Alcoholic cardiomyopathy: an update.

Alcohol-induced cardiomyopathy (AC) is an acquired form of dilated cardiomyopathy (DCM) caused by prolonged and heavy alcohol intake in the absence of other causes. The amount of alcohol required to produce AC is generally considered as >80 g/day over 5 years, but there is still some controversy regarding this definition. This review on AC focuses on pathogenesis, which involves different mechanisms. Firstly, the direct toxic effect of ethanol promotes oxidative stress in the myocardium and activation of the renin-angiotensin system. Moreover, acetaldehyde, the best-studied metabolite of alcohol, can contribute to myocardial damage impairing actin-myosin interaction and producing mitochondrial dysfunction. Genetic factors are also involved in the pathogenesis of AC, with DCM-causing genetic variants in patients with AC, especially titin-truncating variants. These findings support a double-hit hypothesis in AC, combining genetics and environmental factors. The synergistic effect of alcohol with concomitant conditions such as hypertension or liver cirrhosis can be another contributing factor leading to AC. There are no specific cardiac signs and symptoms in AC as compared with other forms of DCM. However, natural history of AC differs from DCM and relies directly on alcohol withdrawal, as left ventricular ejection fraction recovery in abstainers is associated with an excellent prognosis. Thus, abstinence from alcohol is the most crucial step in treating AC, and specific therapies are available for this purpose. Otherwise, AC should be treated according to current guidelines of heart failure with reduced ejection fraction. Targeted therapies based on AC pathogenesis are currently being developed and could potentially improve AC treatment in the future.

miR-92a-3p regulates ethanol-induced apoptosis in H9c2 cardiomyocytes.

The role of miR-92a-3p in the ethanol-induced apoptosis of H9c2 cardiomyocytes remains unclear. In this study, we explored the role of miR-92a-3p in the ethanol-induced apoptosis of H9c2 cardiomyocytes and identified its target genes and signaling pathways. H9c2 cells were cultured with or without 100 mM ethanol for 24 h. The differential expression of miR-92a-3p was verified in H9c2 cells through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). To manipulate the expression of miR-92a-3p, both a mimic and an inhibitor were transfected into H9c2 cells. An Annexin V-fluorescein isothiocyanate/propidium iodide apoptosis detection kit and apoptosis-related antibodies were used for apoptosis detection through flow cytometry and Western blotting, respectively. Target genes were verified through RT-qPCR, Western blotting, and double luciferase reporter gene assays. miR-92a-3p was significantly overexpressed in ethanol-stimulated H9c2 cardiomyocytes (P < 0.001). After ethanol stimulation, H9c2 myocardial cells exhibited increased apoptosis. The apoptosis rate was higher in the miR-92a-3p mimic group than in the control group. However, the apoptosis rate was lower in the miR-92a-3p inhibitor group than in the control group, indicating that miR-92a-3p promotes the ethanol-induced apoptosis of H9c2 myocardial cells. RT-qPCR and Western blotting revealed that the miR-92a-3p mimic and inhibitor significantly regulated the mRNA and protein expression levels of mitogen- and stress-activated protein kinase 2 and cyclic AMP-responsive element-binding protein 3-like protein 2 (CREB3L2), suggesting that miR-92a-3p promotes the apoptosis of H9c2 cardiomyocytes by inhibiting the MSK2/CREB/Bcl-2 pathway. Therefore, the apoptosis of H9c2 cardiomyocytes increases after ethanol stimulation, and miR-92a-3p can directly target MSK2 and CREB3L2, thereby promoting the ethanol-induced apoptosis of H9c2 myocardial cells.

Biventricular Impairment and Ventricular Interdependence in Patients With Alcoholic Cardiomyopathy: Insights Through Cardiac Magnetic Resonance Imaging.

