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Life Extension Magazine April 2012
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Trimetazidine: The Heart Drug You've Never Heard Of

By Carl DeMarco Peer Reviewed by Stephen B. Strum, MD
Trimetazidine: The Heart Drug You've Never Heard Of

Over 82 million Americans are afflicted with some form of cardiovascular disease.1 It remains the number one cause of death in the US.1

Given this killer’s prevalence, you would think that medical officialdom would ensure maturing individuals have access to all available treatment options.

You would be wrong.

Despite over 40 years of published studies,2 a little-known, potentially lifesaving heart drug languishes in clinical and regulatory limbo in this country, a drug that Life Extension® espouses as a compelling target for further research and potential FDA approval.

Available in more than 80 nations around the world, it is unlike any other conventional prescription medication for heart disease on the American market today.

This drug is called as trimetazidine (TMZ).

Also marketed as Vastarel MR in Europe, it modulates mitochondrial metabolism to energize and revive compromised heart tissue. A mountain of scientific research shows it has the capability to protect vulnerable, oxygen-deprived heart muscle before a lethal cardiac event takes place.

In this article you will discover compelling evidence of trimetazidine’s cardioprotective power. You will learn of its capacity to reverse the deadly impact of diminished blood flow to the heart, the principal vascular pathology behind most heart attacks.

Concerns about the lack of long-term data on hard endpoints like heart attack and cardiac mortality make the regulatory path to approval a difficult one for this novel drug. The arduous approval path for a new type of drug to help treat ischemic heart disease is an example of the need to cut burdensome bureaucratic mandates and stimulate the evaluation of better medications for heart disease.

To understand how TMZ affords additional protection for at-risk heart muscle, we begin by outlining the significant limitations and dangers of conventional heart drugs.

Many Medications But Only One Mode of Action

Cardiac ischemia is the medical condition in which blood flow and therefore oxygen delivery to heart tissue is progressively limited, typically by arterial blockage; this is the origin of most heart attacks. Angina is its primary symptom—chest pain often accompanied by a sensation of uncomfortable pressure. Angina is the heart muscle crying out for more oxygen in order to perform its blood pumping function.

It may surprise you to learn that while conventional drugs for cardiac ischemia and angina operate via different mechanisms of action, they induce only one physiological effect: they lower heart muscle demand for oxygen by improving blood flow and reducing cardiac workload.3

This approach may not be effective for all individuals with heart disease. The problem? These drugs do not restore heart tissue already damaged or dysfunctional back to peak efficiency. The powerhouses known as mitochondria in compromised heart muscle cells remain unable to optimally convert fuel into energy for maximum output.4

This may account for a chilling statistic: 88% of patients on conventional medications continue to suffer chronic angina and remain at risk of further cardiac complications.3

While enlightened individuals may support heart cell mitochondrial function using CoQ10 (ubiquionol),5 L-carnitine,6 taurine,7 magnesium,8 PQQ (pyrroloquinoline quinone)9 and other nutrients,10,11 most patients are not told about them by their cardiologist and optimal dosing seldom occurs. Furthermore, the drug TMZ functions via unique cytoprotective mechanisms to support left ventricular function through enhancing coronary blood flow. By shifting energy substrate utilization to glucose through inhibition of fatty acid metabolism, TMZ offers the potential to enhance cardiac muscle cell ATP levels through pathways that may not be attainable with nutrients alone.

Conventional Drugs Used in Treating Angina and Ischemic Heart Disease3,12
Drug Class Examples Mechanism of Action Risks and Side Effects
Antiplatelet Agents Aspirin, clopidogrel Clot prevention by reduction of blood platelet adhesion to vessel walls Gastrointestinal bleeding
Beta Blockers Metoprolol, atenolol Reduce cardiac workload by reduction in heart rate, blood pressure, contractility (“squeeze”) Low blood pressure, dizziness, wheezing; may increase diabetes risk,13 erectile dysfunction
Angiotensin-Converting Enzyme (ACE) Inhibitors Captopril, enalapril Reduce cardiac workload by limiting activity of key enzyme in maintaining blood pressure Low blood pressure, kidney impairment
Calcium Channel Blockers Nifedipine, amlodipine Reduce cardiac workload by reducing contractility (“squeeze”) Slow heart rate, rapid heart rate, dizziness
Nitrates Nitroglycerin Increase cardiac blood flow by dilating coronary arteries Low blood pressure, dizziness, fainting

Heart Protection Through a Unique and Powerful Mechanism

By contrast to existing cardiac drugs, TMZ renders heart muscle optimally functional by enhancing energy output, as opposed to reducing workload.14 This fundamentally distinct mode of action offers aging individuals a complementary and potentially more effective way to ward off heart attack by enhancing the heart’s energy producing function rather than weakening the heart.

