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 ::  Abstract
 :: Introduction
 ::  Materials and Me...
 :: Results
 :: Discussion
 ::  References
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  Table of Contents     
ORIGINAL ARTICLE
Year : 2014  |  Volume : 60  |  Issue : 4  |  Page : 372-376

Cardiac pathology in chronic alcoholics: A preliminary study


1 Department of Pathology (Cardiovascular and Thoracic Division), Seth Gordhandas Sunderdas Medical College, Mumbai, Maharashtra, India
2 Department of Biochemistry, Seth Gordhandas Sunderdas Medical College, Mumbai, Maharashtra, India

Date of Submission10-Dec-2013
Date of Decision03-Feb-2014
Date of Acceptance18-Feb-2014
Date of Web Publication5-Nov-2014

Correspondence Address:
Dr. P Vaideeswar
Department of Pathology (Cardiovascular and Thoracic Division), Seth Gordhandas Sunderdas Medical College, Mumbai, Maharashtra
India
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Source of Support: Research Society, Seth G. S. Medical College and†K.†E.†M. Hospital, Mumbai., Conflict of Interest: None


DOI: 10.4103/0022-3859.143958

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 :: Abstract 

Background: Ethyl alcohol exerts both positive and negative effects on the cardiovascular system. Alcoholic cardiomyopathy, produced by direct or indirect mechanisms, is well-documented. An important, but seldom appreciated effect is an increase in iron deposition in the myocardium, which can add to the cardiac dysfunction. The present study was planned to document the pathological features and iron levels in the cardiac tissue of patients who were chronic alcoholics and correlate these characteristics with the liver pathology and iron content. Materials and Methods: An autopsy-based prospective study of 40 consecutive patients compared with ten age matched controls (no history of alcohol intake). Histopathological changes like the morphology of the cardiac myocytes, degree of fibrosis (interstitial, interfiber, perivascular, and replacement), presence of inflammatory cells, increased capillary network, and adipose tissue deposition were noted and graded. These were also correlated with the liver pathology. The iron content in the heart and liver were measured by using calorimetry. Results: All cases had increased epicardial adipose tissue with epicardial and endocardial fibrosis, prominence of interstitial and interfiber fibrosis, myofiber degeneration, and increased capillary network; this was particularly prominent in patients with cirrhosis. Elemental iron level in heart tissue was raised in the cases relative to controls. Conclusions: Alcohol produces subclinical changes in the myocardium, with an increased iron content, which may be the forerunner for subsequent clinical cardiac dysfunction.


Keywords: Ethyl alcohol, myocardial capillary network, myocardial fibrosis, myocardial iron deposition


How to cite this article:
Vaideeswar P, Chaudhari C, Rane S, Gondhalekar J, Dandekar S. Cardiac pathology in chronic alcoholics: A preliminary study. J Postgrad Med 2014;60:372-6

How to cite this URL:
Vaideeswar P, Chaudhari C, Rane S, Gondhalekar J, Dandekar S. Cardiac pathology in chronic alcoholics: A preliminary study. J Postgrad Med [serial online] 2014 [cited 2019 Nov 14];60:372-6. Available from: http://www.jpgmonline.com/text.asp?2014/60/4/372/143958



 :: Introduction Top


Of all mind-altering substances of use and abuse, ethyl alcohol is the agent with the greatest effect on human health. Alcohol abuse is a major public health problem in the world, with the value of the Disability Adjusted Life Years of up to 4%. It leads to serious social problems as well as adverse effects on different organ systems. Chronic alcoholism leads to significant morbidity and mortality, related principally to changes and subsequent damage to the liver, gastrointestinal tract, and pancreas. [1] Alcohol can have both direct and indirect effects on the heart, with subsequent cardiac dysfunction. [2] The direct effect is mediated by the alcohol itself or its metabolites, while the indirect effect is mediated by thiamine deficiency. [2] An important, but seldom appreciated sequel to chronic alcohol consumption is increased iron deposition in the myocardium, which may accentuate the cardiac dysfunction. [3] We undertook an autopsy-based study to document the pathological features and iron levels in the cardiac tissue of cases of chronic alcoholism and correlated these characteristics with the liver pathology and hepatic iron content. We also matched them with a control group.


