Research Goes Red: Early Experience With a Participant-Centric Registry.

RATIONALE: Cardiovascular disease remains the leading cause of death in women. To address its determinants including persisting cardiovascular risk factors amplified by sex and race inequities, novel personalized approaches are needed grounded in the engagement of participants in research and prevention. OBJECTIVE: To report on a participant-centric and personalized dynamic registry designed to address persistent gaps in understanding and managing cardiovascular disease in women. METHODS AND RESULTS: The American Heart Association and Verily launched the Research Goes Red registry (RGR) in 2019, as an online research platform available to consenting individuals over the age of 18 years in the United States. RGR aims to bring participants and researchers together to expand knowledge by collecting data and providing an open-source longitudinal dynamic registry for conducting research studies. As of July 2021, 15 350 individuals have engaged with RGR. Mean age of participants was 48.0 48.0±0.2 years with a majority identifying as female and either non-Hispanic White (75.7%) or Black (10.5%). In addition to 6 targeted health surveys, RGR has deployed 2 American Heart Association-sponsored prospective clinical studies based on participants' areas of interest. The first study focuses on perimenopausal weight gain, developed in response to a health concerns survey. The second study is designed to test the use of social media campaigns to increase awareness and participation in cardiovascular disease research among underrepresented millennial women. CONCLUSIONS: RGR is a novel online participant-centric platform that has successfully engaged women and provided critical data on women's heart health to guide research. Priorities for the growth of RGR are centered on increasing reach and diversity of participants, and engaging researchers to work within their communities to leverage the platform to address knowledge gaps and improve women's health.

Call to Action for Cardiovascular Disease in Women: Epidemiology, Awareness, Access, and Delivery of Equitable Health Care: A Presidential Advisory From the American Heart Association.

Addressing the pervasive gaps in knowledge and care delivery to reduce sex-based disparities and achieve equity is fundamental to the American Heart Association's commitment to advancing cardiovascular health for all by 2024. This presidential advisory serves as a call to action for the American Heart Association and other stakeholders around the globe to identify and remove barriers to health care access and quality for women. A concise and current summary of existing data across the areas of risk and prevention, access and delivery of equitable care, and awareness and education provides a framework to consider knowledge gaps and research needs critical toward achieving significant progress for the health and well-being of all women.

Frequency and Prognostic Significance of Clinical Fluctuations Before Hospital Arrival in Stroke.

BACKGROUND AND PURPOSE: Clinical fluctuations in ischemic stroke symptoms are common, but fluctuations before hospital arrival have not been previously characterized. METHODS: A standardized qualitative assessment of fluctuations before hospital arrival was obtained in an observational study that enrolled patients with mild ischemic stroke symptoms (National Institutes of Health Stroke Scale [NIHSS] score of 0-5) present on arrival to hospital within 4.5 hours of onset, in a subset of 100 hospitals participating in the Get With The Guidelines-Stroke quality improvement program. The number of fluctuations, direction, and the overall improvement or worsening was recorded based on reports from the patient, family, or paramedics. Baseline NIHSS on arrival and at 72 hours (or discharge if before) and final diagnosis and stroke subtype were collected. Outcomes at 90 days included the modified Rankin Scale, Barthel Index, Stroke Impact Scale 16, and European Quality of Life. Prehospital fluctuations were examined in relation to hospital NIHSS change (admission to 72 hours or discharge) and 90-day outcomes. RESULTS: Among 1588 participants, prehospital fluctuations, consisting of improvement, worsening, or both were observed in 35.5%: 25.1% improved once, 5.3% worsened once, and 5.1% had more than 1 fluctuation. Those who improved were less likely and those who worsened were more likely to receive alteplase. Those who improved before hospital arrival had lower change in the hospital NIHSS than those who did not fluctuate. Better adjusted 90-day outcomes were noted in those with prehospital improvement compared to those without any fluctuations. CONCLUSIONS: Fluctuations in neurological symptoms and signs are common in the prehospital setting. Prehospital improvement was associated with better 90-day outcomes, controlling for admission NIHSS and alteplase treatment. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02072681.

Acute Ischemic Stroke in Patients With COVID-19: An Analysis From Get With The Guidelines-Stroke.

[Figure: see text].

Treatment and Outcomes of Patients With Ischemic Stroke During COVID-19: An Analysis From Get With The Guidelines-Stroke.

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Predictors of Outcomes in Patients With Mild Ischemic Stroke Symptoms: MaRISS.

