The Role of Heparin in Postural Orthostatic Tachycardia Syndrome and Other Post-Acute Sequelae of COVID-19.

The therapeutic management and short-term consequences of the coronavirus disease 2019 (COVID-19) are well known. However, COVID-19 post-acute sequelae are less known and represent a public health problem worldwide. Patients with COVID-19 who present post-acute sequelae may display immune dysregulation, a procoagulant state, and persistent microvascular endotheliopathy that could trigger microvascular thrombosis. These elements have also been implicated in the physiopathology of postural orthostatic tachycardia syndrome, a frequent sequela in post-COVID-19 patients. These mechanisms, directly associated with post-acute sequelae, might determine the thrombotic consequences of COVID-19 and the need for early anticoagulation therapy. In this context, heparin has several potential benefits, including immunomodulatory, anticoagulant, antiviral, pro-endothelial, and vascular effects, that could be helpful in the treatment of COVID-19 post-acute sequelae. In this article, we review the evidence surrounding the post-acute sequelae of COVID-19 and the potential benefits of the use of heparin, with a special focus on the treatment of postural orthostatic tachycardia syndrome.

Index and Repeat Ablation for Atrial Fibrillation in Older versus Younger Patients: A Propensity-Score Matching Analysis.

Catheter ablation is a well-established rhythm control therapy in atrial fibrillation (AF). Although the prevalence of AF increases dramatically with age, the prognosis and safety profile of index and repeat ablation procedures remain unclear in the older population. The primary endpoint of this study was to assess the arrhythmia recurrence, reablation and complication rates in older patients. Secondary endpoints were the identification of independent predictors of arrhythmia recurrence and reablation, including information on pulmonary vein (PV) reconnection and other atrial foci. Older (n=129, ≥70 years) and younger (n=129, <70 years) patients were compared using a propensity-score matching analysis based on age, gender, obesity, hypertension, dyslipidemia, diabetes mellitus, dilated left atrium, severe obstructive sleep apnea, cardiac disease, left systolic ventricular function, AF pattern and ablation technique. Arrhythmia recurrence and reablation were evaluated in both groups using a Cox regression analysis in order to identify predictors. During a 30-month follow-up period, there were no significant differences between older and younger patients in the arrhythmia-free survival (65.1% and 59.7%; log-rank test p=0.403) and complication (10.1% and 10.9%; p>0.999) rates after the index ablation. However, the reablation rate was significantly different (46.7% and 69.2%; p<0.05, respectively). In those patients who underwent reablation procedure (redo subgroups), there were no differences in the incidence of PV reconnection (38.1% redo-older and 27.8% redo-younger patients; p=0.556). However, the redo-older patients had lower reconnected PVs per patient (p<0.01) and lower atrial foci (2.3 and 3.7; p<0.01) than the redo-younger patients. A further important finding was that age was not an independent predictor of arrhythmia recurrence or reablation. Our data reveal that the AF index ablation in older patients had a similar efficacy and safety profile to younger patients. Therefore, age alone must not be considered a prognostic factor for AF ablation but the presence of limiting factors such as frailty and multiple comorbidities.

Postural orthostatic tachycardia syndrome and other related dysautonomic disorders after SARS-CoV-2 infection and after COVID-19 messenger RNA vaccination.

The COVID-19 pandemic has caused a challenge for our society due to the post-acute sequelae of the disease. Persistent symptoms and long-term multiorgan complications, known as post-acute COVID-19 syndrome, can occur beyond 4 weeks from the onset of the COVID-19 infection. Postural orthostatic tachycardia syndrome (POTS) is considered a variety of dysautonomia, which is characterized by chronic symptoms that occur with standing and a sustained increase in heart rate, without orthostatic hypotension. POTS can lead to debilitating symptoms, significant disability, and impaired quality of life. In this narrative review, the etiopathogenic basis, epidemiology, clinical manifestations, diagnosis, treatment, prognosis, and socioeconomic impact of POTS, as well as other related dysautonomic disorders, after COVID-19 infection and SARS-CoV-2 postvaccination, were discussed. After a search conducted in March 2023, a total of 89 relevant articles were selected from the PubMed, Google Scholar, and Web of Science databases. The review highlights the importance of recognizing and managing POTS after COVID-19 infection and vaccination, and the approach to autonomic disorders should be known by all specialists in different medical areas. The diagnosis of POTS requires a comprehensive clinical assessment, including a detailed medical history, physical examination, orthostatic vital signs, and autonomic function tests. The treatment of POTS after COVID-19 infection or vaccination is mainly focused on lifestyle modifications, such as increased fluid and salt intake, exercise, and graduated compression stockings. Pharmacotherapy, such as beta-blockers, fludrocortisone, midodrine, and ivabradine, may also be used in selected cases. Further research is needed to understand the underlying mechanisms, risk factors, and optimal treatment strategies for this complication.

