Choosing the best metabolic treatment in elderly patients with coronary heart disease

V.Yu. Lyshnevska, MD, M.S. Papuha, V.A. Yelnykova, Institute of Gerontology of the National Academy of Medical Sciences of Ukraine, Kyiv

Notwithstanding the advances achieved in the prevention and treatment of coronary heart disease (CHD) in recent years, optimization of its treatment remains among the most relevant problems of contemporary cardiology. The high medical and social relevance of this problem is associated with conditions that aggravate the course of CHD, such as myocardial infarction, heart failure (HF) and sudden coronary death, the incidence of which considerably exceeds the expected value calculated taking into account the implementation of current medical treatment regimens. That is why, there is a continuing search for therapeutic options to increase the life expectancy and the quality of life in patients with CHD, aimed mainly at optimizing the metabolic processes in the myocardium.

The anti-ischemic efficacy of metabolic treatment has long been challenged, and the treatment of CHD has been addressed only from the perspective of cardiac hemodynamics improvement. The action of conventional medicinal products was aimed mainly at reducing the myocardial oxygen demand or increasing oxygen supply. However, medicinal products acting on hemodynamic parameters are usually effective in preventing angina attacks but provide virtually no protection to the myocardial cells against metabolic changes which form the basis for pathological process progression.

It is well-known that normally there is a clear relationship between oxygen demand and its supply to heart muscle cells, ensuring normal metabolism and, consequently, normal functioning of the heart cells. Under normal conditions, the major substrates for energy production in heart muscle cells are free fatty acids (FFAs), the oxidation of which accounts for 60 to 80% of ATP synthesized in the cell, and glucose (20 to 40% of ATP synthesis).

Coronary atherosclerosis leads to an imbalance between oxygen demand and its supply to heart muscle cells, resulting in impaired myocardial perfusion and myocardial ischemia. The lack of oxygen alters the heart muscle cell metabolism. A limited amount of oxygen is distributed between glucose and FFA oxidation, while the activity of both metabolic pathways decreases. In the setting of ischemia, glucose is mostly broken down by anaerobic glycolysis with the formation of pyruvate which is converted to lactate instead of oxidative decarboxylation, potentiating intracellular acidosis. Residual aerobic synthesis of ATP occurs mainly at the expense of FFAs with a so-called shift from glucose oxidation to FFA β-oxidation. This ATP production pathway requires large amounts of oxygen and becomes metabolically less favorable in the ischemic conditions. Excess FFAs and acetyl-CoA inhibit the pyruvate dehydrogenase complex and lead to further uncoupling of glycolysis and oxidative decarboxylation processes and activation of the free-radical oxidation (FRO). Accumulation of FFAs – major FRO substrates – in the cytoplasm causes damage to cardiomyocyte membranes and impairs the functions of cardiomyocytes [1, 2, 9].

The underlying causes of electrophysiological and functional myocardial disorders include intracellular acidosis, local inflammation and peroxidation, ionic imbalance and reduction in the ATP synthesis.

Clinical manifestations of the disease are only the tip of the iceberg here, while its underwater part encompasses metabolic changes in the myocardium due to impaired perfusion.

That is why, the use of medicinal products aimed at myocardial metabolism stabilization is advisable in the combination treatment of patients with CHD.

There are two major focus areas in the metabolic therapy of myocardial diseases: optimizing the processes of energy production and consumption and restoring the balance between FRO intensity and antioxidant protection.

The first group of medicinal products aimed at improving the myocardial energy metabolism in cardiovascular disease were the products which promoted utilization and anabolism of high-energy compounds (ATP). This group traditionally includes the B vitamins (B1, B6, B12, etc.), inosine (Riboxin), inositol (which is also considered a group B vitamin). However, the clinical experience demonstrated low efficacy of such therapy. This was primarily associated with the lack of pharmacological rationale for the use of this group of medicinal products. Administration of exogenous ATP is obviously irrelevant from the pharmacological perspective. Similarly, the use of the ATP precursor inosine cannot guarantee an increase in the “ready-to-use” ATP pool of the myocardial cells. Moreover, there is no evidence of inositol deficiency in the human body. Whole grain, fruits, plants, vegetables and meat are known to contain inositol in the hexaphosphate, phytic acid or other form, hence the absence of its high-energy phosphate form in the human body is clinically unlikely.

Development of trimetazidine, a product which blocks FFA oxidation in hypoxic conditions, opened a new phase of the metabolic therapy. Reducing the rate of FFA oxidation has a favorable effect on the ischemic myocardium metabolism by increasing the alternative energy production via glucose oxidation pathway which utilizes the limited amount of oxygen much more efficiently. In addition, glucose is not metabolized to lactate in this pathway. The cytoprotective effect of trimetazidine on ischemic cells is based on these two mechanisms.

