Wednesday, April 14, 2010

Arteriosclerosis and the breeder rat

Ok, another picture show I composed off line. I'm home next week but there is a lot to do other than use Tinternet. This one is from Wexler's 1964 paper "Spontaneous Coronary Arteriosclerosis in Repeatedly Bred Male and Female Rats". BTW anyone reading it carefully might be tempted to add celibacy to any program of heart health protection. Personally I suspect this is not necessary. Too late now anyway!

Let's look at old rats. If you feed rats a 5% fat diet, with the fat as "heart healthy" corn oil, you can actually make Dean Ornish look like a gourmand.

These rats are old. They are ex breeding rats. They do not have cholesterol poisoning and their diet has been specifically chosen, under a mistaken paradigm, to maximise health, longevity and breeding success.

If you eliminate the impatience of a cardiologist and wait for the rats to age, what do their coronary arteries look like? Bear in mind that rats are supposed to be resistant to arteriosclerosis (But that is probably only at the age a cardiologist can be persuaded to wait until).

First picture is an artery deep in the myocardium. This is where the disease begins in rats:



Notice the contorted internal elastic membrane between the arrows. The elastic lamina is thickened with mucopolysaccharide. There is a neat intimal cushion overlying this area. There is, err, no cholesterol. Oddly enough cholesterol does not seem to rupture elastin fibres! Like Lp(a), the LDL particle would have to carry that flick knife... Which it doesn't.

Next is an epicardial artery. These arteries, especially the left anterior, are particularly interesting because they are not supported by surrounding myocardial muscle so the artery wall is particularly pressure challenged. Apart from the appearance of multiple endothelial cushions overlying shredded elastin there are also dark black areas of "gunk" on the right hand arterial lining area of the artery. These stain positive for calcium.

There is, err, no cholesterol.



Just for fun the authors took another section from the same tissue block as was used for figure 6 and stained it for mucopolysaccharide. The section is nearly identical. This, here in figure 7, clearly shows the extent of the abnormal intima. No cholesterol. Strange that.



Do these rats get ischaemic disease? You bet!



The myocardial necrosis lesions, which are common, do not appear to be directly related to the diseased large arteries. They certainly make me think of Kurt's posts here and here on myocardial damage in marathon runners. The mice don't run, but they do carb load each and every meal. They have no choice. Carbs or starve. To me this suggests that it might actually be the diet used by marathon runners which kills them, rather than the running per se. Though the chronic cardio might well do a great deal of damage to the elastic intima due to the stretching needed to accommodate the high flow generated. But possibly they just eat rather more crap than normal human beings do. Just an idea.

It also begs the question of why cardiologist keep thinking that the cholesterol fed rat (or the equally poisoned Syrian hamster) has anything to do with human arteriosclerosis.

Peter

30 comments:

John said...

I think you brought up an important point that most don't consider when talking about runners (or other endurance athletes). Almost all of them are eating the SAD, just more of it. Here is a link that talks about Michael Phelps' diet--2000 calories from energy drinks alone... http://www.foxnews.com/story/0,2933,403803,00.html

Andrew S said...

That was the same comment that I had wanted to bring up on Kurt's blog -- that marathon runners as a rule eat the carbiest shit they can find -- but his commenting system was sufficiently unfriendly that I was never able to log in to post.

Marathoners don't eat the SAD. They eat a perverted, even higher-carb and lower-fat version of it. They gorge on oatmeal, bagels, and pasta. When they're feeling frisky, they eat a big meal at McD's, you know, for the nutrients.

I see the same thing on the mountain slopes -- nearly everyone going skiing loads up on carbs for breakfast, then stops a couple hours later for more. Bacon will kill you, man.

Stephan said...

Hi Peter,

I bet I know why they used rats that had been bred repeatedly (I assume all males)-- because those are the only ones that survive to old age in a lab environment. Rodents that aren't bred get killed at a young age because it's expensive to keep them around. The lesions probably had nothing to do with the breeding, the researchers probably just used old breeders they had lying around.

In any case, it's interesting. I wonder what the copper content of their chow was.

John said...

Andrew,

Yes, they probably eat a higher proportion of carbs than the SAD. I simply mentioned it to imply excessive sugar and seed oil consumption [as a higher carb diet isn't necessarily worse than the SAD--Kitavan].

Aaron said...