Treatment with a novel oleic-acid-dihydroxyamphetamine conjugation ameliorates non-alcoholic fatty liver disease in obese Zucker rats.

Fatty liver disease is one of the main hepatic complications associated with obesity. To date, there are no effective treatments for this pathology apart from the use of classical fibrates. In this study, we have characterized the in vivo effects of a novel conjugation of oleic acid with an amphetamine derivative (OLHHA) in an animal model of genetic obesity. Lean and obese Zucker rats received a daily intraperitoneal administration of OLHHA (5 mg kg(-1)) for 15 days. Plasma and liver samples were collected for the biochemical and molecular biological analyses, including both immunohistochemical and histological studies. The expression of key enzymes and proteins that are involved in lipid metabolism and energy homeostasis was evaluated in the liver samples. The potential of OLHHA to produce adverse drug reactions or toxicity was also evaluated through the monitoring of interactions with hERG channel and liver cytochrome. We found that OLHHA is a drug with a safe pharmacological profile. Treatment for 15 days with OLHHA reduced the liver fat content and plasma triglyceride levels, and this was accompanied by a general improvement in the profile of plasma parameters related to liver damage in the obese rats. A decrease in fat accumulation in the liver was confirmed using histological staining. Additionally, OLHHA was observed to exert anti-apoptotic effects. This hepatoprotective activity in obese rats was associated with an increase in the mRNA and protein expression of the cannabinoid type 1 receptor and a decrease in the expression of the lipogenic enzymes FAS and HMGCR primarily. However, changes in the mRNA expression of certain proteins were not associated with changes in the protein expression (i.e. L-FABP and INSIG2). The present results demonstrate that OLHHA is a potential anti-steatotic drug that ameliorates the obesity-associated fatty liver and suggest the potential use of this new drug for the treatment of non-alcoholic fatty liver disease.

Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high-fat-diet-induced steatosis in IL-6-deficient mice.

Interleukin-6 (IL-6) has emerged as an important mediator of fatty acid metabolism with paradoxical effects in the liver. Administration of IL-6 has been reported to confer protection against steatosis, but plasma and tissue IL-6 concentrations are elevated in chronic liver diseases, including fatty liver diseases associated with obesity and alcoholic ingestion. In this study, we further investigated the role of IL-6 on steatosis induced through a high-fat diet (HFD) in wild-type (WT) and IL-6-deficient (IL-6(-/-)) mice. Additionally, HFD-fed IL-6(-/-) mice were also chronically treated with recombinant IL-6 (rIL-6). Obesity in WT mice fed a HFD associated with elevated serum IL-6 levels, fatty liver, upregulation of carnitine palmitoyltransferase 1 (CPT1) and signal transducer and activator of transcription-3 (STAT3), increased AMP kinase phosphorylation (p-AMPK), and downregulation of the hepatic lipogenic enzymes fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1). The HFD-fed IL-6(-/-) mice showed severe steatosis, no changes in CPT1 levels or AMPK activity, no increase in STAT3 amounts, inactivated STAT3, and marked downregulation of the expression of acetyl-CoA carboxylase (ACCα/ß), FAS and SCD1. The IL-6 chronic replacement in HFD-fed IL-6 -/-: mice restored hepatic STAT3 and AMPK activation but also increased the expression of the lipogenic enzymes ACCα/ß, FAS and SCD1. Furthermore, rIL-6 administration was associated with aggravated steatosis and elevated fat content in the liver. We conclude that, in the context of HFD-induced obesity, the administration of rIL-6 might contribute to the aggravation of fatty liver disease through increasing lipogenesis.