BACKGROUND: Alcoholic cardiomyopathy (ACM) can lead to progressive cardiac dysfunction and heart failure, but little is known about biventricular impairment and ventricular interdependence (VI) in ACM patients. PURPOSE: To use cardiac MRI to investigate biventricular impairment and VI in ACM patients. STUDY TYPE: Retrospective. POPULATION: Forty-one male patients with ACM and 45 sex- and age-matched controls. FIELD STRENGTH/SEQUENCE: 3.0 T/balanced steady-state free precession sequence, inversion recovery prepared echo-planar imaging sequence and phase-sensitive inversion recovery sequence. ASSESSMENT: Biventricular structure, function, and global strain (encompassing peak strain [PS], peak systolic, and diastolic strain rate), PS of interventricular septal (IVS), microvascular perfusion (including upslope and time to maximum signal intensity [TTM]), late gadolinium enhancement (LGE), and baseline characteristics were compared between the controls and ACM patients. STATISTICAL TESTS: Student's t-test, Mann-Whitney U test, Pearson's correlation, and multivariable linear regression models with a stepwise selection procedure. A two-tailed P value <0.05 was deemed as statistically significant. RESULTS: Compared to control subjects, ACM patients showed significantly biventricular adverse remodeling, reduced left ventricle (LV) global upslope and prolonged global TTM, and the presence of LGE. ACM patients were characterized by a significant decline in all global strain within the LV, right ventricle (RV), and IVS compared with the controls. RV global PS was significantly associated with LV global PS and IVS PS in radial, circumferential, and longitudinal directions. Multivariable analyses demonstrated the longitudinal PS of IVS was significantly correlated with RV global radial PS (ß = 0.614) and circumferential PS (ß = 0.545). Additionally, RV global longitudinal PS (GLPS) was significantly associated with radial PS of IVS (ß = -0.631) and LV GLPS (ß = 1.096). DATA CONCLUSION: ACM patients exhibited biventricular adverse structural alterations and impaired systolic and diastolic function. This cohort also showed reduced LV microvascular perfusion, the presence of LGE, and unfavorable VI. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

ABHD5 protects cardiac function in alcoholic cardiomyopathy via HDAC4-NT to inhibit CAMKII/MEF2 axis.

Excessive intake of Alcohol is associated with a high incidence of alcoholic cardiomyopathy (ACM), which may impair cardiac function. In our study, we explored the Abhydrolase Domain Containing 5 (ABHD5) mechanism in ACM about histone deacetylase 4 (HDAC4) and CaM-CaMKII/MEF2 signaling pathway. Rat models of ACM were established in Wistar rats, and in vitro cell models were constructed in rat cardiomyocytes H9C2 utilizing 12-h of treatment of Alcohol (200 mM) to study the regulatory role of ABHD5 in ACM with the involvement of HDAC4 and CaM-CaMKII/MEF2 signaling pathway, as evidenced by determination of cardiac function, myocardial fibrosis, apoptosis of cardiomyocytes and oxidative stress condition. We found that both ABHD5 mRNA and protein expression was significantly lower in the ACM rats and rat cardiomyocytes H9C2. ACM rats with oe-ABHD5 injection showed repressed myocardial hypertrophy and myocardial fibrosis. Also, overexpression of ABHD5 reduced apoptosis and oxidative stress in H9C2 cells. Mechanistic studies demonstrated that ABHD5 via HDAC4-NT inhibits CAMKII/MEF2 axis. This study highlighted that ABHD5 decreased cardiac hypertrophy and myocardial fibrosis and limited cardiomyocyte apoptosis and oxidative stress injury in ACM.

Reduced myocardial work in asymptomatic heavy alcohol use and its correlation with epicardial adipose tissue volume and serum biomarkers.

BACKGROUND: It is unclear whether long-term heavy alcohol use leads to early cardiac function decline. HYPOTHESIS: Long-term heavy alcohol use developed reduced cardiac function in subclinical status by analyzing myocardial work (MW). Epicardial adipose tissue (EAT) volume and serum biomarkers contribute to identify potential factors sensitive in predicting early cardiac function decline. METHODS: We enrolled 31 asymptomatic participants with heavy alcohol use and 33 age and sex-matching nondrinking individuals. Participants underwent echocardiography, MW analysis, EAT volume measurement, serum biochemical examinations, and body composition assessment. We used multivariate linear regression to identify correlation between MW and total cholesterol (TC), EAT volume, and placental growth factor (PlGF). To determine global work efficiency (GWE) below the normal reference value of 96%, we developed receiver operating curves with area under curve (AUC) to compare different combinations of TC, EAT volume, and PlGF. RESULTS: All 64 participants were male. GWE was reduced in the alcohol use group compared with the control group (96, interquartile range [IQR] = [95-97.75] vs. 97, IQR = [97-98], p = .004). TC was positively associated with GWE (ß = .434, 95% confidence interval [CI] = 0.228 to 1.328, p = .008), whereas EAT volume (ß = -.398, 95% CI = -0.000446 to -0.000093, p = .005) and PlGF (ß = -.493, 95% CI = -1.010 to -0.230, p = .004) were inversely associated with GWE. The most significant AUC for reduced GWE was TC + EAT volume (0.851, 95% CI = 0.671 to 1, p = .006). CONCLUSION: Asymptomatic heavy alcohol use has shown early reduced cardiac function which can be associated with altered fat metabolism, suggesting individuals with alcohol use and abnormal fat metabolism need to be alert to heart damage.

