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Changes in lipid metabolism in the heart with trimetazidine
CHANGES IN LIPID METABOLISM IN THE HEART WITH TRIMETAZIDINE. Aiain Grynberg, INRA-Facuitb de Phrrmacie, Paris, France Trimetazidine (Th42) is an anti-ischemic drug devoid of hemodynamic effect displaying a cyto-protective effect Reduced mitochondria pahnitoyi-camitine p-oxydation, and increased glucose-dependence of ATP production in myocytes suggested that TMZ might contribute to reduce the fatty acid part in ATP production. The report of in vitro inhibition of long chain fatty acid 3-ketoacetyi-CoA thiolase confirmed an effect on g-oxydation. Since cardiomyocytes were not clearly shown to regulate fatty acid uptake, such a mechanism addresses the question of the fate and toxicity of non-oxidized fatty acids. In these ceils, TM2 significantly increased the time-dependent incorporation of phosphoiipid (PL) precursors as well as fatty acid incorporation in membrane structures. In isolated hearts, 10 pM TMZ increased the synthesis of all the PLs from glycerol. At 1 pM, only phosphatidyi-inositoi and cardiolipid synthesis were increased, supporting a mechanism involving the CDPdiacyigiyceroi pathway. Moreover, in viva studies in rats revealed significant changes in lipid biosynthesis in the heart and other organs (liver, cochlea, retina), with a glycerol incorporation increased in PLs and decreased in other lipids. In conclusion, the cardiac anti-anginai properties of TMZ involve a reorganisation of the glycerol-based complex lipid synthesis in cardiomyocytes increasing the structural fate of
fatty acidsanddecreasing theirenergeticfate.
MODIFICATION OF GLUCOSE AND FATTY ACID METABOLISM IN HYPERTROPHIC HEARTS. M. F. Aliard, Pathology and Laboratory Medicine, St. Paul’s Hospital-UBC, Vancouver, B.C. Canada. Cardiac hypertrophy? induced by prolonged pressureor volume-overload, is associated with alterations in myocardial fatty acid and glucose metabolism. Oxidation of fatty acids is reduced in hypertrophied hearts compared to non-hypertrophied hearts, a finding that depends upon the degree of cardiac hypertrophy, the concentration of fatty acid in blood or perfbsate, and the myocardial workload. Glycolysis of exogenous glucose is accelerated in hypertrophied hearts. In contrast, glucose oxidation is not increasedand may, in fact, be lower than that in non-hypertrophied hearts. Consequently, coupling of glucose oxidation to glycolysis in hypertrophied hearts is reduced compared to normal. The alterations in glucose metabolism may be an important factor contributing to the poor function of hypertrophied hearts during reperfusion after ischemia. Stimulation of glucose oxidation by dichloroacetate enhancescoupling of glucose oxidation to glycoiysis and improves recovery of function of hypertrophied hearts after ischemia. This observation supports the concept that modulation of energy metabolism is a useful approach to improve postischemic function of the hypertrophied heart. The potential of alternative means of stimulating glucose oxidation, such as inhibition of fatty acid oxidation, to improve function in this setting is being evaluated.
Metabolic approaches in ischemia Frans C Visser. Dept of Cardiology, VU Medical Centre, Amsterdam, NL For patient management changes in cardiac energy metabolism during ischemia can be used in two different clinical settings: 1) detection of hibernating and stunned (viable) tissue, able to recover in function either spontaneously or after revascularization and 2) protection against ischemic damage in acute coronary syndromes, l)For the detection of viable tissue F-18 deoxyglucose (FDG), C-l 1 acetateand l-123 methylated fatty acids (IFA) can be used. Uptake and turnover of these tracers can be detected by PET and SPECT devices. The use of FDG to predict recovery of hrnction of viable tissue has been well validated in a large number of studies and is considered as the gold standard for assessing viability. Moreover, studies have also shown that FDG uptake has important prognostic value in patients with ischemic heart disease. 2) Acute ischemic tissue can be protected using glucoseinsulin-K+ (GIK). The ECLA study used GIK in the acute phase of myocardial infarction (AMI) and showed improved survival of AMI patients treated with GIK compared to placebo. The use of GIK during coronary bypass surgery showed improved hemodynamics and less complications after surgery compared to placebo. A new development is the use of GIK to detect viable tissue shortly after AMI. We have recently demonstrated that GIK can reliably detect viable tissue and predicts recovery of left ventricular function during follow-up. In conclusion a variety of metabolic interventions can be successfully applied for the diagnosis and treatment of patients with ischemic heart disease.