Background and Purpose: Although most strokes present with mild symptoms, these have been poorly represented in clinical trials. The objective of this study is to describe multidimensional outcomes, identify predictors of worse outcomes, and explore the effect of thrombolysis in this population. Methods: This prospective observational study included patients with ischemic stroke or transient ischemic attack, a baseline National Institutes of Health Stroke Scale (NIHSS) score 0 to 5, presenting within 4.5 hours from symptom onset. The primary outcome was a 90-day modified Rankin Scale score of 0 to 1; secondary outcomes included good outcomes in the Barthel Index, Stroke Impact Scale-16, and European Quality of Life. Multivariable models were created to determine predictors of outcomes and the effect of alteplase. Results: A total of 1765 participants were included from 100 Get With The Guidelines-Stroke participating hospitals (age, 65±14; 42% women; final diagnosis of ischemic stroke, 90%; transient ischemic attack, 10%; 57% received alteplase). At 90 days, 37% were disabled and 25% not independent. Worse outcomes were noted for older individuals, women, non-Hispanic Blacks and Hispanics, Medicaid recipients, smokers, those with diabetes, atrial fibrillation, prior stroke, higher baseline NIHSS, visual field defects, and extremity weakness. Similar outcomes were noted for the alteplase-treated and untreated groups. Alteplase-treated patients were younger (64±13 versus 67±1.4) with higher NIHSS (2.9±1.4 versus 1.7±1.4). After adjusting for age, sex, race/ethnicity, and baseline NIHSS, we did not identify an effect of alteplase on the primary outcome but did find an association with Stroke Impact Scale-16 in the restricted sample of baseline NIHSS score 3­5. Few symptomatic intracerebral hemorrhages were recorded (<1%). Conclusions: A large proportion of stroke patients presenting with low NIHSS have a disabled outcome. Baseline predictors of worse outcomes are described. An effect of alteplase on outcomes was not identified in the overall cohort, but a suggestion of efficacy was noted in the NIHSS 3­5 subgroup. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02072681.

Omega-3 Polyunsaturated Fatty Acid (Fish Oil) Supplementation and the Prevention of Clinical Cardiovascular Disease: A Science Advisory From the American Heart Association.

Multiple randomized controlled trials (RCTs) have assessed the effects of supplementation with eicosapentaenoic acid plus docosahexaenoic acid (omega-3 polyunsaturated fatty acids, commonly called fish oils) on the occurrence of clinical cardiovascular diseases. Although the effects of supplementation for the primary prevention of clinical cardiovascular events in the general population have not been examined, RCTs have assessed the role of supplementation in secondary prevention among patients with diabetes mellitus and prediabetes, patients at high risk of cardiovascular disease, and those with prevalent coronary heart disease. In this scientific advisory, we take a clinical approach and focus on common indications for omega-3 polyunsaturated fatty acid supplements related to the prevention of clinical cardiovascular events. We limited the scope of our review to large RCTs of supplementation with major clinical cardiovascular disease end points; meta-analyses were considered secondarily. We discuss the features of available RCTs and provide the rationale for our recommendations. We then use existing American Heart Association criteria to assess the strength of the recommendation and the level of evidence. On the basis of our review of the cumulative evidence from RCTs designed to assess the effect of omega-3 polyunsaturated fatty acid supplementation on clinical cardiovascular events, we update prior recommendations for patients with prevalent coronary heart disease, and we offer recommendations, when data are available, for patients with other clinical indications, including patients with diabetes mellitus and prediabetes and those with high risk of cardiovascular disease, stroke, heart failure, and atrial fibrillation.

Phytosterol feeding causes toxicity in ABCG5/G8 knockout mice.

Plant sterols, or phytosterols, are very similar in structure to cholesterol and are abundant in typical diets. The reason for poor absorption of plant sterols by the body is still unknown. Mutations in the ABC transporters G5 and G8 are known to cause an accumulation of plant sterols in blood and tissues (sitosterolemia). To determine the significance of phytosterol exclusion from the body, we fed wild-type and ABCG5/G8 knockout mice a diet enriched with plant sterols. The high-phytosterol diet was extremely toxic to the ABCG5/G8 knockout mice but had no adverse effects on wild-type mice. ABCG5/G8 knockout mice died prematurely and developed a phenotype that included high levels of plant sterols in many tissues, liver abnormalities, and severe cardiac lesions. This study is the first to report such toxic effects of phytosterol accumulation in ABCG5/G8 knockout mice. We believe these new data support the conclusion that plant sterols are excluded from the body because they are toxic when present at high levels.

