Alcoholic cardiomyopathy

Alcohol is the most frequently consumed toxic substance in the world. Low to moderate daily intake of alcohol has been shown to have beneficial effects on the cardiovascular system. In contrast, exposure to high levels of alcohol for a long period could lead to progressive cardiac dysfunction and heart failure. Cardiac dysfunction associated with chronic and excessive alcohol intake is a specific cardiac disease known as alcoholic cardiomyopathy(ACM). In spite of its clinical importance, data on ACM and how alcohol damages the heart are limited. In this review, we evaluate available evidence linking excessive alcohol consumption with heart failure and dilated cardiomyopathy. Additionally, we discuss the clinical presentation, prognosis and treatment of ACM.     

Alcoholic cardiomyopathy in mice. Electron microscopic observations

C57B1 mice have been fed a liquid alcohol diet which provided 36% of the calories from alcohol for 15 and 25 week periods. At the time of sacrifice, the heart was prepared for light and electron microscopic examination. Early, most changes occurred in the mitochondria which increased in number, size and finally fused together to form giant forms (megamitochondria). Triglyceride also increased early, but glycogen content remained normal or somewhat reduced. Dehiscence of the intercalated disc was apparent at 15 weeks. The most impressive changes observed at 25 weeks included interstitial oedema, fluid accumulation beneath the sarcolemma and interstitial fibrosis. The mouse appears to be a useful experimental animal model for this disease.     

Normalization of variables of left ventricular function in patients with alcoholic cardiomyopathy after cessation of excessive alcohol intake: an echocardiographic study

An excessive alcohol intake has been reported as one of thepossible causes or risk factors of ‘alcoholic cardiomyopathy’.The possibility that this cardiomyopathy may improve or evenreverse if the alcohol abuse has been terminated has been suggested,but unequivocal echocardiographic documentation of this improvementhas never been described. This study reports the normalization of cardiac chamber dimensionsand of variables of left ventricular function documented byM-mode and cross-sectional echocardiographic follow-up studies,after cessation of excessive consumption of alcohol, in threecases of alcoholic cardiomyopathy.     

肌钙蛋白和C-反应蛋白在缺血性心肌病与扩张型心肌病中的变化

目的探讨肌钙蛋白（cTn-I）和超敏G反应蛋白（hs-CRP）在缺血性心肌病与扩张型心肌病患者中的变化。方法101例心肌病患者行冠脉造影检查，分为缺血性心肌病组（ICM组，53例）和扩张型心肌病组（DCM组，48例）。测定患者在不同NYHA分级时血清cTn-I和hs-CRP浓度。结果ICM患者平均血清hs-CRP浓度高于DCM患者，分别为（4．13±1107）和（2．64±1．19）mg／L；在相同NYHA时，ICM患者的血清hs-CRP浓度明显高于DCM患者（P〈0．01）。ICM患者血清平均cTn-I浓度与DCM患者相似，分别为（0．31±0．27）和（0．34±0．33）μg／L；ICM和DCM患者血清cTn-I浓度在相同NYHA时比较无显著性差异（P〉0．05）。无论是ICM患者还是DCM患者，血清hs-CRP和cTn-I浓度均随心衰程度加重而增高，NYHA Ⅲ和Ⅳ级患者血清hs-CRP和cTn-I浓度明显高于NYHA Ⅰ和Ⅱ级患者（P〈0．01）。结论ICM患者和DCM患者血清hs-CRP和cTn-I浓度随心衰程度加重而增高。ICM患者血清hs-CRP浓度明显高于DCM患者，而两组cTn-I浓度比较无显著性差异。心衰患者cTn-I升高非冠状动脉缺血所致，而与心衰本身有关。     

Regression of dilated-hypokinetic hypertrophic cardiomyopathy by biventricular cardiac pacing.

