Dr. Sandler's 50-Year-Old "How To Prevent Heart Attacks" Has Grown Weak with the Passage of Time

In the late 1950s, physician Dr. Benjamin Sandler published a monograph titled "How To Prevent Heart Attacks".  At the time of its publication, a debate was raging regarding the etiology of myocardial infarction (the medical term for "heart attack").  It was generally agreed upon that coronary atherosclerosis (hardening/thickening of the coronary arteries) and coronary thrombosis (blood clot formation) were somehow associated with myocardial infarction (MI) but there was no consensus regarding exactly how these conditions were pathophysiologically related.  Some believed that heart attacks occurred as a consequence of coronary thrombosis while others believed the opposite, that coronary thrombosis was a consequence of heart attacks.  The first few pages of this paper describe the controversy in more detail:  The Early History and Development of Thrombolysis in Acute Myocardial Infarction.

Dr. Sandler held the latter view.  He believed that a sharp and sudden fall in blood glucose, either relative or absolute, was the "immediate precipitating cause" of heart attacks.  Coronary thrombosis occurred in the aftermath, particularly in arteries more severely affected with atherosclerosis.  According to Dr. Sandler, the heart, like the brain, relies exclusively on glucose for energy production.  If blood glucose were to decrease rapidly, oxygen consumption by the heart would also decrease rapidly because the heart uses oxygen together with glucose to generate energy via aerobic respiration.  In other words, the heart has no need to take up a lot of oxygen when glucose availability is low.  A precipitous fall in glucose and oxygen uptake leads to the accumulation of lactic acid in heart muscle (myocardium) since glucose can now only be "burned" anaerobically (glucose => pyruvic acid => lactic acid).  The lactic acid build-up causes a portion of the heart muscle to go into a sustained cramp and the branch of the coronary artery passing through the cramped area will become kinked causing an obstruction of blood flow.  If the kinked coronary artery is particularly atherosclerotic and the cramp is significantly prolonged, a thrombus will form.  Otherwise, the sufferer will experience an MI with no thrombosis or even thrombosis with no MI.  Dr. Sandler recommended a diet low in carbohydrates because he believed consumption of sugar and starch resulted in the wild blood glucose swings which could lead to heart attacks.

Dr. Sandler based his theory on several facts/observations known at the time:

• Many people have coronary atherosclerosis yet only a relative few suffer recurrent chest pain (angina pectoris) and/or fall victim to a heart attack.  In fact, extensive atherosclerosis is found during autopsies in people who never suffered a heart attack.
• A heart attack can occur with or without coronary thrombosis, and coronary thrombosis can occur without a heart attack.
• Normal coronary arteries have been found on autopsy in individuals who experienced angina pectoris in life.
• Angina pectoris and heart attack pain come on suddenly and can wax and wane over hours, days, or even months, but coronary atherosclerotic lesions are relatively static; hence the condition of the arteries themselves can not adequately explain angina and heart attacks.  Unsteady blood sugar levels offer a much better explanation.  In Dr. Sandler's own words:

"The mechanism causing the chest pain and the eventual heart attack would thus have to be an exceedingly labile one that can come without warning, vary greatly in severity, and disappear spontaneously. Such a mechanism could very readily involve an essential nutrient to the heart muscle which is present in the blood stream, a biochemical dissolved in the blood which is capable of wide fluctuation in short periods of time from normal to abnormal range, and capable of embarrassing the heart muscle during such abnormal fluctuation. There is such a chemical in the blood, an essential nutrient for the heart muscle, essential for normal heart action, which must be available to the heart, every moment of life in order to permit the heart to beat around 70 times per minute, in the adult during rest, for every minute of life. This chemical is called the blood glucose or blood sugar."

First and foremost, Dr. Sandler’s theory relies heavily on his belief that the heart, like the brain*, utilizes only glucose for energy production.  It is now well-established that the heart also utilizes fatty acids, oftentimes as its main fuel source.  In fact, glucose is considered a secondary fuel source for the heart after the fetal and neonatal periods.  So the idea that the heart has an absolute requirement for an unwavering supply of glucose is likely incorrect.  A drop in glucose availability can be met by an increase in fatty acid oxidation if need be.

