Upsala J Med Sci 87: 119-125, 1982 Alcohol Intake, Serum P2-microglobulin and Ventricular Extrasystoles Factors related to death in five-year follow u p of middle-aged men A . Urban Waern', C. Lidell' and K. Hellsing' From the Departments of Internal Medicine' Clinical Chemistry2, University Hospital, U p p s t i l t i . Sttvden ABSTRACT Common causes of death in middle-aged men in Sweden are ischemic heart disease and malignant tumours. In this work the authors relate some findings in a healthy survey of sixty-year old men to mortality in the ensuing five-year follow-up period. Of the original population of 331, 60-year old men 15 sub- jects (4.5%) died. in the follow-up period. The factors tested for relation to death in the follow-up period were: indices of alcohol abuse, serum con- centration of B2-microglobulin and occurrence of ventricular extrasystoles in a long term (6 hrs) ambulatory electrocardiogram. It was found that in seven of the fifteen deceased subjects at least episodical heavy abuse of alcohol had prevailed. This was not evident at the health examination by use of serum gammaglutamyltransferase analysis, nor through the death certificates, but through hospital records and registration at the Temperance Board. Four subjects died (1.2%) of malignant tumours, and three of these subjects had serum-B2-microglobulin values above the 95th percentile in the study popula- tion. An increased risk of death, though statistically not significant, was noted in men with ventricular extrasystoles compared to those without ventri- cular extrasystoles in long term electrocardiogram. However, all men with ventricular extrasystoles ? 30/hour and those with ventricular tachycardia were alive five years later. Among the men w?o died due to ischemic heart disease, ventricular extrasystoles in the long-term electrocardiogram prevailed only in subjects with indices of alcohol intake. Alcohol induced fatal arr- hythmias might thus be the terminating event in middle-aged men with tradition- al risk-factors for ischemic heart disease. MATERIAL AND METHODS All men born in 1915, living in Uppsala were invited to a health examina- tion at their age of sixty years in 1975. The procedures of this health in- vestigation have been described in detail elsewhere (15). A total of 331 60- year old men took part, which corresponded to a participation rate of 78.4%. I I9 L a b o r a t o r y i n v e s t i g a t i o n s c l u d e d a n a l y s i s o f S - p 2 - m i c r o g l o b u l i n ( 6 ) and S-Gammaglutamyltransferase (S-GT) ( 1 1 ) . F u r t h e r m o r e each s u b j e c t was i n s t r u c t e d t o c o l l e c t a l l u r i n e d u r i n g t h e 24 h o u r s f o l l o w i n g t h e h e a l t h e x a m i n a t i o n . A n a l y s i s f o r any con- t e n t s o f e t h y l a l c o h o l i n u r i n e was c a r r i e d o u t a c c o r d i n g t o t h e method b y Bonnichsen e t a1 ( 1 ) . The serum samples were t a k e n i n t h e f a s t i n g s t a t e i n t h e m o r n i n g and i n - M e d i c a l h i s t o r y m o d i f i e d a f t e r C o l l e n ( 2 ) i f he had i n g e s t e d any a l c o h o l i c beverages t h e day p r i o r t o t h e h e a l t h s c r e e n i n g . The r e g i s t e r s o f h o s p i t a l r e c o r d s f o r i n - h o s p i - t a l s t a y a t t h e U n i v e r s i t y H o s p i t a l o f Uppsala were searched. F u r t h e r m o r e t h e r e g i s t e r o f t h e Temperance Board was e v a l u a t e d , f o r s u b j e c t s b e l o n g i n g t o t h e a c t u a l s t u d y p o p u l a t i o n , r e g i s t e r e d , due t o a l c o h o l abuse. Each p a r t i c i p a n t was asked by means o f a s e l f - a d m i n i s t e r e d q u e s t i o n n a i r e Death C e r t i f i c a t e s The d e a t h c e r t i f i c a t e s f o r a l l s u b j e c t s i n t h e s t u d y g r o u p who d i e d i n t h e f i v e y e a r p e r i o d (1975-1980) f o l l o w i n g t h e h e a l t h e x a m i n a t i o n , were o b t a i n e d i n c o p i e s f r o m t h e N a t i o n a l Bureau o f S t a t i s t i c