Saturday, January 25, 2020

Coronary Artery Calcium Score and Scleroderma

Dr Malcolm Kendrik has a very interesting post over on his blog relating to coronary artery calcium scoring. I think it is fair to say that he is not in favour of the test.

My ears pricked up (metaphorically) when he mentioned myositis ossificans, about which he comments "This does not end well".

I have spent some time in the past thinking about pathological arterial calcification, as applied to the aorta of of patients with familial hypercholesterolaemia. Bear in mind that the dietary advice for patients with FH is about the worst you could possibly imagine and, of course, has no evidence base. My thoughts and assorted links are in an old blog post here. At the time I had never heard of Sci-hub so was unable to access this rather neat diagram of the mechanism of action of insulin, Pi and pyrophosphate:

















Back to pathological soft tissue calcification. Clearly the obvious question about myositis ossificans has to be to ask whether it is in part driven by hyperinsulinaemia/hyperglycaemia or both.

As far as I am aware this is not a question which had been asked. It is simply genetic and that's it.

However, a similar question has already been answered in relationship to a serious generalised soft tissue mineralisation condition described as "calcinosis and scleroderma", back in a publication from 1932 (apologies to the person who tweeted the link, I didn't note their name to acknowledge. And twitter is ephemeral). That is too long ago to be listed on Pubmed so if you would like to read it you can go and ask Elsevier how much they would like to charge you for a peek in to the past or you can go to that awful place that none of use ever use to download any paper for free.

CALCINOSIS AND SCLERODERMA: TREATMENT OF A CASE BY USE OF THE KETOGENIC DIET

"Calcinosis and scleroderm" looks to be one of a family of soft tissue calcification diseases. The case report from 1932 describes the complete remission of this extremely unpleasant condition in a child following a period of time on ketogenic diet of the type used at the start of the last century, before dieticians were invented/summoned from Hades.

Did the ketogenic diet resolve this child's pathological calcification by suppressing insulin levels, glucose levels or both? Does it work by lowering alkaline phosphatase production by cells in/around inflammatory lesions? Or by some other mechanism?

Would it do the same for pathological arterial calcification? Given a tool like the ketogenic diet, perhaps there is some logic to CAC testing?

Unless you feel that tissue calcification is an appropriate part of healing until it gets to scleroderma levels...

Peter

28 comments:

JustPeachy said...

Oh, this is fascinating. My grandmother died from Rheumatoid Arthritis, aged 74. She'd had it, at that point, for 50+ years. She, like every one of her ten siblings, had also been diagnosed with Type II diabetes, which she controlled with diet, never needing insulin... though she went the low-fat, limited carb route (i.e. no sugar, but often corn, sweet potatoes, carrots, peas, yogurt, etc). In that last 5 years, she also developed scleroderma. We understood this as part and parcel of the RA... sort of scleroderma = end-stage RA, though I'm not sure that's medically accurate.

Among her siblings, she was the only one who got RA. Of the nine now deceased, she was also the only one who didn't get dementia. I've always wondered if there was a connection. The two still living are doing pretty well.

Any chance you've got more stuff up your sleeve that might shed light on possible connections between hyperinsulinemia, scleroderma, and maybe RA?

Frunobulax said...

I always wanted to look more into calcification. Thanks for giving me a jump start, and a nudge to do it after all! :)

This seems to be such a complex topic. One of the things in the back of my mind is that Gary Fettke mentioned in a talk that cells will accumulate calcium if linoleic acid is used as part of the cell membrane (he didn't give a reference though). I don't think it's the dominant mechanism, as we had artherosclerosis 100 years ago when the amount of dietary LA was much lower. But it makes you wonder, does this happen because LA is inflammatory or is there something else involved?

Obviously there is no consensus on how calcification happens in the first place, so all we have is weak observational stuff. A blog entry that mentiones neither glucose nor oxidized LDL might not make a lot of progress there. (Even though Kendricks Wikipedia entry makes me want to love the guy.) But I wasn't aware of warfarin yet, I wonder if it is in same category as statins -- (perhaps) a bit of protection for a couple of years, but harmful in the long run.