Fuel metabolism aside, Sandler's monograph really shows its age when discussing the role thrombosis plays in myocardial infarction. It is now accepted by the vast majority of the medical community that thrombus formation over "vulnerable" atherosclerotic plaque is the immediate precipitating cause of most heart attacks.  But it's certainly easy to see why Dr. Sandler and other like-minded individuals of his era doubted that coronary thrombosis caused myocardial infarcts.  Autopsy findings, from which most of the data concerning the etiology of MI came from at the time, were not very convincing; some studies found evidence of thrombi in as little as 21% of fatal myocardial infarctions.  However, post-mortem findings along with older autopsy and histology techniques can be unreliable in determining the role thrombus formation plays in heart attacks.  From The Elusive Clot: The Controversy over Coronary Thrombosis in Myocardial Infarction (I have bolded the arguments more applicable to the topic of this blog post):

"What were some of the factors that might have caused the under-reporting of coronary thrombosis in some of these studies?  1)- Studies that included patients dying within an hour of symptoms must surely have included patients with significant coronary narrowing precipitating fatal ventricular arrhythmias in the absence of an occluding thrombus.  2)- Inadequate serial sectioning, usually performed at 3mm to 5mm intervals along the coronary arteries may have missed some ultra-short occluding coronary thrombi in the range of only a millimeter in length.  3)- There was often difficulty in distinguishing older organized thrombi from other types of pathology in diseased arteries.  4)- The use of different criteria of what constituted an acute myocardial infarction resulted in the inclusion of some patients with minor myocardial or endocardial scarring that did not represent infarctions.  5)- Some investigators excluded "non-obstructive" thrombi, not realizing that these may have represented occluding thrombi that had been partially dissolved by intrinsic fibrinolytic mechanisms."

During the mid-1960s, several investigators claimed that their improved autopsy techniques showed that greater than 90% of fatal myocardial infarctions were associated with coronary thrombi, most of them totally occlusive.  This won some, but not all, over to the side of thrombosis being the immediate causative factor in the majority of MI's.  Many more became convinced in the late 1970s / early 1980s when it was shown that infusion of streptokinase, a drug capable of breaking down coronary thrombi, could restore coronary blood flow and improve patient outcome.  Another seminal study of this time period was that of Marcus DeWood and colleagues who, using coronary arteriography, demonstrated for the first time in live patients the commonality of coronary thrombosis in acute myocardial infarction.

Further study into the nature of atherosclerosis and thrombosis has revealed why a seemingly static atherosclerotic plaque can cause intermittent, unsteady chest pain, and why someone can have coronary atherosclerosis, yet no heart trouble.  The fact of the matter is, all atherosclerosis is not the same.  Some is relatively stable, meaning it builds up slowly over many years and is not prone to the rupturing which leads to thrombus formation.  This general category of atherosclerosis can lead to heart problems like stable angina or even MI but oftentimes it's essentially benign.  The atherosclerotic coronary arteries seen in the Masai of Africa are a good example of this.  However, a second general type of atherosclerosis, called vulnerable plaque because of its tendency to rupture, can cause the waxing and waning chest pain Dr. Sandler attributed to unstable blood glucose.  When thrombosis is triggered by vulnerable plaque rupture, the blood clot that forms can be broken down by "endogenous lysis" and then form again.  This transient lysis and formation of a coronary thrombus is responsible for the waxing and waning pain of unstable angina.  If the balance between the two states favors clot formation, then the resulting total occlusion will lead to MI if the lack of blood flow persists for a sufficient amount of time.  When Dr. Sandler suggested that unstable blood sugar provides a better explanation for the intermittent, "labile" pain of angina pectoris than the condition of the coronary arteries themselves, this information about the waxing and waning nature of coronary thrombi was not known.  From CORONARY DISEASE: The Pathophysiology of Acute Coronary Syndromes:

"It is difficult now to perceive why coronary thrombosis was regarded 25 years ago as an inconstant and irrelevant consequence of acute infarction rather than its prime cause. Once angiography was carried out soon after the onset of infarction, and it was realised that the subtending artery was totally blocked but spontaneously reopened with time in many cases (and that this reopening was accelerated by fibrinolytic treatment), thrombosis was seen as a major causal factor in occlusion. Suddenly the clinical world found thrombi to be both dynamic and important. Pathologists had thought thrombi were important but did not realise how dynamic they could be."

