317

TRACE ELEMENTS A N D CARDIOVASCULAR DISEASES

R i c h a r d A . Anderson

U.S. Depar tmen t of A g r i c u l t u r e , ARS B e l t s v i l l e Hunan N u t r i t i o n R e s e a r c h C e n t e r V i t a m i n and M i n e r a l N u t r i t i o n L a b o r a t o r y B e l t s v i l l e , Maryland U.S.A. 20705

Keywords: Trace e l e m e n t s - c a r d i o v a s c u l a r d i s e a s e s - z i n c - c o p p e r - chromium

A b s t r a c t

E v i d e n c e l i n k i n g marginal i n t a k e s o f t h e trace e l e m e n t s , chromium, c o p p e r ,

z i n c and s e l e n i u m , w i t h a b n o r m a l l i p i d m e t a b o l i s m and u l t i m a t e l y c a r d i o v a s c u l a r

d i s e a s e s i s a c c u m u l a t i n g from b o t h a n i m a l and human s t u d i e s . C h r o m i m s u p p l e -

m e n t a t i o n of normal a d u l t men, as well a s d i a b e t i c s , h a s b e e n r e p o r t e d t o

increase h igh d e n s i t y l i p o p r o t e i n c h o l e s t e r o l and d e c r e a s e t r i g l y c e r i d e s and

t o t a l c h o l e s t e r o l . S u b j e c t s w i t h t h e h i g h e s t t o t a l c h o l e s t e r o l and tri-

g l y c e r i d e s u s u a l l y r e spond t h e most to s u p p l e m e n t a l chromium. Improvemen t s i n

l i p i d m e t a b o l i s m , as well as t h o s e i n g l u c o s e m e t a b o l i s m , a p p e a r t o b e r e l a t e d

t o improvements i n i n s u l i n e f f i c i e n c y due l i k e l y t o i n c r e a s e d r e c e p t o r number.

Animal s t u d i e s a l s o i n d i c a t e t h a t improvements i n s e r u n c h o l e s t e r o l , a o r t i c

l i p i d s and p l a q u e f o r m a t i o n s d u e t o s u p p l e m e n t a l chromium a r e a s s o c i a t e d w i t h

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

e l e v a t e d l i p i d l e v e l s and i m p a i r e d h e a r t f u n c t i o n . Animal s t u d i e s i n d i c a t e a n

o b v i o u s d e g r a d a t i o n o f t h e h e a r t m u s c l e s . Z i n c a p p e a r s t o f u n c t i o n i n c a r d i o -

v a s c u l a r d i s e a s e s p r i m a r i l y v i a i t s a n t a g o n i s m w i t h c o p p e r . S e l e n i u m , may a l s o

a f f e c t c a r d i o v a s c u l a r d i s e a s e s s i n c e s e l e n i u m is p o s t u l a t e d t o be i n v o l v e d i n

p l a t e l e t a g g r e g a t i o n . T h e s e d a t a d e m o n s t r a t e t h a t t h e t race e l e m e n t s ,

chromium, c o p p e r , and s e l e n i u m , h a v e b e n e f i c i a l e f fec ts o n r i s k f a c t o r s

a s s o c i a t e d w i t h c a r d i o v a s c u l a r d i s e a s e s suggesting t h a t a d e c r e a s e d r i s k of

c a r d i o v a s c u l a r d i s e a s e may be a c h i e v e d by a d e q u a t e i n t a k e of trace e l m e n t s .

318

Introduct ion

Cardiovascular d i seases a r e t h e leading causes of death i n t h e United

S t a t e s and most i ndus t r i a l i zed nat ions. Despite s u b s t a n t i a l e f f o r t s to.

understand t h e etiology of t hese d i seases and methods t o prevent them, t h e

underlying concepts c o n t r o l l i n g cardiovascular d i seases a r e s t i l l unclear.

Possible d i e t a ry causes of cardiovascular d i seases are l i s t e d i n t a b l e 1.

T h i s l ist is not meant to be inc lus ive bu t to be r ep resen ta t ive of t h e

numerous possible d i e t a r y f a c t o r s t h a t may inf luence cardiovascular diseases .

