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Atherosclerosis: kritchevsky

question: NA was the 
investigator who first showed (1913) that feeding cholesterol to rabbits 
led to aortic deposition of lipid. he was a heavy smoker who, in reply to 
the suggestion that the habit was dangerous, said "no problem, it is all 
due to cholesterol." Based on current knowledge, how would you answer 
him?

today we will get to hear about the disease, atherosclerosis, some 
dietary effects, and what is going on with it today.

a few years ago, 
Science mag's cover had the words "EAT -- DIE" on it. but, you know, 
"don't eat, die anyhow" :)

atherosclerosis isn't new...fatty deposits in 
a vessel wall were found in an egyptian mummy! in general, 
atherosclerosis is a disease of aging people, and until about the 1940s 
people weren't aging so much. in 1900, cancer and heart disease didn't 
make it into the top ten causes of death b/c no one lived long enough to 
get them.

atherosclerosis is a variable combination of changes of the 
intima of arteries, consisting of focal accumulation of lipids and other 
stuff..."

10 AD: Celsus referred to heart attack
1500 AD: Vesalius 
described aortic aneurysms
Fallopius described arterial ossification
etc


Marchand coined term "atherosclerosis" in 1904 b/c he thought it looked 
like oatmeal. This describes going from initial deposit to later 
hardening. In 1911 it was found in mummies....in 1912 they started 
feeding cholesterol to rabbits. in 1950 they learned to separate 
lipoproteins and we're still finding new ones today. in 1973 it was 
suggested it might not be just cholesterol (Benditt). 

americans are 
hysterical. the public thinks fat free = calorie free. but one snackwell 
has more calories than two oreos, and tastes worse!

dietary cholesterol 
---> blood cholesterol ---> aortic cholesterol is no longer the way we 
look at it.
First you have endothelial injury - and what is the injury? 
dunno. then, if you have increased circulating LDL, you eventually may 
form atheroma. but there are many small proteins involved.

you get 
injury, lipids, foam cells, which get under the intima into the muscle. 
these things get bigger and start to occlude the lumen - making it easier 
for a small clot to get stuck. 

another way to look at it - you have the 
artery - thrombogenesis and intimal damage due to oxygen radicals, smooth 
muscle hyperplasia, collagen synthesis, degeneration of elastin...you end 
up with a much narrower artery,making it very dangerous...

happens 
mainly in areas of high turbulence, where blood speeds up. butyou can 
find a 40 yr old man who died of coronary and autopsy shows one plaque 
that killed him. or an 80 yr old guy hit by truck and you open him up and 
wonder how blood ever got through -- so it is luck and  location.

risk 
factors- diet, CO exposure, smoking cigarettes - all these thigns enter 
blood - different proteins, remnants from lipid breakdown, viral 
infection - all react with aortic tissue - form plaque. it's easy to 
study the blood part, but not as easy to study metabolism of the arterial 
wall. we're getting technology that will let us look at the growth and 
regression of the lesions, though - then you won't be guessing anymore. 
you feed it, and plaque will grow or shrink or stay the same. 

we know 
hyperlipidemia increases atherosclerosis
so do diets high in saturated 
fat or peanut oil
natural history of atherosclerosis: until you're about 
10 yrs old, there is none, although in developed world it's really there 
starting from about age 2.
then you get fatty streak visible by staining 
with fat seeking dye - in patients 10 to 20 yrs old. at about 20-30 yrs, 
you get plaques, then 30-45 you get calcification, complications, 
hemorrhage, ulceration, thrombosis.

now, years ago, coronary (premature) 
would occur in 40 yr olds. now, we see it in 60 yr olds. so that is 
something, anyway.

major risk factor combinations: epidemiologists did 
some comparisons of populations. us vs them. they looked at smoking, 
hypertension, and hypercholesterolemia. the framingham study sent out a 
questionnaire, (the gov't did this) to 13,000 people in the city, and 
said they'd do PE on them every 2 years for life, and found that major 
risk factors were smoking, high blood pressure, and high cholesterol. 
those with none of these factors had risk of 23/1000; that doubled in 
those who smoked. those with any two factors had risk icreased 5fold, and 
those with all three had 8x the risk. 

now, we've added maleness, 
obesity to the list of risk factors
remember risk factors are not medical 
diagnoses - they are statistical diagnoses or more colloquially - odds. 
if you worry about having Tb you get a patch test and find out yes or 
now. but there is nothing like that for finding out if you will have a 
coronary. but they can tell you if your cholesterol is high. De Bakey 
said most of his patients had normal cholesterol, though.

we keep 
looking for more risk factors. this is a lifestyle disease...
it's not 
the kind of thing you can figure out quickly. the framingham study was 
good but the big problem was they only got 6500 replies to the 13,000 
surveys. did respondents with predisposition to disease self-select 
themselves?

