Intramyocardial small-vessel disease in chronic alcoholism Stephen M. Factor, M.D. Bronx, N. Y.

The association between chronic alcoholism and clinical cardiac dysfunction has been confirmed by numerous studies over the past decade. 1-6 Postmortem and biopsy investigations of the heart in chronic alcoholism have revealed basically similar gross, light microscopic, ultrastructural, and cytochemical alterations2.7 Less agreement exists, however, regarding the pathogenesis of the myocardial changes. It is as yet unclear whether alcohol is directly toxic to the heart s' ~ or whether it acts indirectly through its primary metabolic product acetaldehyde2 ~ 1~ Magnesium deficiency,~2, 13 altered catecholamine metabolism,14, ~5 or other undefined mechanisms or substances have been implicated by various investigators. Additionally, the proposal has been advanced that the pathologic changes in chronic alcoholic heart disease are not specific for alcohol toxicity, but may instead reflect the effects of chronic ischemia. 16, 17 Most pathologic studies of alcoholic heart disease have focused on the light and electron microscopic alterations of the muscle fiber. If the myocardial alterations in alcoholic cardiomyopathy are secondary to the effects of ischemia, however, it is conceivable that these changes are mediated by disease of the small coronary vessels because large coronary vessel disease is usually absent2 Nevertheless, little attention has been paid to the microvasculature of the myocardiam.

Several clinical and experimental studies have pointed to the existence of small-vessel disease in chronic alcoholism. Pintar and associates ~8 in From the Department of Pathology, Bronx Municipal Hospital Center, and Albert Einstein College of Medicine, Bronx, N. Y. Received for publication July 28, 1975. Reprint requests: Stephen M. Factor, M.D., Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, N. Y. 10461.

November, 1976, Vol. 92, No. 5, pp. 561-575

1965 described significant changes in small intramyocardial vessels of three chronic alcoholics dying of cardiomyopathy. The authors observed vascular edema and degeneration, disorganization of the vessel wall layers, and deposition of PAS-positive material in the subintima. Sohal and Burch, ~5in an experimental study, fed mice a diet containing 15 per cent ethanol by volume for 3 months. They noted ultrastructural changes in myocardial capillaries consisting of swollen and degenerating endothelial cells and narrowing of the vascular lumen. The authors speculated on the role of chronic hypoxia induced by the vascular alterations in the pathogenesis of alcoholic heart disease. Although as yet there is no conclusive evidence for the direct toxicity of alcohol on the heart, the existence, severity, and extent of small-vessel disease in the hearts of chronic alcoholics has been neither sufficiently examined nor critically evaluated. Therefore the following study was instituted to determine the significance and degree of microvascular alterations in chronic alcoholism, and to determine if any of the pathologic changes in alcoholic cardiomyopathy could be attributed to the vascular abnormalities. Materials and methods

The autopsy records of the Bronx Municipal Hospital Center were reviewed for the years 1972 and 1973. All patients under the age of 45 years dying secondary to alcoholic liver disease or chronic alcoholism were selected for further study. A population of relatively young chronic alcoholics was chosen for analysis in order to minimize common cardiovascular complications of aging. It was also considered likely t h a t a young group would probably be heavier drinkers, accounting for their early death from the effects of alcohol. Patients were eliminated if there was

American Heart Journal

561

Factor

any indication of hypertension, stenotic or occlusive coronary atherosclerosis (greater t h a n 25 per cent of the vessel diameter), diabetes mellitus, hemochromatosis, congenital h e a r t disease, history of rheumatic fever or evidence of r h e u m a t i c valvular lesions, syphilis, or systemic vasculitis of any type. Nine patients were identified who fulfilled these criteria. T h e clinical histories of the nine patients were examined. Special a t t e n t i o n was paid to the t y p e and duration of alcohol abuse, the use of medications or drugs which might affect the small vessels, evidence of m a l n u t r i t i o n or chronic anemia, and any s y m p t o m a t o l o g y suggestive of cardiac failure. Since all of these patients were admitted to the hospital with an a c u t e surgical or medical problem, relevant medications were noted which might acutely produce small-vessel changes. Finally, electrocardiographic, radiographic, and l a b o r a t o r y d a t a were examined to determine if any cardiovascular abnormalities were present. Control cases were selected from autopsies performed in 1972-1975. Nine cases were chosen comparable in age to the alcoholic s t u d y group. T h e criteria for selection were identical to those of the study group in respect to the absence of a n y symptoms or pathologic evidence of cardiac disease. None of the patients h a d a history of excessive alcohol intake. Control cases were selected if there was a history of t r a u m a {cutaneous burns), n o n h y p e r t e n s i v e or nonatherosclerotic central nervous system disease, or documented nonalcoholic liver disease. All control patients had acute s y m p t o m a t o l o g y including sepsis, shock, and hemorrhage, similar to the alcoholic group. T h e myocardial tissue was examined and evaluated in the same m a n n e r as the study group. Microvascular abnormalities (see below) were t a b u l a t e d for each case, for the control group as a whole, and for the t h r e e subgroups. T h e original histologic sections t a k e n from the heart by several different prosectors were studied. Wet tissue, which was available in eight out of the nine study cases and seven o u t of nine control cases, was completely sectioned. Tissue was routinely stained with h e m a t o x y l i n and eosin and additional selected sections were stained with periodic acid-Schiff (PAS), Masson's trichrome, and elastic-van Gieson's stains. Cardiac vessels were measured with a m i c r o m e t e r eyepiece. T h e

