In recent years, the use of pharmaceutical agents with significant metabolic effects for the treatment of ischemic heart diseases has gained considerable attention.

These include:

• Atomoxetine
• Ranolazine
• L-carnitine (LC)
• Acetyl-L-carnitine (ALC)

These pharmacological agents are discussed for their roles in heart failure, angina, and other ischemic heart diseases.

Carnitine Carnitine is a naturally occurring biological substance in the human body that plays a crucial role in the production of energy required for the heart and certain other tissues by facilitating the oxidation of long-chain fatty acids.

L-carnitine (LC) is a pharmaceutical formulation with multiple clinical applications, including:

• Correcting carnitine deficiency in patients with chronic fatigue syndrome
• Dialysis patients
• Enhancing exercise tolerance in patients with angina
• Correcting muscle weakness
• Growth retardation
• Motor skill impairment in children and premature infants
• Treatment of toxicity caused by anthracyclines and sodium valproate

Acetyl-L-carnitine (ALC) Acetyl-L-carnitine (ALC) is the esterified form of LC, synthesized by the ALC transferase enzyme in the brain, liver, and kidneys. This substance facilitates the transport of acetyl-CoA during fatty acid oxidation into the mitochondria, increases acetylcholine production, and stimulates protein and phospholipid synthesis in membranes. Like LC, ALC plays a crucial role in mitochondrial function and serves as an important molecule for the transport of free fatty acids and acetyl groups in metabolism and beta-oxidation of free fatty acids. The primary storage of ALC in the body occurs in skeletal and cardiac muscles.

Effects of ALC Supplementation

• Neuroprotective effects in brain ischemia
• Prevention of peripheral nerve damage
• Effective in the treatment of Parkinson’s disease in animal models
• Reduction of cognitive decline in aging
• Treatment of Alzheimer’s disease

Effects of Myocardial Ischemia Myocardial ischemia leads to:

• Reduced carnitine reserves in the heart
• Accumulation of toxic metabolites of fatty acids in the heart
• Inhibition of beta-oxidation
• Reduced ATP production in the myocardium
• Toxic metabolites (including acylcarnitine and beta-hydroxy-acyl-CoA metabolites)

Fatty acids have harmful effects on myocardial recovery during reperfusion.

Metabolite Toxicity

• Membrane damage
• Enzyme attachment to the cytoplasmic membranes of heart cells
• Disruption of ion transport across membranes
• Changes in the integrity of ion channels and transporters
• Activation of signaling pathways
• Activation of protein kinases
• Gene transcription
• Initiation of apoptosis

Side Effects of LC and ALC Administration The administration of drugs like LC and ALC, through mechanisms that are not fully understood, results in the following effects:

• Preservation of metabolism
• Improvement of heart function under ischemic conditions

In a study conducted in 2003, the administration of 5 and 0.5 mM concentrations of ALC and LC 10 minutes before inducing global ischemia (complete ischemia) did not prevent the occurrence of ventricular fibrillation in rats, but the 5 mM concentration reduced the infarct size.

Study Results Adding LC to the Krebs solution as a pharmacological agent in post-conditioning from 10 minutes before the start of reperfusion to 10 minutes afterward showed heart protective effects, including a reduction in infarct size. So far, comparative studies on the protective effects of LC and ALC on infarct size due to regional ischemia and reperfusion are unclear.

Potential Differences Between LC and ALC Effects In a study comparing the effects of LC and ALC during 30 minutes of regional ischemia and 120 minutes of reperfusion in isolated rat hearts, both LC and ALC reduced infarct size compared to the control group. The infarct size was reduced by 43% and 56% with 1.5 and 3 mM LC, respectively, and by 48% and 65% with the same concentrations of ALC.

Reduction of Infarct Area LC and ALC administration during 30 minutes of ischemia and 120 minutes of reperfusion led to a significant reduction in infarct area. Although the decrease in infarct size and infarct area volume was higher with ALC than LC, the effects of both were not statistically significantly different.