I second the notion that I'd like to know the mineral sufficiency of the diet (and age of the rats). If you made sure the rats ate a nutrient dense diet, but very high in carbs -- I'd like to see if the same results would occur.

We already know that a mineral/vitamin insufficient diet high in carbs can cause atherosclerosis.

I would also like to ask -- what happens on a super low carb but high fat diet when the diet may be deficient in certain minerals (like magnesium). Will those rats/individuals might develop similar signs of heart disease over time?

Drs. Cynthia and David said...

Thanks for the interesting paper. Why are such things ignored? The fact that it doesn't fit the paradigm should make it all the more compellingly interesting.

The carb-obsessed diet of runners is my thought (re CVD in this group) as well. It's hard to find anything except sugar and starch to eat at running events (though longer ultras are a little better, with hamburgers and grilled cheese sandwiches, etc.) The proinflammatory overtraining and vegetable oils might contribute too. This group also has a tendency to eat more sugars, with the idea that they can eat anything they want since the exercise keeps cholesterol and triglycerides down and helps with insulin sensitivity, though a lot of runners tend to eat a healthy diet, or at least what they think is a healthy diet, as part of that mindset. It would be nice to see someone test these variables.

Also, today's post at http://www.endurancecorner.com/Alan_Couzens/win_ironman_hawaii
is pretty interesting in emphasizing the importance of fat burning in achieving world class performance. This seems to be most important in ultra events, though I bet superior fat burning helps at any distance. You can't get good at fat burning using carb-dominated fueling.

Cynthia

Bris said...

Dr Kenneth Cooper the "Father of Aerobics" is oppsed to distance running. He favours short (2-3km) realtivel high intensity (~4min/km) runs.

antispirit said...

http://ratfanclub.org/nutreq.html

I don't know if any of you have seen this info before. I'm sure it's fairly prevalent. Rats can vary quite a bit in size, hence the wide ranges for RDA. Every lab block feed I have seen is supplemented with some form of copper. How available it is, well...

What I gleaned from this post was that rats just don't get heart disease like we do. They still do, it's just different. It's like using them as cancer models. Their tumor structure (if I remember correctly) is totally different from most human tumors. This paper suggests to me that -as far as CVD disease goes- rats are not a good analogue. Period.

Or did I misinterpret the "there is no cholesterol" bit?

I'm relatively new to this, so feel free to put me in my place if need be.

antispirit said...

Yes, I said CVD disease. Like ATM machine, only more annoying.

David said...

I don't know what explains the marathon runner results - could just as well be they ate a lot of fat because they thought running made them invincible, like Jim Fixx (remember these were recreational runners, not elite athletes) - but many studies in elite athletes have shown they have lower overall and cardiovascular mortality than the general population, including a recent study I just saw last week (But couldn't find this moment with a quick search)

donny said...

"The arterial lesions remain microscopic in the male but in the female breeder the lesions become more prominent and can be easily recognized grossly."

They offer longer lifespan of female vs male rats as a possible explanation for this. Paired with a crummy diet, maybe the increased nutritional needs of pregnancy (sort of like the increased needs for marathon runners?) ties into this?

I think it's likely that elite athletes live longer for the same reason that they're elite athletes in the first place, because they're metabolically gifted. There are studies showing that mice that choose to exercise more tend to live longer. This isn't the same as showing that forcing mice to run will make them live longer. These mice aren't trying to outrun heart disease, they didn't get all fired up by Dr Oz and take up running, they just have a natural inclination.

Drs. Cynthia and David said...

@ David, I read on Dr. David's site that Jim Fixx outlived his own father, and most likely had high Lp. So he is another example of a runner with a low fat vegetarian diet.

As for diet, here are examples of typical diet advice for runners: http://frayedlaces.blogspot.com/2008/07/nathan-pritikin-diet-for-runners.html
http://frayedlaces.blogspot.com/2009/07/nutrition-for-endurance-athletes.html
http://community.active.com/blogs/NancyClarkRD/2010/02/21/building-your-sports-diet
http://community.active.com/blogs/NancyClarkRD/2010/02/04/training-for-the-boston-marathon-how-to-fuel-for-long-runs
http://community.active.com/blogs/NancyClarkRD/2010/01/19/if-you-don-t-like-to-spend-calories-drinking-milk-ww

I.e., carbs and more carbs, lean meats or vegetarian, low fat dairy, or soy milk instead (where's the K2?), and these are the ones eating a "healthy" version. I see many athletes openly jonesing for doughnuts and other junkfood. Many, like Scott Jurek, advocate vegan diets too. There is a growing fringe group of endurance athletes doing paleo or low carb (see Chuckie V or Jonas Colting), but the message is not widely accepted yet.