 :: Materials and Methods Top


This was an autopsy-based study undertaken after permission from the Ethics Committee of our institute. Data confidentiality was maintained. A total of 40 consecutive patients with a history of chronic alcoholism as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). [4] were taken. Ten age-matched patients without a history of alcohol addiction served as controls. In both groups, the hearts were perfused by the coronary perfusion method, using 10% buffered formalin. After 24 hours, the hearts were cut along the flow of the blood and were meticulously grossed. Sections were taken from the right ventricle (inflow and outflow tract), left ventricle (anterior, posterior, lateral, and septal walls), and the atria, the valves or arteries, as and when required. These were then processed and stained with hematoxylin eosin and elastic van Gieson's stains. Histopathological changes, such as, morphology of cardiac myocytes, interstitial fibrosis (IF), interfiber fibrosis (IFF), perivascular fibrosis, replacement fibrosis, presence of inflammatory cells, increased capillary network, vascular abnormalities, and adipose tissue deposition were noted. The changes were subjectively graded as mild, moderate or severe. The grading was done by the senior author with over 20 years of experience and expertise in cardiovascular pathology. In some cases, to reconfirm the light microscopic finding of increased capillary network, an immunohistochemical marker for endothelial cell CD 34 was also performed. Sections from the liver were taken and stained with the routine stain, and the changes were noted. Based on the liver pathology, the cases were classified into three groups:

Group 1 - cases with non-alcohol-related histology,
Group 2 - cases with non-cirrhotic, alcohol-induced pathology, and
Group 3 - cases with cirrhosis.

For quantitation of elemental iron, sections of the liver and heart (subepicardial portions of the right and left ventricles) were taken during the autopsy, wrapped in aluminum foil, and stored in a deep refrigerator at −20°C. Each tissue was washed thrice with normal saline and distilled water. The tissue samples were kept in the oven for a period of three to four days, to obtain a dry extract, and then were crushed to a powder. The iron was measured by using the calorimetric biochemical method per 100 g of dry tissue. [5] Ten age-matched controls were studied similarly to compare the results of the cases. The results were statistically compared by using the unpaired t-test.


 :: Results Top


Of the 40 patients (13-40 years), 10 patient had a non-alcoholic liver histology, 17 patients (Group 2) had features of alcoholic steatosis, and 13 patients had micronodular cirrhosis. The ages ranged from 25 to 83 years; there were only two women. The causes of death and other ancillary features in the hearts of alcoholic patients have been tabulated in [Table 1].
Table 1: Causes of death and ancillary cardiac findings in study cases (n = 40)

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On gross examination of the hearts, the striking feature in all cases was an increase in the epicardial adipose [Figure 1] tissue, with associated epicardial and endocardial fibrosis (confirmed on microscopy). The adipose tissue was also found in the myocardium with even subendocardial deposits in the right (60 %) and left (22.5 %, [Figure 1]) ventricles. Prominence of IF, IFF, myofiber degeneration, and capillary network [Table 2] and [Figure 2] were seen in patients with cirrhosis. CD 31 immunohistochemical staining highlighted the capillary network [Figure 3]; it was performed in 19 cases (Group 1 - five cases, Group 2 - eight cases, Group 3 - six cases. Replacement fibrosis was seen in 11 patients; only two of these had critical coronary arterial stenosis. Furthermore, the pathology was more prominent in the right ventricle in all subsets. Replacement fibrosis was seen in 10 to 15% of the cases, in all the subgroups studied. Similar histological features were also studied in the control group [Table 3]. Interstitial fibrosis in the left and right heart sections was seen in only one case, of mild grade. Inflammation was seen in only one case and intramyocardial fat deposition was seen in two cases of the control group, in both the left and right heart sections.
Figure 1: (a) External surface of the heart in a 31-year-old male with alcoholic cirrhosis showing significant increase in epicardial fat (RV right ventricle, LV left ventricle); (b) Opened out LV inflow tract showing a uniform layer of adipose tissue all around (LA left atrium, MV mitral valve); (c) Close-up of the anterior free wall showing adipose tissue insinuation (arrows) into the myocardium; (d) Small groups of myofibers separated by adipocytes (Hematoxylin and eosin ×250); (e) Deposits of fat below a thickened fibrotic endocardium (Hematoxylin and eosin ×250)