Looking Back to Look Forward: A Review of FDA's Food Additives Safety Assessment and Recommendations for Modernizing its Program.

Scientists participating in 2 multistakeholder meetings in 2011 and in other events have identified a number of ways in which the methods the U.S. Food and Drug Administration (FDA) uses to assess the safety of chemicals in human food should be improved and updated. We evaluated whether FDA's current methods, including its decision-making process, are outdated, as alleged by its critics. We examined a 1982 report by the Select Committee on GRAS Substances (SCOGS) that included suggestions to enhance food additive safety. FDA established SCOGS to review the safety of "generally recognized as safe" (GRAS) substances in response to a directive by President Nixon. When evaluating FDA's response to SCOGS' suggestions, we found that many remain unresolved and relevant today. Our analysis demonstrates that in many cases FDA has not kept pace with scientific developments. Although difficult to pinpoint, we concluded that this situation became more significant after 1997, when FDA launched the voluntary GRAS notification program aimed at enticing manufacturers to inform the agency of their own safety decisions. Looking forward, we recommend that the agency convene an unbiased and independent expert workgroup to conduct a comprehensive review of FDA's science and decision making and develop a path to modernize food additives safety assessment. Areas of concern include toxicology test guidelines, tools used to predict health outcomes, conflict of interest in manufacturers' decisions, lack of a reassessment strategy, and lack of a definition of harm.

Identification and risk stratification of coronary disease by artificial intelligence-enabled ECG.

Background: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide, driven primarily by coronary artery disease (CAD). ASCVD risk estimators such as the pooled cohort equations (PCE) facilitate risk stratification and primary prevention of ASCVD but their accuracy is still suboptimal. Methods: Using deep electronic health record data from 7,116,209 patients seen at 70+ hospitals and clinics across 5 states in the USA, we developed an artificial intelligence-based electrocardiogram analysis tool (ECG-AI) to detect CAD and assessed the additive value of ECG-AI-based ASCVD risk stratification to the PCE. We created independent ECG-AI models using separate neural networks including subjects without known history of ASCVD, to identify coronary artery calcium (CAC) score ≥300 Agatston units by computed tomography, obstructive CAD by angiography or procedural intervention, and regional left ventricular akinesis in ≥1 segment by echocardiogram, as a reflection of possible prior myocardial infarction (MI). These were used to assess the utility of ECG-AI-based ASCVD risk stratification in a retrospective observational study consisting of patients with PCE scores and no prior ASCVD. The study period covered all available digitized EHR data, with the first available ECG in 1987 and the last in February 2023. Findings: ECG-AI for identifying CAC ≥300, obstructive CAD, and regional akinesis achieved area under the receiver operating characteristic (AUROC) values of 0.88, 0.85, and 0.94, respectively. An ensembled ECG-AI identified 3, 5, and 10-year risk for acute coronary events and mortality independently and additively to PCE. Hazard ratios for acute coronary events over 3-years in patients without ASCVD that tested positive on 1, 2, or 3 versus 0 disease-specific ECG-AI models at cohort entry were 2.41 (2.14-2.71), 4.23 (3.74-4.78), and 11.75 (10.2-13.52), respectively. Similar stratification was observed in cohorts stratified by PCE or age. Interpretation: ECG-AI has potential to address unmet need for accessible risk stratification in patients in whom PCE under, over, or insufficiently estimates ASCVD risk, and in whom risk assessment over time periods shorter than 10 years is desired. Funding: Anumana.

The role of TRAIL in mediating autophagy in myositis skeletal muscle: a potential nonimmune mechanism of muscle damage.

OBJECTIVE: Multinucleated cells are relatively resistant to classic apoptosis, and the factors initiating cell death and damage in myositis are not well defined. We hypothesized that nonimmune autophagic cell death may play a role in muscle fiber damage. Recent reports indicate that TRAIL may induce both NF-κB activation and autophagic cell death in other systems. We undertook this study to investigate the role of TRAIL in cell death and pathogenesis in vitro and in vivo, using myositis muscle tissues from humans and mice. METHODS: Gene expression profiling was performed in myositis patient and control muscle specimens. Immunohistochemistry analysis was performed to confirm the gene array findings. We also analyzed TRAIL-induced cell death (apoptosis and autophagy) and NF-κB activation in vitro in cultured cells. RESULTS: TRAIL was expressed predominantly in myositis muscle fibers, but not in biopsy specimens from normal or other dystrophic-diseased muscle. Autophagy markers were up-regulated in humans with myositis and in mouse models of myositis. TRAIL expression was restricted to regenerating/atrophic areas of muscle fascicles, blood vessels, and infiltrating lymphocytes. TRAIL induced NF-κB activation and IκB degradation in cultured cells that are resistant to TRAIL-induced apoptosis but that undergo autophagic cell death. CONCLUSION: Our data demonstrate that TRAIL is expressed in myositis muscle and may mediate both activation of NF-κB and autophagic cell death in myositis. Thus, this nonimmune pathway may be an attractive target for therapeutic intervention in myositis.

