Number 26, 2005
Cardiovascular effects of exercise

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Trimetazidine improves left ventricular function and quality of life in elderly patients with coronary artery disease
Vitale C, Wajngaten M, Sposato B, et al. Eur Heart J. 2004;25:1814–1821.
Elderly patients have an increased incidence of ischemic dilated cardiomyopathy, often related to diffuse coronary artery disease. Trimetazidine protects ischemic myocardium by improving myocardial utilization of energy during myocardial ischemia. The aim of the present study was to evaluate the effects of trimetazidine on left ventricular function in elderly patients with ischemic heart disease and reduced left ventricular function. Forty-seven elderly patients (40 men and seven women, mean age 78±3 years) were allocated randomly to groups to receive, in addition to standard therapy, either trimetazidine or placebo, and were evaluated by echocardiography at baseline and after 6 months. Trimetazidine and placebo had no effect on either blood pressure or heart rate (changes compared with baseline: systolic blood pressure 2±5 and 4±6mm Hg, diastolic blood pressure 1±6 and 3±4mm Hg, heart rate 3±7 and 5±9 beats/min, for trimetazidine and placebo, respectively). At the end of the study, patients assigned to trimetazidine showed a significantly greater left ventricular function and smaller left ventricular diastolic and systolic diameters and volume indices than patients receiving placebo (left ventricular ejection fraction [LVEF] 34.4±2.3% and 27±2.8%, P<0.0001; left ventricular end-diastolic diameter 58.6±1.9mm and 64±1.7mm, P <0.0001; left ventricular end-systolic diameter 44.5±1.1 and 50±0.8mm, P<0.0001; trimetazidine and placebo, respectively). A significantly smaller wall motion score index was detected in trimetazidine-treated patients than in those allocated to placebo (1.24±0.12 and 1.45±0.19 respectively; P<0.01), and the percentage change in LVEF compared with baseline was also significantly greater in trimetazidine-treated patients. Diastolic function improved significantly in the trimetazidine group, but remained unchanged in the placebo group. At follow-up evaluation, patients receiving trimetazidine showed a greater improvement in angina and NYHA class than patients allocated to placebo. Quality of life improved significantly in all patients treated with trimetazidine, but remained unchanged in those allocated to placebo.

Commentary
Cardiac failure is a major problem and increasing in prevalence as populations age. In spite of all the medical advances and in the presence of optimal evidence-based medicine, the prognosis remains poor. Following on from the concept that cardiac failure is associated with increased free fatty acid concentrations secondary to an increased adrenergic state has come the idea that targeted metabolic therapy might be beneficial. As increased free fatty acids cause mitochondrial uncoupling and impaired left ventricular function with a proarrhythmic potential, their presence along with secondarily decreased glucose oxidation perpetuates the heart failure status. Several small studies have shown that trimetazidine reverses this adverse metabolic state and improves left ventricular function. This new study of 47 elderly patients using trimetazidine in addition to modern standard therapy reports improvement in left ventricular systolic and diastolic function, in addition to quality of life, after 6 months of treatment. The importance of recording a benefit in the presence of optimal conventional therapy should encourage further studies looking at long-term (years of) treatment. Improving the quality of life, is of course, important in itself, but if it can be coupled to a better prognosis, then metabolic therapy will be an essential component of the management cardiac failure.

Nuclear receptor signaling and cardiac energetics
Huss JM, Kelly DP. Circ Res. 2004;95:568–578.
The heart has a tremendous capacity for the generation of ATP, allowing it to function as an efficient pump throughout the life of the organism. The adult myocardium uses either fatty acid or glucose oxidation as its main energy source. Under normal conditions, the adult heart derives most of its energy through oxidation of fatty acids in mitochondria. However, the myocardium has a remarkable ability to switch between carbohydrate and fat as sources of fuel, so that ATP production is maintained at a constant rate in diverse physiological and dietary conditions. This flexibility in selection of fuel is important for normal cardiac function. Although the cardiac capacity for energy conversion and metabolic flux are modulated at many levels, an important mechanism of regulation occurs at the level of gene expression. The expression of genes involved in several energy transduction pathways is dynamically regulated in response to developmental, physiological, and pathophysiological cues. This review is focused on gene transcription pathways involved in short- and long-term regulation of myocardial energy metabolism. Much of our knowledge about cardiac metabolic regulation comes from studies focused on mitochondrial fatty acid oxidation. The genes involved in this key energy metabolic pathway are transcriptionally regulated by members of the nuclear receptor superfamily, specifically the fatty acid activated peroxisome proliferator-activated receptors (PPARs) and the nuclear receptor coactivator, PPAR? coactivator (PGC)-a. The dynamic regulation of the cardiac PPAR/PGC-1 complex in accordance with physiological and pathophysiological states will be described here.