s i n Stockholm. Long-term ECG d a i l y a c t i v i t i e s . A p o r t a b l e one-channel t a p e - r e c o r d e r (HRB2 S R A - H e l l i g e , Sweden) was used. The e l e c t r o d e s were a t t a c h e d i n b i p o l a r l e a d v e r t i c a l l y o v e r s t e r n u m . . A n a l y s i s was c a r r i e d o u t t h r o u g h a scanner w i t h 2 0 - f o l d t i m e c o m p r e s s i o n (Memoport H e l l i g e , Sweden). g r a p h i c p a p e r w i t h paper-speed 125 mm/sec f o r subsequent manual e v a l u a t i o n o f a r r h y t h m i a s . A 6 - h o u r a m b u l a t o r y ECG r e c o r d i n g was c a r r i e d o u t d u r i n g u n r e s t r i c t e d The e l e c t r o c a r d i o g r a m s were f u l l y p r i n t e d o u t on s t a n d a r d e l e c t r o c a r d i o - A r r h y t h m i a c l a s s i f i c a t i o n i n t h e l o n g - t e r m ECG complex (> 0.12 s e c ) , w i t h o u t a p r e c e d i n g P-wave. F r e q u e n t VES were d e f i n e d as a mean h o u r l y c o u n t 530. Complex V E S c o m p r i s e d bigeminy, c o u p l e t s , m u l t i - f o r m i t y , v e n t r i c u l a r t a c h y c a r d i a ( V T ) (> 3 VES c o n s e c u t i v e l y w i t h r a t e > l o 0 p e r m i n ) , and t h e R on T phenomenon (RR-/QT 2 0 . 8 5 ) . A v e n t r i c u l a r e x t r a s y s t o l e (VES) was d e f i n e d as a p r e m a t u r e w i d e QRS RESULTS T a b l e s 1-3 show a l l 15 s u b j e c t s ( 4 . 5 % ) who d i e d i n t h e f i v e y e a r s f o l l o w i n g t h e h e a l t h e x a m i n a t i o n . A l l s u b j e c t s underwent a u t o p s y . Seven 120 s u b j e c t s d i e d o u t s i d e h o s p i t a l . The s u b j e c t s who d i e d a r e grouped i n t h e t h r e e t a b l e s a c c o r d i n g t o causes o f d e a t h , nemely i s c h e m i c h e a r t d i s e a s e ( I H D ) , m a l i g n a n t tumours and o t h e r causes r e s p e c t i v e l y . E i g h t s u b j e c t s d i e d due t o I H D , f o u r s u b j e c t s due t o a m a l i g n a n t tumour and t h e r e m a i n i n g t h r e e o f o t h e r causes. T a b l e 1. S u b j e c t s ( n o 1-8) who d i e d due t o I s c h e m i c h e a r t d i s e a s e ( I H D ) . S u b j e c t S-GT Age a t d e a t h I n d i c e s o f a l c o - R i s k f a c t o r s f o r I H D VES i n No u k a t / l y e a r s h o l i n t a k e ( a b b r e v i a t i o n s se l o n g - t e r m be1 ow) ECG 1 0.70 61 R e g i s t e r e d a t S + Temperance b o a r d 2 0.50 62 3 0.17 62 S HL,HT 0 0 4 0.22 61 0 5 0.68 61 A l c o h o l i s m (Dept o f S P s y c h i a t r y ) . A c u t e a l c o h o l p a n c r e a t i t i s P s y c h i a t r y ) . Pos q u e s t i o n n a r y r e p l y 6 0.38 61 A l c o h o l i s m (Dept o f HL, S 7 0.18 60 A l c o h o l i n u r i n e HL, S 8 0.51 61 Pos q u e s t i o n n a r y r e p l y + - A b b r e v i a t i o n s : HL = H y p e r l i p i d e m i a , HT = H y p e r t e n s i o n , S = Tobacco Smoking, + = o c c u r r e n c e o f VES, 0 = no o c c u r r e n c e o f VES, p e r f o r m e d - = no l o n g t e r m ECG I n d i c e s o f a l c o h o l i n t a k e As can be seen f r o m T a b l e 1-3 i n d i c e s o f a l c o h o l i n t a k e were f o u n d i n 9 o f t h e 15 deceased s u b j e c t s . However, i n t w o o f t h e cases ( n o 8 and no 1 1 ) t h e i n d e x r e g i s t e r e d was a p o s i t i v e r e p l y o f t h e q u e s t i o n n a i r e . These cases c e r t a i n l y r e p r e s e n t e d o c c a s i o n a l i n t a k e . I n t h e r e m a i n i n g 7 s u b j e c t s however, t h e r e were s i g n s o f a t l e a s t e p i s o d i c a l heavy a l c o h o l abuse. F o u r o f t h e f i f t e e n s u b j e c t s were r e g i s t e r e d a t t h e Temperance Board ( 2 7 % ) w h i c h s h o u l d be compared t o 7% i n t h e r e m a i n i n g p o p u l a t i o n a l i v e . Serum B 2 - m i c r o g l o b u l i n s u b j e c t ( n o 1 1 ) t h e tumour was known a t t i m e o f t h e h e a l t h e x a m i n a t i o n . The v a l u e s o f B 2 - m i c r o g l o b u l i n s h o u l d be j u d g e d a g a i n s t t h e mean v a l u e i n t h e r e m a i n i n g p o p u l a t i o n a l i v e w h i c h was 2.05 ? 