things to know:
atherosclerosis is a metabolic disease, not 
a side effect of bad nutrition. people have often compared it to rusting 
in a pipe. the difference is the pipe doesn't metabolize. 
cholesterol is 
an essential ingredient of the plaque, but may not be an initiator of the 
lesion
the first part of thedeposit isn't normal cholesterol - it's 
oxdized form produced by free radicals
most people with atherosclerosis 
have cholesterol levels in the normal range, while many with elevated 
cholesterol have no evidence of atherosclerosis.

cholesterol is a 
component of every cell in your body.it is probably next to water and 
salt the most ubiquitous thing in yoru body. most of it is in your brain- 
so "fathead" is descriptive :)
THE NEXT two major sources are muscle and 
fat. the arteries don't have much.

cholesterol in the liver is converted 
to bile acids, without which you could not digest fat. most cholesterol 
in metabolic sphere is converted into bile acids. it's also made into 
pregnenolone and sent to gonad to make sex hormones or adrenal cortex to 
make corticosteroids. so it is needed for life, needed for cell structure 
(membrane stability). it's the all american compound - leads to life, 
liberty,and pursuit of happiness :)

cholesterol hypothesis, or lipid 
hypothesis, was borne from framingham data. they looked at chol.level, 
and number of events. the hypothesis said if you lowered cholesterol from 
A to B you should lower risk from X to Y - and this policy has driven the 
health programs of the NIH and others. 

now, if you've ever seen normal 
blood serum, you know it is pale yellow and clear. but it contains a lot 
of fat - you just can't see it b/c it is suspended as an emulsion, tied 
to proteins called lipoproteins. 

there are many lipoproteins. using 
ultracentrifugation, you can float it  - lipids are lighter than water. 
the chylomicron is the largest particle and is mostly triglyceride. maybe 
5% cholesterol. if you give blood, they usually tell you not to eat first 
b/cfor a few hours after your meal you have chylomicrons in your blood 
and they are fatty molecules. all these react with tissue lipases to spit 
out triglycerides which are broken into FAs for fuel. so it gets smaller 
- VLDL, IDL - intermediate density - then LDL - the LDL is the bad stuff. 
the amount of cholesterol in your LDL is the problem. then you have HDL 
which are 50% protein, and these are the "good cholesterol" that are 
protective. the HDL doesn't change much,it's the LDL that does. in men, 
there is more LDL - women have a higher HDL:LDL ratio, and this then 
changes after menopause to be more like men. 

buoyant LDL vs dense LDL - 
you can separate LDLs into 6 or 8 classes. the little LDL is what gets 
into your artery. the buoyant stuff doesn't. so you have good bad 
cholesterol and bad bad cholesterol. 
also there is lipoprotein A, which 
looks like LDL with one extra protein.that protein interferes with 
fibrinolysis,preventing clot breakdown. many people think that level of 
lipoprotein A is a better indicator of risk than the other things. so you 
should look for LPa whch is hard to measure.

LDL only have lipoprotein 
B, and HDL have AI, AII, C and E. many people think you should measure A 
to B ratio instead of HDL to LDL ratio. LDL send cholesterol to liver and 
peripheral cells, and HDL is mostly protein.

factors affecting serum 
lipids:
lab factors - method, reliability, drugs, serum vs plasma. some 
people sent a sample of fake serum to about 100 clinical labs and got 100 
answers. a few years ago someone advertised low cholesterol eggs, and 
USDA bought 1500 eggs, and analyzed them - to do that they needed a lab 
to do it right - so they made a cholesterol unknown, which was 
cholesterol dissolved in fat, 800mg/100 gm fat. they sent it to 3 
prominent labs - one found 1200, one found 800, one found 400. so test 
ain'tthat great!
drinking, smoking, and exercising also affect HDL. 
moderate drinking is good. Dr. K advises running from bar to bar to get 
exercise in too.
age, sex, personality are important. really important is 
the season - your cholesterol varies by season!it increases in sept and 
nov and dec through march. it is lowest in summer. 

AHLMAC committee - 
they turn over four people a year - 12 person committee- dr k is on it. 
when he joined it, the chairman asked him if there was anything he wanted 
to know and he asked about cholesterol fluctuation. 

you have a study 
with 20 guys, and you take blood weekly, and group average doesn't 
change,but individual variation is huge.

he asked how much individual 
variation in choleseterol do you see, and they said none. he said 
bullshit. six months later they told him they rechecked,and in every 14 
clinics, it was high in january and low in july. they claimed it was due 
to christmas. he said "even in the jerusalem clinic?" so then NIH did a 
study - a good one - looking at 10 american lipid research clinics - and 
found that yes, it varies with season for some reason. total cholesterol 
and LDL vary inversely to length of day. also in animals (who do not 
celebrate christmas)

so it is important to kn

HDL high in women, 
russians, blacks (really high in black russian women) and low in 
men,americans, whites....
HDL is the one that does't change much.

