LDL cholesterol and carbohydrate, which is the lesser evil (Part II)

（這系列 posts 是看了這個 video 寫的，所以看了這個 video 再讀才有意思）

https://www.youtube.com/watch?v=pzgC3aSqqtk&feature=youtu.be

Plaque, and plaque only, is the thing。 引起冠狀動脈阻塞的原因是血管形成 plaque. 一般公認 （with few disagreements) plaque 形成的原因是 血管壁有發炎 （inflammation) 或 某種損害 （damage) 不再光滑導至 LDL cholesterol got caught/stuck there or embedded (underneath 血管壁）因為 LDl cholesterol 停留在不應存在的地方 導致身體發動 “self defense” 反應，a cascade of very complicated processes that 包括 inflammation.

我不知道這個 video 的醫師是何方人物，但是他們談到 plaque 形成的原因是跟主派 一模一樣的（main stream, 即相信 LDL cholesterol 是導致冠狀動脈阻塞的主因）下面是他們所說的（我聽了幾遍，所以幾乎是 word by word):

“When the artery wall becomes damaged or inflamed, LDL does exactly what it is supposed to do, it brings cholesterol to help the healing process, that if the small LDL [called type B] gets damaged by oxidation, it can penetrate the artery wall, if the inflammation and oxidation continue, the plaque will form.”

所以兩派的人都提到 LDL cholesterol 及 inflammation （這些人說只有 small molecule LDL 才會作怪，這一點大家都同意，但是臨床上沒辦法知道）可是我不了解他們為什麼只怪 inflammation 而對 LDL cholesterol 視而不見. The best analogy: Johnny 看到了一個房子的窗戶破裂了，他就爬入屋內偷東西, 你只說 「偷東西」（inflammation) 而不怪 Johnny (LDL cholesterol)

仔細檢查 plaque 的成分（成分很多，因為 self defense 引起的 inflammation 動用了很多「軍馬」但是包括很多 lipids, 即LDL cholesterol.

既然大家都同意 inflammation plays a big role in the formation of the plaque，那麼吃那些關節炎的藥 （non steroid anti-inflammatory drugs or NSAID) 應該有效，結果是不但沒效，反而會引起 heart attack。下面是 FDA 對所有的 NSAIDs 的 warning：

“NSAIDs cause an increased risk of serious cardiovascular thrombotic events [即血管有血液凝結引起阻塞］，including myocardial infarction I or heart attack”

Go figure！

New England Journal of Medicine (NEJM) 9/21/2017 有一篇重要的文章 （Antiinflammatory Therapy with Canakinumab for Atherosclerosis) canakinumab 是一種 monoclonal antibody targeting interleukin-1β （interleukin-1β plays a big role in inflammatory process) 這是一個 randomized, double-blind trial，共有 10,061 病人參加，48 months later 証明 降低 inflammation (independent of lipid-level lowering, 即跟 LDL cholesterol 是否降低無關）可以減低冠狀動脈阻塞。那些唱反調的人一定非常高興看到這個報告：因為只要降低 inflammation (用C Reaction Protein or CRP test 來証明 inflammation 確有減低）不用降低 LDL cholesterol level 就可以避免或減少冠狀動脈阻塞。

Dr Paul Ridker 是這篇文章的主要作者，Scientific American 1/1/2018 有一篇文章(The Messy facts about Diet and Inflammation), 其作者有訪問 Dr Paul Ridker：

「When I asked Ridker his views on anti-inflammatory diets, he grew uneasy, “This has caught on like wildfire,” he says, “but I have seen extremely little data that says this piece of food is ‘anti-inflammatory.’” He advises his own patients to eat a Mediterranean-type diet, heavy on vegetables, whole grains and fish and light on red meat and processed foods.” (Sorry, Charles, 嚕蛋三層肥肉 was not on Dr Ridker’s recommended list)

我看你們越讀越糊塗了, 這不是我的錯，這個 topic 本來就是如此，我只是希望你們的 confusion is at a higher level, then the purpose of this writing is served.

(看官請看下回分解）

How does heart attack happen? It is not as simple as you thought

A good friend (Lily Chen) sent me a YouTube, saying “myocardial infarct is not caused by obstructing coronary artery after all” (原來心肌梗塞不是心臟血管太狹窄堵塞血不流通).  This is the most important discovery in cardiology the past 15-20 years.  I have mentioned this in my blog shortly after the TV journalist, Tim Russert, had a sudden death while recording voice-over in 2008.

http://doctorjytsai.blogspot.com/2008/06/untimely-death-of-tim-russert.html

But, the statement of “myocardial infarct is not caused by obstructing coronary artery after all” (原來心肌梗塞不是心臟血管太狹窄堵塞血不流通) is not the whole truth; I will elaborate since it is such an important, almost revolutionary concept.

