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.

[The forensic medical evaluation of the changes in the cerebral tissue in the case of sudden death from alcoholic cardiomyopathy]. / Sudebno-meditsinskaia otsenka strukturnykh izmenenii tkani golovnogo mozga v sluchaiakh vnezapnoi smerti ot alkogol'noi kardiomiopatii.

This article presents the results of the retrospective analysis of the protocols of forensic medical autopsies and histological studies of the cerebral tissues together with the data obtained by their statistical treatment. The objective of present work was to study and evaluate the structural changes in the cerebral tissues associated with sudden cardiac death from alcoholic cardiomyopathy. It was shown that the morphological changes in the endothelial lining of the microcirculatory bed of the cerebral tissue can be a consequence of both the direct cytotoxic action of ethanol or its metabolites and the influence of cellular modulators liberation of which results in enhanced vascular permeability associated with trophic disturbances in the tissue. These changes provide a substrate for the development of the dystrophic and necrobiotic processes in the main structural components of the organ in question. The clustering of glial cells around atrophic neutrons or instead of the dead ones in the brain as well as around the microcysts of the cerebral tissue as a compensatory response to the lesion can be in its turn considered as a pathognomonic sign of chronic alcoholic intoxication. The severe dystrophic and destructive processes proceeding in the main components of the histohematological barrier revealed in the cerebral tissue as a result of the present analysis are believed to reflect the toxic action of ethanol and/or its metabolites that play an important role in the development of dyscirculatory disorders responsibly for cerebral tissue hypoxia.

[The morphological changes in the myocardial tissue after sudden cardiac death from alcoholic cardiomyopathy].

This paper was designed to report the results of the retrospective analysis of the protocols of 180 forensic medical autopsy sections stored in the archives of Sankt-Petersburg Bureau of Forensic Medical Expertise and the data of the histological studies of myocardial tissues obtained after sudden cardiac death from alcoholic cardiomyopathy. The study revealed the following most pathognomonic histological criteria for alcoholic heart lesions: the alternation of hypertrophic and atrophic cardiomyocytes in the state of severe parenchymatous degeneration, pronounced mesenchymal fatty dystrophy in combination with pathological changes of the vascular walls (vascular wall plasmatization), sub-endothelial accumulation of the PAS-positive tissue compounds, microcirculatory disorders in the form of erythrocyte stasis with the manifestations of the blood "sludge" phenomenon, and precapillary fibrosis. The signs of severe parenchymatous and stromal vascular dystrophy of the myocardial histohematic barrier (HHB) are supposed to reflect the toxic effects of ethanol and its metabolites that are directly involved in the mechanisms underlying the disturbances of intracellular metabolism and dyscirculatory events leading to the development of heart muscle hypoxia.

[The comparative benchmark analysis of the methods used to verify etiology of myocarditis associated with alcoholic cardiomyopathy].

Immunohistochemical (IHC) methods and polymerase chain reaction (PCR) were employed to study the cases of death from alcoholic cardiomyopathy (ACMP) among the patients presenting with interstitial myocarditis who did not have this condition in their medical histories. IHC studies revealed the expression of anti-parvovirus B19 antibodies in cardiomyocytes (CMC) and inflammatory infiltrate cells of 40% of the patients. These antibodies were expressed in vascular smooth cells and inflammatory infiltrate cells from 70% of the patients. Cardiomyocytes expressed VP1 antigen of enteroviruses. The expression of V 19 parvovirus antigen occurred in 67% of the patients who died from alcoholic cardiomyopathy. The parvovirus V 19 was expressed in a smaller number of cardiomyocytes than enterovirus V1. PCR revealed the presence of parvovirus in 35% of the patients with ACMP compared with 15% of the control subjects. Type 6 herpes simplex virus was identified with the help of PCR in 30% of the patients with alcoholic cardiomyopathy, butonly in 8% of the patients in the control group. It is concluded that the use of immunohistochemical methods and polymerase chain reaction extends the diagnostic potential of histiological studies carried out to elucidate etiology of myocarditis in the patients who died from alcoholic cardiomyopathy.

Alcoholic cardiomyopathy and cardiovascular events - an insight from the Liptov region.