Heart failure quality of care and in-hospital outcomes during the COVID-19 pandemic: findings from the Get With The Guidelines-Heart Failure registry.

AIMS: To assess heart failure (HF) in-hospital quality of care and outcomes before and during the COVID-19 pandemic. METHODS AND RESULTS: Patients hospitalized for HF with ejection fraction (EF) <40% in the American Heart Association Get With The Guidelines©-HF (GWTG-HF) registry during the COVID-19 pandemic (3/1/2020-4/1/2021) and pre-pandemic (2/1/2019-2/29/2020) periods were included. Adherence to HF process of care measures, in-hospital mortality, and length of stay (LOS) were compared in pre-pandemic vs. pandemic periods and in patients with vs. without COVID-19. Overall, 42 004 pre-pandemic and 37 027 pandemic period patients (median age 68, 33% women, 58% White) were included without observed differences across clinical characteristics, comorbidities, vital signs, or EF. Utilization of guideline-directed medical therapy at discharge was comparable across both periods, with rates of implantable cardioverter defibrillator (ICD) placement or prescription lower during the pandemic (vs. pre-pandemic period). In-hospital mortality (3.0% vs. 2.5%, p <0.0001) and LOS (mean 5.7 vs. 5.4 days, p <0.0004) were higher during the pandemic vs. pre-pandemic. The highest in-hospital mortality during the pandemic was observed among patients hospitalized in the Northeast region (3.4%). Among patients concurrently diagnosed with COVID-19 (n = 549; 1.5%), adherence to ICD placement or prescription, prescription of aldosterone antagonist or angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor at discharge were lower, and in-hospital mortality (8.2% vs. 3.0%, p <0.0001) and LOS (mean 7.7 vs. 5.7 days, p <0.0001) were higher than those without COVID-19. CONCLUSION: Among GWTG-HF participating hospitals, patients hospitalized for HF with reduced EF during the pandemic received similar care quality but experienced higher in-hospital mortality than the pre-pandemic period.

Functional status at 30 and 90 days after mild ischaemic stroke.

BACKGROUND/OBJECTIVE: This study compares the global disability status of patients who had a mild ischaemic stroke at 30 and 90 days poststroke, as measured by the modified Rankin Scale (mRS), and identifies predictors of change in disability status between 30 and 90 days. METHODS: The study population included 1339 patients who had a ischaemic stroke enrolled in the Mild and Rapidly Improving Stroke Study with National Institutes of Health (NIH) stroke score 0-5 and mRS measurements at 30 and 90 days. Outcomes were (1) Improvement defined as having mRS >1 at 30 days and mRS 0-1 at 90 days OR mRS >2 at 30 days and mRS 0-2 at 90 days and (2) Worsening defined as an increase of ≥2 points or a worsening from mRS of 1 at 30 days to 2 at 90 days. Demographic and clinical characteristics at hospital arrival were abstracted from medical records, and regression models were used to identify predictors of functional improvement and decline from 30 to 90 days post-stroke. Significant predictors were mutually adjusted in multivariable models that also included age and stroke severity. RESULTS: Fifty-seven per cent of study participants had no change in mRS value from 30 to 90 days. Overall, there was moderate agreement in mRS between the two time points (weighted kappa=0.59 (95% CI 0.56 to 0.62)). However, worsening on the mRS was observed in 7.54% of the study population from 30 to 90 days, and 17.33% improved. Participants of older age (per year OR 1.02, 95% CI 1.00 to 1.03), greater stroke severity (per NIH Stroke Scale (NIHSS) point at admission OR 1.17, 95% CI 1.03 to 1.34), and those with no alteplase treatment (OR 1.72, 95% CI 1.11 to 2.69) were more likely to show functional decline after mutual adjustment. DISCUSSION: A quarter of all mild ischaemic stroke participants exhibited functional changes between 30 and 90 days, suggesting that the 30-day outcome may insufficiently represent long-term recovery in mild stroke and longer follow-up may be clinically necessary. TRIAL REGISTRATION NUMBER: NCT02072681.

