Cardiovascular Risk Factor Management After Hypertensive Disorders of Pregnancy.

Hypertensive disorders of pregnancy (HDP) are associated with significantly increased risk of developing future cardiovascular disease (CVD). Obstetricians play a crucial role in CVD prevention for postpartum women and birthing people with HDP because they are primarily responsible for immediate postpartum management and can assist with care transitions to other health care practitioners for long-term management of CVD risk factors. Standardized calculators can be used to evaluate long-term CVD risk, which can help guide intensity of treatment. Emerging technologies such as remote blood pressure monitoring demonstrate promise for improving outcomes among patients with HDP. After HDP, all patients should be advised of their increased CVD risk. A plan should be made to initiate lifestyle modifications and antihypertensive therapy to achieve optimal blood pressure control with a target of lower than 130/80 mm Hg, assess lipids within 2-3 years of delivery, and evaluate for development of type 2 diabetes. Other CVD risk factors such as nicotine use should similarly be identified and addressed. In this review, we summarize the essential components of managing CVD risk after a pregnancy complicated by HDP, including blood pressure monitoring, risk stratification tools, and evidence-based lifestyle recommendations.

Development and internal validation of the Cleveland Clinic Bleeding Model to predict major bleeding risk at admission in medical inpatients.

BACKGROUND: Guidelines recommend pharmacologic VTE prophylaxis for acutely ill medical patients at acceptable bleeding risk, but only the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) model has been validated for bleeding risk assessment. OBJECTIVES: We developed and internally validated a risk assessment model (RAM) to predict major in-hospital bleeding using risk factors at admission and compared our model with IMPROVE. METHODS: We selected patients admitted to medical services at 10 hospitals in the Cleveland Clinic Health System from 2017 to 2020. We identified major bleeding according to the International Society on Thrombosis and Haemostasis criteria, using a combination of diagnostic codes and laboratory values, and confirmed events with chart review. We fit a least absolute shrinkage selection operator logistic regression model in the training set and compared the discrimination and calibration of our model with the IMPROVE model in the validation set. RESULTS: Among 46 314 admissions, 268 (0.58%) had a major bleed. The final RAM included 16 risk factors, of which prior bleeding (odds ratio [OR] = 4.83), peptic ulcer (OR = 3.82), history of sepsis (OR = 3.26), and steroid use (OR = 2.59) were the strongest. The Cleveland Clinic Bleeding Model had better discrimination than IMPROVE (area under the receiver operating characteristics curve = 0.85 vs 0.70; P < .001) and, at equivalent sensitivity (52%), categorized fewer patients as high risk (7.2% vs 11.8%; P < .001). Calibration was adequate (Brier score = 0.0057). CONCLUSION: Using a large population of medical inpatients with verified major bleeding events, we developed and internally validated a RAM for major bleeding whose performance surpassed the IMPROVE model.

Acute Heart Failure: From The Emergency Department to the Intensive Care Unit.

Acute heart failure (AHF) is a frequent cause of hospitalization around the world and is associated with high in-hospital and post-discharge morbidity and mortality. This review summarizes data on diagnosis and management of AHF from the emergency department to the intensive care unit. While more evidence is needed to guide risk stratification and care of patients with AHF, hospitalization is a key opportunity to optimize evidence-based medical therapy for heart failure. Close linkage to outpatient care is essential to improve post-hospitalization outcomes.

Associations between Present-on-Admission Do-Not-Resuscitate Orders and Short-Term Outcomes in Patients with Pneumonia.

OBJECTIVES: Do-not-resuscitate (DNR) orders are used to express patient preferences for cardiopulmonary resuscitation. This study examined whether early DNR orders are associated with differences in treatments and outcomes among patients hospitalized with pneumonia. METHODS: This is a retrospective cohort study of 768,015 adult patients hospitalized with pneumonia from 2010 to 2015 in 646 US hospitals. The exposure was DNR orders present on admission. Secondary analyses stratified patients by predicted in-hospital mortality. Main outcomes included in-hospital mortality, length of stay, cost, intensive care admission, invasive mechanical ventilation, noninvasive ventilation, vasopressors, and dialysis initiation. RESULTS: Of 768,015 patients, 94,155 (12.3%) had an early DNR order. Compared with those without, patients with DNR orders were older (mean age 80.1 ± 10.6 years vs 67.8 ± 16.4 years), with higher comorbidity burden, intensive care use (31.6% vs 30.6%), and in-hospital mortality (28.2% vs 8.5%). After adjustment via propensity score weighting, these patients had higher mortality (odds ratio [OR] 2.39, 95% confidence interval [CI] 2.33-2.45) and lower use of intensive therapies such as vasopressors (OR 0.83, 95% CI 0.81-0.85) and invasive mechanical ventilation (OR 0.68, 95% CI 0.66-0.70). Although there was little relationship between predicted mortality and DNR orders, among those with highest predicted mortality, DNR orders were associated with lower intensive care use compared with those without (66.7% vs 80.8%). CONCLUSIONS: Patients with early DNR orders have higher in-hospital mortality rates than those without, but often receive intensive care. These orders have the most impact on the care of patients with the highest mortality risk.