Changes i n t h e t o t a l amount of any of t h e t h e f i r s t nine d i e t a r y f a c t o r s l i s t e d

i n t a b l e 1.would a l so a l t e r t h e i n t a k e of t h e e s s e n t i a l t r a c e elements, namely

chromium, copper, i r o n , i o d i n e , selmium and zinc. For example, improvements

i n r i s k f a c t o r s associated w i t h i n t a k e of d i e t a r y f i b e r could a l s o be d u e t o

changes i n t r a c e element intake s ince d i e t a ry f i b e r would l i k e l y contain

s u b s t a n t i a l amounts of t h e e s s e n t i a l t r ace minerals. Likewise, i nc reases i n

d i e t a r y sucrose, which would have a negative impact on r i s k f a c t o r s associated

w i t h cardiovascular d i s e a s e s , would lead to a decreased i n t a k e o f t r ace

elements, s ince sucrose is usua l ly very low i n t r a c e elements and decreases

t race mineral s t a t u s .

The bulk of t he work r e l a t i n g t r a c e elements with cardiovascular d i s e a s e s

i n a c t u a l i t y pe r t a ins t o t h e e f f e c t s of t r a c e elements on r i s k f a c t o r s

associated with cardiovascular d i sease and not t he d i sease i t s e l f . However,

t h i s is where n u t r i t i o n a l i n t e rven t ion may be b e n e f i c i a l by decreasing t h e

r i s k s of developing cardiovascular d i seases and not waiting u n t i l symptoms of

cardiovascular d i seases a r e evident and attempting t o "cure" t h e diseases .

Selenium and Cardiovascular Diseases:

The a s soc ia t ion of selenium w i t h cardiovascular diseases h a s been

discussed i n t h e previous presentat ion and w i l l be discussed only b r i e f l y .

Selenium is postulated to i n c r e a s e p l a t e l e t aggregation by a l t e r i n g t h e

synthesis of p ros t acyc l in , a n agent protect ive against p l a t e l e t aggregation

319

T a b l e 1: P o s s i b l e D i e t a r y C a u s e s of C a r d i o v a s c u l a r Diseases

C a l o r i e s F a t F i b e r P r o t e i n S u c r o s e A l c o h o l Water F a c t o r Calcium Magnesium

Chromium C o p p e r I r o n I o d i n e S e l en i um Z i n c

T a b l e 2: C o r r e l a t i o n of I n s u l i n w i t h L i p i d V a r i a b l e s

L i p i d I n s u l i n F a s t i n g 9 0 M i n D i f f e r e n c e

C h o l e s t e r o l (TC) ** HDLa ** Low d e n s i t y

l i p o p r o t e i n (LDL) **

Very low d e n s i t y l i p o p r o t e i n ( V L D L ) *

T C/H DL

L DL /HDL

**

**

T ri gl yc e r i d e s **

* *

* *

** ** ** ** * *

S i n g l e a s t e r i s k ( * ) i n d i c a t e s t h a t t h e c o r r e l a t i o n w i t h t h e s p e c i f i e d v a r i a b l e was s i g n i f i c a n t a t P 0.01 and d o u b l e a s t e r i s k ( * * I i n d i c a t e s c o r r e l a t i o n was s i g n i f i c a n t a t P 0 .001 . F o r t y - e i g h t male s u b j e c t s t e s t e d 3 times o v e r a 6 mon th p e r i o d . S p e c i f i c d e t a i l s o f t h e s u b j e c t s and methods of a n a l y s e s h a v e b e e n p u b l i s h e d (Anderson e t a l . 1 9 8 3 ) .

a N e g a t i v e c o r r e l a t i o n s .

320

(Schoene e t a l . 1985). Combined d e f i c i e n c y of s e l e n i u m and v i t a m i n E a l s o

p r o d u c e s s e v e r e n e c r o s i s o f t h e h e a r t m u s c l e i n mice a n d p i g s (Commi t t ee on

Biologic E f f e c t s of A t m o s p h e r i c P o l l u t a n t s , 1 9 7 6 ) . An endemic c a r d i o m y o p a t h y ,

Keshan d i s e a s e , which o c c u r s i n humans i n China consuming l ess t h a n 30 ug o f

s e l e n i u m p e r d a y i s p r e v e n t e d b y s e l e n i u n s u p p l e m e n t a t i o n . Keshan disease,

a l t h o u g h p r e v e n t e d b y s e l e n i u m , is b e l i e v e d t o be c a u s e d by a s e c o n d unknown

ma lady supe r imposed on s e l e n i u m d e f i c i e n c y (Chen e t a l . 1 9 8 0 ) .

