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Clinical Benefits of a Metabolic Approach in the Cardiac Rehabilitation of Patients with Coronary Artery Disease
Clinical Benefits of a Metabolic Approach in the Cardiac Rehabilitation of Patients with Coronary Artery Disease Romualdo Belardinelli, MD,* Francesca Lacalaprice, PT, Ernesto Faccenda, PT, and Loretta Volpe, RN Patients referred for cardiac rehabilitation may benefit from combining trimetazidine with exercise training because both treatments produce synergic benefits on the cardiovascular system. There is evidence that trimetazidine improves left ventricular (LV) function in patients with ischemic and diabetic cardiomyopathy by shifting the cellular energy substrate reference from fatty acids to glucose oxidation, and that this effect is associated with a better outcome. Recently, results have demonstrated that trimetazidine improves radial artery endothelium-dependent relaxation related to its antioxidant properties. Similarly, exercise training has been demonstrated to improve diastolic filling and systolic function in patients with ischemic cardiomyopathy, in relation to enhanced perfusion and contractility of dysfunctional myocardium. Patients with viable myocardium, in theory, should have the greatest benefits because trimetazidine improves contractility of dysfunctional hibernating/stunned myocardium, whereas exercise has documented efficacy in improving endothelial vasomotor response of coronary arteries, stimulating coronary collateral circulation and small vessel growth, improving LV function, and increasing functional capacity. At present, there are no published reports about the efficacy of the combination of trimetazidine with exercise training. In this article, we discuss the rationale for using trimetazidine in cardiac rehabilitation, the identification of patients referred for cardiac rehabilitation who might benefit the most from the addition of trimetazidine to standard therapy, and the documented benefits. © 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;98[suppl]:25J–33J)
Patients referred for cardiac rehabilitation may benefit from combining trimetazidine with exercise training because both treatments produce synergic benefits on the cardiovascular system. Trimetazidine is a metabolic modulator that inhibits a key enzyme in fatty acid oxidation and shifts the cellular energy substrate reference from fatty acids to glucose oxidation.1 As a result of this action, trimetazidine ensures additive antianginal efficacy, and both left ventricular (LV) systolic function and diastolic filling are improved in ischemic heart disease (IHD), especially in patients with diabetic cardiomyopathy.2– 4 More recently, trimetazidine improved radial artery endothelium-dependent relaxation in chronic heart failure, which was correlated with decreased plasma levels of lipid free radicals.5 Similarly, exercise training improves diastolic filling and systolic function in patients with ischemic cardiomyopathy, in relation to enhanced contractility6 and perfusion of dysfunctional myocardium.7 Patients with viable myocardium, in theory, should benefit the most from either trimetazidine or exercise
Struttura di Cardiologia Riabilitativa e Preventiva, Presidio Cardiologico “GM Lancisi”, Ancona, Italy. *Address for reprints: Romualdo Belardinelli, MD, Presidio Cardiologico GM Lancisi, Cardiologia Riabilitativa e Preventiva, Via Conca, 71, 60020 Ancona, Italy. E-mail address: [email protected]. 0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.07.006
training because both treatments improve the contractile function of dysfunctional hibernating/stunned myocardium. Exercise training acts by inducing a series of adaptations in myocardial cells and coronary vessels, and trimetazidine modulates the metabolism of myocardial cells. Moreover, exercise training has documented efficacy in improving endothelial vasomotor response of coronary and peripheral arteries and in increasing functional capacity in relation to several adaptations in different areas. In this article, we consider (1) the rationale for using trimetazidine in cardiac rehabilitation, (2) the identification of patients referred for cardiac rehabilitation who might benefit the most from the addition of trimetazidine to standard therapy, and (3) the documented benefits of trimetazidine in treating exercise intolerance in patients with IHD.
Rationale for Using Trimetazidine in Cardiac Rehabilitation Cardiac rehabilitation programs were first introduced in the 1960s when the benefits of ambulation during prolonged hospitalization for coronary events had been documented. Exercise training was the primary component of these programs, and its safety and benefits have been intensively investigated in supervised programs over the years.8 www.AJConline.org
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The main goals of cardiac rehabilitation are (1) to prevent disability resulting from coronary artery disease (CAD), particularly in older persons and those with occupations that involve physical exertion; and (2) to prevent subsequent cardiovascular events, hospitalization, and death from cardiac causes. Thus, cardiac rehabilitation is not only indicated for incapacitated disabled patients, but also for all patients with CAD.8,9 However, when initiating an exercise training program, it is extremely important to identify patients with inducible myocardial ischemia or with chronically dysfunctional viable myocardium and to tailor the regimen so as to reduce symptoms as much as possible. This will improve functional capacity and encourage patients to have a more active lifestyle, with a further decrease in symptoms as well as an improvement in the life expectancy. Thus, it is of utmost importance to optimize the pharmacologic treatment, which usually includes the use of agents, such as -blockers, calcium antagonists, and nitrates, in addition to percutaneous coronary intervention and coronary artery bypass graft surgery, when appropriate. Usually, if a single traditional antianginal agent is ineffective to control symptoms, a second or third agent is added in combination. However, a meta-analysis of several clinical studies has demonstrated that a combination of classic hemodynamically active agents failed to provide a real additive efficacy over monotherapy.10 In addition, the use of maximal doses of hemodynamically active agents may be limited by the development of undesirable side effects, especially in the elderly population and in patients with LV dysfunction. Thus, alternative therapeutic approaches are required to improve the management of patients with angina and thus increase their exercise capacity. The so-called metabolic approach with trimetazidine appears to represent a rational answer to this problem because it addresses the underlying abnormalities in cardiac metabolism that are not affected by conventional “hemodynamically acting” antianginal drugs. The clinical efficacy of trimetazidine has been demonstrated in the Second Trimetazidine in Poland (TRIMPOL II) study11 conducted in 347 patients with stable angina, insufficiently controlled by -blocker monotherapy, in whom the addition of trimetazidine to metoprolol caused a significant improvement in all ergometric and clinical parameters. These findings were recently confirmed in a study of trimetazidine (35 mg) modified release12 in patients still symptomatic with a positive exercise tolerance test despite background therapy with atenolol 50 mg. Again, the addition of trimetazidine to atenolol led to a significant increase in the angina and ischemic thresholds. Thus, we can conclude that the metabolic approach with trimetazidine further increases the effort capacity of patients with CAD undergoing cardiac rehabilitation, thereby producing synergic benefits on the cardiovascular system when used in combination with traditional therapy. Moreover, there is evidence that trimetazidine at an oral dose of 20 mg 3 times daily improves LV function in patients with ischemic cardiomy-
opathy. In patients with LV dysfunction and multivessel CAD, treatment with trimetazidine 20 mg 3 times daily for 8 weeks led to a significant improvement in systolic wall thickening score index at rest and peak dobutamine infusion (13% and 21%, respectively; p ⬍0.001), LV ejection fraction (LVEF) (19.7% and 14.1%; p ⬍0.001), and peak oxygen consumption (15%) (Figure 1). These benefits were obtained without concomitant changes in heart rate and blood pressure, suggesting that the improved cardiac function is because of cytoprotection unrelated to hemodynamic effects. No side effects were observed among treated patients.2 Brottier and colleagues3 had previously demonstrated an improvement in radionuclide LVEF after 6 months of treatment with trimetazidine at the same dose in 18 New York Heart Association (NYHA) class III and IV patients with ischemic cardiomyopathy.3 The LVEF showed a mean improvement of 9.3% at 6 months. Cardiac volume on chest x-rays decreased significantly at 6 months in the trimetazidine group compared with placebo (p ⫽ 0.034). Treated patients also had enhanced functional capacity, as shown by improvement in NYHA functional class (p ⬍0.001). Thus, in patients with ischemic cardiomyopathy, the addition of trimetazidine to conventional treatment significantly improves myocardial function, which is of the utmost importance to increase the effort capacity of patients undergoing cardiac rehabilitation. In another study, Fragasso and associates4 studied the effects of trimetazidine in patients with diabetes mellitus and ischemic cardiomyopathy. Treatment with trimetazidine (20 mg 3 times daily for 15 days, followed by a 6-month period of treatment according to a double-blind crossover design) led to a significant improvement in LVEF (p ⬍0.001 vs placebo for both 2 weeks and 6 months), whereas endothelin-1 decreased significantly (p ⬍0.001 and p ⬍0.03, respectively). Fasting blood glucose also decreased significantly after 2 weeks (p ⫽ 0.02), but no significant change was observed at 6 months. At 2 weeks, 10 of 16 patients improved NYHA functional class by 1 class (p ⫽ 0.019 vs placebo), and 8 patients maintained the improvement at 6 months (p ⫽ 0.018 vs placebo). In summary, trimetazidine improved LV function, NYHA functional class, glucose metabolism, and endothelial function in patients with diabetes and ischemic cardiomyopathy. Similar results were observed in patients with type 2 diabetes and ischemic cardiomyopathy (LVEF, 0.32) who were randomized to receive trimetazidine (20 mg 3 times daily) or placebo for 6 months.13 The LVEF increased by 5.4 ⫾ 0.5% in patients receiving trimetazidine (p ⬍0.05) in relation to significant decreases in LV end-diastolic and end-systolic volumes (⫺8% and ⫺17%, respectively; p ⬍0.05 for both parameters vs placebo). Significant improvements in wall motion score index and diastolic filling mitral inflow pattern (E/A ratio) were also observed only in trimetazidine-treated patients. More recently, the same investigators found improvements in LV function of elderly patients aged 78 ⫾ 3 years with CAD who were treated with trimetazidine at
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Figure 1. Trimetazidine improves the contractile response of chronically dysfunctional myocardium to low-dose dobutamine in ischemic cardiomyopathy. Both resting and peak dobutamine systolic wall thickening score index improved significantly in trimetazidine-treated patients compared with controls. SWTI ⫽ systolic wall thickening index. *p ⬍0.001 versus controls.
