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PloS One 2022Cirrhosis causes alterations in the cardiovascular and autonomic nervous systems and leads to cirrhotic cardiomyopathy (CCM). CCM is defined as cardiac dysfunction...
BACKGROUND
Cirrhosis causes alterations in the cardiovascular and autonomic nervous systems and leads to cirrhotic cardiomyopathy (CCM). CCM is defined as cardiac dysfunction characterized by an impaired systolic responsiveness to stress or exercise, and/or impaired diastolic function, as well as electrophysiological abnormalities, including chronotropic incompetence (CI), in the absence of other known cardiac disease. CI is a common feature of autonomic neuropathy in cirrhosis. The aim of the study is to assess the role of cardiac exercise stress test in the diagnosis of CCM.
METHODS
The analysis included 160 end-stage liver disease (ESLD) patients who underwent a cardiac exercise stress test prior to the orthotopic liver transplantation. CI was defined as the inability to achieve the heart rate reserve (HRR). Pertaining to the therapy with beta-blockers: 80% of HRR was achieved in patients not taking beta-blockers and 62% in patients taking beta-blockers.
RESULTS
In the analyzed population, 68.8% of patients met the criteria for CI. CI was more frequent in the more severe ESLD (with a higher MELD score and in a higher Child-Pugh class). In comparison to the viral hepatitis and other etiologies of ESLD, patients with alcoholic cirrhosis had a significantly lower rest heart rate (HR), lower maximal HR, lower median achieved percentage of maximal predicted HR (MPHR), a smaller percentage of patients achieved ≥ 85% of MPHR and a lower heart rate reserve. No significant relationship between the survival of OLT recipients and presence of chronotropic incompetence regarding to class of Child-Pugh scale, MELD score and etiology of ESLD were found.
CONCLUSIONS
The prevalence of CI is higher among liver transplant candidates than previously described. The altered chronotropic response may differ in regard to the severity of liver disease correlating with both the Child-Pugh and MELD scores, however CI does not seem to influence the long-term survival post OLT. Exercise stress test is a reliable, safe and useful tool for the diagnosis of CCM in liver transplant candidates and should be included in the standard cardiovascular assessment prior to OLT.
Topics: Adrenergic beta-Antagonists; End Stage Liver Disease; Exercise Test; Heart Rate; Humans; Liver Cirrhosis
PubMed: 35913923
DOI: 10.1371/journal.pone.0270784 -
Neuroscience Letters Sep 2021Complex Regional Pain Syndrome (CRPS) is a musculoskeletal pain condition that often develops after limb injury and/or immobilization. Although the exact mechanisms...
Complex Regional Pain Syndrome (CRPS) is a musculoskeletal pain condition that often develops after limb injury and/or immobilization. Although the exact mechanisms underlying CRPS are unknown, the syndrome is associated with central and autonomic nervous system dysregulation and peripheral hyperalgesia symptoms. These symptoms also manifest in alcoholic neuropathy, suggesting that the two conditions may be pathophysiologically accretive. Interestingly, people assigned female at birth (AFAB) appear to be more sensitive to both CRPS and alcoholic neuropathy. To better understand the biobehavioral mechanisms underlying these conditions, we investigated a model of combined CRPS and alcoholic neuropathy in female rats. Animals were pair-fed either a Lieber-DeCarli alcohol liquid diet or a control diet for ten weeks. CRPS was modeled via unilateral hind limb cast immobilization for seven days, allowing for the other limb to serve as a within-subject control for hyperalgesia measures. To investigate the role of circulating ovarian hormones on pain-related behaviors, half of the animals underwent ovariectomy (OVX). Using the von Frey procedure to record mechanical paw withdrawal thresholds, we found that cast immobilization and chronic alcohol drinking separately and additively produced mechanical hyperalgesia observed 3 days after cast removal. We then examined neuroadaptations in AMPA GluR1 and NMDA NR1 glutamate channel subunits, extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB) in bilateral motor and cingulate cortex across all groups. Consistent with increased pain-related behavior, chronic alcohol drinking increased GluR1, NR1, ERK, and CREB phosphorylation in the cingulate cortex. OVX did not alter any of the observed effects. Our results suggest accretive relationships between CRPS and alcoholic neuropathy symptoms and point to novel therapeutic targets for these conditions.