Thanks for tolerating the off-topic discussion Peter.

Cynthia

Taka said...

Look at how the Japanese figured this out:

http://www.vaam-power.com/

a special amino acid mixture used by the giant Asian hornets to turn on fat burning to fuel their "two marathons a day" flights.

As for the athletes: Given their desaturase enzymatic machinery is conditioned by the high volume training to produce more arachidonic (AA) acid than the ordinary sedentary folks, they are at special danger when they stop training and continue their Omega-6 rich diet. Ever saw the NASA studies showing how prostaglandin production goes down in a weightless environment? Well the things like PGFa are produced from AA by the working muscle to activate the muscle stem cells (satellite cells) and grow them stronger (you can literally feel this as the DOMS - delayed onset muscle soreness). Thus AA is "depleted" by heavy training (by turning it into PGs) and the body responds to this by epigenetical modifications to produce AA in larger amounts. The delta-5 desaturase is a key enzyme associated with CHD and all the chonic disease stuff ...

dextery said...

Charles Washington is a long distance runner at http://blog.zeroinginonhealth.com/about/
and he is a zero carber. He posts
his race results and it is stellar.

He was asked by blogger to comment on a column written for the Atlanta Constitution by someone who follows the dogma of carb loading for peak performance.
Charles' response is great.

http://onyx-ii.com/starr-rhapsody/lowcarb/no_carb_runner.html

I especially like the comments about being zero carb and never "hitting the wall" as do most carb loaders. Also zero carb runners rarely have muscle aches.

And Jim Fixx died at age 52 after a morning run...massieve coronary.
From Wiki

Fixx died at the age of 52 of a fulminant heart attack, after his daily run, on Vermont Route 15 in Hardwick. The autopsy revealed that atherosclerosis had blocked one coronary artery 95%, a second 85%, and a third 50%.[citation needed] Some who opposed his beliefs said this was evidence that running was harmful.[2] However, Fixx came from a family where the men had poor health histories. His father suffered a heart attack at age 35, dying of a second at 42.[3]

Now the question is, did SAD so weaken his heart and blocked his arteries that it could not hold up under the beating it was taking by the running exertion?
Would he still be alive today if he was a zero carber?

David said...

Jim Fixx ate lots of fats and donuts and had very high cholesterol (and had been overweight and a multipack a day smoker into his mid 30's). Here is a paper describing the autopsy results of sy mah, who ran more marathans than anyone ever and had zero atherosclerosis at autopsy (and who lived off a low fat, grain-based diet):

http://www.ncbi.nlm.nih.gov/pubmed/2019205

Nathan Pritikin was a low-fat diet guru who ran 5 miles a day and his autopsy published in the NEJM also showed zero atherosclerosis.

Brad Reid said...

David/All,

Dr. Cooper went through a radical change of mind after the deaths of several noted long distance runners. He once believed that one could not log too many miles, that it immunized the cardiovascular system in a manner of speaking. He later changed his beliefs, as I recall, stating that one could get 99% of the benefits from cardio workouts by 30 or so minutes done 4 or 5 times a week. In his mind, anything more than that was about something wholly different that just health and well-being, you know, like an obsession or for competitive reasons.

That amount of cardio work, the 30 or so minutes 4 times a week jibes well with the Paleo crowd, I suspect, who don't think our ancestors were built to run all day but would no doubt assume that there were episodes of extended exercise running down/dodging prey/predators.

Elites versus weekend warriors? Being an elite athlete just means you lift more or have faster times, etc.; it doesn't imply that the elites are working harder. I recall one elite athlete in high school who ran a practice 440 yd. dash and finished in 48 seconds... the last dude crossed the line on the practice run in 54 seconds. The coach yelled at him for not being more like the "elite," who wasn't even breathing all that hard. The duffer responded, "Coach, I just ran as fast as I could for 54 seconds, he ran as fast as he could for 48 seconds. Of course, I am more tired... see how he looks if he runs all-out for another 6 seconds!"

There are plenty of weekend, often overweight marathoners, in some cases who have only trained for a matter of months. At the end of a 4 or 5 hour marathon, my bet is their bodies absorbed a whole lot more grief than the 130 lb. elites who breezed over the course in less than 3 hours. They did more "work."