Heartache in a Bottle: Understanding Alcoholic Cardiomyopathy.

Alcoholic cardiomyopathy (ACM) is a cardiac ailment marked by impaired contraction and dilation of one or both ventricles of the heart. The extent of daily alcohol intake and duration of alcohol abuse are linked to the development of ACM, although the exact thresholds and timeline for alcohol misuse to induce heart dysfunction remain uncertain. Thus, the objective of this systematic review is to comprehensively evaluate the existing knowledge on the specific disease entity, particularly in light of the ongoing issue of alcohol misuse, with the intention of determining if recent advancements and discoveries have significantly altered the understanding of this condition compared to the past century. This systematic review involved a literature search that was conducted on PubMed to identify suitable and appropriate literature for the study. The inclusion criteria encompassed articles that focused on ACM or the relationship between alcohol abuse and cardiac dysfunction, involved human subjects or relevant animal models, were written in the English language, and were published within the last 10 years. The exclusion criteria included duplicates, case reports, letters, editorials, and reviews not specifically addressing ACM. As a result, a total of 18 articles were included in this systematic review. The risk of bias was assessed through the use of the Cochrane risk-of-bias tool for clinical trials. The findings of this systematic review indicated that the likelihood of ACM occurrence significantly rose when the consumption of over 80 g of alcohol per day occurred for at least five years. The systematic review further revealed that ACM is associated with various detrimental changes in the cellular, structural, and histological aspects of the heart muscles, even though the specific clinical and histological characteristics of ACM have yet to be established. In individuals with an extensive history of excessive alcohol abuse, the diagnosis of ACM was reached through the exclusion of other potential causes of the condition. The fundamental approach to treatment lies in abstaining from alcohol. It is crucial to manage symptoms in individuals with secondary heart failure and address any related complications.

Changes in Microcirculation in the Brain, Heart, and Liver in Female Rats with Translational Model of Alcoholic Cardiomyopathy.

We studied some features of blood and lymph microcirculation in the brain, heart, and liver of female rats with developed alcoholic cardiomyopathy. In female rats after 24-week forced consumption of 10% ethanol solution, the size and inotropic function of the heart were measured by echocardiography. Microcirculation in the brain, myocardium, and liver was assessed by laser Doppler flowmetry using LAKK-OP2 and LAZMA-D computerized laser analyzers. Using spectral wavelet analysis, we determined the absolute and normalized to total perfusion amplitudes of microcirculation oscillations reflecting various regulatory mechanisms. Intact animals served as controls. In rats of the experimental group, alcoholic cardiomyopathy completely developed. Under these conditions, the index of microcirculation in the brain, myocardium, and liver significantly decreased. At the same time, there was a redistribution in the brain between shunting and nutritive blood flow in favor of the latter. In the myocardium and liver, this ratio did not change.

Efecto del alcohol sobre el corazón y el sistema cardiovascular: hipertrofia, remodelamiento y disminución del strain. Información actual / Alcohol Impact on the Heart and Cardiovascular System - Hypertrophy, Remodeling and Strain Impairment - Contemporary State-of-the-Art

RESUMEN Datos recientes muestran que el abuso crónico de alcohol puede conducir a disfunción cardiovascular, a partir de dosis de etanol tradicionalmente consideradas bajas, y que la aparición de arritmias, incluyendo la fibrilación auricular, aumenta aún en consumidores de alcohol moderados. Los otros mecanismos comunes del impacto negativo del etanol están relacionados con el desarrollo de hipertensión y su consecuencia directa, la hipertrofia, fibrosis y disfunción diastólica. Debido a que la probabilidad de reversibilidad del remodelamiento cardíaco depende de un diagnóstico temprano de disfunción cardíaca, se debería recomendar la aplicación más amplia de métodos nuevos y más sensibles de evaluación de la función miocárdica, incluyendo el strain longitudinal ventricular izquierdo y derecho, así como de los protocolos adaptados a la ecocardiografía de estrés.