Today, trimetazidine is a relatively well-studied product and is widely used in clinical practice.

Meta-analysis of 12 clinical studies with trimetazidine showed a significant reduction in the number of angina attacks in patients with stable angina. Cardioprotective properties of trimetazidine were established in patients who underwent percutaneous angioplasty and coronary artery bypass graft [12, 13].

Medicinal product Mildronate widely used in the CIS countries has the same mechanism of action and is capable of suppressing the mitochondrial transmembrane transport of long-chain fatty acids only, while allowing the short-chain fatty acids to freely enter the mitochondria where they are oxidized and release energy.

The second relatively new and promising approach to the development of metabolically-acting drugs involves activating the glucose metabolism as opposed to inhibiting the FFA metabolism. The currently used representatives of this class of metabolic modulators include ranolazine and etomoxir. Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor which stimulates the myocardial glucose metabolism, demonstrated potent anti-ischemic activity in patients with stable angina when used as monotherapy (MARISA study) or in combination with a β-blocker (CARISA study) [10, 13]. However, the said products have not been approved in this country yet.

Experience with trimetazidine, Mildronate and ranolazine has demonstrated the feasibility and practicability of achieving the anti-ischemic effect with metabolically-acting drugs. However, despite a relative increase in the role of aerobic glycolysis in the setting of reduced FFA β-oxidation, this type of glycolysis may be not quite efficient if hypoxic conditions persist. Moreover, in the setting of hypoxia and accumulation of FFA pool, the activation of glycolysis may not yield any results. The fact that the stimulation of alternative pathways for the high-energy compound synthesis fails to provide the desired effect is largely attributable to decompensated activation of FRO, a universal mechanism for cellular system damage in the setting of hypoperfusion.

Today, involvement of free radicals in the cardiovascular disease is beyond doubt. The activation of peroxidation processes in angina pectoris is associated with frequent angina attacks causing hypercatecholaminemia which, in turn, stimulates lypolysis, thus increasing the level of FFAs, a readily available substrate for oxidation. 

Myocardial ischemia impairs the oxidative processes in cardiomyocyte mitochondria, leading to the accumulation of citric acid cycle intermediates extremely susceptible to reduction with the formation of free radicals and peroxide compounds which suppress the antioxidant protection system.

As a result, a paradoxical situation occurs: a reduction in the amount of intracellular oxygen leads to increased production of oxygen radicals. Myocardial reperfusion developing after each transient ischemia episode is accompanied by significant (several hundred-fold) activation of free-radical processes and release of lipid peroxides into the circulation. Marked activation of the FRO processes and subsequent response of the body tissues and systems are referred to as ‘oxidative stress’ [6, 11].

This is particularly important in the elderly: one of the key pathogenetic mechanisms for CHD progression and its complications in this age group is associated with the FRO activation (the primary role of FRO activation in CHD pathogenesis in the elderly is based on the established significance of peroxidation processes in aging). That is why, it is advisable to combine the metabolic therapy with antioxidant medicinal products in this population. 

Current medicinal products capable of efficiently resisting the oxidative stress include antioxidant agents which inactivate free radicals and prevent their production, agents involved in antioxidant regeneration or agents with indirect antioxidant activity. The latter, in fact, are not antioxidants but they can either activate the antioxidant system, increase the efficacy of natural antioxidants or prevent the oxidation of potential substrates.

It should be noted that antioxidants are rarely included in the treatment regimens for patients with coronary atherosclerosis. Medical practitioners have a rather ambiguous attitude to these drugs. On the one hand, the pathogenetic base for their use in CHD is beyond doubt; on the other hand, organized studies conducted so far (dedicated mostly to CHD research) did not provide conclusive evidence of their efficacy [6]. One of the possible reasons for the lack of evidence for vitamin efficacy as antioxidants may be the fact that these substances are natural metabolites of the human body with a specific physiological concentration range in the body tissues and matrices. If the concentration of such substance drops below normal, its deficiency immediately manifests itself in a certain dysfunction.

If the concentration of such substance exceeds the normal range while the normal function of the body is preserved, this does not improve the course of physiological processes but, in contrast, may cause overdose symptoms. The systems for inactivation and elimination of such substances exist to prevent the said symptoms.

Therefore, one of the promising areas in the pharmacological search for new effective anti-ischemic drugs is the development of formulations with anti-ischemic, metabolic and antioxidant activities and a minimal amount of side effects.

An example of such a pharmacological agent is Thiotriazolin, a medicinal product with both metabolic and antioxidant effects, developed by domestic pharmaceutical industry.