Topics: Alcohol Drinking; Animals; Central Nervous System Stimulants; Cyclic AMP Response Element-Binding Protein; Ethanol; Female; Gyrus Cinguli; Hindlimb Suspension; Hyperalgesia; MAP Kinase Signaling System; Motor Cortex; Nociception; Rats; Rats, Inbred F344; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate
PubMed: 34280506
DOI: 10.1016/j.neulet.2021.136119 -
Trends in Endocrinology and Metabolism:... Apr 2020Chronic-diabetes-related complications simultaneously compromise both the micro- and macrovascular trees, with target organs considered as the paradigm of large vessel... (Review)
Review
Chronic-diabetes-related complications simultaneously compromise both the micro- and macrovascular trees, with target organs considered as the paradigm of large vessel injury also entailing microangiopathic changes. However, complications independent or partially independent from vascular damage are often overlooked. This includes neuronal dysfunction (e.g., retinal neurodegeneration), interstitial injury (e.g., tubulointerstitial disease), metabolic damage (e.g., in the heart and liver), and nonclassical conditions such as cognitive decline, impaired pulmonary function, or increased risk of cancer. In this scenario, researchers, endocrinologists and primary care physicians should have a holistic view of the disease and pay further attention to all organs and all potential clinical repercussions, which would certainly contribute to a more rational and integrated patient health care.
Topics: Brain Diseases; Diabetes Complications; Diabetic Angiopathies; Diabetic Cardiomyopathies; Diabetic Nephropathies; Diabetic Neuropathies; Humans; Lung Diseases; Neoplasms; Non-alcoholic Fatty Liver Disease
PubMed: 32033865
DOI: 10.1016/j.tem.2020.01.007 -
Journal of Clinical Medicine Feb 2022Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome. To date, NAFLD is the most frequent chronic liver disease seen... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome. To date, NAFLD is the most frequent chronic liver disease seen day by day in clinical practice across most high-income countries, affecting nearly 25-30% of adults in the general population and up to 70% of patients with T2DM. Over the last few decades, it clearly emerged that NAFLD is a "multisystemic disease" and that the leading cause of death among patients with NAFLD is cardiovascular disease (CVD). Indeed, several observational studies and some meta-analyses have documented that NAFLD, especially its advanced forms, is strongly associated with fatal and non-fatal cardiovascular events, as well as with specific cardiac complications, including sub-clinical myocardial alteration and dysfunction, heart valve diseases and cardiac arrhythmias. Importantly, across various studies, these associations remained significant after adjustment for established cardiovascular risk factors and other confounders. Additionally, several observational studies and some meta-analyses have also reported that NAFLD is independently associated with specific microvascular conditions, such as chronic kidney disease and distal or autonomic neuropathy. Conversely, data regarding a potential association between NAFLD and retinopathy are scarce and often conflicting. This narrative review will describe the current evidence about the association between NAFLD and the risk of macro- and microvascular manifestations of CVD, especially in patients with T2DM. We will also briefly discuss the biological mechanisms underpinning the association between NAFLD and its advanced forms and macro- and microvascular CVD.
PubMed: 35207239
DOI: 10.3390/jcm11040968 -
Current Pharmaceutical Design 2019Obesity frequently co-exists with type 2 diabetes mellitus (T2DM), leading to the socalled "diabesity epidemic". The metabolic syndrome (MetS), a cluster of central... (Review)
Review
BACKGROUND
Obesity frequently co-exists with type 2 diabetes mellitus (T2DM), leading to the socalled "diabesity epidemic". The metabolic syndrome (MetS), a cluster of central obesity, hypertension, dysglycemia, insulin resistance and/or atherogenic dyslipidemia, as well as non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of MetS, has been associated with increased cardiovascular disease (CVD), T2DM and chronic kidney disease (CKD) incidence. However, the association between obesity, MetS (including NAFLD) and diabetic microvascular complications is less evident.
METHODS
The present narrative review discusses the associations of obesity, MetS and NAFLD with diabetic kidney disease (DKD), diabetic retinopathy (DR) and diabetic peripheral neuropathy (DPN) as well as cardiac autonomic neuropathy (CAN). The available data on the effects of lifestyle measures and bariatric surgery on these diabetic complications are also briefly discussed.
RESULTS
Overall, both obesity and MetS have been related to DKD, DR and DPN, although conflicting results exist. Links between NAFLD and diabetic microvascular complications have also been reported but data are still limited. Lifestyle intervention and bariatric surgery may prevent the development and/or progression of these microvascular complications but more evidence is needed.
CONCLUSION
Clinicians should be aware of the frequent co-existence of MetS and/or NAFLD in T2DM patients to prevent or treat these metabolic disorders, thus potentially minimizing the risk for both CVD and diabetic microvascular complications.
Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Obesity; Risk Factors
PubMed: 31298151
DOI: 10.2174/1381612825666190708192134 -
European Journal of Neurology Feb 2022We characterized and quantified peripheral nerve damage in alcohol-dependent patients (ADP) by magnetic resonance neurography (MRN) in correlation with clinical and...
BACKGROUND
We characterized and quantified peripheral nerve damage in alcohol-dependent patients (ADP) by magnetic resonance neurography (MRN) in correlation with clinical and electrophysiologic findings.