562

vessels were evaluated only if t h e y were perpendicularly sectioned. Vessels cut t a n g e n t i a l l y were counted as normal. The heart sections were scanned at low power, and the total n u m b e r of i n t r a m y o c a r d i a l and epicardial vessels measuring a p p r o x i m a t e l y 50 to 200 microns were tabulated. Vessels with obvious branching or double vessels within t h e same interstitial c o m p a r t m e n t were c o u n t e d singly. T h e t o t a l n u m b e r of vessels per tissue section was established, and then the a b n o r m a l vessels within the section were studied at higher magnification. The t o t a l n u m b e r of a b n o r m a l vessels was tabulated, and a ratio was established between the abnormal and normal vessels for each tissue section and for the combined sections per case. Ratios were established for the pathologic abnormalities noted below, and t h e n c o n v e r t e d to percentages. Since each vessel often h a d more than one pathologic alteration, the same vessel could be scored more t h a n once in several ratios. Vascular changes were t a b u l a t e d in five broad categories, each of which included alterations of varying severity. Questionable or t r u l y minimal changes were scored as normal. 1. Vascular edema. T h i s category included vessels demonstrating intracellular vacuolization, extracellular vacuoles and microcysts, and loosening and disorganization of the vascular wall layers. T h e presence of proteinaceous fluid, or blood constituents such as leukocytes, e r y t h r o cytes, or platelets within the vascular wall, was also t a b u l a t e d under this heading. 2. Vascular sclerosis. This group was composed of vessels with intimal and medial hyperplasia a n d / o r fibrosis, elastic tissue proliferation, and the deposition of PAS-positive m a t e r i a l in the vessel wall. 3. Perivascular fibrosis. This p e r t a i n e d to concentric perivascular hyaline fibrosis and also looser increased perivascular connective tissue. However, since it was difficult to d e t e r m i n e where the adventitia ended and where fibrosis began, it was decided to score as positive only those vessels surrounded by fibrous connective tissue which encroached upon and appeared to involve the adjacent myocardium. 4. Vascular inflammation. This included the presence within the vascular wall of obvious acute or chronic i n f l a m m a t o r y cells, or cells which have been assumed to be i n f l a m m a t o r y ,

November, 1976, Vol. 92, No. 5

Intramyocardial disease in chronic alcoholism

Table I. C l i n i c a l f e a t u r e s o f t h e s t u d y g r o u p

Case No.

Age~Sex*

Duration of alcoholism (yr.)

1 2 3 4 5 6 7 8 9

27M 37F 37F 41M 31M 43M 37M 41M 31M

> 5 NRt > 5 NR > 2 22 > 5 NR 22

Type and amount of alcohol (per day) 1 qt. whiskey NR 1-2 pints whiskey 1 pint whiskey 1 qt. gin or rum 5-6 pints beer Wine (? amt) 12 cans beer 1 qt. whiskey

Drug abuse None None None None Heroin, methadone Heroin, methadone None None None

Therapeutic drugs Vasopressin

Vasopressin Vasopressin, levarterenol Vasopressin Levarterenol

*Mean age of group: 36.1 years. tNR: Not recorded.

Table II. P a t h o l o g i c a l f e a t u r e s a n d c a u s e s o f d e a t h ( s t u d y g r o u p ) Heart Case No.

Weight (Gm.)

1

400

2

Description

Liver

Varices; gastric ulcers Pneumonia

3

300

Unremarkable

Septicemia

Hepatic failure

4

250

Fatty infiltration

305

Unremarkable

Gastric ulcers; GI hemorrhage Varices; pneumonia

Hepatic failure

5

GI hemorrhage

6

470

Varices

GI hemorrhage

7 8

340 520

Focal hemorrhage; focal pericarditis Unremarkable Focal myocardial necrosis

Cirrhosis; fatty change Cirrhosis; fatty change Cirrhosis; alc. hepatitis Cirrhosis; fatty change Cirrhosisi alc. hepatitis Cirrhosis

GI hemorrhage

350

Focal subendocardial hemorrhages Unremarkable

Cirrhosis Cirrhosis; fatty change

Varices Chronic pancreatitis

GI hemorrhage Unknown

9

400

Fatty change, severe

Acute and chronic pancreatitis

Hemorrhagic pancreatitis

Unremarkable

i.e., A n i t s c h k o w m y o c y t e s . A d d i t i o n a l l y , p e r i v a s cular accumulation of inflammatory cells which appeared to have a direct relationship to a vessel were scored within this category. Diffuse perivascular and interstitital inflammation was noted separately. 5. S u b e n d o t h e l i a l h u m p s . T h i s r e f e r r e d t o t h e presence beneath the endothelium of an asymmetric accumulation of smudgy eosinophilic material, usually acellular and variably compact, which protruded into the vascular lumen. If more than one subendothelial hump was present per

American Heart Journal

Other

Cause of death

Comments

Encephalopathy Macrocytic anemia

Heroin addict; no vasculitis Heroin addict; no vasculitis Hemorrhagic diathesis after resuscitation

vessel, i t w a s s c o r e d singly. I f t h e r e w a s a q u e s t i o n r e g a r d i n g t h e p r e s e n c e o f a h u m p vs. t h e p o s s i b i l i t y of a t a n g e n t i a l v e s s e l s e c t i o n o r t h e b e g i n n i n g of a b r a n c h p o i n t , t h e v e s s e l w a s s c o r e d a s normal. Other parameters were noted but not formally tabulated. These included the presence of inters t i t i a l fibrosis n o t d i r e c t l y r e l a t e d t o vessels, a r e a s o f m y o c a r d i a l fibrosis ( h e a l e d m i c r o i n f a r c t s ) , interstitial inflammation, epicarditis, recent or a c u t e t h r o m b o s i s o f vessels, a n d a r e a s o f a c u t e myocardial infarction.

563

Factor

T a b l e III. Pathological features and causes of d e a t h (control cases)

Case no.

