Search Results for: Scoperti anticorpi che bloccano l’infezione da SARS-CoV-2 nelle cellule

Circulation, Volume 148, Issue Suppl_1, Page A17669-A17669, November 6, 2023. Introduction:Racial, regional, and income disparities have been shown to impact cardiovascular outcomes in postmenopausal women with SARS-CoV-2. Addressing these disparities can improve healthcare equity and outcomes for this vulnerable population.Methods:A retrospective cohort study utilized data from the National Inpatient Sample (NIS)-2020 to examine female patients aged over 55 years who were admitted to hospitals in 2020. The study focused on primary endpoints, specifically major cardiac and cerebrovascular events (MACCE) including all-cause mortality, AMI, cardiac arrest, and stroke. Multivariable logistic regression was used to evaluate the association between demographic factors and cardiovascular outcomes, after controlling for confounding variables.Results:Of the total 547,225 postmenopausal women hospitalized with SARS-CoV-2, 19.8% had MACCE. Racial disparities were significant, as Native American, Hispanic, Asian and African American women exhibited higher rates of MACCE compared to Caucasian women, with odds ratios (OR) of 1.63 (95% CI: 1.33-1.98, p

Circulation, Volume 148, Issue Suppl_1, Page A18758-A18758, November 6, 2023. Background:Over 80% of people with advanced heart failure (HF) experience pain; however, little is known about the relationship between pain and quality of life (QoL).Research Objectives:Examine the relationships between: 1) Total Pain Theory constructs and 2) pain and QoL across time.Methods:A secondary analysis of usual care participants in the ENABLE CHF-PC, a palliative care RCT (ClinicalTrials.gov: NCT02505425). Primary outcome was pain (PROMIS Pain Intensity & Interference). Total Pain constructs include physical and mental health (PROMIS Global Health 10), social support (Multidimensional Scale of Perceived Social Support), and spirituality (Negative Religious Coping). Mixed models assessed the relationships between pain and Total Pain constructs. Cross-lagged path analysis examined the temporal relationship between pain and QoL (baseline, 24-weeks, 48-weeks).Results:Of 205 usual care participants, mean age was 64.15 (SD 9.14), 108 (52.7%) men, and 111 (54.1%) African American. At baseline, participants’ QoL was poor (35.98, SD 10.7) with greater pain interference (54.5, SD 10.70) but not pain intensity (45.09, SD 10.47) compared to the general population. Among Total Pain constructs, only physical health was significant. As physical health decreased, pain intensity (b = -0.80, SE = 0.09, CI = -0.99, -0.62, p < .001) and pain interference (b = -0.69, SE = 0.10, CI = -0.89, -0.49, p < .001) increased. An unadjusted path analysis suggested variable magnitude temporal relations: a significant, large relationship between pain intensity and QoL at baseline (standardized cov. = 0.53), but medium-sized across baseline to 24-weeks (B = 0.28), and across 24- to 48-weeks (B = 0.32). Relationship between pain interference and QoL was also significant at baseline (standardized cov. = 0.54) and across baseline to 24-weeks (B = 0.41).Conclusions:Variability in magnitude of relationships between pain intensity and interference and QoL demonstrates the complex nature of pain in advanced HF.