The antioxidant effect of Thiotriazolin is based on its ability to enhance the compensatory activation of anaerobic glycolysis, reduce the inhibition of oxidation processes in the citric acid cycle while preserving the intracellular ATP pool, and stabilize the heart muscle cell metabolism. Moreover, Thiotriazolin activates the antioxidant enzyme system and suppresses lipid peroxidation processes in the ischemic myocardium areas. The product activates anti-radical enzymes, such as superoxide dismutase, catalase and glutathione peroxidase, and helps reduce the consumption of tocopherol. Thiotriazolin inhibits the formation of initial and final products of lipid peroxidation in the pathologically changed tissues, thus maintaining the structural and functional integrity of the heart muscle cell membranes. Thiotriazolin reduces myocardial sensitivity to adrenergic cardiostimulatory effects of catecholamines, prevents progressive suppression of the myocardial contractile function and increases the heart muscle cell tolerance to hypoxia [8]. 

The efficacy of Thiotriazolin has been demonstrated in multiple experimental and clinical studies [3-5, 8], but the experience of its use in the elderly is limited. It is extremely important to study the anti-ischemic activity of the product in this population of patients, as they constitute the main risk group in terms of incidence and unfavorable prognosis of CHD.

Study Purpose

The purpose of this study was to evaluate the anti-ischemic efficacy of medicinal product Thiotriazolin manufactured by Arterium Corporation (Ukraine) in the elderly patients with CHD. Medicinal product Riboxin manufactured by Halychfarm (Ukraine) was chosen as a comparator.

Materials and methods

A total of 50 ischemic patients aged 60 to 74 (mean age: 67.5±4.5 years) diagnosed with CHD: functional class (FC) II or III stable angina, FC I chronic heart failure were examined.

All patients underwent a treadmill test and 24-hour ECG monitoring at baseline.

Following the initial examination, all patients were divided in two groups of 25 subjects each.

The patients in the first group received 10 injections of Thiotriazolin 2.5% at a dose of 4 mL, followed by tablets at a dose of 60 mg/day for 3 months. After initial examination, the patients in the second group were prescribed 10 injections of Riboxin 2% at a dose of 4 mL, followed by tablets at a dose of 60 mg/day for 3 months.

All patients received background treatment with β-blockers and nitrates pro re nata.

The patients were re-examined after the treatment course, and the anti-ischemic efficacy of Thiotriazolin and Riboxin was evaluated.

Results and Discussion

According to the data obtained, the metabolic therapy with both drugs was well-tolerated by all patients; however, there were differences between Thiotriazolin and Riboxin treatments as to the extent of the anti-ischemic effect.

For instance, according to the treadmill test results, Thiotriazolin significantly increased the duration of physical exercise and the maximum achievable heart rate (HR) at peak exercise, reducing the total mean ST segment shift and the systolic blood pressure (SBP) levels (Table 1).  Riboxin, with its unidirectional action on exercise duration, had a less considerable effect on the total ST segment shift and virtually no effect on the BP level at peak exercise (Figure 1).

The data obtained showed that Thiotriazolin had a statistically significant anti-ischemic effect and a sparing effect on the myocardial function. As expected, the anti-ischemic efficacy of Riboxin was significantly lower, and no sparing effect on the cardiac function was observed with this type of metabolic therapy.

The stress test results were confirmed by the 24-hour ECG monitoring data which showed a significant reduction in the total daily duration of myocardial ischemia and the duration of individual ischemia episodes following the treatment with Thiotriazolin. A reduction in the frequency of ventricular and supraventricular extrasystoles is also worth noting, as it suggests that Thiotriazolin improves the myocardial electrophysiological characteristics.

Riboxin demonstrated a favorable effect on the daily duration of ischemia, but had virtually no effect on the duration of individual myocardial ischemia episodes and showed no significant effect on the frequency and character of heart rhythm disorders (Table 2; Figure 2).

Table 1. Effects of Thiotriazolin and Riboxin on the physical exercise level in elderly patients with CHD (according to the treadmill test data)

* р<0.05

Figure 1. Efficacy of Thiotriazolin versus Riboxin (according to the treadmill test data) in the  lderly patients with CHD (* p<0.05)

Table 2. Anti-ischemic and anti-arrhythmic activity of Thiotriazolin and Riboxin in the elderly patients with CHD (according to the 24-hour ECG monitoring data)

* р<0.05

Figure 2. Efficacy of Thiotriazolin versus Riboxin (according to the 24-hour ECG monitoring data) in the elderly patients with CHD (* p<0.05); VES = ventricular extrasystoles; SVES = supraventricular extrasystoles

 Conclusions

• Thiotriazolin is an effective metabolic drug with anti-ischemic and anti-arrhythmic activities.
• The anti-ischemic efficacy of Thiotriazolin in elderly patients with CHD is significantly greater than that of Riboxin.
• Considering a good tolerability, efficacy and safety of Thiotriazolin, it can be recommended as a metabolic drug for the treatment of CHD in the elderly. 

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