Chronic Mild Stress and COVID-19 Sequelae

Although COVID-19 clinical presentation primarily involves the respiratory system causing bilateral pneumonia, it is becoming increasingly recognized that COVID-19 is in fact a systemic disease. Neurological presentations have been reported in patients with both mild and severe COVID-19 symptoms. As such, elderly individuals are at a significantly higher risk of developing severe COVID-19 as well as neurocognitive consequences due to the presence of comorbidities associated with aging and the direct consequences of infection. Several neurological disorders that have been described in the literature include insomnia, depression, anxiety, post-traumatic stress disorder and cognitive insufficiencies. The potential underlying mechanisms are still incompletely understood but are likely multifaceted, involving both direct neurotrophic effect of SARS-CoV-2 and the indirect consequences related to social isolation in long intensive care units, the use of mechanical ventilation and sedation and the resultant brain hypoxia, systemic inflammation and secondary effects of medications used in treatment of COVID-19. Furthermore, neuro-cardiovascular adaptations resulting from the chronic stress and depression milieu of COVID-19 is expected to contribute negatively to the cardiovascular health of the survivors. It is thus imperative to implement a rigorous monitoring program for COVID-19 survivors, particularly among the elderly population, to assess potential neuro-cognitive and cardiovascular deteriorations

Regulation of expression of CPB2, the gene encoding human thrombin activatable fibrinolysis inhibitor (TAFI): the role for post-transcriptional regulation

Disequilibrium between coagulation and fibrinolysis can lead to severe haemostatic disorders such as thrombosis and hemophilia. Thrombin-activable fibrinolysis inhibitor (TAFI) is a carboxypeptidase B-like pro-enzyme that, once activated, attenuates fibrinolysis. TAFI may also mediate connections between coagulation and inflammation. Studies have associated high plasma TAFI levels with a risk for thrombotic diseases. TAFI plasma concentrations vary substantially within human population, and various hormonal factors and disease states have been shown to have an impact. Regulation of expression of the gene encoding TAFI, CBP2, is likely an important determinant of the role of the TAFI pathway in vivo; this concept motivated the investigations described in this thesis. Our first set of studies lead to the identification of key cis-acting sequences within the 3\u27-untranslated region (3\u27-UTR) of the TAFI mRNA that specify transcript stability. Specifically, we described the presence of one stability element, followed by three instability elements. Furthermore, we identified the trans-acting factor binding to the last instability element. Tristetraprolin (TTP) is capable of binding this sequence, promoting mRNA destabilization and degradation. We also observed that another trans-acting protein factor, HuR, binds the TAFI 3\u27-UTR. We found that TTP and HuR play a crucial role in post-transcriptional regulation of CPB2 transcript. Pro-inflammatory mediators exerted their TAFI protein-lowering effects via TTP-mediated mRNA destabilization in human hepatocellular carcinoma (HepG2) cells. On the other hand, CPB2 mRNA and TAFI protein abundance and transcript stability were increased in THP-1 macrophages in the presence of inflammatory mediators, suggesting the possibility of tissue-specific regulation for CPB2 gene expression. We also obtained preliminary evidence that miR-124, miR-506 and miR-708 decrease endogenous TAFI mRNA and protein in HepG2 cells. Moreover, the recognition site of miR-143 includes the region containing a commonly occurring single nucleotide polymorphism that is associated with lower plasma TAFI concentrations, providing a plausible mechanistic basis for such effect. Taken together, our results provide new knowledge about the crucial role of posttranscriptional regulation in mediating TAFI protein levels. Factors that act in trans to mediate these effects include both proteins (TTP and HuR) and miRNAs (miR-124, miR-143, miR-506 and miR-708)

Longitudinal associations between dietary fructose and sodium and systolic and diastolic blood pressure among US Black and White adults in the CARDIA study

Longitudinal associations between dietary fructose and sodium and systolic and diastolic blood pressure among US Black and White adults in the CARDIA study Authors: Rana Elhamzawy, Daniel Domin, Dragana Komnenov Hypertension is one of the leading risk factors for major adverse cardiovascular events (MACE). Likewise, suboptimal dietary habits, including high fructose and sodium intake, are major contributors to mortality. High dietary fructose alone predisposes to salt-sensitivity of blood pressure, which is an independent, significant cardiovascular risk factor. We previously showed in our rat model of fructose-salt-sensitive hypertension that even a short term (4 weeks) feeding with 20% fructose and 4% salt leads to salt sensitivity of blood pressure. Furthermore, male rats fed fructose and salt had increased aortic stiffness, impaired diastolic function and longitudinal left ventricular strain. Most recently, we showed that when young rats are fed fructose and salt and then switched to a normal diet, subsequent fructose feeding contributes to the salt sensitivity of blood pressure later in life. The present investigation was designed to test the hypothesis that increased fructose and sodium intake in humans leads to increases in systolic and diastolic blood pressure. The study subjects were derived from the CARDIA study, which is a prospective follow-up study aimed to investigate the evolution of cardiovascular risk factors in a biracial cohort of young adults aged 17-35 years at enrollment. Dietary data was obtained from the diet questionnaires which quantified fructose and sodium. Blood pressures obtained at enrollment, years 7, 15 and 30 of follow-up were used in the present study. Multivariate analysis was completed for the factors contributing to the development of hypertension. Moreover, serum uric acid and C-reactive protein were regressed upon high blood pressure diagnosis at year 15 of follow up. Additionally, echocardiography data were regressed upon high blood pressure diagnosis at year 30 of follow up. Dietary fructose and sodium at year 7 of follow up significantly predicted systolic (SBP)(F (2,2922) =11.760,

Impact of dietary fructose and high salt diet: Are preclinical studies relevant to Asian societies?