CLINICAL APPLICATIONS OF TRIMETAZIDINE IN ISCHAEMIC HEART DISEASE Roberto Fermri, Chair of Cardiology, University of Ferrsm,
Italy
Trimetazidine belongs to the so-called metabolic agents for the treatment of iscbaemia. It is a pyperazine compound that inhibits fatty acid oxidation and increases the oxidation of glucose. In addition, it is believed to act at a cellular level, maintaining high energy stores and reducing cell acidosis. Experimental shldies also show that trimetizadine may reduce oxygen free radicals and exert a cytoprotective action on ischaemic myocytes. Trimetizadine does not exert any haemodynamic effects, therefore it offers an unique approach to conventional combination therapy. Unlike other anti-anginals, the anti-ischaemic effects of are not associated with alterations in haemodynamic determinants of myocardial oxygen consumption such as heart rate, systolic blood pressure and the rate-pressure product. In addition, there is some evidence which suggests that trimetazidine could improve left ventricular function in patients suffering from chronic coronary disease or ischaemic cardiomyopathy as well as in patients who experience acute periods of ischaemia during percutaneous transluminal coronary angioplasty. Clinical studies have shown that oral trimetazidine 20mg taken 3 times daily reduces the frequency of angina1 attacks and nitroglycerin use and increases exercise capacity when used as monotherapy in patients with angina pectoris. The clinical effects of himetazidine are rather similar to those of nifedipine 40mg/day and propanolol 120 to 160 mg/day. However, it differs from these agents, in that it does not affect the rate-pressure product during peak exercise or at rest. Adjunct& trimetazidine 6OmgMay reduces the frequency of angina1 attacks and nitroglycerin use and improves exercise capacity in patients with angina pectoris not sufficiently controlled by conventional antiangina1 agents. Furthermore, the drug appears to be more effective than isosorbide dinatrate 30 mg/day when used adjunctively in patients with angina pectoris poorly controlled by propranol 120 mglday. In conclusion, given its different mechanism ofaction, the beneficial effects of trimetazidine can be expected to be additives to the haemodynamic treatment of ischaemia and possibly in patients resistant to the usual agents. We are likely to see increasing interest in this class of drug which offers a novel approach to the treatment of ischaemic heart disease.
A155
fatty acidsanddecreasing theirenergeticfate.
MODIFICATION OF GLUCOSE AND FATTY ACID METABOLISM IN HYPERTROPHIC HEARTS. M. F. Aliard, Pathology and Laboratory Medicine, St. Paul’s Hospital-UBC, Vancouver, B.C. Canada. Cardiac hypertrophy? induced by prolonged pressureor volume-overload, is associated with alterations in myocardial fatty acid and glucose metabolism. Oxidation of fatty acids is reduced in hypertrophied hearts compared to non-hypertrophied hearts, a finding that depends upon the degree of cardiac hypertrophy, the concentration of fatty acid in blood or perfbsate, and the myocardial workload. Glycolysis of exogenous glucose is accelerated in hypertrophied hearts. In contrast, glucose oxidation is not increasedand may, in fact, be lower than that in non-hypertrophied hearts. Consequently, coupling of glucose oxidation to glycolysis in hypertrophied hearts is reduced compared to normal. The alterations in glucose metabolism may be an important factor contributing to the poor function of hypertrophied hearts during reperfusion after ischemia. Stimulation of glucose oxidation by dichloroacetate enhancescoupling of glucose oxidation to glycoiysis and improves recovery of function of hypertrophied hearts after ischemia. This observation supports the concept that modulation of energy metabolism is a useful approach to improve postischemic function of the hypertrophied heart. The potential of alternative means of stimulating glucose oxidation, such as inhibition of fatty acid oxidation, to improve function in this setting is being evaluated.