ABSTRACT The recent data show that chronic overuse of alcohol may lead to cardiovascular dysfunction, starting from traditionally judged as low ethanol doses, and that the burden of arrhythmias, including atrial fibrillation, increases even in moderate alcohol consumers. The other common mechanisms of the disadvantageous impact of ethanol are related to the development of hypertension and its direct aftermath, hypertrophy, fibrosis, and diastolic dysfunction. Since the chance of the reversibility of cardiac remodeling depends on the early diagnosis of cardiac dysfunction, the wider application of novel and sensitive methods of myocardial function assessment, including longitudinal strain of the left and right ventricles, as well as the adapted protocols for stress echocardiography, should be recommended.

Metformin alleviates ethanol-induced cardiomyocyte injury by activating AKT/Nrf2 signaling in an ErbB2-dependent manner.

BACKGROUND: Metformin, a first-line oral anti-diabetic drug, has recently been reported to exert protective effect on various cardiovascular diseases. However, the potential role of metformin in ethanol-induced cardiomyocyte injury is still unknown. Therefore, this study was aimed to investigate the effect of metformin on ethanol-induced cardiomyocyte injury and its underlying mechanism. METHODS AND RESULTS: H9c2 cardiomyocytes were exposed to ethanol for 24 h to establish an ethanol-induced cardiomyocyte injury model, and followed by treatment with metformin in the presence or absence of Lapatinib (an ErbB2 inhibition). CCK8 and LDH assays demonstrated that metformin improved cell viability in cardiomyocytes exposed to ethanol. Furthermore, metformin suppressed cardiomyocyte apoptosis and reduced the expressions of apoptosis-related proteins (Bax and C-CAS-3). In addition, our results showed that metformin activated the AKT/Nrf2 pathway, and then promoted Nrf2 nuclear translocation and the transcription of its downstream antioxidant genes (HO-1, CAT and SOD2), thereby inhibiting oxidative stress. Interestingly, we found that ErbB2 protein expression was significantly inhibited in ethanol-treated cardiomyocytes, which was markedly reversed by metformin. In contrast, Lapatinib largely abrogated the activation of AKT/Nrf2 signaling by metformin, accompanied by the increases in oxidative stress and cardiomyocyte apoptosis, indicating that metformin prevented ethanol-induced cardiomyocyte injury in an ErbB2-dependent manner. CONCLUSION: In summary, our study provides the first evidence that metformin protects cardiomyocyte against ethanol-induced oxidative stress and apoptosis by activating ErbB2-mediated AKT/Nrf2 signaling. Thus, metformin may be a potential novel treatment approach for alcoholic cardiomyopathy.

Identification and management of acute alcohol intoxication.

Acute alcohol intoxication (AAI) is a harmful clinical condition, potentially life-threatening, secondary to the intake of large amounts of alcohol. Clinical manifestations of AAI are characterized by behavioural and neurological symptoms, even if its effects involve several organs and apparatus. Moreover, severe alcohol intoxication can produce a global neurological impairment leading to autonomic dysfunction, respiratory depression, coma and cardiac arrest. The evaluation of blood alcohol concentrations (BAC) is useful to confirm the suspicion of intoxication, both for clinical and legal reasons. Most of patients with AAI are referred to Emergency Departments due to behavioural, social, traumatic or clinical complications. Patient's stabilization is the first step in the management of AAI, in order to support vital functions and to prevent complications. Metadoxine represents a useful drug to increase ethanol metabolism and elimination. Given that AAI could represent a sentinel event of chronic alcohol abuse, patients presenting with acute intoxication should be screened for the presence of an underlying alcohol use disorder and referred to and an alcohol addiction unit to start a multidisciplinary treatment to achieve long term alcohol abstinence. The present review will focus on clinical features, diagnostic criteria and treatment strategies of AAI.

Comprehensive analysis of transcriptomics and metabolomics to understand chronic ethanol induced murine cardiotoxicity.