Commentary
The healthy adult heart primarily uses fatty acids and glucose as fuels to generate the large amounts of energy necessary to maintain cardiac work. Mitochondrial oxidation of these carbon substrates normally produces more than 90% of the ATP used for energy metabolism, whereas glycolysis is normally a minor source of ATP production. However, myocardial selection of fuel is highly influenced by a number of physiological and pathological conditions. For instance, in the hypertrophied and failing heart, dramatic metabolic shifts can occur, including a transition from mitochondrial oxidative metabolism towards a greater dependence on glycolytic metabolism. These metabolic transitions can help the heart adapt to cardiac pathologies, but can also have maladaptive influences. The metabolic switches that occur in the heart under a number of pathological conditions are usually accompanied by dramatic changes in the expression of a number of genes of both fatty acid and carbohydrate metabolism. It is now becoming clear that nuclear receptor signaling has an important role in these changes in gene expression. Important players in this nuclear signaling are the peroxisome proliferator-activated receptors (PPARs). For instance, one PPAR isoform, PPARa, is involved in the transcriptional regulation of a number of enzymes involved in fatty acid oxidation. This paper by Huss and Kelly provides an excellent review of the recent advances made in our understanding of the role of nuclear receptor signaling in the control of cardiac energetics. The authors review, not only how nuclear receptors control cardiac energetics, but also how alterations in this nuclear receptor signaling contribute to or alter the course of various cardiac pathologies. The paper also highlights the therapeutic potential of altering nuclear receptor function as an approach to treating heart disease.

Percutaneous coronary angioplasty compared with exercise training in patients with stable coronary artery disease. A randomized trial
Hambrecht R, Walther C, Möbius-Winkler S, et al. Circulation. 2004;109:1371–1378.
Regular exercise in patients with stable coronary artery disease has been shown to improve myocardial perfusion and to retard disease progression. A randomized study was therefore conducted to compare the effects of exercise training and standard percutaneous coronary intervention (PCI) with stenting on clinical symptoms, angina-free exercise capacity, myocardial perfusion, cost-effectiveness, and frequency of a combined clinical endpoint (death of cardiac cause, stroke, coronary artery bypass grafting, angioplasty, acute myocardial infarction, and worsening angina with objective evidence resulting in admission to hospital). A total of 101 male patients aged 70 years were recruited to the study after routine coronary angiography and allocated randomly to groups for 12 months of exercise training (20min of bicycle ergometry per day) or to PCI. Cost efficiency was calculated as the average expense (in USA dollars) needed to improve the Canadian Cardiovascular Society class status by one class. Exercise training was associated with a higher event-free survival (88%, compared with 70% in the PCI group; P <0.023) and increased maximal oxygen uptake (16%: from 22.7±0.7 to 26.2±0.8mL/kg; P <0.001 compared with baseline, P <0.001 compared with PCI group after 12 months). To gain 1 Canadian Cardiovascular Society class, US$6956 was spent in the PCI group, compared with US$3429 in the training group (P <0.001). Compared with PCI, a 12-month program of regular physical exercise in selected patients with stable coronary artery disease resulted in superior event-free survival and exercise capacity at lower costs, notably because of reductions in re-admissions to hospital and in repeat revascularizations.

Commentary
Percutaneous coronary artery revascularization is performed in a growing number of patients with ischemic heart disease, on the assumption that the procedure ameliorates symptoms and improves prognosis. Several large clinical trials have documented an early symptomatic benefit in patients who have undergone revascularization as compared with medically treated patients. However, follow-up studies have shown this advantage to be lost in a few years.
Much less convincing is the evidence supporting the common belief that PCIs reduce mortality and morbidity in ischemic heart disease. Technical advances in device design and the availability of drug elution stents have rendered PCIs easier to perform and have significantly reduced early and late complications, including restenosis. However, no significant reduction has been reported for morbidity and mortality.
In the meantime, medical therapy also has registered significant progress, with new classes of drug proving effective in acute and chronic coronary syndromes, including metabolic agents, glycoprotein IIb/IIIa inhibitors and hydroxymethyl glutaryl reductase inhibitors.
In this study, the combination of regular physical exercise and standard medical treatment was compared with PCI in 101 patients with stable coronary artery disease. The program of regular exercise proved to be superior to PCI in event-free survival and reduced the overall costs of treatment. This observation adds to a growing body of evidence questioning the ‘superiority’ of PCI over medical treatment and suggests the need for a critical reappraisal of percutaneous revascularization in stable ischemic heart disease. In patients with mild symptoms and in patients with low to moderate risk, optimal medical treatment combined with a correct lifestyle appears to be the initial strategy of choice, and PCI should be reserved for patients who remain symptomatic despite this regimen.