This outcome is achieved via a novel mechanism of action: the metabolic pathway by which the heart converts fuel into energy is favorably altered.

Here’s how it works:

The mitochondria within your heart cells utilize fatty acids to generate the bulk of the energy that fuels heart function; in the presence of disease, the use of fatty acids increases.15 TMZ enables the mitochondria to utilize more glucose as a fuel source.16-18

This shift in heart cell metabolism affords benefits.

To burn fatty acids, mitochondria require much more oxygen and produce more waste products than they do when glucose is the energy source.16,19,20 Under normal conditions that poses no problem, but ischemic heart tissue rapidly loses efficiency and accumulates acid as it continues to try to power itself from fat.21

By converting the preferred fuel source to glucose, fewer damaging acids are produced.16,20,22 Studies show that in the presence of TMZ, acid content in ischemic heart cells is much lower, and energy content is much higher, compared to controls.23-25

This results in faster recovery of heart muscle pumping action once blood flow is restored.26-28 TMZ treatment in animals with experimental ischemia has also been shown to reduce the size of the damaged area following complete blockage of a coronary artery, while improving the ability of the remaining heart muscle to pump blood.29-31 In addition, in both animal and human studies, TMZ treatment reduced the incidence of dangerous arrhythmias that frequently occur in the period following an ischemic event.32-35

Of equal importance, TMZ induces these beneficial effects with no negative impact on so-called “hemodynamics,” the delicate balance of heart rate, blood pressure, and heart muscle contractility that ultimately determines blood flow.16,36 This is in marked contrast to virtually all conventional drugs for angina and ischemia, which may produce potentially serious hemodynamic imbalances.

In addition to these lifesaving effects, TMZ increases plasma levels of the heart-protecting compound adenosine in patients with angina. Adenosine is essential for cellular energy transfer. The result is called “preconditioning”: heart muscle develops a tolerance for limited blood flow instead of dying from it.16,37

TMZ also positively influences gene expression, increasing production of several signaling molecules involved in regulation of heart muscle contractility.16,38 Other signaling molecules involved in endothelial function are also favorably influenced by TMZ.16,39,40

TMZ: A Lifesaving Heart Drug
TMZ: A Lifesaving Heart Drug
  • More than 82 million Americans are afflicted with some form of cardiovascular disease.
  • The majority of these individuals suffer from limited blood flow to the heart (ischemia) resulting in chest pain (angina).
  • Left untreated, ischemia progresses from cardiac muscle damage to loss of heart muscle (heart attack).
  • Conventional heart drugs have limited effectiveness against ischemic heart disease and can produce undesirable side effects on heart rate, blood pressure, and other important parameters of heart health.
  • TMZ is a potentially lifesaving drug that acts via a unique mechanism of action, altering heart cell metabolism to utilize glucose instead of fat.
  • TMZ consequently protects vulnerable or compromised heart muscle tissue from further ischemic damage in a variety of beneficial ways, including increasing blood pumping action, heart muscle wall thickness, and energy content in heart muscle cells.
  • Over 40 years of published studies from around the world support the use of TMZ in the short-term management of ischemic heart disease and heart failure.
  • More clinical study of TMZ’s long-term safety is needed to gain FDA approval of this potentially lifesaving drug.


Ischemia, Angina, Infarction, Heart Failure: A Lethal Progression
Ischemia, Angina, Infarction, Heart Failure: A Lethal Progression

Long before a catastrophic event such as myocardial infarction (heart attack) occurs, pathological changes develop in your heart muscle cells. As partial blockage progresses in the heart’s coronary arteries, blood flow steadily decreases. Tissue that relies on these arteries for blood supply is gradually starved of nutrients and oxygen. Compounding the danger is the singular role the heart plays in overall physiological function: unlike any other muscle, the heart can never rest.

The gradual deprivation of blood flow in an area of heart muscle is called myocardial ischemia. In its very earliest stages, myocardial ischemia may be asymptomatic. (An electrocardiogram performed under the right conditions may detect its presence.)

As myocardial ischemia worsens, deprived heart muscle results in painful angina. Early on, angina may be brought on by exertion or strong emotion, but as the condition progresses less and less effort is required to elicit the symptoms. Patients with angina typically have characteristic findings on an electrocardiogram.

As coronary blood flow worsens, cardiac tissue begins to die. While angina is reversible, this tissue death, known as infarction, is not. A “heart attack” is a myocardial infarction: the irreversible destruction of heart muscle. Some individuals may suffer with myocardial ischemia and even myocardial infarctions without the warning of angina.

Even people who survive heart attacks have permanently weakened heart muscle. This can lead to abnormal heartbeats (arrhythmias) and the chronic inability of the heart to pump enough blood (heart failure).