Computational and biological evaluation of N-octadecyl-N'-propylsulfamide, a selective PPARα agonist structurally related to N-acylethanolamines.

To further understand the pharmacological properties of N-oleoylethanolamine (OEA), a naturally occurring lipid that activates peroxisome proliferator-activated receptor alpha (PPARα), we designed sulfamoyl analogs based on its structure. Among the compounds tested, N-octadecyl-N'-propylsulfamide (CC7) was selected for functional comparison with OEA. The performed studies include the following computational and biological approaches: 1) molecular docking analyses; 2) molecular biology studies with PPARα; 3) pharmacological studies on feeding behavior and visceral analgesia. For the docking studies, we compared OEA and CC7 data with crystallization data obtained with the reference PPARα agonist GW409544. OEA and CC7 interacted with the ligand-binding domain of PPARα in a similar manner to GW409544. Both compounds produced similar transcriptional activation by in vitro assays, including the GST pull-down assay and reporter gene analysis. In addition, CC7 and OEA induced the mRNA expression of CPT1a in HpeG2 cells through PPARα and the induction was avoided with PPARα-specific siRNA. In vivo studies in rats showed that OEA and CC7 had anorectic and antiobesity activity and induced both lipopenia and decreases in hepatic fat content. However, different effects were observed when measuring visceral pain; OEA produced visceral analgesia whereas CC7 showed no effects. These results suggest that OEA activity on the PPARα receptor (e.g., lipid metabolism and feeding behavior) may be dissociated from other actions at alternative targets (e.g., pain) because other non cannabimimetic ligands that interact with PPARα, such as CC7, do not reproduce the full spectrum of the pharmacological activity of OEA. These results provide new opportunities for the development of specific PPARα-activating drugs focused on sulfamide derivatives with a long alkyl chain for the treatment of metabolic dysfunction.

CB1 blockade potentiates down-regulation of lipogenic gene expression in perirenal adipose tissue in high carbohydrate diet-induced obesity.

De novo lipogenesis and hypercaloric diets are thought to contribute to increased fat mass, particularly in abdominal fat depots. CB1 is highly expressed in adipose tissue, and CB1-mediated signalling is associated with stimulation of lipogenesis and diet-induced obesity, though its contribution to increasing fat deposition in adipose tissue is controversial. Lipogenesis is regulated by transcription factors such as liver X receptor (LXR), sterol-response element binding protein (SREBP) and carbohydrate-responsive-element-binding protein (ChREBP). We evaluated the role of CB1 in the gene expression of these factors and their target genes in relation to lipogenesis in the perirenal adipose tissue (PrAT) of rats fed a high-carbohydrate diet (HCHD) or a high-fat diet (HFD). Both obesity models showed an up-regulated gene expression of CB1 and Lxrα in this adipose pad. The Srebf-1 and ChREBP gene expressions were down-regulated in HFD but not in HCHD. The expression of their target genes encoding for lipogenic enzymes showed a decrease in diet-induced obesity and was particularly dramatic in HFD. In HCHD, CB1 blockade by AM251 reduced the Srebf-1 and ChREBP expression and totally abrogated the remnant gene expression of their target lipogenic enzymes. The phosphorylated form of the extracellular signal-regulated kinase (ERK-p), which participates in the CB1-mediated signalling pathway, was markedly present in the PrAT of obese rats. ERK-p was drastically repressed by AM251 indicating that CB1 is actually functional in PrAT of obese animals, though its activation loses the ability to stimulate lipogenesis in PrAT of obese rats. Even so, the remnant expression levels of lipogenic transcription factors found in HCHD-fed rats are still dependent on CB1 activity. Hence, in HCHD-induced obesity, CB1 blockade may help to further potentiate the reduction of lipogenesis in PrAT by means of inducing down-regulation of the ChREBP and Srebf-1 gene expression, and consequently in the expression of lipogenic enzymes.

Evaluation of plasma-free endocannabinoids and their congeners in abstinent cocaine addicts seeking outpatient treatment: impact of psychiatric co-morbidity.