Copper and C a r d i o v a s c u l a r Diseases:

The h y p o t h e s i s t h a t d i e t a r y c o p p e r i n t a k e is i m p o r t a n t i n t h e e t i o l o g y of

c a r d i o v a s c u l a r d i s e a s e s is p r e s e n t l y b e i n g s u b s t a n t i a t e d . E l e c t r o c a r d i o g r a m

i r r e g u l a r i t i e s which d i s a p p e a r e d f o l l o w i n g c o p p e r s u p p l e m e n t a t i o n were r e p o r t e d

i n a h m a n s u b j e c t consuming a d i e t l ow i n c o p p e r (Klevay e t a l . 1 9 8 4 ) . I n

a d d i t i o n , f o u r o f 2Q male s u b j e c t s p a r t i c i p a t i n g i n a s t u d y t o d e t e r m i n e t h e

e f f e c t s o f f e e d i n g d i e t s low i n c o p p e r (1.03 mg/day/2850 k c a l ) c o n t a i n i n g 20%

f r u c t o s e o r s t a r c h e x h i b i t e d h e a r t r e l a t e d a b n o r m a l i t i e s and had to b e removed

f r o m t h e s t u d y (Reiser e t a l . 1 9 8 5 ) . S u b j e c t s consuming f r u c t o s e d i s p l a y e d

s i g n i f i c a n t l y reduced c u p r o z i n c s u p e r o x i d e d i s m u t a s e a c t i v i t y of t h e e r y t h r o -

c y t e s compared t o t h e s u b j e c t s consuming t h e s t a r c h d i e t b u t c e r u l o p l a s m i n

a c t i v i t y and serum c o p p e r were n o t s i g n i f i c a n t l y d i f f e r e n t .

Hearts a n d blood v e s s e l s of ra t s f e d low c o p p e r d i e t s h a v e abnorma l

a m t o m y , c h e m i s t r y and f u n c t i o n . Hearts o f a n i m a l s d e f i c i e n t i n c o p p e r are

g r e a t l y h y p e r t r o p h i e d and show d e g e n e r a t i o n o f t h e m u s c l e f i b e r s , c h r o n i c

i n f l a m a t i o n , and foc i o f n e c r o s i s ; t h e v e n t r i c u l a r a p e x i s u s u a l l y t h e most

s e v e r e l y a f f e c t e d . T h i s h y p e r t r o p h y a n d myopathy o b s e r v e d i n a n i m a l s consuming

a low c o p p e r d i e t is a g g r a v a t e d b y s u c r o s e o r f r u c t o s e i n g e s t i o n ( F i e l d s 1 9 8 5 ) .

P r o b l e m s a s s o c i a t e d w i t h i n s u f f i c i e n t d i e t a r y c o p p e r may be more c o m o n

t h a n p r e v i o u s l y t h o u g h t d u e t o t h e h a b i t u a l l ow l e v e l s of d i e t a r y c o p p e r i n

t h e U.S. and o t h e r i n d u s t r i a l i z e d c o u n t r i e s . The s u g g e s t e d safe a n d a d e q u a t e

d a i l y i n t a k e f o r c o p p e r is two t o t h r e e mg, however t h e a v e r a g e d a i l y i n t a k e

32 1

Of copper is well below 2 mg and may be near 1 mg/day f o r many i n d i v i d u a l s

(F ie lds 1985). Approximatey 1 mg/day is t h e l e v e l consumed i n the study of

Reiser e t a l . (1985) where four of 24 s u b j e c t s developed se r ious ca rd iac

abno rmal i ti e s !

Zinc and Cardiovascular Diseases:

Zinc a l s o appears to a l t e r r i s k f a c t o r s assoc ia ted w i t h card iovascular

d i seases but t h e e f f e c t s of z inc may be i n d i r e c t due to antagonism w i t h copper

a t h i g h d i e t a r y in t akes of z inc . Supplementation of high l e v e l s of z i n c , more

than 10-times t h e Recomnended Die ta ry Allowance ( R D A ) , f o r 5 weeks t o 12 a d u l t

men led t o a s i g n i f i c a n t decrease i n high-density l i p o p r o t e i n (HDL) c h o l e s t e r o l

w i t h no change i n t o t a l cho le s t e ro l (Hooper e t a l . 1980).