Success in Clinical Studies Across Multiple Heart Health Indicators

TMZ boasts an impressive track record in the acute management of both ischemic heart disease (the events leading up to a heart attack) and congestive heart failure (a major consequence of a heart attack).3,41

One of the earliest signs of ischemic heart disease is a change in electrocardiogram readings conducted during mild exercise. One such measure, known as “ST-segment depression,” indicates heart muscle lacking an adequate supply of oxygen to meet the demand of increased cardiac workload (ischemia). Several double-blind, placebo-controlled European studies showed that the addition of TMZ to a standard drug such as a beta blocker could prolong the time that patients could exercise before ST-segment depression appeared.42-44

Ejection Fraction

Unlike ST-segment depression—which is asymptomatic and goes unnoticed in aging individuals with heart disease—the first noticeable sign of ischemia is chest pain or angina, which occurs when the heart muscle is under stress due to physical exertion, strong emotions or other factors. Multiple studies reveal that patients treated with TMZ experience fewer episodes of angina and a longer interval before angina onset in exercise tests compared to patients given placebo or other anti-angina drugs.42,45 In one particularly impressive study, 50 patients with stable angina were treated with the calcium blocker diltiazem with or without the addition of TMZ.44 A remarkable 68% of TMZ recipients experienced fewer angina attacks per week compared with baseline, while only 12% of the control group exhibited the same response.

In still more advanced ischemia, patients eventually lose their ability to tolerate even mild exertion. Many studies demonstrate that TMZ can improve the duration of exercise in patients with ischemic heart disease and peripheral artery disease (“claudication”).44,46-48

Another measure of the severity of angina is the need for patients to use medications such as nitrates to relieve symptoms. Patients taking TMZ are often able to significantly reduce their nitrate intake.49 When we reduce the number of drugs a patient uses we also decrease the chance of adverse side effects as well as healthcare costs.

Ischemic cardiomyopathy is the term for impaired heart muscle tissue with a reduced capacity to pump blood effectively. Through its beneficial shifts in cardiac metabolism, TMZ increases the amount of blood pumped by hearts of patients with severe ischemic cardiomyopathy, at the same time reducing the dysfunctional dilation of the heart’s pumping chambers (ventricles).40,47,50 After a heart attack and the accompanying loss of heart muscle, there is a sharp decrease in blood pumping ability that often persists after successful intervention. When TMZ is added to the drug regimen of patients undergoing common interventions such as cardiac catheterization and coronary artery bypass grafting, studies show improvements in left ventricular function.51-53 (See graph below.) Left ventricular function is in essence a measurement of the heart’s “horse power” i.e., its ability to fire on all cyclinders. TMZ also reduces the frequency of angina attacks during cardiac catheterization procedures and lowers markers of heart muscle damage during surgery.52,54

Glcosylated hemoglobin (Hemoglobin A1C)

Heart failure often follows a heart attack, though it may develop as the result of chronic ischemia without an actual myocardial infarction. Heart failure occurs when the heart muscle is unable to meet the body’s metabolic demand for blood flow. Its symptoms include loss of exercise tolerance, difficulty breathing, and fluid buildup. The failing heart’s pumping chambers are enlarged and exhibit poor muscle contractility.

Studies show that TMZ can improve these and other parameters of heart failure. Patients treated with TMZ exhibit enhanced left ventricular function associated with an increase in their heart muscle’s energy content.14

Patients with coronary artery disease who are given TMZ also experience favorable changes in heart wall thickness, pumping action, and oxygen delivery capacity, without unfavorable changes in heart rate or blood pressure.55

From the patients’ perspective, perhaps the most important index of improvement is how they feel and function in everyday life. Recent studies show that aside from medical parameters of heart health, TMZ improves quality of life in patients with heart disease.56

TMZ may also particularly benefit diabetics, given its power to induce heart muscle to utilize glucose. Human studies have shown significant decreases in glycosylated hemoglobin (HbA1c) in studies comparing TMZ with placebo in type 2 diabetics.17 Patients with diabetes have excessively high levels of circulating fats and their hearts are even more likely than those of normal patients to suffer the metabolic effects of fatty acid metabolism.15,16,40,57,58

More Long-Term Safety Data Needed for FDA Approval

The good news is that TMZ’s short-term safety profile has been well established in animal and human studies. Unlike conventional drugs, it has no detrimental effects on blood pressure or heart rate.16

Unfortunately, few studies have been conducted to determine TMZ’s safety profile with long-term use. Those that do exist offer conflicting evidence.

On the positive side of the ledger, one 2009 study followed 153 patients taking TMZ for three years following coronary artery bypass surgery.59 They continued to show improvements in their hearts’ blood-pumping ability and in their exercise tolerance, as well as lower overall expenses for treatment, compared to controls.