Bob said...

Dr Kendrick has a Wikipedia page? I thought it had been deleted.

https://en.wikipedia.org/wiki/Wikipedia:Articles_for_deletion/Malcolm_Kendrick

cavenewt said...

I just read the Wikipedia editors' discussion page on deleting the Malcolm Kendrick entry, linked by Bob.

Yeesh. The people arguing for keeping the article were cogent and reasonable. The people arguing for deletion were superior and arrogant, and any actual arguments were not, in my opinion, relevant. One of the Deleters accused one of the Keepers of being a sockpuppet created specifically for defending this article. The Keeper pointed out that his account had been created seven or eight years previously. The Deleter accused him of being a sleeper.

I've only had one experience attempting to contribute to a Wikipedia page, one for a rare disease which I have the dubious pleasure of possessing, and for which I run a very small online forum. Unfortunately I had the same unpleasant experience with editors there and gave it up as a bad job. I have a lot more empathy now for those friends of mine who refuse to donate to Wikipedia.

Frunobulax said...

@Bob @cavenewt I just googled him yesterday (his name rang a bell but I wasn't sure where to place him exactly), and I accidentally ended up on https://rationalwiki.org/wiki/Malcolm_Kendrick which can be mistaken with Wikipedia if it's late, you're tired and don't look too closely. :)

It is quite toxic ("cholesterol denialist"). In fact, it seems that everybody who questions statins or the lipid hypothesis is a pseudoscientific witch doctor according to rationalwiki. Ah well, one more page to avoid.

ctviggen said...

While I LOVE Dr. Kendrick, I think he might be misguided in this instance. Let's say you're someone like me, with "normal" LDL (assuming we can ascertain what that means anymore), but incredibly high Lp(a). What test do we have that can tell me anything about atherosclerosis? Or say you're a lean mass hyper-responder of the Dave Feldman type (some of these LMHRs can have LDLs that are incredibly high) or you have FH or ApoE4, and you want something -- anything -- to gauge actual heart attack risk. What are your options? We all know that LDL is useless.

For normal people, your options are basically the CAC scan. For me, I got a CAC scan because of my incredibly high Lp(a) and because I'd been low carb/keto 6 years. Was "saturated fat" "clogging" my arteries? I wanted to find out.

It turns out I got a zero score, which puts me in the bottom 10% of the people my age. This at least puts part of my mind at ease.

Now, does a low CAC score mean you're free of heart disease? Absolutely not. But at least I have some ammunition should my doctor decide to actually look at my Lp(a) and provide one of the drugs that are coming down the line to address this.

As an engineer, I like to be able to test things. And there really is no test that tells progression like the CAC scan.

Ivor Cummins, who is also an engineer and a big fan of Dr. Kendrick, listed studies (Twitter) indicating the CAC scan is a good indicator of heart disease, including soft plaque. In all fairness, Ivor works for a place advocating CAC scans, so perhaps there's a bias there. However, I think Ivor tends to go where the evidence leads him.

While I welcome Dr. Kendrick's ideas on this, I'm not unhappy I got a CAC scan and will likely get another one...sometime in the future, maybe 5-10 years from now.

Bob said...

Hi, ctviggen,

I agree with Dr K on this one. Your question was, What are your options? Same question applies if you come back with a high CAC score, and you're doing everything "right" (low-carb diet, no smoking, no known other risk factors).

What do you do? Me, I would probably worry. There wouldn't be much else to do. I probably wouldn't take a statin. Not sure about aspirin.

It's true that any minute the Grim Reaper can appear. I would prefer not to know he might be right around the corner. There might be reasons for some people to want to know, such as if their condition puts others at risk.

Congratulations on your 0 score. I hope it reflects your reality.

karl said...

I'm not sure the calcification is the problem - some have the narrative that the calcified plaque is stable - less likely to rupture. This sort of fits with my working model of CAD ( I know about it - or I should say that almost everything I thought I knew about CAD turned out to be wrong. )

I think the obsession of looking at the plaque and calcification as if it is the disease is sort of wrong - sort of like looking at burn scars and thinking the scars caused the burn.

