Statins and heart valve disease

[Praline]

Statins show promise as an aid in controlling heart valve disease

By Ronald Kotulak
Tribune science reporter
Published April 12, 2006


Heart valve disease, which leads to 100,000 open heart surgeries a year in the U.S., may be preventable, according to research conducted at Northwestern Memorial Hospital.

Long thought to be the result of wear and tear, for which surgery was the only remedy, heart valve disease now appears to be caused by a potentially reversible chronic inflammatory process, said Dr. Nalini Rajamannan, director of the hospital's center for heart valve disease in the Bluhm Cardiovascular Institute.

Studies in rabbits that develop a similar type of heart valve disease after being fed a high fat diet showed that the family of anticholesterol drugs known as statins reversed some of the disease, Rajamannan said.

"Our findings open the door to the idea that medical therapies such as statins may be able to play a role in preventing or slowing the process and curtailing the need for surgery," said Rajamannan, also a faculty member at Northwestern University's Feinberg School of Medicine.

Genetic and chemical analyses of damaged tissue show that heart valves become stiff and inflexible and begin to leak or malfunction when their genetic programming goes haywire and starts producing cartilage or bone, Rajamannan reported in the online version of the Journal of the American College of Cardiology.

A high-fat diet, the main risk factor in heart disease, also appears to cause valvular disease, she said. The disease process then sets up chronic inflammation in the valves that inappropriately turns on genes that should remain turned off, she said.

Inflammation in the mitral valve turns on genes that produce cartilage like that found in the knee joint, Rajamannan said. In the aortic valve, which is exposed to a stronger flow of blood, abnormal gene activity produces bone tissue, she said.

Dr. Roberto Lang, a University of Chicago heart specialist who was not involved in the study, said the findings were promising because they opened the door to treating the most common causes of valve disease with medications. But, he said, further studies are needed to determine how effective medical treatment might be.

Doctors commonly describe diseased valves, which appear hardened and whitish, as calcified because of the calcium they contain. The buildup of calcium was considered to be a mechanical process of aging.

Rajamannan said she began studying diseased valves because she suspected there might be an underlying biological process causing the damage.

The disease processes either cause valves to leak or to limit the flow of blood through the heart, which normally pumps about 100 gallons of blood every hour. A diseased mitral valve can provoke irregular heartbeats known as atrial fibrillation, which can cause strokes or heart failure. Aortic valve disease also can cause heart failure in addition to arrhythmia, infection and sudden death.

"Once we know the pathways and mechanism of valvular disease, then we can try out therapeutic measures to prevent it," said Dr. Shahbudin Rahimatolla, a University of Southern California cardiologist and a study co-author who is one of the world's leading experts on valvular disease.

Besides statins, new drugs may be developed that stop the abnormal activity of the cartilage and bone genes, he said.

Rajamannan said the next step would be a study in which patients with early valve disease are put on statins to determine if the disease process can be slowed or stopped. Her research is supported by more than $750,000 in grants from the National Institutes of Health and the American Heart Association.

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[tobagotwo]

There is a lot of money available from statin manufacturers to fund anyone who'll attempt to show that statins will cure anything. A new indication would mean an extension of patents, and hundreds of millions of dollars.

It will be interesting to see yet another attempt to prove that statins are good for this. The following article regarding a recent study published in The New England Journal of Medicine is less than a year old, and was originally posted by Hennsylee:

Reuters <http://www.reuters.com>

Lipitor does not prevent narrowing in heart valve
Thu Jun 9, 2005 7:54 AM ET


BOSTON (Reuters) - The popular cholesterol-reducing drug Lipitor made by Pfizer does not prevent obstruction of the heart valve that leads to the aorta, the body's largest artery, according to recent findings published in the New England Journal of Medicine.

In a study conducted to determine whether the drug, also known under its generic name atorvastatin, did more than just reduce cholesterol, doctors found that Lipitor failed to prevent obstructions that can keep the heart from pumping blood adequately.

The condition, known as calcified aortic stenosis, occurs when a key heart valve narrows or becomes blocked, preventing the heart from pumping blood properly and can manifest itself in spite of reductions of cholesterol levels, according to the study.

Surgery is usually required to fix it.

Aortic stenosis affects 3 percent of adults over 75, making it the most common valve defect in North America and Europe and occurs gradually over several decades. By the time symptoms appear, surgery is typically needed to repair or replace the valve.