Impact of Embedding a Venous Thromboembolism Risk Assessment Model in the Electronic Health Record Versus Usual Care: A Cluster-Randomized Trial.

BACKGROUND: There are multiple risk assessment models (RAMs) for venous thromboembolism prophylaxis, but it is unknown whether they increase appropriate prophylaxis. METHODS: To determine the impact of a RAM embedded in the electronic health record, we conducted a stepped-wedge hospital-level cluster-randomized trial conducted from October 1, 2017 to February 28, 2019 at 10 Cleveland Clinic hospitals. We included consecutive general medical patients aged 18 years or older. Patients were excluded if they had a contraindication to prophylaxis, including anticoagulation for another condition, acute bleeding, or comfort-only care. A RAM was embedded in the general admission order set and physicians were encouraged to use it. The decisions to use the RAM and act on the results were reserved to the treating physician. The primary outcome was the percentage of patients receiving appropriate prophylaxis (high-risk patients with pharmacological thromboprophylaxis plus low-risk patients without prophylaxis) within 48 hours of hospitalization. Secondary outcomes included total patients receiving prophylaxis, venous thromboembolism among high-risk patients at 14 and 45 days, major bleeding, heparin-induced thrombocytopenia, and length of stay. Mixed-effects models were used to analyze the study outcomes. RESULTS: A total of 26 506 patients (mean age, 61; 52% female; 73% White) were analyzed, including 11 134 before and 15 406 after implementation of the RAM. After implementation, the RAM was used for 24% of patients, and the percentage of patients receiving appropriate prophylaxis increased from 43.1% to 48.8% (adjusted odds ratio, 1.11 [1.00-1.23]), while overall prophylaxis use decreased from 73.5% to 65.2% (adjusted odds ratio, 0.87 [0.78-0.97]). Rates of venous thromboembolism among high-risk patients (adjusted odds ratio, 0.72 [0.38-1.36]), rates of bleeding and heparin-induced thrombocytopenia (adjusted odds ratio, 0.19 [0.02-1.47]), and length of stay were unchanged. CONCLUSIONS: Implementation of a RAM for venous thromboembolism increased appropriate prophylaxis use, but the RAM was used for a minority of patients. REGISTRATION: URL: https://www.clinicaltrials.gov/study/NCT03243708?term=nct03243708&rank=1; Unique identifier: NCT03243708.

Contemporary Management of Cardiomyopathy and Heart Failure in Pregnancy.

Cardiovascular disease is the primary cause of pregnancy-related mortality and morbidity in the United States, and maternal mortality has increased over the last decade. Pregnancy and the postpartum period are associated with significant vascular, metabolic, and physiologic adaptations that can unmask new heart failure or exacerbate heart failure symptoms in women with known underlying cardiomyopathy. There are unique management considerations for heart failure in women throughout pregnancy, and it is imperative that clinicians caring for pregnant women understand these important principles. Early involvement of multidisciplinary cardio-obstetrics teams is key to optimizing maternal and fetal outcomes. In this review, we discuss the unique challenges and opportunities in the diagnosis of heart failure in pregnancy, management principles along the continuum of pregnancy, and the safety of heart failure therapies during and after pregnancy.

A Novel Risk Assessment Model Predicts Major Bleeding Risk at Admission in Medical Inpatients.