That being said - I think Kendrick is also correct - the results of a CAC score don't lead to any possible change in intervention. Contrast that with a postprandial BG test - I can learn what I can and can not eat.

The other bit - I think emotional stress is a causative factor - testing CAC or LDL thus appears to potentially cause net harm - inducing needless stress by getting people to obsess over in-actionable tests.

Re Lp(a) - I have this trait - but I'm not so sure it is as clear as the medical systems' narrative - there is this troubling Italian paper:

https://www.ncbi.nlm.nih.gov/pubmed/20014954

And the little detail that it is quite common in centenarians.
https://www.ncbi.nlm.nih.gov/pubmed/9543111

I've seen zero evidence that trying to address Lp(a) levels helps people live longer - that research hasn't been done and interventions always carry the chance of unintended consequences that can be harmful. My hunch is the best type of LDL and CAC tests is to not bother running them - they do not lead to changes or useful interventions.

Doing interventions that have not been tested is gambling - quite possible to do harm.

Ferinstance - if the intervention reduces the calcification - is it possible it is increasing unstable plaque? Of course if you have CAD you want to do something - I would focus on increasing muscle mass and keeping postprandial BG below 110 -- much better use of our limited time and focus.

Peter said...

Hi JustPeachy,

You have to wonder if your grandmother simply had a pancreas of steel and was chronically hyperinsulinaemia but maintained normal function because the insulin could be driven high enough to match the insulin resistance. That would put the calcification late in life in to the category of insulin induced. RA itself is, at best hypothesis, an auto immune response where antibodies to the urease produced by Proteus mirabillis, most commonly in the urinary tract. This antibody cross reacts with human a specific human collagen. Chronic damage plus chronic hyperinsulinaemia might drive calcification. Ebringer suggests some interventions to help with RA, personally I’d consider LC with restricted protein. Proteus is also found in the gut so the beneficial effects of LC on GI health would probably help…

Also the terminology around scleroderma is very, very mess and you often wonder which condition papers are referring to!

Peter

Peter said...

Frunobulax, cholesterol denialist is, absolutely, a badge of honour.

Peter

Peter said...

Bob and ctviggen,

It depends. If you feel that calcification is response to injury, stabilising and beneficial, you might not want to get rid of it. If you feel that it is secondary to chronic hyperinsulinaemia you might want to ask yourself what your insulin levels are in the aftermath of a typical “doing everything right” meal might be. There is, without a doubt, a spectrum of what is needed to be done to maintain normal blood insulin levels in addition to normal blood glucose levels. Then of course there is the question of what is “normal” for post prandial insulin and what is “necessary” to maintain this in the aftermath of an “ideal” meal… And what you might want to trade off with enjoyment vs stress/micromanaging.

I completely agree that worrying about your score will be distinctly unhelpful! But if you are “lowish carb” and come up with a CAC score of 700 you might want to know and might want consider a little more information and maybe make some adjustments.

Peter

Frunobulax said...

@karl Frankly I don't get your argument. Let's stick to the scar analogy: Obviously removing the scars won't help with the wounds. But if we see more and more scars, then we know that there were fresh wounds.

So even if we assume that calcified plaque is not a problem (which may or may not be correct, I'd assume that it's a question of the extent and location -- if it's incorrect then aiming for plaque reduction is obviously not the right thing to do), a person that stops the calcification process knows that he's doing something right, while a person that sees increasing calcification will have to question if his/her prevention strategy works.

Me, I'll take science over faith here. If CAC score is the best predictor of artherosclerosis that we have, then that's what we should use as metric to judge prevention strategies, even if there is some margin of error. Even if it's only one tool in the shed, among others.

@Peter Oh yes, I'm known as a cholesterol denialist too ;)
However it's so sad to see such misguided crusades. There is a necessity to warn people about quacks, and I used to think that sites like quackwatch are a good idea. I know enough people who believe in esoteric bs like ghost healers that claim to have a phone line to god (telling them how to heal people). Those quacks often keep up an outside appearance of science, fooling people that have no scientific training.