As part of the study, 155 volunteers with signs of calcified aortic stenosis were given a placebo or Lipitor, which like other drugs known as statins slow the narrowing of small heart arteries caused by heart disease.

After a little more than two years, the team led by Joanna Cowell of Royal Infirmary in Edinburgh found that the drug brought cholesterol levels down as expected but produced no real improvement as far as obstructions are concerned.

"Aortic stenosis progresses despite intensive reductions in serum cholesterol concentrations," the Cowell team concluded.

The study was funded in part by an educational award from Pfizer, a grant from the British Heart Foundation and the Welcome Trust Clinical Resource Facility in Scotland.

In an editorial in the New England Journal of Medicine, Raphael Rosenhek of the Vienna General Hospital in Austria agreed, saying that prescribing statins "is not justified" unless a patient has another, more established, reason for taking the medicine.
_____

© Reuters 2005. All rights reserved. Republication or redistribution of Reuters content, including by caching, framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.

Best wishes,

 

[MrP]

I've heard from many sources statins show promise. Neither of these articles describe detailed specifics regarding experiments, methodology of observation and measurement, margin of error, etc. for one to draw a conclusion one way or another. Good science and intelligent research will prevail in the end....have faith. The cost and effort will be worth the knowledge gained!

 

[hensylee]

my conclusion is that they can keep all the statins away from me.

 

[aussigal]

My Cardio doesnt think I as BAVer needed statins...
yet the guy I saw for a 2nd opinion seemed to be one who likes to prescribe lots of drugs according to other patients of his I have spoken with...well he did want me on the Lipitor "just-because" it was available and might help ...
I tried them for a month and my Cholesterol levels stayed low as they always have been and I developed extra cramps and aches in my legs...
My regular cardio said chuck-em out...I didnt need them...voila!...no more leg-aches.
just my experience

 

[Andyrdj]

Calcification

Calcification

It seems to me that there must be another calcification cause for prosthetic tissue valves, as they are composed of dead cells. So the calcification cannot be arising from the surface of the prosthetic valve.

Conceivably it might arise from cells striking the valve and sticking to it. However, red blood corpuscles have no nuclear material, so aren't likely to be the cause. Could be white blood cells?

Further info on this would be greatly interesting

 

[tobagotwo]

The reason I replied to the rabbit study article with this article about the human study was not simply to dispute the rabbit "study" (which was a hugely disproportionate conclusion drawn from 32 bunnies in just eight weeks). It's because there are inherent risks in doctors prescribing statins to people who may not have cholestrol problems, and I'd hate to see people rush out to get statins, thinking their disease process will stop or even reverse. Doctors have been prescribing statins for this already, and no data has surfaced to say it has had any beneficial effect in humans in real life whatsoever.

I've heard from many sources statins show promise. Neither of these articles describe detailed specifics regarding experiments, methodology of observation and measurement, margin of error, etc. for one to draw a conclusion one way or another. Good science and intelligent research will prevail in the end....have faith. The cost and effort will be worth the knowledge gained!

I agree with the sentiment. However, the human study was readily available to locate and read through the information provided in the Reuters article, if someone were interested.

Here is the study, published in the New England Journal of Medicine. It's a thorough and well-documented work. I've read it, and anyone here can, too. It's good science and intelligent research, and shouldn't be brushed aside by anyone who hasn't read it: http://content.nejm.org/cgi/content/full/352/23/2389

For those who prefer less reading, here is the link to the abstract: http://content.nejm.org/cgi/content/abstract/352/23/2389

The study was funded by two statin manufacturers, by the way - and the results were surely not what they had been hoping for.

Perhaps we could define the "many sources" that tell us that statins "show promise" for this purpose, so we can compare the good science and intelligent research of those statements with with the NEJM-published findings of valid research work. It would help us to know if they're based in fact, and not just rumors propogated in the medical community by those who have a financial or professional stake in extending statin patents.

It's a marketing staple that if you say something long enough and loudly enough, some people will believe it, whether it's true or not.

As long as those unproven whispers (and they are unproven) exist in the medical community, statin manufacturers will continue to profit from off-indication prescribing by doctors who've been swayed, whether it helps or even winds up hurting the patients involved. (Yes, it's legal for doctors to prescribe off-indication.) Unfortunately, there are significant side effects sometimes associated with the use of statins, particularly for those who do not have high cholesterol.