doses of 20 mg 3 times daily in addition to standard therapy for 6 months.14 Similar to previous reports, both LV systolic and diastolic function were improved, as well as NYHA functional class. Evidently, modulation of myocardial energy metabolism with trimetazidine improves not only contractile performance of dysfunctional myocardium but also diastolic filling, and these beneficial effects translate into improvements in LV function and functional capacity in patients with ischemic cardiomyopathy with or without diabetes. The improved ventricular function with trimetazidine at rest and during stress is of particular clinical importance when attempting to improve the exercise training capacity of patients with CAD and to maintain the patients with diabetes in the infraischemic zone when undergoing cardiac rehabilitation. Recent interest has focused on the antioxidant properties of trimetazidine and on its potential beneficial effect on endothelial function. As demonstrated by Fragasso and colleagues,4 trimetazidine decreases plasma endothelin-1 levels in patients with ischemic cardiomyopathy and diabetes. In chronic heart failure, plasma endothelin-1 levels are increased in parallel with the severity of cardiovascular dysfunction, and the endothelium-dependent vasorelaxation is impaired because of altered vascular homeostasis. A possible mechanism may be that trimetazidine inhibits endothelin-1 release by decreasing the deleterious effects of chronic ischemia. Previous studies have shown the reduction in intracellular acidosis and the preservation of intracellular phosphocreatine and adenosine triphosphate (ATP) levels after trimetazidine in animal models of myocardial ischemia. Moreover, there is evidence that trimetazidine reduces the loss of intracellular potassium induced by oxygen free
radicals in red cells as well as the membrane content of peroxidated lipids.15 Nitric oxide seems to blunt signaling by endothelin, the principal peptide responsible for vascular smooth muscle cell contraction, by slowing its release. In conditions of chronic shear stress, nitric oxide appears to be a critical mediator of the decrease in endothelin release. In fact, endothelin decrease is abrogated by nitric oxide inhibitors and potentiated by phosphodiesterase inhibitors. An antioxidant effect of trimetazidine is suggested by a reduction in systemic markers of oxidant stress, such as malondialdehyde and hydroperoxides. There is evidence that free radicals are increased in chronic heart failure in both experimental and clinical studies.16,17 Prasad and associates18 have found that leukocyte-mediated production of oxygen-derived free radicals is increased 4-fold in patients with heart failure compared with control subjects. Free radicals generated under conditions of oxidant stress induce significant tissue damage and modifications of lipids and proteins in the vasculature. Lipid peroxidation generates hydroperoxides from polyunsaturated fatty acids (PUFA), when hydroxyl radicals come into contact with PUFA, generating a stable oxygen species (H2O) and a PUFA radical, which in turn rearranges to form a conjugated diene reacting with molecular oxygen to form a PUFA–peroxyl radical. Lipid peroxides can yield lipid peroxyl radicals, which can react with nitric oxide to form lipid peroxynitrites. In chronic heart failure, there is also a reduction in cardiac antioxidant enzymes, which worsens oxidative stress.19 Recently, Belardinelli and associates5 have demonstrated that trimetazidine improves endothelium-dependent vasodilation in a group of 51 patients with ischemic cardiomyopathy and chronic heart failure (mean age, 51.4 ⫾ 6 years), and this effect was correlated both with decreased plasma levels of
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malondialdehyde and hydroperoxides and with enhanced functional capacity. No change in endothelium-independent vasorelaxation was detected. The improvement in endothelial function may be the result of a direct or an indirect effect of trimetazidine on the endothelium (Figure 2). In fact, trimetazidine, as a metabolic modulator in the presence of dysfunctional viable myocardium, improves LV function and cardiovascular efficiency, which may shift the balance between endothelial vasodilating and vasoconstricting substances in favor of the former. Improvements in functional capacity are correlated with improvements in endothelium-dependent vasorelaxation, and a reduction in oxidative stress may enhance endothelial function by decreasing the rate of inactivation of nitric oxide by products of lipid peroxidation and reactive oxygen species.20 On the other hand, trimetazidine may exert a direct effect on endothelial cells, acting as a lipid barrier permeable transition metal chelator, protecting the endothelium from free radicals.21 This action may be of particular importance in diabetes and in conditions of high oxidative stress in which low-density lipoprotein oxidation and DNA oxidative damage may directly injure endothelial cells and cause abnormal gene expression and altered signal transduction.
Identification of Patients Referred for Cardiac Rehabilitation Who Might Benefit the Most from the Addition of Trimetazidine to Standard Therapy The results of previous studies emphasized that major benefits are obtained with trimetazidine when hibernating/ stunned myocardium is present. In fact, both better control of angina symptoms and improvement in LV function have been observed after the addition of trimetazidine to standard therapy in the human clinical model of ischemic cardiomyopathy with multivessel CAD and ⱖ1 cardiovascular risk factors. This model is characterized by a scenario of viable and nonviable cells, with areas of hibernating/stunned dysfunctional myocardium mixed with necrotic and normal myocardium, fed by coronary arteries with multiple atherosclerotic lesions of different severity. The optimization of cellular energy metabolism by trimetazidine improves ATP resynthesis through inhibition of fatty acid oxidation and stimulation of glucose oxidation. Patients with diabetes with multiple CAD and dysfunctional myocardium have been studied in more detail because this model is associated with metabolic and functional abnormalities that may undergo improvement after the addition of a metabolic modulator agent. Patients with diabetes have a greater incidence of CAD, which is in part related to concomitant cardiovascular risk factors, such as hypertension, blood lipid abnormalities, obesity, and physical inactivity.22 They have a higher incidence of silent ischemia, greater mortality during and after an acute myocardial infarction (MI), and an increased rate
of complications, including LV dysfunction and heart failure. The main metabolic abnormality of the diabetic heart is the decreased ability to oxidize pyruvate as a consequence of phosphorylation inhibition of pyruvate dehydrogenase because of upregulation of pyruvate dehydrogenase kinase.23 Patients with diabetes have high circulating free fatty acid and ketone body concentrations in the plasma, resulting in greater levels of acetyl coenzyme A and reduced nicotinamide adenine dinucleotide in mitochondria and inhibition of pyruvate dehydrogenase. Studies in animal models of diabetes suggest that the reduction in fatty acid oxidation and/or the direct stimulation of pyruvate oxidation improves myocardial function during ischemia and reperfusion.24 Glucose and insulin infusions in patients with acute MI caused a 29% reduction in mortality at 1 year compared with conventional therapy.25 This effect was more marked in patients with a low cardiovascular risk profile and any previous insulin treatment (52% reduction). These benefits are likely because of reduced plasma free fatty acid and ketone body levels, resulting in less inhibition of pyruvate dehydrogenase activity and more efficient production and utilization of ATP. Cardiovascular disease in patients with diabetes has several components, including cardiac, macrovascular, and microvascular diseases, that create a vicious cycle of progressively worsening abnormalities.26 A typical condition in patients with diabetes is multiple CAD with dysfunctional myocardium, the so-called diabetic cardiomyopathy. Coronary lesions are typically multiple at a different maturative state in the same vessels and frequently extend to the distal end of the coronary tree. After several years, the disease can spread to all major coronary vessels, causing functional and structural abnormalities in cardiomyocytes. Chronic ischemia generates hibernating myocardium with depressed contractility and consequent regional LV dysfunction. When the amount of dysfunctional myocardium becomes relevant, ventricular insufficiency and heart failure will develop, causing clinical deterioration.27 Recently, we studied 34 clinically stable patients with diabetes and documented multivessel CAD (29 men and 5 women; mean age, 54 ⫾ 9 years; LVEF, 0.38 ⫾ 0.06).28 Of these, 24 patients had type 2 diabetes, and 10 had type 1 diabetes. Patients were randomized to receive trimetazidine 20 mg 3 times daily (T group, n ⫽ 19), or placebo (C group, n ⫽ 15) for 3 months. 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 using a 2-day stress (Bruce)–rest protocol (500 MBq 99mTc-tetrofosmin). Quantitative measurements of LV volumes from gated perfusion SPECT images were obtained from which LVEF was calculated. All patients completed the protocol, and no side effects were reported. At 3 months, trimetazidine-treated patients had a significant improvement in systolic wall thickening index (1.7 ⫾ 0.9 vs 2.3 ⫾ 0.9, p ⬍0.05) and
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Figure 2. Common effects of trimetazidine and exercise in the cardiovascular system and their possible interaction. Both trimetazidine and exercise improve left ventricular (LV) function, the former through metabolic modulation, the latter through intermittent bouts of increased shear stress. In ischemic cardiomyopathy, exercise improves myocardial perfusion through ⱖ4 mechanisms: improvement in endothelium-dependent relaxation of coronary vessels, arterial remodeling (Glagov effect), coronary collateral circulation (arteriogenesis), and small vessel growth (angiogenesis). The improvement in LV function is associated with enhanced endothelial function. Trimetazidine’s effect on the endothelium is direct and indirect. Trimetazidine directly reduces nitric oxide inactivation through decreased production of lipid peroxidation (LOONO.). This effect is associated with decreased plasma levels of systemic markers of oxidative stress, such as malondialdehyde and hydroperoxides, and endothelin-1 as well. Trimetazidine’s indirect effect on the endothelial function depends on its anti-ischemic properties and on contractility of dysfunctional myocardium, which both contribute to improve LV function. Exercise, through increased shear stress, stimulates both endothelial nitric oxide synthase (e-NOS) and extracellular superoxide dismutase (ec-SOD) expressions in endothelial cells and subendothelial smooth muscle cells, respectively, determining increased nitric oxide synthesis and decreased nitric oxide inactivation by free radicals. The improvement in endothelium-dependent vasorelaxation contributes to the enhancement of functional capacity.