[

Age~Sex*

Primary diagnosis

10

40F

40% 30 flame burns

11

38M

40% 2~ and 3~ f l a m e burns

12

40F

13

37F

14

37M

40% 2~ and 3~ f l a m e burns Malignant glioma of thalamus Parietal arteriovenous malformation

15

43F

16

22M

17 18

I

Other

[

Acute pneumonia; respiratory insufficiency Necrotizing laryngobronchitis; stress ulcers; hemolytic anemia Bronchopneumonia; wound infection Cerebral edema; meningitis; bronchopneumonia Subarachnoid hemorrhage; bronchopneumonia Massivepulmonary emboli

Causes of death Sepsis Shock Sepsis

Drug addict

Cerebral edema

Multiple operative procedures (4 too. course)

Subarachnoid hemorrhage

Middlecerebral artery embolus with encephalomalacia Post-hepatitic cirrhosis Acute gastric ulcer; esophageal varices

Acute pulmonary emboli

26M

Wilson'sdisease

30F

Acute viral hepatitis

Massive GI hemorrhage Acute viral hepatitis (hepatic failure)

Cirrhosis; esophageal varices Diffusegastric hemorrhage

Comment

Massive GI hemorrhage

Post-transfusion hepatitis; congenital abnormalities; ? congenital toxoplasmosis

*Mean age of group: 34.7. Results

There were seven m e n and two w o m e n in the study group (see Table I). T h e m e a n age was 36.1 years (range, 27 to 43 years}. All nine p a t i e n t s were known chronic alcoholics who had been drinking heavily for at least several years prior to their terminal admissions. In cases 6 and 9 the patients admitted to alcohol abuse for 22 years. There were four whiskey drinkers, two beer drinkers, and one drinker each of wine and gin. I n case 2 the type of alcoholic beverage was n o t recorded. All nine patients were generally described as well nourished, a l t h o u g h patient 9 h a d lost 35 p o u n d s in the year preceding admission. T h e five p a t i e n t s who presented with acute upper g a s t r o i n t e s t i n a l hemorrhage could not be evaluated for chronic anemia. Only patient 3, a m o n g the four r e m a i n i n g nonbleeding patients, was noted to have a m a c r o cytic and h y p o c h r o m i c anemia with a h e m a t o c r i t of 24 volumes per cent. T w o patients, Nos. 5 a n d 6, had been heroin addicts in the past, and were allegedly on m e t h a d o n e m a i n t e n a n c e . N e i t h e r patient had a history of chronic viral hepatitis or of vascular complications of drug abuse. N o n e of the patients h a d a history of cardiac s y m p t o m s , although several had episodic shortness of b r e a t h

564

and dyspnea relieved by paracentesis. T h e r e was no indication of cardiomegaly noted on physical examination or chest x-ray. T h e electrocardiogram was u n r e m a r k a b l e in all patients in w h o m it was recorded. The major pathologic findings and cause of death are summarized in Tables I I and I I I . Within the alcoholic group three p a t i e n t s died of hepatic failure, four died of massive variceal hemorrhage, and one died of a c u t e h e m o r r h a g i c pancreatitis. P a t i e n t 8 had a sudden cardiopulm o n a r y arrest of u n k n o w n etiology outside of the hospital, was resuscitated, b u t died 2 days after admission secondary to complications of anoxia. Eight of the nine patients h a d m i c r o n o d u l a r cirrhosis, whereas p a t i e n t 9 h a d severe hepatic f a t t y change w i t h o u t cirrhosis. W i t h i n the control group, two patients died of sepsis, two died of massive u p p e r gastrointestinal hemorrhage, and one each died as the result of b u r n shock, subarachnoid hemorrhage, cerebral edema, acute p u l m o n a r y emboli, and acute hepatic failure. The alcoholic hearts, with two exceptions, were not remarkably enlarged. T h e m e a n cardiac weight was 370 grams. Only the h e a r t s in cases 6

November, 1976, Vol. 92, No. 5

I n t r a m y o c a r d i a l d i s e a s e in c h r o n i c a l c o h o l i s m

T a b l e IV. P e r c e n t a g e of v a s c u l a r a b n o r m a l i t i e s p e r case ( s t u d y g r o u p )

Case No.

Total vessels p e r case

1 2 3 4 5 6 7 8 9

86 125 50 163 75 128 66 111 190 _

Totals*

_

994

*Computed as follows: % =

Vascular edema

Perivascular fibrosis

Vascular sclerosis

Subendothelial hump

Vascular inflammation

~)

~)

~)

~)

~)

10 42 54 53 32 48 64 56 -57 .-_ 48

52 25 54 39 21 48 32 59 .45 42

14 21 30 22 35 45 50 50 47

6 21 10 6 0 27 18 10 . 15 13

10 8 10 2 17 9 18 16 16

.

.

36

total abnormal vessels per group X

11

100.

total vesselsexamined

T a b l e Y. P e r c e n t a g e of v a s c u l a r a b n o r m a l i t i e s ( c o n t r o l g r o u p ) Total vessels per case

Vascular edema

Perivascular qbrosis

Vascular sclerosis

Subendothelial hump

~)

(%)

Vascular inflammation

~)

~)

~)

181 117 107 405

37 23 16 27

10 10 11 10

26 16 18 21

08 03 01 05

0 01 01 01

63 70 125 258

27 23 24 25

05 06 06 06

10 0 11 08

02 01 01 01

02 0 02 02

16 17 18 Totals

111 92 8...44 287

36 15 17 24

41 18 07 24

14 22 o6 14

0 07 o__6 09

05 05 0 04

Totaisforgroup

950

26

13

15

03

02

Case No. ~ a u m a group:

10 11 12 Totals CNS group:

13 14 15 Totals Hepatic group:

a n d 8 exceeded 400 grams. N o n e o f t h e h e a r t s w a s described as flabby, a n d n o n e h a d o v e r t c o r o n a r y a t h e r o s c l e r o s i s or m u r a l t h r o m b i . S e v e r a l h e a r t s h a d focal, p r o b a b l y t e r m i n a l , s u b e n d o c a r d i a l h e m o r r h a g e s a n d No. 8 h a d f o c a l m y o c a r d i a l necrosis. W i t h t h e e x c e p t i o n of case 8, t h e h e a r t s were g e n e r a l l y d e s c r i b e d as u n r e m a r k a b l e . Microscopically, however, careful e x a m i n a t i o n of t h e s m a l l vessels of t h e m y o c a r d i u m r e v e a l e d significant alterations. T h e t o t a l n u m b e r of vessels s t u d i e d p e r case a n d t h e p e r c e n t a g e of a b n o r m a l vessels for t h e a l c o h o l i c g r o u p is