Circulation, Volume 148, Issue Suppl_1, Page A15298-A15298, November 6, 2023. Background:Infection rates are high in heart transplant (HT) patients due to the need for immunosuppressive medication. MicroRNAs (miR) are non-coding RNAs, that regulate gene expression and are promising biomarkers for identifying patients at risk for infection.Hypothesis:MiR profiles can identify HT patients who are at increased risk for developing an infection.Methods:HT patients who were prospectively enrolled from 2015-2018 had miR-sequencing performed. Incident infection after HT hospital discharge along with the epidemiologic characteristics of the infection were collected from the EMR. An opportunistic infection (OI) is an infection which is less virulent in a healthy host but can cause severe disease in those immunosuppressed. A time-to-event analysis was performed using miR expression at two weeks post-HT in multivariable modeling, and the Benjamini-Hochberg procedure was used to correct for false discovery.Results:The cohort included 46 patients with a median age of 56 years (IQR: 49, 62), 33% (N=15) were Female sex, 41% (N=19) were Black, and 80% (N=37) were supported with an LVAD prior to HT. Post-HT infection occurred in 59% of patients (N=27) and median time to infection was 341 days (IQR: 85, 859). Hospitalization was required in 56% (N=15) of infections. Respiratory tract and OIs were the most common infection type (Figure A). The most common microorganisms implicated were CMV (28%) and SARS-COV-2 (19%) (Figure B). After correction for false discovery, we identified 15 miRs associated with infection risk. The 5 miRs with strongest effect size and their corresponding hazard ratios include: miR-21 2.5(95% CI: 1.3, 4.7), miR-130b 8.6 (95%CI: 1.9, 39.3), miR-192 0.3 (95%CI: 0.1, 0.6), miR-218 2.6 (95%CI: 1.3, 5.1) and miR-484 0.3 (95%CI: 0.1, 0.7).Conclusion:While the burden of post-HT infections is high and contributes to patient morbidity, novel plasma miRs can potentially play a role in identifying patients at risk for infections after HT.

Circulation, Volume 148, Issue Suppl_1, Page A16646-A16646, November 6, 2023. Introduction:Approximately 30 % of patient with Post-acute COVID-19 Syndrome (PACS) develop postural orthostatic tachycardia syndrome (POTS). The pathophysiological mechanisms behind PACS and associated POTS remain largely unknown.Hypothesis:PACS and POTS-specific phenotype are associated with dysregulation of proteins involved in cardiovascular regulation.Methods:We recruited 20 (19 female) patients with PACS and POTS (age 39±11 years, 18±3 months after SARS-CoV-2 infection) and 22 patients (all female) with PACS without POTS (age 44±11years, 19±3 months after SARS-CoV-2 infection). Head-up TILT test was performed in both groups. Age- and sex matched healthy volunteers (n=21; 20 female, age 43±6 years) without- (n=16) and with (n=5) a history of SARS-Cov-2 infection but without symptoms served as control group. Plasma levels of 700 proteins involved in cardiovascular regulation was analysed using Proximity Extension Assay (Olink® Explore 384 Cardiometabolic Assays I and II).Results:Several proteins were dysregulated both in patients with PACS and POTS (n=206/700, 29%) and in PACS patients without POTS (201/700=29%) compared to healthy controls (figure 1A). Only 13 proteins were uniquely up- and 3 down-regulated in PACS and POTS compared to healthy controls (figure 1B). Gene ontology pathway enrichment analysis revealed upregulation of pathways controlling inflammation, hemostasis, platelet activation and apoptosis in PACS compared to healthy controls (figure 1C).Conclusions:PACS is associated with a substantial protein dysregulation regardless of concomitant POTS up to 18 months after a mild primary SARS-CoV-2 infection. This suggests that PACS-associated POTS exist on a background of protein dysregulation but other pathophysiological mechanisms for PACS-induced POTS need to be established. Whether the dysregulated proteins observed in PACS constitute potential treatment target should be explored.