Although it's clear that Dr. Sandler's theory doesn't hold up exactly as written, is there any credence to it at all?  Moderate to severe hypoglycemia can increase certain aspects of heart function such as heart rate, peripheral systolic blood pressure, and myocardial contractility, so it can be argued that someone with a compromised heart could experience deleterious cardiac consequences if their blood sugar plummets.  There is a case report that features the experiences of a woman who sometimes has chest pain when she's hypoglycemic, but this is balanced by the case report of a man who experiences chest pain when he's hyperglycemic.  It's been shown that patients hospitalized with acute MI who experienced episodes of hypoglycemia had increased mortality compared to MI patients who did not experience hypoglycemia, but only if their hypoglycemia was spontaneous (not caused by insulin therapy).  MI patients whose hypoglycemic events were brought about by overly-aggressive insulin therapy had no increased mortality risk.  Spontaneous hypoglycemia is an indication of a more fragile metabolic state so it's not very surprising that it would be associated with an increased risk of death.  However, this does not mean hypoglycemia is the cause of the increased risk; the fact that there was no increased mortality in the insulin-induced hypoglycemic patients demonstrates that low blood sugar per se is probably not harmful.  This tells me that the case for hypoglycemia-induced angina and MI's is not particularly strong, although it may occur in certain individuals.

Why is all this important?  Myocardial infarction, unstable angina, etc. are not medically treated according to Dr. Sandler's ideas regarding unsteady blood sugar (although I have nothing against his dietary recommendations per se), but are treated as pathologies of the coronary arteries/thrombosis which science has made a very strong case for.  I think the harm may come from the fact that some people believe Sandler's theory is absolutely true; I've seen it around the internet.  The danger, IMHO, is that one of these people, when experiencing suspicious chest pain, may decide to treat themselves with diet or maybe even acutely with the proverbial glass of orange juice that diabetics are told to take when their blood sugar gets too low.  When it comes to myocardial infarction and related conditions, getting evaluated and treated quickly by licensed medical professionals is of the essence.  A few hours, even a few minutes, can mean the difference between life and death.


*Under “normal” mixed diet conditions, the brain essentially relies upon glucose exclusively. Under very low carbohydrate conditions, the brain relies more and more on ketones although it still has an absolute requirement for a small amount of glucose. However, the brain, unlike the heart, cannot directly utilize fatty acids for fuel.

Lifting Weights Makes Your Heart Unhappy Says Trainer-to-the-Stars Tracy Anderson

For those of you who don't know, Tracy Anderson is currently one of Hollywood's most in-demand fitness trainers for women. She promises that strict adherence to her special method of diet and exercise will result in a "teeny-tiny" feminine physique. She is most famous (or infamous) for stating that women should never lift more than 3 pounds because that will create bigger, bulkier arm muscles. Instead she recommends all women work their arms like this: Teeny-Tiny Arms Series. In addition to traditional weight lifting, Tracy has also railed against yoga, running, pilates, and just about any other form of exercise that is not the Tracy Anderson Method because they all can cause unsightly muscle growth. Of course, it can be argued that muscle growth is a perfectly natural adaptation to training, but Tracy could always counter with the argument that callus formation is a perfectly natural adaptation to friction but who wants big old nasty calluses all over their bodies? So there you have it.

If the whole "bulky, manly muscles" thing isn't enough to deter women from ever lifting anything much heavier than a can of soup again, Tracy has now revealed in her newly-released, thoroughly unreferenced book Tracy Anderson's 30-Day Method: The Weight-Loss Kick-Start that Makes Perfection Possible that weight lifting is downright unhealthy for your heart. On page 28 she writes: "...you're building muscles that are more prone to injury. You're tearing down your joints. You're destroying your structure. And your heart probably isn't happy about it." And before you think that yoga is safe, consider this pertinent piece of information again from page 28: "...too much Downward Dog can lead to vascular damage."

