasing. To mark the 40th anniversary of the Bethesda Conference, the National Heart, Lung, and Blood Institute and the American Heart Association cosponsored the "Bending the Curve in Cardiovascular Disease Mortality: Bethesda + 40" symposium. The objective was to examine the immediate and long-term outcomes of the 1978 conference and understand the current environment. Symposium themes included trends and future projections in cardiovascular disease (in the United States and internationally), the evolving obesity and diabetes epidemics, and harnessing emerging and innovative opportunities to preserve and promote cardiovascular health and prevent cardiovascular disease. In addition, participant-led discussion explored the challenges and barriers in promoting cardiovascular health across the lifespan and established a potential framework for observational research and interventions that would begin in early childhood (or ideally in utero). This report summarizes the relevant research, policy, and practice opportunities discussed at the symposium.

Emerging Role of Platelet-Endothelium Interactions in the Pathogenesis of Severe SARS-CoV-2 Infection-Associated Myocardial Injury.

Cardiovascular dysfunction and disease are common and frequently fatal complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Indeed, from early on during the SARS-CoV-2 virus pandemic it was recognized that cardiac complications may occur, even in patients with no underlying cardiac disorders, as part of the acute infection, and that these were associated with more severe disease and increased morbidity and mortality. The most common cardiac complication is acute cardiac injury, defined by significant elevation of cardiac troponins. The potential mechanisms of cardiovascular complications include direct viral myocardial injury, systemic inflammation induced by the virus, sepsis, arrhythmia, myocardial oxygen supply-demand mismatch, electrolyte abnormalities, and hypercoagulability. This review is focused on the prevalence, risk factors and clinical course of COVID-19-related myocardial injury, as well as on current data with regard to disease pathogenesis, specifically the interaction of platelets with the vascular endothelium. The latter section includes consideration of the role of SARS-CoV-2 proteins in triggering development of a generalized endotheliitis that, in turn, drives intense activation of platelets. Most prominently, SARS-CoV-2-induced endotheliitis involves interaction of the viral spike protein with endothelial angiotensin-converting enzyme 2 (ACE2) together with alternative mechanisms that involve the nucleocapsid and viroporin. In addition, the mechanisms by which activated platelets intensify endothelial activation and dysfunction, seemingly driven by release of the platelet-derived calcium-binding proteins, SA100A8 and SA100A9, are described. These events create a SARS-CoV-2-driven cycle of intravascular inflammation and coagulation, which contributes significantly to a poor clinical outcome in patients with severe disease.

Supermeres are functional extracellular nanoparticles replete with disease biomarkers and therapeutic targets.

Extracellular vesicles and exomere nanoparticles are under intense investigation as sources of clinically relevant cargo. Here we report the discovery of a distinct extracellular nanoparticle, termed supermere. Supermeres are morphologically distinct from exomeres and display a markedly greater uptake in vivo compared with small extracellular vesicles and exomeres. The protein and RNA composition of supermeres differs from small extracellular vesicles and exomeres. Supermeres are highly enriched with cargo involved in multiple cancers (glycolytic enzymes, TGFBI, miR-1246, MET, GPC1 and AGO2), Alzheimer's disease (APP) and cardiovascular disease (ACE2, ACE and PCSK9). The majority of extracellular RNA is associated with supermeres rather than small extracellular vesicles and exomeres. Cancer-derived supermeres increase lactate secretion, transfer cetuximab resistance and decrease hepatic lipids and glycogen in vivo. This study identifies a distinct functional nanoparticle replete with potential circulating biomarkers and therapeutic targets for a host of human diseases.

Mitochondrial quality surveillance: mitophagy in cardiovascular health and disease.

Selective autophagy of mitochondria, known as mitophagy, is a major quality control pathway in the heart that is involved in removing unwanted or dysfunctional mitochondria from the cell. Baseline mitophagy is critical for maintaining fitness of the mitochondrial network by continuous turnover of aged and less-functional mitochondria. Mitophagy is also critical in adapting to stress associated with mitochondrial damage or dysfunction. The removal of damaged mitochondria prevents reactive oxygen species-mediated damage to proteins and DNA and suppresses activation of inflammation and cell death. Impairments in mitophagy are associated with the pathogenesis of many diseases, including cancers, inflammatory diseases, neurodegeneration, and cardiovascular disease. Mitophagy is a highly regulated and complex process that requires the coordination of labeling dysfunctional mitochondria for degradation while simultaneously promoting de novo autophagosome biogenesis adjacent to the cargo. In this review, we provide an update on our current understanding of these steps in mitophagy induction and discuss the physiological and pathophysiological consequences of altered mitophagy in the heart.

