Thiamine mediated reversal of left ventricular dysfunction in patients with alcoholic cardiomyopathy.

This study aimed to evaluate the effect of thiamine supplementation on left ventricular (LV) systolic function in patients of alcoholic cardiomyopathy(ACM) presenting with acute heart failure(HF). 11 newly diagnosed patients were included. They were treated with 3 days of intravenous(IV) therapy with thiamine followed by oral supplementation. LVEF was 30% at baseline which improved by 45% and 53% along with reduction in LV dimensions over 3 and 6 months respectively. The study suggests the benefit of thiamine supplementation on LVEF in ACM patients with HF.

On the Mechanism of Cardioprotective Effect of Fabomotizole in Alcoholic Cardiomyopathy.

The molecular mechanisms underlying the cardioprotective effect of fabomotizole were studied using the translational rat model of alcoholic cardiomyopathy developed by us. It was shown that intraperitoneal administration of fabomotizole (15 mg/kg) for 28 days to animals with alcoholic cardiomyopathy contributes to normalization of the expression of mRNA of genes of regulatory proteins СаМ (p=0.00001), Ерас1 (p=0.021), and Ерас2 (p=0.018) and receptors RyR2 (p=0.0031) and IP3R2 (p=0.006) in the myocardium of the myocardium of the left ventricle that is enhanced in control animals (p<0.05). These changes were accompanied by echocardiographically documented decrease in the degree of left ventricle remodeling and improvement of its inotropic function.

FGF21: a promising therapeutic agent for alcoholic cardiomyopathy?†.

The metabolic regulator fibroblast growth factor 21 (FGF21) has been reported as a cardioprotective factor regulating cardiac remodeling in several cardiac diseases. In a recent issue of The Journal of Pathology, Ferrer-Curriu, Guitart-Mampel et al investigated FGF21 in alcoholic cardiomyopathy (ACM). They showed that FGF21 deficiency aggravates alcohol-induced cardiac damage and dysfunction by exacerbating mitochondrial alterations, oxidative stress, and lipid metabolic dysregulation, suggesting FGF21 as a promising therapeutic agent in ACM. Paradoxically, FGF21 cardiac and circulating levels correlate with cardiac damage and oxidative stress in patients with ACM, pointing to FGF21 as a potential biomarker of alcohol-induced cardiac damage. Further studies are needed to address when FGF21 can be used as a diagnostic biomarker and when it can be used as a therapeutic agent to treat ACM. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The protective effect of fibroblast growth factor-21 in alcoholic cardiomyopathy: a role in protecting cardiac mitochondrial function.

Alcoholic cardiomyopathy (ACM) resulting from chronic alcohol misuse is one of the main contributors leading to heart failure and cardiovascular mortality. Fibroblast growth factor 21 (FGF21) is a well-established cardioprotective factor. We aimed to study the role of FGF21 in experimentally induced models and clinical affected patients with cardiac damage due to chronic alcohol consumption. We found that circulating FGF21 levels and cardiac FGF21 and ß-klotho protein levels were increased in subjects with chronic alcohol consumption. As an experimental model of ACM, we fed wild-type and Fgf21 knockout (Fgf21-/- ) mice with a 4% alcohol liquid diet for 4 and 12 weeks. FGF21 circulating levels and FGF21 expression in the myocardium were also increased in wild-type mice after chronic alcohol intake. Fgf21-/- mice develop a higher degree of cardiac hypertrophy, fibrosis, and cardiac dysfunction after chronic alcohol consumption than wild-type mice. Moreover, the myocardium of Fgf21-/- mice showed signs of metabolic deregulation, oxidative stress, and mitochondrial dysfunction after alcohol intake. Finally, human cardiac biopsies from patients with chronic alcohol consumption developing ACM presented a higher degree of oxidative stress which positively correlated with the FGF21 protein levels in the myocardium. We conclude that plasma levels and cardiac myocyte FGF21 expression were induced in response to chronic alcohol consumption. The lack of FGF21 aggravated cardiac damage produced by ACM, in association with enhanced mitochondrial and oxidative stress, thus pointing to FGF21 as a protective agent against development of alcohol-induced cardiomyopathy. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Atorvastatin reduces alcohol-induced endoplasmic reticulum stress in AC16 cardiomyocytes.