Cocaine is associated with serious health problems including psychiatric co-morbidity. There is a need for the identification of biomarkers for the stratification of cocaine-addicted subjects. Several studies have evaluated circulating endocannabinoid-related lipids as biomarkers of inflammatory, metabolic and mental disorders. However, little is known in substance use disorders. This study characterizes both free N-acyl-ethanolamines (NAEs) and 2-acyl-glycerols in abstinent cocaine addicts from outpatient treatment programs who were diagnosed with cocaine use disorder (CUD; n = 88), and age-/gender-/body mass-matched healthy control volunteers (n = 46). Substance and mental disorders that commonly occur with substance abuse were assessed by the semi-structured interview 'Psychiatric Research Interview for Substance and Mental Diseases' according to the 'Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision' (DSM-IV-TR) and plasma-free acyl derivatives were quantified by a liquid chromatography-tandem mass spectrometry system. The results indicate that plasma acyl derivatives are altered in abstinent cocaine-addicted subjects with CUD (CUD subjects). While NAEs were found to be increased, 2-acyl-glycerols were decreased in CUD subjects compared with controls. Multivariate predictive models based on these lipids as explanatory variables were developed to distinguish CUD subjects from controls providing high discriminatory power. However, these alterations were not influenced by the DSM-IV-TR criteria for cocaine abuse and dependence as cocaine trait severity measure. In contrast, we observed that some free acyl derivatives in CUD subjects were found to be affected by the diagnosis of some co-morbid psychiatric disorders. Thus, we found that the monounsaturated NAEs were significantly elevated in CUD subjects diagnosed with mood [N-oleoyl-ethanolamine and N-palmitoleoyl-ethanolamine (POEA)] and anxiety (POEA) disorders compared with non-co-morbid CUD subjects. Interestingly, the coexistence of alcohol use disorders did not influence the circulating levels of these free acyl derivatives. In summary, we have identified plasma-free acyl derivatives that might serve as reliable biomarkers for CUD. Furthermore, we found that monounsaturated NAE levels are also enhanced by co-morbid mood and anxiety disorders in cocaine addicts. These findings open the way for the development of new strategies for cocaine addiction diagnosis and treatment.

IL-6 cooperates with peroxisome proliferator-activated receptor-α-ligands to induce liver fatty acid binding protein (LFABP) up-regulation.

BACKGROUND: LFABP plays a critical role in the uptake and intracellular transport of fatty acids (FA) and other peroxisome proliferator-activated receptor alpha (PPARα) ligands. PPARα activation by PPARα ligands bound to LFABP results in gene expression of FA oxidation enzymes and de novo LFABP. The cytokine IL-6 is involved in regulating liver lipid oxidation. AIMS: To study the ability of IL-6 to modulate the expression of the LFABP in hepatocytes. METHODS: HepG2 and mouse primary hepatocytes were used to test LFABP mRNA and protein expression after IL-6 and PPARα-ligand treatments. Mice lacking IL-6 and wild-type C57Bl/6 were subjected to a fasting/re-feeding cycle to monitor hepatic LFABP mRNA kinetics after food intake. RESULTS: In hepatocyte cultures, IL-6 treatment stimulated a LFABP mRNA sustained expression. Combined treatment of IL-6 plus PPARα ligands further enhanced LFABP gene and protein expression. In contrast, pretreatment with the PPARα-antagonist GW-6471 prevented the up-regulation of LFABP mRNA induced by IL-6 in the late phase of LFABP kinetics. Furthermore, the up-regulation of LFABP mRNA observed in the liver of wild-type mice 8 h after re-feeding was absent in mice lacking IL-6. CONCLUSIONS: IL-6 induces LFABP kinetics in hepatocytes and is partially dependent on PPARα. The maximum increase in LFABP expression occurs when the stimulation with IL-6 and PPARα-ligands takes place simultaneously. The in vivo results indicate a postprandial regulation of LFABP that correlates with the presence of IL-6. These effects may have important implications in the postprandial increase in FA uptake and intracellular trafficking in the liver.

Elaidyl-sulfamide, an oleoylethanolamide-modelled PPARα agonist, reduces body weight gain and plasma cholesterol in rats.

