Lessening AGE damage helps prevent cardiac dysfunction

Benfotiamine Averts
Cardiomyopathy

Advanced glycation endproduct (AGE) accumulation and AGE receptor
(RAGE) upregulation are implicated in diabetic cardiomyopathy
By Will Block

Do not go gentle into that good night,
Old age should burn and rave at close of day;
Rage, rage against the dying of the light.

—Dylan Thomas

A

ccording to the American Diabetes Association, there are an estimated 23.6 million people in the United States (8% of the population) with diabetes.1 Yet only 17.9 million have been diagnosed. Of these, 90% are type 2 diabetics. To make matters worse, it is estimated that there are 57 million people with prediabetes, a condition also referred to as borderline diabetes, impaired glucose tolerance, and impaired fasting glucose. With the growing obesity “epidemic” feeding it as a principal risk factor, prediabetes has been declared America’s largest healthcare epidemic. And while progression to type 2 diabetes mellitus is not inevitable for prediabetics, the conversion rate is high. Approximately 25% convert within three to five years from its initial onslaught.2

Diabetes Escalates the Risk of Death from Cardiovascular Disease

One of the deadliest consequences of diabetes is that it leads to cardiac dysfunction. As a matter of fact, diabetes is the greatest risk factor for coronary artery disease, and nearly one-third of all diabetics in the U.S. are diagnosed with diabetic heart disease. Indeed, epidemiological and clinical trial data have confirmed the greater incidence and prevalence of heart failure in diabetes. Furthermore, two-thirds of diabetics will eventually die of some sort of cardiovascular disease, the leading cause of death in the U.S. One sort of cardiovascular disease is cardiomyopathy, a disease characterized by a deterioration of the function of the myocardium, the heart muscle. Called diabetic cardiomyopathy (DCM) when precipitated by diabetes, this disease often renders its victims susceptible to arrhythmia or sudden cardiac death or both.3 It is a growing concern.

Diabetic Cardiomyopathy—Diagnosed When Ventricular Dysfunction Develops

Aside from large vessel disease and advancing atherosclerosis—which are very common in diabetes—DCM is diagnosed when ventricular dysfunction develops in patients with diabetes. This may occur even without the presence of coronary atherosclerosis and hypertension. Among DCM’s principle characteristics are prolonged ventricular dilation, the excessive growth of heart muscle cells (myocyte hypertrophy), the scarring and thickening of heart tissue (interstitial fibrosis), and reduced or stabilized systolic function in the presence of diastolic dysfunction.

It is widely accepted that the complications observed in diabetes are related to hyperglycemia. However, other factors are responsible for the development of heart failure in DCM, including: 1) angiopathy of small blood vessels in the body (microangiopathy), 2) disease of the autonomic nervous system (autonomic neuropathy), and 3) metabolic alterations that result in abnormal glucose use and increased fatty acid oxidation. Also responsible for DCM are: 4) excessive free radical activity, and 5) alterations in calcium metabolism.

The First Signs of DCM

It is sad to say that DCM is a silent disease, with a long latency period during which there are no overt symptoms. Its first signs may be mild left ventricular diastolic dysfunction.* Typically, this has little effect on ventricular filling (with blood). At the same time, other left-ventricular dysfunctions may manifest, including alterations between the volume of blood and pressure (ventricular compliance), an increase in ventricular size and the mass (ventricular hypertrophy), or both. This may be spotted through irregularities in the jugular venous pulse, and the cardiac apical impulse (See the sidebar, “Listening to Your Heart”).


* During diastolic function, the ventricles of the heart fill with blood. This follows the systole (contraction) in which blood is pumped via the left ventricle into the arteries, or pumped via the right ventricle to the lungs. The diastole is a period of relaxing for the ventricles; it originates from the Greek word meaning dilation.