The evolution of hypertrophic cardiomyopathy (HCM) towards dilatation and hypokinesis is an increasingly recognized complication with a high incidence of adverse outcomes, including sudden cardiac death, requiring defibrillator implantation and cardiac transplantation. It is generally regarded as the irreversible 'burnt-out' end-stage manifestation of HCM. We report one of the first cases of profound regression of the dilated-hypokinetic state by the application of biventricular pacing and cardiac resynchronization therapy (CRT). Reviewing the literature on the role of pacing in HCM and the energetic rationale for CRT in HCM prompts us to suggest that further systematic studies are needed urgently to assess the role of CRT in HCM variants.     

Relationship Between Serum Levels of Anti-Low-Density Lipoprotein-Acetaldehyde-Adduct Antibody and Aldehyde Dehydrogenase 2 Heterozygotes in Patients With Alcoholic Liver Injury

We prepared low-density lipoprotein (LDL)-acetaldehyde-adduct (hereafter abbreviated as LDL-adduct) and anti-LDL-adduct antibody by using Watanabe hyperlipidemic rabbits, and determined values of serum anti-LDL-adduct antibody levels by the ELISA method in healthy adults and patients with alcoholic liver injury. In the nondrinking group in healthy adults, values of anti-LDL-adduct antibody levels were 25 ± 13 μ g/ml, and there was no significant difference between moderate drinkers without diseases and the nondrinking group in healthy adults. Values of anti-LDL-adduct antibody in alcoholic disease groups, 17 ± 9 μ g/ml for the patients with the fatty liver group, 21 ± 14 μ g/ml for the hepatic fibrosis group, 70 ± 21 μ g/ml for the alcoholic hepatitis group, 41 ± 50 μ g/ml for the alcoholic cirrhosis group, and 19 ± 18 μ g/ml for the alcoholic pancreatitis group. Examinations of aldehyde dehydrogenase 2 (ALDH2) genetic variations by the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method in the healthy group and the liver injury group revealed a tendency for patients with ALDH2¹/2² in the liver injury group to have relatively mild liver lesions. When comparing anti-LDL-adduct antibody levels between ALDH2 genetic variations, those for the patients with ALDH2¹/2¹ (36 ± 40 μ g/ml) were significantly higher than those for patients with ALDH¹/2² (11 ± 5 μ g/ml). Results of the present study suggest that genetic variation may influence the progression of liver injury.     

Divergence of Ethanol and Acetaldehyde Kinetics and of the Disulfiram-Alcohol Reaction between Subjects with and without Alcoholic Liver Disease

Despite standardization, marked interindividual variation in the severity of the disulfiram-alcohol reaction (DAR) has been observed. We studied the DAR in 51 consecutive alcoholics with ( n = 16) and without ( n = 35) significant alcoholic liver disease. Clinical signs of the DAR were much weaker in the patients with compared with those patients without liver disease. Because acetaldehyde is thought to be the main cause of the DAR, we studied ethanol and acetaldehyde kinetics in 13 patients (6 females, 7 males) with alcoholic liver disease (documented by biopsy, clinical and/or radiological findings, and by quantitative liver function) [galactose elimination capacity (GEC) 4.2 ± SD 1.0 mg/min/kg; aminopyrine breath test (ABT) 0.14 ± 0.10% dose × kg/mmol CO₂] and 13 age- and sex-matched controls (alcoholics without significant liver disease, GEC 7.1 ± 0.7; ABT 0.81 ± 0.35). Clinical signs of acetaldehyde toxicity during the DAR (flush, nausea, tachycardia, and blood pressure drop) were absent in alcoholic liver disease, but clearly evident in controls. Blood ethanol kinetics were similar in both groups, C_max and area under the concentration-time curve (AUC) being 6.27 ± 1.82 and 368.9 ± 72.9 mmol × min/liter in alcoholic liver disease, and 6.62 ± 1.71 and 377.6 ± 124.5 in controls, respectively. In contrast, there was a strong ( p < 0.001) difference in C_max and AUC of acetaldehyde, respective values being 33.46 ± 21.52 and 1463.8 ± 762.5 μmol × min/liter in alcoholic liver disease, and 110.87 ± 56.00 and 4162.0 ± 2424.6 in controls. We hypothesize that the lack of disulfiram-induced acetaldehyde retention in the alcoholic liver disease group may be due to decreased formation of disulfiram metabolites.     