The evolutionary concepts of heart attack

Some of the material of this post comes from an article (with a title of “Coronary Thrombosis”) in June 1, 1950 issue of Scientific American, written by Dr. Paul White, a cardiologist at Massachusetts General Hospital, a Harvard Medical School professor.  Dr. White was most famous for being the doctor for President Eisenhower when he was stricken by heart attack in 1955.

The sudden death of a seemingly healthy man/woman was considered an act of gods over the age; he or she must have done something terribly bad to evoke the wrath of gods.  Back in 1700 a French physician, Theophile Bonet, had proved complete blockage of coronary artery in one person who died suddenly.

Lancisi, Pope Clement’s physician, also proved those who had a sudden death all died of natural causes by doing post-mortem examinations in 1707.  President Eisenhower had a first-rate physician, so had Pope Clement.

The artery is more animated and dynamic than a pipe

It is logical to think the cause of heart attack (myocardial infarct) is caused by the progressive narrowing (stenosis) of coronary artery until complete blockage, just like the clogging of the pipe under the sink.

Doctors had the second thought when it was discovered that most of the heart attacks occur in the setting that there was less than 50% blockage.  Subsequent studies learned that the plaque builds up in the inner lining of the coronary artery over the years or decades, and it is the rupture of the plaque, leading to formation of clot (thrombus) that completely blocks the artery.

The cardiologists are dealing with a more animated and dynamic coronary artery, not a pipe; they would prefer leaving the "honor" of being called a "plumber" to urologists.

The blocked artery cuts off the blood supply to the heart muscles (myocardium) distal to the point of blockage, leading to the necrosis/infarction/death of the heart muscles; the ischemia (compromise of circulation) may trigger the lethal ventricular arrhythmia.

Plaque, and the plaque only, is the thing

Atherosclerosis (hardening of arteries) begins at the build-up of the plaque in the inner lining of coronary artery many years or decades before the heart attack strikes.

(The above photo is taken from an article in New England Journal of Medicine)

The top panel shows most of the plaques initially expand outwardly, causing little or no narrowing of the lumen of the artery.  But, given enough time it will grow inward causing the stenosis (narrowing) of the lumen.  As a matter of fact, most of the plaques rupture when they cause some degrees of narrowing, all be it less than 50% stenosis in most cases.  The rupture leads to clot (thrombus) formation that blocks the artery.

The bottom panel shows a large inwardly grown plaque significantly narrows the lumen of the artery and a tiny clot (thrombus) will completely blocks it.  A disruption of the endothelial cells in the inner lining is called “erosion” that produces the same effect of “rupture”.

The middle panel shows if one survives the rupture/erosion of the plague, a scar will be formed, constricting the artery, causing narrowing of the lumen (stenosis).  A fibrotic (with deposition of calcium) plaque may be more stable, not vulnerable to rupture. But one will be symptomatic with chest pain upon exertion; for exercise will increase the demand of more oxygen for myocardium that a narrowed artery cannot meet.

Why a non-obstructive plaque is more dangerous than an obstructive one?

If a growing plaque pushes inward causing the narrowing of the lumen of coronary artery, thus compromising the circulation, in which case one may develop chest pain upon exertion (called angina) and seeks medical attention.

If an outwardly expanding plaque ruptures before causing the narrowing of the lumen, then one will never have any symptoms (chest pain/tightness/pressure or shortness of breath) until the heart attack strikes.

Cholesterol, plaque and statins (cholesterol-lowering drug)

Lipids (cholesterol) are the major components of the plaque.  The benefits of taking statins, the likes of Lipitor, Pravachol, Crestor and Zocor, are not only lowering the LDL (bad cholesterol) level, but “stabilizing” the plaque as some theories suggest.

From 2003 to 2013, the death rate from heart attack fell about 38% according a CDC data.  One cannot say doctors are not doing good jobs.  The reasons are multifactorial, but statins should get the most credits in my view.

Mild disease of the coronary artery may not be a good thing

So if a plaque is present (i.e. one has atherosclerosis or hardening of artery), what matters is not how much it blocks the artery, but how stable it is.

If one does cardiac catheterization (with injection of contrast the coronary arteries can be visualized) it shows “mild” disease, say showing 15% or 30% or anything less than 50% stenosis, one needs to be treated as aggressively as the more severe cases.  One school of thought is that a larger plaque that causes more narrowing of the lumen may be more stable, thus less vulnerable to rupture.  Unfortunately one cannot tell a plaque is a stable one or not on cardiac catheterization.

That is not to say the more narrowing of the artery the better.  If one has a large plaque that causes severe stenosis, say greater than 75%, if it were to rupture, a small clot (thrombus) will completely block the artery easily.  Conversely a small stenosis, say less than 15% will take a relatively large clot to block the artery.