Metabolic approaches in ischemia Frans C Visser. Dept of Cardiology, VU Medical Centre, Amsterdam, NL For patient management changes in cardiac energy metabolism during ischemia can be used in two different clinical settings: 1) detection of hibernating and stunned (viable) tissue, able to recover in function either spontaneously or after revascularization and 2) protection against ischemic damage in acute coronary syndromes, l)For the detection of viable tissue F-18 deoxyglucose (FDG), C-l 1 acetateand l-123 methylated fatty acids (IFA) can be used. Uptake and turnover of these tracers can be detected by PET and SPECT devices. The use of FDG to predict recovery of hrnction of viable tissue has been well validated in a large number of studies and is considered as the gold standard for assessing viability. Moreover, studies have also shown that FDG uptake has important prognostic value in patients with ischemic heart disease. 2) Acute ischemic tissue can be protected using glucoseinsulin-K+ (GIK). The ECLA study used GIK in the acute phase of myocardial infarction (AMI) and showed improved survival of AMI patients treated with GIK compared to placebo. The use of GIK during coronary bypass surgery showed improved hemodynamics and less complications after surgery compared to placebo. A new development is the use of GIK to detect viable tissue shortly after AMI. We have recently demonstrated that GIK can reliably detect viable tissue and predicts recovery of left ventricular function during follow-up. In conclusion a variety of metabolic interventions can be successfully applied for the diagnosis and treatment of patients with ischemic heart disease.
CLINICAL APPLICATIONS OF TRIMETAZIDINE IN ISCHAEMIC HEART DISEASE Roberto Fermri, Chair of Cardiology, University of Ferrsm,
Italy
Trimetazidine belongs to the so-called metabolic agents for the treatment of iscbaemia. It is a pyperazine compound that inhibits fatty acid oxidation and increases the oxidation of glucose. In addition, it is believed to act at a cellular level, maintaining high energy stores and reducing cell acidosis. Experimental shldies also show that trimetizadine may reduce oxygen free radicals and exert a cytoprotective action on ischaemic myocytes. Trimetizadine does not exert any haemodynamic effects, therefore it offers an unique approach to conventional combination therapy. Unlike other anti-anginals, the anti-ischaemic effects of are not associated with alterations in haemodynamic determinants of myocardial oxygen consumption such as heart rate, systolic blood pressure and the rate-pressure product. In addition, there is some evidence which suggests that trimetazidine could improve left ventricular function in patients suffering from chronic coronary disease or ischaemic cardiomyopathy as well as in patients who experience acute periods of ischaemia during percutaneous transluminal coronary angioplasty. Clinical studies have shown that oral trimetazidine 20mg taken 3 times daily reduces the frequency of angina1 attacks and nitroglycerin use and increases exercise capacity when used as monotherapy in patients with angina pectoris. The clinical effects of himetazidine are rather similar to those of nifedipine 40mg/day and propanolol 120 to 160 mg/day. However, it differs from these agents, in that it does not affect the rate-pressure product during peak exercise or at rest. Adjunct& trimetazidine 6OmgMay reduces the frequency of angina1 attacks and nitroglycerin use and improves exercise capacity in patients with angina pectoris not sufficiently controlled by conventional antiangina1 agents. Furthermore, the drug appears to be more effective than isosorbide dinatrate 30 mg/day when used adjunctively in patients with angina pectoris poorly controlled by propranol 120 mglday. In conclusion, given its different mechanism ofaction, the beneficial effects of trimetazidine can be expected to be additives to the haemodynamic treatment of ischaemia and possibly in patients resistant to the usual agents. We are likely to see increasing interest in this class of drug which offers a novel approach to the treatment of ischaemic heart disease.
A155