Circulation, Volume 148, Issue Suppl_1, Page A14911-A14911, November 6, 2023. Background:SARS-CoV-2 infection can result in cardiac complications, including myocarditis, left ventricular dysfunction, arrhythmias, and acute myocardial injury. Reports of effusive constrictive pericarditis (CP) are rare, and recommendations on management are limited.Description of Case:A 30-year-old male with recurrent episodes of effusive pericarditis after SARS-CoV-2 infection 11 months prior and anasarca presents with worsening fatigue, dyspnea, and weight gain. His echocardiogram showed pericardial thickening, annulus reversus, and interventricular septal bounce. Computed tomography showed pericardial thickening and a complex pericardial effusion. Right and left heart catheterization revealed elevated filling pressures, equalization of diastolic pressures, and ventricular discordance (Figure 1). Infection, malignancy, and autoimmune etiologies of CP were ruled out.Decision Making:The patient was initiated on anti-inflammatory therapy and aggressively diuresed with no improvement in his symptoms. Given recurrent episodes of pericarditis with constriction, the patient underwent a radical pericardiectomy with posterior pericardial release. The pericardium was 1 cm thick with severe fibrosis. Surgical pathology showed acute and chronic pericarditis with negative testing for Mycobacterium tuberculosis.Conclusion:Idiopathic, post-cardiac surgery and post-mediastinal radiation are the most common causes of CP. Acute pericarditis is a known complication of SARS-CoV-2 infection, but ongoing inflammation leading to CP is rare. CP presents with signs of heart failure and should be considered in patients with persistent symptoms of pericarditis.

Circulation, Volume 148, Issue Suppl_1, Page A15320-A15320, November 6, 2023. Introduction:Infection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV2) and the subsequent development of COVID-19 is associated with an increased risk of pulmonary embolisms (PE). We sought to determine the trends in PE-related mortality in the United States from 1999 to 2021.Methods:We analyzed all deaths occurring in the US using the US Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database from 1999 to 2021. The Multiple Cause-of-Death Public Use record death certificates were used to select PEs as the primary or contributing cause of death using relevant ICD-10 codes. PE-related age-adjusted mortality rates (AAMR) per 100,000 persons were calculated and standardized to the US population in 2000. We calculated annual percent changes (APC) and corresponding 95% confidence intervals (CI). We also conducted subgroup analyses to examine mortality trends by age, sex, and racial/ethnic groups.Results:From 1999 to 2013 and between 2013 and 2019, APC for PE-related mortality remained relatively stable, corresponding to -0.4% (95% CI: -0.6 to -0.2) and 1.3% (95% CI: 0.6 to 2.1), respectively. Between 2019 and 2021, PE-related mortality increased from 9.2 to 14.1 per 100,000 populations per year, corresponding to an APC of 21.7% (95% CI: 18.3 to 25.3). There was a similar pattern of increase among individuals < or ≥65 years. Men had a significantly greater increase in APC, 24.6% (95% CI: 20.5 to 28.9), when compared to women, 18.9% (95% CI: 15.0 to 22.9). All racial/ethnic groups experienced an increase in PE-related mortality between 2019 and 2021 but the increase was more pronounced among minority groups including Non-Hispanic Blacks, Hispanics and Native American/Alaskan Natives.Conclusion:PE-related mortality significantly increased during the COVID pandemic, and the increase was disproportionately greater among men and racial/ethnic minorities.

Circulation, Volume 148, Issue Suppl_1, Page A14877-A14877, November 6, 2023. The cellular entry of the SARS-CoV-2 virus depends on the binding of spike (S) protein to its biological ligand, ACE2. Although the virus commonly causes respiratory distress, cardiac injury can occur in COVID-19 patients, which is consistent with the expression of ACE2 in myocytes. Previous reports indicate SARS-CoV-2 proteins can target cardiac mitochondria and suppress mitochondrial function via enhancing MPTP pore opening and perturbing cardiac bioenergetics. To explore the underlying mechanism of the effect of SARS-CoV-2 on cardiac mitochondria, we measured the interactions of SARS-CoV-2 proteins with swine heart mitochondria in vitro. Incubation of recombinant S protein with isolated mitochondria significantly decreased state-3 oxygen consumption rate (OCR, 95.10 vs 65.68 nmol/min/mg) and FCCP uncoupling OCR (82.94 vs 66.95 nmol/min/mg). We further detected that S protein impaired the enzymatic activities of electron transport chain (ETC) (by 15.62% to 34.44%). However, S protein had no effect on TCA cycle enzymes, indicating the involvement of mitochondrial membrane components in decreased OCR by S proteins. Recombinant nucleocapsid (N) protein of SAR-CoV-2 had no effect on the OCR and ETC activities of swine mitochondria. S proteins decreased the intensity of mitochondrial heme spectrum determined by dithionite reduction with UV/VIS spectroscopy (by 17.52% hemea, 15.82% hemec1). The results were further assessed using isolated complex III (Cx3) and complex IV (Cx4). Treatment of isolated Cx3 and Cx4 with S protein decreased the spectral intensities of hemeaand hemec1. The spectra of both Cx3 and Cx4 were not affected by N protein. The results suggested S protein downregulates redox potentials of ETC in swine mitochondria. Treatment of swine mitochondria with S proteins enhanced superoxide (.O2–) generation by Cx1 (by 43.7%) and by Cx3 (by 10.9-fold) assessed by EPR and cytochromecreduction assays. However, we detected S proteins modestly decreased.O2–generation by swine mitochondria under state-2 condition (by 9.52%), indicating impairing pH gradient by S protein. In conclusion, the spike protein of SARS-CoV-2 virus mediates mitochondrial dysfunction of swine heart via impairing the redox function and increasing.O2–generation.

