- Email: [email protected]
Preventive cardiology: strategies for the prevention and treatment of coronary artery disease JoAnne Micale Foody, Editor, Totowa, NJ: Humana Press, 2001. ISBN 0-89603-811-4
BOOK REVIEW
Preventive Cardiology: Strategies for the Prevention and Treatment of Coronary Artery Disease JoAnne Micale Foody, Editor Totowa, NJ: Humana Press, 2001. ISBN 0-89603-811-4 INTRODUCTION Despite a considerable decrease in the incidence of primary and secondary cardiac events in recent decades, coronary artery disease (CAD) continues to be responsible for the highest mortality and morbidity rates of any disease in the United States. Within this book’s 350 plus pages of text, 27 contributors review significant risk factors for CAD and provide useful preventative and therapeutic intervention strategies. Included are discussions of the unstable plaque, endothelial function, pharmacology, exercise, tomography, inflammation and infection, tobacco and women and coronary artery disease. Of particular interest to nutrition scientists are chapters on the roles of antioxidants, dyslipidemias, diabetes, hyperinsulinism, obesity, and homocysteine in the pathogenesis of CAD. These chapters are comprehensive, concise, and well written. The book’s shortcomings are that discussion of the relation of stress to CAD and consideration of unconventional therapies are not included. There are more than 7000 publications cited in Medline on stress and CAD and more than 24 000 on stress and cardiovascular disease. Clearly, stress is very important in the etiology of CAD, and failure to include it in a volume on preventive cardiology is a serious oversight. Equally serious is omission of unconventional nutritional therapies in the prevention and management of CAD and congestive heart failure; the remainder of this review explains why this is so.
CONGESTIVE HEART FAILURE Management of congestive heart failure (CHD; or congestive heart disease) continues to pose a significant challenge to cardiologists and internists. The long-term survival of patients has not been improved despite pharmacologic therapies, including treatment of hematologic abnormalities, fluid overload, and neuroendocrine stimulation. The disorder is characterized by metabolic abnormalities, such as accumulation of calcium in the myocardium, that result in decreased energy production, increased oxidative stress, protease activation, and, ultimately, destruction of the myocardium. Because myocardial energy production is aerobic, it depends on a constant supply of nutrient cofactors. These include L-carnitine, coenzyme Q10 (CoQ10), and taurine.
L-CARNITINE L-carnitine is synthesized from lysine and methionine, with iron and vitamins C, B6, and niacin as obligatory cofactors. Carnitine is synthesized primarily in the liver and kidney; hepatic and renal disorders limit its endogenous synthesis. The best dietary sources of carnitine are animal products. Approximately 250 mg is in-
Nutrition 18:209 –210, 2002 ©Elsevier Science Inc., 2002. Printed in the United States. All rights reserved.
Editor: Michael J. Glade, PhD
gested in a mixed diet, although much less is consumed by vegetarians. Carnitine is required for transport of long-chain fatty acids from cytoplasm into mitochondria to undergo -oxidation and indirectly activates pyruvate dehydrogenase, thus promoting glucose oxidation and reducing lactate and hydrogen accumulation in the myocardium. Carnitine also binds cardiotoxic short-chain acyl groups and releases free coenzyme A. There is as much as a 50 to 1 intracellular to extracellular carnitine concentration gradient, which is maintained by a sodiumdependent plasma membrane active transport system. Myocardial deficits in carnitine occur during heart failure, acute myocardial infarction, and ischemia. This is due to various molecular changes in the myocardium, causing impairment of fatty acid oxidation. Supplemental L-propionylcarnitine has exhibited favorable effects in congestive heart failure. For example, Caponnetto et al. conducted a randomized, double-blind, placebo-controlled study on 50 patients with New York Heart Association (NYHA) class II congestive heart failure.1 Patients receiving 1.5 g of Lpropionylcarnitine for 6 mo exhibited significant increases in left ventricular shortening fraction, left ventricular ejection fraction, stroke volume and cardiac index, and significant reduction in systemic vascular resistance compared with patients receiving placebo. Patients undergoing hemodialysis often exhibit symptoms of cardiovasular disease, including angina, arrhythmia, electrocardiographic abnormalities and hypotension. Because hemodialysis is associated with a progessive and substantial loss of carnitine from muscle (including heart muscle) and the ratio of free to total plasma carnitine is abnormally low following hemodialysis, supplemental carnitine is epecially important in these patients. Administration of L-carnitine