By contrast, ominous symptoms manifested in a 2011 report describing 21 patients who had been taking TMZ for several years.60 Seventeen of these patients had Parkinson’s disease-like symptoms, three had disturbances in range of motion while walking, and one had restless leg syndrome. Sixteen of these patients recovered normal function after going off TMZ, while the other five experienced significant reduction in symptoms after discontinuing TMZ.

These results represent only a small fraction of the number of people taking TMZ worldwide. Nonetheless, clinical study of TMZ’s long-term safety is warranted. Without such studies this potentially lifesaving heart drug is unlikely to gain FDA approval.3 The need for long-term studies, however, should not preclude the short-term use of TMZ, which could save many American lives.

Summary

Over 82 million Americans are afflicted with some form of cardiovascular disease. The majority of these individuals suffer limited blood flow to the heart (ischemia) resulting in chest pain (angina). Left untreated, ischemia progresses from cardiac muscle damage to heart attack. Conventional heart drugs have limited effectiveness against ischemic heart disease and produce undesirable side effects on heart rate, blood pressure, and other important parameters of heart health.

TMZ is a unique drug that acts via a distinct mechanism of action, altering heart cell metabolism to utilize glucose instead of fat. TMZ has been shown to protect vulnerable or compromised heart muscle tissue from further ischemic damage in a variety of ways, including increased blood pumping action, heart muscle wall thickness, and energy content in heart muscle cells. Over 40 years of published studies from around the world support the use of TMZ in the management of ischemic heart disease and heart failure. A shortage of studies supporting safety of long-term use of TMZ is keeping this potential lifesaving heart drug from being available to Americans—even for short-term use!

New Questions on Trimetazidine
New Questions on Trimetazidine

Trimetazidine (TMZ) was first approved as a cardiovascular drug in Europe in 1965, and has long been considered to have a good safety profile.61 And indeed, large surveillance studies have shown a rate of general adverse effects similar to those of comparable drugs, neither worse nor better.

Over the past few years, however, concerns have been raised about one particular kind of drug reaction that’s common both to trimetazidine and to a host of other drugs with similar chemical structures. The molecular core of all of these drugs (which include many popular anti-seizure, anti-hypertension, and antidepressant agents) can interact with brain receptors for the neurotransmitter dopamine.61,62

That interaction can cause so-called extrapyramidal symptoms, many of which are remarkably similar to those seen in Parkinson’s disease: slow or stiff movements, speech disturbances, and a classical hand tremor at rest. Gait disturbances and loss of equilibrium are also possible.63

Such reactions are more than inconvenient; in older people especially, they can increase the risks of falls and therefore of fractures.64

The precise incidence of these reactions is as yet unclear, though it appears to be low and comparable to other drugs that can cause those symptoms.61 Two studies shed some light on the subject, both involving patients who came to a neurology clinic for their symptoms.

The first study, published in 2005, was conducted to better quanitfy the risk of drug-induced movement disorders related to trimetazidine.65 The researchers tracked the incidence of trimetazidine use and movement problems like drug-induced Parkinson’s and tremors in 10,258 patients treated at a neurology clinic in Europe. Of these 10,258 patients, 130 were treated with trimetazidine, and 56 of these patients (43%) experienced an adverse effect on motor function. Drug-induced Parkinsonism was observed in 10 patients (7.6%) treated with trimetazidine only, with an additional 10 patients (7.6%) simultaneously receiving other drugs potentially capable of inducing movement disorders. Treatment with trimetazidine worsened previously diagnosed Parkinson’s disease in 12 patients, and trimetazidine induced tremors in 9 patients. A 2011 study, also of patients coming to a neurology clinic, reports on a series of 21 cases of extrapyramidal symptoms in people taking trimetazidine, all but one of whom had been taking the drug for several years.61 Seventeen of the 21 subjects had typical Parkinson’s-like symptoms, three had gait disorders, and one had restless leg syndrome. Discontinuation of the trimetazidine led to complete resolution of symptoms in 16 patients, and significant reduction in the other five.

Some European authorities now advocate for removal of trimetazidine from the market entirely, claiming that the risk-benefit ratio is unacceptably high.64 Others are more circumspect, recommending instead that patients and their physicians monitor for side effects, and discontinue the drug only if and when symptoms occur.61 Fortunately, in the vast majority of cases reported, withdrawal of the drug leads to rapid resolution of these symptoms.61 It may be that TMZ should only be prescribed for several months to restore cardiac output in those with severe heart muscle damage. These patients could then initiate or continue taking nutrients like ubiquinol CoQ10, carnitine, taurine, and PQQ for long term maintenance of heart muscle cell mitochondrial output.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.

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