METHODS
Thirty-one adult patients with a history of excessive alcohol consumption and age-/sex-matched healthy controls were prospectively examined. After detailed neurologic and electrophysiologic testing, the patient group was subdivided into ADP with alcohol-related polyneuropathy (ALN) and without ALN (Non-ALN). 3T MRN with anatomical coverage from the proximal thigh down to the tibiotalar joint was performed using dual-echo 2-dimensional relaxometry sequences with spectral fat saturation. Detailed quantification of nerve injury by morphometric (cross-sectional area [CSA]) and microstructural MRN markers (proton spin density [ρ], apparent T2-relaxation-time [T2 ]) was conducted in all study participants.
RESULTS
MRN detected nerve damage in ADP with and without ALN. A proximal-to-distal gradient was identified for nerve T2-weighted (T2w)-signal and T2 in ADP, indicating a proximal predominance of nerve lesions. While all MRN markers differentiated significantly between ADP and controls, microstructural markers were able to additionally differentiate between subgroups: tibial nerve ρ at thigh level was increased in ALN (p < 0.0001) and in Non-ALN (p = 0.0052) versus controls, and T2 was higher in ALN versus controls (p < 0.0001) and also in ALN versus Non-ALN (p = 0.0214). T2w-signal and CSA were only higher in ALN versus controls.
CONCLUSIONS
MRN detects and quantifies peripheral nerve damage in ADP in vivo even in the absence of clinically overt ALN. Microstructural markers (T2 , ρ) are most suitable for differentiating between ADP with and without manifest ALN, and may help to elucidate the underlying pathomechanism in ALN.
Topics: Adult; Alcoholic Neuropathy; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Peripheral Nervous System Diseases; Tibial Nerve
PubMed: 34564924
DOI: 10.1111/ene.15127 -
Journal of Internal Medicine Aug 2023Nonalcoholic fatty liver disease (NAFLD) is considered a multisystem disease, as it is bidirectionally linked to other cardiometabolic disorders, such as type 2 diabetes...
INTRODUCTION
Nonalcoholic fatty liver disease (NAFLD) is considered a multisystem disease, as it is bidirectionally linked to other cardiometabolic disorders, such as type 2 diabetes (T2D). However, the long-term risk for microvascular outcomes in NAFLD is unclear.
METHODS
Using the outpatient part of the nationwide Swedish Patient Register in the time period between 01/01/2002 and 12/31/2019, we identified all individuals with a first NAFLD diagnosis (N = 6785) and matched these (age, sex, and municipality) with up to 10 reference individuals from the general population (N = 61,136). Using population-based registers, we ascertained the development of microvascular diseases. The primary outcome was defined as a composite outcome of any diagnosis representative of microvascular disease (chronic kidney disease, retinopathy, or neuropathy). As secondary outcomes, we separately examined the risk of each specific microvascular outcome. Hazard ratios (aHR, adjusted for cirrhosis and time-varying T2D, hypertension, and hyperlipidemia) for the outcomes were calculated by Cox proportional-hazards models.
RESULTS
Median follow-up was 5.7 years. The incidence rate of microvascular diseases was >twofold higher in patients with NAFLD (10.8 per 1000 person-years [95% confidence interval (CI) = 9.9-11.8]) versus reference individuals (4.7 per 1000 person-years [95%CI = 4.5-4.9]). NAFLD was independently and positively associated with the development of microvascular diseases compared to non-NAFLD subjects (aHR = 1.45 [95%CI = 1.28-1.63]). When stratifying the analysis by follow-up time, sex, or age categories, results remain virtually unchanged.
CONCLUSIONS
NAFLD is positively and independently associated with the development of microvascular diseases. The risk for development of microvascular diseases should be taken into account in the personalized risk assessment of individuals with NAFLD.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Cohort Studies; Diabetes Mellitus, Type 2; Liver Cirrhosis; Risk Assessment; Risk Factors
PubMed: 37259481
DOI: 10.1111/joim.13673 -
Experimental Eye Research Jul 2021Peroxisome Proliferator-Activated Receptors (PPARs) are a family of nuclear receptors that play essential roles in modulating cell differentiation, inflammation, and... (Review)
Review
Peroxisome Proliferator-Activated Receptors (PPARs) are a family of nuclear receptors that play essential roles in modulating cell differentiation, inflammation, and metabolism. Three subtypes of PPARs are known: PPAR-alpha (PPARα), PPAR-gamma (PPARγ), and PPAR-beta/delta (PPARβ/δ). PPARα activation reduces lipid levels and regulates energy homeostasis, activation of PPARγ results in regulation of adipogenesis, and PPARβ/δ activation increases fatty acid metabolism and lipolysis. PPARs are linked to various diseases, including but not limited to diabetes, non-alcoholic fatty liver disease, glaucoma and atherosclerosis. In the past decade, numerous studies have assessed the functional properties of PPARs in the eye and key PPAR mechanisms have been discovered, particularly regarding the retina and cornea. PPARγ and PPARα are well established in their functions in ocular homeostasis regarding neuroprotection, neovascularization, and inflammation, whereas PPARβ/δ isoform function remains understudied. Naturally, studies on PPAR agonists and antagonists, associated with ocular pathology, have also gained traction with the development of PPAR synthetic ligands. Studies on PPARs has significantly influenced novel therapeutics for diabetic eye disease, ocular neuropathy, dry eye, and age-related macular degeneration (AMD). In this review, therapeutic potentials and implications will be highlighted, as well as reported adverse effects. Further investigations are necessary before any of the PPARs ligands can be utilized, in the clinics, to treat eye diseases. Future research on the prominent role of PPARs will help unravel the complex mechanisms involved in order to prevent and treat ocular diseases.