Background: Venous thromboembolism (VTE) is the leading cause of preventable hospital death in the US. Guidelines from the American College of Chest Physicians and American Society for Hematology recommend providing pharmacological VTE prophylaxis to acutely or critically ill medical patients at acceptable bleeding risk, but there is currently only one validated risk assessment model (RAM) for estimating bleeding risk. We developed a RAM using risk factors at admission and compared it with the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) model. Methods: A total of 46,314 medical patients admitted to a Cleveland Clinic Health System hospital from 2017-2020 were included. Data were split into training (70%) and validation (30%) sets with equivalent bleeding event rates in each set. Potential risk factors for major bleeding were identified from the IMPROVE model and literature review. Penalized logistic regression using LASSO was performed on the training set to select and regularize important risk factors for the final model. The validation set was used to assess model calibration and discrimination and compare performance with IMPROVE. Bleeding events and risk factors were confirmed through chart review. Results: The incidence of major in-hospital bleeding was 0.58%. Active peptic ulcer (OR = 5.90), prior bleeding (OR = 4.24), and history of sepsis (OR = 3.29) were the strongest independent risk factors. Other risk factors included age, male sex, decreased platelet count, increased INR, increased PTT, decreased GFR, ICU admission, CVC or PICC placement, active cancer, coagulopathy, and in-hospital antiplatelet drug, steroid, or SSRI use. In the validation set, the Cleveland Clinic Bleeding Model (CCBM) had better discrimination than IMPROVE (0.86 vs. 0.72, p < .001) and, at equivalent sensitivity (54%), categorized fewer patients as high-risk (6.8% vs. 12.1%, p < .001). Conclusions: From a large population of medical inpatients, we developed and validated a RAM to accurately predict bleeding risk at admission. The CCBM may be used in conjunction with VTE risk calculators to decide between mechanical and pharmacological prophylaxis for at-risk patients.

Duration of Severe Acute Respiratory Syndrome Coronavirus 2 Natural Immunity and Protection Against the Delta Variant: A Retrospective Cohort Study.

BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown to be highly protective against reinfection and symptomatic disease. However, effectiveness against the Delta variant and duration of natural immunity remain unknown. METHODS: This retrospective cohort study included 325 157 patients tested for SARS-CoV-2 via polymerase chain reaction (PCR) from 9 March 2020 to 31 December 2020 (Delta variant analysis) and 152 656 patients tested from 9 March 2020 to 30 August 2020 (long-term effectiveness analysis) with subsequent testing through 9 September 2021. The primary outcome was reinfection, defined as a positive PCR test >90 days after the initial positive test. RESULTS: Among 325 157 patients tested before 31 December 2020, 50 327 (15.5%) tested positive. After 1 July 2021 (Delta dominant period), 40 (0.08%) initially positive and 1494 (0.5%) initially negative patients tested positive. Protection of prior infection against reinfection with Delta was 85.4% (95% confidence interval [CI], 80.0-89.3). For the long-term effectiveness analysis, among 152 656 patients tested before 30 August 2020, 11 186 (7.3%) tested positive. After at least 90 days, 81 (0.7%) initially positive and 7167 (5.1%) initially negative patients tested positive. Overall protection of previous infection was 85.7% (95% CI, 82.2-88.5) and lasted up to 13 months. Patients aged >65 years had slightly lower protection. CONCLUSIONS: SARS-CoV-2 infection is highly protective against reinfection with Delta. Immunity from prior infection lasts at least 13 months. Countries facing vaccine shortages should consider delaying vaccinations for previously infected patients to increase access.

Echocardiography in suspected coronavirus infection: indications, limitations and impact on clinical management.

OBJECTIVES: To describe the use of echocardiography in patients hospitalised with suspected coronavirus infection and to assess its impact on clinical management. METHODS: We studied 79 adults from a prospective registry of inpatients with suspected coronavirus infection at a single academic centre. Echocardiographic indications included abnormal biomarkers, shock, cardiac symptoms, arrhythmia, worsening hypoxaemia or clinical deterioration. Study type (limited or complete) was assessed for each patient. The primary outcome measure was echocardiography-related change in clinical management, defined as intensive care transfer, medication changes, altered ventilation parameters or subsequent cardiac procedures within 24 hours of echocardiography. Coronavirus-positive versus coronavirus-negative patient groups were compared. The relationship between echocardiographic findings and coronavirus mortality was assessed. RESULTS: 56 patients were coronavirus-positive and 23 patients were coronavirus-negative with symptoms attributed to other diagnoses. Coronavirus-positive patients more often received limited echocardiograms (70% vs 26%, p=0.001). The echocardiographic indication for coronavirus-infected patients was frequently worsening hypoxaemia (43% vs 4%) versus chest pain, syncope or clinical heart failure (23% vs 44%). Echocardiography changed management less frequently in coronavirus-positive patients (18% vs 48%, p=0.01). Among coronavirus-positive patients, 14 of 56 (25.0%) died during hospitalisation. Those who died more often had echocardiography to evaluate clinical deterioration (71% vs 24%) and had elevated right ventricular systolic pressures (37 mm Hg vs 25 mm Hg), but other parameters were similar to survivors. CONCLUSIONS: Echocardiograms performed on hospitalised patients with coronavirus infection were often technically limited, and their findings altered patient management in a minority of patients.

