A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators.

Obesity and type 2 diabetes have reached pandemic proportion. ALDH2 (acetaldehyde dehydrogenase 2, mitochondrial) is the key metabolizing enzyme of acetaldehyde and other toxic aldehydes, such as 4-hydroxynonenal. A missense Glu504Lys mutation of the ALDH2 gene is prevalent in 560 million East Asians, resulting in reduced ALDH2 enzymatic activity. We find that male Aldh2 knock-in mice mimicking human Glu504Lys mutation were prone to develop diet-induced obesity, glucose intolerance, insulin resistance, and fatty liver due to reduced adaptive thermogenesis and energy expenditure. We find reduced activity of ALDH2 of the brown adipose tissue from the male Aldh2 homozygous knock-in mice. Proteomic analyses of the brown adipose tissue from the male Aldh2 knock-in mice identifies increased 4-hydroxynonenal-adducted proteins involved in mitochondrial fatty acid oxidation and electron transport chain, leading to markedly decreased fatty acid oxidation rate and mitochondrial respiration of brown adipose tissue, which is essential for adaptive thermogenesis and energy expenditure. AD-9308 is a water-soluble, potent, and highly selective ALDH2 activator. AD-9308 treatment ameliorates diet-induced obesity and fatty liver, and improves glucose homeostasis in both male Aldh2 wild-type and knock-in mice. Our data highlight the therapeutic potential of reducing toxic aldehyde levels by activating ALDH2 for metabolic diseases.

Role of spleen density in predicting postoperative complications in patients with acute mesenteric ischemia.

BACKGROUND: Acute mesenteric ischemia (AMI) is a life-threatening surgical emergency with a poor prognosis. This study assessed the association of diffuse reduction of spleen density (DROSD) with postoperative complications and identified risk factors for adverse outcomes in AMI patients after surgery. METHODS: Patients who were diagnosed with AMI and underwent surgical operations between April 2006 and July 2021 were enrolled. Spleen density was assessed using preoperative non-enhanced computed tomography. The lowest quartile of spleen density in all patients was regarded as the cutoff value for DROSD. Univariate and multivariate analyses were performed to determine the risk factors related to postoperative outcomes after surgery. RESULTS: According to the diagnostic cutoff, patients with a spleen density ≤49.07 HU were defined as DROSD. In a cohort of 97 patients, 34.0% developed complications within 30 days of surgery. The multivariate analysis illustrated that DROSD was an independent risk factor for prognostic outcomes in AMI patients after surgery. CONCLUSION: Patients with low spleen density were prone to postoperative complications. As an imaging method, preoperative assessment of spleen density is a novel predictor that can be used clinically to identify high-risk AMI patients with poor prognosis.

The psoas muscle density as a predictor of postoperative complications and 30-day mortality for acute mesenteric ischemia patients.

OBJECTIVE: Low muscle mass and quality is associated with poor surgical outcomes. Psoas muscle density (PMD)is a validated surrogate for muscle quality that can be easily measured from a clinical computed tomography (CT) scan. The objective of this study was to investigate the association between PMD and short-term postoperative outcomes in patients with acute mesenteric ischemia (AMI). METHODS: From April 2006 and September 2019, the clinical data of all patients who underwent surgical intervention with a preoperative diagnosis of AMI and had preoperative non-contrast CT images available were retrospectively reviewed. PMD was measured by CT at the third lumbar vertebra. The lowest quartile of PMD for men and women in all patients was used as sex-specific cut-off values for low PMD. Univariate and multivariate analyses evaluating risk factors of postoperative complications and 30-day mortality were performed. RESULTS: The cohort consisted of 88 patients with a mean age of 58.8 ± 16.2 years, of whom 21 (23.9%) patients had low PMD based on the diagnostic cut-off values (40.5 HU for men and 28.4 HU for women), 35 (39.8%) patients developed complications within 30 days of the operation, and 10 (11.3%) patients died within 30 days of surgery. Low PMD patients had a higher risk of postoperative complications and 30-day mortality than patients without low PMD patients. In a multivariate analysis, low PMD and low psoas muscle area (PMA) were independent predictors of postoperative complications. However, only low PMD remained an independent risk factor for 30-day mortality. CONCLUSIONS: Preoperative assessment of the PMD on CT can be a practical method for identifying AMI patients at risk for postoperative complications and 30-day mortality.