I suppose many of the very frequent deaths in marathon events occur from the average Joe group, but both groups likely suffer untold and unseen damage.

Brad

donny said...

David; you posted this

http://www.ncbi.nlm.nih.gov/pubmed/2019205

"A world record marathon runner with silent ischemia without coronary atherosclerosis.

A 62-year-old world record marathon runner was found to have silent ischemia manifested by a very abnormal stress test, whereas at autopsy nine months later, there was virtually no coronary atherosclerosis nor other disease of the coronary microvasculature. However, there was focal fibrosis of the papillary muscles consistent with remote ischemia secondary to possible CV. It is postulated that endurance-related high catecholamine levels might have been responsible."

There may not have been atherosclerosis; but there is evidence of the sort of cardiovascular stress that might lead to atherosclerosis if the healing process were to be somehow compromised.

Of course, he didn't die from this ischemia, he died from lymphoma, cancer. Your other example, Nathan Pritikin also died of cancer.


This is too little information to go around insisting that a high carb, low fat diet paired with excessive endurance exercise causes cancer. But by the same token, it's also too small a sample for this to prove that this lifestyle won't cause atherosclerosis; all that this establishes is that it didn't cause atherosclerosis in these two people. Although it may or may not have caused excessive cardiovascular stress in at least one of them

antispirit said...

Here's a question-

How does the biochemical party that is "cancer" affect atherosclerosis? This may seem facetious, but can cancer prevent that particular vector of cardiovascular disorder? Simultaneously, could it engender or at least allow for a more cryptic or atypical form of CV disorder?

Or am I envisioning the arrow of causation too "late in the game", pathologically speaking?

Peter said...

Hi David, I make no pretense to know about Jim Fixx's nutritional binges, but I do recall that he advocated a non supplemented vegetarian diet. That's fine if you want to develop hyperhomocyteinameia due to B12 deficiency, certainly if you go vegan. It reminds me of T C Fry, who almost certainly died by that route. Plus comments from McDougall, who is certainly in a position to report anecdote of devout vegans dying of hyperhomocysteinaemia, despite his explicit direct personal advice to supplement B12. Anyone who is vegan without B12 supplementation deserves whatever they get.

The link to the athlete is excellent. CV disease without cholesterol. It's so weird people are hung up on cholesterol as the cause of CV disease. Increased sympothoadrenal tone is an excellent candidate for damaging arteries. And, of course, it is elevated for hours after a carb loading meal, never mind during a 5 hour run.

You didn't mention Lance Armstrong either. He is as dead as Fixx, except medicine has patched him up so far. If he had happened to develop pancreatic cancer rather than testicular cancer then the outcome would have been very different.

Stephan, there was a throw away comment that they were females because the males died young. There's no information about hows and whys, or any of the diet compiositions in terms of copper.


Antispirit, my rat just gets a portion of what we eat... BTW, I feel elderly rats are excellent models for human CVD. This is difficult while one is hung up on Keys' hypothesis and cholesterol poisoned models, but even kids do these non lipid changes. And they can die of CVD from them without a lipid in sight (though it's not normal). I have this nice neat (and probably wrong) concept that failed glucose control gives CVD and adequate glucose control via hyperinsulinaemia promotes cancer growth through ILGF1 stimulation.

donny, I'd qualify that comment about Pritkin. He killed himself. Suicide, along with many other mental disorders and various cancers, is "associated" with low cholesterol... I really don't envy the guy having to be that depressed.....

Peter

Kurt G. Harris MD said...

@Andrew

Perhaps you didn't notice I raised that possibility in the original article when I said:

"Could “cardio” promote atherosclerosis and myocardial damage by being confounded by diet? That is, could the wheat, carbohydrate and linoleic acid found in low fat “healthy” diets be more prevalent in marathon runners by virtue of their greater caloric intake of this noxious garbage?

That’s a possibility."

For this to be true, though, it would have to be true that the runners are not just eating the SAD, but substantially worse than the SAD, as that is already the control diet. We are not comparing runners to LCHF or paleo enthusiasts, here.

Another point would be that if it is all diet, we must explain why obesity and other indices of health so affected by diet are apparently better in the runners, yet they have more infarcts and coronary disease. The diet is selectively causing this end-point of inflammation? Or the inflammatory diathesis and cytokine soup engendered by inadequate recovery combined with chronically elevated catecholamines and shear stress is particularly bad for cardiovascular health?

