Search

Endotoxins carried within LDL are cleared from the circulation via hepatic LDL receptor (LDLR)-mediated endocytosis. Proprotein convertase subtilisin-kexin type 9 (PCSK9) reduces this clearance by down-regulating LDLR density on hepatocytes. In addition to hepatocytes, vascular endothelial cells also express receptor targets of PCSK9, including LDLR. Therefore, we hypothesized that PCSK9 may regulate vascular endothelial cell uptake of lipopolysaccharide (LPS) and alter the vascular endothelial cell inflammatory response.We found that LPS is internalized by human umbilical vein vascular endothelial cells (HUVECs) and LPS uptake dose-dependently increased with increasing LDL concentration. Intracellular LPS co-localized with LDL. PCSK9 and, separately, blocking antibodies against LDLR, dose-dependently decreased the vascular endothelial cell uptake of LPS and, furthermore, inhibition of endocytosis using Dynasore blocked LPS uptake. In contrast, blocking antibodies against TLR4 did not alter LPS uptake. PCSK9 decreased the LPS-induced proinflammatory response (IL-6 and IL-8 gene expression and protein secretion, and VCAM-1/ICAM-1 expression) in vascular endothelial cells. In addition, a decrease in PCSK9 and increase in LDLR, mediated by triciribine or siPCSK9, increased LPS uptake and the LPS-induced proinflammatory response. Similar results were also found in aortic vascular tissue from Pcsk9Our data suggest that, similar to PCSK9 treatment in hepatocytes, PCSK9 reduces vascular endothelial cell uptake of LPS via LDLR-mediated endocytosis. Consequently, PCSK9 decreases the LPS-induced proinflammatory response in vascular endothelial cells. These results raise the possibility that PCSK9 inhibition may have additional effects on vascular endothelial inflammation via this alternative pathway, beyond the known effects of PCSK9 inhibition on LDL lowering and hepatic endotoxin clearance.

The ability to effectively clear infection is fundamental to host survival. Sepsis, defined as dysregulated host response to infection, is a heterogenous clinical syndrome that does not uniformly clear intact bacterial or sterile infection (i.e., lipopolysaccharide). These findings were further associated with increased survival in DJ-1 deficient animals exposed to intact bacteria relative to DJ-1 deficient challenged with lipopolysaccharide. We analyzed bacterial and lipopolysaccharide clearance in bone marrow macrophages (BMM) cultured ex vivo from wild-type and DJ-1 deficient mice. Importantly, we demonstrated that DJ-1 deficiency in BMM promotes Rubicon-dependent increase in L3C-associated phagocytosis, non-canonical autophagy pathway used for xenophagy, during bacterial but not lipopolysaccharide infection. In contrast to DJ-1 deficient BMM challenged with lipopolysaccharide, DJ-1 deficient BMM exposed to intact bacteria showed enhanced Rubicon complexing with Beclin-1 and UVRAG and consistently facilitated the assembly of complete autophagolysosomes that were decorated with LC3 molecules. Our data shows DJ-1 impairs or/and delays bacterial clearance and late autophagolysosome formation by binding to Rubicon resulting in Rubicon degradation, decreased L3C-associated phagocytosis, and decreased bacterial clearance in vitro and in vivo - implicating Rubicon and DJ-1 as critical regulators of bacterial clearance in experimental sepsis.

BACKGROUNDThe COVID-19 pandemic could impact frequency and mortality of non-COVID-19 community-acquired pneumonia (CAP). Changes in frequency, patient mix, treatment, and organ dysfunction could cascade together to increase mortality of CAP during compared to pre-COVID-19.METHODSHospitalized CAP patients at St. Paul’s Hospital, Vancouver, Canada pre- (fiscal years 2018/2019 and 2019/2020) and during COVID-19 pandemic (2020/2021 and 2021/2022) were evaluated.RESULTSIn 5219 CAP patients, there was no significant difference pre-versus during pandemic in mean age, gender and Charlson co-morbidity score. However, hospital mortality increased significantly from pre-versus during COVID-19 (7.5% versus 12.1% respectively, [95% CI for difference: 3.0-6.3%], pCONCLUSIONS AND RELEVANCEThe COVID-19 pandemic was associated with increases in hospital mortality, ICU admission and invasive mechanical ventilation rates of non-COVID-19 CAP and a transient, one year frequency decrease. There was no winter seasonality of CAP during the COVID-19 pandemic era. Future pandemic planning for CAP hospital care is needed.What is already known on this topicThe COVID-19 pandemic could impact frequency and mortality of non-COVID-19 community-acquired pneumonia (CAP). No prior study has examined this hypothesis.What this study addsThe COVID-19 pandemic was associated with increases in hospital mortality, ICU admission and invasive mechanical ventilation rates of non-COVID-19 CAP and a transient, one year frequency decrease. There was no winter seasonality of CAP during the COVID-19 pandemic era.How this study might affect research, practice or policyFuture pandemic planning for CAP hospital care is needed.