Beta-arrestins in the context of cardiovascular diseases: Focusing on angiotensin II type 1 receptor (AT1R).

Cardiovascular diseases are the leading cause of death worldwide. The renin-angiotensin-aldosterone system is one of the major regulators of cardiovascular homeostasis and the angiotensin II type 1 receptor (AT1R) mediates the main deleterious effects resulting from the hyperactivation of this hormonal system. Beta-arrestins are multifunctional proteins that regulate the desensitization and internalization of G protein-coupled receptors. After the discovery of beta-arrestins, many efforts have been made towards characterizing and distinguishing this new signaling pathway for drug discovery. Here, we summarize recent advances that address the beta-arrestin signaling in the cardiovascular system, focusing on the activation of the AT1R.

Antibodies against Angiotensin II Type 1 and Endothelin 1 Type A Receptors in Cardiovascular Pathologies.

Angiotensin II receptor type 1 (AT1R) and endothelin-1 receptor type A (ETAR) are G-protein-coupled receptors (GPCRs) expressed on the surface of a great variety of cells: immune cells, vascular smooth cells, endothelial cells, and fibroblasts express ETAR and AT1R, which are activated by endothelin 1 (ET1) and angiotensin II (AngII), respectively. Certain autoantibodies are specific for these receptors and can regulate their function, thus being known as functional autoantibodies. The function of these antibodies is similar to that of natural ligands, and it involves not only vasoconstriction, but also the secretion of proinflammatory cytokines (such as interleukin-6 (IL6), IL8 and TNF-α), collagen production by fibroblasts, and reactive oxygen species (ROS) release by fibroblasts and neutrophils. The role of autoantibodies against AT1R and ETAR (AT1R-AAs and ETAR-AAs, respectively) is well described in the pathogenesis of many medical conditions (e.g., systemic sclerosis (SSc) and SSc-associated pulmonary hypertension, cystic fibrosis, and allograft dysfunction), but their implications in cardiovascular diseases are still unclear. This review summarizes the current evidence regarding the effects of AT1R-AAs and ETAR-AAs in cardiovascular pathologies, highlighting their roles in heart transplantation and mechanical circulatory support, preeclampsia, and acute coronary syndromes.

Non-COVID-19 patients in times of pandemic: Emergency department visits, hospitalizations and cause-specific mortality in Northern Italy.

The COVID-19 pandemic forced healthcare services organization to adjust to mutating healthcare needs. Not exhaustive data are available on the consequences of this on non-COVID-19 patients. The aim of this study was to assess the impact of the pandemic on non-COVID-19 patients living in a one-million inhabitants' area in Northern Italy (Bologna Metropolitan Area-BMA), analyzing time trends of Emergency Department (ED) visits, hospitalizations and mortality. We conducted a retrospective observational study using data extracted from BMA healthcare informative systems. Weekly trends of ED visits, hospitalizations, in- and out-of-hospital, all-cause and cause-specific mortality between December 1st, 2019 to May 31st, 2020, were compared with those of the same period of the previous year. Non-COVID-19 ED visits and hospitalizations showed a stable trend until the first Italian case of COVID-19 has been recorded, on February 19th, 2020, when they dropped simultaneously. The reduction of ED visits was observed in all age groups and across all severity and diagnosis groups. In the lockdown period a significant increase was found in overall out-of-hospital mortality (43.2%) and cause-specific out-of-hospital mortality related to neoplasms (76.7%), endocrine, nutritional and metabolic (79.5%) as well as cardiovascular (32.7%) diseases. The pandemic caused a sudden drop of ED visits and hospitalizations of non-COVID-19 patients during the lockdown period, and a concurrent increase in out-of-hospital mortality mainly driven by deaths for neoplasms, cardiovascular and endocrine diseases. As recurrencies of the COVID-19 pandemic are underway, the scenario described in this study might be useful to understand both the population reaction and the healthcare system response at the early phases of the pandemic in terms of reduced demand of care and systems capability in intercepting it.

