Frailty, Sarcopenia, Cachexia, and Malnutrition in Heart Failure.

With global aging, the number of patients with heart failure has increased markedly. Heart failure is a complex condition intricately associated with aging, organ damage, frailty, and cognitive decline, resulting in a poor prognosis. The relationship among frailty, sarcopenia, cachexia, malnutrition, and heart failure has recently received considerable attention. Although these conditions are distinct, they often exhibit a remarkably close relationship. Overlapping diagnostic criteria have been observed in the recently proposed guidelines and position statements, suggesting that several of these conditions may coexist in patients with heart failure. Therefore, a comprehensive understanding of these conditions is essential, and interventions must not only target these conditions individually, but also provide comprehensive management strategies. This review article provides an overview of the epidemiology, diagnostic methods, overlap, and prognosis of frailty, sarcopenia, cachexia, and malnutrition in patients with heart failure, incorporating insights from the FRAGILE-HF study data. Additionally, based on existing literature, this article discusses the impact of these conditions on the effectiveness of guideline-directed medical therapy for patients with heart failure. While recognizing these conditions early and promptly implementing interventions may be advantageous, further data, particularly from well-powered, large-scale, randomized controlled trials, are necessary to refine personalized treatment strategies for patients with heart failure.

Left Ventricular End-Systolic Diameter May Predict Persistent Heart Failure with Reduced Ejection Fraction.

Patients with persistent heart failure (HF) with reduced ejection fraction (HFrEF) have a poorer prognosis than those with HF with improved ejection fraction (HFimpEF). However, data on the predictive value of echocardiographic parameters for persistent HFrEF are lacking. We retrospectively studied 443 patients who were diagnosed with HFrEF (EF ≤ 40%) during hospitalization and underwent echocardiography at the 1-year follow-up. We divided them into the 2 groups: HFimpEF (EF > 40%) and persistent HFrEF group at 1-year follow-up, and assessed the predictive value of echocardiographic parameters at discharge for persistent HFrEF. In total, 301/443 patients (68%) were diagnosed with persistent HFrEF and 142/443 (32%) with HFimpEF at the 1-year follow-up. Kaplan-Meier analysis revealed that the persistent HFrEF group had a poorer prognosis than the HFimpEF group (log-rank, P < 0.001). Receiver operating characteristic curve analysis revealed that left ventricular end-systolic diameter (LVESD) had the highest area under the curve (AUC) (0.70; 95% confidence interval [CI]: 0.64-0.75; cutoff value: 55 mm) among various echocardiographic parameters. LVESD was an independent predictor of persistent HFrEF at the 1-year follow-up (odds ratio: 1.07, 95%CI: 1.02-1.12) upon multivariable logistic regression analysis. The incidence of persistent HFrEF was higher in patients with an LVESD ≥ 55 mm than in those with an LVESD < 55 mm (81% versus 55%, Fisher's exact test, P < 0.001). In conclusion, an LVESD (≥ 55 mm) was associated with persistent HFrEF. Focusing on LVESD in daily practice may help clinicians with risk stratification for decision-making regarding management in patients with advanced HF refractory to guideline-directed medical therapy.

Analyzing drilling noise in rotational atherectomy: Improving safety and effectiveness through visualization and anomaly detection using autoencoder-A preclinical study.

Background and Aims: As the population of aging societies continues to grow, the prevalence of complex coronary artery diseases, including calcification, is expected to increase. Rotational atherectomy (RA) is an essential technique for treating calcified lesions. This study aimed to assess the usefulness of the drilling noise produced during rotablation as a parameter for evaluating the safety and effectiveness of the procedure. Methods: A human body model mimicking calcified stenotic coronary lesions was constructed using plastic resin, and burrs of sizes 1.25 and 1.5 mm were utilized. To identify the noise source during rotablation, we activated the ROTAPRO™ rotablator at a rotational speed of 180,000 rpm, recording the noise near the burr (inside the mock model) and advancer (outside). In addition to regular operation, we simulated two major complications: burr entrapment and guidewire transection. The drilling noise recorded in Waveform Audio File Format files was converted into spectrograms for analysis and an autoencoder analyzed the image data for anomalies. Results: The drilling noise from both inside and outside the mock model was predominantly within the 3000 Hz frequency domain. During standard operation, intermittent noise within this range was observed. However, during simulated complications, there were noticeable changes: a drop to 2000 Hz during burr entrapment and a distinct squealing noise during guidewire transection. The autoencoder effectively reduced the spectrogram data into a two-dimensional representation suitable for anomaly detection in potential clinical applications. Conclusion: By analyzing drilling noise, the evaluation of procedural safety and efficacy during RA can be enhanced.