OBJECTIVES Multiple organ failure in critically ill patients is associated with poor prognosis, but biomarkers contributory to pathogenesis are unknown. Previous studies support a role for Fas cell surface death receptor (Fas)-mediated apoptosis in organ dysfunction. Our objectives were to test for associations between soluble Fas and multiple organ failure, identify protein quantitative trait loci, and determine associations between genetic variants and multiple organ failure. DESIGN Retrospective observational cohort study. SETTING Four academic ICUs at U.S. hospitals. PATIENTS Genetic analyses were completed in a discovery (n = 1,589) and validation set (n = 863). Fas gene expression and flow cytometry studies were completed in outpatient research participants (n = 250). INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS In discovery and validation sets of critically ill patients, we tested for associations between enrollment plasma soluble Fas concentrations and Sequential Organ Failure Assessment score on day 3. We conducted a genome-wide association study of plasma soluble Fas (discovery n = 1,042) and carried forward a single nucleotide variant in the FAS gene, rs982764, for validation (n = 863). We further tested whether the single nucleotide variant in FAS (rs982764) was associated with Sequential Organ Failure Assessment score, FAS transcriptional isoforms, and Fas cell surface expression. Higher plasma soluble Fas was associated with higher day 3 Sequential Organ Failure Assessment scores in both the discovery (β = 4.07; p < 0.001) and validation (β = 6.96; p < 0.001) sets. A single nucleotide variant in FAS (rs982764G) was associated with lower plasma soluble Fas concentrations and lower day 3 Sequential Organ Failure Assessment score in meta-analysis (-0.21; p = 0.02). Single nucleotide variant rs982764G was also associated with a lower relative expression of the transcript for soluble as opposed to transmembrane Fas and higher cell surface expression of Fas on CD4+ T cells. CONCLUSIONS We found that single nucleotide variant rs982764G was associated with lower plasma soluble Fas concentrations in a discovery and validation population, and single nucleotide variant rs982764G was also associated with lower organ dysfunction on day 3. These findings support further study of the Fas pathway as a potential mediator of organ dysfunction in critically ill patients.

Introduction. Lactate and central venous oxygen saturation (ScvO2) reflect tissue hypoperfusion but each measure is confounded by many additional factors. These confounding factors differ between lactate and ScvO2. Objectives. We postulated that combined assessment of lactate and ScvO2 may yield information beyond that of each measure alone. Specifically we sought to determine whether lactate has different characteristics and predictive value at different levels of ScvO2. Material and methods. We conducted a retrospective analysis of a Derivation cohort and a Validation Cohort of sepsis patients with lactate and ScvO2 measured within the first 4 hours of intensive care unit admission and 12 hours after resuscitation. Patients were grouped according to: 1) ScvO2 < 60 %; 2) 60 % ≤ ScvO2 < 80 %; 3) ScvO2 ≥ 80 %. Results. Lactate was negatively correlated with ScvO2 in the ScvO2 < 60 % group in both cohorts but was not correlated with ScvO2 in the other ScvO2 groups. Using receiver operator characteristic analysis in the Derivation Cohort, in the ScvO2 ≥ 80 % group lactate was predictive of 28-day mortality with an area under the ROC curve (AUC) of 0.94 and an optimal threshold lactate of 3.0 mmol/L. Using this threshold in the ScvO2 ≥ 80 % groups, 28-day mortality was 32.7 %. Conclusions. Lactate has different characteristics and predictive value at different levels of ScvO2. When ScvO2 < 60 % correlation between lactate and ScvO2 is consistent with a degree of oxygen supply limitation. When ScvO2 ≥ 80 % lactate > 3.0 mmol/L is predictive of mortality.

BACKGROUND:Prediction of severity of Post-COVID-19 condition is not clear. We determined whether hospital course variables correlated with objective and subjective outcomes 3- and 6-months post-COVID-19 onset.METHODS:Adults admitted to hospital with acute COVID-19 were recruited (Feb 15, 2020-April 1, 2021) from two tertiary hospitals in Vancouver, Canada. We recorded baseline characteristics, COVID severity score, organ function, ICU and hospital length of stay. Survivors were evaluated at 3- and 6-months post- COVID-19 onset: subjective: University of California San Diego Shortness of Breath Score, EuroQol 5D Visual Analogue Scale, Frailty Index; Objective: functional capacity (6-minute walk test), pulmonary (pulmonary function tests), cardiac (echocardiography, BNP), renal (creatinine), hepatic (AST, ALT, bilirubin), and coagulation (aPTT, INR, D-dimers, fibrinogen).RESULTS:In 133 post-COVID-19 patients (age 62 ± 14 years, 65% male with frequent comorbidities [hypertension (42%), diabetes (29%), chronic cardiac (22%)), 42% were admitted to Intensive Care Unit: 23%, 23% and 2% required ventilation, vasopressors or renal support, respectively. One-third had restrictive lung function (CONCLUSIONS:Early organ dysfunction predicts later objective pathology especially restrictive lung disease and a pro-coagulant state. These hypothesis-generating findings require further validation in additional patients.