We have modelled elaidyl-sulfamide (ES), a sulfamoyl analogue of oleoylethanolamide (OEA). ES is a lipid mediator of satiety that works through the peroxisome proliferator-activated receptor alpha (PPARα). We have characterised the pharmacological profile of ES (0.3-3 mg/kg body weight) by means of in silico molecular docking to the PPARα receptor, in vitro transcription through PPARα, and in vitro and in vivo administration to obese rats. ES interacts with the binding site of PPARα in a similar way as OEA does, is capable of activating PPARα and also reduces feeding in a dose-dependent manner when administered to food-deprived rats. When ES was given to obese male rats for 7 days, it reduced feeding and weight gain, lowered plasma cholesterol and reduced the plasmatic activity of transaminases, indicating a clear improvement of hepatic function. This pharmacological profile is associated with the modulation of both cholesterol and lipid metabolism regulatory genes, including the sterol response element-binding proteins SREBF1 and SREBF2, and their regulatory proteins INSIG1 and INSIG2, in liver and white adipose tissues. ES treatment induced the expression of thermogenic regulatory genes, including the uncoupling proteins UCP1, UCP2 and UCP3 in brown adipose tissue and UCP3 in white adipose tissue. However, its chronic administration resulted in hyperglycaemia and insulin resistance, which represent a constraint for its potential clinical development.

Adiponectin promoter activator NP-1 reduces body weight and hepatic steatosis in high-fat diet-fed animals.

Enhancement of adiponectin level has been shown to have beneficial effects, including antiobesity, antidiabetic, and hepatoprotective effects. This evidence supports the therapeutic utility of adiponectin in complicated obesity. The present study characterized the in vivo effects of sustained adiponectin release by NP-1, a new class of thiazol derivative that increases adiponectin levels. Acute administration of NP-1 reduced feeding, increased plasma adiponectin, and improved insulin sensitivity without inducing malaise, as revealed by conditioned taste aversion studies. Short-term (7 days) treatment with NP-1 also reduced feeding and body weight gain and increased phosphorylation of AMPK in muscle, a main intracellular effector of adiponectin. NP-1 was also evaluated in diet-induced obesity, and adult male Wistar rats were fed two different types of diet: a standard high-carbohydrate/low-fat diet (SD) and a high-fat diet (HFD). Once obesity was established, animals were treated daily with NP-1 (5 mg/kg) for 14 consecutive days. Chronic NP-1 induced body weight loss and reduction of food intake and resulted in both a marked decrease in liver steatosis and an improvement of biochemical indexes of liver damage in HFD-fed rats. However, a marked induction of tolerance in adiponectin gene transcription and release was observed after chronic NP-1 with respect to the acute actions of this drug. The present results support the role of adiponectin signaling in diet-induced obesity and set in place a potential use of compounds able to induce adiponectin release for the treatment of obesity and nonalcoholic fatty liver, with the limits imposed by the induction of pharmacological tolerance.

Synthesis of fatty acid amides of catechol metabolites that exhibit antiobesity properties.

A series of fatty acid amides of 3,4-methylenedioxymethamphetamine (MDMA) catechol metabolites were synthesized in order to evaluate their biological activities. Upon administration, all synthesized compounds resulted in negative modulation of food intake in rats. The most active compounds have affinity for the CB(1) receptor and/or PPAR-α; part of their biological activity may be caused by these double interactions.

Social network of PESCA (Open Source Platform for eHealth).

Information and Communication Technologies (ICTs) are revolutionizing how healthcare systems deliver top-quality care to citizens. In this way, Open Source Software (OSS) has demonstrated to be an important strategy to spread ICTs use. Several human and technological barriers in adopting OSS for healthcare have been identified. Human barriers include user acceptance, limited support, technical skillfulness, awareness, resistance to change, etc., while Technological barriers embrace need for open standards, heterogeneous OSS developed without normalization and metrics, lack of initiatives to evaluate existing health OSS and need for quality control and functional validation. The goals of PESCA project are to create a platform of interoperable modules to evaluate, classify and validate good practices in health OSS. Furthermore, a normalization platform will provide interoperable solutions in the fields of healthcare services, health surveillance, health literature, and health education, knowledge and research. Within the platform, the first goal to achieve is the setup of the collaborative work infrastructure. The platform is being organized as a Social Network which works to evaluate five scopes of every existing open source tools for eHealth: Open Source Software, Quality, Pedagogical, Security and privacy and Internationalization/I18N. In the meantime, the knowledge collected from the networking will configure a Good Practice Repository on eHealth promoting the effective use of ICT on behalf of the citizen's health.