Direct Oral Anticoagulants Affect Activated Clotting Time During and Bleeding Events After Percutaneous Coronary Intervention.

Inappropriately high activated clotting time (ACT) during percutaneous coronary intervention (PCI) is associated with an increased risk of bleeding events. However, whether the prescription of direct oral anticoagulants (DOACs) affects ACT kinetics during heparin use and adverse clinical events in patients who underwent PCI remains unclear. We aimed to evaluate the relations between ACT changes during and adverse clinical events after PCI in patients who were prescribed DOAC. This observational study included 246 patients who underwent PCI at the 2 cardiovascular centers who were not receiving warfarin and whose ACT was recorded immediately before and 30 minutes after injection of unfractionated heparin. Patients were divided into 2 groups according to DOAC prescription at the time of the index PCI: DOAC users (n = 31) and nonusers (n = 215). Any bleeding and systemic thromboembolic events were investigated until 30 days after PCI. The average age of this population was 70.5 years, and 66.3% were male. Average ACT was significantly higher in DOAC users than nonusers both before and 30 minutes after unfractionated heparin induction (157.2 ± 30.1 vs 131.8 ± 25.1 seconds, p <0.001; 371.1 ± 122.2 vs 308.3 ± 82.2 seconds, p <0.001; respectively). The incidence of systemic thromboembolism after PCI was low and comparable between the 2 groups (0% vs 3.7%, p = 0.60). However, the rate of any bleeding event was significantly higher in DOAC users than in nonusers (16.1% vs 4.7%, p = 0.028). Patients receiving DOAC have higher ACT during PCI and higher incidence of bleeding events than those not receiving DOAC.

Optimal lipid-lowering therapy in patients who were functionally deferred percutaneous coronary intervention.

Deferral of percutaneous coronary intervention (PCI) for functionally insignificant stenosis, defined as fractional flow reserve (FFR) > 0.80, is associated with favorable long-term prognoses. The lower-the-better strategy for low-density lipoprotein cholesterol (LDL-C) management is an established non-angioplasty therapy to improve the clinical outcomes of patients undergoing PCI. We examined the optimal LDL-C management in cases of intermediate coronary stenosis with deferred PCI on the basis of FFR values. This observational study included 273 consecutive patients with a single target vessel and deferred PCI with an FFR > 0.80. Patients with an FFR of 0.81-0.85 (n = 93) and those with FFR > 0.85 (n = 180) were classified into the lower (< 100 mg/dL) and higher (≥ 100 mg/dL) LDL-C groups. The endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), including death, non-fatal myocardial infarction, ischemic stroke, heart failure hospitalization, and unplanned revascularization. Patients with an FFR of 0.81-0.85 had a significantly higher MACCE rate than those with an FFR > 0.85 (log-rank, p = 0.003). In patients with an FFR of 0.81-0.85, the lower LDL-C group showed a significantly lower MACCE rate than the higher LDL-C group (log-rank, p = 0.006). However, the event rate did not differ significantly between the two groups in patients with FFR > 0.85 (log-rank, p = 0.84). Uncontrolled LDL-C levels were associated with higher MACCE rates in cases with deferred PCI due to an FFR of 0.81-0.85. This high-risk population for adverse cardiovascular events should receive strict LDL-C-lowering therapy.

The interaction between physical frailty and prognostic impact of heart failure medication in elderly patients.