LVEF (0.43 ⫾ 0.06 vs 0.38 ⫾ 0.06, p ⫽ 0.007) compared with control patients. These effects were similar in patients with type 1 and type 2 diabetes. No changes were observed in myocardial defects (SD score: T, 8.2 ⫾ 2.4; C, 8.9 ⫾ 2.1; p ⫽ 0.38). Total exercise time was also improved in trimetazidine-treated patients (from 440 ⫾ 140 seconds to 530 ⫾ 145 seconds, p ⬍0.05), whereas no change was observed in controls. We conclude that in patients with diabetic cardiomyopathy, trimetazidine improves LV 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 contractility of dysfunctional myocardium and functional capacity. The differentiation between viable and nonviable myocardium is an important diagnostic issue in patients referred not only for revascularization but also for cardiac rehabilitation. In fact, it has been estimated that 25%– 40% of patients with chronic CAD and LV dysfunction have the potential for significant improvement in systolic performance after revascularization. Metabolic activity in myocardial regions with reduced blood flow is an accurate clinical marker of viability, with a mean sensitivity and specificity of 93% and 58%, and mean positive predictive value and negative predictive value of 71% and 86%, respectively.29 The identification of myocardial viability predicts the improvement in functional capacity after cardiac rehabilitation and the clinical outcome in patients with ischemic cardiomyopathy. We studied 71 consecutive patients (mean age, 56 ⫾ 9 years) with chronic heart failure secondary
to ischemic cardiomyopathy (LVEF ⬍0.40).30 Patients were randomized into 2 matched groups. One group (n ⫽ 36) underwent supervised exercise training at 60% of peak oxygen consumption 3 times a week for 10 weeks, and a control group (n ⫽ 35) did not exercise. The presence of viable myocardium at baseline by low-dose dobutamine echocardiography identified patients with improved peak oxygen consumption at the end of the training program, with a sensitivity of 70% and a specificity of 77%. Patients with viable myocardium at baseline had higher peak oxygen consumption as well as a lower systolic wall thickening score index after exercise training. The improvement in contractility was more marked among less dysfunctional myocardial segments on initial evaluation. Moreover, trained patients had a significantly lower occurrence of cardiac events during follow-up (22% vs 51%, p ⬍0.001). Patients with cardiac events had a significantly higher systolic wall thickening index on initial evaluation. Independent predictors of cardiac events during 23 ⫾ 6 months of follow-up were the pre–post training difference in LVEF at peak dobutamine infusion and the presence of viable response at baseline (p ⫽ 0.004 and p ⫽ 0.008, respectively). The log-rank test demonstrated that trained patients had a significantly lower probability of cardiac events during follow-up than did sedentary control patients (p ⬍0.001). These results suggest that in patients with ischemic cardiomyopathy and heart failure, the presence of hibernating dysfunctional myocardium represents an important premise to obtain successive improvements in functional capacity and LV function after exercise training. The precise mechanisms by which these
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beneficial effects may occur have not yet been fully elucidated. As recently demonstrated, both improvements in myocardial perfusion and coronary endothelial function seem to play a role.7,31 Nonetheless, peripheral adaptations cannot be excluded, as suggested by changes in neurohormones, metabolic substances, inflammatory mediators, and skeletal muscle cells.32–34 Thus, the identification of viable myocardium in patients with ischemic cardiomyopathy is an important diagnostic issue because it may identify patients who will improve LV function and event-free survival (Table 1). Recently, trimetazidine was shown to improve endothelium-dependent vasorelaxation in chronic heart failure, which was correlated with decreased plasma levels of lipid free radicals.5 The increase in radial artery diameter to acetylcholine was more marked after trimetazidine in patients with ⬎2 coronary risk factors (Figure 3). A possible explanation may be that patients with ⬎2 coronary risk factors have a greater oxidative stress, as confirmed by the higher plasma levels of malondialdehyde and hydroperoxides. Therefore, this subgroup of patients should be more responsive to antioxidant treatment, as previously suggested by Heitzer and coworkers,17 who found that co-infusion of vitamin C improved acetylcholine-induced vasodilation in patients with CAD with an adverse outcome. On the basis of this evidence, conditions of high oxidative stress should take advantage of the addition of trimetazidine to standard therapy and should also be considered for a program of cardiac rehabilitation.
Documented Effects of Trimetazidine on Exercise Training Response Despite the potentially favorable premises suggested by the effects of trimetazidine or exercise training used separately, there are no published reports about the effects of trimetazidine in patients referred for cardiac rehabilitation. Our laboratory investigated the effects of trimetazidine combined with exercise training in 2 conditions: ischemic cardiomyopathy and peripheral arterial obstructive disease. Ischemic cardiomyopathy: We studied 86 patients (72 men and 14 women; mean age, 59 ⫾ 9 years) with IHD and LV dysfunction (LVEF, 0.38 ⫾ 0.07) who were referred for cardiac rehabilitation (unpublished data). All patients had had a previous MI, 45 underwent coronary artery bypass surgery, and 35 underwent percutaneous transluminal coronary angioplasty in 1 (18 patients), 2 (17 patients), and 3 (5 patients) major coronary arteries. Coronary risk factors were present in 72 patients (diabetes in 36). Patients were randomized to 3 matched groups. The first group received trimetazidine orally at doses of 20 mg 3 times daily for 8 weeks in addition to standard medications and underwent a supervised program of exercise training at 60% of peak oxygen consumption 3 times a week for 8 weeks (trimetazidine plus training, n ⫽ 30). A second group completed the
exercise training program without receiving trimetazidine (training, n ⫽ 30), and a third group neither exercised nor received trimetazidine (control, n ⫽ 26). On study entry and at 8 weeks, all subjects underwent Doppler echocardiography, cardiopulmonary exercise testing, and vasomotor reactivity of the brachial artery. Peak oxygen consumption was significantly increased in the trimetazidine plus training group and in the training-only group, whereas it was unchanged in control subjects. LVEF improved in the trimetazidine plus training group as well as in the training-only group as a result of reduction in end-systolic volume. No changes were observed in controls. The endothelium-dependent vasorelaxation was also improved in the trimetazidine plus training group and in the training-only group, whereas no changes were observed in control patients. Only 1 patient stopped trimetazidine because of diarrhea. No other side effects were reported. The results of the present investigation indicate that the combination of trimetazidine with exercise training potentiates the effect of exercise training and brings about more marked improvements in functional capacity, LV systolic function, and the endothelium-dependent relaxation of the brachial artery than exercise training alone in patients with ischemic cardiomyopathy referred for cardiac rehabilitation. Peripheral arterial obstructive disease: In another study, we added trimetazidine (20 mg 3 times daily) to standard medications in 24 patients with peripheral arterial obstructive disease (unpublished data). Patients were randomized into 2 groups. The first group (n ⫽ 12) received trimetazidine for 4 weeks and exercised on a treadmill 3 times a week for 4 weeks. The second group exercised with the same protocol without receiving trimetazidine. The exercise protocol was supervised, based on the intensity of treadmill exercise triggering leg pain (on– off protocol). All patients underwent a treadmill exercise test (Bruce protocol) on study entry and at 4 weeks. Patients who received trimetazidine and exercised had a significantly greater improvement in total exercise time (from 236 ⫾ 98 seconds to 318 ⫾ 110 seconds, p ⬍0.0001) and time to onset of leg pain (from 168 ⫾ 86 seconds to 224 ⫾ 102 seconds, p ⬍0.0001) compared with patients who did not receive trimetazidine (from 224 ⫾ 102 seconds to 284 ⫾ 98 seconds, and from 155 ⫾ 79 seconds to 185 ⫾93 seconds, respectively). Both studies indicate that the combination of trimetazidine and exercise training can bring about more marked benefits than exercise training alone in patients with ischemic cardiomyopathy and peripheral arterial obstructive disease. We speculate that trimetazidine potentiates the effects of exercise training on dysfunctional myocardium and on endothelial cells (Figure 1). Trimetazidine, by shifting the energy substrate reference from fatty acids to glucose oxidation, improves contractility of myocardial cells by decreasing cellular acidosis and increasing ATP production. This action improves LV performance and cardiovascular
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Table 1 Pathology, substrate, and documented effects of trimetazidine Pathology
Substrate
Trimetazidine Dosage
Documented Effects
Ischemic/diabetic cardiomyopathy
Viable myocardium
20 mg tid
Ischemic heart disease
Stunned myocardium
20 mg tid
Chronic heart failure
High oxidative stress Viable myocardium
20 mg tid
Peripheral arterial obstructive disease
Chronically hypoperfused cells
20 mg tid
Improvements in: Myocardial contractility LV ejection fraction LV volumes Functional capacity Reduction in the number of anginal attacks Increased time to ST downsloping and time to angina Increase in work capacity Reduction in systemic markers of oxidant stress Improvement in endothelium-dependent vasorelaxation Improvement in LV function Increase in functional capacity Increased time to onset of claudication Increase in exercise tolerance
LV ⫽ left ventricular.