非缺血性心肌病与缺血性心肌病患者心脏再同步治疗的疗效分析

目的 探讨非缺血性心肌病与缺血性心肌病患者接受心脏再同步治疗(CRT)短期及长期疗效的差异.方法 对50例心力衰竭合并束支阻滞符合CRT指南标准的患者行CRT,按照病因分为非缺血性心肌病组和缺血性心肌病组,对其术前、术后1和6个月行超声心动图、QRS时限、脑钠肽(BNP)、心功能(NYHA分级)检测并随访其长期的生存率.结果 50例患者均成功接受CRT,两组术后1个月各项检查结果较术前有显著改善,但两组间差异无统计学意义,术后6个月两组间各项指标比较差异有统计学意义.平均随访(2.04±1.21)年,两组患者5年生存率比较差异有统计学意义.结论 非缺血性心肌病与缺血性心肌病患者CRT疗效差异有统计学意义,可在术前利用心肌核素扫描检测存活心肌数量进而评估CRT疗效.     

Protein synthesis in the hippocampal slice: Transient inhibition by glutamate and lasting inhibition by ischemia

Protein synthesis was measured in hippocampal slices which were exposed to glutamate (1 mM or 10 mM) or which were deprived of glucose and oxygen (in vitro ischemia) for 15 min. Glutamate at 1 mM, a concentration estimated to occur duringin vivo ischemia did not affect protein synthesis. Ten mM glutamate inhibited protein synthesis immediately after exposure (50% of control values) and reduced ATP levels to about 30% of the control. After two hours, slices fully recovered their protein synthesis and energy metabolism. The effect of 10 mM glutamate was not receptor-mediated, as NMDA, AMPA, or metabotropic receptor antagonists failed to block the glutamate effect. Immediately after ischemia, protein synthesis was reduced to 30% of control values, and 2 hours later it was still depressed to one-half of control values. Energy charge, however, recovered completely. Ischemic inhibition of protein synthesis was not reversed by glutamate receptor antagonists. The data indicate that inhibition of protein synthesis in hippocampal slices during ischemia is not glutamate-dependent.     

Age-related alterations in cardiac protein turnover

The influence of aging on cardiac protein turnover in rats was studied in vitro and in vivo. Hearts were perfused in vitro on a modified Langendorff perfusion apparatus with buffer containing cycloheximide to inhibit protein synthesis, and the rate of phenylalanine release into the perfusate was measured as an index of protein degradation. Phenylalanine release from hearts of $\text{1-}\text{to}\text{2}\text{1}\text{2}\text{-}\text{month-old}$ rats was 0.22 ± 0.013 nmol/mg wet wt/h compared to 0.16 ± 0.011 nmol/mg/h from hearts of 10- to 14-month-old animals (P < 0.005). This represents a 27% decrease in the rate of cardiac protein degradation in perfused hearts of older rats. When insulin was present in the perfusate the difference in cardiac protein degradation rates between animals in these age groups was similar (21% decrease in older animals, P < 0.01). Protein turnover in vivo was measured by the constant infusion technique using [¹⁴C]tyrosine. The fractional rate of cardiac protein degradation decreased from 14.8 ± 1.06%/day at $\text{1}\text{1}\text{2}$ months of age to 10.8 ± 0.91%/day at 12 months of age (P < 0.05). The rate of protein synthesis was also slower in the older rats, decreasing from 19.6 ± 1.63%/day at $\text{1}\text{1}\text{2}$ months to 10.8 ± 0.91%/day at 12 months (P < 0.005). In senile (24-month-old) hooded rats the fractional rates of cardiac protein synthesis and degradation were further reduced to 6.7 ± 0.29%/day compared to 12.4 ± 0.61%/day for 12-month-old rats of the same strain (P < 0.005). Thus, we conclude that cardiac protein degradation and synthesis decrease with aging.     

