Measurement of endothelial function and its clinical utility for cardiovascular risk

Over the past two decades, the central role of the endothelium in the initiation, progression, and clinical sequelae of atherosclerosis has been increasingly recognized. Assessment of the pathobiology of the endothelium and its ability to act as a potential therapeutic target remains an area of active research interest. Whilst endothelial function has been shown to be a marker for risk of cardiovascular events in high-risk groups, there remains considerable debate about the most appropriate way to assess this. We discuss the different clinical methods to assess endothelial function, focusing on flow-mediated dilatation (FMD) of the brachial artery, highlighting the importance of using a standardized methodology, as well as discussing the clinical limitations of using FMD in individuals

A study of prevalence of peripheral arterial disease in type 2 diabetes mellitus using ankle-brachial index and its correlation with coronary artery disease and its risk factors

Background: Peripheral arterial disease (PAD) is one of the macrovascular complications of type 2 diabetes mellitus (T2DM). There is significant difference in the reported prevalence of PAD and its associated risk factors between Indian and Western studies. The purpose of this study was to examine the PAD complicating T2DM, in particular the influence of PAD on the risk of CAD.Methods: Randomly selected 100 T2DM patients presented to Guru Nanak Dev hospital were included. In addition to a detailed history and physical examination, anthropometric parameters like body mass index was measured. CAD in patients was diagnosed by a history of angina, ECG changes, any past history of CAD or any treatment taken for CAD. Ankle brachial index (ABI) was measured. Data was collected systematically and analyzed according to the standard statistical methods.Results: The prevalence of PAD was 15%. CAD was present in 31%. PAD was found to be significantly correlated with age, duration of diabetes, smoking, systolic blood pressure, diastolic blood pressure, prevalence of BMI >25 kg/m2, HbA1c and serum HDL ≤40 mg%. Old age, high HbA1c level, and dyslipidaemia were found to be significant independent predictors of CAD.Conclusions: Using ABI authors found evidence of PAD in 15% patients of T2DM. The prevalence of CAD was higher in patients with PAD. So, there is definite and strong correlation between PAD and CAD. Thus, the early diagnosis of PAD should alert the clinician to a high probability of underlying CAD

Role of Nutrition in Alcoholic Liver Disease: Summary of the Symposium at the ESBRA 2017 Congress.

The symposium, "Role of Nutrition in Alcoholic Liver Disease", was held at the European Society for Biomedical Research on Alcoholism Congress on 9 October 2017 in Crete, Greece. The goal of the symposium was to highlight recent advances and developments in the field of alcohol and nutrition. The symposium was focused on experimental and clinical aspects in relation to the role of different types of dietary nutrients and malnutrition in the pathogenesis of alcoholic liver disease (ALD). The following is a summary of key research presented at this session. The speakers discussed the role of dietary fats and carbohydrates in the development and progression of alcohol-induced multi-organ pathology in animal models of ALD, analyzed novel nutrition-related therapeutics (specifically, betaine and zinc) in the treatment of ALD, and addressed clinical relevance of malnutrition and nutrition support in ALD. This summary of the symposium will benefit junior and senior faculty currently investigating alcohol-induced organ pathology as well as undergraduate, graduate, and post-graduate students and fellows

Phosphatidylethanolamine Methyltransferase Deficiency Exacerbates Acute Alcohol-Induced Liver Injury

Alcohol-associated liver disease (ALD) is a global burden of healthcare and remains a major cause of morbidity and mortality worldwide. ALD includes a spectrum of injuries that progresses from hepatic steatosis, alcoholic hepatitis to alcohol-associated cirrhosis and even hepatocellular carcinoma with continued alcohol misuse. The development of ALD depends on several factors, including genetics. The liver enzyme phosphatidylethanolamine methyltransferase (PEMT) catalyzes three sequential methyl transfers to phosphatidylethanolamine, generating phosphatidylcholine (PC). The PC generated with PEMT-mediated catalysis is preferentially used in very-low-density-lipoprotein (VLDL) assembly and is required for its normal biogenesis and secretion (1-3). Alcohol affects the methylation potential and impairs PEMT activity, which by inhibiting VLDL synthesis contributes to the development of hepatic steatosis. Polymorphisms in the human PEMT gene causing loss of function confer susceptibility to metabolic-associated steatohepatitis. Based on these considerations, we hypothesized that PEMT deletion would exacerbate alcohol-induced liver injury. Animal Handling and Diet: Male and female wildtype (WT) and PEMT knock out (KO) mice (12 weeks of age) were subjected to ethanol binge feeding model. The animals were gavaged with maltose dextrin or ethanol (5g/Kg BW) twice, 12 hours apart. The mice were euthanized eight hours after the second dose, where the blood and liver were collected for the following analyses: AST and ALT levels: Serum AST and ALT were analyzed using a VITROS 5.1 FS Chemistry System. Hepatic histopathology: Neutral-buffered formalin fixed liver sections stained with hematoxylin & eosin (H & E) and picrosirius red were imaged using a Keyence BZ-810 microscope. HPLC Analysis: Liver tissues were homogenized in 0.5N perchloric acid and subjected to HPLC analysis to determine S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) levels (3,4) The SAM:SAH ratio, or methylation index, was calculated, as detailed (3,4). Triglyceride Quantification: Lipids were extracted by Folch method (6) and triglyceride levels were quantified using the Thermo DNA Kit (3,4). Enzymatic Activity: Lysosomal acid lipase and proteasome activities were determined in liver homogenates, as detailed (7) Statistical Analyses: Data are expressed as mean values ± standard error (SE). Values not sharing a common subscript letter are statistically different, p \u3c 0.05. We found deletion of PEMT exacerbates acute alcohol-induced liver injury in both males and females as evidenced by: •Increased AST and ALT levels •Increased fat accumulation by histopathological assessment •Decreased SAM levels causing a reduction in the methylation potential •Increased hepatic triglycerides •Decreased lysosomal acid lipase activity •Decreased proteasome activityhttps://digitalcommons.unmc.edu/surp2022/1036/thumbnail.jp

