Number 25, 2004
Heart failure in diabetes

Novel approaches in the treatment of diabetes mellitus diabetic cardiomyopathy

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Romualdo Belardinelli
Lancisi Heart Institute, Ancona, Italy
Correspondence: Romualdo Belardinelli, Lancisi Heart Institute, via Rismondo 5, 60100 Ancona, Italy.
Tel: +39 71 5965344, fax: + 39 71 36819

Introduction
Diabetes is a chronic, progressively worsening disease associated with a variety of complications [1]. Patients with diabetes have a greater incidence of coronary artery disease, which is in part related to concomitant cardiovascular risk factors, such as hypertension, blood lipid abnormalities, obesity, and physical inactivity. A cardiovascular event is responsible for 75% of deaths in individuals with type 2 (non insulin-dependent) diabetes, and more than 50% of medical expenditures related to diabetes result from admissions to hospital as a result of cardiovascular disease.

Metabolic dysfunction in the diabetic heart
Diabetes mellitus impairs glucose uptake and glycolysis of myocardial cells, depending in part on downregulation of the expression of glucose transporter (GLUT). Studies in animals have shown that diabetes decreases both GLUT 1 and GLUT 4 isoforms, which translocate from the intracellular pool into the plasma membrane in response to chemical and physical stimuli such as insulin or ischemia [2,3]. This decrease is prevented by chronic treatment with insulin and is improved by aerobic exercise, such as running or cycling [4].
A common metabolic dysfunction in diabetes is a decrease in the rate of carbohydrate oxidation as a result of a decrease in mitochondrial pyruvate oxidation. Pyruvate decarboxylation – the key reaction in glucose oxidation – is catalyzed by pyruvate dehydrogenase (PDH), and the rate of pyruvate oxidation is dependent on the degree of phosphorylation of PDH, and also on the concentration of its substrates and products in the mitochondria. Diabetes is typically associated with a decrease in total PDH activity, as the dephosphorylated active form is proportionally reduced [5]. In the case of myocardial ischemia – a condition that frequently occurs without symptoms in individuals with diabetes – glucose oxidation is reduced, and this reduction is more pronounced in diabetic hearts in which PDH inhibition is more marked, along with a more accelerated rate of fatty acid oxidation [6]. The decreased ability to oxidize pyruvate appears to be a major contributor to the poor outcome in patients with diabetes who have coronary artery disease [7]. In contrast, activation of PDH with dichloroacetate results in improved contractility in both nondiabetic and diabetic hearts [8], suggesting that the addition of a metabolic modulator can improve the metabolic dysfunction and myocardial contractility.
The treatment of diabetes is aimed at two goals: elimination of symptoms of hyperglycemia, and prevention of vascular complications, both micro- and macrovascular. Given that the leading cause of morbidity and mortality in patients with diabetes is atherosclerotic vascular disease, the therapeutic approach should be targeted towards improving the blood supply and preventing the progression of atherosclerosis (Table I).

Table 1. Therapeutic goals in patients with diabetes mellitus. (Data from the American Diabetes Association [15].)

Lifestyle changes and control of cardiovascular risk factors
The American Heart Association designated diabetes as a “coronary risk equivalent”, and indicated that patients with diabetes belong in the same risk category as those with known cardiovascular disease [9]. Patients with diabetes frequently have concomitant coronary risk factors such as hypertension, dyslipidemia, and obesity, which contribute to worsening their coronary artery disease and to accelerating the progression of atherosclerosis. Thus, in the clinical management of patients with diabetes, attention must be given both to major cardiovascular risk factors, such as cigarette smoking, hypertension, hypercholesterolemia, and hypertriglyceridemia, and to underlying risk factors (overweight/obesity, physical inactivity, and adverse nutrition) [9]. All these risk factors generate similar common abnormalities, such as endothelial dysfunction, prothrombotic state, inflammation, and excessive oxidation, which are involved in the pathogenesis of the atherosclerotic process. As the majority of coronary risk factors are potentially reversible, the first line of treatment of patients with diabetes should be based on modification of lifestyle and correction of concomitant risk factors.
Aerobic exercise is considered a treatment of choice in diabetes, because it reduces blood pressure and improves the lipoprotein profile and glycemic control. In addition, exercise reduces the prothrombotic state [10]. In a recent study, moderate physical activity, such as brisk walking for at least 150 minutes per week, combined with a low caloric, low-fat diet, reduced the incidence of diabetes by 58% in 3234 nondiabetic persons with increased fasting and post-load plasma glucose concentrations. The lifestyle intervention was significantly more effective than metformin, which was associated with a 31% decrease in the incidence of diabetes [11]. To prevent one case of diabetes during a period of 3 years, 6.9 persons would have to participate in the lifestyle intervention program, and 13.9 would have to receive metformin. Physical inactivity impairs insulin sensitivity, contributes importantly to development of obesity, and increases blood pressure. In contrast, aerobic exercise of moderate intensity improves endothelial function and induces a series of beneficial adaptations that improve vasomotor function and delay the progression of atherosclerosis (Figure 1).