Figure 3. Radial arterial diameter response to crescent doses of acetylcholine (Ach) 7.5, 15, and 30 g/min after 4 weeks of oral doses of trimetazidine 20 mg 3 times daily in patients with ischemic cardiomyopathy with ⱕ1 and ⬎2 coronary risk factors. Patients with ⬎2 coronary risk factors have a higher oxidative stress, as demonstrated by greater plasma levels of lipid peroxidation products (malondialdehyde and hydroperoxides).5 Patients with higher oxidative stress have a significantly greater vasodilation to Ach than patients with lower oxidative stress. *p ⬍0.0001 by analysis of variance.
efficiency and reduces endothelial dysfunction. In addition, regular aerobic exercise improves the endothelium-dependent vasorelaxation of peripheral as well as coronary arteries. This effect is associated with greater vascular expression of endothelial nitric oxide synthase and extracellular superoxide dismutase and is related to an increase in shear stress produced by blood flow on the inner arterial wall. Exercise training improves cardiovascular efficiency through different mechanisms. Neurohormonal activation is reduced in trained patients, in conjunction with improved autonomic balance and decreased plasma levels of inflammatory and vasoconstricting substances, such as tumor necrosis factor–␣, interleukin-1 and interleukin-6, angiotensin II, and endothelin-1.35 At the subcellular level, exercise training improves calcium reuptake of sarcoplasmic reticulum and improves oxygen diffusing capacity of the coronary vessels.36,37 Both effects contribute to improve resting peak
diastolic filling rate, which correlates with increased cardiac index during exercise.6 Cardiac output is also increased at submaximal and peak exercise in relation to decreased endsystolic volume index and decreased afterload. In patients with ischemic cardiomyopathy, exercise training enhances contractility of dysfunctional myocardium, which correlates with improved myocardial perfusion on thallium scintigraphy.7 Exercise directly stimulates new vessel growth in the presence of hypoxia, and this effect may partly explain the development of coronary collaterals. It is possible that in the presence of significant coronary artery stenosis, intermittent exercise, by inducing short periods of ischemia, may stimulate vascular endothelial growth factor expression and increased adenosine concentration in the myocardium, which both can induce neoangiogenesis. Dipyridamole—an inhibitor of adenosine uptake by myocardial cells— enhances collateral-dependent flow and regional function during ex-
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ercise in a human model of IHD.38 Nitric oxide seems to exert a tonic dilating effect on coronary collateral vessels developed as a result of myocardial ischemia.39 As a matter of fact, collateral flow is significantly reduced by a nitric oxide synthase inhibitor (L-NAME). Another hypothesis may be that exercise reduces endothelial dysfunction in segments of coronary vessels with intact endothelium. However, as previously demonstrated, intermittent exercise induces vasoconstriction at the level of stenoses. Thus, in chronic heart failure caused by IHD, there are at least 2 different mechanisms of improvement in myocardial perfusion after exercise training that can be hypothesized: exercise-induced ischemia that stimulates neoangiogenesis, and shear stress–mediated endothelium-dependent relaxation of coronary segments with intact endothelium. Both mechanisms may interact and potentiate each other.35 Moreover, exercise improves the endothelium-dependent relaxation of conduit and resistance arteries, which is correlated with functional capacity and is predictive of a favorable outcome. In conditions of high oxidative stress (ie, chronic heart failure or diabetes), trimetazidine reduces free radicals and improves the endothelium-dependent vasorelaxation through its metabolic effect and through a direct effect on endothelial cells (see above).
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Conclusion Currently, there is evidence that cardiac rehabilitation improves functional capacity, LV function, and the clinical outcome of patients with CAD. Thus, optimization of pharmacologic treatment is of utmost importance, and the use of trimetazidine, a metabolic antianginal agent, seems to be a rational way to ensure the optimal decrease in symptoms and improvement in cardiac function. Moreover, there is preliminary evidence that the combination of trimetazidine with exercise training provides greater improvements in LV function and aerobic capacity than exercise training given alone, thereby producing synergic benefits on the cardiovascular system. This combination has been tested in patients with ischemic cardiomyopathy and peripheral arterial obstructive disease. Both treatments are well tolerated and the incidence of side effects is very low. These preliminary results should encourage further studies in a larger population. 1. Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A tiolase. Circ Res 2000;86:580 –588. 2. Belardinelli R, Purcaro A. Effects of trimetazidine on the contractile response of chronically dysfunctional myocardium to low-dose dobutamine in ischaemic cardiomyopathy. Eur Heart J 2001;22:2164 –2170. 3. Brottier L, Barat JL, Combe C, Boussens B, Bonnet J, Bricand H. Therapeutic value of a cardioprotective agent in patients with severe ischaemic cardiomyopathy. Eur Heart J 1990;11:207–212. 4. Fragasso G, Piatti PM, Monti L, Palloshi A, Setola E, Puccetti P, Calori G, Lopaschuk GD, Margonato A. Short- and long-term bene-
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20. 21.
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ficial effects of trimetazidine in patients with diabetes and ischemic cardiomyopathy. Am Heart J 2003;146:E18 –E25. Belardinelli R, Solenghi M, Volpe L, Purcaro A. Trimetazidine improves endothelial dysfunction in chronic heart failure: an antioxidant effect? Circulation 2001;104(suppl II):1612 [abstract]. Belardinelli R, Georgiou D, Cianci G, Berman N, Ginzton L, Purcaro A. Exercise training improves left ventricular diastolic filling in patients with dilated cardiomyopathy: clinical and prognostic implications. Circulation 1995;91:2775–2784. Belardinelli R, Georgiou D, Ginzton L, Cianci G, Purcaro A. Effects of moderate exercise training on thallium uptake and contractile response to low-dose dobutamine of dysfunctional myocardium in patients with ischemic cardiomyopathy. Circulation 1998;97:553–561. Giannuzzi P, Saner H, Björnstad H, Fioretti P, Mendes M, CohenSolal A, Dugmore L, Hambrecht R, Hellemans I, McGee H, et al. Secondary prevention through cardiac rehabilitation: position paper of the Working Group on Cardiac Rehabilitation and Exercise Physiology of the European Society of Cardiology. Eur Heart J 2003;24:1273– 1278. Rehabilitation after cardiovascular diseases, with special emphasis on developing countries: report of a WHO Expert Committee. World Health Organ Tech Rep Ser 1993;831:1–122. Klein W, Jackson G, Tavazzi L. Efficacy of monotherapy compared with combined antianginal drugs in the treatment of chronic stable angina pectoris: a meta-analysis. Coron Artery Dis 2002;13:427– 436. Szwed H, Sadowski Z, Elikowski W, Koronkiewicz A, Mamcarz A, Orszulak W, Skibinska E, Szymczak K, Swiatek J, Winter M. Combination treatment in stable effort angina using trimetazidine and metoprolol: results of a randomized, double-blind, multicentre study (TRIMPOL II). Eur Heart J 2001;22:2267–2274. Sellier P, Broustet JP. Assessment of anti-ischemic and antianginal effect at trough plasma concentration and safety of trimetazidine MR 35 mg in patients with stable angina pectoris: a multicenter, doubleblind, placebo-controlled study. Am J Cardiovasc Drugs 2003;3:361– 369. Rosano GM, Vitale C, Sposato B, Mercuro G, Fini M. Trimetazidine improves left ventricular function in diabetic patients with coronary artery disease: a double-blind placebo-controlled study. Cardiovasc Diabetol 2003;2:16 –24. Vitale C, Wajngaten M, Sposato B, Gebara O, Rossini P, Fini M, Volterrani M, Rosano GM. Trimetazidine improves left ventricular function and quality of life in elderly patients with coronary artery disease. Eur Heart J 2004;25:1814 –1821. Maridonneau-Parini K, Harpey C. Effects of trimetazidine on membrane damage induced by oxygen free radicals in human red cells. Br J Clin Pharmacol 1985;20:148 –151. Wiemer G, Itter G, Malinski T, Linz W. Decreased nitric oxide availability in normotensive and hypertensive rats with failing hearts after myocardial infarction. Hypertension 2001;38:1367–1371. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 2001;104:2673– 2678. Prasad K, Gupta JB, Kalra J, Bharadwaj B. Oxygen free radicals in volume overload heart failure. Mol Cell Biochem 1992;111:55–59. Baumer AT, Flesch M, Wang X, Shen Q, Feuerstein GZ, Bohm M. Antioxidative enzymes in human hearts with idiopathic dilated cardiomyopathy. J Mol Cell Cardiol 2000;32:121–130. Loscalzo J. Nitric oxide insufficiency, platelet activation, and arterial thrombosis. Circ Res 2001;88:756 –762. Tselepis A, Doulias PT, Lourida E, Glantzounis G, Tsimohiannis E, Galaris D. Trimetazidine protects low-density lipoproteins from oxidation and cultured cells exposed to H2O2 from DNA damage. Free Radic Biol Med 2001;30:1357–1364. Eschwege E, Simon D, Balkau B. The growing burden of diabetes in the world population. International Diabetes Federation Bulletin 1997;42:14 –19.
