The influence of sex hormones on cerebrovascular function

The disproportionate rise in cerebrovascular disease risk for females in the first 10 years post-menopause indicates a role for ovarian sex hormones (i.e., oestrogen and progesterone) in healthy cerebrovascular function and regulation. However, the exact influence of changing sex hormones across the lifespan on the cerebrovasculature is yet to be elucidated. The primary aim of this thesis was to determine the influence of sex hormones on cerebrovascular function. A systematic review and meta-analysis established that hormone replacement therapy in post-menopausal females has the potential to improve cerebrovascular function, as reflected by a significant reduction in pulsatility index. Further, the effects of changing sex hormones in other hormone groups (e.g., menstrual cycle, menopause) remains unclear due to the substantial heterogeneity and limited evidence in the literature. Subsequently, three experimental studies examined measures of cerebrovascular function across the menstrual cycle, between males and females, and between pre- and post-menopausal females. Firstly, cerebrovascular responsiveness (indexed via measures of middle/posterior cerebral blood flow velocity (MCAv/PCAv) responses to altered arterial partial pressure of carbon dioxide (CO2)) across the menstrual cycle revealed a greater MCAv-CO2 responsiveness to hypocapnia during ovulation (O) when compared to the early follicular (EF) phase. Assessment of sex differences showed cerebrovascular-CO2 responsiveness to hypo- and hypo-to-hypercapnia was greater in females during EF in the PCA, and females during O in the MCA, when compared to males. Use of passive heat stress as an additional perturbation did not change cerebrovascular-CO2 responsiveness across the menstrual cycle, while a diminished PCA responsiveness to hypercapnia during heat stress was only evident in males. Finally, pre-menopausal females were shown to have an improved MCAv-CO2 responsiveness to hypercapnia compared to post-menopausal females, irrespective of menstrual phase. Preliminary data indicates possible differences between pre- and post-menopausal females in internal carotid artery (ICA) responsiveness to hypercapnia, and in cerebral autoregulation (indexed via MCAv responses to repeated squat-to-stand-induced changes in blood pressure). Collectively, these findings indicate that 1) acute fluctuations in oestrogen across the menstrual cycle can alter the vasoconstrictive capacity of the MCA, while progesterone appears to counteract the effects of oestrogen. 2) Sex differences in cerebrovascular-CO2 responsiveness are dependent on menstrual phase and the insonated vessel, and differences are present even when females are early follicular phase of the menstrual cycle. Further, cerebrovascular responses to passive heating are sex specific. Finally, 3) post-menopausal females have a blunted MCAv responsiveness to hypercapnia compared to pre-menopausal females. Overall, the findings that pre-menopausal females exhibit improved intracranial cerebrovascular-CO2 responsiveness compared to both young males and post-menopausal females supports the premise that sex hormones play a protective role in cerebrovascular function

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Stratified analyses refine association between TLR7 rare variants and severe COVID-19

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

International audienc