OBJECTIVES: To investigate the effects of atorvastatin on the ultrastructure and lipid metabolism of AC16 cardiomyocytes in response to alcohol-induced endoplasmic reticulum stress (ERS). DESIGN: The expression of the ERS-related factor GRP78 in the established ERS model was determined by western blotting. Alcohol-exposed cardiomyocytes were treated with various concentrations of atorvastatin, and GRP78 expression was measured. Cardiomyocyte ultrastructure was observed and SREBP-1c and triglyceride (TG) levels were evaluated. RESULTS: Exposure to ethanol for 0, 12, 24, and 48 h significantly affected GRP78 expression (0.19 ± 0.02, 0.27 ± 0.03, 0.39 ± 0.01, and 0.64 ± 0.02, respectively). GRP78 expression in the 1, 10, and 100 µmol L-1 atorvastatin-treated groups was 0.50 ± 0.04, 0.38 ± 0.03, and 0.24 ± 0.01, respectively, and significantly different from control group expression (0.19 ± 0.02); the expression in the alcohol group was 0.64 ± 0.02. Alcohol-treated AC16 cells had significantly larger and fewer mitochondria and disorganized cristae, often replaced by vacuoles. These aberrations decreased with increasing atorvastatin concentrations. SREBP-1c expression also differed significantly among all atorvastatin-treated and control groups (0.47 ± 0.04, 0.39 ± 0.03, and 0.31 ± 0.02; normal 0.25 ± 0.02; alcohol 0.56 ± 0.03). TG expression differed significantly between the 10 and 100 µmol L-1 groups (26.84 ± 1.63, 23.11 ± 2.05) and the alcohol group (36.35 ± 2.41). CONCLUSIONS: Atorvastatin inhibited the expression of the ERS-related factor GRP78 in response to alcohol exposure, improved cell morphology, and enhanced lipid metabolism in a cellular model of alcoholic cardiomyopathy.

A novel biocompatible chitosan-Selenium nanoparticles (SeNPs) film with electrical conductivity for cardiac tissue engineering application.

Cardiomyopathy is the leading cause of mortality in the world and economic burdens on national economies. A cardiac patch approach aims at regenerating an infracted heart by providing healthy functional cells to the injured region via a film carrier substrate, and providing mechanical and electrical support. Selenium acts as an important element in the prevention and treatment of cardiovascular diseases but their health-related effects have not been fully explored. Limitation is the fact that cardiac electrophysiology was only globally personalized, thus missing the potential localized pathological features in vivo. The epidemiological aspects of plasma levels of selenium and other lipid parameters in cardiomyopathy patients (30 nos) from South Tamilnadu, India were studied. The epidemiological data showed significant differences between plasma selenium, Glutathione per oxidase (Gpx) and High reactive-C Protein in cardiomyopathy patients when compared to the control. As a novel approach, in the present study chitosan-Selenium nanoparticles (SeNPs) film was used to produce electrical conductivity in the cardiac patches. The prepared chitosan-SeNPs film was characterized by Scanning Electron microscopy with Energy Dispersive X ray spectrum (SEM-EDX). The electrical and mechanical properties of the chitosan-SeNPs film were also studied. The chitosan-SeNPs film had compression of elastic modulus (67.1% elongation) and tensile strength of 419 kPa. The electrical conductivity of chitosan-SeNPs film was measured as 0.0055S cm-1. The H9C2 cells were very well grown in chitosan-SeNPs film and proliferated. In our study, we confirm the potential of SeNPs-chitosan film for use as substrates to grown cellular behavior via electrical stimulation, mechanical strength and as biocompatible film for cardiac tissue engineering applications.