AIMS: Frailty is highly prevalent and associated with poor prognoses in elderly patients with heart failure (HF). However, the potential effects of physical frailty on the benefits of HF medications in elderly patients with HF are unclear. We aimed to determine the influence of physical frailty on the prognosis of HF medications in elderly patients with HF with reduced and mildly reduced ejection fraction (HFr/mrEF). METHODS AND RESULTS: From the combined HF database of the FRAGILE-HF and Kitasato cohorts, hospitalized HF patients with a left ventricular ejection fraction < 50% and age ≥ 65 years were analysed. Patients treated with or without renin-angiotensin-aldosterone system inhibitors (RAASi) and beta-blockers at discharge were compared. Physical frailty was defined by the presence of ≥3 items on the Japanese version of the Cardiovascular Health Study criteria. The primary endpoint was all-cause mortality rate. Among the 1021 enrolled patients, 604 patients (59%) received both RAASi and beta-blockers, and 604 patients (59%) were diagnosed as physically frail. Patients receiving both RAASi and beta-blockers showed a significantly lower 1 year mortality than those not receiving either, even after adjusting for covariates (hazard ratio: 0.50, 95% confidence interval: 0.34-0.75). This beneficial effect of both medications on 1 year mortality was comparable between patients with and without physical frailty (hazard ratio: 0.53 and 0.51, respectively; P for interaction = 0.77). CONCLUSIONS: The presence of physical frailty did not interact with the beneficial prognostic impact of RAASi and beta-blocker combination therapy in elderly patients with HFr/mrEF.

Renin-angiotensin system inhibitor exerts prognostic effects in HFpEF patients with low baseline chloride level.

BACKGROUND: Few interventions have shown improved prognosis in patients with heart failure and preserved ejection fraction (HFpEF). Serum chloride levels, which are affected by serum renin secretion, are associated with the prognosis of HFpEF patients. However, the relationship between serum chloride levels and the effects of renin-angiotensin system inhibitors (RASi) in HFpEF patients remains unclear. We investigated whether the prognostic benefit of RASi depends on baseline serum chloride levels in HFpEF patients. METHODS: This observational study included 506 hospitalized patients with HFpEF (ejection fraction ≥50%) who were discharged. They were divided into two categories based on serum chloride levels at admission (cutoff level: 101 mEq/L) according to previous reports. In each chloride category, all-cause mortality, the primary endpoint, was compared between patients who received RASi and those who did not. RESULTS: Patients who received RASi had a significantly lower mortality rate after discharge than those who did not, but only in the lower chloride category (log-rank, P = 0.001). Multivariable Cox regression analysis confirmed the effect of risk reduction by RASi on all-cause mortality in the lower chloride category (adjusted hazard ratio: 0.31, 95% confidence interval: 0.11-0.84). The prognostic advantages of RASi were evident in the lower chloride category, but not in the higher chloride category, at admission (P for interaction = 0.027). CONCLUSION: RASi administration was associated with an improved prognosis only in HFpEF patients with a low baseline serum chloride level. Clinicians should consider RASi administration if patients' serum chloride levels are low, to improve the long-term prognosis of HFpEF patients.

Prognostic impact of guideline-directed medical therapy in patients with heart failure on regular hemodialysis.

BACKGROUND: Renin-angiotensin system inhibitor (RASi) and ß-blocker provide prognostic benefits as guideline-directed medical therapy (GDMT) in patients with heart failure and reduced ejection fraction (HFrEF). However, there is limited data for the favorable effects in such patients receiving regular hemodialysis. We aimed to evaluate the prognostic impact of RASi and ß-blocker in patients with HFrEF who receive regular hemodialysis. METHODS: In this retrospective, single-center, observational study, from 2110 consecutive patients hospitalized for HF and who survived to discharge, 97 with HFrEF who received regular hemodialysis were included for analysis. They were classified into three groups according to prescribed medication at discharge following index hospitalization: both RASi and ß-blocker (Dual-GDMT group: n = 55), either RASi or ß-blocker (Mono-GDMT group: n = 34), and neither RASi nor ß-blocker (No-GDMT group: n = 8). The primary endpoint was a composite of all-cause death and rehospitalization for heart failure. RESULTS: The mean age was 66 years and 79% of the patients were men. During the median follow-up of 501 days, the primary endpoint occurred in 43 patients (44%). Kaplan-Meier analysis revealed that the Dual-GDMT group had the lowest rates of the primary endpoint (log-rank test for trend: p < 0.001). Even after adjustment for diverse covariates (multivariate Cox regression), the Dual-GDMT (hazard ratio [HR]: 0.04, 95% confidence interval (CI): 0.005-0.32) and Mono-GDMT (HR: 0.08, 95% CI: 0.01-0.50) groups had better prognoses than the No-GDMT group. CONCLUSIONS: The prescription of RASi and/or ß-blocker was associated with a lower adverse-event rate after discharge in patients with HFrEF who were on regular hemodialysis.