Reinfection Rates Among Patients Who Previously Tested Positive for Coronavirus Disease 2019: A Retrospective Cohort Study.

BACKGROUND: Protection afforded from prior disease among patients with coronavirus disease 2019 (COVID-19) infection is unknown. If infection provides substantial long-lasting immunity, it may be appropriate to reconsider vaccination distribution. METHODS: This retrospective cohort study of 1 health system included 150 325 patients tested for COVID-19 infection via polymerase chain reaction from 12 March 2020 to 30 August 2020. Testing performed up to 24 February 2021 in these patients was included. The main outcome was reinfection, defined as infection ≥90 days after initial testing. Secondary outcomes were symptomatic infection and protection of prior infection against reinfection. RESULTS: Of 150 325 patients, 8845 (5.9%) tested positive and 141 480 (94.1%) tested negative before 30 August. A total of 1278 (14.4%) positive patients were retested after 90 days, and 62 had possible reinfection. Of those, 31 (50%) were symptomatic. Of those with initial negative testing, 5449 (3.9%) were subsequently positive and 3191 of those (58.5%) were symptomatic. Protection offered from prior infection was 81.8% (95% confidence interval [CI], 76.6-85.8) and against symptomatic infection was 84.5% (95% CI, 77.9-89.1). This protection increased over time. CONCLUSIONS: Prior infection in patients with COVID-19 was highly protective against reinfection and symptomatic disease. This protection increased over time, suggesting that viral shedding or ongoing immune response may persist beyond 90 days and may not represent true reinfection. As vaccine supply is limited, patients with known history of COVID-19 could delay early vaccination to allow for the most vulnerable to access the vaccine and slow transmission.

Treatment and Outcomes of Inpatient Hypertension Among Adults With Noncardiac Admissions.

Importance: Despite high prevalence of elevated blood pressure (BP) among medical inpatients, BP management guidelines are lacking for this population. The outcomes associated with intensifying BP treatment in the hospital are poorly studied. Objectives: To characterize clinician response to BP in the hospital and at discharge and to compare short- and long-term outcomes associated with antihypertensive treatment intensification. Design, Setting, and Participants: This cohort study took place from January 1 to December 31, 2017, with 1 year of follow-up at 10 hospitals within the Cleveland Clinic Hospitals health care system. All adults admitted to a medicine service in 2017 were evaluated for inclusion. Patients with cardiovascular diagnoses were excluded. Demographic and BP characteristics were used for propensity matching. Exposures: Acute hypertension treatment, defined as administration of an intravenous antihypertensive medication or a new class of an oral antihypertensive treatment. Main Outcomes and Measures: The association between acute hypertension treatment and subsequent inpatient acute kidney injury, myocardial injury, and stroke was measured. Postdischarge outcomes included stroke and myocardial infarction within 30 days and BP control up to 1 year. Results: Among 22 834 adults hospitalized for noncardiovascular diagnoses (mean [SD] age, 65.6 [17.9] years; 12 993 women [56.9%]; 15 963 White patients [69.9%]), 17 821 (78%) had at least 1 hypertensive BP recorded during their admission. Of these patients, 5904 (33.1%) were treated. A total of 8692 of 106 097 cases (8.2%) of hypertensive systolic BPs were treated; of these, 5747 (66%) were treated with oral medications. In a propensity-matched sample controlling for patient and BP characteristics, treated patients had higher rates of subsequent acute kidney injury (466 of 4520 [10.3%] vs 357 of 4520 [7.9%]; P < .001) and myocardial injury (53 of 4520 [1.2%] vs 26 of 4520 [0.6%]; P = .003). There was no BP interval in which treated patients had better outcomes than untreated patients. A total of 1645 of 17 821 patients (9%) with hypertension were discharged with an intensified antihypertensive regimen. Medication intensification at discharge was not associated with better BP control in the following year. Conclusions and Relevance: In this cohort study, hypertension was common among medical inpatients, but antihypertensive treatment intensification was not. Intensification of therapy without signs of end-organ damage was associated with worse outcomes.