Prognostic Impact and Predictors of Ejection Fraction Recovery in Patients With Alcoholic Cardiomyopathy.

INTRODUCTION AND OBJECTIVES: Recovery of left ventricular ejection fraction (LVEF) has been described in alcoholic cardiomyopathy (ACM) after a period of alcohol withdrawal. Nevertheless, the prognostic impact of LVEF recovery in ACM and its determinants have not been studied. We sought to define the role of LVEF improvement in the long-term outcome of ACM and to identify predictors of LVEF recovery in these patients. METHODS: We evaluated 101 ACM patients during a median follow-up period of 82 months [interquartile range 36-134]. RESULTS: At latest follow-up, 42 patients (42%) showed substantial LVEF recovery defined as an absolute increase in LVEF ≥ 10% to a final value of ≥ 40%. Patients who recovered LVEF had better outcomes than patients who did not (heart transplant or cardiovascular death 1% vs 30%; P <.001). A QRS with <120ms (OR, 6.68; 95%CI, 2.30-19.41), beta-blocker therapy (OR, 3.01; 95%CI, 1.09-8.28), and the absence of diuretics (OR, 3.35; 95%CI, 1.08-10.42) predicted LVEF recovery in multivariate analysis. Although alcohol cessation did not predict LVEF recovery, none of the patients (n=6) who persisted with heavy alcohol consumption recovered LVEF. The rate of patients who recovered LVEF did not differ between abstainers and moderate drinkers (44% vs 45%; P=.9). CONCLUSIONS: The LVEF recovery is associated with an excellent prognosis in ACM. Beta-blocker treatment, QRS <120ms and absence of diuretics are independent predictors of LVEF recovery. LVEF recovery is similar in moderate drinkers and abstainers.

[Thiamine (vitamin B1) treatment in patients with alcohol dependence]. / Le traitement par thiamine (vitamine B1) dans l'alcoolodépendance.

Thiamine deficiency (vitamin B1) is common in patients with alcohol dependence. Cognitive impairments may be an early consequence of thiamine deficiency. Wernicke's encephalopathy is underdiagnosed and undertreated. In patients with established Wernicke's encephalopathy, parenteral thiamine 200-500mg three times a day should be given for 3-5 days, followed by oral thiamine 250-1000mg/day. In patients with suspected Wernicke's encephalopathy, parenteral thiamine 250-300mg should be given two times a day for 3-5 days, followed by oral thiamine 250-300mg/day. In patients at high risk of thiamine deficiency, parenteral thiamine 250-500mg/day should be given for 3-5 days, followed by oral thiamine 250-300mg/day. In patients at low risk (with uncomplicated alcohol dependence), oral thiamine 250-500mg/day should be given for 3-5 days, followed by oral thiamine 100-250mg/day.

Alcoholic cardiomyopathy: pathophysiologic insights.

Alcoholic cardiomyopathy (ACM) is a specific heart muscle disease found in individuals with a history of long-term heavy alcohol consumption. ACM is associated with a number of adverse histological, cellular, and structural changes within the myocardium. Several mechanisms are implicated in mediating the adverse effects of ethanol, including the generation of oxidative stress, apoptotic cell death, impaired mitochondrial bioenergetics/stress, derangements in fatty acid metabolism and transport, and accelerated protein catabolism. In this review, we discuss the evidence for such mechanisms and present the potential importance of drinking patterns, genetic susceptibility, nutritional factors, race, and sex. The purpose of this review is to provide a mechanistic paradigm for future research in the area of ACM.

[Roles of PYK2 and caveolin-1 in alcoholic cardiomyopathy and the effect of drug intervention].