LDL is 
the one that changes.

we think the apoprotein makes a difference. apoE 
is found in VLDL. if you are E2 type, atherosclerosis is low, and drugs 
work easily. if you are E3/E4 or E3 E3, you have lesions evenwith normal 
cholesterol, and drugs do not work well anyway.

if you have a lot of 
receptors, you have low blood cholesterol. if you have few receptors, 
cholesterol has to stay in your blood, right? smaller, denser particles 
are more susceptible to oxidation than bigger ones.

low cholesterol 
isn't good either. you want moderation- maybe around 180-210. not lower 
than that. then, something else happens. some guy did a study - he looked 
at HCT plus 1/10 of cholesterol level - so say 45 + 20 = 65. if this 
number was low, these people would die in 6-8 mos no matter how they said 
they felt. no one ever followed it up. 

stress and cholesterol levels - 
during exams, med students had high cholesterol. also during tax season, 
accountants had high cholesterol. 

ex: group of 37 - before exams, 191 
mg/dl. during exams, 235 mg/dl
group of 13 -  190 before, 247 during.


this is interesting. psychological factors were studied in Israel - at 
the port of Haifa, they interviewed the white collar guys...those with 
work problems had higher amount of coronary disease. those with work and 
personal problems had a MUCH higher amount of disease. 

a study at the 
dupont company some years back found that most of heart disease was in 
men who have responsibility with no authority. monkey study in monkeys 
either stressed or unstressed found much less intimal cholesterol 
deposition in unstressed monkeys. they found that the fattest alpha males 
had least deposition. then they found that the severely stressed animals 
had bigger deposits.

they did a study at the pentagon - where there is 
the largest group of highly stressed middle aged american men in the 
world. they did cholesterol tests q 2 mos on these guys and found huge 
fluctuations. avg level of fluctuation was 25%. a fluctuation of 50% or 
more was associated with occurence of a coronary.

animal studies: 

rabbit atherosclerosis - historically, the rabbit is animal of choice for 
study,only b/c it was first studied.
criticisms of rabbit study - rabbit 
is a herbivore not designed to handle cholesterol - if you discuss 
cholesterol around rabbits his cholesterol goes up. but you can easily 
induce atherosclerosis. saturated fat is worse than unsaturated fat. but 
cholesterol you eat isn'tthe problem.the fat and protein you eat is what 
raises your blood cholesterol. 

[he is officially out of time now...]

chicken is no longer used as a  model. but estrogen, low protein, and 
thiouracil will cause atherosclerosis in the chicken.

rat 
atherosclerosis - to cause it,you have to do so much bad stuff to it that 
it isn't worth it. rats have a huge capacity for keeping serum 
cholesterol stable. so it's very difficult to induce atherosclerosis 
without removing parts of the rat....or creating other deficiencies...so 
studying the rats isn't that useful.

[i'm not writing stuff down about 
the rats...]
other rodents are difficult to study this in,too.
[i'm also 
not writing stuff down about these rodents b/c it doesn't seem germane to 
the question at hand....]

dog atherosclerosis - cholesterol and 
thiouracil or semisynthetic diet plus cholesterol can produce lesions. 
dogs fed table scraps have cholesterol at 265. adding cooking oil, 
coconut oil, will drive the level up. if owner is fat, dog is often fat, 
too.

lesions in cats are hard to produce. 
pig - great model- much like 
people (or vice versa...). difficulty - pigs are large and difficult to 
handle, and very expensive to study. 

we'd like to study monkeys too,but 
they again - not all are the same. Cebus monkeys get lesions from high 
fat/high cholesterol diets over two years...but looking at various 
species, with similar cholesterol levels, there are varying amounts of 
atherosclerosis. 

[yada yada carbs, monkeys, etc]

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fat 
facts:

fat is the most efficient energy source
there is a lower limit 
below which menstruation and conception do not occur
lipids are important 
in structure and function of cell membranes
nerves have lipids in their 
structure
lipids insulate the body and protect important body organs

lipids provide EFAs, carry fat soluble vitamins, andmore.
FA -> metabolic 
fuel, transport
FA derivaties -> FA storage, transport,membranes
etc.

in 
1950 a study was done- [he says that many studies are "unpublished 
observations..."]. When Ike Eisenhower had his heart attack,that's when 
people got excited about cholesterol...so this study was done, andthey 
segregated 40 men from the group. 10 w/lowest cholesterol, 10 w/highest, 
10 who ate most chol, 10 who ate least. then 40 controls. men who had 
coronaries had higher cholesterol in blood than controls. but in no case 
did it have anything to do with cholesterol intake.  those with highest 
intake of cholesterol had lower chlesterol levels than those who ate the 
least cholesterol. so there are many steps on the pathway to consider.