(The above photo is taken from Dr. Paul White’s article, “Coronary thrombosis” in Scientific American)

This is to show prescient Dr. White was.  There is a heart disease called Wolff Parkinson White (WPW) syndrome, that “White” is Dr. Paul White.  Keep in mind that Dr. White wrote this article in 1950.

Dr. White wrote,

“It is always in a diseased, badly narrowed, atherosclerotic coronary artery that a thrombus, or clot, rather suddenly forms one day to present the clinical picture which we call coronary thrombosis.”

What he wrote in 1950 is still 100% correct today.  He knew the clot forms rather suddenly on top of a “diseased, badly narrowed, atherosclerotic coronary artery” that built up over the years or decades.

A disease free coronary artery is one clean without plaque.  A coronary artery that has plaque is not disease free even though it has no narrowing/stenosis of the lumen.  Thus no plaque, no narrowing, no rupture, no heart attack!

Dr. White wrote,

“. . . The stage is all set before the thrombus is laid down in the diseased artery.  Just how the blood is triggered to clot is not yet fully clear. Most often, perhaps, a thrombus begins to form on a roughened bit of the inner lining of the artery, or at a very much narrowed place in the vessel. Within minutes or hours the thrombus grows large enough to block the blood flow and to cause the various symptoms and signs that follow.”

What Dr. White described in 1950 was similar to what we call plaque rupture leading to clot.

How the blood clot (thrombus) forms after plaque rupture?

The mechanism of how clot was formed that triggered heart attack was not fully elucidated in Dr. White’s time (1950s), but it is well understood now.  We even had thrombolytic therapy (medicines to dissolve the clots). One needs the full knowledge of coagulation cascades to fully understand the mechanism; it is beyond the scope of this writing.

Suffice it to say that platelets play a crucial role in clot formation; that is why anti-platelets aggregation (preventing platelets to lump together) drugs, such as aspirin and Plavix (clopidogrel) are so important in treating and preventing heart attack.

The following is the YouTube that Lily Chen sent to me.  Dr. 洪惠風 did a good job, telling the complicated story in less than five minutes.  This writing is to further explain; less people would misunderstand and take “narrowing of coronary artery” (心臟血管太狹窄) out of equation in causing heart attack.

In fact, about 5 to 15% (depending on which report one reads) of the heart attack are caused by steadily progressive narrowing of the lumen to the point of complete occlusion by plaque that never ruptured.

為什麼心臟病總是突然發作洪惠風主任

http://m.youtube.com/watch?feature=youtu.be&v=Ab5DpN8hNNk

The reputation of HDL as a good cholesterol is crumbling

We have been led to believe that those who are endowed with high HDL have low risk for heart attack.  But the foundation of that concept seemed to be falling apart with the recent studies.

There is no controversy about “reduce LDL (bad cholesterol), reduce heart attack”; this has been proved by numerous studies.  Pfizer’s Lipitor reduced heart attack by one third.  With most statins became generic, the big pharmaceutical companies have an eye on HDL, aiming to further reduce the residual risk left by the statins.  And this is how they ran into trouble.

Last December Merck announced their raising-HDL drug (Tredaptive) failed to reduce the heart-disease risk compared with taking statin alone.  Tredaptive is niacin combined with a drug that prevents the flushing adverse effect of niacin.

Scientists are at loss to explain this discrepancy.  Theories abound.  May be not all HDL are created equal; the one raised by drug may not be the same as the one made by one’s genes.  May be the HDL got unduly credit for the protective effect; may be some unknown conditions that are associated with high HDL do the job.  And so no and on.

Many experts still believe the ‘good HDL hypothesis”; the epidemiology studies are hard to refute.  But, Dr. Kathiresan from MGH (Massachusetts General Hospital) is not so sure.  About 2.6 percent of the population has a variation of the endothelial lipase gene that gives higher HDL.  In the Lancet article (published online 5/17/12 and print 8/11/12), Dr. Kathiresan (and numerous authors) reported that they found absolutely no association between the HDL-boosting variant and risk for heart disease.    This was also reported in a 5/17/12 New York Times article.

I am reluctant to write medical news like this, lest the public get more confused.  But this is the true spirit of evidence based medicine; the real science is backed by good data.  Science is to get to the bottom of the truth; science is not afraid to tear down the ‘truth’ of what we used to believe.

We should keep open minded in this puzzle; the dust hasn’t settled yet.

Broken Heart Syndrome: 哀慟欲絕 = 碎心症

I gave a talk in the Taiwanese Bible Study (in Pittsburgh) on Nov. 26 and Katy wrote a report sending to the World Journal (世界日報).  I’ll continue to post what I talked.  Here is the Broken Heart Syndrome.