OBJECTIVE: To explore the protein expressions of PYK2 (protein-rich tyrosine kinase-2) and caveolin-1 in alcoholic cardiomyopathy (ACM) dog model and the effect of early drug intervention. METHODS: A total of 28 adult dogs were randomly divided into 4 groups: (i): alcohol-fed; (ii): alcohol plus valsartan, an angiotensin receptor blocker (ARB); (iii): alcohol plus carnitine; (iv): control group. At Month 6, the cardiac functions of all animals were evaluated by echocardiography. The concentrations of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in cardiac tissue were detected by chronometry. The protein expressions of collagen types I and III were determined by ELISA (enzyme-linked immunosorbent assay) while those of PYK2 and caveolin-1 evaluated by immunohistochemistry. The internal relationship of PYK2, caveolin-1, MDA and collagen types I & III was analyzed. RESULTS: Compared with the control group, the contents of SOD and GSH-Px significantly decreased in the alcohol, valsartan and carnitine groups while MDA significantly increased in the alcohol and carnitine groups. The relative contents in each group were as follows: MDA [alcohol: (28 ± 5) U/mg Pro; valsartan: (33 ± 13) U/mg Pro; carnitine: (33 ± 10) U/mg Pro], GSH-Px [alcohol: (188 ± 37) U/g Pro; valsartan: (362 ± 29) U/g Pro; carnitine: (282 ± 29) U/g Pro and MDA [alcohol: (19.4 ± 3.0) nmol/mg Pro; carnitine: (10.8 ± 2.1) nmol/mg Pro]. Compared with the control group, the concentration of collagen typeI significantly increased in the alcohol, valsartan and carnitine groups. In the alcohol-fed group, the protein expression of PYK2 gradually increased with the progression of ACM while that of caveolin-1 stayed at a low level. Through the interventions of valsartan and carnitine, the protein expression of PYK2 significantly increased while that of caveolin-1 significantly decreased (all P < 0.01). CONCLUSION: Alcohol promotes the myocardial oxidative stress and fibrosis through an elevated expression of PYK2 and a lowered expression of caveolin-1. Then a deterioration of cardiac structures and functions occur.

Oral leucine enhances myocardial protein synthesis in rats acutely administered ethanol.

Acute alcohol ingestion induces an inhibition of myocardial protein synthesis by impairing mRNA translation initiation. Elevating plasma leucine (Leu) concentrations via oral gavage stimulates mRNA translation initiation in several tissues, although the effect in heart has not been well defined. The experiments described herein were designed to test the effects of a gavage solution containing Leu on protein synthesis and potential mechanisms important in accelerating mRNA translation initiation in cardiac muscle of rats given ethanol acutely to mimic "binge" dinking. Gavage with Leu stimulated protein synthesis and enhanced the assembly of the active eukaryotic initiation factor (eIF)4G.eIF4E complex. Increased assembly of the active eIF4G.eIF4E complex was associated with a 130% rise in phosphorylation of eIF4G(Ser(1108)) and a decreased assembly ( approximately 30%) of inactive eIF4E-binding protein1 (4EBP1).eIF4E complex in rats-administered ethanol. The reduced assembly of the 4EBP1.eIF4E complex was associated with an increase in phosphorylation of 4EBP1 in the hyperphosphorylated gamma-form following Leu gavage. Phosphorylation of mammalian target of rapamycin on Ser(2448), an upstream regulator of phosphorylation of 4EBP1, was elevated following Leu gavage. Neither the phosphorylation of 70-kDa ribosomal protein S6 kinase on Thr(389) nor eIF4E phosphorylation was increased following Leu gavage under any condition. Leu gavage accelerates myocardial protein synthesis following acute ethanol intoxication by enhancing eIF4G.eIF4E complex assembly through increased phosphorylation of eIF4G and decreased association of 4EBP1 with eIF4E.

[Change of concentration endothelin-1 in rats on a background of alcohol and /or mildronate treatment].