AIM: This study was conducted to study the association between alcohol consumption and cardiovascular events and echocardiographical parameters in 100 consumers with the average daily dose <120 g and ≥120 g of alcohol per day during a 4-year follow-up. METHODS: 100 patients/heavy alcohol consumers (on average ≥ 80 g daily), with no cardiovascular disease, divided into 2 groups, underwent a baseline echocardiographic and clinical evaluation and were followed-up for cardiovascular events, biochemical analysis and rhythm disorder for 4 years. RESULTS: Data regarding the dose and duration of alcohol consumption showed a low correlation and nonlinear character between the duration of alcohol consumption and monitored parameters. There were no differences between the groups in the echo-parameters ejection fraction EF (p=0.43), in the diameter of left atrium LA (p=0.51). Left chamber - LVEDD - was slightly bigger in the group with a heavier drinking pattern (p=0.09). There were no differences in biochemical parameters between the groups. When comparing these two groups of consumers the percentage of diabetes mellitus (p=0.283), episodes of heart failure (p=0.308), atrial fibrillation (p=0.652), cerebral vascular accident (p=0.722) and delirium (p=0.559) were not significantly different; only 2 subjects suffered from myocardial infarction during the follow-up. CONCLUSION: We conclude, that no significant differences (p<0.05) between the two groups of heavy alcohol consumers were observed in echo parameters, biochemical values and cardiovascular events (Tab. 4, Ref. 28).

[Alcoholic heart disease].

We present in this review contemporary views on pathogenesis of alcoholic cardiomyopathy. Alcoholic cardiomyopathy has features of dilated cardiomyopathy and is manifested by increased volume and hypertrophy of the left ventricle, diminished contractile capacity, and when decompensated - by lowering of cardiac output. Pathogenic action of alcohol on cardiomyocytes leads to activation of apoptosis, dysfunction of intracellular organelles, alterations of the system of myofilaments, disorder of intracellular homeostasis of calcium. Ethanol metabolite acetaldehyde, products of minor pathway of catecholamine metabolism, changes in the endocannabinoid system, and activation of processes of lipid peroxidation all contribute to the myocardial damage. The basis of pathogenesis of alcoholic cardiomyopathy constitute proliferation of microperoxisomes and disbalance between acyloxidase and catalase leading to accumulation of hydrogen peroxide inside myocytes.

Alcoholic cardiomyopathy in patients with alcoholic liver cirrhosis: a study across 10†years.

BACKGROUND AND OBJECTIVES: Available data regarding cardiomyopathy in patients with alcoholic liver cirrhosis (ALC) are very limited because it often requires multidisciplinary assessments. The study aims to evaluate the prevalence of alcoholic cardiomyopathy in ALC and their clinical correlations. METHODS: Adult ALC patients without a previous diagnosis of cardiovascular diseases between January 2010 and December 2019 were included in the study. The prevalence rate of alcoholic cardiomyopathy in patients with ALC was calculated together with a 95% confidence interval (CI) using the Clopper-Pearson exact method. RESULTS: A total of 1022 ALC patients were included. Male patients predominated (90.5%). ECG abnormalities were observed in 353 patients (34.5%). Prolonged QT interval was most common in ALC patients with ECG abnormalities, which occurred in 109. Thirty-five ALC patients underwent the cardiac MRI examination and only one patient was found with cardiomyopathy. The estimated prevalence rate of alcoholic cardiomyopathy in all the ALC patients was 0.0286 (95% CI, 0.0007-0.1492). There was no statistical difference regarding the prevalence rate between the group of patients with ECG abnormalities and the group without ECG abnormalities (0.0400 vs. 0.0000, P  = 1.000). CONCLUSION: Although ECG abnormalities, especially QT prolongation, existed in a proportion of ALC patients, cardiomyopathy in the patient population was not common. Further larger-sample studies based on cardiac MRI are needed to verify our results.

Unilateral lobar pulmonary edema.

INTRODUCTION: Pulmonary edema is usually bilateral, but unilateral lobar pulmonary edema can also be encountered in clinical practice. CLINICAL PICTURE: We describe a case of unilateral lobar pulmonary edema in a patient without known cardiac history. It was first presentation of underlying cardiac disease in our patient and was difficult to differentiate from pneumonia. CONCLUSION: Unilateral pulmonary edema can mimic as pneumonia. Clinician should be aware of differential diagnosis of pulmonary edema, otherwise it can lead to unnecessary investigation and delay in starting definitive treatment.

