Serotonin reuptake inhibitors and cardiovascular disease

Selective serotonin re-uptake inhibiting drugs (SSRIs) are widely used for endogenous depression. In addition to depleting the nerve terminals of serotonin they also lower blood platelet serotonin levels. Platelet aggregation is a major component of acute coronary syndromes, including sudden death, and also of limb ischaemia. Platelet-released serotonin causes constriction of diseased blood vessels. The recent literature has revealed a number of reports of association between the treatment of depression with SSRIs and reduced events caused by intra-arterial thrombosis. The effects of serotonin and serotonin depletion upon intracoronary thrombosis, diseased blood vessels, blood platelets and bleeding are discussed with recommendations for future research into the potential cardiovascular benefits of SSRIs and serotonin 5HT2A antagonists

Coronary vessel supersensitivity to noradrenaline in the presence of chronic sympathetic denervation.

It is well known that there is usually super-sensitivity to the normal neurotransmitter in chronically denervated organs. The present consensus of opinion is that there is no super-sensitivity of response of myocardial arteriolar resistance vessels to nor-adrenaline after chronic sympathetic denervation; this opinion was tested. We re-analysed the data in the literature on innervated myocardium, plus the effect of chronic sympathetic myocardial denervation induced by surgery plus phenol application. We found that the opinion is based on studies of isolated epicardial arteries. Studies of resistance vessels mostly ignore an important confounding factor, in that myocardial blood flow (MBF) within myocardium is heterogeneous under all circumstances. This heterogeneity is partly related to similar heterogeneity in myocardial oxygen consumption (MVO2), and partly to heterogeneity in local noradrenaline, as assessed by 11C-hydroxyephidrine positron emission tomography. The local volume of distribution of 11C-hydroxyephedrine in innervated myocardium was inversely correlated to local MBF, at the same perfusion pressure, i.e., increasing vasoconstriction with increasing tissue noradrenaline. In chronically denervated myocardium, local MBF was lower for any given amount of noradrenaline, showing the existence of supersensitivity of the resistance vessels. This factor may have a deletereous effect in diabetic patients with cardiac autonomic neuropathy

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

BACKGROUND: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. METHODS: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. FINDINGS: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. INTERPRETATION: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. FUNDING: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript

Chronic cardiac denervation affects the speed of coronary vascular regulation

OBJECTIVE: We tested the hypothesis that the rate of adaptation of coronary metabolic vasodilatation and autoregulation is modulated by the cardiac nerves. METHODS: Anaesthetised dogs (seven innervated (control) and seven with denervated hearts) were subjected to controlled pressure perfusion of the left main coronary artery. Heart rate was controlled by pacing. RESULTS: The steady state autoregulation curves and metabolic regulation curves were similar in the two groups. A sudden increase or decrease in heart rate was associated with a faster response (22% shorter half-times) in the innervated than the denervated dogs (P < 0.001). A sudden increase or decrease in coronary arterial perfusion pressure was associated with a slower response (24% longer half-times) in the innervated than the denervated hearts (P < 0.005). CONCLUSIONS: We conclude that the speed of response to metabolic and perfusion pressure changes is partly mediated by cardio-cardiac reflexes. Reflex coronary vasodilatation appears to reinforce the metabolic vasodilatation of a heart rate increase and oppose the vasoconstriction in response to increased perfusion pressur