Alcohol abuse has attracted public attention and long-term alcohol exposure can lead to alcohol-featured non-ischemic dilated cardiomyopathy. However, the precise underlying mechanisms of alcoholic cardiomyopathy remain to be elucidated. This study aimed to comprehensively characterize alcohol abuse-mediated effects on downstream metabolites and genes transcription using a multi-omics strategy. We established chronic ethanol intoxication model in adult male C57BL/6 mice through 8 weeks of 95% alcohol vapor administration and performed metabolomics analysis, mRNA-seq and microRNA-seq analysis with myocardial tissues. Firstly, ethanol markedly induced ejection fraction reductions, cardiomyocyte hypertrophy, and myocardial fibrosis in mice with myocardial oxidative injury. In addition, the omics analysis identified a total of 166 differentially expressed metabolites (DEMs), 241 differentially expressed genes (DEGs) and 19 differentially expressed microRNAs (DEmiRNAs), respectively. The results highlighted that alcohol abuse mainly interfered with endogenous lipids, amino acids and nucleotides production and the relevant genes transcription in mice hearts. Based on KEGG database, the affected signaling pathways are primarily mapped to the antigen processing and presentation, regulation of actin cytoskeleton, AMPK signaling pathway, tyrosine metabolism and PPAR signaling pathway, etc. Furthermore, 9 hub genes related to oxidative stress from DEGs were selected based on function annotation, and potential alcoholic cardiotoxic oxidative stress biomarkers were determined through establishing PPI network and DEmiRNAs-DEGs cross-talk. Altogether, our data strongly supported the conclusion that ethanol abuse characteristically affected amino acid and energy metabolism, nucleotide metabolism and especially lipids metabolism in mice hearts, and underlined the values of lipids signaling and oxidative stress in the treatment strategies.

Alcohol and Heart Failure.

Alcohol is the most frequently consumed toxic substance in the world and remains a major global public health issue, with one in three adults consuming it worldwide. Alcohol use is a leading risk factor for disease, contributing to over 60 acute and chronic health conditions, with a particularly complex association with cardiovascular disease. Chronic excessive alcohol consumption is associated with a range of cardiac complications, including decreased myocardial contractility, hypertension, arrhythmias, MI and heart failure. However, low-level alcohol consumption is believed to have a protective effect against ischaemic heart disease and diabetes. In most cohort studies, small to moderate amounts of alcohol consumption have not been linked to heart failure, indicating a threshold effect of alcohol with individual (possibly genetic) predisposition rather than a continuous effect of exposure. This review article explores the potential benefits of alcohol on the heart, the association between alcohol use and alcoholic cardiomyopathy and the epidemiology, clinical correlates and management of alcoholic cardiomyopathy.

National, regional, and global cardiomyopathy burden from 1990 to 2019.

Objective: To examine the incidence of cardiomyopathy including both alcoholic cardiomyopathy (AC) and other cardiomyopathy (OC) in 204 nations and regions over the 1990-2019 period. Methods: The present study was conducted using data derived from the GBD 2019 study coordinated by the Institute for Health Metrics and Evaluation (IHME). The GBD 2019 study included epidemiological data pertaining to 369 diseases/injuries, 286 causes of death, and 87 risk factors in 204 nations and regions. For this study, we adopt published estimates pertaining to the prevalence rates, mortality rates, and disability-adjusted life years (DALYs) associated with cardiomyopathy. The Bayesian mixed-effects DisMod-MR 2.1 meta-regression tool, which was designed to analyze GBD data, was used to estimate the prevalence of OC and AC. The GBD data are subdivided into 21 global regions based on characteristics such as geographical proximity and epidemiological similarity. The overall burden of cardiomyopathy was assessed by combining AC- and OC-related data, 95% confidence intervals were calculated based on standardized error values determined based upon the width of the 95% UI divided by 1.96 × 2. Results: Globally, there were an estimated 0.71 million (95% UI: 0.55-0.92) AC cases and 3.73 million (95% UI: 2.92-4.72) OC cases in 2019. The age-standardized cardiomyopathy, AC, and OC prevalence rates (per 100,000 persons) in 2019 were 56.0 (95% CI: 43.82-71.17), 8.51 (95% UI: 6.6-11.01), and 47.49 (95% UI: 37.22-60.16), respectively. In total, the respective numbers of global deaths attributed to AC and OC were 0.07 million (95% UI: 0.06-0.08) and 0.24 million (95% UI: 0.19-0.26). The age-standardized mortality rate for cardiomyopathy in 2019 was 3.97 (95% CI: 3.29-4.39), with respective mortality rates of 0.86 (95% UI: 0.72-0.99) and 3.11 (95% UI: 2.57-3.4) for AC and OC. At the global level in 2019, 2.44 million (95% UI: 2.04-2.78) DALYs were attributed to AC, while 5.72 million (95% UI: 4.89-6.33) DALYs were attributed to OC. From 1990 to 2019, cardiomyopathy age-standardized prevalence rates declined by -0.49% (95% CI: -0.57 to -0.41), with those for AC and OC having respectively declined by -0.32% (95% UI: -0.36 to -0.28) and -0.17% (95% UI: -0.21 to -0.13). The age-standardized AC and OC mortality rates declined by -0.36% (95% UI: -0.5 to -0.26) and -0.39% (95% UI: -0.44 to -0.29), despite 24.8 and 30.2% increases, respectively, in the numbers of AC- and OC-related deaths during the same period. Conclusion: Previous studies have estimated the risk factors that influence the burden of multiple cardiovascular diseases (CVD). Among them, some studies related to the GBD database on cardiomyopathy data suggest that alcohol intake, gender are factors in the development of AC, and the burden of AC and OC is not limited to developed or less developed countries. Otherwise, this study mainly focused on cardiomyopathy, and analyzed multiple indicators from national, regional, and age-standard dimensions to identify potential risk factors including prevalence, deaths, years lived with Disability-adjusted life years (DALYs) that influence the development of AC and OC. To our knowledge, this study is the first to have systematically assessed the burden of AC and OC as of 2019 at the national, regional, and global levels and calculated DALYs to achieve a better evaluation of disease risk and quality of life of the population. The number of cases, deaths and DALYs of cardiomyopathy showed an overall increasing trend and obvious geographical differences in the past three decades. The burden of cardiomyopathy remains a persistent threat to global public health. These results provide an epidemiological foundation that can guide public health efforts and policymakers.