[Pathology of the heart conducting system in the thanatogenesis of sudden death from alcoholic cardiomyopathy and coronary heart disease].

The present literature review is focused on the contribution of various pathological changes in the heart conducting system to the tanatogenesis of sudden death from alcoholic cardiomyopathy and coronary heart disease viewed from the perspective of a forensic medical expert. The currently available data on the disorders in the heart conducting system in the subjects with these diseases are presented. Various aspects of pathology of the heart conducting system are considered in the modern and historical contexts. The prospects for the further investigations into the tanatogenic mechanisms of sudden death by reason of alcoholic cardiomyopathy and coronary heart disease are outlined.

Moderate excess alcohol consumption and adverse cardiac remodelling in dilated cardiomyopathy.

OBJECTIVE: The effect of moderate excess alcohol consumption is widely debated and has not been well defined in dilated cardiomyopathy (DCM). There is need for a greater evidence base to help advise patients. We sought to evaluate the effect of moderate excess alcohol consumption on cardiovascular structure, function and outcomes in DCM. METHODS: Prospective longitudinal observational cohort study. Patients with DCM (n=604) were evaluated for a history of moderate excess alcohol consumption (UK government guidelines; >14 units/week for women, >21 units/week for men) at cohort enrolment, had cardiovascular magnetic resonance and were followed up for the composite endpoint of cardiovascular death, heart failure and arrhythmic events. Patients meeting criteria for alcoholic cardiomyopathy were not recruited. RESULTS: DCM patients with a history of moderate excess alcohol consumption (n=98, 16%) had lower biventricular function and increased chamber dilatation of the left ventricle, right ventricle and left atrium, as well as increased left ventricular hypertrophy compared with patients without moderate alcohol consumption. They were more likely to be male (alcohol excess group: n=92, 94% vs n=306, 61%, p=<0.001). After adjustment for biological sex, moderate excess alcohol was not associated with adverse cardiac structure. There was no difference in midwall myocardial fibrosis between groups. Prior moderate excess alcohol consumption did not affect prognosis (HR 1.29, 95% CI 0.73 to 2.26, p=0.38) during median follow-up of 3.9 years. CONCLUSION: DCM patients with moderate excess alcohol consumption have adverse cardiac structure and function at presentation, but this is largely due to biological sex. Alcohol may contribute to sex-specific phenotypic differences in DCM. These findings help to inform lifestyle discussions for patients with DCM.

Alcohol Intake in Patients With Cardiomyopathy and Heart Failure: Consensus and Controversy.

Alcohol is often cited to be a common cause of cardiomyopathy and heart failure. However, in most available population-based studies, a modest-to-moderate alcohol consumption has been associated with favorable effects on the cardiovascular system, including a lowered risk of heart failure, compared with no alcohol consumption. Available genetic epidemiological data have not supported a causal association between alcohol consumption and heart failure risk, suggesting that alcohol may not be a common cause of heart failure in the community. Data linking alcohol intake with cardiomyopathy risk are sparse, and the concept of alcoholic cardiomyopathy stems mainly from case series of selected patients with dilated cardiomyopathy, where a large proportion reported a history of excessive alcohol intake. This state-of-the-art paper addresses the current knowledge of the epidemiology of alcoholic cardiomyopathy and the role of alcohol intake in patients with non-alcohol-related heart failure. It also offers directions to future research in the area. The review questions the validity of current clinical teaching in the area. It is not well known how much alcohol is needed to cause disease, and the epidemiological pathways linking alcohol consumption to cardiomyopathy and heart failure are not well understood. Until more evidence becomes available, caution is warranted before labeling patients as having alcoholic cardiomyopathy due to a risk of neglecting other contributors, such as genetic causes of cardiomyopathy. In non-alcohol-related heart failure, it is unknown whether total abstinence is improving outcomes (compared with moderate drinking). Ideally, randomized clinical trials are needed to answer this question.

[Alcoholic cardiomyopathy--still a topical diagnosis]. / Alkoholová kardiomyopatia--diagnóza stále aktuálna.