Glutathione Protects the Developing Heart from Defects and Global DNA Hypomethylation Induced by Prenatal Alcohol Exposure.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is caused by prenatal alcohol exposure (PAE), the intake of ethanol (C2 H5 OH) during pregnancy. Features of FASD cover a range of structural and functional defects including congenital heart defects (CHDs). Folic acid and choline, contributors of methyl groups to one-carbon metabolism (OCM), prevent CHDs in humans. Using our avian model of FASD, we have previously reported that betaine, another methyl donor downstream of choline, prevents CHDs. The CHD preventions are substantial but incomplete. Ethanol causes oxidative stress as well as depleting methyl groups for OCM to support DNA methylation and other epigenetic alterations. To identify more compounds that can safely and effectively prevent CHDs and other effects of PAE, we tested glutathione (GSH), a compound that regulates OCM and is known as a "master antioxidant." METHODS/RESULTS: Quail embryos injected with a single dose of ethanol at gastrulation exhibited congenital defects including CHDs similar to those identified in FASD individuals. GSH injected simultaneously with ethanol not only prevented CHDs, but also improved survival and prevented other PAE-induced defects. Assays of hearts at 8 days (HH stage 34) of quail development, when the heart normally has developed 4-chambers, showed that this single dose of PAE reduced global DNA methylation. GSH supplementation concurrent with PAE normalized global DNA methylation levels. The same assays performed on quail hearts at 3 days (HH stage 19-20) of development, showed no difference in global DNA methylation between controls, ethanol-treated, GSH alone, and GSH plus ethanol-treated cohorts. CONCLUSIONS: GSH supplementation shows promise to inhibit effects of PAE by improving survival, reducing the incidence of morphological defects including CHDs, and preventing global hypomethylation of DNA in heart tissues.

Changes in Social Behavior Over Time During the COVID-19 Pandemic.

Public health recommendations aimed at limiting the spread of SARS-CoV-2 have encouraged social distancing and masks as economies across the United States re-open. Understanding adherence to these guidelines will inform further efforts to reduce transmission. In this repeated cross-sectional survey study, we describe changes in social behavior in Ohio during periods of declining and rising cases. While essential activities remained consistent over time, more individuals attended gatherings of 10 or more people as cases rose, particularly in the 18-29 age group. A majority of individuals wore masks. It appears necessary to continue limiting gatherings and encourage mask-wearing, particularly among younger groups.

Design and performance testing of a novel emergency ventilator for in-hospital use.

BACKGROUND: The rapidly evolving COVID-19 pandemic has led to increased use of critical care resources, particularly mechanical ventilators. Amidst growing concerns that the health care system could face a shortage of ventilators in the future, there is a need for an affordable, simple, easy to use, emergency stockpile ventilator. METHODS: Our team of engineers and clinicians designed and tested an emergency ventilator that uses a single limb portable ventilator circuit. The circuit is controlled by a pneumatic signal with electronic microcontroller input, using air and oxygen sources found in standard patient rooms. Ventilator performance was assessed using an IngMar ASL 5000 breathing simulator, and it was compared with a commercially available mechanical ventilator. RESULTS: The emergency ventilator provides volume control mode, intermittent mandatory ventilation and continuous positive airway pressure. It can generate tidal volumes between 300 and 800 mL with <10% error, with pressure, volume, and waveforms substantially equivalent to existing commercial ventilators. CONCLUSIONS: We describe a cost effective, safe, and easy to use ventilator that can be rapidly manufactured to address ventilator shortages in a pandemic setting. It meets basic clinical needs and can be provided for emergency use in cases requiring mechanical ventilation because of complications due to respiratory failure from infectious diseases.

Investigating the Link between Lynch Syndrome and Breast Cancer.