0.48 m g / l . T a b l e 2 shows t h e s u b j e c t s who d i e d due t o a m a l i g n a n t tumour. I n one 121 Table 2. Subjects (no 9-12) who died due to a malignant tumor. Subject S-p2 S-GT Age at death Origin of Indices of alcohol intake No mg/l ukat/l years ma1 .tumor 9 2.40 2.34 61 Kidney 10 3.82 0.23 63 Lungs Registered at Temperance Board Alcoholism (Dept of Psy- chi atry) 1 1 2.92 0.20 61 Prostata Pos questionnary reply 12 4.28 0.70 64 Gal 1 bladder Table 3. Subjects No Subjects (no 13-15) who died of other causes than IHD and malignant tumor. S-GT Age at death Cause of death Indices of alcohol intake ukat/l years 13 0.24 62 Amyotrofic lateral scle- rosis 14 0.64 62 Perforating Acute alcohol pancreatitis ulcus ventri- cul i Pos questionnary reply aortic aneurysm Reg at Temperance Board 15 0.33 64 Ruptured Reg at Temperance Board A1 coho1 i sm (Dept of Psychiatry) Long-term ECG subjects in the entire screened population. VES were noted in 121 of these recordings (41.4%). Among the eight subjects who died due to IHD seven under- went long-term ECG, four of these had VES on the long-term ECG, but none however had VT, frequent VES or R/T as defined above. The risk of death due to IHD was 3 times higher in men with VES compared to those without VES. This difference was however not statistically significant (p = 0.2, Fischers exact test). Technically satisfactory long-term ECG recording were obtained in 292 DISCUSSION Increased alcohol intake has been shown by several authors (3, 8, 10) to be related to higher mortality and morbidity, of all causes compared to that among low consumers and abstainers. In our study nearly half of the deceased men had indicators of at least epidosical alcohol abuse. This was not dis- closed by the S-GT values which previously (13, 14, 16, 17) has been related 122 to increased alcohol intake, and in only one of the subjects alcoholismus chronicus was mentioned in the death certificate as contributory cause o f death. Increased alcohol intake as contributory, or main cause of death, is certainly underreported in the National Statistics on mortality. Further one might speculate if those subjects whose findings suggested at least episodical heavy abuse of alcohol, voluntarily had abstained from alcohol intake the weeks preceding the health examination. The reported rapid decrease of S-GT activity ( T 1 7-10 days) at alcohol abstention might thus explain the un- 2 foreseen low S-GT values. Serum microglobulin is a small protein (m.w. 11.800), reported by some authors (9, 12, 13) to show elevated serum concentrations in patients suffer- ing from malignant tumours. In our study only four (1.2%) of the originally investigated population had died due to a malignant tumour in the five-year follow-up period. However, in three of these four subjects the serum D2-microglobulin values were found above the 95th percentile in the entire population. The erytrocyte sedimenta- tion rate (ESR) was not elevated in any of these cases, nor were there any other signs of inflammatory disorders or decreased renal function, the latters (5, 12) have been reported as important causes of elevated serum P2-micro- globulin. Further studies are needed to clarify the possible role of serum D 2 - microglobulin as a possible early circulating marker of a malignant tumour. Some studies ( 4 , 7 ) performed, have not found a correlation between occur- rence of VES and fatal outcome of IHD. Hinkle et a1 (7) investigated 283 actively employed men with a median age of 55 years, with continous 6 hours ambulatory ECG. They found that frequently occuring VES (>lO/lOOO) was associated with a ten fold increase in the risk of developing death due to IHD, in comparison to men without VES. As in our study deaths due to IHD, was not predicted by occurrence of VT or coupled VES. increased 3 times if VES were noted, during a 6 hour continous recording. 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