Percutaneous Coronary Intervention Outcomes Among Patients With Alcoholic Cardiomyopathy: An Analysis of the National Inpatient Sample.

Introduction High consumption of alcohol has an enormous toll on the health status of individuals. A direct affectation of cardiac integrity concerns cardiologists, primary care physicians, and the healthcare system because this increases the disease burden. Alcoholic cardiomyopathy (ACM) results from the enormous consumption of alcohol over a long period of time. The prevalence varies between regions and sex and ranges between 4% and 40%. Viewing the entire spectrum of cardiomyopathies, ACM makes up about 4% of all cardiomyopathies. However, it causes dilated-type cardiomyopathy and is the second most common cause of dilated cardiomyopathy. We sought to explore the outcomes of percutaneous coronary intervention (PCI) among patients with ACM. Methods This was a retrospective, cross-sectional study of the National Inpatient Sample (NIS) for hospital discharges in the United States between 2012 and 2014. We identified the number of patients with a primary or secondary diagnosis of ACM using the International Classification of Diseases, Ninth Revision (ICD-9) code of 4.255. Using the ICD-9 codes for PCI (00.66, 36.01, 36.02, 36.05, 36.06, 36.07, and 17.55), we identified patients diagnosed with ACM who underwent a PCI (ACPCI). The racial and sexual prevalence, hospital length of stay (LOS), mortality, cost of hospitalization, and cardiovascular outcomes (ventricular fibrillation (VF) and atrial fibrillation (AF)) were compared between patients with and without ACM who underwent a PCI. Results A total of 2,488,293 PCIs were performed between 2012 and 2014. Of these, there were a total of 161 admissions for ACM. About 93% (151) of the ACM PCI group were men. Ethnic distribution revealed a majority of Caucasians with 69% (98), and blacks and Asians at 13.4% (19) and 11.3% (16), respectively. The mean age was 59.8 (SD = 9). The patients with ACPCI were likely to stay longer in the hospital, with an average stay of 6.6 days (SD = 6.2) compared to patients without ACM undergoing PCI (NOACPCI) (3.7 days; SD = 5.0) (p = 0.0001). The mean cost of hospital admission for patients with ACPCI was $120,225 (SD = 101,044), while that of those without ACM who underwent PCI (NOACPCI) was $87,936 (SD = 83,947) (p = 0.0001). A higher death rate during hospitalization (3.7%) was recorded in the ACPCI category vs. 2.3% in patients without ACM who underwent PCI (p = 0.0001). Patients with ACPCI had a higher prevalence of AF (30.4%) than VF (7.5%). Conclusion The ACPCI group had overall poorer hospital outcomes. The majority affected were older Caucasian men with an increased prevalence of AF, higher cost of hospitalization, and longer hospital stays. Further studies are needed to explore the burden of long-term alcohol consumption on cardiovascular disease treatment outcomes.

Extrahepatic Manifestations in Alcoholic Liver Disease.