has been found to ameliorate cardiac dysfunction in so many hemodialysis patients that it prompted one research group to recommend it as routine therapy.2 In a recent multicenter, double-blind, placebo-controlled, randomized study,3 carnitine supplementation, for 12 mo after myocardial infarction, produced significant attenuation of left ventricular dilation and significantly smaller increases in end-diastolic and end-systolic volumes compared with survivors receiving placebo. In another randomized, double-blind, placebo-controlled trial of L-carnitine,4 2 g/d for 28 d was given to 51 patients with suspected myocardial infarction. The mean infarct size as assessed by cardiac enzymes and electrocardiography was significantly reduced in the carnitine group compared with 50 patients receiving placebo. NYHA class III and IV heart failure, left ventricular enlargement, and total arrythmias also were significantly lower in the carnitine-supplemented group.4
COENZYME Q10 CoQ10, also known as ubiquinone, is a rate-limiting carrier for electron passage through the mitochondrial electron transport chain, acts as a lipophilic antioxidant, and is an oxidationinhibiting component of low-density lipoproteins. CoQ10 is synthesized endogenously from cholesterol by the hydroxymethylglutaryl coenzyme A reductase pathway. Accordingly, drugs that inhibit hydroxymethylglutaryl coenzyme A reductase also may reduce tissue CoQ10 concentrations. CoQ10 is found in foods and the estimated typical daily intake is 3 to 5 mg. Fish, poultry, and meat are the best sources, but soy 0899-9007/02/$22.00
210 and canola oils and nuts also are good sources. CoQ10 is not highly labile to heat during cooking. CoQ10 has been used as a cardioprotective agent in Japan for decades in treatment of heart failure, ischemic heart disease, and cardiotoxic chemical intoxication. Numerous experimental studies have supportd its use in ischemia and reperfusion injury, in which reactive oxygen species are generated.5 Studies of CoQ10 supplementation in cardiac disease have produced inconsistent results, despite deficits of myocardial CoQ10 of up to 50%. Dosage is probably an important variable; most of the studies failing to observe beneficial effects have used daily doses of 100 mg or less. In addition, formulations of CoQ10 differ widely in bioavailability. Although additional studies are needed, there is enough evidence to warrant CoQ10 supplementation in patients with CHD by using at least 100 mg twice a day of a highly bioavailable formulation.
TAURINE Taurine is an amino acid that lacks a carboxyl group and therefore does not participate in protein synthesis. It is biosynthesized from methionine and cysteine in the mature individual but not in the neonate. Taurine is found mostly in foods from animal sources. Human milk, but not cow’s milk, is a good source. Taurine is very important in the modulation of intracardiocyte calcium concentrations through promotion of calcium release from the sarcoplasmic reticulum and stimulation of the sarcolemmal sodium-calcium exchanger. Taurine also exhibits antioxidant properties and neutralizes toxic aldehydes, including malondialdehyde and acetaldehyde. Taurine is taken up into the myocardial cell by active transport. The taurine transporter is promoted by calmodulin and inhibited by protein kinase C. Reductions in cardiac taurine content in acute myocardial ischemia and CHD coincide with increasing circulating tumor necrosis factor-␣ and interleukin-6 concentrations. Cytokine-induced inhibition of taurine uptake may be reversible with taurine supplementation. Taurine accounts for over one-fourth of the total free amino acid pool in the heart, its concentration being four times that of glutamic acid, the next most abundant cardiac amino acid. Important cardiovascular effects exerted by taurine include maintenance of intracellular calcium concentrations within a range associated with optimal cardiac contractility, with antiarrythmic and positive inotropic effects on cardiac muscle. Taurine inhibits platelet aggregability and may exert a hypotensive effect. Plasma malondialdehyde and lipid peroxide concentrations are significantly increased in CHD and increased oxidative stress is related to disease severity. Because taurine neutralizes malondiadehyde and modulates calcium flux, taurine supplementation could be beneficial in CHD. However, studies of taurine supplementation in CHD are limited. The Heart Failure Research with Taurine Group reported that
Nutrition Volume 18, Number 2, 2002 breathlessness on exertion improved in 39% of patients given 3 g/d of taurine for 1 y, whereas only 15% of patients given placebo exhibited similar improvement. In addition, about 75% of those given taurine exhibited overall clinical improvement compared with about 25% of those given placebo. Patient self-assessments of energy level and edema of extremities favored taurine supplementation over placebo.