Belardinelli et al/Clinical Benefits of a Metabolic Approach in the Cardiac Rehabilitation of Patients with Coronary Artery Disease 23. Garvey WT, Hardin D, Juhaszova M, Dominguez JH. Effects of diabetes on myocardial glucose transport system in rats: implications for diabetic cardiomyopathy. Am J Physiol 1993;264:H837–H844. 24. Paulson DJ, Kopp SJ, Peace DG, Tow JP. Improved postischemic recovery of cardiac pump function in exercised trained diabetic rats. J Appl Physiol 1988;65:187–193. 25. Malmberg K, Ryden L, Efendic S, Herlitza J, Nicola P, Waldenströma A, Wedela H, Welin L. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol 1995;26:57– 65. 26. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002;287: 2570 –2581. 27. Stanley WC, Lopaschuk GD, Hall JL, McCormack JG. Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions: potential for pharmacologic interventions. Cardiovasc Res 1997;33:243–257. 28. Belardinelli R, Cianci G, Gigli M, Perna GP. Trimetazidine improves left ventricular systolic function in ischemic cardiomyopathy. Circulation 2004;110(suppl II):3051 [abstract]. 29. Bax JJ, Poldermans D, Elhendy A, Boersma E, Rahimtoola SH. Sensitivity, specificity, and predictive accuracies of various noninvasive techniques for detecting hibernating myocardium. Curr Probl Cardiol 2001;26:141–188. 30. Belardinelli R, Georgiou D, Purcaro A. Low dose dobutamine echocardiography predicts improvement in functional capacity after exercise training in patients with ischemic cardiomyopathy: prognostic implication. J Am Coll Cardiol 1998;31:1027–1034. 31. Hornig B, Maier V, Drexler H. Physical training improves endothelial function in patients with chronic heart failure. Circulation 1996;93: 210 –214.
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32. Hambrecht R, Niebauer J, Fiehn E, Kälberer B, Offnera B, Hauer K, Riede U, Schlierf G, Kübler W, Schuler G. Physical training in patients with stable chronic heart failure: effects on cardiorespiratory fitness and ultrastructural abnormalities of leg muscles. J Am Coll Cardiol 1995;25:1239 –1249. 33. Radaelli A, Coats AJ, Leuzzi S, Piepoli M, Meyer TE, Calciati A, Finardi G, Bernardi L, Sleight P. Physical training enhances sympathetic and parasympathetic control of heart rate and peripheral vessels in chronic heart failure. Clin Sci 1996;91:92–94. 34. Tyni-Lenne R, Gordon A, Jansson E, Bermann G, Sylven C. Skeletal muscle endurance training improves peripheral oxidative capacity, exercise tolerance, and health-related quality of life in women with chronic congestive heart failure secondary to either ischemic cardiomyopathy or idiopathic dilated cardiomyopathy. Am J Cardiol 1997; 80:1025–1029. 35. Piña IL, Apstein CA, Balady GJ, Belardinelli R, Chaitman BR, Duscha BD, Fletcher BJ, Fleg JL, Myers JN, Sullivan MJ, for the American Heart Association Committee on Exercise, Rehabilitation, and Prevention. Exercise and heart failure: a statement from the American Heart Association Committee on Exercise, Rehabilitation, and Prevention. Circulation 2003;107:1210 –1225. 36. Stehno-Bittel L, Laughlin MH, Sturek M. Exercise training depletes sarcoplasmic reticulum Ca in coronary smooth muscle. J Appl Physiol 1991;71:1764 –1773. 37. Laughlin MH, McAllister RM. Exercise training-induced coronary vascular adaptation. J Appl Physiol 1992;73:2209 –2225. 38. Belardinelli R, Belardinelli L, Shryock JC. Effects of dipyridamole on coronary collateralization and myocardial perfusion in patients with ischemic cardiomyopathy. Eur Heart J 2001;22:1205–1213. 39. Frank MW, Harris KR, Ahlin KA, Klocke FJ. Endothelium-derived relaxing factor (nitric oxide) has a tonic vasodilating action on coronary collaterals vessels. J Am Coll Cardiol 1996;27:658 – 663.
Patients referred for cardiac rehabilitation may benefit from combining trimetazidine with exercise training because both treatments produce synergic benefits on the cardiovascular system. Trimetazidine is a metabolic modulator that inhibits a key enzyme in fatty acid oxidation and shifts the cellular energy substrate reference from fatty acids to glucose oxidation.1 As a result of this action, trimetazidine ensures additive antianginal efficacy, and both left ventricular (LV) systolic function and diastolic filling are improved in ischemic heart disease (IHD), especially in patients with diabetic cardiomyopathy.2– 4 More recently, trimetazidine improved radial artery endothelium-dependent relaxation in chronic heart failure, which was correlated with decreased plasma levels of lipid free radicals.5 Similarly, exercise training improves diastolic filling and systolic function in patients with ischemic cardiomyopathy, in relation to enhanced contractility6 and perfusion of dysfunctional myocardium.7 Patients with viable myocardium, in theory, should benefit the most from either trimetazidine or exercise
Struttura di Cardiologia Riabilitativa e Preventiva, Presidio Cardiologico “GM Lancisi”, Ancona, Italy. *Address for reprints: Romualdo Belardinelli, MD, Presidio Cardiologico GM Lancisi, Cardiologia Riabilitativa e Preventiva, Via Conca, 71, 60020 Ancona, Italy. E-mail address: [email protected]. 0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.07.006
training because both treatments improve the contractile function of dysfunctional hibernating/stunned myocardium. Exercise training acts by inducing a series of adaptations in myocardial cells and coronary vessels, and trimetazidine modulates the metabolism of myocardial cells. Moreover, exercise training has documented efficacy in improving endothelial vasomotor response of coronary and peripheral arteries and in increasing functional capacity in relation to several adaptations in different areas. In this article, we consider (1) the rationale for using trimetazidine in cardiac rehabilitation, (2) the identification of patients referred for cardiac rehabilitation who might benefit the most from the addition of trimetazidine to standard therapy, and (3) the documented benefits of trimetazidine in treating exercise intolerance in patients with IHD.