American Heart Journal

s u m m a r i z e d i n T a b l e I V a n d for t h e c o n t r o l g r o u p in T a b l e V, T h e m o s t f r e q u e n t a l t e r a t i o n n o t e d was v a s c u l a r e d e m a , w h i c h w a s p r e s e n t i n 48 p e r c e n t of t h e vessels f r o m all n i n e a l c o h o l i c cases ( T a b l e IV). T h i s c o m p a r e s w i t h a n i n c i d e n c e of 26 p e r c e n t i n t h e c o n t r o l group, T h e c h a n g e s c o n s i s t e d of b o t h i n t r a c e l l u l a r a n d e x t r a c e l l u l a r e d e m a . E m p t y - l o o k i n g v a c u o l e s were f r e q u e n t l y n o t e d w i t h i n t h e cells of t h e i n t i m a a n d m e d i a . T h i s w a s possibly of little c o n s e q u e n c e , a n d m a y h a v e b e e n the r e s u l t of t e r m i n a l a n t e m o r t e m c h a n g e s or

565

Factor

Fig. 1. There is extensive vascular disorganization, with large clear spaces and focal sclerosis producing disruption and separation of the vessel wall layers. (Trichrome; •

Fig. 2. The vessel lumen is on the upper right. There are several subendothelial cystic spaces in which obvious red blood cells can be seen. There is a gap (arrow) between the endothelial cells through which the erythrocytes appear to pass. (Hematoxylin and eosin; • 1,000.) p o s t m o r t e m autolysis. More significant was the presence of edema, which appeared to be extracellular. There was separation of individual cells within the vessel wall by clear spaces, which often extended into the media. W h e n these changes were more p r o n o u n c e d and confluent, there was marked separation and disorganization of the vessel wall layers {Fig. 1). Occasionally, subendo-

566

thelial micr0cysts were present filled with eosinophilic material. Infrequently, these m i c r o c y s t s were noted to contain e r y t h r o c y t e s or leukocytes (Figs. 2 and 3). Irregular cystic spaces were also noted in the media of several larger vessels (50 to 200 microns) which contained basophilic m a t e r i a l most likely representing intercellular g r o u n d substance.

November, 1976, Vol. 92, No. 5

Intramyocardial disease in chronic alcoholism

Fig. 3. A large subendothelial microcyst on the right contains several mononuclear leukocytes (arrows) and red blood cell fragments (arrowheads). The fibrillar material within the cyst is stained eosinophilic. (Trichrome; x400).

Fig. 4. This edematous vessel with focal intimal sclerosis is surrounded by loose perivascular fibrosis which impinges upon the adjacent myocardium. The loose fibrous tissue contains both inflammatory cells and erythrocytes. (Hematoxylin and eosin; x 160.) Perivascular fibrosis was the second m o s t c o m m o n a b n o r m a l i t y noted, occurring in 42 per cent of the t a b u l a t e d vessels in the alcoholic group (Table IV) and 13 per cent in the c o n t r o l group (Table V). It f r e q u e n t l y was associated with interstitial and m y o c a r d i a l fibrosis. T h e perivascular fibrosis was p r e d o m i n a n t l y of two types. Loose, poorly organized fibrous connective

American Heart Journal

tissue extended from the adventitia to involve the myocardial fibers a d j a c e n t to the interstitial c o m p a r t m e n t (Fig. 4). This form of fibrosis was often associated with increased n u m b e r s of chronic inflammatory cells, e x t r a v a s a t e d erythrocytes, and hemosiderin-laden m a c r o p h a g e s in the perivascular interstitium. No active vasculitis was noted. Denser, more organized perivascular

567

Factor

Fig. 5. Dense, concentric perivascular fibrosis surrounds this vessel with striking intimal proliferation and edema and medial sclerosis. (Trichrome; • 63.)

Fig. 6. There is circumferential vascular sclerosis and relatively dense perivascular fibrosis, producing narrowing of the lumen. The vessel wall is focally infiltrated by Anitschkow myocytes, which cannot be resolved at this magnification. (Hematoxylin and eosin; • 160.) fibrosis consisted of concentric, hyalinized, variably acellular fibrous tissue (Fig. 5). T h i s f o r m of fibrosis was usually n o t associated w i t h increased interstitial i n f l a m m a t i o n . I t was c o m m o n l y seen within papillary muscles, b u t was also s c a t t e r e d t h r o u g h o u t the m y o c a r d i a l sections e x a m i n e d . Although not t a b u l a t e d s e p a r a t e l y f r o m the looser, less organized fibrosis, t h e concentric fibrosis generally was the less c o m m o n of t h e t w o forms. 568

Vascular sclerosis was n o t e d in 36 per cent of the vessels examined in the alcoholic group (Table IV), c o m p a r e d to 15 per cent of the vessels in the control group (Table V). Several t y p e s of a b n o r m a l i t y were a p p a r e n t . S u b e n d o t h e l i a l intim a l thickening was noted, similar in c o m p o s i t i o n and staining characteristics to t h e s u b e n d o t h e l i a l h u m p s described below. T h e m a j o r difference, however, was t h a t the sclerosis was n o t nodular, b u t was a linear i n t i m a l thickening occurring November, 1976, Vol. 92, No. 5

Intramyocardial disease in chronic alcoholism

Fig. 7. There is asymmetric vascular sclerosis and focal vascular wall edema with extensive disruption and duplication of black-staining elastic tissue. (Elastic-van Gieson; • 100.)