Circulation, Volume 148, Issue Suppl_1, Page A14202-A14202, November 6, 2023. Introduction:Although evidence-based practice of has progressed, little is known about underlying mechanisms of chest pain symptoms in patients with post-acute sequelae of COVID-19 (PASC) and preferred approaches for their assessment. Several mechanisms underlying COVID-19-related endothelial dysfunction have been proposed. The purpose of this study was to explore the prevalence of vasospastic angina as a cause of chest pain in PASC patients.Methods:We retrospectively reviewed 273 consecutive patients who presented to an outpatient unit for cardiovascular PASC between June 2021 and March 2023. After the initial evaluation with electro- and echocardiography, coronary computed tomography angiography or cardiac magnetic resonance imaging were performed to rule out obstructive coronary artery disease and myopericarditis if patients had intermittent chest pain and had no contraindications to these tests. When the patients’ chest pain mainly occurred at night and in the morning or was resolved by nitrates, invasive coronary angiography and acetylcholine provocation testing were performed to diagnose vasospastic angina.Results:Eight of 273 patients with PASC underwent acetylcholine provocation testing. The median time from the diagnosis of SARS-CoV2 infection to acetylcholine provocation testing was 197 (interquartile range, 120-542) days. The mean age of the patients was 37.1 years; two required oxygen support during acute COVID-19; and none had previous history of cardiovascular disease (Figure). Five of the 8 patients showed acetylcholine-induced multivessel coronary vasospasm and were diagnosed as vasospastic angina. Their chest pain improved with calcium channel blockers and nitrates, whereas nonfatal myocardial infarction occurred in one patient after the diagnosis of vasospastic angina.Conclusions:Our observational case series suggest that vasospastic angina should be considered as a potential cause of PASC.

Circulation, Volume 148, Issue Suppl_1, Page A18350-A18350, November 6, 2023. Introduction:Coronavirus Disease 2019 (COVID-19) has been associated with adverseoutcomes among hospitalized patients with pulmonary hypertension (PH) based onlimited studies. The objective of our retrospective study was to utilize theNational Inpatient Sample (NIS) database to compare in-hospital mortality andother secondary clinical outcomes between COVID-19 patients with PH andCOVID-19 patients without PH.Hypothesis:We hypothesizedthat there would be a significant increase in inpatient mortality and othercomplications among hospitalized COVID-19 patients with PH.Methods:Patientsages 18 years and older admitted to a hospital in the United States betweenJanuary 1, 2020 and December 31, 2020 with COVID-19 were included in our studyand stratified into two cohorts.Results:Aftermultivariate adjustment, we found that COVID-19 patients with PH hadsignificantly higher in-hospital mortality, increased lengths of stay, andhigher costs of hospitalization when compared to COVID-19 patients without PH.We also noted that COVID-19 with PH had increased dependence on invasive andnon-invasive positive pressure ventilation suggestive of more severerespiratory failure. Furthermore, our data demonstrated that COVID-19 patientswith PH were at risk of pulmonary embolism and myocardial infarction. Also,Hispanic and Native American COVID-19 patients with PH remained at anindependently elevated risk for in-hospital mortality when compared to otherracial groups.Conclusions:To our knowledge this isthe largest study evaluating outcomes among COVID-19 patients with PH.In-hospital complications, especially pulmonary embolism, present a clinicalmechanism for the observed inpatient mortality. Given the significant mortalityand complications associated with COVID-19 infection and pulmonaryhypertension, we recommend vaccination against SARS-CoV-2 and aggressivenon-pharmacologic preventative measures.