Has anyone noticed how long statins have been prescribed for people, and that no one has been able to put together any statistics that show statins affect valvular stenosis in all this time? Including the people who would most profit by such a revelation? If they had any case at all for a new indication, the statin manufacturers would be storming the walls of the FDA as we speak.

The rabbit study's abstract is here: http://heart.bmjjournals.com/cgi/content/abstract/91/6/806 A fee is required to view the study itself.

A very inclusive, extended article on the rabbit study appears here: http://www.theheart.org/viewArticle.do?simpleName=176938

From theHeart.org: Aortic valve disease is due to hypercholesterolemia and calcification; statins may stall the progression Mon, 03 Jun 2002 20:00:00by Fran Lowry

...Rajamannan divided 48 New Zealand White rabbits into three groups: Group 1 (the control group) was fed a normal diet, group 2 was fed a cholesterol diet, and group 3 was fed a cholesterol diet plus atorvastatin (3 mg/kg per day). After 8 weeks, the animals were sacrificed and their aortic valves were examined for the presence of macrophages, proliferation cell nuclear antigen (PCNA), cholesterol, high-sensitivity C-reactive protein (hsCRP), and osteopontin, a glycosylated phosphoprotein that is important in mineralization.

Bone markers expressed
The investigators report that all of these markers were significantly increased in the cholesterol-fed animals compared to the controls. However, all markers, with the exception of hsCRP, were reduced by atorvastatin.

The investigators conclude: "These findings of increased macrophages, PCNA levels, and bone matrix proteins in the aortic valve during experimental hypercholesterolemia provide evidence of a proliferative atherosclerosis-like process in the aortic valve associated with the transformation to an osteoblast-like phenotype that is inhibited by atorvastatin."

The rabbit study did not include actually creating any apatitic calcification in rabbits. It was specifically designed to prove that aortic calcification is caused by hypercholesterolemia (high cholesterol). It focused on determining a way to create hypercholestemia in rabbits, an unnatural condition in a rodent. Then the animals were sacrificed after eight weeks, and searched for chemical markers that were similar to those that might be found in a calcified aorta. No aortic calcification was actually created. No effort was made to determine if humans who have calcified aortic valves also have high cholesterol or arterial plaque.

A look at the real patient base would make that appear a very misguided assumption. Most people on this site have low or normal cholesterol levels, rather than high. Good cholesterol levels and a lack of significant arterial plaque are frequently associated with bicuspid aortic valves. I had a badly calcified (tri-leaflet) aortic valve, but my cholesterol is fine, and during the catheterization before the AVR, the interventional cardiologist described the cleanliness of my arteries as "fantastic." Guess I wouldn't make a good rabbit.

More from the article:

...Rajamannan says that patients who exhibit early valve roughening or changes, which are relatively easily detected with a stethoscope in the physician's office, should perhaps be put on a statin..."So, we propose putting patients on statins when we hear this murmur."

I note that, rather than being relatively easy to detect, that murmur is in reality often not heard until the disease progression is quite pronounced for many of us.

It's also an enormous jump from an eight-week study on 32 rabbits (16 of the 48 were controls) to recommending that all human patients be given statins as soon as a murmur is detected. It's patently irresponsible.

It would be nice to believe that there is a simple explanation for valvular calcification, and a readily available drug already out there that would stop stenosis in its tracks, and even reverse it. However, the assumption that arterial plaque and apatitic calcification of heart valves are the same or even have similar causes seems facile at best.

They're not of the same composition, and the calcification is site-specific. The arterial plaque can appear anywhere in the bloodstream, including the valve site, even when stenosis or calcification is not present. Further, the aortic calcification frequently appears in the absence of any significant arterial plaque or elevated cholesterol levels.

The crossover between this and apatitic calcification? They discuss finding "bone markers," which might be in the right ballpark for actual apatite formation. On further reading the bone markers are not actually osteoblasts (bone-making cells). Instead they're an "osteoblast-like" phenotype, without further description.

While the exact mechanism remains undescribed, anticalcification treatments for tissue valves are based on chemically locking up surface molecules on the tissue of the valves. This prevents components in the blood from interacting with them to form a base attractive to calcium and phosphorus, which produce apatite (bones and teeth are also forms of apatite). That it's associated with blood chemicals is a fair assumption, as a xenograft in the mitral valve position, which moves in a way that allows the blood to linger against its surface, calcifies more rapidly than the same valve in the aortic position.