Rationale for Using Trimetazidine in Cardiac Rehabilitation Cardiac rehabilitation programs were first introduced in the 1960s when the benefits of ambulation during prolonged hospitalization for coronary events had been documented. Exercise training was the primary component of these programs, and its safety and benefits have been intensively investigated in supervised programs over the years.8 www.AJConline.org
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The main goals of cardiac rehabilitation are (1) to prevent disability resulting from coronary artery disease (CAD), particularly in older persons and those with occupations that involve physical exertion; and (2) to prevent subsequent cardiovascular events, hospitalization, and death from cardiac causes. Thus, cardiac rehabilitation is not only indicated for incapacitated disabled patients, but also for all patients with CAD.8,9 However, when initiating an exercise training program, it is extremely important to identify patients with inducible myocardial ischemia or with chronically dysfunctional viable myocardium and to tailor the regimen so as to reduce symptoms as much as possible. This will improve functional capacity and encourage patients to have a more active lifestyle, with a further decrease in symptoms as well as an improvement in the life expectancy. Thus, it is of utmost importance to optimize the pharmacologic treatment, which usually includes the use of agents, such as -blockers, calcium antagonists, and nitrates, in addition to percutaneous coronary intervention and coronary artery bypass graft surgery, when appropriate. Usually, if a single traditional antianginal agent is ineffective to control symptoms, a second or third agent is added in combination. However, a meta-analysis of several clinical studies has demonstrated that a combination of classic hemodynamically active agents failed to provide a real additive efficacy over monotherapy.10 In addition, the use of maximal doses of hemodynamically active agents may be limited by the development of undesirable side effects, especially in the elderly population and in patients with LV dysfunction. Thus, alternative therapeutic approaches are required to improve the management of patients with angina and thus increase their exercise capacity. The so-called metabolic approach with trimetazidine appears to represent a rational answer to this problem because it addresses the underlying abnormalities in cardiac metabolism that are not affected by conventional “hemodynamically acting” antianginal drugs. The clinical efficacy of trimetazidine has been demonstrated in the Second Trimetazidine in Poland (TRIMPOL II) study11 conducted in 347 patients with stable angina, insufficiently controlled by -blocker monotherapy, in whom the addition of trimetazidine to metoprolol caused a significant improvement in all ergometric and clinical parameters. These findings were recently confirmed in a study of trimetazidine (35 mg) modified release12 in patients still symptomatic with a positive exercise tolerance test despite background therapy with atenolol 50 mg. Again, the addition of trimetazidine to atenolol led to a significant increase in the angina and ischemic thresholds. Thus, we can conclude that the metabolic approach with trimetazidine further increases the effort capacity of patients with CAD undergoing cardiac rehabilitation, thereby producing synergic benefits on the cardiovascular system when used in combination with traditional therapy. Moreover, there is evidence that trimetazidine at an oral dose of 20 mg 3 times daily improves LV function in patients with ischemic cardiomy-
opathy. In patients with LV dysfunction and multivessel CAD, treatment with trimetazidine 20 mg 3 times daily for 8 weeks led to a significant improvement in systolic wall thickening score index at rest and peak dobutamine infusion (13% and 21%, respectively; p ⬍0.001), LV ejection fraction (LVEF) (19.7% and 14.1%; p ⬍0.001), and peak oxygen consumption (15%) (Figure 1). These benefits were obtained without concomitant changes in heart rate and blood pressure, suggesting that the improved cardiac function is because of cytoprotection unrelated to hemodynamic effects. No side effects were observed among treated patients.2 Brottier and colleagues3 had previously demonstrated an improvement in radionuclide LVEF after 6 months of treatment with trimetazidine at the same dose in 18 New York Heart Association (NYHA) class III and IV patients with ischemic cardiomyopathy.3 The LVEF showed a mean improvement of 9.3% at 6 months. Cardiac volume on chest x-rays decreased significantly at 6 months in the trimetazidine group compared with placebo (p ⫽ 0.034). Treated patients also had enhanced functional capacity, as shown by improvement in NYHA functional class (p ⬍0.001). Thus, in patients with ischemic cardiomyopathy, the addition of trimetazidine to conventional treatment significantly improves myocardial function, which is of the utmost importance to increase the effort capacity of patients undergoing cardiac rehabilitation. In another study, Fragasso and associates4 studied the effects of trimetazidine in patients with diabetes mellitus and ischemic cardiomyopathy. Treatment with trimetazidine (20 mg 3 times daily for 15 days, followed by a 6-month period of treatment according to a double-blind crossover design) led to a significant improvement in LVEF (p ⬍0.001 vs placebo for both 2 weeks and 6 months), whereas endothelin-1 decreased significantly (p ⬍0.001 and p ⬍0.03, respectively). Fasting blood glucose also decreased significantly after 2 weeks (p ⫽ 0.02), but no significant change was observed at 6 months. At 2 weeks, 10 of 16 patients improved NYHA functional class by 1 class (p ⫽ 0.019 vs placebo), and 8 patients maintained the improvement at 6 months (p ⫽ 0.018 vs placebo). In summary, trimetazidine improved LV function, NYHA functional class, glucose metabolism, and endothelial function in patients with diabetes and ischemic cardiomyopathy. Similar results were observed in patients with type 2 diabetes and ischemic cardiomyopathy (LVEF, 0.32) who were randomized to receive trimetazidine (20 mg 3 times daily) or placebo for 6 months.13 The LVEF increased by 5.4 ⫾ 0.5% in patients receiving trimetazidine (p ⬍0.05) in relation to significant decreases in LV end-diastolic and end-systolic volumes (⫺8% and ⫺17%, respectively; p ⬍0.05 for both parameters vs placebo). Significant improvements in wall motion score index and diastolic filling mitral inflow pattern (E/A ratio) were also observed only in trimetazidine-treated patients. More recently, the same investigators found improvements in LV function of elderly patients aged 78 ⫾ 3 years with CAD who were treated with trimetazidine at
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Figure 1. Trimetazidine improves the contractile response of chronically dysfunctional myocardium to low-dose dobutamine in ischemic cardiomyopathy. Both resting and peak dobutamine systolic wall thickening score index improved significantly in trimetazidine-treated patients compared with controls. SWTI ⫽ systolic wall thickening index. *p ⬍0.001 versus controls.
doses of 20 mg 3 times daily in addition to standard therapy for 6 months.14 Similar to previous reports, both LV systolic and diastolic function were improved, as well as NYHA functional class. Evidently, modulation of myocardial energy metabolism with trimetazidine improves not only contractile performance of dysfunctional myocardium but also diastolic filling, and these beneficial effects translate into improvements in LV function and functional capacity in patients with ischemic cardiomyopathy with or without diabetes. The improved ventricular function with trimetazidine at rest and during stress is of particular clinical importance when attempting to improve the exercise training capacity of patients with CAD and to maintain the patients with diabetes in the infraischemic zone when undergoing cardiac rehabilitation. Recent interest has focused on the antioxidant properties of trimetazidine and on its potential beneficial effect on endothelial function. As demonstrated by Fragasso and colleagues,4 trimetazidine decreases plasma endothelin-1 levels in patients with ischemic cardiomyopathy and diabetes. In chronic heart failure, plasma endothelin-1 levels are increased in parallel with the severity of cardiovascular dysfunction, and the endothelium-dependent vasorelaxation is impaired because of altered vascular homeostasis. A possible mechanism may be that trimetazidine inhibits endothelin-1 release by decreasing the deleterious effects of chronic ischemia. Previous studies have shown the reduction in intracellular acidosis and the preservation of intracellular phosphocreatine and adenosine triphosphate (ATP) levels after trimetazidine in animal models of myocardial ischemia. Moreover, there is evidence that trimetazidine reduces the loss of intracellular potassium induced by oxygen free
radicals in red cells as well as the membrane content of peroxidated lipids.15 Nitric oxide seems to blunt signaling by endothelin, the principal peptide responsible for vascular smooth muscle cell contraction, by slowing its release. In conditions of chronic shear stress, nitric oxide appears to be a critical mediator of the decrease in endothelin release. In fact, endothelin decrease is abrogated by nitric oxide inhibitors and potentiated by phosphodiesterase inhibitors. An antioxidant effect of trimetazidine is suggested by a reduction in systemic markers of oxidant stress, such as malondialdehyde and hydroperoxides. There is evidence that free radicals are increased in chronic heart failure in both experimental and clinical studies.16,17 Prasad and associates18 have found that leukocyte-mediated production of oxygen-derived free radicals is increased 4-fold in patients with heart failure compared with control subjects. Free radicals generated under conditions of oxidant stress induce significant tissue damage and modifications of lipids and proteins in the vasculature. Lipid peroxidation generates hydroperoxides from polyunsaturated fatty acids (PUFA), when hydroxyl radicals come into contact with PUFA, generating a stable oxygen species (H2O) and a PUFA radical, which in turn rearranges to form a conjugated diene reacting with molecular oxygen to form a PUFA–peroxyl radical. Lipid peroxides can yield lipid peroxyl radicals, which can react with nitric oxide to form lipid peroxynitrites. In chronic heart failure, there is also a reduction in cardiac antioxidant enzymes, which worsens oxidative stress.19 Recently, Belardinelli and associates5 have demonstrated that trimetazidine improves endothelium-dependent vasodilation in a group of 51 patients with ischemic cardiomyopathy and chronic heart failure (mean age, 51.4 ⫾ 6 years), and this effect was correlated both with decreased plasma levels of
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malondialdehyde and hydroperoxides and with enhanced functional capacity. No change in endothelium-independent vasorelaxation was detected. The improvement in endothelial function may be the result of a direct or an indirect effect of trimetazidine on the endothelium (Figure 2). In fact, trimetazidine, as a metabolic modulator in the presence of dysfunctional viable myocardium, improves LV function and cardiovascular efficiency, which may shift the balance between endothelial vasodilating and vasoconstricting substances in favor of the former. Improvements in functional capacity are correlated with improvements in endothelium-dependent vasorelaxation, and a reduction in oxidative stress may enhance endothelial function by decreasing the rate of inactivation of nitric oxide by products of lipid peroxidation and reactive oxygen species.20 On the other hand, trimetazidine may exert a direct effect on endothelial cells, acting as a lipid barrier permeable transition metal chelator, protecting the endothelium from free radicals.21 This action may be of particular importance in diabetes and in conditions of high oxidative stress in which low-density lipoprotein oxidation and DNA oxidative damage may directly injure endothelial cells and cause abnormal gene expression and altered signal transduction.