Even though extensive experimental as well as clinical evidence exists for adverse cardiac effects of alcohol, pathogenesis and incidence of alcoholic cardiomyopathy is not fully understood. From the genetic level and understanding of the pathogenesis of the toxic effects of alcohol on the heart we come to discuss the diagnosis and treatment of the disease that, in the context of co-morbidities and complications (hypertension, diabetes, arrhythmias, heart failure), continues to represent an significant clinical entity with an important impact on patient prognosis.

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.

Perioperative considerations in patients with cirrhotic cardiomyopathy.

PURPOSE OF REVIEW: This review aims to identify specific criteria for cirrhotic cardiomyopathy, examine the correlation with perioperative adverse outcomes and explore options for hemodynamic monitoring. RECENT FINDINGS: Cirrhotic cardiomyopathy is characterized by an increase in cardiac output, blunted systolic contractile response to stress, diastolic dysfunction and electrophysiological abnormalities. Adverse events due to cirrhotic cardiomyopathy are not as well characterized, but evidence suggests that some cardiovascular complications during surgery and in the postoperative period are caused by an impaired response to physiological stress. New developments in hemodynamic monitoring using not only thermodilution technology provide more reliable information about cardiac performance than pressure-derived measures. Transesophogeal echocardiography also offers the physician new information including the ability to visualize heart structures, shape, and function. SUMMARY: To detect cirrhotic cardiomyopathy, physicians must conduct a systematic examination of the patient. Overt manifestations of cirrhotic cardiomyopathy often only become evident after a patient is exposed to physiological or drug-induced stress. Appropriate hemodynamic monitoring is a cornerstone in the perioperative management of cirrhotic patients.

Clinical profile and prognostic factors of alcoholic cardiomyopathy in tribal and non-tribal population.

OBJECTIVE: Alcoholic cardiomyopathy (ACM) is a leading cause of non-ischaemic dilated cardiomyopathy (DCM) in tribal and non-tribal population. However, no study has been done depicting the correlation between clinical profile and prognosis of ACM in tribal and non-tribal population. This study also defines the long-term outcome and prognostic markers of ACM. METHODS: We studied 290 patients with ACM who were evaluated in our institute between January 2013 and December 2016. The primary endpoint of the study was all-cause mortality. Statistical analysis was done by using Kaplan-Meier survival curves for the assessment of all-cause mortality and Cox regression for the assessment of risk factors. RESULTS: After a median follow-up period of 3.75 years (IQR: 3-4 years), 50 patients with ACM (37.3%) died among tribal population while 14 patients (9%) died among non-tribal population. Independent predictors of all-cause mortality in ACM identified by Cox regression were left ventricular ejection fraction (LVEF) (HR: 0.883; 95% CI 0.783 to 0.996; p=0.043), QRS duration (HR: 1.010; 95% CI 1.007 to 1.017; p=0.005) and Child-Turcotte-Pugh (CTP) Scoring (HR: 12.332; 95% CI 6.999 to 21.728; p<0.001) at admission. The Kaplan-Meier survival probability estimate was 95.1% at 1 year and all-cause mortality was found to be higher in patients with QRS>120 ms, LVEF ≤35%, CTP Grade B/C than patients with QRS≤120 ms, LVEF >35% and CTP Score A, respectively (log-rank χ²=55.088, p<0.001; log-rank χ²=32.953, p<0.001; log-rank χ²=139.764, p<0.001, respectively). CONCLUSION: Our study indicated increased morbidity and mortality in tribal population. LVEF, QRS duration and CTP Scoring at the time of presentation were found to be the independent prognostic markers of patients with ACM.

Characteristics of subjects with alcoholic cardiomyopathy and sudden cardiac death.