Frequency of Cardiovascular Complications and Its Association with Prognosis of COVID-19 Patients.

Coronavirus disease 2019 (COVID-19) may lead to acute respiratory disease; cardiovascular, gastrointestinal, and coagulation complications; and even death. One of the major complications is cardiovascular disorders, including arrhythmias, myocarditis, pericarditis, and acute coronary artery disease. The aim of this study was to evaluate the frequency of cardiovascular complications and to determine its association with the prognosis of COVID-19 patients. In a prospective analytic study, 137 hospitalized COVID-19 patients were enrolled. During hospitalization, an electrocardiogram (ECG) was performed every other day, and laboratory tests such as cardiac troponin I (cTnI) and creatine kinase-MB (CK-MB) were done 0, 6, and 12 hours after admission. These tests were repeated for patients with chest pain or ECG changes. Patients were categorized into three groups (improved, complicated, and expired patients) and assessed for the rate and type of arrhythmias, cardiac complications, lab tests, and outcomes of treatments. There was no significant relationship among the three groups related to primary arrhythmia and arrhythmias during treatment. The most common arrhythmia during hospitalization and after treatment was ST-T fragment changes. There was a significant age difference between the three groups (P = 0.001). There was a significant difference among the three groups for some underlying diseases, including diabetes mellitus (P = 0.003) and hyperlipidemia (P = 0.004). In our study, different types of arrhythmias had no association with patients' outcomes but age over 60 years, diabetes mellitus, and hyperlipidemia played an important role in the prognosis of COVID-19 cases.

Cardiometabolic Alterations in the Interplay of COVID-19 and Diabetes: Current Knowledge and Future Avenues.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease 2019 [COVID-19]) pandemic has raged for almost two years, with few signs of a sustained abatement or remission [...].

Application of the Pluripotent Stem Cells and Genomics in Cardiovascular Research-What We Have Learnt and Not Learnt until Now.

Personalized regenerative medicine and biomedical research have been galvanized and revolutionized by human pluripotent stem cells in combination with recent advances in genomics, artificial intelligence, and genome engineering. More recently, we have witnessed the unprecedented breakthrough life-saving translation of mRNA-based vaccines for COVID-19 to contain the global pandemic and the investment in billions of US dollars in space exploration projects and the blooming space-tourism industry fueled by the latest reusable space vessels. Now, it is time to examine where the translation of pluripotent stem cell research stands currently, which has been touted for more than the last two decades to cure and treat millions of patients with severe debilitating degenerative diseases and tissue injuries. This review attempts to highlight the accomplishments of pluripotent stem cell research together with cutting-edge genomics and genome editing tools and, also, the promises that have still not been transformed into clinical applications, with cardiovascular research as a case example. This review also brings to our attention the scientific and socioeconomic challenges that need to be effectively addressed to see the full potential of pluripotent stem cells at the clinical bedside.

Jeopardy of COVID-19: Rechecking the Perks of Phytotherapeutic Interventions.

The novel coronavirus disease (COVID-19), the reason for worldwide pandemic, has already masked around 220 countries globally. This disease is induced by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). Arising environmental stress, increase in the oxidative stress level, weak immunity and lack of nutrition deteriorates the clinical status of the infected patients. Though several researches are at its peak for understanding and bringing forward effective therapeutics, yet there is no promising solution treating this disease directly. Medicinal plants and their active metabolites have always been promising in treating many clinical complications since time immemorial. Mother nature provides vivid chemical structures, which act multi-dimensionally all alone or synergistically in mitigating several diseases. Their unique antioxidant and anti-inflammatory activity with least side effects have made them more effective candidate for pharmacological studies. These medicinal plants inhibit attachment, encapsulation and replication of COVID-19 viruses by targeting various signaling molecules such as angiotensin converting enzyme-2, transmembrane serine protease 2, spike glycoprotein, main protease etc. This property is re-examined and its potency is now used to improve the existing global health crisis. This review is an attempt to focus various antiviral activities of various noteworthy medicinal plants. Moreover, its implications as prophylactic or preventive in various secondary complications including neurological, cardiovascular, acute kidney disease, liver disease are also pinpointed in the present review. This knowledge will help emphasis on the therapeutic developments for this novel coronavirus where it can be used as alone or in combination with the repositioned drugs to combat COVID-19.

