Heart and Metabolism

Number 27, 2005
Metabolic approach in heart failure
Metabolic link between ischemia and cardiac dysfunction

William C. Stanley
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
Correspondence: Professor William C. Stanley, Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106-4970, USA.
Tel: +12163685585, fax: +12163683952, e-mail: wcs4@case.edu

Abstract

Myocardial contractile power is dependent upon the breakdown of ATP to fuel contractile shortening and the uptake of Ca²⁺ into the sarcoplasmic reticulum at the end of systole. Energy for resynthesis of ATP comes from aerobic metabolism in the mitochondria, fueled by the combustion of fatty acids, and to a lesser extent glucose and lactate. Traditional drugs for chronic angina work through a reduction of the need for ATP by suppressing heart rate, blood pressure, and cardiac contractility. Excessive fatty acid oxidation during stress-induced ischemia has been shown to contribute to the development of angina and wall motion dysfunction, and improvement in contractile function has been documented with drugs that partially inhibit myocardial fatty acid oxidation. Trimetazidine, an inhibitor of the fatty acid oxidation enzyme, 3-ketoacyl coenzyme A thiolase, reduces the symptoms of demand-induced ischemia. Patients with ischemic heart disease and angina frequently have left ventricular dysfunction, a condition termed “ischemic cardiomyopathy“, and recent studies have shown that trimetazidine not only reduces the symptoms of angina, but also improves ventricular function in patients with ischemic cardiomyopathy. ? Heart Metab. 2005;27:30–33.

Keywords: Angina, heart failure, metabolism, mitochondrial, trimetazidine

Classically, the heart is considered a pump, generating mechanical power and heat as products. The power generated by the heart is fueled by high rates of myocardial blood flow, oxygen consumption, and carbon fuel combustion. The chemical energy for the mechanical work of the heart comes from ATP – the energy “currency_ of the cell (Figure 1). ATP is broken down to ADP and inorganic phosphate, to drive cardiac muscle contraction and to fuel the Ca²⁺-ATPase to pump Ca²⁺ into the sarcoplasmic reticulum and allow diastolic relaxation [1]. ADP is rapidly resynthesized to ATP in the mitochondria by oxidative phosphorylation. This is driven by the oxidation of fatty acids, glucose, and lactate, delivering reduced nicotinamide adenine dinucleotide (NADH) to the electron transport chain, consuming oxygen, and forming ATP. In the healthy heart, the breakdown of ATP is exquisitely matched to ATP synthesis, and there is never a significant decrease in myocardial ATP concentration, even with large increases in cardiac power output, such as occurs with intense exercise [1].

Figure 1. Cardiac function is dependent upon a constant supply of ATP to maintain contraction, relaxation, and ion homeostasis. ATP is made aerobically in the mitochondria. During ischemia, anaerobic ATP formation is activated in the cytosol from glycolysis. P_i, inorganic phosphate.