After fluid administration for vasodilatory shock, vasopressors are commonly infused. Causes of vasodilatory shock include septic shock, post-cardiovascular surgery, post-acute myocardial infarction, postsurgery, other causes of an intense systemic inflammatory response, and drug -associated anaphylaxis. Therapeutic vasopressors are hormones that activate receptors—adrenergic: α1, α2, β1, β2; angiotensin II: AG1, AG2; vasopressin: AVPR1a, AVPR1B, AVPR2; dopamine: DA1, DA2. Vasopressor choice and dose vary widely because of patient and physician practice heterogeneity. Vasopressor adverse effects are excessive vasoconstriction causing organ ischemia/infarction, hyperglycemia, hyperlactatemia, tachycardia, and tachyarrhythmias. To date, no randomized controlled trial (RCT) of vasopressors has shown a decreased 28-day mortality rate. There is a need for evidence regarding alternative vasopressors as first-line vasopressors. We emphasize that vasopressors should be administered simultaneously with fluid replacement to prevent and decrease duration of hypotension in shock with vasodilation. Norepinephrine is the first-choice vasopressor in septic and vasodilatory shock. Interventions that decrease norepinephrine dose (vasopressin, angiotensin II) have not decreased 28-day mortality significantly. In patients not responsive to norepinephrine, vasopressin or epinephrine may be added. Angiotensin II may be useful for rapid resuscitation of profoundly hypotensive patients. Inotropic agent(s) (e.g., dobutamine) may be needed if vasopressors decrease ventricular contractility. Dopamine has fallen to almost no-use recommendation because of adverse effects; angiotensin II is available clinically; there are potent vasopressors with scant literature (e.g., methylene blue); and the novel V1a agonist selepressin missed on its pivotal RCT primary outcome. In pediatric septic shock, vasopressors, epinephrine, and norepinephrine are recommended equally because there is no clear evidence that supports the use of one vasoactive agent. Dopamine is recommended when epinephrine or norepinephrine is not available. New strategies include perhaps patients will be started on several vasopressors with complementary mechanisms of action, patients may be selected for particular vasopressors according to predictive biomarkers, and novel vasopressors may emerge with fewer adverse effects.

BACKGROUND AND AIM: The impact of household income, a surrogate of socioeconomic status, on hospital readmission rates for patients with decompensated cirrhosis has not been well characterized. METHODS: The Nationwide Readmission Database from 2012 to 2014 was used to study the association of lower median household income on 30-, 90-, and 180-day hospital readmission rates for patients with decompensated cirrhosis. RESULTS: From the 42 679 001 hospital admissions contained in the sample, there were 82 598 patients with decompensated cirrhosis who survived a hospital admission in the first 6 months of the year. During a uniform 6-month follow-up period, 25 914 (31.4%), 39 928 (48.3%), and 47 496 (57.5%) patients were readmitted at 30, 90, and 180 days, respectively. After controlling for demographic and clinical confounders, patients residing in the three lowest income quartiles were significantly more likely to be readmitted at 30 days than those in the fourth quartile (first quartile, odds ratio [OR] 1.32 [95% confidence interval, CI, 1.17–1.47, P < 0.01]; second quartile, OR 1.25 [95% CI 1.13–1.38, P < 0.01]; and third quartile, OR 1.08 [95% CI 0.97–1.20, P = 0.07]). The association between lower socioeconomic status and the higher risk of readmissions persisted at 90 days (first quartile, OR 1.21 [95% CI 1.14–1.30, P < 0.01]) and 180 days (first quartile, OR 1.32 [95% CI 1.20–1.44, P < 0.01]). CONCLUSION: Patients with decompensated cirrhosis residing in the lowest income quartile had a 32% higher odds of hospital readmissions at 30, 90, and 180 days compared with those in the highest income quartile.

There have been multiple waves in the COVID-19 pandemic in many countries. We sought to compare mortality and respiratory, cardiovascular and renal dysfunction between waves in 3 Canadian provinces.We conducted a substudy of the ARBs CORONA I study, a multicentre Canadian pragmatic observational cohort study that examined the association of pre-existing use of angiotensin receptor blockers with outcomes in adults admitted to hospital with acute COVID-19 up to April 2021 from 9 community and teaching hospitals in 3 Canadian provinces (British Columbia, Ontario and Quebec). We excluded emergency department admissions without hospital admission, readmissions and admissions for another reason. We used logistic and 0-1-inflated β regression models to compare 28-day and in-hospital mortality, and the use of invasive mechanical ventilation, vasopressors and renal replacement therapy (RRT) between the first 3 waves of the COVID-19 pandemic in these provinces.A total of 520, 572 and 245 patients in waves 1, 2 and 3, respectively, were included. Patients in wave 3 were on average younger and had fewer comorbidities than those in waves 1 and 2. The unadjusted 28-day mortality rate was significantly lower in wave 3 (7.8%) than in wave 1 (18.3%) (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.24-0.78) and wave 2 (16.3%) (OR 0.46, 95% CI 0.27-0.79). After adjustment for differences in baseline characteristics, the difference in 28-day mortality remained significant (adjusted OR wave 3 v. wave 1: 0.46, 95% CI 0.26-0.81; wave 3 v. wave 2: 0.52, 95% CI 0.29-0.91). In-hospital mortality findings were similar. Use of invasive mechanical ventilation or vasopressors was less common in waves 2 and 3 than in wave 1, and use of RRT was less common in wave 3 than in wave 1.Severity of illness decreased (lower mortality and less use of organ support) across waves among patients admitted to hospital with acute COVID-19, possibly owing to changes in patient demographic characteristics and management, such as increased use of dexamethasone. Continued application of proven therapies may further improve outcomes.ClinicalTrials.gov, no. NCT04510623.