SARS-CoV-2, Cardiovascular Diseases, and Noncoding RNAs: A Connected Triad.

Coronavirus Disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is characterized by important respiratory impairments frequently associated with severe cardiovascular damages. Moreover, patients with pre-existing comorbidity for cardiovascular diseases (CVD) often present a dramatic increase in inflammatory cytokines release, which increases the severity and adverse outcomes of the infection and, finally, mortality risk. Despite this evident association at the clinical level, the mechanisms linking CVD and COVID-19 are still blurry and unresolved. Noncoding RNAs (ncRNAs) are functional RNA molecules transcribed from DNA but usually not translated into proteins. They play an important role in the regulation of gene expression, either in relatively stable conditions or as a response to different stimuli, including viral infection, and are therefore considered a possible important target in the design of specific drugs. In this review, we introduce known associations and interactions between COVID-19 and CVD, discussing the role of ncRNAs within SARS-CoV-2 infection from the perspective of the development of efficient pharmacological tools to treat COVID-19 patients and taking into account the equally dramatic associated consequences, such as those affecting the cardiovascular system.

Hospitalizations and emergency department visits trends among elderly individuals in proximity to death: a retrospective population-based study.

Acute healthcare services are extremely important, particularly during the COVID-19 pandemic, as healthcare demand has rapidly intensified, and resources have become insufficient. Studies on specific prepandemic hospitalization and emergency department visit (EDV) trends in proximity to death are limited. We examined time-trend specificities based on sex, age, and cause of death in the last 2 years of life. Datasets containing all hospitalizations and EDVs of elderly residents in Friuli-Venezia Giulia, Italy (N = 411,812), who died between 2002 and 2014 at ≥ 65 years, have been collected. We performed subgroup change-point analysis of monthly trends in the 2 years preceding death according to sex, age at death (65-74, 75-84, 85-94, and ≥ 95 years), and main cause of death (cancer, cardiovascular, or respiratory disease). The proportion of decedents (N = 142,834) accessing acute healthcare services increased exponentially in proximity to death (hospitalizations = 4.7, EDVs = 3.9 months before death). This was inversely related to age, with changes among the youngest and eldest decedents at 6.6 and 3.5 months for hospitalizations and at 4.6 and 3.3 months for EDVs, respectively. Healthcare use among cancer patients intensified earlier in life (hospitalizations = 6.8, EDVs = 5.8 months before death). Decedents from respiratory diseases were most likely to access hospital-based services during the last month of life. No sex-based differences were found. The greater use of acute healthcare services among younger decedents and cancer patients suggests that policies potentiating primary care support targeting these at-risk groups may reduce pressure on hospital-based services.

Role of ACE2-Ang (1-7)-Mas axis in post-COVID-19 complications and its dietary modulation.

Severe acute respiratory syndrome-coronavirus-2 (COVID-19) virus uses Angiotensin-Converting Enzyme 2 (ACE2) as a gateway for their entry into the human body. The ACE2 with cleaved products have emerged as major contributing factors to multiple physiological functions and pathogenic complications leading to the clinical consequences of the COVID-19 infection Decreased ACE2 expression restricts the viral entry into the human cells and reduces the viral load. COVID-19 infection reduces the ACE2 expression and induces post-COVID-19 complications like pneumonia and lung injury. The modulation of the ACE2-Ang (1-7)-Mas (AAM) axis is also being explored as a modality to treat post-COVID-19 complications. Evidence indicates that specific food components may modulate the AAM axis. The variations in the susceptibility to COVID-19 infection and the post-COVID its complications are being correlated with varied dietary habits. Some of the food substances have emerged to have supportive roles in treating post-COVID-19 complications and are being considered as adjuvants to the COVID-19 therapy. It is possible that some of their active ingredients may emerge as the direct treatment for the COVID-19.