Of course, these anti-quack crusaders usually don't care about science themselves and seem to target all people that cut into profits of the pharma industry, and they often hit harder if the pharma criticism is valid.

In the end, I'm considered a nutjob by many (as I'm a cholesterol denialist, and eat a diet with lots of fat, can you believe it?) and a minion of the pharma industry by others (as I question whether it's god or the guy with the horns that gives those advise to the mediums). Ah well :)

Pernickety said...

Peter, given many autoimmune conditions appear to have a dietary trigger (e.g. gluten, casein, wheat germ agglutinin and other lectins, etc.) and you have previously written about a number of these before, are you aware of any links between Sjogren's Syndrome and particular foods? Asking as someone with pSS-related neuropathy and vasculitis, plus currently undergoing testing to rule out MALT lymphoma. So learning of any diet/lifestyle changes I can use as adjuvant treatments to get this under control is a high priority!
Here is a link to the most recent paper I could find detailing the B cell dysregulation that is thought to play a role in the development of primary SS, in case that helps you or anyone else in answering my query. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819875/

Peter said...

Hi Pernickety,

It has never even occurred to me that SS was anything other than atypical coeliac disease. I guess you could qualify that as increased intestinal permeability due to coeliac or non-coeliac gluten sensitivity allows the immune system to see more intestinal antigens than it otherwise might, so coeliac disease must be joined by anything else which increases intestinal permeability, ie other lectins etc. The mechanisms will no doubt involve lots of molecular shrapnel but the bomb will be GI permeability. The first hit I got on Duckduckgo was this blog post https://www.verywellhealth.com/celiac-disease-and-sjogrens-syndrome-562622. Sounds very plausible to me on a quick scan.

Peter

Pernickety said...

Thanks Peter! Every member of my family has been tested for coeliac for a variety of ailments, but we were all negative on biopsy so told there was no problem continuing to eat gluten. As you've highlighted before, coeliac doesn't always present in the gut, plus other molecules like lectins could be causing the issues. Sounds like we've all got increased intestinal permeability but it'll be hard to convince my family members to try eliminating foods to see if it'll help.
I believe I recall you mentioning that you've done a PEG400 test which was normal on your hybrid Dr K diet. Do you think there would be any worth in doing a PEG400 test now as I'm still symptomatic, then repeating it once I've adhered strictly to a PKD-style diet for a couple of months? I follow their basic principles and have seen improvements, but living with people who make my old favourite meals frequently proves quite challenging to not pick at their food, even when I suffer the consequences...

Peter said...

Yes, I did a PEG400 test and was not just normal, my curve simply duplicated the lower limits of normality right across all of the molecular weights. That is very, very very normal, within the limits of the test. The result took ages to come through. While I waited I went full blown PKD (no cheese or alcohol for the first month, very high fat) and my spinal and finger arthritis resolved enough that I'm now on a more relaxed plant free diet eight months later, a little more cheese but still minimal alcohol. Fat adjusted to keep me 62 point something kgs. So I got the improvement despite having normal PEG400 result before I started. I'm left feeling that response to treatment is a lot more significant than whether a GI biopsy conforms to the WHO guidelines for giving you a particular label of coeliac or a PEG400 results says you do/don't have a problem...

Socially keto is very easy compared to the PKD. Even the more relaxed but still plant free diet I eat nowadays is a social catastrophe.

Peter

karl said...

@Frunobulax

Measuring the rate of scar formation is all that one can do with CAC. We don't have good treatments for CAD. There are a lot of narratives where people tell us to do X,Y, or Z to fix CAD - only for the most part these interventions are untested and don't appear to work - some will turn out to do harm. Many of these interventions appear to me to mostly boost the ego of the ones parroting them - in their calm, all knowing voice they just 'know' things..

If there was a tested intervention that not only reduced the rate of CAC increase - but actually shows a decrease in mortality - it would get me interested (all-cause mortality is hard to fudge).