Prognostic Impact of Landiolol in Patients with Acute Heart Failure and Atrial Fibrillation with Rapid Ventricular Rates: A Pilot Observational Study.

INTRODUCTION: Guidelines recommend ventricular rate control to <130 bpm during atrial fibrillation (AF) in patients with acute decompensated heart failure (ADHF) to avoid aggravating deteriorations in cardiac outputs. We aimed to evaluate the prognostic impact of landiolol in patients with ADHF and AF. METHODS: This observational study included 60 patients who were urgently hospitalized with ADHF and presented with AF and a heart rate (HR) ≥130 bpm at admission. The patients were assigned to the landiolol group (n = 37) or the reference group (n = 23) based on their intravenous landiolol use within 24 h after admission. The primary endpoint was death from any cause. RESULTS: The groups' baseline characteristics were similar. A significant HR reduction occurred in the landiolol group at 2 h after admission. Compared with the reference group, the HR was significantly lower (111.6 vs. 97.9 bpm, p = 0.02) and the absolute HR reduction was greater (-32.2 vs. -50.0 bpm, p = 0.006) in the landiolol group at 48 h after admission. The landiolol group's mortality rate was significantly lower than that in the reference group (log-rank test, p = 0.032). landiolol use within 24 h after admission was independently associated with lower all-cause mortality (adjusted hazard ratio: 0.15, 95% confidence interval: 0.02-0.92). CONCLUSION: Patients with ADHF and AF who received landiolol for rate control during the acute phase had better prognoses than those who did not receive landiolol.

Prognosis and diastolic dysfunction predictors in patients with heart failure and recovered ejection fraction.

There is limited data on whether diastolic dysfunction in patients with heart failure (HF) and recovered ejection fraction (HFrecEF) is associated with worse prognosis. We retrospectively assessed 96 patients diagnosed with HFrecEF and created ROC curve of their diastolic function at the 1-year follow-up for the composite endpoint of cardiovascular death and HF readmission after the follow-up. Eligible patients were divided into two groups according to the cutoff value of E/e' ratio (12.1) with the highest AUC (0.70). Kaplan-Meier analysis showed that HFrecEF with high E/e' group had a significantly poorer prognosis than the low E/e' group (log-rank, p = 0.01). Multivariate Cox regression analysis revealed that the high E/e' group was significantly related to the composite endpoint (hazard ratio 5.45, 95% confidence interval [CI] 1.23-24.1). The independent predictors at discharge for high E/e' ratio at the 1-year follow-up were older age and female sex after adjustment for covariates (odds ratio [OR] 1.07, 95% CI 1.01-1.13 and OR 4.70, 95% CI 1.08-20.5). In conclusion, HFrecEF with high E/e' ratio might be associated with a poor prognosis. Older age and female sex were independent predictors for a sustained high E/e' ratio in patients with HFrecEF.

Left ventricular systolic function affects right atrial pressure as prognosticator in patients with heart failure.

The effect of the left ventricular ejection fraction (LVEF) on the prognostic impact of the right atrial pressure (RAP) in patients with heart failure (HF) requires clarification. We aimed to investigate whether LVEF affects the prognostic impact of RAP estimated from inferior vena cava (IVC) measurements in patients hospitalized with HF. Initially, this observational study included 1349 consecutive patients urgently hospitalized with HF. After patient exclusions, 506 and 484 patients with reduced (< 40%) and with non-reduced (≥ 40%) LVEF, respectively, were assigned according to maximum IVC diameter and its collapsibility, to the Normal-RAP (diameter ≤ 2.1 cm; collapsibility ≥ 50%), High-RAP (diameter > 2.1 cm; collapsibility < 50%), and Intermediate-RAP (others) groups. The endpoint comprised cardiovascular death after discharge and hospitalization for HF recurrence. During the observation period, 247 (49%) patients with LVEF < 40% and 178 (37%) patients with LVEF ≥ 40% experienced the endpoint. The patient subgroups with LVEF < 40% had comparable event rates (ptrend = 0.10). The High-RAP subgroup with LVEF ≥40% had a higher event rate than the other subgroups (p < 0.001). The RAP independently predicted the endpoint in patients with LVEF ≥ 40% (hazard ratio: 1.26; 95% confidence interval: 1.01-1.59). The interaction between the RAP groups and LVEF regarding the primary endpoint was significant (pinteraction = 0.007). Stratifying patients with HF according to IVC measurements may predict the post-discharge cardiovascular prognoses of patients with non-reduced LVEF, but not that of patients with reduced LVEF.