Association of pre-existing comorbidities with mortality and disease severity among 167,500 individuals with COVID-19 in Canada: A population-based cohort study.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) has infected 1.9% of the world population by May 2, 2021. Since most previous studies that examined risk factors for mortality and severity were based on hospitalized individuals, population-based cohort studies are called for to provide evidence that can be extrapolated to the general population. Therefore, we aimed to examine the associations of comorbidities with mortality and disease severity in individuals with COVID-19 diagnosed in 2020 in Ontario, Canada. METHODS AND FINDINGS: We conducted a retrospective cohort study of all individuals with COVID-19 in Ontario, Canada diagnosed between January 15 and December 31, 2020. Cases were linked to health administrative databases maintained in the ICES which covers all residents in Ontario. The primary outcome is all-cause 30-day mortality after the first COVID-19 diagnosis, and the secondary outcome is a composite severity index containing death and hospitalization. To examine the risk factors for the outcomes, we employed Cox proportional hazards regression models and logistic regression models to adjust for demographic, socio-economic variables and comorbidities. Results were also stratified by age groups. A total of 167,500 individuals were diagnosed of COVID-19 in 2020 and included in the study. About half (43.8%, n = 73,378) had at least one comorbidity. The median follow-up period were 30 days. The most common comorbidities were hypertension (24%, n = 40,154), asthma (16%, n = 26,814), and diabetes (14.7%, n = 24,662). Individuals with comorbidity had higher risk of mortality compared to those without (HR = 2.80, 95%CI 2.35-3.34; p<0.001), and the risk substantially was elevated from 2.14 (95%CI 1.76-2.60) to 4.81 (95%CI 3.95-5.85) times as the number of comorbidities increased from one to five or more. Significant predictors for mortality included comorbidities such as solid organ transplant (HR = 3.06, 95%CI 2.03-4.63; p<0.001), dementia (HR = 1.46, 95%CI 1.35-1.58; p<0.001), chronic kidney disease (HR = 1.45, 95%CI 1.34-1.57; p<0.001), severe mental illness (HR = 1.42, 95%CI%, 1.12-1.80; p<0.001), cardiovascular disease (CVD) (HR = 1.22, 95%CI, 1.15-1.30), diabetes (HR = 1.19, 95%, 1.12-1.26; p<0.001), chronic obstructive pulmonary disease (COPD) (HR = 1.19, 95%CI 1.12-1.26; p<0.001), cancer (HR = 1.17, 95%CI, 1.09-1.27; p<0.001), hypertension (HR = 1.16, 95%CI, 1.07-1.26; p<0.001). Compared to their effect in older age groups, comorbidities were associated with higher risk of mortality and severity in individuals under 50 years old. Individuals with five or more comorbidities in the below 50 years age group had 395.44 (95%CI, 57.93-2699.44, p<0.001) times higher risk of mortality compared to those without. Limitations include that data were collected during 2020 when the new variants of concern were not predominant, and that the ICES databases do not contain detailed individual-level socioeconomic and racial variables. CONCLUSION: We found that solid organ transplant, dementia, chronic kidney disease, severe mental illness, CVD, hypertension, COPD, cancer, diabetes, rheumatoid arthritis, HIV, and asthma were associated with mortality or severity. Our study highlights that the number of comorbidities was a strong risk factor for deaths and severe outcomes among younger individuals with COVID-19. Our findings suggest that in addition of prioritizing by age, vaccination priority groups should also include younger population with multiple comorbidities.

Complication and Sequelae of COVID-19: What Should We Pay Attention to in the Post-Epidemic Era.

COVID-19 is widespread worldwide and seriously affects the daily life and health of humans. Countries around the world are taking necessary measures to curb the spread. However, COVID-19 patients often have at least one organ complication and sequelae in addition to respiratory symptoms. Controlling the epidemic is only a phased victory, and the complication and sequelae of COVID-19 will need more attention in the post-epidemic era. We collected general information from over 1000 articles published in 2020 after the COVID-19 outbreak and systematically analyzed the complication and sequelae associated with eight major systems in COVID-19 patients caused by ACE2 intervention in the RAS regulatory axis. The autoimmune response induced by 2019-nCoV attacks and damages the normal tissues and organs of the body. Our research will help medical workers worldwide address COVID-19 complication and sequelae.