OBJECTIVE: Lynch syndrome is an inherited genetic disorder associated with a predisposition to early-onset colorectal and endometrial cancers, but breast cancer risk in these patients is debated. The aim of this study is to evaluate breast cancer rates in a cohort of Lynch syndrome patients, as well as to identify women who may be eligible for additional breast cancer specific genetic testing or enhanced breast surveillance (contrast-enhanced magnetic resonance imaging (MRI) screening). MATERIALS AND METHODS: Using a hereditary colorectal cancer registry at a single academic institution for identification of patients with Lynch syndrome, a retrospective chart review was performed of 188 women with DNA mismatch repair (MMR) mutations. The Tyrer-Cuzick model was used to estimate breast cancer risk in patients without breast cancer. RESULTS: The prevalence of breast cancer differed based on mutation type (p=0.0043), as 27% of women with a PMS2 mutation were diagnosed with breast cancer, compared to 3%, 4%, and 9% in MLH1, MSH2, and MSH6 patients. The average age at diagnosis for women with a PMS2 mutation was 46.7 years. Additionally, 7.5% of unaffected women had an estimated lifetime risk of breast cancer greater than 20%. 46/188 (24.4%) of patients were eligible for breast specific genetic testing. CONCLUSION: Our analysis suggests that Lynch syndrome patients with PMS2 mutations may be at higher risk of developing breast cancer. Additionally, the personal and family history of cancer suggests crossover in eligibility for breast specific genetic testing in a significant number of patients (16.5-24.4%). Also, many women are eligible for enhanced breast surveillance (7.5%) which would otherwise not be offered.

Novel Role of Macrophage Migration Inhibitory Factor in Upstream Control of the Unfolded Protein Response After Ethanol Feeding in Mice.

BACKGROUND: Macrophage migration inhibitory factor (MIF), a pluripotent immune regulator, is an emerging mediator in alcohol-related liver disease (ALD). MIF is associated with ALD progression through its chemokine- and cytokine-like activities. METHODS: Mechanistic studies into the role of MIF in ethanol (EtOH)-induced liver injury were performed in Mif-/- mice and in C57BL/6J mice treated with a small-molecule MIF antagonist, MIF098, after Gao-Binge (acute-on-chronic) EtOH feeding, an EtOH feeding protocol associated with hepatic neutrophilia and induction of the unfolded protein response (UPR). RESULTS: The MIF axis, for example, MIF and MIF receptors invariant polypeptide of major histocompatibility complex, class II antigen-associated (CD74), CXCR2, CXCR4, and CXCR7, was enhanced in the livers of alcoholic hepatitis (AH) patients as compared to healthy controls. Mif-/- mice were protected from hepatocellular injury after Gao-Binge feeding, independent of neutrophilia and inflammation, but were associated with the UPR. Interestingly, the UPR signature in AH patients and in mice following Gao-Binge feeding was biased toward cell death with increased expression of pro-cell death CCAAT-enhancer-binding protein homologous protein (CHOP) and decreased prosurvival GRP78. The UPR and liver injury 6 hours after binge were prevented both in Mif-/- mice and in MIF098-treated mice. However, both MIF interventions led to increased liver injury and exacerbated the hepatic UPR 9 hours after binge. Induction of upstream UPR signaling and expression of CHOP protein by thapsigargin in alpha mouse liver 12 hepatocytes were blunted by coexposure to MIF098, directly connecting MIF to UPR in hepatocytes. CONCLUSIONS: The current study revealed that, in addition to its cytokine/chemokine functions, MIF is an upstream regulator of UPR in response to EtOH feeding in mice. Importantly, both MIF and UPR can either protect or contribute to liver injury, dependent upon the stage or severity of EtOH-induced liver injury.

Complement Factor D protects mice from ethanol-induced inflammation and liver injury.