CONCLUDING REMARKS The clinical evidence for the use of carnitine therapy in cardiac disease is well documented. Admittedly, there is a lack of definitive clinical evidence that CoQ10 and taurine are as therapeutically effective. However, there is voluminous experimental evidence supporting the use of both agents. There certainly is evidence supporting the use of antioxidants in protecting the myocardium from oxidative stress. It is important to note that supplementation of a single nutrient is less likely to ameliorate the abnormalities that are present in the damaged myocardium than is supplementation with a full complement of nutrients. Consequently, it is even more remarkable that favorable results have occurred when L-carnitine, CoQ10, or taurine has been studied individually. Moreover, de novo synthesis of these conditionally essential nutrients by damaged myocardium is unlikely to be adequate to maintain their physiologic and biochemical functions. Consequently, relatively large daily intakes are likely to be required for therapeutic results. The inclusion of information on the potential therapeutic uses of these nutrients would enhance this otherwise excellent book’s stature as a textbook of truly “preventive cardiology.” Perhaps this deficit will be addressed in future editions.
Barry S. Kendler, PhD, CNS, FACN Manhattan College Bronx, New York, USA PII S0899-9007(01)00789-4
REFERENCES 1. Caponnetto S, Canale C, Masperone A, et al. Efficacy of L-propionyl carnitine treatment in patients with left ventricular dysfunction. Eur Heart J 1994;15:1267 2. van Es A, Henny FC, Kooistra MP, et al. Amelioration of cardiac function by L-carnitine administration in patients on haemodialysis. Contrib Nephrol 1992; 98:28 3. Iliceto S, Scrutinio D, Bruzzi P, et al. Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: The CEDIM Trial. Am Coll Cardiol 1995;26:380 4. Singh RB, Niaz MA, Agarwal P, et al. A randomized, double-blind placebocontrolled trial of L-carnitine in suspected acute myocardial infarction. Postgrad Med J 1996;72:45 5. Hanaki Y, Sugiyama S, Ozawa T, et al. Coenzyme Q10 and coronary artery disease. Clin Invest 1993;71:S112
Preventive Cardiology: Strategies for the Prevention and Treatment of Coronary Artery Disease JoAnne Micale Foody, Editor Totowa, NJ: Humana Press, 2001. ISBN 0-89603-811-4 INTRODUCTION Despite a considerable decrease in the incidence of primary and secondary cardiac events in recent decades, coronary artery disease (CAD) continues to be responsible for the highest mortality and morbidity rates of any disease in the United States. Within this book’s 350 plus pages of text, 27 contributors review significant risk factors for CAD and provide useful preventative and therapeutic intervention strategies. Included are discussions of the unstable plaque, endothelial function, pharmacology, exercise, tomography, inflammation and infection, tobacco and women and coronary artery disease. Of particular interest to nutrition scientists are chapters on the roles of antioxidants, dyslipidemias, diabetes, hyperinsulinism, obesity, and homocysteine in the pathogenesis of CAD. These chapters are comprehensive, concise, and well written. The book’s shortcomings are that discussion of the relation of stress to CAD and consideration of unconventional therapies are not included. There are more than 7000 publications cited in Medline on stress and CAD and more than 24 000 on stress and cardiovascular disease. Clearly, stress is very important in the etiology of CAD, and failure to include it in a volume on preventive cardiology is a serious oversight. Equally serious is omission of unconventional nutritional therapies in the prevention and management of CAD and congestive heart failure; the remainder of this review explains why this is so.
CONGESTIVE HEART FAILURE Management of congestive heart failure (CHD; or congestive heart disease) continues to pose a significant challenge to cardiologists and internists. The long-term survival of patients has not been improved despite pharmacologic therapies, including treatment of hematologic abnormalities, fluid overload, and neuroendocrine stimulation. The disorder is characterized by metabolic abnormalities, such as accumulation of calcium in the myocardium, that result in decreased energy production, increased oxidative stress, protease activation, and, ultimately, destruction of the myocardium. Because myocardial energy production is aerobic, it depends on a constant supply of nutrient cofactors. These include L-carnitine, coenzyme Q10 (CoQ10), and taurine.
L-CARNITINE L-carnitine is synthesized from lysine and methionine, with iron and vitamins C, B6, and niacin as obligatory cofactors. Carnitine is synthesized primarily in the liver and kidney; hepatic and renal disorders limit its endogenous synthesis. The best dietary sources of carnitine are animal products. Approximately 250 mg is in-
Nutrition 18:209 –210, 2002 ©Elsevier Science Inc., 2002. Printed in the United States. All rights reserved.