Next is the development of ventricular systolic dysfunction characterized by effort intolerance and fatigue (symptomatic heart failure). This is serious territory, with significant consequences for the quality of life. In this phase, the jugular venous pulse may become elevated, with apical impulse readings that indicate volume overload. Systolic mitral murmur may also be common. (See the sidebar, “Listening to Your Heart.”) At the same time, in 60% of patients without structural heart disease, these changes are accompanied by certain electrocardiographic changes. As DCM progresses, prolonged QT interval—a measure of the time between the start of the Q wave and the end of the T wave—is pronounced, indicative of fibrosis. Once again, DCM does not necessarily include atherosclerosis or hypertension, at least not concomitantly. Thus there may be no changes in perfusion or in levels of atrial natriuretic peptide—a powerful vasodilator—until very late stages of DCM, when hypertrophy (overgrowth of heart tissue) and fibrosis become significantly pronounced.

Listening to Your Heart

The “songs” of your heart are the sounds generated by your beating heart that result from the cascading of blood that flows through it. In the broadest sense, this is called your heartbeat. In medicine, these sounds are important indications of your cardiovascular health, and through a process called cardiac auscultation, your doctor makes use of a stethoscope to listen for these sounds. What is heard may sound like a bassdrum, but to the ears of a trained physician the variations of your heart song provide important information about its condition and your health.

When you are healthy, what can be heard are two normal heart sounds, frequently described as a lubb and a dub. These take place sequentially with each heart beat. Respectively, these are the first heart sound (S1) and second heart sound (S2) that are produced, like a wind instrument, by the closing of your heart valves, the atrioventricular valves and semilunar valves, respectively. The atrioventricular valves are small valves that prevent backflow from the ventricles into the heart chambers during contraction. The semilunar valves are located at the base of both the pulmonary trunk (pulmonary artery) and the aorta. In addition to these normal sounds that these valves make, other sounds may be present. These are distinctly different from the lubb-dub and include heart murmurs, adventitious sounds, and gallop rhythms S3 and S4.

Of principle importance, when present, are heart murmurs. These sounds are generated by tumultuous blood flow, which may emanate from either inside or outside the heart. Your physician may interpret heart murmurs in one of two ways: either they are physiological (benign) or pathological (abnormal). If a murmur is caused by a narrowing of a blood vessel (stenosis) that restricts the opening of a heart valve resulting in blood flow turbulance, it is abnormal and of concern. There are other causes of abnormal murmurs including valvular insufficiency (aka regurgitation). In this case, blood is allowed to backflow when a valve closure is not complete. The various murmurs can be heard in different parts of the cardiac cycle, depending on their cause.

Extra heart sounds

The heart sounds known as gallop rhythms are rarer and, as with murmurs, may be normal or abnormal. Constituting a third heart sound, gallops refer to the rhythm and stress of S1 (lubb) followed by S2 (dub) and S3 (the 3rd heart sound) together. It is heard at the beginning of diastole, when the heart fills with blood, after S2 and is lower in pitch than S1 or S2 as it is not of valvular origin. Interestingly, the third heart sound is benign in youth and some trained athletes. Yet if it re-emerges later in life it may signal cardiac problems like a failing left ventricle as in dilated congestive heart failure.

S3 is generally thought to result from the oscillation of blood back and forth between the walls of the ventricles precipitated by inrushing blood. The third heart sound does not occur until the middle third of diastole. This is because during the early part of diastole, the ventricles are not filled sufficiently to create enough tension for reverberation. It may also be a result of tensing of the heart strings (chordae tendineae) during rapid filling and expansion of the ventricle.

Alternatively, an S3 heart sound indicates increased volume of blood within the ventricle. An S3 heart sound may be right-sided or left-sided. To distinguish between a left- and right-sided S3 is to note whether it increases in intensity with inspiration or expiration. A right-sided S3 will increase on inspiration whereas a left-sided S3 will increase on expiration.