Though liver is the most commonly affected organ in patients with chronic and excessive intake of alcohol, no organ is immune to toxic effects of alcohol and patients with alcohol-related liver disease (ALD) can suffer from a wide list of extrahepatic manifestations involving gastrointestinal tract, central and peripheral nervous systems, cardio vascular system, musculo-skeletal system, disruption of nutritional status, endocrinological abnormalities, hematological abnormalities and immune dysfunction. These extrahepatic organ involvements are usually overlooked by hepatologists and physicians who are mostly focused on managing life threatening complications of ALD. As a result, there is delayed diagnosis, delay in the initiation of appropriate treatment and late referral to other specialists. Some of these manifestations are of utmost clinical importance (e.g. delirium tremans and Wernicke's encephalopathy) because an early diagnosis and treatment can lead to full recovery while delayed or no treatment can result in death. On the other hand, several extrahepatic manifestations are of prognostic significance (such as alcoholic cardiomyopathy and malignancies) in which there is an increased risk of morbidity and mortality. Hence, a clear understanding and awareness of the extrahepatic manifestations of ALD is quintessential for proper management of these patients.

Myocardial Injury Caused by Chronic Alcohol Exposure-A Pilot Study Based on Proteomics.

Chronic alcohol exposure can cause myocardial degenerative diseases, manifested as cardiac insufficiency, arrhythmia, etc. These are defined as alcoholic cardiomyopathy (ACM). Alcohol-mediated myocardial injury has previously been studied through metabolomics, and it has been proved to be involved in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway concerning unsaturated fatty acids biosynthesis and oxidative phosphorylation, which tentatively explored the mechanism of ACM induced by chronic drinking. To further study alcohol-induced myocardial injury, myocardial specimens from a previously successfully established mouse model of ACM were subjected to histological, echocardiographic, and proteomic analyses, and validated by real-time quantitative polymerase chain reaction (qPCR). Results of histopathology and echocardiography showed the hypertrophy of cardiomyocytes, the dilation of ventricles, and decreased cardiac function. Proteomic results, available via ProteomeXchange with identifier PXD032949, revealed 56 differentially expressed proteins (DEPs) were identified, which have the potential to be involved in the KEGG pathway related to fatty acid biosynthesis disorders, lipid metabolism disorders, oxidative stress, and, ultimately, in the development of dilated cardiomyopathy (DCM). The present study further elucidates the underlying effects of myocardial injury due to chronic alcohol intake, laying a foundation for further studies to clarify the potential mechanisms of ACM.

Detecting Concealing Heart Failure in a Young Alcohol-Related Liver Failure Patient Using the Most Basic Pathophysiological Principle.

Long-term alcohol abuse can cause alcohol-related liver injury (acute alcoholic hepatitis, acute liver failure, hepatic steatosis, fibrosis, or cirrhosis), as well as cardiac injury. Alcoholic cardiomyopathy is a severe consequence of chronic alcohol abuse. Incidence of alcoholic cardiomyopathy ranges from 1-2% of all heavy alcohol users. In the United States, excess alcohol consumption contributes to more than 10% of cases of heart failure. Here, we present a case of a 41-year-old male patient with severe alcohol abuse who presented with signs and symptoms of liver failure and was found to have severe left ventricular systolic dysfunction and dilated cardiomyopathy. More interestingly, the detection of heart failure in this patient was convoluted but also represented an amazing example of how the most basic pathophysiological principles help answer clinical questions in a perplexing scenario. The patient is a 41-year-old Caucasian male with severe alcohol abuse who presented with complaints of diffuse yellowish discoloration of skin, fatigue, and "feeling not like himself" for six weeks. A review of systems revealed mild exertional dyspnea and bilateral lower extremity swelling. Physical exam was remarkable for diffuse jaundice involving the whole body, tachycardia, and trace edema in the lower extremity bilaterally. Otherwise, lungs were clear to auscultation, normal heart sounds with regular heart rate and rhythm, no Jugular vein distention, and no carotid bruits were appreciated. Labs showed elevated total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), ammonia, and lactate levels. Notably, venous blood gas (VBG) showed metabolic acidosis with compensating respiratory alkalosis with normal potential Hydrogen (pH). An electrocardiogram showed sinus tachycardia. Treatment was started for acute alcoholic liver failure, with intravenous fluids, intravenous prednisolone, and Clinical Institute Withdrawal Assessment for Alcohol (CIWA) protocol. The patient's liver function markers went down stably. However, the patient's mental status got worse and his lactate levels continued to rise. He was prescribed empirical antibiotics with a pan Computed tomography (CT) scan to look for any source of infection which revealed no meaningful positive findings. Surprisingly and interestingly, the venous blood gas pH started to trend up demonstrating alkalotic pH which contrasted the initial normal pH on admission. The metabolic acidosis was seemingly "over-compensated" by respiratory alkalosis. It was speculated that another underlying pathology existed to count for respiratory alkalosis. Chest X-ray (CXR) showed cardiomegaly but no pneumonia. An echocardiogram showed severe left ventricular systolic dysfunction with an Ejection Fraction of 20% and dilated left ventricle. The treatment direction was switched from treating liver failure to targeting heart failure with intravenous diuretics. The patient's mental status improved remarkably after three days of diuresis and the patient was finally discharged to a nursing home and followed up with Cardiology.