Alcoholic cardiomyopathy is specific cardial pathology characteristic for chronic consumption of alcohol. Endothelin-1 is an endothelium-derived potent vasoconstrictor peptide, which level directly influence the severity of this condition. Mildronate is an antiischemic drug. It inhibits carnitine biosynthesis (suppress beta-oxidation of the fatty acids) and increases the production of nitric oxide in the vascular endothelium. The aim of the study was to establish how Mildronate influences concentration of ET-1 in blood of rats on a background of chronic consumption of alcohol and at abstinence. White rats (n=28) instead of drinking water were taking 15% ethanol with the following regimens: A) three-week alcohol consumption, B) after 3 weeks of alcohol consumption on a background of alcohol they took mildronate, C) four-week alcohol consumption; D) after 4 weeks alcohol consumption they took only mildronate. Concentration of ET-1 in the group A was 6,00 +/- 0,35 fmol/ml, in the group B - 4,82 +/- 0,31 fmol/ml, in the group C - 13,25 +/- 0,49 fmol/ml and in the group D - 9,17 +/- 0,17 fmol/ml. Consumption of alcohol concentration ET-1 in blood high, for this purpose it is enough also 3-week alcohol consumption; the concentration of ET-1 progressively elevates with increase of duration of alcohol consumption; mildronate lowers concentration of ET-1 both on the background of alcohol consumption and on the background of acceptance of alcohol; under influence of mildronate the condition is improved in parallel the with complete alcohol consumption and acceptance of alcohol.

[A man with the combination of dry and wet beriberi]. / Een man met de combinatie van droge en natte beriberi.

A 34-year-old alcoholic man had neurological and cardiac symptoms. The patient was admitted to the hospital for acute painful sensory disturbances and severe weakness of the feet. Neurological and electrophysiological investigation revealed axonal sensorimotor polyneuropathy that was most prominent in the legs. Cardiac assessment showed signs and symptoms of heart failure due to a high-output state. Blood analysis showed a low thiamine concentration of 58 nmol/l (lower reference limit: 80). Therefore, a diagnosis of combined wet beriberi with cardiomyopathy and dry beriberi with axonal polyneuropathy was made. The treatment of beriberi is simple and effective and consists of thiamine supplementation in conjunction with diuretic treatment. With this approach, the patient recovered fully. Patients with beriberi have a good prognosis, particularly when the diagnosis is made at an early stage.

Case 4: A patient with systemic hypertension and congestive heart failure.

Hypertension in the setting of symptomatic congestive heart failure requires aggressive treatment. The optimal antihypertensive agent in such patients is one that effectively controls blood pressure without compromising the failing heart.

The alcoholic cardiomyopathies--genuine and pseudo.

Two types of genuine alcoholic cardiomyopathies can produce congestive heart failure, an acute fulminate hyperkinetic type with high cardiac output and a hypokinetic type with a low cardiac output, both of which respond to thiamine. When the chronic alcoholic develops a dilated cardiomyopathy with congestive heart failure without a history of significant malnutrition, then they do not respond to thiamine. This may be explained by a study in which mice given a myotropic virus plus alcohol developed more frequent and severe viral cardiomyopathies than those not fed alcohol. This suggests that a chronic dilated cardiomyopathy in an alcoholic may not be the direct result of the alcohol but secondary to a viral myocarditis. This suggests that the preferred terminology for a dilated cardiomyopathy in an alcoholic who does not respond to thiamine and good nutrition should simply be a dilated cardiomyopathy in an alcoholic. We should assume that the cardiomyopathy is possibly of viral etiology.

Ethyl alcohol and dilative cardiomyopathy.

The ethanol-induced dilative cardiomyopathy has a complex clinical and paraclinical picture because of the direct action of the alcohol and the indirect action of its metabolites on human myocardium and neuroendocrine system. Ventricular arrhythmias, atrial arrhythmias, and heart failure are significant and show a great sensitivity of the conduction system. Working myocardium is also affected, which is proved by the impaired systolic and diastolic function of the heart and by the nitroglycerine-resistant isovolumetric relaxation time.

