The renin-angiotensin system (RAS) is fundamental to COVID-19 pathobiology, due to the interaction between the SARS-CoV-2 virus and the angiotensin-converting enzyme-2 (ACE2) co-receptor for cellular entry. The prevailing hypothesis is that SARS-CoV-2-ACE2 interactions lead to an imbalance of the RAS, favoring pro-inflammatory Ang II related signaling at the expense of the anti-inflammatory Ang-(1-7) mediated alternative pathway. Indeed, multiple clinical trials targeting this pathway in COVID-19 are underway. Therefore, precise measurement of circulating RAS components is critical to understand the interplay of the RAS on COVID-19 outcomes. Multiple challenges exist in measuring the RAS in COVID-19 including improper patient controls, ex-vivo degradation and low concentrations of angiotensins, and unvalidated laboratory assays. Here, we conducted a prospective pilot study to enroll thirty-three moderate and severe COVID-19 patients and physiologically matched COVID-19 negative controls to quantify the circulating RAS. Our enrollment strategy led to physiologic matching of COVID-19 negative and positive moderate hypoxic respiratory failure cohorts, in contrast to the severe COVID-19 cohort which had increased severity of illness, prolonged ICU stay and increased mortality. Circulating Ang II and Ang-(1-7) levels were measured in the low picomolar (pM) range. We found no significant differences in circulating RAS peptides or peptidases between these three cohorts. The combined moderate and severe COVID-19 positive cohorts demonstrated a mild reduction in ACE activity compared to COVID-19 negative controls (2.2±0.9x105 vs. 2.9±0.8x105 RFU/mL, p=0.03). These methods may be useful in designing larger studies to physiologically match patients and quantify the RAS in COVID-19 RAS augmenting clinical trials.
Background Heart rate variability ( HRV ) is associated with vascular risk factors for dementia, but whether HRV is associated with specific domains of cognitive performance is unclear. Methods and Results In the Multi‐Ethnic Study of Atherosclerosis (N=3018; mean age 59.3±9.2 years), we assessed the relationship of 10‐second HRV to scores on tests of global cognitive performance (Cognitive Abilities Screening Instrument), processing speed (Digit Symbol Coding), and working memory (Digit Span). HRV was computed as the SD of normal‐normal intervals (SDNN) and root mean square of successive differences (RMSSD) at Exam 1 (2000–2002) and Exam 5 (2010–2012). Cognitive tests were administered at Exam 5. We report regression coefficients (β [95% CI]) representing cognitive test score change per 2‐fold increase in HRV . After adjustment for age, race/ethnicity, sex, education, apolipoprotein E genotype, and cardiovascular risk factors and incident disease, higher Exam 1 (β=0.37 [0.06, 0.67]) and Exam 5 (β=0.31 [0.04, 0.59]) SDNN were associated with better Cognitive Abilities Screening Instrument performance. Higher Exam 1 (β=0.80 [0.17, 1.43]) and Exam 5 (β=0.63 [0.06, 1.20]) SDNN , and Exam 5 RMSSD (β=0.54 [0.01, 1.08]) were associated with better Digit Symbol Coding performance. Finally, higher Exam 5 SDNN was associated with better Digit Span performance (β=0.17 [0.01, 0.33]). Associations were attenuated after adjustment for resting heart rate. Conclusions Higher HRV is generally associated with better cognitive performance in this multi‐ethnic cohort of aging adults, and further study of the relationship of autonomic function to cognition is warranted.