Prognostic impact of right ventricular function affected by pulmonary hypertension in hospitalized heart failure patients.

BACKGROUND: Pulmonary hypertension (PH) may affect right ventricular (RV) function; however, the prognostic implications of RV function in patients with heart failure and PH remain unclear. We aimed to investigate the impact of RV function on the prognosis of hospitalized heart failure patients with and without PH. METHODS: This observational study initially included 1,349 consecutive hospitalized heart failure patients. After excluding patients who died in hospital, whose left ventricular (LV) function was preserved, and whose echocardiography data were incomplete, 573 patients with heart failure and reduced LV ejection fractions (HFrEF) were analyzed. The patients were grouped according to RV dysfunction that was defined as an RV-tissue Doppler imaging systolic velocity (RV-TDI s') of ≤9.5 cm/s. The primary endpoint was a composite of cardiovascular death and rehospitalization as a consequence of heart failure. RESULTS: Overall, the patients with reduced RV function had significantly higher event rates than those with preserved RV function (log-rank test p = 0.01). This prognostic impact was observed in the patients with PH (p = 0.001) and was not evident among the patients without PH (p = 0.39). In the patients with PH, reduced RV function independently predicted the prognosis after adjusting for the covariates (adjusted hazard ratio: 3.12; 95% confidence interval: 1.44 to 6.73). CONCLUSION: RV dysfunction that was estimated during hospitalization using the RV-TDI s', which is a simply determined index, may predict clinical outcomes in hospitalized patients with HFrEF and PH after discharge, but not in those without PH.

Nutritional status during hospitalization is associated with the long-term prognosis of patients with heart failure.

AIMS: The CONtrolling NUTritional status (CONUT) score represents the nutritional status of patients with heart failure (HF). Although high CONUT scores on admission are associated with increased risks of cardiovascular (CV) events in patients with HF, the impact of CONUT changes during hospitalization on their long-term prognosis is unclear. This study aimed to investigate the impact of CONUT score changes on the clinical outcomes of patients with HF after discharge. METHODS AND RESULTS: This observational study included 1705 patients hospitalized with HF who were discharged alive. The patients were categorized depending on their CONUT scores at admission and discharge into persistently high, high at admission and normal at discharge, normal at admission and high at discharge, and persistently normal CONUT groups. The primary endpoint was a composite of CV death and readmission for HF after discharge. The primary endpoint occurred in 652 patients (38%) during the median 525 day follow-up period. Patients with persistently high CONUT scores had the highest composite endpoint rate (log-rank trend test: P < 0.001). After adjusting for covariates, the hazard ratio for the composite outcome was significantly lower for the patients with high CONUT scores at admission and normal CONUT scores at discharge than that for those with persistently high CONUT scores (hazard ratio: 0.69; 95% confidence interval: 0.49-0.98). CONCLUSIONS: Nutritional status changes in patients with HF that occurred during hospitalization were associated with CV events after discharge. Improving the nutritional status of patients may improve their clinical outcomes.

A case of heterozygous familial hypercholesterolemia requiring strict low-density lipoprotein cholesterol management with proprotein convertase subtilisin/kexin 9 inhibitor after coronary artery bypass grafting.

Heterozygous familial hypercholesterolemia (HeFH) is a common, autosomal dominant, genetic disease that results in premature atherosclerotic cardiovascular disease secondary to high-level low-density lipoprotein cholesterol (LDL-C) exposure. We present a 68-year-old male patient with HeFH who was diagnosed with acute coronary syndrome at 9 months after coronary artery bypass grafting, although his LDL-C level was decreased to 77 mg/dL from 213 mg/dL. The emergency coronary angiography revealed that all bypass grafts were occluded, and the large atherosclerotic plaque burden was observed even in right internal thoracic artery (RITA) by intravascular ultrasound examination. Emergency percutaneous coronary intervention (PCI) was performed to his RITA bypass graft. After strict LDL-C management with proprotein convertase subtilisin/kexin 9 (PCSK-9) inhibitors, re-stenosis was not observed at the PCI site and the atherosclerotic plaque burden in his graft drastically disappeared. The high-risk HeFH patients, including those suffering from coronary bypass graft stenosis despite receiving medical therapy, might need stricter management of lipid profile with PCSK-9 inhibitors. .