Inhibition of acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) prevents dietary cholesterol-associated steatosis by enhancing hepatic triglyceride mobilization.

Acyl-CoA:cholesterol O-acyl transferase 2 (ACAT2) promotes cholesterol absorption by the intestine and the secretion of cholesteryl ester-enriched very low density lipoproteins by the liver. Paradoxically, mice lacking ACAT2 also exhibit mild hypertriglyceridemia. The present study addresses the unexpected role of ACAT2 in regulation of hepatic triglyceride (TG) metabolism. Mouse models of either complete genetic deficiency or pharmacological inhibition of ACAT2 were fed low fat diets containing various amounts of cholesterol to induce hepatic steatosis. Mice genetically lacking ACAT2 in both the intestine and the liver were dramatically protected against hepatic neutral lipid (TG and cholesteryl ester) accumulation, with the greatest differences occurring in situations where dietary cholesterol was elevated. Further studies demonstrated that liver-specific depletion of ACAT2 with antisense oligonucleotides prevents dietary cholesterol-associated hepatic steatosis both in an inbred mouse model of non-alcoholic fatty liver disease (SJL/J) and in a humanized hyperlipidemic mouse model (LDLr(-/-), apoB(100/100)). All mouse models of diminished ACAT2 function showed lowered hepatic triglyceride concentrations and higher plasma triglycerides secondary to increased hepatic secretion of TG into nascent very low density lipoproteins. This work demonstrates that inhibition of hepatic ACAT2 can prevent dietary cholesterol-driven hepatic steatosis in mice. These data provide the first evidence to suggest that ACAT2-specific inhibitors may hold unexpected therapeutic potential to treat both atherosclerosis and non-alcoholic fatty liver disease.

Combined therapy of dietary fish oil and stearoyl-CoA desaturase 1 inhibition prevents the metabolic syndrome and atherosclerosis.

BACKGROUND: Stearoyl-CoA desaturase 1 (SCD1) is a critical regulator of energy metabolism and inflammation. We have previously reported that inhibition of SCD1 in hyperlipidemic mice fed a saturated fatty acid (SFA)-enriched diet prevented development of the metabolic syndrome, yet surprisingly promoted severe atherosclerosis. In this study we tested whether dietary fish oil supplementation could prevent the accelerated atherosclerosis caused by SCD1 inhibition. METHODS AND RESULTS: LDLr(-/-), ApoB(100/100) mice were fed diets enriched in saturated fat or fish oil in conjunction with antisense oligonucleotide (ASO) treatment to inhibit SCD1. As previously reported, in SFA-fed mice, SCD1 inhibition dramatically protected against development of the metabolic syndrome, yet promoted atherosclerosis. In contrast, in mice fed fish oil, SCD1 inhibition did not result in augmented macrophage inflammatory response or severe atherosclerosis. In fact, the combined therapy of dietary fish oil and SCD1 ASO treatment effectively prevented both the metabolic syndrome and atherosclerosis. CONCLUSIONS: SCD1 ASO treatment in conjunction with dietary fish oil supplementation is an effective combination therapy to comprehensively combat the metabolic syndrome and atherosclerosis in mice.

Association of Kidney Disease With Outcomes in COVID-19: Results From the American Heart Association COVID-19 Cardiovascular Disease Registry.