Rapid testing of tissue valves is done in animals like sheep, which calcify valves at an astonishing rate, doing in months what occurs over years in humans. While these animal models are not precisely mapped to human responses, they can provide general trending and insights. These animal studies have shown that anticalcification treatments do extend the useful life of xenograft valves in a situation of severe calcific duress.

However, rodents are not used for this type of testing, as they aren't particularly good models. Note that researchers don't choose to use large farm animals for studies unless they have to, due to food and housing costs, space considerations, and other practical concerns.

The valid transference of that "fast data" to years of actual human use is still in the making. My valve is part of that evolving data, along with other treated Medtronic and Edwards valves (and St. Jude valves outside the US).

To sum it up: 1) The rabbit study was just 32 rabbits in eight weeks and rather flawed in hypothesis, size, test subject type, and conclusion. 2) The state of all significant human medical research on the subject is that statins do not reduce or reverse valve calcification.

Best wishes,

 

[MrP]

Bob,
First, I do not work for one of the drug companies and have no monetary interest in any of them. Also, I'm not brain-washed by their marketing efforts and am not prejudiced one way or another regarding statins. And I didn't dismiss lightly the study you referenced, although I didn't read the entire detailed research report (only the summary you initially provided). Results of this study certainly are disappointing, and especially after an earlier study by the Mayo Clinic in 2002 showed potential promise of using statins in treating valve disease. Although the more recent research in Scotland yielded unfavorable results, I think you'll agree good science practice would be to repeat this study and with a larger sample over a longer period of time.

I believe Yale Medical is currently conducting research on statins and aortic disease. And I think Duke also has an ongoing research project (can't recall specifics now). Wake Forest Medical in July 2005 published a report that statins may be associated with lower mortality in patients with diastolic heart failure. In 2005 John Hopkins' research showed reduced stroke risk after surgery for statin users.

The Heart Center of Bonn Germany also recently published results of a study to assess "aortic valve probes for valvar C reactive protein (CRP) presence, the relation between valvar and serum CRP, and a possible modification of CRP by statin medication. CRP was found in a large series of degenerative aortic valves, more often in bioprostheses than in native cusps. Serum CRP concentrations may reflect inflammatory processes within the aortic valve. The association of statin treatment with decreases in both valvar and serum CRP concentrations may explain known pleiotropic effects of statins in patients with aortic stenosis."

There are other studies, and I'll try to dig up results later.

 

[tobagotwo]

There is no intention to brand any site members as statin lackeys. I would have no reason to think anyone here would gain financially from statins. I think people may not be fully aware of the extent of the effects of opinion makers within the medical field, and the amazing amount of money that can be generated by a drug being prescribed for off-label uses.

As far as the rest, remember, we are not talking about the cholesterol-reducing benefits of Lipitor and other statins, which have been proven and are approved indications for prescription.

The problem I had was that this carefully-executed, randomized, double-blind, 2-year, human-based program (excellent science), accepted by a world-recognized medical magazine, was put in the same sentence with an eight-week, 32-bunny experiment, from which outrageous proposals were made, and both were dismissed as having inadequate information.

That sets them incorrectly as equals in the eye of a casual reader, and also as equally dismissable. These two studies are nowhere in the same league as research goes, and the Edinburgh study certainly doesn't bear being ignored on any reasonable grounds. That's where the concern lies, with people who might take that to mean that taking statins would be a good idea to reduce valve disease. That's a potentially unsafe and definitely scientifically unsupportable path.

Again, with all the valve patients who have been taking statins for years, there isn't plain evidence of a benefit related to the valve disease. And there should be some by now, if it were so. That's one reason why the results of the study in Scotland, while disappointing, are not surprising. Anything statistically significant would have surfaced by now, especially with so many people looking for it.

I was unable to locate any statin work listed in the Yale Medical Site's listing of active research studies, although it may be unlisted. I'm not sure of the relevance of the Wake Forest and Johns Hopkins items, as they have no bearing on valves. The Mayo Clinic work was done as an initial review of patient records, not an actual experiment following specific individuals with standardized measurements. It was intended to determine if a further study such as the one done in Scotland would be worth pursuing, rather than as a definitive study in its own right. Here's another study done in a similar, review-type method: http://www.medicalnewstoday.com/medicalnews.php?newsid=40910

The Heart Center of Bonn is studying the genetic (pleiotropic) influence over some aspects of cell characteristics (phenotypes) caused by the use of statins, and its possible relationship to the effects of statins on c-reactive protein. That's not a proposal that statins will reduce valve disease, but rather a study of the effects of statins' interactions with CRP and their effect on cell characteristics.