A Novel ALDH2 Activator AD-9308 Improves Diastolic and Systolic Myocardial Functions in Streptozotocin-Induced Diabetic Mice.

Diabetes mellitus has reached epidemic proportion worldwide. One of the diabetic complications is cardiomyopathy, characterized by early left ventricular (LV) diastolic dysfunction, followed by development of systolic dysfunction and ventricular dilation at a late stage. The pathogenesis is multifactorial, and there is no effective treatment yet. In recent years, 4-hydroxy-2-nonenal (4-HNE), a toxic aldehyde generated from lipid peroxidation, is implicated in the pathogenesis of cardiovascular diseases. Its high bioreactivity toward proteins results in cellular damage. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is the major enzyme that detoxifies 4-HNE. The development of small-molecule ALDH2 activator provides an opportunity for treating diabetic cardiomyopathy. This study found that AD-9308, a water-soluble andhighly selective ALDH2 activator, can improve LV diastolic and systolic functions, and wall remodeling in streptozotocin-induced diabetic mice. AD-9308 treatment dose-dependently lowered serum 4-HNE levels and 4-HNE protein adducts in cardiac tissue from diabetic mice, accompanied with ameliorated myocardial fibrosis, inflammation, and apoptosis. Improvements of mitochondrial functions, sarco/endoplasmic reticulumcalcium handling and autophagy regulation were also observed in diabetic mice with AD-9308 treatment. In conclusion, ADLH2 activation effectively ameliorated diabetic cardiomyopathy, which may be mediated through detoxification of 4-HNE. Our findings highlighted the therapeutic potential of ALDH2 activation for treating diabetic cardiomyopathy.

Role of Frailty and Comorbidity Status in Predicting Morbidity and Mortality in Patients with Acute Mesenteric Ischemia.

BACKGROUND: This study was performed to determine the association of frailty and comorbidity status with postoperative morbidity and mortality in patients with acute mesenteric ischemia (AMI). METHODS: Patients diagnosed with AMI between April 2006 and September 2019 were enrolled in this study. Frailty was evaluated by sarcopenia which was diagnosed by third lumbar vertebra psoas muscle area (PMA). Comorbidity status was evaluated by the Charlson Comorbidity Index (CCI) score. Univariate and multivariate analyses evaluating the risk factors for postoperative morbidity and mortality were performed. RESULTS: Of the 174 patients, 86 were managed conservatively and 88 underwent surgery. In surgically managed patients, 39.8% developed complications within 30 days of surgery. Ten patients died within 30 days of the operation. In the univariate analyses, white blood cell >10 g/L, low PMA, CCI score ≥2, and bowel resection were associated with postoperative complications. Multivariate analysis revealed that low PMA, CCI score ≥2, and bowel resection were independent predictors of postoperative complications. CONCLUSIONS: This study demonstrated that low PMA, CCI score ≥2, and bowel resection were independent risk factors for postoperative complications in patients with AMI. Preoperative assessment of frailty using PMA and the evaluation of comorbidity status using CCI may serve as helpful tools in preoperative risk assessment and should be integrated into scoring systems for surgically treated AMI.

The Use of the Angiosome Concept for Treating Infrapopliteal Critical Limb Ischemia through Interventional Therapy and Determining the Clinical Significance of Collateral Vessels.