Fig. 8. Two small subendothelial humps are present in this otherwise relatively normal vessel. The surface covering of endothelial cells can be appreciated. Serial sections revealed that these humps did not represent a vascular branch point. (Hematoxylin and eosin; • 400.) along one portion of a vessel wall. A s y m m e t r i c medial sclerosis was also noted, in which i n t i m a l and medial fibrosis occurred along a s h o r t segment of the vessel wall. T h i s t y p e of sclerosis usually did not m a r k e d l y e n c r o a c h u p o n t h e vascular lumen. M a j o r e n c r o a c h m e n t a n d n a r rowing of the l u m e n often was p r e s e n t w h e n t h e sclerosis affected the entire vessel wall in a s y m m e t r i c a l fashion (Fig. 6). T r i c h r o m e stains revealed increased connective tissue within scleAmerican Heart Journal

rotic vessel walls and stains for elastica revealed reduplication and f r a g m e n t a t i o n of elastic fibers (Fig. 7). Subendothelial h u m p s were p r e s e n t in 13 per cent of all vessels t a b u l a t e d in the alcoholic group (Table IV), and in 3 per cent of the vessels in the control group (Table V). T h e h u m p s consisted of subendothelial a c c u m u l a t i o n s of b r i g h t l y eosinophilic, PAS-positive m a t e r i a l with a g r a n u l a r a n d occasionally hyalinized a p p e a r a n c e (Fig. 8). T h e 569

Factor

Fi9. 9. Several typical Anitschkow myocytes are present within the intima and media of this vessel. Two cells with a central longitudinal mass of chromatin can be seen to the right of center (arrows). (Hematoxylin and eosin; • 400.)

Fig. 10. A characteristic caterpillar-like chromatin pattern can be seen in this Anitschkow myocyte which is lying within the intima. The vessel lumen is on the upper left. (Hematoxylin and eosin; • 1,000.)

h u m p s were generally acellular, a l t h o u g h m o n o nuclear cells and cell fragments were i n f r e q u e n t l y noted within the eosin0philic material. T h e h u m p s protruded into the vascular l u m e n s and ranged in size from 10 t o 25 microns. Only the larger h u m p s occurring in the smaller vessels appeared to significantly n a r r o w the vascular lumen. I n the rare vessels which h a d more t h a n

570

one hump, however, there appeared to be m a r k e d narrowing and distortion of the v a s c u l a r c h a n nel. T h e most u n u s u a l and u n e x p e c t e d finding in this study was the observation of A n i t s c h k o w m y o c y t e s and rarely other i n f l a m m a t o r y cells within the intima and media of 11 per cent of the vessels examined in the alcoholic group (Table

November, 1976, Vol. 92, No. 5

Intramyocardial disease in chronic alcoholism

Fig. 11. A sclerotic vessel on the left is lying within an area of myocardium which reveals extensive replacement by fibroblasts, chronic inflammatory cells, and capillaries (case 9). (Hematoxylin and eosin; x 63.) IV), and in 2 per cent of the vessels in the c o n t r o l group (Table V). N o n e of these 18 cases h a d gross or microscopic evidence of r h e u m a t i c h e a r t disease, nor did there a p p e a r to be increased n u m b e r s of Anitschkow cells in t h e interstitium. Yet unequivocal Anitschkow m y o c y t e s with a typical caterpillar-like c h r o m a t i n p a t t e r n w h e n viewed in longitudinal section, or a n owl's-eye a p p e a r a n c e when seen in cross section, were n o t e d (Figs. 9 and 10). No fibrinoid necrosis or h e a v y i n f l a m m a t o r y infiltrate was identified in association With these cells. T h e y could easily be separated histologically f r o m b o t h e n d o t h e l i a l cells and the elongated s m o o t h muscle cells c o m p o s i n g the vascular wall. I t was n o t possible to determine if the Anitschkow cell originated f r o m the adventia, periadventitial connective tissue, or the vascular lumen. M o n o n u c l e a r cells with i n d e n t e d nuclei a n d a rim of c y t o p l a s m r e s e m b l i n g circulating monocytes, were rarely n o t e d sticking to the endothelium. T h e significance of these circulating cells in relation to the presence of Anitschkow m y o c y t e s within t h e vessel wall could not be determined. Despite the lack of cardiac s y m p t o m s in the nine alcoholic cases, a n d despite the absence of gross cardiac abnormalities suggesting a diagnosis of alcoholic c a r d i o m y o p a t h y , all nine cases d e m o n s t r a t e d varying degrees of m y o c a r d i a l alteration. Myofiber a t r o p h y a n d v a r i a b i l i t y in size, associated with edema, fibrosis, a n d chronic

American Heart Journal

i n f l a m m a t i o n o f the i n t e r s t i t i u m were n o t e d focally in cases 1, 2, 4, 6, 8, a n d 9. T h e m o s t severe changes were present in case 9, in which t h e r e was extensive interstitial fibrosis, chronic i n f l a m m a tion, and active fibroblastic proliferation (Fig. 11). Focal acute m y o c a r d i a l necrosis was n o t e d in cases 2 and 8, but this was a t t r i b u t e d to t e r m i n a l tissue hypoxia. Focal areas of m y o c a r d i a l ischemia were only rarely n o t e d in t h e control group. It should be pointed o u t t h a t t h e m e t h o d s utilized in this s t u d y h a v e produced a q u a n t i t a tive index of vascular a b n o r m a l i t i e s in b o t h the alcoholic and control groups. Since q u a l i t a t i v e abnormalities were n o t t a b u l a t e d , it is difficult to compare the raw figures f r o m one group to the other. As a subjective observation, however, the vascular abnormalities in the control group, w i t h one exception, did n o t a p p r o a c h the severity of the changes described in t h e alcoholic group. Endothelial disruption, large s u b e n d o t h e l i a l spaces with loosening of the vessel wall layers, marked vascular sclerosis, a n d onion skin-like perivascular fibrosis were n o t c o m m o n l y n o t e d in the control group. T h e one exception was case 16, in which changes, p a r t i c u l a r l y perivascular fibrosis, c o m p a r a b l e to the alcoholic p a t i e n t s were seen. This p a t i e n t h a d a p o s t h e p a t i t i c cirrhosis with multiple congenital a b n o r m a l i t i e s a n d questionable congenital toxoplasmosis. I t is u n c l e a r whether these diseases c o n t r i b u t e d to t h e cardiac