Both research and practice in critical care medicine have long been defined by syndromes. Though clinically recognizable entities, these are in fact loose amalgams of heterogeneous states, within which responses to therapy may vary. Mounting translational evidence suggests the current syndrome-based framework of critical illness should be reconsidered. Moreover, research done during the COVID-19 pandemic illustrates how the study of a more biologically homogeneous condition – respiratory failure due to SARS-CoV-2 infection – can increase the efficiency with which actionable results are generated. We discuss recent findings from basic science and clinical research in critical care, and explore how these might inform a new conceptual model of critical illness. De-emphasizing syndromes, we focus instead on the underlying biological changes that underpin critical illness states, and that may be amenable to treatment. We hypothesize that such an approach will accelerate translational critical care research, leading to a richer understanding of the pathobiology of critical illness, and of the proximate determinants of ICU outcomes. The specificity and granularity gained will support the design of more effective clinical trials, and inform a more precise, effective practice at the bedside.

Acute kidney injury (AKI) is a potentially fatal complication of Coronavirus Disease-2019 (COVID-19). Binding of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, to its viral receptor, angiotensin converting enzyme 2 (ACE2), results in viral entry and may cause AKI.We performed a systematic review and meta-analysis of the frequencies of AKI and renal replacement therapy (RRT) in critically ill COVID-19 patients and compared those frequencies with patients who were infected by respiratory viruses that bind or downregulate ACE2 (ACE2-associated viruses) and viruses that do not bind nor downregulate ACE2 (non-ACE2-associated viruses).Systematic review and meta-analysis.Observational studies on COVID-19 and other respiratory viral infections reporting AKI and RRT were included. The exclusion criteria were non-English articles, non-peer-reviewed articles, review articles, studies that included patients under the age of 18, studies including fewer than 10 patients, and studies not reporting AKI and RRT rates.Adult COVID-19, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and influenza patients.We extracted the following data from the included studies: author, year, study location, age, sex, race, diabetes mellitus, hypertension, chronic kidney disease, shock, vasopressor use, mortality, intensive care unit (ICU) admission, ICU mortality, AKI, and RRT.We systematically searched PubMed and EMBASE for articles reporting AKI or RRT. AKI was defined by authors of included studies. Critical illness was defined by ICU admission. We performed a random effects meta-analysis to calculate pooled estimates for the AKI and RRT rate within each virus group using a random intercept logistic regression model.Of 23 655 hospitalized, critically ill COVID-19 patients, AKI frequencies were not significantly different between COVID-19 patients (51%, 95% confidence interval [CI]: 44%-57%) and critically ill patients infected with ACE2-associated (56%, 95% CI: 37%-74%,Limitations of this study include the heterogeneity of definitions of AKI that were used across different virus studies. We could not match severity of infection or do propensity matching across studies. Most of the included studies were conducted in retrospective fashion. Last, we did not include non-English publications.Our findings suggest that viral ACE2 association does not significantly alter the rates of AKI and RRT among critically ill patients admitted to the ICU. However, the rate of RRT is lower in patients with COVID-19 or ACE2-associated viruses when compared with patients infected with non-ACE2-binding viruses, which might partly be due to the lower frequencies of shock and use of vasopressors in these two virus groups. Prospective studies are necessary to demonstrate whether modulation of the ACE2 axis with Renin-Angiotensin System inhibitors impacts the rates of AKI and whether they are beneficial or harmful in COVID-19 patients.L’insuffisance rénale aiguë (IRA) est une complication potentiellement mortelle de la maladie à coronavirus-2019 (COVID-19). Obligatoire du Coronavirus 2 du Syndrome Respiratoire Aigu Sévère (SARS-CoV-2), le virus responsable du COVID-19, à son récepteur, l’enzyme de conversion de l’angiotensine 2 (ACE2), entraîne une entrée virale et peut provoquer une IRA.Nous avons effectué une revue systématique et une méta-analyse des fréquences de l’IRA et de la thérapie de remplacement renal (RRT) chez les patients COVID-19 gravement malades et a comparé ces fréquences avec les patients qui ont été infectés par des voies respiratoires virus qui lient ou régulent négativement l’ACE2 (virus associés à l’ACE2) et les virus qui ne régulent pas négativement ni ne lient l’ACE2 (virus non associés à l’ACE2).Revue systématique et méta-analyse. Des études d’observation sur le COVID-19 et d’autres infections virales respiratoires signalant une AKI et une RRT ont été incluses. Les critères d’exclusion étaient des articles non anglophones, des articles non évalués par des pairs, des articles de revue, des études incluant des patients moins de 18 ans, les études incluant moins de 10 patients et les études ne rapportant pas les taux d’IRA et de RRT.Adultes COVID-19, syndrome respiratoire aigu sévère (SRAS), syndrome respiratoire du Moyen-Orient (MERS) et malades de la grippe.Nous avons extrait les données suivantes des études incluses : auteur, année, lieu de l’étude, âge, sexe, race, diabète sucré, hypertension, maladie rénale chronique, état de choc, utilisation de vasopresseurs, mortalité, admission en unité de soins intensifs (USI), Mortalité en soins intensifs, AKI et RRT.Nous avons systématiquement recherché dans PubMed et EMBASE les articles rapportant AKI ou RRT. AKI a été défini par les auteurs des études incluses. La maladie grave a été définie par l’admission aux soins intensifs. Nous avons effectué une méta-analyse à effets aléatoires pour calculer estimations regroupées pour le taux d’IRA et de RRT au sein de chaque groupe de virus à l’aide d’un modèle de régression logistique d’interception aléatoire.Sur 23 655 patients hospitalisés et gravement malades COVID-19, les fréquences AKI n’étaient pas significativement différentes entre patients COVID-19 (51 %, intervalle de confiance à 95 % [IC] : 44 %-57 %) et patients gravement malades infectés par l’ACE2 associé (56 %, IC à 95 % : 37 % à 74 %, P = 0,610) ou des virus non associés à l’ACE2 (63 %, IC à 95 % : 43 % à 79 %,Les limites de cette étude incluent l’hétérogénéité des définitions de l’IRA qui ont été utilisées pour différents virus études. Nous n’avons pas pu faire correspondre la gravité de l’infection ou faire une correspondance de propension entre les études. La plupart des études incluses ont été menées de manière rétrospective. Enfin, nous n’avons pas inclus les publications non anglophones.Nos résultats suggèrent que l’association virale ACE2 ne modifie pas de manière significative les taux d’IRA et de RRT parmi les patients gravement malades admis aux soins intensifs. Cependant, le taux de RRT est plus faible chez les patients atteints de COVID-19 ou associés à l’ACE2 virus par rapport aux patients infectés par des virus ne se liant pas à l’ACE2, ce qui pourrait être dû en partie à la plus faible fréquences de choc et utilisation de vasopresseurs dans ces deux groupes de virus. Des études prospectives sont nécessaires pour démontrer si la modulation de l’axe ACE2 avec les inhibiteurs du système rénine-angiotensine a un impact sur les taux d’IRA et si ells sont bénéfiques ou nocifs chez les patients COVID-19.