PR, honolulu, and framingham populations were studied - coronary rate and 
diet were checked. 
in PR 1900 w/o coronary, 286 who had coronary

honolulu: 7000 w/o and 264 with
framingham 780 w/o, 79 with

what were 
factors? all the guys with coronaries ate fewer calories than the guys 
w/o them. the guys with them ate more carbs and/or complex carbs (fiber) 
and drank less alcohol. cholesterol and fat intake were the same in every 
pair. 
these data show that possibly other factors exist that make the 
difference -but this wasn't followed up. 

most food has the same amt of 
cholesterol. egg, stick of butter has a lot. shrimp have a lot compared 
to other meats. but they are included in low fat diets b/c they have 
little fat. big source of cholesterol is really the egg- though not much 
is absorbed, so.

ignatawski's summary: newborn rabbits fed milk and egg 
yolk do not grow as well as controls, and die w/in four mos. 
animal diet 
leads to anemia
rabbits fed animal diets had cirrhosis, nephritis, 
atherosclerosis, kidney hypertrophy

unfortunately, ignatawski wasn't in 
charge. 

data show 

study of 6 men with diets w/diff amts of protein, 
carb,fat - all using vegetable protein. normal diet - cholesterol about 
272. using only veg fat sources, cholesterol went down. when returned to 
regular diet, it wentback up.

study in italy with soy protein-


[more 
about rabbits...   one to one ratio of animal to vegetable 
fats...something i didn't catch.]

fiber hypothesis says: diets rich in 
foods containing plant cell walls are protective against "western 
diseases" and diet poor in plant cell walls are possibly causative.but, a 
high fiber diet isn't a low fiber diet to which you have added fiber.

different types of fiber - brans = insoluble, fruit/veg = soluble fiber

gums delay gastric emptying
bran increases transit time
gums reduce blood 
cholesterol, control glycemia, and promote fermentatoin
so do fruits, 
veggies, legumes.
pectin is a gum present in many fruits.
bran doesn't 
really do these things.


fiber in hyperlipidemia study - most change 
came about in men fed oat bran, which contains a gum.

to get 10 gm of 
dietary fiber, one must eat a pound of white bread, half a pound of 
frozen brocolli, over a pound of apples or oranges...

another good stat 
- as wine consumption goes up, risk of heart disease goes down. this is 
the "french paradox." french eat more meat  than any other europeans and 
have the lowest risk of heart disease. we do not know why. maybe 
lifestyle? french do not eat standing up, they relax and eat three meals 
a day. 

vitamin c also produces a similar curve.

obesity promotes 
hypertension which promotes atherosclerosis

niacin - nicotinic acid - 
has a few drawbacks, namely flushing and itching in some people and liver 
problems in other people - and no derivative works - but it helps to slow 
progression of atherosclerosis

CHD syndrome: HDL low, triglycerides 
high, glucose high, insulin high, and you are fat. these people have 
increased risk of heart disease and some people think it is assicated 
with hyperinsulinemia. 

proposed role: genes and environment get 
together and cause insulin resistance, hyperinsulinemia, glucose 
intolerance,increased triglycerides, decrased HDL, increased BP, all this 
stuff gets connected to CHD.

heart disease and cancer both may be 
related to insulin resistance, actually.

what does initial damage to 
endothelium?? 
1. hyperhomocysteinemia - when making methionine or 
cysteine you add a methyl group and get a homocysteine, but normally 
continues to cysteine. but in some people you keep the homocysteine andit 
gets together with LDL and goes into the artery and causes a problem. 
this was suggested by some guy a while ago....he got fired by Harvard for 
publishing this suggestion. but today, we see that yes, this is true, 
they found it in the framingham study. so if they'd believed him 30 yrs 
ago, we'd be ahead by now.
2. CMV- may cause some tissue damage that 
predisposes to atherosclerosis
3. respiratory chlamydia - c.pneumoniae - 
first seen about 5 yrs ago by someone doign routine serology - all these 
heart dz patients had c.pneumonia. this might really be something. 
mareck's disease in chickens predisposes them to it, too.

good news- 
lifespan is increasing. lots of people like to talk about paleolithic 
diet - but those people only lived to be 15 so of course they didn't get 
heart disease and cancer!

in PA there is a high death rate from heart 
disease on the map from 1961
most of it on east coast, some in NV, then 
little in the midwest. 
in 1986, midwest is still ok, east coast is 
worse...but what was considered high is lower than what was considered 
low before. so we are doing better overall.

since 1979 HD rates down 26%

b/w 1980 and 1992 total deaths in us down 14%


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