Identification of Patients Referred for Cardiac Rehabilitation Who Might Benefit the Most from the Addition of Trimetazidine to Standard Therapy The results of previous studies emphasized that major benefits are obtained with trimetazidine when hibernating/ stunned myocardium is present. In fact, both better control of angina symptoms and improvement in LV function have been observed after the addition of trimetazidine to standard therapy in the human clinical model of ischemic cardiomyopathy with multivessel CAD and ⱖ1 cardiovascular risk factors. This model is characterized by a scenario of viable and nonviable cells, with areas of hibernating/stunned dysfunctional myocardium mixed with necrotic and normal myocardium, fed by coronary arteries with multiple atherosclerotic lesions of different severity. The optimization of cellular energy metabolism by trimetazidine improves ATP resynthesis through inhibition of fatty acid oxidation and stimulation of glucose oxidation. Patients with diabetes with multiple CAD and dysfunctional myocardium have been studied in more detail because this model is associated with metabolic and functional abnormalities that may undergo improvement after the addition of a metabolic modulator agent. Patients with diabetes have a greater incidence of CAD, which is in part related to concomitant cardiovascular risk factors, such as hypertension, blood lipid abnormalities, obesity, and physical inactivity.22 They have a higher incidence of silent ischemia, greater mortality during and after an acute myocardial infarction (MI), and an increased rate
of complications, including LV dysfunction and heart failure. The main metabolic abnormality of the diabetic heart is the decreased ability to oxidize pyruvate as a consequence of phosphorylation inhibition of pyruvate dehydrogenase because of upregulation of pyruvate dehydrogenase kinase.23 Patients with diabetes have high circulating free fatty acid and ketone body concentrations in the plasma, resulting in greater levels of acetyl coenzyme A and reduced nicotinamide adenine dinucleotide in mitochondria and inhibition of pyruvate dehydrogenase. Studies in animal models of diabetes suggest that the reduction in fatty acid oxidation and/or the direct stimulation of pyruvate oxidation improves myocardial function during ischemia and reperfusion.24 Glucose and insulin infusions in patients with acute MI caused a 29% reduction in mortality at 1 year compared with conventional therapy.25 This effect was more marked in patients with a low cardiovascular risk profile and any previous insulin treatment (52% reduction). These benefits are likely because of reduced plasma free fatty acid and ketone body levels, resulting in less inhibition of pyruvate dehydrogenase activity and more efficient production and utilization of ATP. Cardiovascular disease in patients with diabetes has several components, including cardiac, macrovascular, and microvascular diseases, that create a vicious cycle of progressively worsening abnormalities.26 A typical condition in patients with diabetes is multiple CAD with dysfunctional myocardium, the so-called diabetic cardiomyopathy. Coronary lesions are typically multiple at a different maturative state in the same vessels and frequently extend to the distal end of the coronary tree. After several years, the disease can spread to all major coronary vessels, causing functional and structural abnormalities in cardiomyocytes. Chronic ischemia generates hibernating myocardium with depressed contractility and consequent regional LV dysfunction. When the amount of dysfunctional myocardium becomes relevant, ventricular insufficiency and heart failure will develop, causing clinical deterioration.27 Recently, we studied 34 clinically stable patients with diabetes and documented multivessel CAD (29 men and 5 women; mean age, 54 ⫾ 9 years; LVEF, 0.38 ⫾ 0.06).28 Of these, 24 patients had type 2 diabetes, and 10 had type 1 diabetes. Patients were randomized to receive trimetazidine 20 mg 3 times daily (T group, n ⫽ 19), or placebo (C group, n ⫽ 15) for 3 months. 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 using a 2-day stress (Bruce)–rest protocol (500 MBq 99mTc-tetrofosmin). Quantitative measurements of LV volumes from gated perfusion SPECT images were obtained from which LVEF was calculated. All patients completed the protocol, and no side effects were reported. At 3 months, trimetazidine-treated patients had a significant improvement in systolic wall thickening index (1.7 ⫾ 0.9 vs 2.3 ⫾ 0.9, p ⬍0.05) and
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Figure 2. Common effects of trimetazidine and exercise in the cardiovascular system and their possible interaction. Both trimetazidine and exercise improve left ventricular (LV) function, the former through metabolic modulation, the latter through intermittent bouts of increased shear stress. In ischemic cardiomyopathy, exercise improves myocardial perfusion through ⱖ4 mechanisms: improvement in endothelium-dependent relaxation of coronary vessels, arterial remodeling (Glagov effect), coronary collateral circulation (arteriogenesis), and small vessel growth (angiogenesis). The improvement in LV function is associated with enhanced endothelial function. Trimetazidine’s effect on the endothelium is direct and indirect. Trimetazidine directly reduces nitric oxide inactivation through decreased production of lipid peroxidation (LOONO.). This effect is associated with decreased plasma levels of systemic markers of oxidative stress, such as malondialdehyde and hydroperoxides, and endothelin-1 as well. Trimetazidine’s indirect effect on the endothelial function depends on its anti-ischemic properties and on contractility of dysfunctional myocardium, which both contribute to improve LV function. Exercise, through increased shear stress, stimulates both endothelial nitric oxide synthase (e-NOS) and extracellular superoxide dismutase (ec-SOD) expressions in endothelial cells and subendothelial smooth muscle cells, respectively, determining increased nitric oxide synthesis and decreased nitric oxide inactivation by free radicals. The improvement in endothelium-dependent vasorelaxation contributes to the enhancement of functional capacity.
LVEF (0.43 ⫾ 0.06 vs 0.38 ⫾ 0.06, p ⫽ 0.007) compared with control patients. These effects were similar in patients with type 1 and type 2 diabetes. No changes were observed in myocardial defects (SD score: T, 8.2 ⫾ 2.4; C, 8.9 ⫾ 2.1; p ⫽ 0.38). Total exercise time was also improved in trimetazidine-treated patients (from 440 ⫾ 140 seconds to 530 ⫾ 145 seconds, p ⬍0.05), whereas no change was observed in controls. We conclude that in patients with diabetic cardiomyopathy, trimetazidine improves LV 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 contractility of dysfunctional myocardium and functional capacity. The differentiation between viable and nonviable myocardium is an important diagnostic issue in patients referred not only for revascularization but also for cardiac rehabilitation. In fact, it has been estimated that 25%– 40% of patients with chronic CAD and LV dysfunction have the potential for significant improvement in systolic performance after revascularization. Metabolic activity in myocardial regions with reduced blood flow is an accurate clinical marker of viability, with a mean sensitivity and specificity of 93% and 58%, and mean positive predictive value and negative predictive value of 71% and 86%, respectively.29 The identification of myocardial viability predicts the improvement in functional capacity after cardiac rehabilitation and the clinical outcome in patients with ischemic cardiomyopathy. We studied 71 consecutive patients (mean age, 56 ⫾ 9 years) with chronic heart failure secondary
to ischemic cardiomyopathy (LVEF ⬍0.40).30 Patients were randomized into 2 matched groups. One group (n ⫽ 36) underwent supervised exercise training at 60% of peak oxygen consumption 3 times a week for 10 weeks, and a control group (n ⫽ 35) did not exercise. The presence of viable myocardium at baseline by low-dose dobutamine echocardiography identified patients with improved peak oxygen consumption at the end of the training program, with a sensitivity of 70% and a specificity of 77%. Patients with viable myocardium at baseline had higher peak oxygen consumption as well as a lower systolic wall thickening score index after exercise training. The improvement in contractility was more marked among less dysfunctional myocardial segments on initial evaluation. Moreover, trained patients had a significantly lower occurrence of cardiac events during follow-up (22% vs 51%, p ⬍0.001). Patients with cardiac events had a significantly higher systolic wall thickening index on initial evaluation. Independent predictors of cardiac events during 23 ⫾ 6 months of follow-up were the pre–post training difference in LVEF at peak dobutamine infusion and the presence of viable response at baseline (p ⫽ 0.004 and p ⫽ 0.008, respectively). The log-rank test demonstrated that trained patients had a significantly lower probability of cardiac events during follow-up than did sedentary control patients (p ⬍0.001). These results suggest that in patients with ischemic cardiomyopathy and heart failure, the presence of hibernating dysfunctional myocardium represents an important premise to obtain successive improvements in functional capacity and LV function after exercise training. The precise mechanisms by which these
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beneficial effects may occur have not yet been fully elucidated. As recently demonstrated, both improvements in myocardial perfusion and coronary endothelial function seem to play a role.7,31 Nonetheless, peripheral adaptations cannot be excluded, as suggested by changes in neurohormones, metabolic substances, inflammatory mediators, and skeletal muscle cells.32–34 Thus, the identification of viable myocardium in patients with ischemic cardiomyopathy is an important diagnostic issue because it may identify patients who will improve LV function and event-free survival (Table 1). Recently, trimetazidine was shown to improve endothelium-dependent vasorelaxation in chronic heart failure, which was correlated with decreased plasma levels of lipid free radicals.5 The increase in radial artery diameter to acetylcholine was more marked after trimetazidine in patients with ⬎2 coronary risk factors (Figure 3). A possible explanation may be that patients with ⬎2 coronary risk factors have a greater oxidative stress, as confirmed by the higher plasma levels of malondialdehyde and hydroperoxides. Therefore, this subgroup of patients should be more responsive to antioxidant treatment, as previously suggested by Heitzer and coworkers,17 who found that co-infusion of vitamin C improved acetylcholine-induced vasodilation in patients with CAD with an adverse outcome. On the basis of this evidence, conditions of high oxidative stress should take advantage of the addition of trimetazidine to standard therapy and should also be considered for a program of cardiac rehabilitation.