OBJECTIVES: Proprotein convertase subtilisin/kexin type 9 is a central regulator of lipid metabolism and has been implicated in regulating the host response to sepsis. Proprotein convertase subtilisin/kexin type 9 loss-of-function is associated with improved sepsis outcomes in the adult host through increased hepatic bacterial clearance. Thus, there is interest in leveraging proprotein convertase subtilisin/kexin type 9 inhibitors as a therapeutic strategy in adults with sepsis. We sought to validate this association in children with septic shock and in a juvenile murine model of sepsis. DESIGN: Prospectively enrolled cohort of children with septic shock; experimental mice. SETTING: Seventeen participating institutions; research laboratory. PATIENTS AND SUBJECTS: Five-hundred twenty-two children with septic shock; juvenile (14 d old) and adult (10–14 wk) mice with constitutive proprotein convertase subtilisin/kexin type 9 null and wildtype control mice (C57BL/6). INTERVENTIONS: Proprotein convertase subtilisin/kexin type 9 single-nucleotide polymorphisms, serum proprotein convertase subtilisin/kexin type 9, and lipid profiles in patients. Cecal slurry murine model of sepsis; survival studies in juvenile and adult mice, assessment of lipoprotein fractions, bacterial burden, and inflammation in juvenile mice. MEASUREMENTS AND MAIN RESULTS: PCSK9 loss-of-function genetic variants were independently associated with increased odds of complicated course and mortality in children with septic shock. PCSK9, low-density lipoprotein, and high-density lipoprotein concentrations were lower among patients with complicated course relative to those without. PCSK9 concentrations negatively correlated with proinflammatory cytokine interleukin-8. Proprotein convertase subtilisin/kexin type 9 loss-of-function decreased survival in juvenile mice, but increased survival in adult mice with sepsis. PCSK9 loss-of-function resulted in low lipoproteins and decreased hepatic bacterial burden in juvenile mice. CONCLUSIONS: In contrast to the adult host, proprotein convertase subtilisin/kexin type 9 loss-of-function is detrimental to the juvenile host with septic shock. PCSK9 loss-of-function, in the context of low lipoproteins, may result in reduced hepatic bacterial clearance in the juvenile host with septic shock. Our data indicate that children should be excluded in sepsis clinical trials involving proprotein convertase subtilisin/kexin type 9 inhibitors.