The problem is while we know that CAC is associated with CAD - yet, it is not CAD. I'm done with the idea that we should be treating test results and pretending it is the same thing as the disease.

They said the same thing with LDL tests - LDL is not CAD - and most treatments that lower it have worse mortality or at least no benefit (I think there are about 15 interventions that lower LDL) - the tiny improvement with statins may have to do with the NO system - and if you believe the research, it appears statins actually increase CAC scores - yet people live a tiny bit longer. We still hear bad cholesterol/good cholesterol - yet LDL and HDL are both part of the innate immune system - and HDL is not one thing - some types are associated with increased CAD(I think you could argue that there are probably 100 distinct types of HDL - not a thing - but a class of things) . So treating lipoprotien levels didn't work - and $B are wasted tracking levels and misinforming patients.

So back to CAC - lets say you find some intervention and now your CAC level does not increase - but you are unaware that the amount of non-calcified - unstable plaque has increased - are you better or worse off? There is a phrase in medicine - Primum non nocere - First do no harm. Prescribing/recommending untested interventions can do harm.

Unless there is a tested actionable intervention, CAC should be left for use in research and for people that have money they need to get rid of.

As someone with skin-in-the-game, I focus on tight BG control via diet, maintaining (increasing) muscle mass, and gamble that interventions that improve NO function matter.

I think Kendrick is right to focus on causation - I grew up with leaded gasoline, was exposed long term to PPI's, ate too many carbs - swallowed a lot of stress - likely causes of my CAD.

But with the result of a CAC test - would it change any of my interventions? No - I don't want high BG for a long list of reasons - I don't want to have low muscle mass - so if a test doesn't lead to improved interventions, it has no value.

I get it that there is this urge/desperation to do something - reality is not fair - but it is where I live. Selling desperate people tests that are not going to lead to better outcomes is immoral in my world.

Frunobulax said...

@karl I think the truth about statins is completely lost in the noise of the populistic battle. Some of the crucial side effects materialize only after many years (like t2d), some of the studies justifying statins (like the Jupiter study) both use a special population (high CRP) and a short timespan (less than 2 years on average) where those long-term side effects won't influence the result. They do something besides affecting cholesterol (they seem to lower inflammation, for example), but to me the jury is out which patient group would profit from taking statins. Dave Feldman has a nice talk on this, crunching numbers (https://www.youtube.com/watch?v=UZv00mMiB9M). As far as I'm concerned, I wouldn't even consider statins unless I had both a high CRP and a previous heart attack or stroke.

You (and Kendrick) raise some valid points, and there are famous precendents in the past where a hasty and harmful intervention (low fat diet) was done to prevent CAD, based on one indicator (cholesterol). We need studies, asap. (Which would take 10 or more years even if we started right now.) But please note that I think there is a difference between lowering CAC and stopping CAC growth. We can surely debate on whether it's a worthy goal to lower CAC (which could do harm), but Ockhams razor suggests that it's a good thing if your CAC doesn't rise any further.

There is a theoretical possibility that higher calcification is caused by calcifying unstable plaques without forming new unstable plaques, but if the calcification keeps growing over the years then there have to be additional unstable plaques. So if your CAC keeps rising, you're doing something wrong. And that's IMHO a very valuable information, even though it doesn't help you with what you should do differently. (The negation of A -> B is !B -> !A.)

As for the intervention, there are different ways to control BG and insulin. If my CAC keeps growing I would consider switching to a different diet, for example to carnivore (from keto), or I might check if there are other tweaks (like the fat composition in the diet, or maybe increase fiber/polyphenols and whatnot) that could influence calcification.

Stuart said...

There is an alternate test for CVD the ADMA test.
https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/83651

There was a British firm that provided a blood spot test which I am unable to find now. I tired it but my results were poor as NOxide from beets and some foods give me a an almost instant migraine.
Aged garlic seems to work lowering risk of CVD as it is anti microbial and likely has something to do with reducing pathogens entry from the gut barrier but also gives me migraines.
An alternative test is the carotid ultrasound equally good.
https://vascularsurgery.ucsf.edu/conditions--procedures/carotid-ultrasound.aspx
We all seem to have some calcification with age enough for them to declare one with CVD and recommend a statin and asprin! Being early 70s I have a bit so just keep the BG low.