Interestingly, the only type of valve disease mentioned in the bunny article was degenerative valve disease (A.K.A. "senile calcification"). BAV owners would be a stretch for this type of theory, as they frequently have less arterial plaque than other people in their age groups.

Should a larger study be done? Perhaps, if anyone actually thinks it will produce a different result. There could be one or several going on right now, of which I am unaware.

The point is that there is no impetus to say the jury's still out. There is a definitive and accepted study that says that statins don't affect valve disease in any measurable amount. If future research can find a segment of the population it may help, that would be wonderful. But the data for a cure or even an ameliorating factor of any significance simply don't exist, even with all these patient-years of statin usage to rummage through, and manufacturers eager to find it.

Best wishes,

 

[MrP]

There were several limitations in the Scottish (SALTIRE) study, including small patient sample (77 patients in each group), short follow-up (25 months afg), high drop-out rate (30% at 24 months), and the inclusion of patients with moderate/severe aortioc stenosis. These limitations were compounded by the variability of the outcome variables, namely aortic jet velocity and aortic calcium score.

Should a larger study be done? Perhaps, if anyone actually thinks it will produce a different result. There could be one or several going on right now, of which I am unaware.
The point is that there is no impetus to say the jury's still out.
Best wishes,

There are two ongoing trials that will provide a more definitive answer to the use of statins in treating aortic valve stenosis: the Canadian ASTRONOMER study and the European SEAS study...see the link below for more details.

http://www.cardiologyrounds.ca/crus/cardcdn060705_eng.pdf

 

[tobagotwo]

The linked text from the St. Michaels Hospital of the University of Toronto Cardiology Rounds July, 2005, states the belief that there should be more studies, and points to two that hadn't begun at the time the presentation was given at the school.

The presenter, Dr. Oudit, is a cardiology trainee at St. Michael’s Hospital.

While pointing out that "These limitations were compounded by the variability of the outcome variables, namely aortic jet velocity and aortic calcium score," it should be noted that they are the standards used for all such trials, as Dr. Oudit admits elsewhere in his presentation,

As such, in clinical trials, aortic valve calcification (assessed by computerized tomography) and aortic jet velocity (assessed by transthoracic echocardiography) are the two surrogates used to monitor the progression of valvular aortic stenosis.

Conclusion he states about statin therapy for aortic stenosis in the linked text:

Until the results of these trials become available, statin therapy cannot be specifically recommended to slow the progression of disease in patients with VAS.

Which he restates in the last paragraph for emphasis:

Until the results of these trials become available, statin therapy can only be specifically recommended based on conventional indications.

Conventional indications means it can be prescribed to lower cholesterol levels.

Which is not dissimilar to what I posted: "That's where the concern lies, with people who might take that to mean that taking statins would be a good idea to reduce valve disease. That's a potentially unsafe and definitely scientifically unsupportable path."

Best wishes,

 

[twinmaker]

I am on Lipitor solely because of some calcification on my aortic valve. I've had my mitral valve replaced because of rheumatic heart disease. My cholesterol has always been low (about 122). My electrophysiologist wanted me to try the Lipitor, so I did. I started out on 10mg. a day but decided to go to 5mg. a day. I wasn't having any problems with muscle cramps or stuff like that but rather with gastro problems. I'm not having any problems on the 5mg. a day and figure it can't hurt. Don't know if it will help though either. LINDA

 

[MrP]

The Bonn study I referenced was not a genetic study at all.

The Heart Center of Bonn is studying the genetic (pleiotropic) influence over some aspects of cell characteristics (phenotypes) caused by the use of statins, and its possible relationship to the effects of statins on c-reactive protein. That's not a proposal that statins will reduce valve disease, but rather a study of the effects of statins' interactions with CRP and their effect on cell characteristics.