Genetic variants are associated with altered clinical outcome of patients with sepsis and cardiovascular diseases. Common gene signaling pathways may be involved in the pathophysiology of these diseases. A better understanding of genetic commonality among these diseases may enable the discovery of important genes, signaling pathways, and therapeutic targets for these diseases. We investigated the common genetic factors by a systematic search of the literature. Twenty-four genes (ADRB2, CD14, FGB, FV, HMOX1, IL1B, IL1RN, IL6, IL10, IL17A, IRAK1, MASP2, MBL, MIR608, MIF, NOD2, PCSK9, PPARG, PROC, SERPINE1, SOD2, SVEP1, TF, TIRAP, TLR1) were extracted as reported genetic variations associated with altered outcome of both sepsis and cardiovascular diseases. Of these genes, the adverse allele (or combinations) was same in nine (ADRB2, FV, HMOX1, IL6, MBL, MIF, NOD2, PCSK9, SERPINE1), and the effect appears to be in the same direction in both sepsis and cardiovascular disease. Shared gene signaling pathways suggest that these are true biological results and could point to overlapping drug targets in sepsis and cardiovascular disease.

Rationale: High-density lipoprotein (HDL) cholesterol (HDL-C) levels decline during sepsis, and lower levels are associated with worse survival. However, the genetic mechanisms underlying changes in HDL-C during sepsis, and whether the relationship with survival is causative, are largely unknown.Objectives: We hypothesized that variation in genes involved in HDL metabolism would contribute to changes in HDL-C levels and clinical outcomes during sepsis.Methods: We performed targeted resequencing of HDL-related genes in 200 patients admitted to an emergency department with sepsis (Early Infection cohort). We examined the association of genetic variants with HDL-C levels, 28-day survival, 90-day survival, organ dysfunction, and need for vasopressor or ventilatory support. Candidate variants were further assessed in the VASST (Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock Trial) cohort (n = 632) and St. Paul's Hospital Intensive Care Unit 2 (SPHICU2) cohort (n = 203).Measurements and Main Results: We identified a rare missense variant in CETP (cholesteryl ester transfer protein gene; rs1800777A) that was associated with significant reductions in HDL-C levels during sepsis. Carriers of the A allele (n = 10) had decreased survival, more organ failure, and greater need for organ support compared with noncarriers. We replicated this finding in the VASST and SPHICU2 cohorts, in which carriers of rs1800777-A (n = 35 and n = 12, respectively) had significantly reduced 28-day survival. Mendelian randomization was consistent with genetically reduced HDL levels being a causal factor for decreased sepsis survival.Conclusions: Our results identify CETP as a critical regulator of HDL levels and clinical outcomes during sepsis. These data point toward a critical role for HDL in sepsis.

OBJECTIVES: Severe acute respiratory syndrome-related coronavirus-2 binds and inhibits angiotensin-converting enzyme-2. The frequency of acute cardiac injury in patients with coronavirus disease 2019 is unknown. The objective was to compare the rates of cardiac injury by angiotensin-converting enzyme-2-binding viruses from viruses that do not bind to angiotensin-converting enzyme-2. DATA SOURCES: We performed a systematic review of coronavirus disease 2019 literature on PubMed and EMBASE. STUDY SELECTION: We included studies with ten or more hospitalized adults with confirmed coronavirus disease 2019 or other viral pathogens that described the occurrence of acute cardiac injury. This was defined by the original publication authors or by: 1) myocardial ischemia, 2) new cardiac arrhythmia on echocardiogram, or 3) new or worsening heart failure on echocardiogram. DATA EXTRACTION: We compared the rates of cardiac injury among patients with respiratory infections with viruses that down-regulate angiotensin-converting enzyme-2, including H1N1, H5N1, H7N9, and severe acute respiratory syndrome-related coronavirus-1, to those with respiratory infections from other influenza viruses that do not bind angiotensin-converting enzyme-2, including Influenza H3N2 and influenza B. DATA SYNTHESIS: Of 57 studies including 34,072 patients, acute cardiac injury occurred in 50% (95% CI, 44-57%) of critically ill patients with coronavirus disease 2019. The overall risk of acute cardiac injury was 21% (95% CI, 18-26%) among hospitalized patients with coronavirus disease 2019. In comparison, 37% (95% CI, 26-49%) of critically ill patients with other respiratory viruses that bind angiotensin-converting enzyme-2 (p = 0.061) and 12% (95% CI, 7-22%) of critically ill patients with other respiratory viruses that do not bind angiotensin-converting enzyme-2 (p < 0.001) experienced a cardiac injury. CONCLUSIONS: Acute cardiac injury may be associated with whether the virus binds angiotensin-converting enzyme-2. Acute cardiac injury occurs in half of critically ill coronavirus disease 2019 patients, but only 12% of patients infected by viruses that do not bind to angiotensin-converting enzyme-2.