Metabolic modulators
Cardiovascular disease in patients with diabetes has several components, including cardiac, macrovascular, and microvascular diseases, which create a vicious cycle of progressive and worsening abnormalities. A typical condition in patients with diabetes is multiple coronary artery stenoses with dysfunctional myocardium, the so-called diabetic cardiomyopathy. Coronary lesions are typically multiple and at different maturative states in the same vessels. Furthermore, lesions frequently extend to the distal end of the coronary tree. After years, the disease spreads to all major coronary vessels, causing functional and structural abnormalities in the myocardial cells. Chronic ischemia generates hibernating myocardium with depressed contractility and consequent regional left ventricular dysfunction. When dysfunction is sufficiently severe, heart failure will develop, causing clinical deterioration.
As previously mentioned, activation of PDH with dichloroacetate results in improved contractility in both nondiabetic and diabetic hearts, suggesting that the addition of a metabolic modulator can improve the metabolic dysfunction and myocardial contractility [8]. Trimetazidine – a piperazine derivative – is used as antianginal agent for its particular properties: it selectively inhibits mitochondrial long-chain 3-ketoacyl coenzyme A thiolase, resulting in inhibition of fatty acid oxidation and increased glucose oxidation. Under conditions of chronic reduction in coronary blood flow, free fatty acid concentrations are increased as a result of the lipolytic action of sympathetic activation, causing a reduction in myocardial contractility and increases in cAMP concentrations and oxygen consumption, with no concomitant increase in myocardial work. A shift toward glucose oxidation, requiring less oxygen than β-oxidation, is likely to benefit hypoperfused myocardium, because ATP production per mole of oxygen consumed is about 12% greater when glucose, rather than fatty acid, is the preferred energy substrate. In patients with ischemic cardiomyopathy and depressed left ventricular function, trimetazidine (20mg three times daily) produced significant improvements in systolic wall thickening score index (SWTI) and left ventricular ejection fraction (LVEF) (19% and 14%, respectively; P <0.001 compared with placebo) after 2 months [16]. These benefits were obtained without changes in heart rate and blood pressure, suggesting that the cytoprotective effect induced by trimetazidine was unrelated to hemodynamic modifications. The improvement in contractility was more evident in territories chronically hypoperfused, suggesting that the presence of hibernating myocardium is essential to obtain a beneficial effect with trimetazidine. As left ventricular dysfunction that results from macro- and microvascular coronary alterations is frequent in patients with diabetes, it has been suggested that trimetazidine may help to improve contractility and left ventricular function in combination with standard medications.
Recently, we studied 34 clinically stable patients with diabetes mellitus and documented multivessel coronary artery disease (29 men, five women; mean age 54±9 years, ejection fraction 0.38±0.6) [17]. Twenty-four patients had type 2 (noninsulin-dependent) diabetes mellitus, and 10 had type 1 (insulin-dependent) diabetes mellitus. Patients were allocated randomly to two groups: one group received trimetazidine (20mg three times daily) for 3 months (group T, n=19), and the other received a placebo for the same period (group C, n=15). Medications were unchanged during the study. On study entry and at 3 months, all patients underwent gated single photon emission computed tomography (SPECT) myocardial scintigraphy with a 2-day stress (Bruce)–rest procedure (500 MBq tetrofosmin). Quantitative measurements of left ventricular volumes were obtained from the gated perfusion SPECT images and from these the ejection fraction was automatically calculated. All patients completed the procedure and no side effects were reported. On initial evaluation, there were no differences between the two groups with respect to the severity of perfusion defects (summed difference score [SDS] 8.9±2.2 in group T and 8.6±2 in group C), SWTI (2.2±0.8 in group T and 2.3±0.9 in group C), and LVEF (37±6% in group T and 38±6% in group C). At 3 months, however, as compared with control patients, those treated with trimetazidine had a significant improvement in SWTI (1.7±0.9 compared with 2.3±0.9; P <0.05) and LVEF (43±6% compared with 38±6%, P=0.007). These results were similar in patients with type 1 or type 2 diabetes. No changes were observed in myocardial perfusion defects (SDS 8.2±2.4 in group T and 8.9±2.1 in group C; P=0.38). Total exercise time was also improved in trimetazidine-treated patients (from 440±140s to 530±145s; P <0.05), whereas no change was observed in controls. One example of changes in myocardial performance after trimetazidine is shown in Figure 2. We conclude that, in patients with diabetic cardiomyopathy, trimetazidine improves left ventricular systolic function and functional capacity without significant changes in myocardial defects, suggesting that a direct cytoprotective effect on myocardial cells may translate into improvements in the contractility of dysfunctional myocardium and functional capacity. We need to confirm these preliminary results in larger clinical trials. ▪

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REFERENCES

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