Statin sales will be approaching 1-TrillionU$$ in 2020. so it a real up hill battle.

Bob said...

Karl,

"I think Kendrick is right to focus on causation - I grew up with leaded gasoline, was exposed long term to PPI's, ate too many carbs - swallowed a lot of stress - likely causes of my CAD."

Very similar here. Just replace the PPI's with SoCal air pollution. Yet, here I am at 65, wondering why I've been spared an "event" so far.

Great comment overall.

"Unless there is a tested actionable intervention, CAC should be left for use in research and for people that have money they need to get rid of."

As Instapundit likes to say, "Harsh but fair".

Justin said...
This comment has been removed by the author.
Gyan said...

I wonder if the hypothesis that calcification is promoted or caused by a deficiency in Vit-K2 is tenable in view of comments here?

Passthecream said...

Frunobulax - smart poodle. But statin side effects only took a month or two to show up for me and I could switch them off and on by stopping or starting the damn pills. That would satisfy Karl's insistence on a single parameter. The point being though, that everyone responds differently. Chocolate has taken a bashing here recently but cacao has some association with cad risk-lowering. However it is full of histamine, phenolics, weird flavonoids god knows what else so hard to tease appart. Perhaps as proposed, it is the fat contrnt which us beneficial? I'm in the diy white chocolate camp atm. None of that nasty brown stuff.

Btw I first misread your alias, the Zappa days of childhood being long past, and thought it was Funorbollix. I might use that one myself. :))

Frunobulax said...

@passthecream Yeah, some people experience side effects from statins within a few days. But much scarier is the study where they found that Alzheimer patients would improve their score significantly by dropping statins, and the score would drop right back to old levels once they started taking them again. But I'd assume that the effect is slow and gradual. I once suffered from side effects from other drugs, it took years to develop them, but then a single dose would send me into madness.

I think chocolate is highly individual. It's high in oxalates and theobromine, and we have vastly different abilities to detox those.

I guess you could call Zappa the godfather of sceptics and bs spotters ;) Never gets old.

karl said...

@Frunobulax

For the record - I once did take a CAC test - I already knew I had CAD. I know there are some that are pushing the narrative that you can see the progress - change your interventions - but lots of problems. The test scores have noise in them - I have looked at countless interventions, but what I have realized over the years, is just how little we know. When this started, I thought I knew a few things that would help - almost all of what I "knew" was wrong. And - interventions have the potential to do harm.

We can lower our toxic metal exposure, keep BG in tight bounds - maintain healthy muscle mass - but beyond that - most interventions are quite marginal statistically - and we should consider hidden harms.

Re-Statins
I got particularly terrible side effects from statins - acute anxiety - worst anxiety I every experienced. Took time to figure out which med caused it - started and stopped the meds 4 times to be sure. Some people would want give up their life if exposed to that harm - I was lucky I knew how to figure it out.

Passthecream said...

Karl "acute anxiety - worst anxiety I every experienced"

Ditto. A more irrational kind of anxiety than ever before. Plus insomnia. Plus leg pains and general mental fog. Ugggh.

Eric said...

Wouldn't normal blood pressure be an indication that artery calcification is not an issue?

HeyJude said...

@Frunobulax, @Passthecream,
I too experienced terrible side effects from rosuvastatin @5mg. I became overtly hostile on multiple occasions in less than 14 days on the meds. Could have been an over-the-top anxiety response. I discontinued the drug and had no more reactions. I mentioned that it caused me to become hostile to my cardiologist recently and he laughed and said "that's impossible". I said it had never happened before or since. His response: "well it had nothing at all to do with the statin. Only 1 percent of people have problems with statins and that is myopathy." He was not the least bit interested in my genetics tests that revealed I had reduced CYP3A4 (*1/*22) and poor CYP3A5 (*3/*3) and increased myopathy risk SLCO1B1 531T>C T/C and ABCG2 421C>A A/C.