Background Emerging evidence links acute kidney injury (AKI) in patients with COVID-19 with higher mortality and respiratory morbidity, but the relationship of AKI with cardiovascular disease outcomes has not been reported in this population. We sought to evaluate associations between chronic kidney disease (CKD), AKI, and mortality and cardiovascular outcomes in patients hospitalized with COVID-19. Methods and Results In a large multicenter registry including 8574 patients with COVID-19 from 88 US hospitals, data were collected on baseline characteristics and serial laboratory data during index hospitalization. Primary exposure variables were CKD (categorized as no CKD, CKD, and end-stage kidney disease) and AKI (classified into no AKI or stages 1, 2, or 3 using a modification of the Kidney Disease Improving Global Outcomes guideline definition). The primary outcome was all-cause mortality. The key secondary outcome was major adverse cardiac events, defined as cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, new-onset nonfatal heart failure, and nonfatal cardiogenic shock. CKD and end-stage kidney disease were not associated with mortality or major adverse cardiac events after multivariate adjustment. In contrast, AKI was significantly associated with mortality (stage 1 hazard ratio [HR], 1.72 [95% CI, 1.46-2.03]; stage 2 HR, 1.83 [95% CI, 1.52-2.20]; stage 3 HR, 1.69 [95% CI, 1.44-1.98]; versus no AKI) and major adverse cardiac events (stage 1 HR, 2.17 [95% CI, 1.74-2.71]; stage 2 HR, 2.70 [95% CI, 2.07-3.51]; stage 3 HR, 3.06 [95% CI, 2.52-3.72]; versus no AKI). Conclusions This large study demonstrates a significant association between AKI and all-cause mortality and, for the first time, major adverse cardiovascular events in patients hospitalized with COVID-19.

Trends in Patient Characteristics and COVID-19 In-Hospital Mortality in the United States During the COVID-19 Pandemic.

Importance: In-hospital mortality rates from COVID-19 are high but appear to be decreasing for selected locations in the United States. It is not known whether this is because of changes in the characteristics of patients being admitted. Objective: To describe changing in-hospital mortality rates over time after accounting for individual patient characteristics. Design, Setting, and Participants: This was a retrospective cohort study of 20 736 adults with a diagnosis of COVID-19 who were included in the US American Heart Association COVID-19 Cardiovascular Disease Registry and admitted to 107 acute care hospitals in 31 states from March through November 2020. A multiple mixed-effects logistic regression was then used to estimate the odds of in-hospital death adjusted for patient age, sex, body mass index, and medical history as well as vital signs, use of supplemental oxygen, presence of pulmonary infiltrates at admission, and hospital site. Main Outcomes and Measures: In-hospital death adjusted for exposures for 4 periods in 2020. Results: The registry included 20 736 patients hospitalized with COVID-19 from March through November 2020 (9524 women [45.9%]; mean [SD] age, 61.2 [17.9] years); 3271 patients (15.8%) died in the hospital. Mortality rates were 19.1% in March and April, 11.9% in May and June, 11.0% in July and August, and 10.8% in September through November. Compared with March and April, the adjusted odds ratios for in-hospital death were significantly lower in May and June (odds ratio, 0.66; 95% CI, 0.58-0.76; P < .001), July and August (odds ratio, 0.58; 95% CI, 0.49-0.69; P < .001), and September through November (odds ratio, 0.59; 95% CI, 0.47-0.73). Conclusions and Relevance: In this cohort study, high rates of in-hospital COVID-19 mortality among registry patients in March and April 2020 decreased by more than one-third by June and remained near that rate through November. This difference in mortality rates between the months of March and April and later months persisted even after adjusting for age, sex, medical history, and COVID-19 disease severity and did not appear to be associated with changes in the characteristics of patients being admitted.

CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance.

Mutations of Comparative Gene Identification-58 (CGI-58) in humans cause triglyceride (TG) accumulation in multiple tissues. Mice genetically lacking CGI-58 die shortly after birth due to a skin barrier defect. To study the role of CGI-58 in integrated lipid and energy metabolism, we utilized antisense oligonucleotides (ASOs) to inhibit CGI-58 expression in adult mice. Treatment with two distinct CGI-58-targeting ASOs resulted in ∼80-95% knockdown of CGI-58 protein expression in both liver and white adipose tissue. In chow-fed mice, ASO-mediated depletion of CGI-58 did not alter weight gain, plasma TG, or plasma glucose, yet raised hepatic TG levels ∼4-fold. When challenged with a high-fat diet (HFD), CGI-58 ASO-treated mice were protected against diet-induced obesity, but their hepatic contents of TG, diacylglycerols, and ceramides were all elevated, and intriguingly, their hepatic phosphatidylglycerol content was increased by 10-fold. These hepatic lipid alterations were associated with significant decreases in hepatic TG hydrolase activity, hepatic lipoprotein-TG secretion, and plasma concentrations of ketones, nonesterified fatty acids, and insulin. Additionally, HFD-fed CGI-58 ASO-treated mice were more glucose tolerant and insulin sensitive. Collectively, this work demonstrates that CGI-58 plays a critical role in limiting hepatic steatosis and maintaining hepatic glycerophospholipid homeostasis and has unmasked an unexpected role for CGI-58 in promoting HFD-induced obesity and insulin resistance.