OBJECTIVE: To study social and clinical characteristics of victims of sudden cardiac death (SCD) due to alcoholic cardiomyopathy (ACM). METHODS: The study population comprised a subset of Fingesture cohort. All subjects were verified SCD victims determined to have ACM as cause of death in medico-legal autopsy between 1998 and 2017 in Northern Finland. The Finnish Population Register Centre provided SCD victims' last place of residence. Population data of residential area were obtained from Statistics Finland. RESULTS: From a total of 5869 SCD victims in Fingesture cohort, in 290 victims the cause of SCD was ACM (4.9%; median age 56 (50-62) years; 83% males). In 64 (22.1%) victims, the diagnosis of cardiac disease was made prior to death and in 226 (77.9%) at autopsy. There were no significant differences in autopsy findings between victims with or without known cardiac diagnosis, but steatohepatitis (94.5%) and liver cirrhosis (64,5%) were common in both groups. Alcoholism was more often recorded in the known cardiac disease group (64.1% vs 47.3%, p=0.023). Majority were included in the working age population (ie, under 65 years) (54.8% and 53.1%, p=0.810). In high-income communities, 28.8% of ACM SCD victims had previously diagnosed cardiac disease, the proportion in the middle-income and low-income communities was 18.6% (p=0.05). CONCLUSIONS: Majority of SCD victims due to ACM did not have previously diagnosed cardiac disease, but documented risk consumption of alcohol was common. This emphasises the importance of routine screening of alcohol consumption and signs of cardiomyopathy in heavy alcohol users in primary healthcare.

Alcohol abuse and heart failure.

Alcoholic patients who consume >90 g of alcohol a day for >5 years are at risk of developing asymptomatic alcoholic cardiomyopathy (ACM). Those patients who continue to drink may become symptomatic and develop signs and symptoms of heart failure (HF). This distinct form of congestive HF is responsible for 21-36% of all cases of non-ischaemic dilated cardiomyopathy in Western Society. Without complete abstinence, the 4 year mortality for ACM is close to 50%. This short review summarizes the experimental and clinical evidence regarding the role of alcohol in the pathophysiology of ACM and HF.

Outcomes and Effect of Treatment According to Etiology in HFrEF: An Analysis of PARADIGM-HF.

OBJECTIVES: The purpose of this study was to compare outcomes (and the effect of sacubitril/valsartan) according to etiology in the PARADIGM-HF (Prospective comparison of angiotensin-receptor-neprilysin inhibitor [ARNI] with angiotensin-converting-enzyme inhibitor [ACEI] to Determine Impact on Global Mortality and morbidity in Heart Failure) trial. BACKGROUND: Etiology of heart failure (HF) has changed over time in more developed countries and is also evolving in non-Western societies. Outcomes may vary according to etiology, as may the effects of therapy. METHODS: We examined outcomes and the effect of sacubtril/valsartan according to investigator-reported etiology in PARADIGM-HF. The outcomes analyzed were the primary composite of cardiovascular death or HF hospitalization, and components, and death from any cause. Outcomes were adjusted for known prognostic variables including N terminal pro-B type natriuretic peptide. RESULTS: Among the 8,399 patients randomized, 5,036 patients (60.0%) had an ischemic etiology. Among the 3,363 patients (40.0%) with a nonischemic etiology, 1,595 (19.0% of all patients; 47% of nonischemic patients) had idiopathic dilated cardiomyopathy, 968 (11.5% of all patients; 28.8% of nonischemic patients) had a hypertensive cause, and 800 (9.5% of all patients, 23.8% of nonischemic patients) another cause (185 infective/viral, 158 alcoholic, 110 valvular, 66 diabetes, 30 drug-related, 14 peripartum-related, and 237 other). Whereas the unadjusted rates of all outcomes were highest in patients with an ischemic etiology, the adjusted hazard ratios (HRs) were not different from patients in the 2 major nonischemic etiology categories; for example, for the primary outcome, compared with ischemic (HR: 1.00), hypertensive 0.87 (95% confidence interval [CI]: 0.75 to 1.02), idiopathic 0.92 (95% CI: 0.82 to 1.04) and other 1.00 (95% CI: 0.85 to 1.17). The benefit of sacubitril/valsartan over enalapril was consistent across etiologic categories (interaction for primary outcome; p = 0.11). CONCLUSIONS: Just under one-half of patients in this global trial had nonischemic HF with reduced ejection fraction, with idiopathic and hypertensive the most commonly ascribed etiologies. Adjusted outcomes were similar across etiologic categories, as was the benefit of sacubitril/valsartan over enalapril. (Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure; NCT01035255).

[The importance of biochemical studies for practical forensic-medical expert examination].

Sudden death along with differential diagnosis of deaths from coronary heart disease and alcoholic cardiomyopathy is a challenging problem in practical forensic medicine. Relevant investigations demonstrated the possibility to address it using a battery of biochemical methods, such as measurement of blood glucose level in heart cavities, lactate dehydrogenase activity in myocardium, etc.