Complement plays a crucial role in microbial defense and clearance of apoptotic cells. Emerging evidence suggests complement is an important contributor to alcoholic liver disease. While complement component 1, Q subcomponent (C1q)-dependent complement activation contributes to ethanol-induced liver injury, the role of the alternative pathway in ethanol-induced injury is unknown. Activation of complement via the classical and alternative pathways was detected in alcoholic hepatitis patients. Female C57BL/6J [wild type (WT)], C1q-deficient ( C1qa-/-, lacking classical pathway activation), complement protein 4-deficient ( C4-/-, lacking classical and lectin pathway activation), complement factor D-deficient ( FD-/-, lacking alternative pathway activation), and C1qa/FD-/- (lacking classical and alternative pathway activation) mice were fed an ethanol-containing liquid diet or pair-fed control diet for 4 or 25 days. Following chronic ethanol exposure, liver injury, steatosis, and proinflammatory cytokine expression were increased in WT but not C1qa-/-, C4-/-, or C1qa/FD-/- mice. In contrast, liver injury, steatosis, and proinflammatory mediators were robustly increased in ethanol-fed FD-/- mice compared with WT mice. Complement activation, assessed by hepatic accumulation of C1q and complement protein 3 (C3) cleavage products (C3b/iC3b/C3c), was evident in livers of WT mice in response to both short-term and chronic ethanol. While C1q accumulated in ethanol-fed FD-/- mice (short term and chronic), C3 cleavage products were detected after short-term but not chronic ethanol. Consistent with impaired complement activation, chronic ethanol induced the accumulation of apoptotic cells and fibrogenic responses in the liver of FD-/- mice. These data highlight the protective role of complement factor D (FD) and suggest that FD-dependent amplification of complement is an adaptive response that promotes hepatic healing and recovery in response to chronic ethanol. NEW & NOTEWORTHY Complement, a component of the innate immune system, is an important pathophysiological contributor to ethanol-induced liver injury. We have identified a novel role for factor D, a component of the alternative pathway, in protecting the liver from ethanol-induced inflammation, accumulation of apoptotic hepatocytes, and profibrotic responses. These data indicate a dual role of complement with regard to inflammatory and protective responses and suggest that accumulation of apoptotic cells impairs hepatic healing/recovery during alcoholic liver disease.

Hepatic Immune System: Adaptations to Alcohol.

Both the innate and adaptive immune systems are critical for the maintenance of healthy liver function. Immune activity maintains the tolerogenic capacity of the liver, modulates hepatocellular response to various stresses, and orchestrates appropriate cellular repair and turnover. However, in response to heavy, chronic alcohol exposure, the finely tuned balance of pro- and anti-inflammatory functions in the liver is disrupted, leading to a state of chronic inflammation in the liver. Over time, this non-resolving inflammatory response contributes to the progression of alcoholic liver disease (ALD). Here we review the contributions of the cellular components of the immune system to the progression of ALD, as well as the pathophysiological roles for soluble and circulating mediators of immunity, including cytokines, chemokines, complement, and extracellular vesicles, in ALD. Finally, we compare the role of the innate immune response in health and disease in the liver to our growing understanding of the role of neuroimmunity in the development and maintenance of a healthy central nervous system, as well as the progression of neuroinflammation.

Supplementation with the Methyl Donor Betaine Prevents Congenital Defects Induced by Prenatal Alcohol Exposure.

BACKGROUND: Despite decades of public education about dire consequences of prenatal alcohol exposure (PAE), drinking alcohol during pregnancy remains prevalent. As high as 40% of live-born infants exposed to alcohol during gestation and diagnosed with fetal alcohol syndrome have congenital heart defects that can be life-threatening. In animal models, the methyl donor betaine, found in foods such as wheat bran, quinoa, beets, and spinach, ameliorated neurobehavioral deficits associated with PAE, but effects on heart development are unknown. METHODS: Previously, we modeled a binge drinking episode during the first trimester in avian embryos. Here, we investigated whether betaine could prevent adverse effects of alcohol on heart development. Embryos exposed to ethanol (EtOH) with and without an optimal dose of betaine (5 µM) were analyzed at late developmental stages. Cardiac morphology parameters were rapidly analyzed and quantified using optical coherence tomography. DNA methylation at early stages was detected by immunofluorescent staining for 5-methylcytosine in sections of embryos treated with EtOH or cotreated with betaine. RESULTS: Compared to EtOH-exposed embryos, betaine-supplemented embryos had higher late-stage survival rates and fewer gross head and body defects than seen after alcohol exposure alone. Betaine also reduced the incidence of late-stage cardiac defects such as absent vessels, abnormal atrioventricular (AV) valves, and hypertrophic ventricles. Furthermore, betaine cotreatment brought measurements of great vessel diameters, interventricular septum thickness, and AV leaflet volumes in betaine-supplemented embryos close to control values. Early-stage 5-methycytosine staining revealed that DNA methylation levels were reduced by EtOH exposure and normalized by co-administration with betaine. CONCLUSIONS: This is the first study demonstrating efficacy of the methyl donor betaine in alleviating cardiac defects associated with PAE. These findings highlight the therapeutic potential of low-concentration betaine doses in mitigating PAE-induced birth defects and have implications for prenatal nutrition policies, especially for women who may not be responsive to folate supplementation.