We investigated acute and chronic effects of CB1 cannabinoid receptor blockade in renin‐angiotensin system‐dependent hypertension using rimonabant (SR141716A), an orally active antagonist with central and peripheral actions. In transgenic (mRen2)27 rats, a model of angiotensin II‐dependent hypertension with increased body mass and insulin resistance, acute systemic blockade of CB1 receptors significantly reduced blood pressure within 90 min but had no effect in Sprague‐Dawley rats. No changes in metabolic hormones occurred with the acute treatment. During chronic CB1 receptor blockade, (mRen2)27 rats received daily oral administration of SR141716A (10 mg/kg/day) for 28 days. Systolic blood pressure was significantly reduced within 24 h, and at Day 21 of treatment values were 173 mmHg in vehicle versus 149 mmHg in drug‐treated rats (P < 0.01). This accompanied lower cumulative weight gain (22 vs. 42 g vehicle; P < 0.001), fat mass (2.0 vs. 2.9% of body weight; P < 0.05), and serum leptin (2.8 vs. 6.0 ng/mL; P < 0.05) and insulin (1.0 vs. 1.9 ng/mL; P < 0.01), following an initial transient decrease in food consumption. Conscious hemodynamic recordings indicate twofold increases occurred in spontaneous baroreflex sensitivity (P < 0.05) and heart rate variability (P < 0.01), measures of cardiac vagal tone. The beneficial actions of CB1 receptor blockade in (mRen2)27 rats support the interpretation that an upregulated endocannabinoid system contributes to hypertension and impaired autonomic function in this angiotensin II‐dependent model. We conclude that systemic CB1 receptor blockade may be an effective therapy for angiotensin II‐dependent hypertension and associated metabolic syndrome.
Background Vascular risk scores are associated with incident dementia. Information regarding their association with cognitive performance and decline in racially/ethnically diverse cohorts is lacking. Methods In 4392 Multi-Ethnic Study of Atherosclerosis participants (aged 60.1±9.4 years; 53% women; 41% white, 11% Chinese-American, 26% African-American, 21% Hispanic), we compared associations of Exam 1 (2000-02) Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE), Framingham stroke (FSRP), and atherosclerotic disease pooled cohort equation (ASCVD-PCE) risk scores with Exam 5 (2010-12) Cognitive Abilities Screening Instrument (CASI), Digit Symbol Coding (DSC), and Digit Span (DS) cognitive test performance using multivariable linear regression, and examined racial/ethnic interactions. In 1838 participants with repeat CASI data at Exam 6 (2016-18), we related risk scores to odds of a 1-standard deviation (SD) decline in CASI performance using multivariable logistic regression. Results SD increments in each risk score were associated with worse cognitive performance. CAIDE had stronger associations with CASI performance than the FSRP and ASCVD-PCE, but associations of ASCVD-PCE with the DSC and DS were similar to CAIDE (difference in β [95% CI] = -0.57 [-1.48, 0.34] and -0.21 [-0.43, 0.01], respectively). Race/ethnicity modified associations. For example, associations between CAIDE and CASI were greater in African-Americans and Hispanics than whites (difference in β = 0.69 [0.02, 1.36] and 1.67 [0.95, 2.39], respectively). Risk scores were comparably associated with decline in CASI performance. Conclusions Antecedent vascular risk scores are associated with cognitive performance and decline in the four most common US racial/ethnic groups, but associations differ among risk scores and by race/ethnicity.
Introduction:Little is known about how antecedent vascular risk factor (VRF) profiles impact late-life brain health. Methods: We examined baseline VRFs, and cognitive testing and neuroimaging measures (β-amyloid [Aβ] PET, MRI) in a diverse longitudinal cohort (N = 159; 50% African-American, 50% White) from Wake Forest's Multi-Ethnic Study of Atherosclerosis Core. Results: African-Americans exhibited greater baseline Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE), Framingham stroke risk profile (FSRP), and atherosclerotic cardiovascular disease risk estimate (ASCVD) scores than Whites. We observed no significant racial differences in Aβ positivity, cortical thickness, or white matter hyperintensity (WMH) volume. Higher baseline VRF scores were associated with lower cortical thickness and greater WMH volume, and FSRP and CAIDE were associated with Aβ. Aβ was cross-sectionally associated with cognition, and all imaging biomarkers were associated with greater 6-year cognitive decline. Discussion: Results suggest the convergence of multiple vascular and Alzheimer's processes underlying neurodegeneration and cognitive decline.
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