Background: Angiotensin receptor blockers (ARBs) and/or angiotensin-converting enzyme (ACE) inhibitors could alter mortality from coronavirus disease 2019 (COVID-19), but existing meta-analyses that combined crude and adjusted results may be confounded by the fact that comorbidities are more common in ARB/ACE inhibitor users. Methods: We searched PubMed/MEDLINE/Embase for cohort studies and meta-analyses reporting mortality by preexisting ARB/ACE inhibitor treatment in hospitalized COVID-19 patients. Random effects meta-regression was used to compute pooled odds ratios for mortality adjusted for imbalance in age, sex, and prevalence of cardiovascular disease, hypertension, diabetes mellitus, and chronic kidney disease between users and nonusers of ARBs/ACE inhibitors at the study level during data synthesis. Results: In 30 included studies of 17,281 patients, 22%, 68%, 25%, and 11% had cardiovascular disease, hypertension, diabetes mellitus, and chronic kidney disease. ARB/ACE inhibitor use was associated with significantly lower mortality after controlling for potential confounding factors (odds ratio 0.77 [95% confidence interval: 0.62, 0.96]). In contrast, meta-analysis of ARB/ACE inhibitor use was not significantly associated with mortality when all studies were combined with no adjustment made for confounders (0.87 [95% confidence interval: 0.71, 1.08]). Conclusions: ARB/ACE inhibitor use was associated with decreased mortality in cohorts of COVID-19 patients after adjusting for age, sex, cardiovascular disease, hypertension, diabetes, and chronic kidney disease. Unadjusted meta-analyses may not be appropriate for determining whether ARBs/ACE inhibitors are associated with mortality from COVID-19 because of indication bias. Résumé: Introduction: Les antagonistes des récepteurs de l'angiotensine (ARA) et/ou les inhibiteurs de l'enzyme de conversion de l'angiotensine (IECA) feraient varier la mortalité liée à la COVID-19, mais il est possible que les méta-analyses actuelles qui combinaient les résultats bruts et ajustés soient invalidées du fait que les comorbidités sont plus fréquentes chez les utilisateurs d'ARA/IECA. Méthodes: Nous avons effectué des recherches dans les bases de données PubMed/MEDLINE/Embase pour trouver des études de cohorte et des méta-analyses qui portent sur la mortalité associée à un traitement préexistant par ARA/IECA chez les patients hospitalisés atteints de la COVID-19. Nous avons utilisé la métarégression à effets aléatoires pour calculer les rapports de cotes regroupés de mortalité ajustés en fonction du déséquilibre de l’âge, du sexe, et de la prévalence des maladies cardiovasculaires, de l'hypertension, du diabète sucré et de l'insuffisance rénale chronique entre les utilisateurs et les non-utilisateurs d'ARA/IECA dans le cadre de l’étude durant la synthèse des données. Résultats: Dans les 30 études portant sur 17 281 patients, 22 %, 68 %, 25 % et 11 % avaient respectivement une maladie cardiovasculaire, de l'hypertension, le diabète sucré et de l'insuffisance rénale chronique. L'utilisation des ARA/IECA a été associée à une mortalité significativement plus faible après avoir tenu compte des facteurs confusionnels potentiels (rapport de cotes 0,77 [intervalle de confiance à 95 % : 0,62, 0,96]). En revanche, la méta-analyse sur l'utilisation des ARA/IECA n'a pas été associée de façon significative à la mortalité lorsque toutes les études ont été combinées sans ajustement sur les facteurs confusionnels (0,87 [intervalle de confiance à 95 % : 0,71, 1,08]). Conclusions: L'utilisation des ARA/IECA a été associée à la diminution de la mortalité au sein des cohortes de patients atteints de la COVID-19 après l'ajustement en fonction de l’âge, du sexe, des maladies cardiovasculaires, de l'hypertension, du diabète et de l'insuffisance rénale chronique. Les méta-analyses non ajustées peuvent ne pas permettre de déterminer si les ARA/IECA sont associés à la mortalité liée à la COVID-19 en raison du biais d'indication.

Background: The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis. Methods: We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5949), iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk; n=882), Copenhagen General Population Study (n=2068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St Paul’s Intensive Care Unit 2 (n=203), and Vasopressin Versus Norepinephrine Infusion in Patients With Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor, anacetrapib, in adult female APOE*3-Leiden mice with or without human CETP expression using the cecal-ligation and puncture model of sepsis. Results: A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio, 1.44 [95% CI, 1.22–1.70]; P P =0.03), whereas there was no effect of anacetrapib on the survival of APOE*3-Leiden mice that did not express CETP (50.0% versus 42.9%, Log-rank P =0.87). Conclusions: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis.