Documented Effects of Trimetazidine on Exercise Training Response Despite the potentially favorable premises suggested by the effects of trimetazidine or exercise training used separately, there are no published reports about the effects of trimetazidine in patients referred for cardiac rehabilitation. Our laboratory investigated the effects of trimetazidine combined with exercise training in 2 conditions: ischemic cardiomyopathy and peripheral arterial obstructive disease. Ischemic cardiomyopathy: We studied 86 patients (72 men and 14 women; mean age, 59 ⫾ 9 years) with IHD and LV dysfunction (LVEF, 0.38 ⫾ 0.07) who were referred for cardiac rehabilitation (unpublished data). All patients had had a previous MI, 45 underwent coronary artery bypass surgery, and 35 underwent percutaneous transluminal coronary angioplasty in 1 (18 patients), 2 (17 patients), and 3 (5 patients) major coronary arteries. Coronary risk factors were present in 72 patients (diabetes in 36). Patients were randomized to 3 matched groups. The first group received trimetazidine orally at doses of 20 mg 3 times daily for 8 weeks in addition to standard medications and underwent a supervised program of exercise training at 60% of peak oxygen consumption 3 times a week for 8 weeks (trimetazidine plus training, n ⫽ 30). A second group completed the
exercise training program without receiving trimetazidine (training, n ⫽ 30), and a third group neither exercised nor received trimetazidine (control, n ⫽ 26). On study entry and at 8 weeks, all subjects underwent Doppler echocardiography, cardiopulmonary exercise testing, and vasomotor reactivity of the brachial artery. Peak oxygen consumption was significantly increased in the trimetazidine plus training group and in the training-only group, whereas it was unchanged in control subjects. LVEF improved in the trimetazidine plus training group as well as in the training-only group as a result of reduction in end-systolic volume. No changes were observed in controls. The endothelium-dependent vasorelaxation was also improved in the trimetazidine plus training group and in the training-only group, whereas no changes were observed in control patients. Only 1 patient stopped trimetazidine because of diarrhea. No other side effects were reported. The results of the present investigation indicate that the combination of trimetazidine with exercise training potentiates the effect of exercise training and brings about more marked improvements in functional capacity, LV systolic function, and the endothelium-dependent relaxation of the brachial artery than exercise training alone in patients with ischemic cardiomyopathy referred for cardiac rehabilitation. Peripheral arterial obstructive disease: In another study, we added trimetazidine (20 mg 3 times daily) to standard medications in 24 patients with peripheral arterial obstructive disease (unpublished data). Patients were randomized into 2 groups. The first group (n ⫽ 12) received trimetazidine for 4 weeks and exercised on a treadmill 3 times a week for 4 weeks. The second group exercised with the same protocol without receiving trimetazidine. The exercise protocol was supervised, based on the intensity of treadmill exercise triggering leg pain (on– off protocol). All patients underwent a treadmill exercise test (Bruce protocol) on study entry and at 4 weeks. Patients who received trimetazidine and exercised had a significantly greater improvement in total exercise time (from 236 ⫾ 98 seconds to 318 ⫾ 110 seconds, p ⬍0.0001) and time to onset of leg pain (from 168 ⫾ 86 seconds to 224 ⫾ 102 seconds, p ⬍0.0001) compared with patients who did not receive trimetazidine (from 224 ⫾ 102 seconds to 284 ⫾ 98 seconds, and from 155 ⫾ 79 seconds to 185 ⫾93 seconds, respectively). Both studies indicate that the combination of trimetazidine and exercise training can bring about more marked benefits than exercise training alone in patients with ischemic cardiomyopathy and peripheral arterial obstructive disease. We speculate that trimetazidine potentiates the effects of exercise training on dysfunctional myocardium and on endothelial cells (Figure 1). Trimetazidine, by shifting the energy substrate reference from fatty acids to glucose oxidation, improves contractility of myocardial cells by decreasing cellular acidosis and increasing ATP production. This action improves LV performance and cardiovascular
Belardinelli et al/Clinical Benefits of a Metabolic Approach in the Cardiac Rehabilitation of Patients with Coronary Artery Disease
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Table 1 Pathology, substrate, and documented effects of trimetazidine Pathology
Substrate
Trimetazidine Dosage
Documented Effects
Ischemic/diabetic cardiomyopathy
Viable myocardium
20 mg tid
Ischemic heart disease
Stunned myocardium
20 mg tid
Chronic heart failure
High oxidative stress Viable myocardium
20 mg tid
Peripheral arterial obstructive disease
Chronically hypoperfused cells
20 mg tid
Improvements in: Myocardial contractility LV ejection fraction LV volumes Functional capacity Reduction in the number of anginal attacks Increased time to ST downsloping and time to angina Increase in work capacity Reduction in systemic markers of oxidant stress Improvement in endothelium-dependent vasorelaxation Improvement in LV function Increase in functional capacity Increased time to onset of claudication Increase in exercise tolerance
LV ⫽ left ventricular.
Figure 3. Radial arterial diameter response to crescent doses of acetylcholine (Ach) 7.5, 15, and 30 g/min after 4 weeks of oral doses of trimetazidine 20 mg 3 times daily in patients with ischemic cardiomyopathy with ⱕ1 and ⬎2 coronary risk factors. Patients with ⬎2 coronary risk factors have a higher oxidative stress, as demonstrated by greater plasma levels of lipid peroxidation products (malondialdehyde and hydroperoxides).5 Patients with higher oxidative stress have a significantly greater vasodilation to Ach than patients with lower oxidative stress. *p ⬍0.0001 by analysis of variance.
efficiency and reduces endothelial dysfunction. In addition, regular aerobic exercise improves the endothelium-dependent vasorelaxation of peripheral as well as coronary arteries. This effect is associated with greater vascular expression of endothelial nitric oxide synthase and extracellular superoxide dismutase and is related to an increase in shear stress produced by blood flow on the inner arterial wall. Exercise training improves cardiovascular efficiency through different mechanisms. Neurohormonal activation is reduced in trained patients, in conjunction with improved autonomic balance and decreased plasma levels of inflammatory and vasoconstricting substances, such as tumor necrosis factor–␣, interleukin-1 and interleukin-6, angiotensin II, and endothelin-1.35 At the subcellular level, exercise training improves calcium reuptake of sarcoplasmic reticulum and improves oxygen diffusing capacity of the coronary vessels.36,37 Both effects contribute to improve resting peak
diastolic filling rate, which correlates with increased cardiac index during exercise.6 Cardiac output is also increased at submaximal and peak exercise in relation to decreased endsystolic volume index and decreased afterload. In patients with ischemic cardiomyopathy, exercise training enhances contractility of dysfunctional myocardium, which correlates with improved myocardial perfusion on thallium scintigraphy.7 Exercise directly stimulates new vessel growth in the presence of hypoxia, and this effect may partly explain the development of coronary collaterals. It is possible that in the presence of significant coronary artery stenosis, intermittent exercise, by inducing short periods of ischemia, may stimulate vascular endothelial growth factor expression and increased adenosine concentration in the myocardium, which both can induce neoangiogenesis. Dipyridamole—an inhibitor of adenosine uptake by myocardial cells— enhances collateral-dependent flow and regional function during ex-
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The American Journal of Cardiology (www.AJConline.org) Vol 98 (5A) September 4, 2006
ercise in a human model of IHD.38 Nitric oxide seems to exert a tonic dilating effect on coronary collateral vessels developed as a result of myocardial ischemia.39 As a matter of fact, collateral flow is significantly reduced by a nitric oxide synthase inhibitor (L-NAME). Another hypothesis may be that exercise reduces endothelial dysfunction in segments of coronary vessels with intact endothelium. However, as previously demonstrated, intermittent exercise induces vasoconstriction at the level of stenoses. Thus, in chronic heart failure caused by IHD, there are at least 2 different mechanisms of improvement in myocardial perfusion after exercise training that can be hypothesized: exercise-induced ischemia that stimulates neoangiogenesis, and shear stress–mediated endothelium-dependent relaxation of coronary segments with intact endothelium. Both mechanisms may interact and potentiate each other.35 Moreover, exercise improves the endothelium-dependent relaxation of conduit and resistance arteries, which is correlated with functional capacity and is predictive of a favorable outcome. In conditions of high oxidative stress (ie, chronic heart failure or diabetes), trimetazidine reduces free radicals and improves the endothelium-dependent vasorelaxation through its metabolic effect and through a direct effect on endothelial cells (see above).
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Conclusion Currently, there is evidence that cardiac rehabilitation improves functional capacity, LV function, and the clinical outcome of patients with CAD. Thus, optimization of pharmacologic treatment is of utmost importance, and the use of trimetazidine, a metabolic antianginal agent, seems to be a rational way to ensure the optimal decrease in symptoms and improvement in cardiac function. Moreover, there is preliminary evidence that the combination of trimetazidine with exercise training provides greater improvements in LV function and aerobic capacity than exercise training given alone, thereby producing synergic benefits on the cardiovascular system. This combination has been tested in patients with ischemic cardiomyopathy and peripheral arterial obstructive disease. Both treatments are well tolerated and the incidence of side effects is very low. These preliminary results should encourage further studies in a larger population. 1. Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A tiolase. Circ Res 2000;86:580 –588. 2. Belardinelli R, Purcaro A. Effects of trimetazidine on the contractile response of chronically dysfunctional myocardium to low-dose dobutamine in ischaemic cardiomyopathy. Eur Heart J 2001;22:2164 –2170. 3. Brottier L, Barat JL, Combe C, Boussens B, Bonnet J, Bricand H. Therapeutic value of a cardioprotective agent in patients with severe ischaemic cardiomyopathy. Eur Heart J 1990;11:207–212. 4. Fragasso G, Piatti PM, Monti L, Palloshi A, Setola E, Puccetti P, Calori G, Lopaschuk GD, Margonato A. Short- and long-term bene-
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