Saturday, August 29, 2009

Cholesterol, never mind LCAT, try ACAT

Just a quickie. More from the killing fields.

Those poor folks with heterozygous FH are such a playground for cardiologists. My latest accidental find was ACAT inhibition using pactimibe. Medscape describes it this way:

"Pactimibe was in development as an ACAT1 inhibitor, intended to make available more free cholesterol for reverse cholesterol transport, which theoretically could reduce lipid accumulation within atherosclerotic lesions."

Oh, this link works in Safari but not Firefox... Not worth reading, the quote is all you need anyway!

OK, stop foam cell generation and ship out the evil cholesterol (maybe using enhanced LCAT? That'll be next) to HDL for reverse transport. CAPTIVATE-ing idea. I think they were a bit unlucky with this one.

Combined endpoint was deaths, heart attacks and strokes. One out of 438 on placebo, 10 out of 443 on treatment. That's a relative risk of errr, umm... arithmetic fails me.

My biggest worry about drugs being developed based on the lipid hypothesis is that at some time they're going to repeat, again by fluke, the small success of the statins. We'll get a drug which does a little good, a lot of harm and conveniently forget about those who died on pactimibe, torcetrapib or which ever LCAT enhancing drug gets developed. Keeping up the failure rate must be quite difficult, but this continued failure is our best hope for getting some research on heart disease started.


BTW this drug works really well in genetically hypercholesterolaemic rabbits. No one is suggesting the the WHHL rabbit is a crap model for any sort of arteriosclerosis based on the people injured in this study. OK, I am. It looks like crap model to me.


gunther gatherer said...

Hi Peter.

I was wondering if you knew anything about fructose malabsorption, which seems to have similar effects to celiac and with almost the same affected population (and especially 30-40% of central europeans, which includes you and me).

It stands to reason that this would have to be factored into much of the avoidance of fruits and vegetables that we've discussed on this blog, and why some people seem to do better on them and some not.

Stephen Guy-Clarke said...

Why do Eskimos, who typically eat a diet loaded with animal fat, have very low rates of heart disease?
The answer is that high cholesterol isn’t the cause of heart disease - oxidised cholesterol is.
That’s the opinion of many alternative physicians including Philip Lee Miller MD, founder and director of the Los Gatos Longevity Institute in California. ‘ I’m one of those people who have been saying for 30 years that cholesterol does not cause heart disease,’
he says. ‘It’s a recruit in the process, like a soldier is a recruit in a war, but it does not cause the war.’
Dr Miller, like the majority of medical professionals, recognises that the lowering of LDL cholesterol plays a critical role in preventing hardening of the arteries. He knows that excess cholesterol in the bloodstream can be subjected to oxidation (the same oxygen-sparked, cell destroying process that rusts iron or turns an apple brown after it has been cut). The destructive process of oxidation is literally inflammatory - it’s like a fire in the body.‘The immune system, your body’s fire service, rushes foam cells to the area to douse the blaze. But just as firemen sometimes have to axe down a door to get into a burning building, the anti-inflammatory process can damage the lining of the artery. This roughened, injured area is a perfect foundation for the build-up of plaque, the truly evil plug that clogs arteries and triggers heart attacks’.

‘Oxidized LDL starts an inflammatory reaction that the body tries to heal, but the healing causes more problems than it resolves, ‘ says Dr Miller. The best way to prevent this heart-hurting process, he says, is to prevent the oxidation of LDL cholesterol - and the best way to do that, he adds, is to make sure you get enough of the antioxidants vitamin E, vitamin C, and glutathione.

Antioxidants work by calming unstable oxygen molecules called free radicals, which are responsible for oxidising cells. When antioxidants neutralise free radicals, they are on a type of suicide mission. The antioxidants themselves are oxidised or, in chemical terms, reduced.

Fortunately, the body has a system to help ensure that there are always plenty of antioxidants available, Dr Miller says. When vitamin C is oxidised, vitamin E comes to the rescue, donating some of its molecules to restore the vitamin C to its full antioxidant
status. In the process, the vitamin E is reduced, but the glutathione replenishes it. That’s why you need all three nutrients, says Dr Miller.

Peter said...

Hi Stephan, I think these ideas are quite reasonable. One thing I would like to know is whether consuming plant derived antioxidants suppresses the production of glutathione. I'm betting yes.

Gunther, I've got various papers on fructose malabsorption/intolerance well down the pile. Fructose is at least as good as fibre for triggering IBS, people with fructose malabsorption apparently learn to avoid fructose (and sucrose) at an early age by simple trial and error (less so now I guess with the emphasis and low fat foods for health!). There was a phase of using intravenous fructose as a caloric source before Intralipid came in for use in human intensive care units. If you are genetically fructose intolerant and some joker runs in a litre of intravenous fructose you end up in the mortuary! Mmmmmm fructose....