And on that note, I'm going to start getting my affairs in order. I've been lifting weights and practicing yoga for close to 20 years; a heart attack is surely around the corner! I just hope they make caskets big enough to accommodate my bulked-up corpse...

;~)

In Defense of Glyceroneogenesis Researchers (not that they really need it)

A few days ago, Jimmy Moore aired an interview he did with Gary Taubes in which they discussed a myriad of topics.  Jimmy asked Gary if there was anything he would change in his book Good Calories, Bad Calories based on new information he had come across since its publication. Gary answered that he wished he hadn't stated that dietary carbohydrates were absolutely required to store fat in fat tissue because he has since learned that a process called glyceroneogenesis casts doubt on that assertion.  As someone who has written about glyceroneogenesis and low carb diets, I'm glad Taubes is spreading the word.

What I have a problem with is a comment left at Jimmy's site that comes across as biased against and dismissive of the scientists who elucidated glyceroneogenesis:

"I actually had a look again at one of the so called ‘studies’ explaining this Glyceroneogenesis process in this post:

http://adipo-insights.blogspot.com/2009/09/is-fable-of-unfettered-fat-burning.html

This study is basically flawed, even a layman like me can see things such as the fact that the test subjects were not keto-adapted and I believe that a total different set of rules apply for people who are not keto-adapted. There are some other flaws too, and I think at the end the basic biochemistry that Gary mentioned to in GCBC will carry more weight (take up a bigger part of a pie-chart of total processes) at the end."

I'm not sure what study this person is referring to since I didn't reference any study (i.e. primary research) concerning glyceroneogenesis, only two review papers, but the quotation marks around the word studies, as well as the term so called, indicates to me that this person believes that the glyceroneogenesis research to date is either worthless, corrupted, laughable, or some combination of the three.  I agree that keto-adaptation may affect the rate of glyceroneogenesis, but the fact that these researchers haven't examined that particular condition yet doesn't make their research "flawed".  These scientists are not trying to prove or disprove any low carbohydrate diet theory; they are trying to understand basic biochemistry.  And yes, glyceroneogenesis, although not well known, is a very important component of basic biochemistry because the ability to re-esterify fatty acids is critical to human metabolism.

I find it more than a bit ironic that an individual who appears to be an ardent fan of Taubes' Good Calories, Bad Calories would criticize the work of researchers who behave similarly to the "real" scientists lauded in the book.  In this article, Richard Hanson, Ph.D., one of the discoverers of the glyceroneogenic pathway, tells us how his and his colleagues' desire to answer an intriguing question, brought about by a scientific observation, led them on the journey to uncover glyceroneogenesis:

"By 1967 it had been well established that both pyruvate carboxylase and PEPCK-C were involved in hepatic and renal gluconeogenesis. So it was a real surprise that year when John Ballard and I found pyruvate carboxylase in adipose tissue, a tissue that did not make glucose. We proposed that pyruvate carboxylase played an anaplerotic role (i.e. it replenished citric acid cycle anions) during lipogenesis in adipose tissue, because citrate efflux from the mitochondria depletes intermediates of the citric acid cycle. This is similar to the function of the enzyme in the liver during gluconeogenesis. We came to the totally incorrect conclusion that there were both mitochondrial and cytosolic forms of the pyruvate carboxylase in adipose tissue. It turned out that it is easy to break mitochondria during their isolation from adipose tissue and thus release the enzyme. In the same year, John and I, together with Gilbert Leveille, reported that adipose tissue also contained PEPCK-C. What was this gluconeogenic enzyme doing in a tissue that does not make glucose?"

And the rest is scientific history.  Something tells me Gary would approve.

Some Thoughts on VLDL, Carbs, & Insulin

A reader asked me to comment on the article below.  He recognized that the author was wrong when he wrote that LDL breaks down into VLDL and was wondering about the rest of the information in the article.  I decided to make my reply a separate post since there is much to discuss here. 

Question: What is VLDL cholesterol? Can it be harmful?

Answer:
from Thomas Behrenbeck, M.D.

Very-low-density lipoprotein (VLDL) cholesterol is a type of lipoprotein. Although you may hear about VLDL, your VLDL level usually isn't reported to you as a part of a routine cholesterol test.