5 71

Factor

microvasculature abnormalities. Even with this case included in the control group, however, the tabulated subtotals for the hepatic patients (cases 16 to 18) did not differ appreciably from those of the tr au m a and central nervous system patients or from those of the control group as a whole. The differences between the alcoholic and control groups were not statistically analyzed because of the small sample population. However, comparison of the data in Tables IV and V reveals a two- to threefold increase in the incidence of major vascular abnormalities (vascular edema, perivascular fibrosis, and vascular sclerosis) when the alcoholic group is compared to the control group. The less significant abnormalities, subendothelial humps and vascular inflammation, were approximately five times more common in the alcoholic group. Admittedly, within the small sample population studied, there was a degree of overlap which makes absolute diagnosis of alcoholic heart disease on the basis of vascular pathologic changes difficult; however, the over-all trend suggests a definitively increased incidence of damaged vessels in the alcoholic heart. Discussion

Alcoholic heart disease has been estimated to account for up to 3 per cent of cardiac patients in large municipal and veterans hospitalsY ~ A syndrome consisting predominantly of cardiomegaly, tachycardia, and cardiac failure is associated with chronic alcoholism, 3 probably occurring independently of vitamin deficiency,~ malnutrition, ~ and known cardiotoxic substances present in alcohol such as cobalt. ~, ~ A preclinical form of heart disease in chronic alcoholics, manifested by decreased cardiac output and elevated left ventricular end-diastolic pressures, has been described in alcoholics without radiographic evidence of cardiomegaly or symptoms of heart failure:~, 20 A similar group of patients comprised the present study. It has been exceedingly difficult to define the etiologic agent or agents involved in the pathogenesis of alcoholic heart disease. Most studies, by necessity, have dealt with chronically ill adult patients who have varying nutritional intake, uncontrolled vitamin and electrolyte levels, increased susceptibility to infections, as well as the normal afflictions associated with aging. In addition, the amount and type of alcohol ingested

572

is often an unknown variable. Animal studies have produced contradictory results. Whereas Burch and associates, 17 using the mouse, have reported evidence supporting the concept of direct alcohol toxicity on the heart, their results have been disputed by Hall and Rowlands, 21 who were not able to induce toxic changes. In h u m a n subjects, Regan 8 has documented the effects on myocardial function of large doses of alcohol administered acutely and chronically. Others, however, doubt the direct etiologic connection between alcohol and heart disease. ~ Less debatable is the relative constancy of the pathologic changes reported by various observers. Despite the occasional severity of clinical alcoholic heart disease, the pathologic alterations described by light microscopy are relatively minimal, and consist of variable fibrosis, lipid deposition, and interstitial edema. ~, 5.7 Ultrastructurally, dilatation of the sarcoplasmic reticulum and mitochondrial degeneration have been reported by Alexander. 23 Cytochemical study has revealed varying degrees of myocardial enzyme depletion. 24 These alterations are strikingly nonspecific, and may only reflect electrolyte imbalance or tissue anoxia. TM 17 As noted in the introduction, almost all pathologic studies of alcoholic heart disease have focused on myofiber alterations, with little attention paid to the intramyocardial vessels. However, if tissue anoxia plays a major role in the pathogenesis of alcoholic cardiomyopathy, abnormal intramyocardial small coronary arteries may be the mediators of this anoxia, since the epicardial coronary arteries are usually normal2 The report by Pintar and associates 18 in 1965 has been cited in numerous papers as evidence for the existence of small-vessel disease in alcoholic heart disease. Yet the vascular abnormalities were only briefly described in the course of reporting three cases of alcoholic cardiomyopathy, without comments on the frequency of the changes. Since 1965. to the best of our knowledge, there have been no reported systematic studies of the cardiac microvasculature in chronic alcoholism. The present study has at t em pt ed to define the types and frequency of vascular alterations in the hearts of chronic alcoholics without overt cardiomyopathy. Pintar and associates ~8considered vascular wall edema to be the primary abnormality of the microvasculature in chronic alcoholism. This

November, 1976, Vol. 92, No. 5

Intramyocardial disease in chronic alcoholism

edema was felt to be the consequence of increased vascular permeability, resulting in the passage of protein-rich plasma through the endothelium, where it accumulated between the vascular wall layers. Organization of this fluid would then result in gra~lual occlusion of small vessels with subsequent anoxic effects on small areas of myocardium. Observation of vascular wall edema was noted by Benchimol and Schlesinger ~5 in their study of beriberi heart disease. In the present report, vascular wall edema was the most common abnormality seen, occurring in 48 per cent of the vessels examined. Several experimental studies relevant to vascular pathology in alcoholism have been reported. Constantinides ~ has found t h a t m a ny agents produce either necrosis of arterial endothelium or widening of intercellular gaps, allowing the passage of circulating macromolecules into the vascular wall, where they accumulate. Among the agents which he studied, serotonin and the cathecholamines induced enlarged endothelial cell junctions and intracellular and extracellular fluid concentration. In circumstances other t han alcoholism, such as pheochromocytoma or iatrogenic administration, excessive catecholamines are known to produce myocardial injury of unknown etiology, with vascular damage being one of the postulated mechanisms. ~ Of interest in this regard is the work of James and Bear, 1~who have observed that acetaldehyde, the principal first metabolic product of ingested alcohol, releases myocardial and adrenal stores of norepinephrine as well as serotonin. It is as yet unclear whether these released amines play a role in the induction of the vascular changes in alcoholic he art diseas Experimentally, the effect of ethanol administration on the myocardial capillaries of mice has been studied by Sohal and Burch. 15 T h e y noted swelling and degeneration of endothelial cells and the passage of erythrocytes through junctional gaps in the endothelial lining. Eventually, narrowing and irregularity of the vascular lumen resulted. The authors considered the possibility that chronic hypoxia due to the vascular alterations might play a role in the production of alcoholic myocardial disease. T h e y also speculated that the pathologic changes were the result of the altered metabolism of serotonin and other biogenic amines secondary to the administered ethanol.