The effects of diphtheria toxin on guinea-pig myocardial protein synthesis

The effects of diphtheria toxin on protein synthesis have been studied in the guinea-pig myocardium by means of cell-free systems. The effect of the toxin is located at the site of aminoacyl-tRNA transferring enzyme activity, as in other tissues. No effect on aminoacyl-tRNA synthetase activity was observed. The in vivo injection of a massive dose of diphtheria toxin had no effect on the aminoacyl-tRNA transferring enzyme activity of myocardial cytoplasmic fractions.     

Successful treatment of end-stage hypertrophic cardiomyopathy with biventricular cardiac pacing.

The beneficial use of biventricular pacing is reported in a patient with end-stage hypertrophic cardiomyopathy, intraventricular conduction delay and echocardiographic evidence of intraventricular dyssyncrony. Marked improvement in clinical status, left ventricular ejection fraction and peak VO2 were observed. As far as we know, this is the first report of a beneficial effect of a biventricular device in this subset of patients, and may be worth further investigation.     

Ethanol metabolism by HeLa cells transduced with human alcohol dehydrogenase isoenzymes: control of the pathway by acetaldehyde concentration

Background: Human class I alcohol dehydrogenase 2 isoenzymes (encoded by the ADH1B locus) have large differences in kinetic properties; however, individuals inheriting the alleles for the different isoenzymes exhibit only small differences in alcohol elimination rates. This suggests that other cellular factors must regulate the activity of the isoenzymes. Methods: The activity of the isoenzymes expressed from ADH1B*1, ADH1B*2, and ADH1B*3 cDNAs was examined in stably transduced HeLa cell lines, including lines which expressed human low K_m aldehyde dehydrogenase (ALDH2). The ability of the cells to metabolize ethanol was compared with that of HeLa cells expressing rat class I alcohol dehydrogenase (ADH) (HeLa‐rat ADH cells), rat hepatoma (H4IIEC3) cells, and rat hepatocytes. Results: The isoenzymes had similar protein half‐lives in the HeLa cells. Rat hepatocytes, H4IIEC3 cells, and HeLa‐rat ADH cells oxidized ethanol much faster than the cells expressing the ADH1B isoenzymes. This was not explained by high cellular NADH levels or endogenous inhibitors; but rather because the activity of the β1 and β2 ADHs was constrained by the accumulation of acetaldehyde, as shown by the increased rate of ethanol oxidation by cell lines expressing β2 ADH plus ALDH2. Conclusion: The activity of the human β2 ADH isoenzyme is sensitive to inhibition by acetaldehyde, which likely limits its activity in vivo. This study emphasizes the importance of maintaining a low steady‐state acetaldehyde concentration in hepatocytes during ethanol metabolism.     

心脏磁共振对肥厚型心肌病应用价值的研究

肥厚型心肌病(HCM)是最常见的遗传性心肌病,在普通人群中其发病率为1/500,HCM临床表现多样,主要发病机制是心肌细胞肥厚、排列紊乱、心肌纤维化及胶原沉积以及不稳定的心电活动容易导致恶性心律失常所致。近年来心脏磁共振(CMR)被广泛应用于HCM的诊断以及与其他疾病的鉴别诊断,CMR不仅能够准确评估心室功能、心室壁厚度,并且钆延迟强化(LGE)能够无创检测心肌纤维化及瘢痕。重要的是越来越多的研究证明LGE与HCM等多种心血管病的发生相关,并可以预测其发生。本文将回顾相关文献,总结CMR对HCM的应用价值,使CMR更好的应用于临床。     

Protein synthesis in prolonged cardiac arrest

Cardiac protein synthesis has been found to increase as pressure stress is applied both in vivo and in vitro, but the relationship between contraction, per se, and protein synthesis has not been characterized. A cardiac preparation with right ventricular loading and controlled coronary flow was used to examine the possibility of such a relation, in vitro. In both aerobically perfused contracting and high K⁺ arrested hearts, ATP, creatine phosphate, potassium and glycogen levels were maintained, and lactate production was at low levels. Incorporation of [¹⁴C]lysine into right and left ventricular protein was the same in contracting and aerobically perfused arrested hearts after 3 h of perfusion. In contrast, anoxia induced arrest decreased incorporation of lysine into protein with a more profound drop in [¹⁴C]lysine incorporation in the left ventricle. Alterations of protein synthesis in 3 h of anoxia were associated with a fall in ATP (greater in the left ventricle than in the right ventricle), creatine phosphate, glycogen and potassium with a sharp rise in lactate production. These changes in anoxia were minimized when anoxic hearts were concomitantly perfused with high K⁺ (16 mEq/l). The data indicate that cardiac arrest associated with metabolic integrity in this preparation produced little change in protein synthesis and suggest that a baseline rate of protein synthesis occurs in such tissue which is not dependent on contraction, per se.     