7

The e f f e c t s of z inc on card iovascular d i seases do not appear t o pose an

important hea l th problem s ince t h e normal d i e t a r y i n t a k e of z inc is not

excessive and is usua l ly cons iderably l e s s t h a n t h e R D A . However, i n d i v i d u a l s

who take excess ive amounts of supplemental z i n c may be inc reas ing t h e i r r i s k s

of cardiovascular abnormal i t ies .

Chromium and Cardiovascular Diseases:

Evidence l i nk ing marginal chromium in t akes w i t h abnormal l i p i d metabolism

and u l t imate ly card iovascular d i seases i s rap id ly accumulating from both animal

and human s tud ie s . Ind iv idua l s t h a t died of coronary a r t e r y d i sease were

reported to have s i g n i f i c a n t l y lower concent ra t ions of chromium i n a o r t i c

t i s s u e s compared to s u b j e c t s dying from a c c i d e n t s , al though t h e chromium

concent ra t ion of o t h e r t i s s u e s was s imi l a r (Schroeder e t a l , 1 9 7 0 ) . Sub jec t s

w i t h coronary a r t e r y d i s e a s e have a l s o been reported to have lower s e r m

chromium than s u b j e c t s f r e e of d i sease (Neman e t a l . 1978; Simonoff e t a l .

1984). Serum chromium corre la ted highly (P<O.Ol) w i t h t h e appearance of

coronary a r t e r y d i s e a s e , whereas e l eva t ed serum t r i a c y l g l y c e r o l co r re l a t ed

l e s s s i g n i f i c a n t l y and there was no c o r r e l a t i o n between o the r r i s k f a c t o r s

such as serun c h o l e s t e r o l , body weight or blood pressure w i t h t h e inc idence of

322

c o r o n a r y a r t e r y d i sease (Newman et a l . 1 9 7 8 ) . However , chromim v a l u e s

r e p o r t e d i n t h e s e p r e v i o u s l y ci ted s t u d i e s are h i g h e r t h a n p r e s e n t l y a c c e p t e d

v a l u e s a d t h e data s h o u l d b e i n t e r p r e t e d w i t h c a u t i o n .

Chromium s u p p l a n e n t a t i o n h a s a l s o been shown t o improve b lood l i p i d s .

C h r o m i m s u p p l e m e n t a t i o n (200 ug d a i l y , 5 d a y s a week f o r 1 2 weeks) of 1 2 a d u l t

men r e s u l t e d i n s i g n i f i c a n t decreases i n se rum t r i g l y c e r i d e s a n d i n c r e a s e s i n

HDL-cho les t e ro l compared t o t h e p l a c e b o s u b j e c t s (Riales and A l b r i n k , 1 9 8 1 ) .

Chromium s u p p l a n e n t a t i o n ( 6 0 0 ug chromium as ch romiun chlor ide d a i l y ) o f

p a t i e n t s b e i n g t reated f o r d i abe te s a l s o led to s i g n i f l c a n t i n c r e a s e s i n

HDL-cholesterol (Mossop 1 9 8 3 ) . Se rum HDL-cho les t ro l i n c r e a s e d i n 1 2 of 13

s u b j e c t s t a k i n g C r w i t h a mean i n c r e a s e of more t h a n 25 p e r c e n t . Numerous

s t u d i e s h a v e a l s o r e p o r t e d improvemen t s i n l i p i d p a r a m e t e r s f o l l o w i n g

s u p p l e m e n t a t i o n of brewer's y e a s t t h a t was h i g h i n chromim (see r e v i e w , Bore1

a n d Ander son 1 9 8 4 ) . However, e f fec ts due t o s u p p l e m e n t a t i o n w i t h h i g h

c h r o m i m brewer's y e a s t are d i f f i c u l t t o i n t e r p r e t d u e t o t h e h o s t of o t h e r

n u t r i e n t s t h a t are a l s o p r e s e n t i n t h e y e a s t .