Among other findings, the Bonn study showed statins reduced CRP or inflammation on calcified aortic valves...native and bioprosthetic. Here's the URL link to the Bonn study abstract. A small fee is required for the full article...excellent reading.

http://heart.bmjjournals.com/cgi/content/abstract/92/4/495


The most important positive pleiotropic effects of statins are antiinflammatory, antiproliferative, and antithrombotic ones, improving endothelial dysfunction and others.

PLEIOTROPIC EFFECTS ? DEFINITION
Drugs usually have multiple effects; through an analogy
with single genes which affect more than one
system or determine more than one phenotype, they are
currently referred to as ?pleiotropic effects? (from the
Greek ?pleion,? meaning more, and ?tropos,? meaning
direction or turn). These may be related or unrelated to
primary mode of action of the drug. Pleiotropic effects
may emerge during preclinical and clinical studies in
drug development, but more often than not, they are discovered
a posteriori long after the therapeutic agent is
marketed (the same situation occurs in use of statins).
They may be undesirable and recognized as adverse side
effects, they may be neutral, or they may be beneficial,
enhancing the desirable effect of a drug.

See the following URL link below for an excellent paper on the pleiotropic effects of statins.

http://www.tsoc.org.tw/magazine/pdf/305.pdf

Statins are overall well tolerated, although there are potential negative side effects. The paper referenced above also discusses this in scientific detail.

The University of California at San Diego is conducting an exhaustive trial to evaluate negative side effects of statins....see URL below.

http://72.14.203.104/search?q=cache...statins+valve+trial&hl=en&gl=us&ct=clnk&cd=45


More to come....

 

[tobagotwo]

It's perfectly legal for the doctor to prescribe any medication for whatever benefit he reasonably feels you may reap from it. Presumably, you would be informed if the drug is being prescribed for a non-approved indication. It's sensible for you to work with your physician to determine if off-indication prescription of a product is a valid risk for you, having a perceived benefit larger than the risks associated with taking the drug.

The brain uses cholesterols in a variety of functions, especially related to learning and memory. Although the brain comprises only two percent of the body's total weight, at any given time it contains over a quarter of the body's cholesterol. There are FDA MedWatch Adverse Events reports of cognitive implications for some people who were given statins for high cholesterol. There are concerns that if that is the case, those who have low to normal cholesterol who are given statins may have a greater risk of such complications.

The 2003 Wagstaff Report (http://www.medscape.com/viewarticle/458867_print) noted after a vigorous search through available study documents gleaned from the US government, that "available prospective studies show no cognitive or antiamyloid benefits for any statin. In addition, case reports raise the possibility that statins, in rare cases, may be associated with cognitive impairment, though causality is not certain."

So strong is the statin hold on the medical community, that researchers pushed aside their own negative results on the following study which attempted to show that statins protect the elderly from Alzheimer's and dementia:

Rea and his colleagues studied 2,798 older people who had no sign of cognitive problems at the study's start. The team also kept track of those who developed dementia, including Alzheimer's, over a six-year period. They also noted whether participants were taking statin drugs such as Lipitor or Zocor. Participants took cognitive and memory tests throughout the study. The researchers found that those who took statins developed dementia or Alzheimer's at about the same rate as those who were not taking the drugs. The findings are reported in the Archives of Neurology.

Although team leader Thomas Rea admits, "We did not find any evidence of protection," the article says the researchers are not ready to give up on statins. They've changed their focus now to this thought, from Arizona researcher Larry Sparks: "Maybe if you start giving these drugs when people are 50 instead of 75, you'll get a better effect."

Statin manufacturers must love these guys...

The question has to be raised at some point: are they looking for a cure for Alzheimer's, or are they really trying desperately to prove something about statins?

Please also note, these calcification studies are not looking at BAV- or illness-induced calcifications, as they don't appear to be of a similar genesis to senile calcification, and show even less prospect of being positively affected by anticholesterol medications.

Best wishes,

 

[MrP]

Indeed, there are studies looking at pleiotropic effects of statins to treat BAV (and aortic disease, including aneurysms).

Please also note, these calcification studies are not looking at BAV- or illness-induced calcifications, as they don't appear to be of a similar genesis to senile calcification, and show even less prospect of being positively affected by anticholesterol medications.

Researches in the Netherlands are looking at effects of statin in treating BAV....see http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=437

"Prospective Randomized Trial of the Effects of Rosuvastatin on the Progression of Stenosis in Adult Patients with Congenital Aortic Stenosis."