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Figure 2: (a) Focal interfiber fibrosis highlighted by elastic van Gieson stain (×250); (b) Cytoplasmic vacuolation of myofibers (Hematoxylin and eosin ×400); (c) Mild perivascular fibrosis with an inflammatory infiltrate (Hematoxylin and eosin ×400)

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Figure 3: (a) Increased capillary network around myofibers (Hematoxylin and eosin ×400), highlighted by (b) Immunohistochemical positivity for CD 34 (×400)

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Table 2: Cardiac findings and iron content in study cases (n = 40)

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Table 3: Cardiac findings and iron content in control cases (n = 10)

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The iron concentrations in the livers and hearts of different groups and controls have been mentioned in [Table 2] and [Table 3]. We found that the mean value for the iron level in the heart tissues of the cases was 12.66 μg/100 g of dry tissue and for controls it was 11.49 μg/100 g of dry tissue; and the corresponding values of the iron level in the liver tissues were 33.46 μg/100 g of dry tissue for the cases and 26.01 μg/100 g of dry tissue for the controls. The difference was found to be statistically significant (P < 0.0001, unpaired t-test).


 :: Discussion Top


Several disease processes can affect the heart and the liver, synchronously or metachronously. As an interaction exists between cardiac and hepatic functions, they can be classified into heart diseases affecting the liver, liver diseases affecting the heart, and a simultaneous involvement of both organs. [6] Although the liver is the primary target, regular alcohol intake affects the cardiovascular system, sooner or later, depending upon the amount and duration of consumption. In this situation, alcohol behaves as a double-edged sword, exerting both positive and negative effects. Light-to-moderate drinking affords protection against coronary artery disease, while heavy drinkers (as seen in our cohort of patients) are prone to systemic hypertension, cardiac rhythm disorders, hemorrhagic stroke, and alcoholic cardiomyopathy (A-CMP). [7]

Patients with a long-term (5 to 15 years) history of heavy alcohol consumption develop dilated heart muscle disease, designated as A-CMP, which is responsible for 21 to 36% of all cases of non-ischemic dilated cardiomyopathy. [2],[8] The ultrastructural changes of alcohol-induced injury, such as, intracellular organelle dysfunction or protein alterations, produce discernable pathological features in the form of left ventricular dilatation, reduced or normal left ventricular thickness, myocyte loss or apoptosis, interstitial fibrosis with myofibrillar y disruption, and concomitant myofiber hypertrophy, with paradoxical increased left ventricular mass. [9] In this autopsy study of 40 consecutive patients with a history of alcohol abuse, we have demonstrated significant interstitial and inter-fiber fibrosis in a majority of the patients. Furthermore, myofiber degeneration and interstitial inflammation were the other ancillary features noted. These changes were consistent with A-CMP, [2],[8] The other features noted consistently were an increase in adipose tissue, especially in the epicardium; and epicardial and endocardial fibrosis, which has not been documented as yet or may have been overlooked. Importantly, we also found specific vascular features like increased capillary network and prominence along with focal endothelial proliferation. There is no study to date, in the literature, to compare the above features of capillary prominence in the heart interstitium as an effect of chronic alcoholism in humans. However, these changes are consistent with the studies done in lower animals, in experimental models. [10] This may also explain the decreased incidence of coronary artery disease; only 5% of the patients in this study had significant coronary atherosclerosis. It is to be noted that A-CMP has a asymptomatic stage, which is clinically characterized by an impairment of the left ventricular function (reduced contractility, prolonged relaxation, decreased ejection fraction, and decreased stroke volume), before culminating into overt features of heart failure, that is, the symptomatic stage. [7] None of our patients had cardiac symptoms that could have been attributed to the effects of alcohol; echocardiography was not done in any of the patients.