Circulation, Volume 148, Issue Suppl_1, Page A15405-A15405, November 6, 2023. Introduction:Post-acute sequelae of SARS-CoV-2 infection consist of pulmonary and extrapulmonary conditions, including a higher incidence of type 2 diabetes, but it remains unknown whether other cardiometabolic pathways are impacted by infection.Research Question:Does SARS-CoV-2 infection predict worsening cardiometabolic risk factors?Methods:Using data from OneFlorida+ (a PCORnet CRN), we compared changes over time in body mass index (BMI), systolic blood pressure (SBP) and low-density lipoprotein (LDL). We compared an Exposed cohort with a positive SARS-CoV-2 test or COVID-19 diagnosis code between March 2020 – January 2022 (n = 75,217; age: 48.5 y, 64% female), relative to a contemporary Unexposed cohort of adult patients with negative SARS-CoV-2 tests (n = 240,575; age: 52.7 y, 61% female), and an age/sex-matched Historical control cohort (March 2018 – January 2020; n = 75,217; age: 48.5 y, 64% female). We used multiple imputation for missingness in demographic and clinical factors and inverse probability weighting for confounding and loss to follow-up. We used doubly robust marginal structural models to estimate baseline and longitudinal differences in cardiometabolic indicators by cohort.Results:At the start of the follow-up period, adjusted for covariates and relative to the Exposed, the Unexposed (BMI: -0.5 [-0.6,-0.4] kg/m2, SBP: -0.5 [-0.8,-0.2] mmHg, LDL: -7.7 [-14.5, -1.0] mg/dL) and Historical control (BMI: -0.4 [-0.5,-0.3] kg/m2, SBP: -1.0 [-1.5,-0.6] mmHg, LDL: 12.5 [-58.3, 83.3] mg/dL) cohorts had better cardiometabolic profiles (Figure). Relative to changes in the Exposed, control cohorts displayed faster decreases in BMI (Unexposed only), slower increases in SBP, and no changes in LDL during the follow-up period.Conclusions:SARS-CoV-2 infection was associated with weight retention and a rise in blood pressure. Longer follow-up can help identify stability and impacts of these cardio-metabolic indices on events and mortality.

Circulation, Volume 148, Issue Suppl_1, Page A14153-A14153, November 6, 2023. Background:Post-acute sequela of COVID-19 (PASC) is a complication of SARS-CoV-2 causing persistent symptoms and impaired functional status. We studied the effect of P2Y12 inhibitors on health-related Quality of Life (QoL) at 90 days in critically ill patients hospitalized for COVID-19.Methods:Adults hospitalized for COVID-19 who were randomized in the P2Y12 inhibitor domain of ACTIV-4a platform trial between February 2021 and June 2022. Participants were to receive usual care and either P2Y12 inhibitor (ticagrelor preferred) or no P2Y12 inhibitor for 14-days or until hospital discharge, whichever was sooner. The QoL primary outcome was determined by the EQ-5D-5L utility and visual analog scores, standardized and validated instruments. A Bayesian model estimated difference in health related QoL by randomization status adjusting for risk factors.Results:Among 1,502 participants, 860 critically ill patients were administered English and Spanish translations of EQ-5D-5L at 90-days. Median age was 57 years (IQR: 47, 65), 37% were female, 49% were under-represented minorities, and 10% resided in Spain. In those assigned to P2Y12 inhibitor, the mean EQ-5D-5L utility score was better in those assigned to usual care (adjusted difference: 0.08, 95% CrI: 0.03, 0.13; posterior probability of superiority [defined as a mean difference > 0] was 99.9%). Better health related QoL was also observed with assignment to P2Y12 inhibitors; EQ-5D-5L visual analog score adjusted difference: 5.30 (95% Crl: -0.49, 10.84), probability of superiority: 96.4% (table 1).Conclusion:In secondary analysis of an international randomized trial of critically ill participants with COVID-19, treatment with a P2Y12 inhibitor vs usual care was associated with improved quality of life at 90-days and may decrease symptoms of PASC following hospital discharge.