Also, the following paper from researchers in Toronto is available for a small fee, "Can statin therapy alter the natural history of bicuspid aortic valves?"...."However, a question that has probably crossed the minds of many is whether statins, by virtue of their powerful cholesterol-reducing and pleiotropic anti-inflammatory and immune modulatory effects can change the natural history of BAV disease if introduced early?" See link below.

http://ajpheart.physiology.org/cgi/content/citation/288/6/H2547

Closing paragraph, "Clearly, it would be an attractive proposition to suggest that early intervention with a widely used and relatively safe pharmacological agent could alter the natural history of the most common congenital cardiac abnormality. We believe that the time has come for cardiac surgeons and cardiologists to evaluate this premise, initially in a small select group of patients, to test whether statin therapy will hold the same promise of disease modification in BAV as it has in the world of atherosclerosis. However, it is important to stress that there remains a lack of knowledge regarding the natural history of the disease. The notion that 1–2% of the population has a BAV is based on large autopsy database studies. Clinically, the problem is even more complicated because transthoracic echocardiography may not be sensitive enough to identify the presence or absence of a BAV. The time required for a competent and nonstenotic BAV to calcify is unknown."



Although not specific to BAV patients but nevertheless interesting, there's a recent research paper entitled, "Statins: A Valuable Tool for the Prevention/Regression of Abdominal Aortic Aneurysms"...see link below.

http://www.ingentaconnect.com/content/ben/vdp/2006/00000003/00000001/art00007

And the url link below describes findings at Yale that indicates oddly enough, as Bob pointed out earlier, there's a significant association of decreased calcium buildup in those with ascending aortic aneurysms.

http://www.yale.edu/opa/newsr/05-09-13-02.all.html

more to come.....

 

[MrP]

From what I've read, an increased dosage of 40mg shows the most promise.

I am on Lipitor solely because of some calcification on my aortic valve. I've had my mitral valve replaced because of rheumatic heart disease. My cholesterol has always been low (about 122). My electrophysiologist wanted me to try the Lipitor, so I did. I started out on 10mg. a day but decided to go to 5mg. a day. I wasn't having any problems with muscle cramps or stuff like that but rather with gastro problems. I'm not having any problems on the 5mg. a day and figure it can't hurt. Don't know if it will help though either. LINDA

 

[tobagotwo]

The Netherlands study is not underway. It was proposed for November of last year, but is not listed in the active studies on that website (0 resulaten gevonden voor ISRCTN56552248 in trials). I hope it does get funded and done.

The genetics I posted about are the genes of the cells which are altered - in what is called the pleiotropic effect, where the cells grow ("turn") to perform a function based on the effects or effect ripples of the stimulatory agent (statin, in this case), rather than the developing in the form or function expected. This is/was just a different way of stating the same thing that was quoted as a definition. "A study of the effects of statins' interactions with CRP and their effect on cell characteristics" was and is a valid description of the study. The study does not show or attempt to show that statins reduce the amount or rate of calcification. It discusses the reduction of C-reactive protien on the surface of the valves, natural and replacement.

The Greek paper (Ingentaconnect: $51 to those who are interested) states that "Statin therapy has been demonstrated not only to prevent expansion, but also to reduce aneurysmal size." The miracle drug for aneurisms is Cozaar, which is a combination of Losartan potassium and hydrochlorothiazide. Cozaar is not a statin.

The other papers are position papers, again based on atherosclerosis being causative or caused by the same agents as valvular calcification, even though the two are often exclusive of each other in BAV patients. The differences in development are also apparent to the Totonto group proposing the study, "However, it is important to stress that there remains a lack of knowledge regarding the natural history of the disease."

The Yale study discusses the high percentage of BAV patients who lack the atherosclerosis prominent in their peers. It doesn't talk about a lessening of calcium buildup in BAV patients - as many BAV owners with heavily calcified valves and otherwise intensely clean arteries will attest.

Atherosclerosis is an amalgam of materials, mostly spongy in nature, and not primarily a buildup of calcium. Valvular calcification is primarily a buildup of apatite (calcium, phosphorus, and other impurities) with some of those sclerotic components present in lesser amounts. Aortic apatitic calcification is very hard and brittle, much like the crust that forms on showerheads in areas that have hard water.

Best wishes,

 

[MrP]

With regards to statin treatment for aortic stenosis, I like to think that there remains hope.