The pathogenetic mechanisms for the clinicopathological changes are not exactly known, but they may be multifactorial. A genetic vulnerability and deleterious influence of ethanol and its metabolites like acetaldehyde and fatty acid ethyl esters lead to myocyte loss, intracellular organelle dysfunction, abnormalities in calcium homeostasis, contractile protein alterations, and neurohormonal activation. [11] Furthermore, cirrhosis can also potentiate effects of alcohol or by itself can lead to a cirrhotic cardiomyopathy. [12] An important, but seldom appreciated effect is an increased iron deposition on the heart, in the myocardium, accentuating cardiac dysfunction. Osna [3] has stated that in vivo whole-body retention studies have demonstrated a two-fold increase in intestinal iron absorption and upregulation of transferrin receptor-1 in chronic alcoholics. Nicolas et al.[13] in their study on transgenic mice have demonstrated the central role of hepcidin in iron metabolism in the heart and liver; the hepatic synthesis of this protein is regulated by iron and inflammation. We found that the mean value of the iron level in the heart tissue in our cases was 12.66 μg/100 g of dry tissue; and for controls it was 11.49 μg/100 g of dry tissue; and the corresponding values of iron level in the liver tissue were 33.46 μg/100 g of dry tissue for the cases and 26.00 μg/100 g of dry tissue for the controls. We concluded that the elemental iron level in the heart tissue was raised in the cases as compared to the controls. However, there is no exact normal range of heart tissue iron available, done by any validated or standardized method in literature to date, to compare our results, as ours is a pilot study. Although there is no such similar study in humans available for comparing our results in literature, this can encourage larger and more detailed studies to be undertaken, to elucidate the effect of chronic alcoholism on the heart, with reference to tissue iron levels and their variation in different conditions. The methods to quantify the iron level in heart tissues are still in the experimental phase also need to be standardized and validated. Only after completion of a detailed study of a similar kind, with a larger number of cases and controls, can more accurate and detailed values and parameters be given.

 
 :: References Top

1.
Babor T, Caetano R, Caswell S, Edwards G, Giesbrech N, Grahan K. Alcohol: No ordinary commodity: The Global Burden of Alcohol Consumption. Oxford: Oxford University Press; 2003. p. 57-92.   Back to cited text no. 1
    
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Piano MR. Alcoholic cardiomyopathy. Incidence, clinical characteristics, and pathophysiology. Chest 2002;121:1638-50.   Back to cited text no. 2
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3.
Harrison-Findik DD. Role of alcohol in the regulation of iron metabolism. World J Gastroenterol 2007;13:4925-30.  Back to cited text no. 3
[PUBMED]    
4.
Global Status Report on Alcohol 2004. World Health Organization. Department of Mental Health and Substance Abuse Geneva 2004. Available from: http://www.who.int/substance_abuse/publications/alcohol/en/index.html. [Last accessed on 2009 Jan 1].  Back to cited text no. 4
    
5.
Rebouche CJ, Wilcox CL, Widness JA. Microanalysis of non-heme iron in animal tissues. J Biochem Biophys Methods 2004;58:239-51.  Back to cited text no. 5
    
6.
Møller S, Bernardi M. Interactions of the heart and the liver. Eur Heart J 2013;34:2804-11.  Back to cited text no. 6
    
7.
Klatsky AL. Alcohol and cardiovascular health. Physiol Behav 2010;100:76-81.  Back to cited text no. 7
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Laonigro I, Correale M, Di Biase M, Altomare E. Alcohol abuse and heart failure. Eur J Heart Fail 2009;11;453-62.  Back to cited text no. 8
    
9.
George A, Figueredo VM. Alcoholic cardiomyopathy: A review. J Card Fail 2011;17:844-9.  Back to cited text no. 9
    
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Mall G, Mattfeldt T, Rieger P, Volk B. Morphometric analysis of the rabbit myocardium after chronic ethanol feeding - early capillary changes. Basic Res Cardiol 1982;77:57-67.  Back to cited text no. 10
    
11.
Ren J, Wold LE. Mechanisms of alcoholic heart disease. Ther Adv Cardiovasc Dis 2008;2:497- 506.  Back to cited text no. 11
    
12.
Pellicori P, Torromeo C, Calicchia A, Ruffa A, Di Iorio M, Cleland JG, et al. Does cirrhotic cardiomyopathy exist? 50 years of uncertainty. Clin Res Cardiol 2013;102:859-64.   Back to cited text no. 12
    
13.
Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA 2001;98:8780-5.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]

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