Number 37, 2007
Go with the flow

Clinical benefits of a metabolic approach in the treatment of ischemic heart disease: focus on Vastarel MR

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Mario Marzilli
Postgraduate School of Cardiology, University of Siena, Siena, Italy
Correspondence: Professor Mario Marzilli, Postgraduate School of Cardiology, University of Siena, Policlinico Le Scotte, Viale Bracci, 53100 Siena, Italy. Tel: +39 0577 585375, +39 0577 585374; fax: +39 0577 23112; e-mail: marzilli@unisi.it

Introduction
Chronic stable angina is the initial manifestation of ischemic heart disease in approximately 50% of patients. It is difficult to estimate the number of patients with chronic chest pain syndromes, but clearly it is measured in the millions. In the USA, the reported annual incidence of angina is 213/100 000 population older than 30 years, and about 50% of patients presenting at hospital with myocardial infarction have preceding angina. Given that, in the USA, there are 1 100 000 patients with myocardial infarction each year, and about 50% of these (550 000) survive until admission to hospital, it can be estimated that there are 30 patients with stable angina for every patient with infarction who is admitted to hospital. As a result, the number of patients with stable angina in the USA can be estimated as 30 × 550 000, or 16 500 000 [1]. If we include in this estimation all industrialized countries, the figures become incredibly high.
Ischemic heart disease is important, not only because of its prevalence, but also because of its associated morbidity and mortality. Despite the well documented recent decline in cardiovascular mortality, ischemic heart disease remains the leading single cause of death in the western world. The morbidity associated with this disease is also considerable: each year, millions of patients experience myocardial infarction, or are admitted to hospital for unstable angina. Beyond the need for admission to hospital, many patients with chronic chest pain syndromes are temporarily unable to perform normal activities for hours or days, thereby experiencing a reduced quality of life.

Myocardial revascularization: promise unfulfilled
Great hopes were inspired by the introduction of surgical and percutaneous myocardial revascularization techniques that promised to be safe and effective alternatives for the control of symptoms in patients resistant to optimal medical therapy. These techniques rapidly gained great popularity, but, unfortunately, they do not seem to have lived up to initial expectations, in either the short or the long term. According to the data from the Bypass Angioplasty Revascularization Investigation [2], about 30% of patients never return to work after coronary revascularization, and 15–20% of patients rate their own health as fair or poor despite revascularization.
Two more recent studies, one comparing clinical outcomes of patients treated medically with those of patients who underwent revascularization [3], and another comparing percutaneous transluminal coronary angioplasty and coronary artery bypass grafting [4], provided additional data on long-term prognosis, and cast additional doubts on the effective benefits of these procedures in patients with chronic ischemic heart disease. The first of these studies, although indicating that revascularized patients do better than patients treated medically, revealed that, at follow-up, many revascularized patients complain of angina, that most continue to receive antianginal medication, and that about 10% suffered either death or myocardial infarction within 2.5 years [3]. The second study, which was designed as a comparison between state-of-the-art surgical revascularization and percutaneous revascularization in multivessel coronary disease, proved the two strategies to be equally effective and safe. However, within 1 year, 10% of patients who had undergone revascularization had suffered a major adverse cardiac event, regardless of the procedure received [4].
It can be concluded that, despite increasing pharmacological and mechanical treatment options, ischemic heart disease continues to be associated with considerable patient mortality and morbidity. Obviously, this also translates in an enormous economic burden. The estimates of the direct and indirect costs associated with chronic stable angina are measured in tens of billions of dollars. Given the epidemiologic and economic magnitude of the problem, the need for more effective therapies is self-evident.

The broad clinical profile of chronic ischemic heart disease: implications for treatment
On the basis of current guidelines, the management of ischemic heart disease has progressively broadened to include risk-factor modification, patient education, and pharmacologic therapy. The pharmacologic agents fall into two categories:

1. Classic antianginal agents such as β-blockers, calcium antagonists, and nitrates.
2. Drugs for secondary prevention, such as aspirin, clopidogrel, statins, and angiotensin-converting enzyme inhibitors.

Role of cardiac energy metabolism in the pathogenesis of myocardial ischemia
Significant progress has been made in recent years in understanding the role of cardiac energy metabolism in the pathogenesis of myocardial ischemia, and the better understanding of metabolic derangements associated with ischemia and reperfusion is being translated into innovative therapeutic approaches [7].
In normoxic conditions, the healthy heart derives most of its energy from the free fatty acid pathway that accounts for approximately two-thirds of energy (ATP) production, other sources of energy being derived from glucose oxidation and lactate. In hypoxic conditions, myocardial cells respond to mild-to-moderate ischemia by accelerating glucose uptake to generate sufficient ATP to maintain ionic gradients and calcium homeostasis. Severe ischemia rapidly induces an imbalance between the coronary blood supply and the requirement of cardiac tissue for oxygen, producing functional, metabolic, and morphological alterations to the myocardium, including arrhythmia, failure of contractility, and electrophysiological abnormalities. At the cellular level, glucose uptake is decreased and conversion to lactate is increased, lactate uptake by the heart is switched to lactate production, and pyruvate is mostly transformed into lactate, thus increasing cell acidosis. The free fatty acid pathway is slowed down, resulting in reduced production of ATP. These various forms of metabolic damage lead to a disruption of cell homeostasis, alterations in membrane structure, and, ultimately, cell death [7].
Given this pathophysiologic background, and given the failure of classic hemodynamic agents in many patients, it seems logical to consider the pharmacologic manipulation of cardiac energy metabolism as an alternative therapeutic option for patients with myocardial ischemia.

Optimization of cardiac energy metabolism: trimetazidine
Optimization of cardiac energy metabolism is based on promoting cardiac glucose oxidation. This has been proved to enhance the function of the heart and to protect myocardial tissues against ischemia-reperfusion injury. Stimulation of myocardial glucose oxidation can be achieved either directly or indirectly through inhibition of fatty acid β-oxidation. A new class of metabolic agents, known as the 3-ketoacyl coenzyme A thiolase (3-KAT) inhibitors, is able to elicit an increase in glucose and lactate combustion secondary to partial inhibition of fatty acid oxidation, achieving demonstrable clinical benefits in patients with ischemic heart disease [8].
A modified-release formulation of the first 3-KAT inhibitor, trimetazidine MR, is now available for clinical use. Its optimized pharmacologic profile has made a twice-daily administration regimen possible, and provides round-the-clock cardioprotection. This new formulation has been shown to improve antianginal efficacy, to enhance anti-ischemic properties in ischemic patients with ventricular dysfunction, to exert a cardioprotective action in patients undergoing coronary artery bypass grafting or percutaneous coronary intervention, and to be of particular value in high-risk subgroups such as the elderly or patients with diabetes [8].

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