American Heart Journal

Magnesium deficiency has been incriminated as a contributing factor in alcoholic cardiomyopathy. Its effects on the heart have been studied by Wener and associates. 12 They noted that chronic magnesium deficiency in dogs induced focal intimal disruption in small myocardial vessels, as well as edema and degeneration of the media. Adventitial edema was also occasionally present. In medium-sized myocardial vessels, loose arrangement of the vessel wall with a suggestion of edema was not ed. The vascular changes described in their paper were remarkably similar to m any of the abnormalities noted in the present study. It is known that magnesium deficiency commonly occurs in chronic alcoholism. 13 Lim and Jacob ~8 found diminished skeletal muscle magnesium levels in nine of 10 chronic alcoholics studied. It is conceivable that many or all of these mechanisms may have played a role in the pathogenesis of the vascular edema observed in the present study. The experimental data suggesting that the edema is secondary to endothelial cell damage, widening of intercellular gaps, and diffuSion of plasma into the vascular wall are supported by the observation of erythrocytes and leukocytes within intimal spaces (Figs. 2 and 3). Very little is known about the fate of edema fluid, macromolecules, or even cells which have permeated into the intima. It is unclear how these substances are specifically handled by vascular wall myocytes and inflammatory cells, and how the presence of edema fluid elicits the various forms of microvascular pathology described in this report. Future study will be required to define the precise mechanisms involved; however, a possible sequence can be proposed. Localized vascular wall injury leading to focal subendothelial accumulation of plasma protein and macromolecules may induce vascular wall myocytes to deposit PAS-positive basement membrane-like material, elastin, and collagen. The end result would be a subendothelial hump. This sequence has been proposed by Haerem 29 in a study of identical lesions in 215 consecutive autopsies. More extensive endothelial injury could result in either partial or circumferential vascular sclerosis. Vascular sclerosis of varying severity was a relatively common finding in this study, occurring in 36 per cent of the examined vessels. The presence of increased connective tissue and reduplicated elastic fibers in these lesions may thus be secondary to a diffuse induc-

5 73

Factor

tion of vascular wall myocytes by edema fluid to produce these substances. Finally, perivascular fibrosis may be the result of organization of edema fluid which has diffused through the entire vascular wall into the interstitial space. Similar fibrosis was present around edematous mediumsized vessels of the hypomagnesemic dogs described by Wener and associates. 1~ T h e frequency of the abnormality in this study (42 per cent} suggests th at it occurs with great regularity in chronic alcoholics. Further evidence of a primary toxic vascular injury in chronic alcoholism is suggested by the observation of vascular wall inflammation in 11 per cent of the vessels in this study. T he inflammation consisted predominantly of individual or occasionally aggregated typical Anitschkow myocytes within the intima or media. Anitschkow myocytes have been noted as a camponent of the vessel wall in rheumatic vasculitis 3~ but to the best of our knowledge they have never been described in nonrheumatic cardiac disease. None of the nine patients of this study had any clinical or pathologic evidence of antecedent rheumatic heart disease. Anitschkow myocytes were rarely noted in the control group within vessel walls. which were otherwise tabulated as abnormal. Additionally, they have occasionally been seen within intramyocardial vessel walls in patients with sickle-cell anemia, congestive cardiomyopathy, and ischemic and hypertensive heart disease (personal observations, unpublished}. Therefore, if in fact Anitschkow myocytes represent a histiocytic cell, we must assume that their presence in the vascular wall is a reaction to vascular injury of unknown etiology. Additionally, they may play an important role in the organization of the material which permeates into the vessel. Despite the clinical absence of cardiac symptomatology in this group of nine patients, the severity and frequency of the vascular abnormalities was reflected in the e x t e n t of the myocardial pathology. Interstitial and myocardial degenerative changes were noted with varying degrees of severity in the entire group. Although it is possible that the acute administration of vasopressin and levarterenol to several of the patients in this group (see Table I} may have induced vascular and myocardial alterationsJ 7 31 it is unlikely that any of the more chronic changes described were caused by these agents. It is probable that the etiology of small-vessel

574

disease in chronic alcoholism is multicausal. Th e cardiac microvasculature appears to have a limited response to varying toxic agents, whether they be catecholamines, serotonin, cobalt, or alcohol, as well as to varying deficiencies such as thiamine or magnesium. The end result is the induction of endothelial damage, vascular edema, and subsequent vascular and perivascular sclerosis. The nonspecific myocardial alterations reported in chronic alcoholism may then be the consequence of the vascular disease. T he results of this study suggest t hat more attention should be paid to the microvasculature in alcoholic cardiomyopathy, and possibly in other nonatherosclerotic myocardial diseases.

Summary A morphologic study of the small (50 to 200 micron) intramyocardial coronary arteries was performed, The cases chosen for study were selected from a relatively young group of patients without clinical evidence of alcoholic cardiomyopathy or pathologic evidence o f large coronary artery disease, in order to evaluate alterations in the small vessels which could possibly be attributed to the chronic alcoholic state. F i v e basic vascular abnormalities were described. The most common alteration found in all nine cases was vascular wall edema (48 per cent), followed by perivascular fibrosis (42 per cent), vascular sclerosis (36 per cent), subendothelial humps (13 per cent), and vascular wall inflammation (11 per cent). The significance and pathogenesis of these changes were discussed. Primary endothelial cell damage was proposed as a common pathogenic mechanism for all five types of vascular abnormality. It was suggested t h a t following endothelial damage, fluid and macromolecules penetrate into the vessel wall or into the perivascular space where, by incompletely understood processes, they induce vascular wall myocytes to produce collagen, elastin, and basement membrane-like substances. Evidence supporting this mechanism was derived from the common observation of vascular wall edema, from the occasional presence of erythrocytes and leukocytes within the vessel wall, and from experimental data in the literature. Several possible etiologic agents were implicated in the pathogenesis of endothelial and vessel wall injury. These included alcohol itself, acetaldehyde, biogenic amines, and magnesium