Here's a great article from the European Heart Journal, entitled "Statin therapy of calcific aortic stenosis: hype or hope?"

http://eurheartj.oxfordjournals.org/cgi/content/abstract/27/7/773

The rationale for treatment with statins is clearly outlined. "Targeted drug therapy to prevent the progression of calcific aortic valve disease should ideally be based on the knowledge of risk factors and the molecular pathogenesis of the disease. Intriguingly, statins may influence both risk factors and inflammatory pathways by lowering lipid levels and exerting anti-inflammatory properties, respectively. The term ?pleiotropic effects? is used to denote beneficial cholesterol-independent statin effects. These pleiotropic effects include anti-oxidation, improvement of endothelial function, anti-thrombotic actions, plaque stabilization, reduction of the vascular inflammatory process, and modulation of the T-cell activation."

The mechanism of action of statins is described in detail.

Inflammation as a therapuetic target of statins in valve calcification is reviewed in detail. "In conclusion, administration of statins may be able to tackle several inflammatory pathways leading to valve calcification..."

In vitro studies and animal studies are reviewed. Clinical studies and further directions of research are discussed. Many retrospective studies are reviewed as well. The SALTIRE (Scottish) trial is discussed in detail, including limitations of the SALTIRE trial and a good perspective on what was learned from this trial. Results of the ASTRONOMER and SEAS trials are eagery awaited.

"Further research should concentrate on the basic mechanisms involved in the pathogenesis of the disease."

"In summary, the concept of medical therapy of calcific aortic stenosis remains debated. Although, a major recent study showed no benefit of statin therapy, there is still hope that the disease may not represent an irrevocable destiny. The results of the ongoing trials are awaited eagerly. Meanwhile, patients with calcific aortic stenosis should be managed according to national and international clinical guidelines."

I like the concept of hope.

 

[tobagotwo]

Hope doesn't need to rest on statins, or any other current drug. Wanting a thing to be so and feeling it ought to be so, don't make the thing so.

There will eventually be other compounds that will be more effective than statins on c-reactive proteins, which you already realize are much more accurate measures of heart and artery danger than cholesterols.

There may come an understanding about how valves calcify. There may be a compound that is "painted" onto valves via catheter, or an anticalcification treatment that lasts 30 years that makes one replacement biological valve a permanent fix for a larger set of the population. There may be a carbon valve developed that is so slick, it doesn't need anticoagulation therapy.

I believe in hope, too. I just don't find compelling evidence, either scientific or anecdotal, that statins are an answer for calcifying valves. As this latest Europaper states, "Although, a major recent study showed no benefit of statin therapy, there is still hope that the disease may not represent an irrevocable destiny." There is no reason to believe that hope is gone if this drug set doesn't prove to be the answer.

As the paper also states, "Meanwhile, patients with calcific aortic stenosis should be managed according to national and international clinical guidelines."


Best wishes,

 

[MrP]

Thanks Bob for all your words and time. My hopes are centered around what's best for others and our children. My mechanical valve and prosthetic aorta will last long enough to get me to the end.
I must say I continue to believe the jury is indeed still out on the use of statins to treat this disease. Regardless of whether or not statins prove to be a valid therapy, I have faith in the scientific method and know that the "axiomatic cum pragmatic epistemology of science" (thank you F.A. Matsen!), will prevail in the end. Good medical trials, like good physics experiments, must yield results that can be replicated by others and ultimately give us better understanding and insight into our world and physiology. One study does not make good science, as you'll no doubt agree. The ASTRONOMER and SEAS trials will at a minimum validate results of the SALTIRE trial, or indeed results may show the antiinflammatory effects of statins may make a difference in treating calcified aortic valves. I really think it is a stretch to think there will be a drug to reverse severe calcification of aortic valves (like the use of vinegar to clean your coffee maker), but we may get lucky some day and be able to treat this disease early on in detection before too much damage results...perhaps even with statins.
As for me...I am a fixed-up BAV patient...confirmed clean coronary arteries and remaining aorta...consistent with other BAVers and Yale findings...but high LDL cholesterol (family history of high cholesterol). I used to live without concern for my BAV..read plenty of cardiovascular risk factors until recent years. Not sure why BAV patients are excluded from some of these trials but hope the Netherlands trial is completed. I'll have to write to those folks and find out what's really going on. Three's still so much to learn!
Best,
MrP