Myocardial ischemia occurs when the delivery of oxygenated blood to the myocardium does not meet the requirement for the aerobic synthesis of ATP in the mitochondria to support the normal cardiac function at a given heart rate, afterload, preload, and contractility. Normally, the heart generates ATP from the oxidation of fatty acids, glucose, and lactate, with the majority (60–90%) coming from fatty acids [1]. When there is a mismatch between oxygen delivery to the myocardium and the demand for ATP, there is activation of glycolysis in an attempt to generate ATP anaerobically (Figure 1). Myocardial glycogen stores are broken down, the heart takes up more glucose, and the heart switches from lactate consumption to lactate production. The decrease in ATP and the accumulation of lactate reduce the pH in the cell and result in Ca²⁺ overload and contractile dysfunction. The breakdown of ATP generates adenosine and causes ion channel dysfunction, leading to an increase in extracellular adenosine, K⁺, and H⁺, which can activate cardiac afferent sensory nerve fibers, and triggers the classic symptom of myocardial ischemia: angina pectoris.
Traditional treatments for ischemia act by restoring the balance between oxygen delivery and the myocardial demand for oxygen. Most bouts of myocardial ischemia occur during stress caused by either physical exercise or emotional stress, and are the result of a reduced coronary flow reserve. This can occur either as a result of classic coronary artery disease when there is a lesion at the macrovascular level, or as a result of smaller, more diffuse lesions, or even microvessel dysfunction. In any case, these patients do not have the ability to increase myocardial blood flow to meet the normal requirement for delivery of oxygenated blood. Traditional treatments for chronic stable angina pectoris are aimed at increasing blood flow to the myocardium via coronary vasodilatation (eg, with nitrates), and at reducing the oxygen requirement of the ischemic tissue by decreasing heart rate, arterial blood pressure, and cardiac contractility (with ß-blockers, calcium channel antagonists, or nitrates) [2]. These hemodynamic approaches are effective at reducing anginal symptoms and improving exercise tolerance, but many patients continue to suffer from angina, despite optimal treatment with these drugs [2].
During stress-induced angina (such as occurs with exercise or a dobutamine stress test) there is a failure to increase myocardial oxygen consumption and aerobic formation of ATP (Figure 1), which triggers the anaerobic formation of ATP and lactate production even though there is a relatively high residual rate of oxygen consumption by the myocardium [3–5]. Studies in large animals have shown that this residual aerobic formation of ATP is largely supported by the oxidation of fatty acids [3,4,6,7]. Importantly, the oxidation of fatty acids inhibits the oxidation of glucose in the mitochondria, and acts to drive the conversion of pyruvate to lactate in the cytosol [2,7,8]. Thus the high residual rates of fatty acid oxidation during myocardial ischemia contribute to the production of lactate.
In addition to traditional hemodynamic treatments for angina, metabolic treatment is available, through the partial inhibition of myocardial fatty acid oxidation with trimetazidine [2,9]. Inhibition of myocardial fatty acid oxidation increases glucose and pyruvate oxidation, and decreases the production of lactate during demand-induced ischemia [7]. Trimetazidine inhibits the enzyme of fatty acid ß-oxidation, long-chain 3-ketoacyl coenzyme A thiolase (3-KAT). In clinical trials, this agent has been found not to affect heart rate, or arterial blood pressure at rest or during exercise, but to be as effective as calcium channel antagonists or ß-adrenergic antagonists at improving exercise time to the onset of angina or 1mm depression in the ST segment [9]. Moreover, trimetazidine has an additive effect in reducing the symptoms of exercise-induced angina when used in combination with either a calcium channel antagonist or a ß-adrenergic receptor antagonist [9].
Patients with ischemic heart disease and angina frequently have left ventricular dysfunction and heart failure. This condition is termed “ischemic cardiomyopathy_, and is treated with suppressors of the renin–angiotensin system (angiotensin-converting enzyme inhibitors or angiotensin antagonists), and with traditional antianginal therapies. Results of recent clinical studies have demonstrated that treatment with trimetazidine significantly improves left ventricular function in this population. In a double-blind study of 38 patients with ischemic cardiomyopathy, Bellardinelli and Purcaro [10] showed that 12 weeks of treatment with trimetazidine improved the contractile response during a dobutamine stress test, increased peak oxygen consumption during a graded exercise test, and increased left ventricular ejection fraction at rest, compared with placebo (Figure 2) [10]. Vitale et al [11] observed a similar response in 47 elderly patients with coronary artery disease with left ventricular dysfunction. Compared with standard treatment, 6 months of treatment with trimetazidine reduced the frequency of angina attacks, reduced left ventricular end-diastolic and end-systolic volumes, and increased resting ejection fraction (from 29% at pretreatment to 34% after treatment with trimetazidine, compared with values of 29% and 27% with placebo). In addition, there was an improvement in the quality of life score with trimetazidine compared with placebo.

Figure 2. Treatment with trimetazidine 20mg three times a day for 12 weeks increases left ventricular ejection fraction (LVEF) in patients with contractile dysfunction and coronary artery disease. Pre, before treatment; Post, after treatment. (Drawn from data present in Bellardinelli and Purcaro [10], with permission.)

Approximately 20–30% of European and North American patients with angina or heart failure are also diagnosed with diabetes. Diabetes is a major risk factor for heart disease, and is associated with diastolic left ventricular dysfunction, accelerated myocardial fatty acid oxidation, and impaired oxidation of glucose by the heart. One would speculate that metabolic treatments for angina and ischemic cardiomyopathy would be particularly effective in this population. Rosano et al [12] studied 32 patients with type 2 diabetes and ischemic cardiomyopathy who were allocated randomly to groups to receive either treatment with trimetazidine or placebo, for 6 months [12]. Unlike those who received placebo, the trimetazidine-treated group achieved a reduction in left ventricular end-diastolic and end-systolic diameters (Figure 3) and increased ejection fraction.

Figure 3. Treatment with trimetazidine for 6 months in patients with type 2 diabetes with coronary artery disease and left ventricular dysfunction results in a reduction in left ventricular end-diastolic and end-systolic diameters, as assessed by echocardiography. Pre, before treatment; Post, after treatment. (Modified from Rosano et al [12], with permission.)

Taken together, these findings support the concept that, in these patient populations, cardiac dysfunction is caused by high rates of myocardial fatty acid oxidation, and that partial inhibition of this fatty acid oxidation with trimetazidine results in improved cardiac function.

Summary
Patients with ischemic heart disease and angina frequently have left ventricular dysfunction and heart failure – a condition termed “ischemic cardiomyopathy_. The primary effect of ischemia is reduced myocardial oxygen consumption and impaired formation of ATP in the mitochondria. This triggers an acceleration of glycolysis, and production of lactate and H⁺. During demand-induced ischemia, the myocardium continues to have a relatively high residual oxygen consumption that is fueled largely by fatty acid oxidation which, in turn, inhibits glucose oxidation, and drives the conversion of pyruvate to lactate, which has detrimental effects on cell function. Results of recent clinical studies demonstrate that treatment with trimetazidine significantly improves left ventricular function in this population of patients. ?

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Number 27, 2005Metabolic approach in heart failure Metabolic link between ischemia and cardiac dysfunction

Number 27, 2005Metabolic approach in heart failure

Number 27, 2005
Metabolic approach in heart failure
Metabolic link between ischemia and cardiac dysfunction

Number 27, 2005
Metabolic approach in heart failure