Animal s t u d i e s a l s o s u b s t a n t i a t e t h e improvemen t s i n l i p i d s d u e t o

s u p p l e m e n t a l chromium. Rats, mice a n d g u i n e a p i g s f e d i n s u f f i c i e n t d i e t a r y

chromium d i s p l a y e l e v a t e d c h o l e s t e r o l and t r i g l y c e r i d e l e v e l s . I n r a b b i t s fed

a h igh c h o l e s t e r o l d i e t , s u b s e q u e n t i n t r a p e r i t o n e a l a d m i n i s t r a t i o n o f 20 ug

p o t a s s i u m c h r o m a t e p e r d a y led to a r e d u c t i o n i n t h e s ize of a o r t i c p l a q u e s

a n d a decrease i n a o r t i c cho le s t e ro l c o n c e n t r a t i o n (Abraham et a l . 1 9 8 2 ) .

D i e t a r y i n t a k e of c h r o m i m is s u b o p t i m a l and is u s u a l l y o n l y a p p r o x i m a t e l y

50 p e r c e n t o f t h e minimum suggested safe a n d a d e q u a t e i n t a k e (Ander son a n d

Kozlovsky 1 9 8 5 ) .

i m p o r t a n t h e a l t h problem p e r t a i n i n g t o i n c r e a s e d r i s k f a c t o r s a s s o c i a t e d w i t h

c a r d i o v a s c u l a r diseases.

T h e r e f o r e , i n s u f f i c i e n t d i e t a r y chromium a p p e a r s to be a n

323

Trace Elements. I n s u l i n and Cardiovascular Diseases :

Chromium and copper, t h e two t r a c e elements t h a t appea r t o have t h e l a r g e s t

e f f e c t s on card iovascular d i s e a s e s , b o t h e f f e c t i n s u l i n and i t s func t ion

(F ie lds 1984; Bore1 and Anderson 1984). The common t i e between these two t r a c e

elements may be t h e i r r e l a t ed e f f e c t s on i n s u l i n l e v e l s and func t ion . R i s k

f a c t o r s assoc ia ted w i t h card iovascular d i sease c o r r e l a t e w i t h f a s t i n g i n s u l i n ,

i n s u l i n response to a g lucose l o a d and the d e l t a i n s u l i n va lues (Table 2 ) . We

tes ted 48 male s u b j e c t s on t h r e e s e p a r a t e occasions over a 6 month period and

f a s t i n g i n s u l i n , .90 m i n i n s u l i n i n response to a g lucose load (1 g glucose/kg

body w t ) and t h e d i f f e rence i n f a s t i n g and 90 min i n s u l i n were co r re l a t ed w i t h

t he designated l i p i d va r i ab le s . I t is i n t e r e s t i n g to note t h a t t h e t o t a l

cho le s t e ro l : HDL c h o l e s t e r o l r a t i o , which is one of t h e bes t p r e d i c t o r s of

cardiovascular problems was h igh ly co r re l a t ed (P<O. 001) w i t h a l l t h r e e i n s u l i n

var iab les t e s t ed . T h e LDL/HDL r a t i o was a l s o highly co r re l a t ed w i t h a l l 3

i n s u l i n va r i ab le s t e s t e d . The concent ra t ion of high-density l i p o p r o t e i n

c h o l e s t e r o l , t h e p r o t e c t i v e forms of c h o l e s t e r o l , was inve r se ly co r re l a t ed

w i t h i n s u l i n as would be expected s ince higher l e v e l s of HDL a re assoc ia ted

w i t h decreased r i s k s of card iovascular d i seases .

I n summary, card iovascular d i seases may be due to and/or a r e assoc ia ted

w i t h s eve ra l f a c t o r s . Trace elements should be considered a s some of t h e prime

candidates to inf luence card iovascular d i seases . Changes i n any of t h e major

d i e t a r y ing red ien t s such a s , p r o t e i n , f a t , carbohydrate or f i b e r would a l s o

l e a d to changes i n t r a c e elements. However, sys temat ic i n t e rven t ion s t u d i e s

i n humans have not been performed employing any of t h e s e f a c t o r s and t h e r e f o r e

cause and e f f e c t r e l a t ionsh ips between card iovascular d i s e a s e s and t r a c e

elements have not been documented conclusively.

324

References

Anderson, R . A . , M.M. Po lansky , N.A. Bryden, E.E. R o g i n s k i , W . Mer tz & W . Glinsmann: Chromim supplementa t ion of human s u b j e c t s : effects on g l u c o s e , i n s u l i n and l i p i d v a r i a b l e s . Metabolism 1983, 32, 894-899.

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