Friday, October 22, 2010

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.


Paul Jaminet said...

Very nice post, LynnMarie! I love learning history.

Your last paragraph is very important and could be made even stronger. The risk of heart attacks is highest postprandially, when blood glucose and triglycerides are elevated, and taking sugary drinks will probably increase the risk further.

LynMarie Daye said...

Thanks for the compliment AND for mentioning that MI risk increases post-prandially. Do you have an opinion on the mechanism(s)?

Anonymous said...

do you have any ideas about what can be the reasons of a heart ache after eating a 'compound meal' consisting of both carbs and fats, but feeling just fine after eating just 'carbs' or 'zero-carbs'?

LynMarie Daye said...

The mixed meal could be causing a digestive issue, like GERD (acid reflux). Some people experience rather severe chest pain from this instead of the more common "burning" sensation. It may also have something to do with the gallbladder. However, this cannot be assumed to be the cause. I cannot stress this enough: ALL CHEST PAIN MUST BE EVALUATED BY A QUALIFIED MEDICAL PROFESSIONAL!!! If you are experiencing this Anonymous, please see a physician.