Since both substances exist biologically in the body and can be converted into each other enzymatically, it is not surprising that they exhibit similar effects as drugs (qualitatively, not quantitatively). Studies have shown that:

• In humans, ALC has better bioavailability and gastrointestinal absorption than LC.
• Other findings suggest that ALC penetrates mitochondria more effectively than LC, which could explain the more prominent heart protection observed with ALC compared to LC.

LC and AC Play Key Roles in Arrhythmia LC and acyl-CoA molecules are key players in arrhythmogenesis. In animal studies, LC consumption resulted in:

• Reduction of high-energy phosphate loss during ischemic periods
• Decreased tissue necrosis
• Preservation of mitochondrial function
• Improved mechanical and electrophysiological heart function

Benefits of LC Administration LC administration in an ischemic isolated dog heart model resulted in a significant reduction of ventricular arrhythmias, as it reduced the size of the necrotic heart region.

Effects of Oral LC Supplementation Daily oral administration of 2 grams of LC for 28 days significantly reduced the occurrence of arrhythmias and congestive heart failure in patients with acute myocardial infarction.

Studies have also shown that ALC provides effective protection under brain ischemic conditions. Researchers have shown that administering 5 mM ALC and LC shortly before global ischemia reduces infarct size and inhibits cell death.

Methodological Differences in Ischemia The duration of ischemia and reperfusion, the duration of drug administration, and the varying concentrations of LC and ALC used in studies may explain differences in results. In particular, in studies where only the 5 mM concentration of LC or ALC reduced infarct size significantly, prolonged drug administration could be a factor influencing the effectiveness of protection.

Global vs. Regional Ischemia In global ischemia, no drug enters the heart during ischemia, while in regional ischemia, part of the coronary circulation remains partially open, allowing the Krebs solution to flow. This difference in ischemia type plays a role in the varied effects of drugs in the aforementioned studies. Although the exact reasons for the heart protective effects of LC and ALC remain unclear, further studies are needed to better understand these mechanisms.

Introduction of Multiple Mechanisms Additional mechanisms proposed include the administration of LC and ALC, which increases fatty acid transfer into mitochondria and stimulates beta-oxidation during ischemia. This reduces the accumulation of toxic fatty acid metabolites in mitochondria, especially molecules like LCAC and acyl-CoA, and even their transport out of mitochondria. This results in a protective effect against the detergent-like activity of these molecules on mitochondrial membranes, thereby preserving their function in fatty acid metabolism and reducing arrhythmias and other harmful effects of reperfusion injury.

Effects of Increased Glucose Oxidation

Increasing glucose oxidation during reperfusion, while simultaneously inhibiting the transfer of fatty acids into mitochondria, as opposed to ischemia, leads to increased ATP production, resulting in enhanced contractile power and heart compliance, as well as a reduction in the necrotic area. On the other hand, increasing glucose oxidation reduces lactate and H+ ion accumulation, thereby preventing intracellular acidosis in myocardial cells during ischemia, which aids in the faster recovery of ischemic heart function during reperfusion. Increased blood flow to tissues by dilating their blood vessels, inhibiting the harmful effects of free radicals released during reperfusion, and the resistance of heart cells to R/I damage (by stabilizing heart cell membranes) have also been attributed to this. Perhaps a combination of these mechanisms plays a role in their cardiac protective effects.

Conclusion

Overall, the results of this study showed that the protective effects of administering LC and ALC were evident, including a reduction in infarct size and infarct area, without significant statistical differences between the two. Among the proposed mechanisms for these effects, the reduction of toxic metabolites from fatty acids, especially LCAC under ischemic conditions, increased glucose oxidation during reperfusion, and consequently the reduction of lactate and H+ ion accumulation, resulting in the inhibition of acidosis in myocardial cells during ischemia, as well as the inhibition of harmful effects of free radicals released during reperfusion, are more prominently noted. Conducting additional studies may help better identify the effects of these drugs and their protective mechanisms.

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• L-Carnitine 250 mg
• L-Carnitine 1000 mg