Also rare, the fourth heart sound (S4) may sometimes be heard in healthy children and in trained athletes, but when audible in an adult, it is called a presystolic gallop or atrial gallop. This is because it is produced by the sound of blood being forced into a stiff/hypertrophic ventricle. In adults, it is a sign of a pathology, usually a left ventricle that is failing, but can also reflect other conditions such as restrictive cardiomyopathy. S4 occurs just after atrial contraction (aka the “atrial kick”) at the end of diastole and immediately before S1. It produces a rhythm sometimes called the “Tennessee” gallop; think of S4 as the “tenn-” syllable. If S3 and S4 are also present, the result is a quadruple gallop. When the heart beats rapidly, S3 and S4 may merge to produce what is called a summation gallop.

There are No Current Conventional Treatments for DCM

To repeat, DCM is a distinct primary disease process that is independent of coronary artery disease, and can lead to heart failure in those with diabetes. Curiously, even though experimental diabetes models have determined a range of novel molecular targets for this condition, to date none has been proven in humans. Currently, there is not a single clinically effective treatment for DCM.

Undoubtedly, due to the hyperglycemia involved in diabetes, a logical treatment is rigorous glycemic control through diet (see “Durk Pearson & Sandy Shaw’s 21st Century Weight Loss Program, Addendum to Part I” in the March 2007 issue of Life Enhancement, and many articles thereafter). Conventional medicine advocates the use of the drugs sulfonylureas and metformin. However, because there is such a obvious correlation between elevated glycemia and the development of DCM, it is of supreme importance to keep control glucose concentrations low. The downside of such intensive therapy is weight gain along with dangerous hypoglycemic episodes. Indeed, the quality of life of the patient on these drugs can go into a downspin.

On the conventional horizon, there are a number of experimental drugs under consideration for alternative hypoglycemic therapy. Among these treatments are thiazolidinediones—which are PPARγ agonists (see “The Antidiabetes Trigger” in the March issue) and insulin sensitizers, which can help control glucose concentration, as well as lower free fatty acids and triglycerides, known to be major participants in the abnormalities seen in DCM. These are not without problems of their own, and should be used with caution because of safety issues.

The list of drugs goes on and includes angiotensin-converting enzyme (ACE) and beta blockers, which are often used together. Regrettably, there is always a cost to pay, especially when the number of drugs employed spirals upwards, and these and other drugs have adverse effects on glycemia. Their use, in some ways, is like throwing kerosene on a fire to extinguish it.

Slowing or Averting the Onset of DCM

Shifting gears to a nonconventional perspective, a new study on diabetic cardiomyopathy—designed to investigate the role of advanced glycation endproducts (AGE) and AGE receptors (RAGE) in this disease—has found that it may be possible to slow or even avert the onset of DCM.4 This builds on recent evidence that has implicated a pathogenic role for AGEs in the generation of diabetic complications in various organs, including the heart. AGEs are varied compounds that accumulate in the tissues of diabetics due to the biomolecular glomming together of sugar molecules and proteins. These hybrid molecules are created by several factors including increased reactive carbohydrate substrate availability, oxidative condition favoring glycation, and impaired detoxification.

AGEs have been thought to participate in the pathogenesis of cardiovascular diseases through direct biochemical alterations of tissue/cellular material via the crosslinking of macromolecules, or through RAGE-mediated release cytokines with proinflammatory properties and reactive oxygen species. Despite these understandings, the phenomenon of AGE-RAGE (and their interactions) donating to the pathogenesis of DCM has not been clarified.

Summarizing what we have already described, DCM is apparently the result of compromised systolic and diastolic function. In the DCM study, the researchers set out to determine the AGE-RAGE involvement. Heart function was assessed in isolated control and streptozotocin-induced diabetic hearts of mice following in vivo RAGE gene knockdown using RNA interference. Then the researchers evaluated cardiomyocyte mechanical properties, with polymerase chain reaction and immunoblot technologies.