Topics: Animals; Eye Diseases; Homeostasis; Humans; Ligands; Lipid Metabolism; Peroxisome Proliferator-Activated Receptors
PubMed: 34010603
DOI: 10.1016/j.exer.2021.108617 -
Frontiers in Immunology 2018alcohol exposure is emerging as a major risk factor for lifelong aberrant neuroimmune function. Fetal alcohol spectrum disorder encompasses a range of behavioral and... (Review)
Review
alcohol exposure is emerging as a major risk factor for lifelong aberrant neuroimmune function. Fetal alcohol spectrum disorder encompasses a range of behavioral and physiological sequelae that may occur throughout life and includes cognitive developmental disabilities as well as disease susceptibility related to aberrant immune and neuroimmune actions. Emerging data from clinical studies and findings from animal models support that of fetal alcohol exposure may reprogram the developing central nervous system leading to altered neuroimmune and neuroglial signaling during adulthood. In this review, we will focus on the consequences of low to moderate prenatal alcohol exposure (PAE) on neuroimmune interactions during early life and at different stages of adulthood. Data discussed here will include recent studies suggesting that while abnormal immune function is generally minimal under basal conditions, following pathogenic stimuli or trauma, significant alterations in the neuroimmune axis occur. Evidence from published reports will be discussed with a focus on observations that PAE may bias later-life peripheral immune responses toward a proinflammatory phenotype. The propensity for proinflammatory responses to challenges in adulthood may ultimately shape neuron-glial-immune processes suspected to underlie various neuropathological outcomes including chronic pain and cognitive impairment.
Topics: Age Factors; Alcoholic Beverages; Animals; Disease Models, Animal; Disease Susceptibility; Female; Fetal Alcohol Spectrum Disorders; Humans; Maternal Exposure; Neuralgia; Neurogenic Inflammation; Neuroglia; Neuroimmunomodulation; Pregnancy; Prenatal Exposure Delayed Effects; Spinal Cord
PubMed: 29910801
DOI: 10.3389/fimmu.2018.01107 -
Acta Pharmacologica Sinica Aug 2014Alcohol use disorders (AUD) are defined as alcohol abuse and alcohol dependence, which create large problems both for society and for the drinkers themselves. To date,... (Review)
Review
Alcohol use disorders (AUD) are defined as alcohol abuse and alcohol dependence, which create large problems both for society and for the drinkers themselves. To date, no therapeutic can effectively solve these problems. Understanding the underlying mechanisms leading to AUD is critically important for developing effective and safe pharmacological therapies. Benzodiazepines (BZs) are used to reduce the symptoms of alcohol withdrawal syndrome. However, frequent use of BZs causes cross-tolerance, dependence, and cross-addiction to alcohol. The FDA-approved naltrexone and acamprosate have shown mixed results in clinical trials. Naltrexone is effective to treat alcohol dependence (decreased length and frequency of drinking bouts), but its severe side effects, including withdrawal symptoms, are difficult to overcome. Acamprosate showed efficacy for treating alcohol dependence in European trials, but two large US trials have failed to confirm the efficacy. Another FDA-approved medication, disulfiram, does not diminish craving, and it causes a peripheral neuropathy. Kudzu is the only natural medication mentioned by the National Institute on Alcohol Abuse and Alcoholism, but its mechanisms of action are not yet established. It has been recently shown that dihydromyricetin, a flavonoid purified from Hovenia, has unique effects on GABAA receptors and blocks ethanol intoxication and withdrawal in alcoholic animal models. In this article, we review the role of GABAA receptors in the treatment of AUD and currently available and potentially novel pharmacological agents.
Topics: Acamprosate; Alcohol Deterrents; Alcohol Drinking; Alcoholism; Animals; Benzodiazepines; Disulfiram; Ethanol; Fructose; Humans; Naltrexone; Narcotic Antagonists; Neuroprotective Agents; Plant Preparations; Receptors, GABA-A; Taurine; Topiramate
PubMed: 25066321
DOI: 10.1038/aps.2014.50