[The fibrinolytic system in patients with dilated myocardiopathy]. / Estudio del sistema fibrinolítico en pacientes con miocardiopatía dilatada.

OBJECTIVES: To study the fibrinolytic system in dilated cardiomyopathy (DCM) patients, and the relationship between the degree of severity (NYHA degree), and the presence of complications (atrial fibrillation, intracavity thrombus, and peripheral embolism). We also analyzed the influence of the antithrombotic therapy on the fibrinolysis's proteins. PATIENTS AND METHODS: We included 18 patients, stratified in two etiologic groups: 9 with idiopathic and 9 with ethyl DCM. The fibrinolytic system was investigated through the plasma levels of antigenic and functional t-PA and PAI-1. We also carried out a venous occlusion test to investigate the fibrinolytic the fibrinolytic activity in t-PA secretion. The clinical aspects were recorded. We included 30 healthy individuals matched for age and sex, as controls. RESULTS: The antigenic levels of t-PA and PAI-1, were significantly higher in the DCM group than in the control group (p < 0.01). The venous occlusion test responses were normal. No relationship between the fibrinolytic parameters and clinical data were observed. DISCUSSION: The high levels of antigenic t-PA found in DCM patients were considered as a vascular injury marker, and a atherothrombotic risk factor. Furthermore, there is a hypofibrinolytic condition shown by a PAI-1 augmentation. In conclusion, we are prone to consider long term oral anticoagulation in the management of DCM patients.

Alcoholic cardiomyopathy.

Clinical observations over the past two decades have pointed to the relationship between heart disease and alcohol abuse, usually without evident malnutrition or cirrhosis. While the prevalence of heart failure in the alcoholic population is now known, subclinical abnormalities of left ventricular function in noncardiac alcoholics who were normotensive have a high prevalence with or without some degree of ventricular hypertrophy by echocardiogram. This is frequently a diastolic rather than systolic abnormality. Congestive cardiomyopathy is not infrequently associated with high diastolic arterial blood pressures. Intoxication itself may contribute to blood pressure elevation. Angina pectoris in the absence of significant coronary disease is another presentation. Although the history may not be readily obtained, the major diagnostic feature in this entity is the history of ethanol ingestion in intoxicating amounts for at least 10 years, often marked by periods of spree drinking. While the course of congestive cardiomyopathy may be progressively downhill in individuals who continue to be actively alcoholic after the onset of heart failure, in one series one third of the patients became abstinent. These patients had a 4 year mortality that was persistently one-sixth of the alcoholic group. Management of heart failure is traditional in these patients. Atrial arrhythmias have been shown to occur during the early ethanol withdrawal phase in patients without other clinical evidence of heart disease. Sudden death in a segment of the alcoholic population is considered arrhythmia related and is commonly associated with cigarette use. Identification of the addicted individual is the essential element to management.

[Antioxidant therapy in the arrhythmic form of alcoholic heart damage]. / Antioksidantnaia terapiia pri aritmicheskoi forme alkogol'nogo porazheniia serdtsa.

The impact of antioxidative therapy with dibunol on the clinical course of an arrhythmic type of alcoholic damage was studied. A total of 20 patients with Stage II chronic alcoholism (mean age 38.1 +/- 1.9 years) and ventricular premature contraction were examined. The diagnosis of cardiac alcoholic damage was established after comprehensive studies. The effects of dibunol on the pattern of ventricular arrhythmias were tested by 24--hour Holter monitoring: control, on days 10 and 20 of therapy. The daily dosage of dibunol was 20 mg per kg body weight. The results of studies suggest that dibunol exerts a beneficial effect on the clinical course of the disease and the nature of ventricular arrhythmias by reducing the number of ventricular extrasystoles by 51.4%.