Circulation, Volume 148, Issue Suppl_1, Page A17307-A17307, November 6, 2023. Introduction:It is well known that SARS-Co-V2 infection can induce ER stress-associated activation of unfolded protein response (UPR) in various host cells which may contribute to the pathogenesis of COVID-19. However, the interplay between SARS-Co-V2 infection and UPR signaling in pre-existing ER stress associated pathological conditions has not been well elucidated.Hypothesis:We hypothesizedthat modulation of a pre-existing ER stress in host cells could attenuate susceptibility to SARS-CoV-2 infection by activating a range of cellular defense.Methods:Increasing concentrations of Tunicamycin (Tm) and Thapsigargin (Tg) have been used to induce ER stress in Huh-7 cells. After 6h treatment, cells were infected with SARS-CoV-2 pseudotyped particles (SARS-CoV-2pp) for 48 p.i. SARS-Co-V2-2pp entry was measured using Bright GloTMluciferase assay. Cell viability was measured by cell titer Glo®luminescent cell viability assay. The mRNA and protein expression of UPR markers were evaluated using RT-qPCR and Western blot methods.Results:Tm (5 μg/ml) and Tg (1 μM) efficiently inhibited SARS-CoV-2pp entry into cells without any cytotoxic effect. Chemical ER stress-induced inhibition of SARS-CoV-2pp entry was associated with significant reduction of ACE2 expression in Tg-infected cells but not with Tm. Strikingly, Tm and Tg revealed differential effects in modulating the expression of ER stress genes in infected cells. Both Tm and Tg significantly reduced the expression of stress-inducible ER chaperone GRP78/BIP in infected cells. In contrast, the IRE1-XBP1s and PERK-eIF2α-ATF4-CHOP signaling pathways were downregulated in Tg-infected cells only. Additionally, insulin-mediated glucose uptake, phosphorylation of Ser307IRS-1 and downstream p-AKT were enhanced in Tg-infected cells without any change in ERK phosphorylation.Conclusions:These findings suggest that pre-existing ER stress could modulate a specific UPR response in infected cells capable of counteracting the stress-inducible elements signaling, thereby depriving SARS-Co-V2 of essential components for their entry and replication. Pharmacological manipulation of ER stress in host cells might provide new therapeutic strategies to alleviate SARS-CoV-2 infection.

Circulation, Volume 148, Issue Suppl_1, Page A16513-A16513, November 6, 2023. Introduction:In contrast to normal chest X-ray, lung computed tomography (CT), and physiological lung and cardiac functions, many patients with long COVID syndrome suffer from shortness of breath.Hypothesis:The aim of this study was to quantify the pulmonary blood and airway volumes of long COVID patients compared with that of healthy controls.Methods:Patients with long COVID syndromes were included if they had PCR-verified previous (≥3 months) SARS-CoV-2 infection, had normal laboratory (e.g. inflammation, coagulation, cardiac or other organ) parameter, normal pulmonary morphology (chest X-ray and CT) and function (spirometry and body plethysmography). The lung CT images were postprocessed by Functional Respiratory imaging analysis by using 3D reconstruction with automated lung vessel segmentation algorithm. Data of the quantitative images were compared with age, gender, and BMI-matched healthy controls.Results:Thirty patients (45±13 years, 37% male, 25.9±4.3 kg/m^2) at a median time of 256 (118-574) days after a confirmed COVID infection and 30 healthy controls (55±7y, 37% male, 26.3±2.7 kg/m^2) were included. All long COVID patients complained of dyspnoea and 14 (48.3%) patients reported thoracic pain. The total pulmonary blood volume was significantly lower in the long COVID patients compared to controls (190±24.3 mL/m^2 vs230.6±26.2 ml/m^2, p