Phosphatidylethanolamine N-methyltransferase (PEMT) Knockout Mice Exhibit Worse Alcohol-Induced Liver Injury than Wildtype Mice

Phosphatidylethanolamine N-methyltransferase (PEMT) is an enzyme that catalyzes the successive transfer of 3 methyl groups from S-adenosylmethionine (SAM) to phosphatidylethanolamine (PE) to generate phosphatidylcholine (PC). PC is vital for exporting fat out of the liver, ultimately preventing hepatic steatosis. Alcohol also induces steatosis partly through damaging this pathway, so the purpose of this study was to investigate the relationship between alcohol and PEMT in the liver. PEMT -/- (KO) and wild-type (WT) mice were subjected to a chronic + binge alcohol treatment, and both serum and liver samples were analyzed. Triglyceride quantification, SAM and S-adenosylhomocysteine (SAH) levels, and histological analyses were performed on liver samples, while ALT levels were determined from serum samples. Our study showed that ethanol-fed PEMT KO mice exhibited worse liver injury compared to other treatment groups. Our results show increased triglyceride levels, increased ALT levels, decreased SAM:SAH ratio, and increased liver to body weight ratio. From these findings, we conclude that additional liver damage is observed with the combination of alcohol feeding and absence of the PEMT enzyme. The mechanism by which these two factors affect one another is a key area of future study.https://digitalcommons.unmc.edu/surp2021/1016/thumbnail.jp

Isoaspartate, Carbamoyl phosphate synthase-1, and carbonic anhydrase-III as biomarkers of liver injury

We had previously shown that alcohol consumption can induce cellular isoaspartate protein damage via an impairment of the activity of protein isoaspartyl methyltransferase (PIMT), an enzyme that triggers repair of isoaspartate protein damage. To further investigate the mechanism of isoaspartate accumulation, hepatocytes cultured from control or 4-week ethanol-fed rats were incubated in vitro with tubercidin or adenosine. Both these agents, known to elevate intracellular S-adenosylhomocysteine levels, increased cellular isoaspartate damage over that recorded following ethanol consumption in vivo. Increased isoaspartate damage was attenuated by treatment with betaine. To characterize isoaspartate-damaged proteins that accumulate after ethanol administration, rat liver cytosolic proteins were methylated using exogenous PIMT and 3H-S- adenosylmethionine and proteins resolved by gel electrophoresis. Three major protein bands of ~75-80 kDa, ~95-100 kDa, and ~155-160 kDa were identified by autoradiography. Column chromatography used to enrich isoaspartate-damaged proteins indicated that damaged proteins from ethanol-fed rats were similar to those that accrued in the livers of PIMT knockout (KO) mice. Carbamoyl phosphate synthase-1 (CPS-1) was partially purified and identified as the ~160kDa protein target of PIMT in ethanol-fed rats and in PIMT KO mice. Analysis of the liver proteome of 4-week ethanol-fed rats and PIMT KO mice demonstrated elevated cytosolic CPS-1 and betaine homocysteine S-methyltransferase-1 when compared to their respective controls, and a significant reduction of carbonic anhydrase-III (CA-III) evident only in ethanol-fed rats. Ethanol feeding of rats for 8 weeks resulted in a larger (~2.3-fold) increase in CPS-1 levels compared to 4- week ethanol feeding indicating that CPS-1 accumulation correlated with the duration of ethanol consumption. Collectively, our results suggest that elevated isoaspartate and CPS-1, and reduced CA-III levels could serve as biomarkers of hepatocellular injury

Case report:peri-device leakage after percutaneous left atrial appendage occlusion: plug, clip, or amputate?

BACKGROUND: Although peri-device leakage is frequently observed after left atrial appendage occlusion (LAAO), there is no consensus on the optimal management strategy. It is unknown whether additional plugging should be preferred over surgical exclusion of the LAA, as experience with additional plugging is limited. CASE SUMMARY: In this case report, we demonstrate the clinical implications of additional plugging and surgical exclusion in a 65-year-old male patient with peri-device leakage and recurrent thromboembolic events. After the recurrence of paroxysmal atrial fibrillation (AF) and a transient ischaemic attack despite adequate anticoagulation, the patient was opted for re-do pulmonary vein isolation and LAAO with a Watchman device. Due to multiple ischaemic strokes and recurrent AF in combination with significant peri-device leakage, additional plugging with a second device was performed. Post-procedurally, the patient had another ischaemic stroke and persisting peri-device leakage was observed during follow-up. Due to progressive symptoms of AF and patient’s preference to discontinue DOAC, he underwent a Cox MAZE IV procedure, including amputation of the LAA with both devices. Within six months after surgery, the patient experienced two more ischaemic events. In the following two years, the patient remained free of any cerebrovascular accidents or recurrence of AF. DISCUSSION: Additional plugging of peri-device leakage is not always successful in stroke prevention. In combination with recurrent AF, progressive symptoms, contraindication for oral anticoagulation, and patient’s preference, surgical LAA exclusion could be preferred over additional plugging