November, 1976, Vol. 92, No. 5

Intramyocardial disease in chronic alcoholism

d e f i c i e n c y . I t is p r o b a b l e , h o w e v e r , t h a t t h e r e a r e multiple etiologic factors which affect the small cardiac vessels of the chronic alcoholic. Finally, the proposal was advanced that the nonspecific pathology of the myocardium in chronic alcoholism may be a result of ischemia secondary to disease of the small intramyocardial coronary arteries. I would like to express my appreciation to Dr. Luis Biempica who kindly reviewed the manuscript and made helpful suggestions, to Ms. Connie Verutes for secretarial assistance, and to Mr. Hugh Carrasco and Mr. Danny Abbruzzese who prepared the histologic sections. REFERENCES

1. Alexander, C. S.: Idiopathic heart disease. Analysis of 100 cases, with special reference to chronic alcoholism, Am. J. Med. 41:1213, 1966. 2. Koide, T., Machida, K., Nakanishi, A., Ozeki, K., Mashima, S., and Koni, H.: Cardiac abnormalities in chronic alcoholism, Jap. Heart J. 13:418, 1972. 3. Evans, W.: Alcoholic myocardiopathy, Prog. Cardiovasc. Dis. 7:151, 1964. 4. Demakis, J. G., Proskely, A., Rahimtoola, S. H., Jamil, M., Sutton, G. C., Rosen, K. M., Gunnar, R. M., and Tobin, J. R. Jr.: The natural course of alcoholic cardiomyopathy, Ann. Intern. Med. 80:293, 1974. 5. Brigden, W.: Alcoholic cardiomyopathy, Cardiovasc. Clin. 4:197, 1972. 6. Burch, G. E., and DePasquale, N. P.: Alcoholic cardiomyopathy, Am. J. Cardiol. 23:723, 1969. 7. Morales, A. R.: Cardiomyopathies: Congenital and acquired, in Edwards, J. E., editor: The heart, Baltimore, 1974, The Williams & Wilkins Company, pp. 221-225. 8. Regan, T. J.: Ethyl alcohol and the heart, Circulation 44:957, 1971. 9. Gould, L.: Cardiac effects of alcohol, AM. HEART J. 79:422, 1970. 10. James, T. N., and Bear, E. S.: Effects of ethanol and acetaldehyde on the heart, AM. HEART J. 74:243, 1967. 11. Mitchell, J. H., and Cohen, L. S.: Alcohol and the heart, Mod. Concepts Cardiovasc. Dis. 39 (Suppl):109, 1970. 12. Wener, J., Pintar, K., Simon, M. A., Motola, R., Friedman, R., Mayman, A., and Schucher, R.: The effects of prolonged hypomagnesemia on the cardiovascular system in young dogs, AM. HEART J. 67:221, 1964.

American Heart Journal

13. Fankushen, D., Raskin, D , Dimich, A., and Wallach, S. E.: The significance of hypomagnesemia in alcoholic patients, Am. J. Med. 37:802, 1964. 14. Anton, A. H.: Ethanol and urinary catecholamines in man, Clin. Pharmacol. Ther. 6:462, 1965. 15. Sohal, R. S., and Burch, G. E.: Effect of ethanol ingestion on the myocardial capillaries of mice, Cardiovasc. Res. 3-369, 1969. 16. Morin, Y., and Cote, G.: Toxic agents and cardiomyopathies, Cardiovasc. Clin. 4:251, 1972. 17. Burch, G. E., Colcolough, H. L., Harb, J. M., and Tsui, C. Y.: The effect of ingestion of ethyl alcohol, wine, and beer on the myocardium of mice, Am. J. Cardiol. 27:522, 1971. 18. Pintar, K., Wolanskyj, B. M., and Buggay, E. R.: Alcoholic cardiomyopathy, Can. Med. Assoc. J. 93:103, 1965. 19. Robbins, S, L.: Cardiac pathology-A look at the last five years, Hum. Pathol. 5:9, 1974. 20. Asokan, S. K., Frank, M. J., and Witham, A. C.: Cardiomyopathy without cardiomegaly in alcoholics, AM. HEART J. 81:13, 1972. 21. Hall, J. L., and Rowlands, D. T. Jr.: Cardiotoxicity of alcohol, Am. J. Pathol. 60:153, 1970. 22. Goodwin, J. F., and Oakley, C. M.: The cardiomyopathies, Br. Heart J. 34:545, 1972. 23. Alexander, C. S.: Electron microscopic observation in alcoholic heart disease, Br. Heart J. 29:200, 1967. 24. Ferrans, V., Hibbs, R., Weilbaecher, D., Black, W., Walsh, J., and Burch, G.: Alcoholic cardiomyopathy. A histochemical study, AM. HEART J. 69:748, 1965. 25. Benchimol, A. B., and Schlesinger, P.: Beriberi heart disease. AM. HEART J. 46:245, 1953. 26. Constantinides, F.: The important role of endothelial changes in atherogenesis, in Shimamoto, T., Numano, F., and Addison, G. M., editors: Atherogenesis, Amsterdam, 1972, Excerpta Medica Foundation, pp. 51-65. 27. Haft, J. I.: Cardiovascular injury induced by sympathetic catecholamines, Prog. Cardiovasc. Dis~ 17:73, 1974. 28. Lim, P., and Jacob, E.: Magnesium status of alcoholic patients, Metabolism 21:1045, 1972. 29. Haerem, J. W.: Cusion-like intimal lesions and platelet aggregates in intramyocardial arteries of man, Acta Pathol. Microbiol. Scand. 77-73, 1969. 30. Hall, E. M., and Anderson, L. R.: The incidence of rheumatic stigmas in hearts which are usually considered non-rheumatic, AM. HEART J. 25:64, 1943. 31. Nakano, J.: Cardiovascular actions of vasopressin, Jap. Circ. J. 37:363, 1973.

575

Intramyocardial small-vessel disease in chronic alcoholism.

Intramyocardial small-vessel disease in chronic alcoholism Stephen M. Factor, M.D. Bronx, N. Y. The association between chronic alcoholism and clinic...
8MB Sizes 0 Downloads 0 Views