SARS-CoV-2 enters cells by binding to angiotensin-converting enzyme 2 (ACE2), and COVID-19 infection may therefore induce changes in the renin-angiotensin system (RAS). To determine the effects of COVID-19 on plasma RAS components, we measured plasma ACE, ACE2, and angiotensins I, (1-7), and II in 46 adults with COVID-19 at hospital admission and on days 2, 4, 7 and 14, compared to 50 blood donors (controls). We compared survivors vs. non-survivors, males vs. females, ventilated vs. not ventilated, and angiotensin receptor blocker (ARB) and angiotensin-converting enzyme (ACE) inhibitor-exposed vs. not exposed. At admission, COVID-19 patients had higher plasma levels of ACE (p=0.012), ACE2 (p=0.001) and angiotensin-(1-7) (pClinical Trial Registration: https://clinicaltrials.gov/ Unique Identifier: NCT04510623

BACKGROUND: The ABO histo-blood group is defined by carbohydrate modifications and is associated with risk for multiple diseases, including acute respiratory distress syndrome (ARDS). We hypothesized that genetically determined blood subtype A1 is associated with increased risk of ARDS and markers of microvascular dysfunction and coagulation. METHODS: We conducted analyses in 3 cohorts of critically ill trauma and sepsis patients (n = 3710) genotyped on genome-wide platforms to determine the association of the A1 blood type genotype with ARDS risk. We subsequently determined whether associations were present in FUT2-defined nonsecretors who lack ABO antigens on epithelium, but not endothelium. In a patient subgroup, we determined the associations of blood type with plasma levels of endothelial glycoproteins and disseminated intravascular coagulation (DIC). Lastly, we tested whether blood type A was associated with less donor lung injury recovery during human ex vivo lung perfusion (EVLP). RESULTS: The A1 genotype was associated with a higher risk of moderate to severe ARDS relative to type O in all 3 populations. In sepsis, this relationship was strongest in nonpulmonary infections. The association persisted in nonsecretors, suggesting a vascular mechanism. The A1 genotype was also associated with higher DIC risk as well as concentrations of thrombomodulin and von Willebrand factor, which in turn were associated with ARDS risk. Blood type A was also associated with less lung injury recovery during EVLP. CONCLUSION: We identified a replicable association between ABO blood type A1 and risk of ARDS among the critically ill, possibly mediated through microvascular dysfunction and coagulation. FUNDING: NIH HL122075, HL125723, HL137006, HL137915, DK097307, HL115354, HL101779, and the University of Pennsylvania McCabe Fund Fellowship Award.

Systolic contraction of the left ventricle is due to sliding of myosin filaments past actin filaments within sarcomeres, which are very simple contractile units. How can these simple sarcomere building blocks yield the complex functional characteristics of the left ventricle? That is, the ventricle must respond to changes in an individual’s level of activity and organ function to deliver all of the oxygen and metabolites required by all organ systems. Function of the ventricle can be understood by first considering that muscle tension-length properties assembled into a three-dimension ventricular chamber yield ventricular pressure-volume properties. Diastolic and systolic properties of the ventricle can be explained by considering cardiac muscle to have a time-varying elastance (ΔP/ΔV). Elastance is maximum (Emax) near end systole which indicates that end-systolic properties can be characterized by an end-systolic pressure-volume relationship (ESPVR) with a slope of Emax, which is synonymous with contractility. The sloped ESPVR means that stroke volume (and hence cardiac function) is decreased by an increase in afterload, a decrease in contractility, and a decrease in diastolic compliance, and vice versa. Area on a pressure-volume diagram has units of energy, or work. It follows that myocardial oxygen consumption is directly related to pressure-volume area on a ventricular pressure–volume diagram. Thus, consideration of the cardiac cycle illustrated on a ventricular pressure-volume diagram yields an understanding of underlying features which determine cardiac function and the myocardial oxygen consumption that is required to generate these functional characteristics.

OBJECTIVES Treatment in a disproportionately minority-serving hospital has been associated with worse outcomes in a variety of illnesses. We examined the association of treatment in disproportionately minority hospitals on outcomes in patients with sepsis across the United States. DESIGN Retrospective cohort analysis. Disproportionately minority hospitals were defined as hospitals having twice the relative minority patient population than the surrounding geographical mean. Minority hospitals for Black and Hispanic patient populations were identified based on U.S. Census demographic information. A multivariate model employing a validated algorithm for mortality in sepsis using administrative data was used. SETTING The National Inpatient Sample from 2008 to 2014. PATIENTS Patients over 18 years of age with sepsis. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS A total of 4,221,221 patients with sepsis were identified. Of these, 612,217 patients (14.5%) were treated at hospitals disproportionately serving the black community (Black hospitals), whereas 181,141 (4.3%) were treated at hospitals disproportionately serving the Hispanic community (Hispanic hospitals). After multivariate analysis, treatment in a Black hospital was associated with a 4% higher risk of mortality compared to treatment in a nonminority hospital (odds ratio, 1.04; 95% CI, 1.03-1.05; p < 0.01). Treatment in a Hispanic hospital was associated with a 9% higher risk of mortality (odds ratio, 1.09; 95% CI, 1.07-1.11; p < 0.01). Median hospital length of stay was almost 1 day longer at each of the disproportionately minority hospitals (nonminority hospitals: 5.9 d; interquartile range, 3.1-11.0 d vs Hispanic: 6.9 d; interquartile range, 3.6-12.9 d and Black: 6.7 d, interquartile range, 3.4-13.2 d; both p < 0.01). CONCLUSIONS Patients with sepsis regardless of race who were treated in disproportionately high minority hospitals suffered significantly higher rates of in-hospital mortality.