Prognostic impact of additional mineralocorticoid receptor antagonists in octogenarian heart failure patients.

AIMS: Guideline-directed medical therapy (GDMT) including beta-blockers and renin-angiotensin system inhibitors is shown to reduce mortality risk in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF). However, there is little evidence about the efficacy of additional administration of mineralocorticoid receptor antagonists (MRAs) with GDMT in patients ≥80 years presenting with HF. We aimed to investigate the prognostic impact of GDMT with MRA in relation to the age of patients with HF. METHODS AND RESULTS: This observational study included patients admitted for HF with reduced LVEF who were discharged alive; among them, 224 patients were ≥80 years, and 661 patients were <80 years. Both populations were divided into three groups depending on whether they received GDMT with or without MRA or single/no GDMT drugs (GDMT+MRA+, GDMT+MRA-, or non-GDMT, respectively). The primary endpoint was all-cause mortality. In patients ≥80 years, all-cause mortality was the lowest in the GDMT+MRA+ group (log-rank trend, P = 0.034), and no significant differences were observed between the GDMT+MRA- and non-GDMT groups. Multivariate Cox regression analysis revealed that GDMT+MRA+ was superior to GDMT+MRA-, even after adjusting for parameters at discharge (hazard ratio: 0.32, 95% confidence interval: 0.11-0.99). In patients <80 years, GDMT reduced all-cause mortality; however, additional MRA was not associated with an improved outcome. CONCLUSIONS: The results of this study suggest that additional MRA to GDMT at discharge is one of the therapeutic options for elderly HF patients with reduced LVEF. This finding is not well documented in previous clinical trials.

WWP1 knockout in mice exacerbates obesity-related phenotypes in white adipose tissue but improves whole-body glucose metabolism.

White adipose tissue (WAT) is important for maintenance of homeostasis, because it stores energy and secretes adipokines. The WAT of obese people demonstrates mitochondrial dysfunction, accompanied by oxidative stress, which leads to insulin resistance. WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is a member of the HECT-type E3 family of ubiquitin ligases and is associated with several diseases. Recently, we demonstrated that WWP1 is induced specifically in the WAT of obese mice, where it protects against oxidative stress. Here, we investigated the function of WWP1 in WAT of obese mice by analyzing the phenotype of Wwp1 knockout (KO) mice fed a high-fat diet. The levels of oxidative stress markers were higher in obese WAT from Wwp1 KO mice. Moreover, Wwp1 KO mice had lower activity of citrate synthase, a mitochondrial enzyme. We also measured AKT phosphorylation in obese WAT and found lower levels in Wwp1 KO mice. However, plasma insulin level was low and glucose level was unchanged in obese Wwp1 KO mice. Moreover, both glucose tolerance test and insulin tolerance test were improved in obese Wwp1 KO mice. These findings indicate that WWP1 participates in the antioxidative response and mitochondrial function in WAT, but knockdown of WWP1 improves whole-body glucose metabolism.

Identification of WWP1 as an obesity-associated E3 ubiquitin ligase with a protective role against oxidative stress in adipocytes.

White adipose tissue (WAT) is not only the main tissue for energy storage but also an endocrine organ that secretes adipokines. Obesity is the most common metabolic disorder and is related to alterations in WAT characteristics, such as chronic inflammation and increasing oxidative stress. WW domain containing E3 ubiquitin protein ligase 1 (WWP1) is a HECT-type ubiquitin E3 ligase that has been implicated in various pathologies. In the present study, we found that WWP1 was upregulated in obese WAT in a p53-dependent manner. To investigate the functions of WWP1 in adipocytes, a proteome analysis of WWP1 overexpression (OE) and knockdown (KD) 3T3-L1 cells was performed. This analysis showed a positive correlation between WWP1 expression and the abundance of several antioxidative proteins. Thus, we measured reactive oxygen species (ROS) in WWP1 OE and KD cells. Consistent with the proteome results, WWP1 OE reduced ROS levels, whereas KD increased them. These findings indicate that WWP1 is an obesity-inducible E3 ubiquitin ligase that can protect against obesity-associated oxidative stress in WAT.