Broken heart syndrome mimics acute myocardial infarction (heart attack); it was first reported in Japan in 1991. Over the years I had my doubt.  Patients had acute heart attack following acute emotional distress in most of the cases, such as upon hearing an unexpected death of a loved one, encountering an armed robbery or death threat, or a car accident, etc.  I thought these patients must have had significant or critical underlying coronary artery disease (CAD) before encountering these events, which just simply push him or her off the cliff.  Now I am convinced I was wrong.

 

The classic heart attack occurs following the total occlusion of a coronary artery, but the coronary arteries prove normal and patent in the coronary angiography (done thru a cardiac catheterization) The above photo was from New England Journal of Medicine (NEJM) reporting a 93-year-old lady with heart attack.  No acute emotional stress prior to the onset of heart attack.  But she had another heart attack 4 years earlier that followed a colon surgery.

It is also called Apical Ballooning Syndrome as all the cases have apical diskinesia (the apex of the heart—left ventricle—fails to contract during the systolic/contraction phase that leads to a characteristic finding seen in cardiac catheterization.  It looks like tako- (octopus) tsubo (pot), the octopus catching pot used in Japan, hence the name of Tako-tusbo cardiomyopathy.  

The left lower panel of the above photo shows the heart (left ventricle) in the diastolic/relaxing phase, and the right lower panel systolic/contracting phase.  One will see the apex of the left ventricle fails to contract (akinesia—kinesia means motion, thus akinesia means no motion, no contraction), yielding a takotsubo shape. 

The presentation of the Broken Heart Syndrome is very similar to classic acute heart attack (chest pain, shortness of breath, characteristic EKG changes, etc.), except troponin (an enzyme released from the damaged heart muscles) may be normal or only mildly elevated.  The temporary heart (left ventricle) dysfunction often improved within days and complete recovery in 6 weeks in majority of the cases, whereas the classic heart attack often leads to a more permanent damage and more lasting dysfunction.

The suspected theory is too much catecholamine (adrenaline and noradrenaline) that “stun” the heart leading to temporary heart muscle dysfunction.  The detailed mechanisms remain elusive.  This theory gives another name of this disease (Stress-induced cardiomyopathy).  

This disease has been recognized as a distinct disease entity in the States as well as in the Europe.  It must have been around for ages, it was just never recognized until 1991, thanks to the Japanese doctor, whoever (s)he is (I haven’t got time to do the search yet).  The ICD-9-CM code is 429.83.  The frequency of which is unknown, some estimate it may comprise of up to 1-2% of all heart attacks.  Theoretically it can be fatal, although the mortality is also unknown.  驚死 (scared to death) is real!  So for the sake of your heart, don’t worry, be happy. 

Broken heart has been around in literature for ages, medicine lags behind and finally catches up; medicine imitates literature/art.  柔腸寸斷 (tender bowel broken into pieces) is another Chinese literary term to describe the one stricken with extreme despair, sorrow, grief and despondency (哀慟欲絕).  I am afraid that it may be a long while for medicine to come up with a disease entity to fit “柔腸寸斷”, if it ever can be.  It may sound condescending, but it also tells the more imaginative and abstract nature of Chinese literature.  

The followings are reports of Broken Heart Syndrome from various prestigious medical journals or institutions in the US and Europe.

  

Cholesterol: the most highly decorated molecule in biology

In my “The omnipotent and omnipresent carbon and why organic chemistry is essential to doctors” post, I basically said carbon atom is the most highly decorated atom.  Dr. Michael Brown and Dr. Joseph Goldstein said, in their 1985 Nobel Lecture, that “cholesterol is the most highly decorated small molecule in biology.  Thirteen Nobel Prizes have been awarded to scientists who devoted major parts of their careers to cholesterol.”  (Dr. Brown and Dr. Goldstein identified cholesterol LDL receptor and the mechanism of LDL receptor endocytosis, that which is also seen in other molecules.)

(The photo is from Brown and Goldstein’s Nobel Lecture illustrating LDL receptor-mediated pathway of cholesterol homeostasis.)

The 1928, 1939, 1947, and 1950 prizes were awarded to the work that led to the elucidation of cholesterol structure.  Otto Diels’ Nobel Lecture in 1950 began with “Cholesterol was discovered as long ago as 1789”.  I have mentioned Diels-Alder reaction in the synthesis of the 6-carbon aromatic ring, which cholesterol has.

The 1964 Prize went to the study of the cholesterol biosynthetic pathway that involves no less than 30 steps, and this was followed by the award in the following year (1965) for stereochemical synthesis of cholesterol.  The 1969 Prize went to the concept of conformation, which is important in stereochemistry and the work was done on cholesterol.  The 1975 Prize also went to stereochemistry and enzyme-catalyzed reactions and establishes the orientation of all of the hydrogen atoms in cholesterol molecules.  And of course, 1985 saw the Nobel glory of Brown and Goldstein.

I think the honor of the most highly decorated molecule has since been replaced by DNA, and that will be another boring post that you have to endure.