Fructose consumption, especially in food additives and sugar-sweetened beverages, has gained increasing attention due to its potential association with obesity and metabolic syndrome. The relationship between fructose and a high-salt diet, leading to hypertension and other deleterious cardiovascular parameters, has also become more evident, especially in preclinical studies. However, these studies have been modeled primarily on Western diets. The purpose of this review is to evaluate the dietary habits of individuals from China, Japan, and Korea, in light of the existing preclinical studies, to assess the potential relevance of existing data to East Asian societies. This review is not intended to be exhaustive, but rather to highlight the similarities and differences that should be considered in future preclinical, clinical, and epidemiologic studies regarding the impact of dietary fructose and salt on blood pressure and cardiovascular health worldwide

The Effects of Different Antihypertensives, Steroids, and Beta Blockers on COVID-19 Outcomes in a CKD and Non-CKD Cohort in Detroit, Michigan

Initial studies during the COVID-19 pandemic reported angiotensin converting enzyme 2 inhibitors (ACE2i) could be associated with worse disease course due to potential increase in ACE2 receptors which SARS-CoV2 virus uses for cellular entry. Subsequent studies refuted such concerns, reporting that continued use of ACEis and angiotensin receptor blockers (ARBs) in hypertensive individuals is protective. However, there remains a paucity of data evaluating effects of various antihypertensive medications, steroids, and beta blockers in chronic kidney disease (CKD) populations and in individuals with normal kidney function. This study was designed to evaluate the potential risks associated with antihypertensive medications and COVID-19 outcomes in a cohort of mostly Black and Caucasian patients admitted to the Detroit Medical Center for COVID-19. We collected data from 330 patients using inclusion criteria of age \u3e 18 years and a positive SARS-CoV2 PCR test. We used the mean, standard deviation/standard error of mean, and percentages when appropriate for the description of patient characteristics. Group differences (CKD vs. non-CKD) were compared using the Pearson χ2 test. P-values of \u3c0.05 were regarded as significant. On regression analyses, the odds of death during hospitalization for COVID-19 infection was not significantly associated with either biological sex, race, or CKD status in our sample population. The odds of dying in the hospital were higher in patients who were on calcium channel blockers (OR 2.99, 95% CI 1.29-6.93) and steroids (OR 4.23, 95% CI 1.17-15.31). The only significance for ICU admission was obtained for steroid use (OR 1.872, 95% CI 1.059-3.311)

Fructose‐induced salt‐sensitive blood pressure differentially affects sympathetically mediated aortic stiffness in male and female Sprague‐Dawley rats

Abstract Hypertension is the leading risk factor for major adverse cardiovascular events (MACE). Aortic stiffness and sympathoexcitation are robust predictors of MACE. Combined high fructose and sodium intake increases arterial pressure, aortic stiffness, renin, and sympathetic nerve activity in male rats. We hypothesized that activation of the renin angiotensin system (RAS) and/or the sympathetic system mediates aortic stiffness in rats with fructose‐induced salt‐sensitive blood pressure. Male and female Sprague‐Dawley rats ingested 20% fructose or 20% glucose in drinking water with 0.4% NaCl chow for 1 week. Then, fructose‐fed rats were switched to 4% NaCl chow (Fru + HS); glucose‐fed rats remained on 0.4% NaCl chow (Glu + NS, controls for caloric intake). After 2 weeks, mean arterial pressure (MAP) and aortic pulsed wave velocity (PWV) were evaluated at baseline or after acute intravenous vehicle, clonidine, enalapril, losartan, or hydrochlorothiazide. Baseline global longitudinal strain (GLS) was also assessed. MAP and PWV were greater in male Fru + HS versus Glu + NS male rats (p < 0.05 and p < 0.001, respectively). PWV was similar between the female groups. Despite similarly reduced MAP after clonidine, PWV decreased in Fru + HS versus Glu + NS male rats (p < 0.01). Clonidine induced similar decreases in MAP and PWV in females on either diet. GLS was lower in Fru + HS versus Glu + NS male rats and either of the female groups. Thus, acute sympathoinhibition improved aortic compliance in male rats with fructose salt‐sensitive blood pressure. Female rats retained aortic compliance regardless of diet. Acute RAS inhibition exerted no significant effects. Male rats on fructose high salt diet displayed an early deficit in myocardial function. Taken together, these findings suggest that adult female rats are protected from the impact of fructose and high salt diet on blood pressure, aortic stiffness, and early left ventricular dysfunction compared with male rats

Hypertension Associated with Fructose and High Salt: Renal and Sympathetic Mechanisms

Hypertension is a leading cause of cardiovascular and chronic renal disease. Despite multiple important strides that have been made in our understanding of the etiology of hypertension, the mechanisms remain complex due to multiple factors, including the environment, heredity and diet. This review focuses on dietary contributions, providing evidence for the involvement of elevated fructose and salt consumption that parallels the increased incidence of hypertension worldwide. High fructose loads potentiate salt reabsorption by the kidney, leading to elevation in blood pressure. Several transporters, such as NHE3 and PAT1 are modulated in this milieu and play a crucial role in salt-sensitivity. High fructose ingestion also modulates the renin-angiotensin-aldosterone system. Recent attention has been shifted towards the contribution of the sympathetic nervous system, as clinical trials demonstrated significant reductions in blood pressure following renal sympathetic nerve ablation. New preclinical data demonstrates the activation of the renal sympathetic nerves in fructose-induced salt-sensitive hypertension, and reductions of blood pressure after renal nerve ablation. This review further demonstrates the interplay between sodium handling by the kidney, the renin-angiotensin-aldosterone system, and activation of the renal sympathetic nerves as important mechanisms in fructose and salt-induced hypertension