Clinical outcome of cardiac resynchronization therapy in dilated-phase hypertrophic cardiomyopathy

Backgrounds Clinical trials have demonstrated that cardiac resynchronization therapy (CRT) is effective in patients with “non-is?chemic cardiomyopathy”. However, patients with dilated-phase hypertrophic cardiomyopathy (DHCM) have been generally excluded from such trials. We aimed to compare the clinical outcome of CRT in patients with DHCM, idiopathic dilated cardiomyopathy (IDCM), or ischemic cardiomyopathy (ICM). Methods A total of 312 consecutive patients (DHCM: n = 16; IDCM: n = 231; ICM: n = 65) undergoing CRT in Fuwai hospital were studied respectively. Response to CRT was defined as reduction in left ventricular end-systolic volume (LVESV) ? 15% at 6-month follow-up. Results Compared with DHCM, IDCM was associated with a lower total mortality (HR: 0.35, 95% CI: 0.13–0.90), cardiac mortality (HR: 0.29; 95% CI: 0.11–0.77), and total mortality or heart failure (HF) hospitalizations (HR: 0.34, 95% CI: 0.17–0.69), independent of known confounders. Compared with DHCM, the total mortality, cardiac mortality and total mortality or HF hospitalizations favored ICM but were not statistically significant (HR: 0.59, 95% CI: 0.22–1.61; HR: 0.59, 95% CI: 0.21–1.63; HR: 0.54, 95% CI: 0.26–1.15; respectively). Response rate to CRT was lower in the DHCM group than the other two groups although the differences didn’t reach statistical significance. Conclusions Compared with IDCM, DHCM was associated with a worse outcome after CRT. The clinical outcome of DHCM patients receiving CRT was similar to or even worse than that of ICM patients. These indicate that DHCM behaves very differently after CRT.     

Effects of ethanol and acetaldehyde on myocardial ornithine decarboxylase activity.

Intraperitoneal ethanol or acetaldehyde had no effect on myocardial ornithine decarboxylase activity in the rat. When given with propranolol there was a decrease in enzyme activity.In the isolated, perfused heart, high concentrations of acetaldehyde inhibited the enzyme activity, while ethanol had no effect.Ethanol or acetaldehyde had no direct effect on the cytosolic enzyme activity.It is suggested that ethanol or its metabolites both directly inhibit myocardial ornithine decarboxylase activity and indirectly stimulate it by catecholamine release. The inhibitory effect appears to be mediated through a diminished rate of synthesis of the enzyme.     

Alcoholic hepatitis: The pivotal role of Kupffer cells

Kupffer cells play a central role in the pathogenesis of alcoholic hepatitis (AH). It is believed that alcohol increases the gut permeability that results in raised levels of serum endotoxins containing lipopolysaccharides (LPS). LPS binds to LPS-binding proteins and presents it to a membrane glycoprotein called CD14, which then activates Kupffer cells via a receptor called toll-like receptor 4. This endotoxin mediated activation of Kupffer cells plays an important role in the inflammatory process resulting in alcoholic hepatitis. There is no effective treatment for AH, although notable progress has been made over the last decade in understanding the underlying mechanism of alcoholic hepatitis. We specifically review the current research on the role of Kupffer cells in the pathogenesis of AH and the treatment strategies. We suggest that the imbalance between the pro-inflammatory and the anti-inflammatory process as well as the increased production of reactive oxygen species eventually lead to hepatocyte injury, the final event of alcoholic hepatitis.