The anecdotal observation that runners eat carby junk food is appealing, but where I live the runners seem to eat no worse than the rest of the populace and in anecdotal cases (some I know personally) eat much better.

So I for one need to see a real study proving the runners really ate "worse" than the SAD eating controls in both Germany and Minnesota before I chalk it all up to diet.

Also, if you want to comment on main posts outside the free-for- all of the forums, just send me an email. 150 others have done so. It's not unfriendly, but it does require a modicum of effort.

@Peter

Nice work

The scars in your rats seem to correspond to the non-classic LGE areas in the human runners in the German study. These may be due to microvascular occlusions. The human runners had more subendocardial infarcts in classic epicardial vascular territories as well as non-classic infarcts.

blogblog said...

Are runners "unintentially" self-medicating with exercise to treat an underlying CVD pathology?

Elite athletes aren't "working hard". I VO2max tested an elite runner (VO2max = 80). His heart rate reached 213bpm during the test yet he was quite relaxed 2-3 minutes after the test. Athletes like this find a 6 minute mile to be almost effortless.

Peter said...

Thanks Kurt, I've got some more pictures from humans with GAG disorders which are quite nice too.

Blogblog, I also see the use of exercise as a patch on insulin resistance. Athletes can tolerate intramyocyte triglycerides without insulin resistance because their exercise burns these IMTs on a regular basis. There is anecdote around that a sprained ankle in a chronic runner can precipitate diabetes in a few weeks. If so they were already metabolically broken but were patched up with exercise....

Peter

David said...

Thanks Peter and others for the comments... Pritikin killed himself because he was dying of cancer, not because he was depressed. He had clear coronaries as documented by the NEJM. I eat low-carb, just still not as confident that high or moderate carb is as deadly as some here... If Peter's next heart scan shows a zero score I might be convinced, but then again, he managed to get a very low score despite years on a diet that I believed he described as comprising mostly rice and vegetable oils - so carbs and vegetable oils clearly didn't harm him too bad.

David

blogblog said...

Peter,
I have noticed that my desire to exercise has dropped massively as I have gradually switched from SAD to a VLC diet. I typically spent 2hrs/day exercising on a SAD. This has dropped to walking around 30 mins/day on a VLC (<40g carbs/day). However I am now far leaner than I was when exrcising heavily.

blogblog said...

Sir Steve Redgrave spent much of his very impressive rowing career battling diabetes and chronic IBD (almost certainly due to constant carb loading). I suspect his wife (a medical doctor) told him that these serious health problems were due to a LACK of carbohydrate and fibre.

Winalot said...

BlogBlog,

I remember seeing a TV programme on Redgrave where he ate Mars Bars and Biscuits and said he could "get away with it" due to the volumne of training he did.

Shortly after he reduced the volume and transitioned into retirement he was diagnosed with diabetes.

As Kurt mentioned; Exercise is good for fitness but not for health.

WP

Michael Barker said...

I logged between 4,000 and 5,000 miles a year on a bicycle in city traffic for near 15 years. I, like most of my friends, were very in to "healthy eating". This was basically the SAD diet. It involved tons of carbs almost constantly. I tended to stay way from sugars and instead ate brown rice, pastas, fruits and salads.

Typically on a long ride, I ate bananas and candy bars to keep from bonking. Due to sport's advice the amount of carbs taken in by most strenuous exercisers is way more than the average person would take in.

I am a diabetic now. OK, I'm a ketosis prone T2, which is weird in itself but I can't help but wonder about what I did to my pancreas and other body systems through all those years and what is happening to my friends, who fueled themselves on those low-fat, high carb "healthy diets".

Mike

Wolfstriked said...

I feel bad for Micheal Phelps then.What will happen to someone who eats this meal below...just for breakfast alone.

http://paretoraw.files.wordpress.com/2009/08/mike-p-a-day.jpg

blogblog said...

I studied exercise physiology at university (2006-09). We were never taught that high volume/high intensity exercise prevents disease. In fact we were taught that high volume exercise is essentially an addiction with potentially serious health consequences.

However it is widely accepted by exercise scince researchers that regular moderate activity (eg brisk walking)is highly beneficial.

ebaytips said...

The sad part is tha many look up to Michael Phelps, and there is dough in my mind that many will start eating the way he does with out the excesice program and just increate their fat, then wonder what happen.
Thank you for the great post
Steve