Benfotiamine Helps Inhibit the Elevation of AGE, RAGE, and Collagen Crosslinking

Diabetes significantly promoted the formation of AGE and RAGE levels in heart muscle cells. However, when control and diabetic mice subsets were fed with the AGE-formation inhibitor benfotiamine (80 mg/kg/d) for six weeks immediately following induction of diabetes the results were clear.* Benfotiamine significantly lessened diabetes-induced elevation of AGE, RAGE, and collagen crosslinking, yet it did this without affecting hypertriglyceridemia and hypercholesterolemia, conditions that frequently occur in diabetes. The data showing that benfotiamine negated diabetes-induced AGE accumulation is consistent with reports from non-cardiac tissues.5


* The human equivalent would be about 550 mg of benfotiamine per day for a 85 kg (187 lb) person.


Also noteworthy, when the RAGE gene was prevented from working (through gene knockdown), diabetes-induced cardiac contractile dysfunction was eliminated. This is consistent with the finding that AGE directly upregulated cardiac RAGE mRNA and deteriorated cardiomyocyte contractile function reminiscent of diabetes. Furthermore, the researchers also determined that the AGE and diabetes-elicited alterations were nullified by an anti-RAGE antibody and silencing RNA-RAGE, respectively. Thus, they concluded, it is probably true that the AGE-RAGE interaction is essential to cardiac dysfunction and the onset of DCM.


The use of benfotiamine to
inhibit AGE formation or
silence the disturbance of the
AGE-RAGE interaction may play an
important role in our health future.


Providing more fuel for their conclusions, serum AGE was elevated in the diabetic mice, correlating positively with what is known about both type 1 and type 2 diabetics with left ventricular diastolic dysfunction. Also, the fact that benfotiamine negated diabetes-induced reduction in myocardial collagen solubility suggests that inhibition of AGE-induced collagen crosslink may contribute, at least in part, to the beneficial effect of benfotiamine against diabetic cardiac dysfunction.6

Even though the DCM study suggests that benfotiamine alleviates diabetes-induced cardiomyocyte dysfunction through inhibition of the AGE-RAGE axis, there is another possible explanation. Benfotiamine also blocks the hexosamine and diacylglycerolprotein kinase C pathways in addition to the AGE pathway, and that possibility may downplay somewhat the emphasis of the researchers’ conclusions. It is known that inhibition of either hexosamine or diacylglycerol-protein kinase C pathway can benefit diabetic heart function. Another piece of information: interrupting the AGE-RAGE interaction inhibits angiogenic signal which may exert a secondary effect on diabetic cardiac complication through altered blood vessel formation.

But that aside, the DCM study strongly suggests that a link between the AGE-RAGE interaction and cardiac contractile dysfunction exists in diabetes. Moreover, because of what else is known about the cardiac contractile function in diabetes, the use of either AGE formation inhibitors such as benfotiamine, or the disturbance of the AGE-RAGE interaction (such as through silencing RAGE) to lessen diabetes-induced cardiac dysfunction may play an important role in our health future.

References

  1. http://www.diabetes.org/diabetes-statistics/prevalence.jsp
  2. Nathan DM, Davidson MB, DeFronzo RA, Heine RJ, Henry RR, Pratley R, Zinman B; American Diabetes Association. Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes Care 2007 Mar;30(3):753-9.
  3. Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser SL, Jameson JL, eds. Harrison’s Principles of Internal Medicine, 16th edn. New York, NY: McGraw-Hill;2005.
  4. Ma H, Li SY, Xu P, Babcock SA, Dolence EK, Brownlee M, Li J, Ren J. Advanced glycation endproduct (AGE) accumulation and AGE receptor (RAGE) upregulation contribute to the onset of diabetic cardiomyopathy. J Cell Mol Med 2008 Oct 13. [Epub ahead of print]
  5. Stirban A, Negrean M, Stratmann B, Gawlowski T, Horstmann T, Gotting C et al. Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Diabetes Care 2006; 29(9): 2064-71.
  6. Ceylan-Isik AF, Wu S, Li Q, Li SY, Ren J. High-dose benfotiamine rescues cardiomyocyte contractile dysfunction in streptozotocin-induced diabetes mellitus. J Appl Physiol


Will Block is the publisher and editorial director of Life Enhancement magazine.

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