There are several types of cholesterol, each made up of lipoproteins and fats. Each type of lipoprotein contains a mixture of cholesterol, protein and a type of fat (triglyceride), but in varying amounts.

Of the lipoprotein types, VLDL contains the highest amount of triglyceride. Because it contains a high level of triglyceride, having a high VLDL level means you may have an increased risk of coronary artery disease (CAD), which can lead to a heart attack or stroke.

There's no simple, direct way to measure VLDL cholesterol, which is why it's normally not mentioned during a routine cholesterol screening. VLDL cholesterol is usually estimated as a percentage of your triglyceride value. A normal VLDL cholesterol level is between 5 and 40 milligrams per deciliter.

So you can see from this why eating carbohydrates causes your VLDL to rise. VLDL is made up of mostly triglycerides, which require glycerol in order to be formed. The more glycerol present in your body, the more triglycerides your body will have to create. It's interesting that this particular type of triglyceride that effects the LDL is made in the liver.

As we learned in Taubes, when we eat food, it is broken down and all the various acids go to fat tissue first before being added to the bloodstream. So in terms of glycerol, this is added to the bloodstream and once the stream reaches adipose tissue, the glycerol undergoes the esterification process for passage in and out. Esterification is the formation and breakdown of triglycerides. These triglycerides are offered to every cell, muscle and tissue in the body as they travel through the blood stream. All of us should know that we can only have a small amount of sugar in our bloodstream at any point in time -- so this idea that we use all this sugar for energy is nonsensical to say the least.

Anyway, when it makes its rounds through the bloodstream and there are no takers, it goes to the liver where it is sent out on lipoproteins. This is the beginning of breaking the LDL down into VLDL which is a bad thing. This is why you have seen me write that the body sends sugar to one of 4 places in order to get rid of it, not for some beneficial purpose. It's true that our bodies require a steady amount of blood sugar, but this sugar is not that which is derived from eating carbohydrates, regardless of how similar it is in composition. The sugar you eat goes to fat. The liver produces the small amount that we require and anything beyond that requirement either goes to fat or degrades our cholesterol. Under ZC (zero carbohydrate) circumstances, our bodies are perfectly capable of making whatever sugar we require. We are not required to have any of this from our diet.

First I have to say that it is rather suspicious to me that an M.D. would have his "facts" so messed up.  Graduating from medical school certainly doesn't mean you know everything but this is BAD!  For what it's worth, I don't believe this person is really a physician.  An individual can present themselves any way they want on the Internet, and I believe we have ourselves a poser here.

It's difficult to discuss the article point by point since honestly I can't make heads nor tails of it, so I'm simply going to discuss some thoughts I have on VLDL, diet, and coronary artery disease as a whole.  The best way to begin is to explain briefly how VLDL are formed.  Their synthesis takes place in the liver where a molecule of apolipoprotein B-100 (apo B) forms a complex with phospholipids and cholesterol encasing a core of cholesteryl esters and triglycerides.  VLDL function primarily as carriers for triglycerides and as such contain many more triglycerides than cholesteryl esters.  VLDL enter the bloodstream and travel to various tissues, most notably fat tissue and muscle, where they are acted upon by the enzyme lipoprotein lipase (LPL) which releases some of the triglycerides so that they can be stored (in fat tissue) or used for energy production (in muscle).  As they lose their triglyceride cargo, VLDL become smaller and denser and eventually end up as LDL (low density lipoproteins).  This is a very simplified description; if you would like something much more in-depth, I suggest this article: Plasma Lipoproteins: Composition, Structure, and Biochemistry.

As for carbohydrate intake causing fasting VLDL to rise, it often does but this is not necessarily a harmful occurrence.  The amount of VLDL in the blood is the result of the rate of VLDL production together with the rate of VLDL clearance.  It is generally thought that an elevated VLDL level caused by increased production is harmful (or at least associated with harm) while an elevated VLDL level caused by decreased clearance is not.  It all comes down to insulin resistance.