Circulation, Volume 148, Issue Suppl_1, Page A19002-A19002, November 6, 2023. Background:SARS-CoV-2 swept across the globe, overwhelming healthcare systems across the world regardless of borders and socioeconomic factors. COVID pneumonia (CP) can result in ARDS and increased pulmonary artery pressures. Pulmonary hypertension (PHT) is generally a chronic cardiopulmonary disease that is associated with progressive vascular remodeling. We aimed to assess the impact of underlying PHT on CP patients with a large sample size.Methods:We utilized the National Inpatient Sample from 2020 to identify 1,058,815 hospitalized adults with CP. These hospitalizations were further stratified based on the presence of PHT. A multivariate regression model was used to adjust for confounders and analyze the variables.Results:Of those who were admitted for CP, 24,284 (2.3%) had PHT. In-hospital mortality was higher in those with PHT (19.6% vs 10.9%; p

Circulation, Volume 148, Issue Suppl_1, Page A15524-A15524, November 6, 2023. Coronavirus Disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The emergence of this virus has led to millions of deaths and the long-term cardiovascular and respiratory consequences of COVID-19 continue to pose a massive threat to public health. While recent studies have demonstrated that SARS-CoV-2 may enter kidney epithelial cells via angiotensin converting enzyme 2 (ACE2)-independent mechanisms by inducing receptor-independent macropinocytosis, it is currently unknown whether this process also occurs in cell types directly relevant to SARS-CoV-2-associated cardiovascular disease or pneumonia. Here, we investigated the ability of SARS-CoV-2 spike protein subunits to stimulate macropinocytosis in alveolar epithelial cells and macrophages. Flow cytometry analysis of fluid-phase marker internalization demonstrated that SARS-CoV-2 spike protein subunits S1, the receptor binding domain (RBD) of S1, and S2 stimulate macropinocytosis in both human and murine macrophages, but not in human lung epithelial cells. Pharmacological and genetic inhibition of macropinocytosis substantially decreased spike protein-induced macropinocytosis in macrophages bothin vitroandin vivo. High resolution scanning electron microscopy (SEM) imaging confirmed spike protein-induced plasma membrane activities characteristic of macropinocytosis. Mechanistic studies demonstrated that inhibition of protein kinase C and phosphoinositide 3-kinase in macrophages blocks SARS-CoV-2 spike protein-induced macropinocytosis. Further, pharmacological blockade of ACE2 did not inhibit macropinocytosis in SARS-CoV-2 spike protein-treated cells. To our knowledge, these results demonstrate for the first time that SARS-CoV-2 spike protein subunits stimulate macropinocytosis in macrophages. These results may contribute to a better understanding of SARS-CoV-2 infection and its cardiovascular and respiratory complications.

Circulation, Volume 148, Issue Suppl_1, Page A16514-A16514, November 6, 2023. Introduction:The purpose of this study was to compare rubidium-82 positron emission tomography (82Rb PET) myocardial perfusion imaging (MPI) findings and quantitative image quality measures between the digital silicone photomultipliers (SiPM) scanner and a conventional scanner.Methods:We studied 24 consecutive patients (mean age 71.2±2.2 years) who underwent two clinically indicated rest/stress82Rb PET MPI examinations on two scanners, one using a SiPM-based PET scanner (Biograph Vision, Siemens Healthineers) and the other using a conventional photomultiplier tube (PMT)-based PET scanner (Discovery 710, GE Healthcare). Inclusion criteria were: 1) interval between the scans