Heart Protection During Ischemia
Shifting from fat to glucose oxidation to produce energy
The heart pumps about 60 to 100 times a minute nonstop, ensuring adequate circulation and oxygenation for the body. But for the cardiac muscle cell to perform such a feat, there has to be a sustainable and adequate source of energy for myocyte contraction. Aside from that, energy production has to be efficient so that the heart muscle will not have to exert too much effort for it to function.
Energy used by the myocyte for contraction is in the form of adenosine triphosphate (ATP). ATP is produced significantly from the susbtrate Acetyl Coenzyme-A (Acetyl-CoA) through a perpetual process called the Kreb's Cycle, also known as Tricarboxylic Acid or Citric Acid Cycle. Acetyl CoA is a product of fat and carbohydrate metabolism.
According to Dr. Ricardo Fernando, diabetologist and head of the Institute for the Study of Diabetes Foundation (ISDF), carbohydrate metabolism is more efficient than fat metabolism. It produces 12-percent more ATP per oxygen molecule than fatty-acid breakdown (beta-oxidation). Carbohydrate metabolism is the ideal process for energy production in the heart because it creates more ATP and uses less oxygen.
Said Fernando in a lecture during the recent convention of the Philippine Diabetes Association: "Fatty-acid metabolism produces 60 percent of the ATP in the cardiomyocyte, but beta- oxidation, which converts fatty acids to Acetyl CoA, uses up a lot of oxygen. Glucose metabolism, the other major source of energy occurs in two steps-glycolysis, which does not need oxygen, and carbohydrate oxidation, which needs much less oxygen than beta-oxidation."
Carbohydrate metabolism will benefit persons whose oxygen delivery to the heart is impaired or reduced. Fernando explained that this is because energy production can still be met without increasing the oxygen demand. An example would be in case of ischemic heart disease (IHD) where the microvascular or coronary blood flow is compromised, reducing blood perfusion and oxygen delivery to the heart.
On the other hand, diseases like diabetes and dyslipidemia, marked by increased insulin resistance and overproduction of free fatty acids, causes a shift in the energy production of the heart to favor beta-oxidation. When this happens, less energy is produced but more oxygen is utilized, said Fernando.
These problems become very evident in persons suffering from metabolic syndrome-a condition where insulin resistance, dyslipidemia, diabetes, ischemic heart disease, and obesity coexist. In such patients a significant stress on the cardiac muscle stems from reduced oxygen delivery to the myocyte coupled with inefficient oxygen utilization to produce energy.
Switching Pathways
According to Fernando, the cardiac muscles can be influenced to shift its source of energy from fat to carbohydrate metabolism. This can be achieved by blocking 3-Ketoacyl-CoA Thiolase (3-KAT), one of the four enzymes essential in beta-oxidation.
Fernando said this is what trimetazidine (Vastarel) does to induce a shift from beta-oxidation to carbohydrate metabolism for energy production, which would benefit patients suffering from obesity, diabetes, hypertension, dyslipidemia, and coronary heart disease. Noting that these lifestyle disorders are all characterized by insulin resistance, he said the increased free fatty acid metabolism under these conditions aggravates the imbalance between glucose metabolism and beta-oxidation and harms the patient. But a shift from the predominantly oxygen-hungry fatty-acid metabolism to the more efficient glucose metabolism would ensure adequate energy despite limited oxygen delivery, he stressed.
There is another benefit of trimetazidine. It stabilizes myocyte cell membranes through incorporation of inositol into the membrane. "This gives Vastarel an additive protective effect that further reduces the cytotoxic effects of fatty acid accumulation in ischemia," said Fernando.
Late last year, Servier Philippines launched Vastarel MR, a 35mg modified release tablet with a hydrophilic matrix that allows controlled sustained release of the drug for twice-daily dosing and better patient compliance.
Fernando said this new preparation "optimizes cardiac energy metabolism by protecting the heart against metabolic changes during ischemia."
Lucio Victor Jr., MD
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