Ectopic accumulation of ceramide in cardiomyocytes modulates alcoholic cardiomyopathy via the TLR4-dependent pathway.

BACKGROUND AND AIMS: Excessive alcohol consumption predisposes drinkers to develop alcoholic cardiomyopathy. Although cardiomyocyte loss is the hallmark of cardiomyopathy, the underlying mechanism remains elusive. This study examined the potential mechanism of alcohol-induced cardiomyocyte death in a mouse model of alcoholic cardiomyopathy. METHODS: We established the alcoholic cardiomyopathy mouse model using C57BL/6J mice and confirmed it via echocardiography and histological examination. The cardiac ceramide content and profile were analyzed with a triple-quadrupole mass spectrometer. The molecular mechanism underlying the accumulation of ceramide due to chronic alcohol consumption and ceramide-induced cardiomyocyte death were investigated by in vivo and in vitro models. Finally, we established a TLR4 mutation model to explore the function of TLR4 in CH3/HeJ mice. RESULTS: Cardiac lipotoxicity that followed alcohol exposure resulted mainly in C16:0-, C18:0-, and C24:1-ceramide aggregation. Genes encoding the sphingosine hydrolysis enzymes (SMPD1 and SMPD2) rather than de novo synthetic biomarkers were markedly upregulated. Exogenous ceramide mimics (C6-ceramide) werenderlying the accumulation of ceramide observed to cause H9C2 cardiomyocyte-like cell death, which was consistent with results under palmate acid (PA) treatment. As a ceramide precursor, PA induces intracellular ceramide generation through TLR4 signaling, which can be abolished by an inhibitor of ceramide synthesis. Furthermore, mechanistic investigations demonstrated that pharmacological or genetic inhibition of TLR4 attenuated PA-induced cell death and corresponding ceramide production. Moreover, global mutation of TLR4 in CH3/HeJ mice significantly reduced the accumulation of C24:0, C24:1, OH_C24:1, and total ceramide following alcohol challenge. CONCLUSIONS: Our findings demonstrate that ceramide accumulation plays a crucial role in alcoholic cardiomyopathy, effects that are partially mediated through the TLR4-dependent pathway.

Knockdown of lectin-like oxidized low-density lipoprotein-1 ameliorates alcoholic cardiomyopathy via inactivating the p38 mitogen-activated protein kinase pathway.

LOX-1 triggers myocardial fibrosis, but its roles and mechanisms in alcoholic cardiomyopathy and the involvement of the downstream signaling pathways had not been fully reported. We planned to explore how LOX-1 facilitated myocardial fibrosis in alcoholic cardiomyopathy. The in vitro and in vivo alcoholic cardiomyopathy model was established by alcohol treatment to rats' cardiac fibroblasts and rats, respectively. Masson staining was conducted to observe the collagen deposition and the IHC assay was executed to evaluate the contents of collagen I and III in vitro and in vivo. The cardiac tissues were also observed under TEM and the cardiac function of rats was evaluated using UCG. The expression levels of LOX-1 and P38MAPK in cardiac fibroblasts and tissues at both mRNA and protein levels were analyzed by RT-qPCR and western blot, respectively. Alcohol treatment could trigger collagen deposition, cell hypertrophy, fibrotic changes and increased the expression levels of LOX-1 and P38MAPK both in vivo and in vitro. It also deteriorated the cardiac function of rats in vivo. Overexpression of LOX-1 in vitro could aggravate the fibrotic changes while knockdown of LOX-1 ameliorated the fibrotic effects of alcohol treatment both in vitro and in vivo such as reduction of collagen deposition, relief of cell hypertrophy and inactivation of the P38MAPK signaling pathway. We concluded that knockdown of LOX-1 exerted anti-fibrotic effects via inhibiting P38MAPK signaling in alcoholic cardiomyopathy both in vitro and in vivo. Our findings highlighted that LOX-1 could become a potential therapeutic target in the treatment of alcoholic cardiomyopathy.