It's often stated that insulin drives VLDL synthesis by the liver; this is a very misleading statement.  Believe it or not, insulin acutely inhibits liver VLDL production, particularly the large triglyceride-rich "bad" VLDL1.  This makes sense because after eating, triglycerides in chylomicrons would be competing for clearance with triglycerides in VLDL.  By slowing down production of VLDL, chylomicrons can be cleared from the circulation more efficiently.  Insulin slows down VLDL synthesis in several ways, the most obvious being via inhibition of fat cell lipolysis so that less fatty acids are delivered to the liver for triglyceride synthesis.  Insulin also exerts several direct effects on the liver itself such as increasing the degradation of apo B.  If an individual's fat cells (some experts assert that visceral fat cells are more important in this regard) and liver are resistant to the actions of insulin, it's easy to see why they would have an elevated VLDL concentration.  It's also interesting to speculate if elevated VLDL triglycerides may merely be a marker for insulin resistance and not harmful to the coronary arteries in and of themselves.  Consider people with the rare genetic condition called Fredrickson type V hyperlipidemia.  These individuals have extremely high VLDL and triglyceride concentrations due to decreased peripheral clearance caused by a deficiency of lipoprotein lipase.  Yet when their vascular endothelial function (an indication of coronary artery disease risk) was compared to subjects with normal triglyceride levels, no significant difference was found.  If VLDL triglycerides per se cause harm to the vascular endothelium, surely people with an average serum triglyceride concentration of 1914 mg/dl would exhibit some measurable degree of endothelial dysfunction over and above individuals with normal triglyceride levels.  Yet they don't appear to.  It's also important to note that Fredrickson type V hyperlipidemia does not seem to be associated with an increased risk of CAD.

Which brings us to the notion of moderately elevated VLDL being physiologically unremarkable when due to decreased peripheral clearance.  It has been shown that carbohydrate-induced hypertriglyceridemia is caused primarily by decreased clearance not increased production, assuming the person is insulin sensitive and the carbohydrates are mostly starches and not sugars.  It's been theorized that this reduction in VLDL triglyceride clearance "may reflect a homeostatically appropriate down-regulation of the LPL activity of skeletal muscle".  In other words, when one consumes a lot of carbohydrates especially without a lot fat, muscles will preferentially switch to using more glucose for fuel and therefore will not need to take up as much fat from the circulation, hence the reduction in skeletal muscle LPL activity.

How high can triglycerides go on a low sugar, high carbohydrate diet and still be considered "safe"?  In my opinion, a triglyceride concentration up to about 150 mg/dl is acceptable based on the fact that several CAD-free populations consuming their native high carbohydrate/low fat diets have such a level.  It's important to note however that the higher the carbohydrate-to-fat ratio, the higher the triglyceride concentration will generally be.  This means that a moderate amount of carbohydrates shouldn't lead to a 150 mg/dl triglyceride level if everything is working as it should.  That level of triglycerides on a moderate carbohydrate diet could indicate insulin resistance.

What this all means in the real world is this:  if an individual who has a fasting triglyceride concentration of 70 mg/dl on a standard Western diet (indicating that they are probably insulin sensitive) begins a high carb/low sugar/low fat diet (let's say 65% carbohydrate, 20% fat) and their triglyceride level elevates to 130 mg/dl, this is most likely a benign, totally appropriate change.  In this case, an elevation of triglycerides is most likely not a bad thing.

The Latest Low-Carb vs. Low-Fat Diet Study is Available Online for FREE!

The much talked about low-fat/low-carb diet comparison study published this month in the Annals of Internal Medicine can be found online for free.  As far as I know, it's not supposed to be free as several bloggers have stated that they had to purchase the full text version.  I've asked Stargazey at Low-Carb for You to confirm if this version is the same as the one she purchased.  She hasn't gotten back to me yet, but it sure appears to be a valid copy.  Here it is if you want to take a look at it:  Weight and Metabolic Outcomes After 2 Years on a Low-Carbohydrate Versus Low-Fat Diet.  Click on "Original Version (PDF)".  Here's a direct link to the PDF if for some reason the first link doesn't work:  http://www.annals.org/content/suppl/2010/08/03/153.3.147.DC2/0000605-201008030-00005-v1.pdf.

Happy Reading!