BACKGROUND: The purpose of this study was to evaluate the clinical significance of the involvement of collateral vessels in interventional therapy based on the angiosome concept for infrapopliteal critical limb ischemia (CLI). METHODS: We enrolled 486 patients with unilateral infrapopliteal CLI (Rutherford Stage 5 or 6) treated at 2 hospitals from January 2005 to December 2014. Using the angiosome concept, the patients were categorized into 3 groups: the direct revascularization (DR) group, the indirect revascularization through collaterals (IR-tc) group, and the indirect revascularization without collaterals (IR-wc) group. The data from 1 year of follow-up after the initial surgery were analyzed for all 3 groups. RESULTS: During the 1-year follow-up, the unhealed ulcer rate of the IR-wc group was significantly higher than that of the DR group (83.4% vs. 31.7%, P < 0.001) and the IR-tc group (83.4% vs. 34.8%, P < 0.001). Furthermore, the limb salvage rate of the IR-wc group was significantly lower than that of the DR group (70.4% vs. 89.2%, P < 0.001) and the IR-tc group (70.4% vs. 85.4%, P = 0.0013). However, there were no differences in the unhealed ulcer rate or the limb salvage rate between the DR group and the IR-tc group (31.7% vs. 34.8%, P = 0.096 and 89.2% vs. 85.4%, P = 0.2834, respectively). In addition, within the IR-wc group, the unhealed ulcer rate of diabetic patients was higher than that of patients without diabetes (90.0% vs. 74.6%, P = 0.0116), but there was no difference in the limb salvage rate between diabetic and nondiabetic patients. No differences in the unhealed ulcer rate or the limb salvage rate were found between diabetic and nondiabetic patients in the other 2 groups. CONCLUSIONS: Following the angiosome model of perfusion for endovascular therapy, directly revascularizing the feeding artery and indirectly achieving revascularization through collaterals can effectively prompt the healing of ulcers and decrease the amputation rate in patients with infrapopliteal CLI. Collateral vessels play a crucial role in the treatment of ischemic foot.

Incidence and risk factors of early deep venous thrombosis after varicose vein surgery with routine use of a tourniquet.

INTRODUCTION: The incidence of early deep venous thrombosis (DVT) following varicose vein surgery (traditional open stripping) with routine use of a tourniquet remains unknown. MATERIALS AND METHODS: A retrospective analysis of all patients who underwent varicose vein surgery with a tourniquet in the authors' unit between 1 January 2012 and 30 November 2013 was undertaken. Cases of postoperative DVT were identified from the unit database, and re-assessments conducted 1, 3 and 6 months after the initial diagnosis were recorded from the outpatient department. RESULTS: Out of 1461 patients, 113 (7.7%) developed postoperative DVT. Nineteen (1.3%) patients had proximal DVT, and 94 (6.4%) patients had isolated distal DVT. The risk factors for postoperative DVT included old age (≥65 years), female sex and gastrocnemius vein dilation (GVD). GVD was found to be a significant independent risk factor for the occurrence of DVT, with an odds ratio of 2.437 (95% confidence interval 1.644-3.611). Five patients with distal DVT (5.7%) and eight patients with proximal DVT (44.4%) still exhibited a thrombus at 6-month follow-up, but with decreased size and at various stages of resolution. CONCLUSIONS: This study found a higher incidence of postoperative DVT (7.7%) with routine use of a tourniquet during varicose vein surgery than has been reported previously. Among the factors examined, GVD had the highest predictive power for postoperative DVT. Both distal and proximal DVT were associated with acceptable outcomes.

Femorofemoral bypass allowed limb preservation after late diagnosis of left common iliac artery thrombosis due to blunt trauma: A case report.

OBJECTIVE: Acute common iliac artery occlusion which results from blunt abdominal trauma is rare and potentially leads to a late diagnosis. METHODS: We report a case of a 58-year-old patient who suffered a late diagnosed acute left common iliac artery occlusion secondary to abdominal trauma. An emergency exploratory laparotomy was performed to stop intra-abdominal bleeding, while his left limb ischemia was not noticed until 32 h later and femorofemoral bypass was then successfully performed for revascularization. Compartment syndrome was observed postoperatively, and fasciotomy was performed promptly. The wound was temporarily covered with Vaccum Sealing Drainage due to high skin tension. Patient underwent skin-grafting after leg swelling subsided. RESULTS: The follow-up turned out that these managements were valid in the preservation of the limb viability. CONCLUSIONS: This case highlights the prudent recognition of the acute lower extremity ischemia in the abdominal trauma and immediate remedy for acute iliac artery occlusion after a late diagnosis.