Editor: Michael J. Glade, PhD
gested in a mixed diet, although much less is consumed by vegetarians. Carnitine is required for transport of long-chain fatty acids from cytoplasm into mitochondria to undergo -oxidation and indirectly activates pyruvate dehydrogenase, thus promoting glucose oxidation and reducing lactate and hydrogen accumulation in the myocardium. Carnitine also binds cardiotoxic short-chain acyl groups and releases free coenzyme A. There is as much as a 50 to 1 intracellular to extracellular carnitine concentration gradient, which is maintained by a sodiumdependent plasma membrane active transport system. Myocardial deficits in carnitine occur during heart failure, acute myocardial infarction, and ischemia. This is due to various molecular changes in the myocardium, causing impairment of fatty acid oxidation. Supplemental L-propionylcarnitine has exhibited favorable effects in congestive heart failure. For example, Caponnetto et al. conducted a randomized, double-blind, placebo-controlled study on 50 patients with New York Heart Association (NYHA) class II congestive heart failure.1 Patients receiving 1.5 g of Lpropionylcarnitine for 6 mo exhibited significant increases in left ventricular shortening fraction, left ventricular ejection fraction, stroke volume and cardiac index, and significant reduction in systemic vascular resistance compared with patients receiving placebo. Patients undergoing hemodialysis often exhibit symptoms of cardiovasular disease, including angina, arrhythmia, electrocardiographic abnormalities and hypotension. Because hemodialysis is associated with a progessive and substantial loss of carnitine from muscle (including heart muscle) and the ratio of free to total plasma carnitine is abnormally low following hemodialysis, supplemental carnitine is epecially important in these patients. Administration of L-carnitine has been found to ameliorate cardiac dysfunction in so many hemodialysis patients that it prompted one research group to recommend it as routine therapy.2 In a recent multicenter, double-blind, placebo-controlled, randomized study,3 carnitine supplementation, for 12 mo after myocardial infarction, produced significant attenuation of left ventricular dilation and significantly smaller increases in end-diastolic and end-systolic volumes compared with survivors receiving placebo. In another randomized, double-blind, placebo-controlled trial of L-carnitine,4 2 g/d for 28 d was given to 51 patients with suspected myocardial infarction. The mean infarct size as assessed by cardiac enzymes and electrocardiography was significantly reduced in the carnitine group compared with 50 patients receiving placebo. NYHA class III and IV heart failure, left ventricular enlargement, and total arrythmias also were significantly lower in the carnitine-supplemented group.4
COENZYME Q10 CoQ10, also known as ubiquinone, is a rate-limiting carrier for electron passage through the mitochondrial electron transport chain, acts as a lipophilic antioxidant, and is an oxidationinhibiting component of low-density lipoproteins. CoQ10 is synthesized endogenously from cholesterol by the hydroxymethylglutaryl coenzyme A reductase pathway. Accordingly, drugs that inhibit hydroxymethylglutaryl coenzyme A reductase also may reduce tissue CoQ10 concentrations. CoQ10 is found in foods and the estimated typical daily intake is 3 to 5 mg. Fish, poultry, and meat are the best sources, but soy 0899-9007/02/$22.00
210 and canola oils and nuts also are good sources. CoQ10 is not highly labile to heat during cooking. CoQ10 has been used as a cardioprotective agent in Japan for decades in treatment of heart failure, ischemic heart disease, and cardiotoxic chemical intoxication. Numerous experimental studies have supportd its use in ischemia and reperfusion injury, in which reactive oxygen species are generated.5 Studies of CoQ10 supplementation in cardiac disease have produced inconsistent results, despite deficits of myocardial CoQ10 of up to 50%. Dosage is probably an important variable; most of the studies failing to observe beneficial effects have used daily doses of 100 mg or less. In addition, formulations of CoQ10 differ widely in bioavailability. Although additional studies are needed, there is enough evidence to warrant CoQ10 supplementation in patients with CHD by using at least 100 mg twice a day of a highly bioavailable formulation.
TAURINE Taurine is an amino acid that lacks a carboxyl group and therefore does not participate in protein synthesis. It is biosynthesized from methionine and cysteine in the mature individual but not in the neonate. Taurine is found mostly in foods from animal sources. Human milk, but not cow’s milk, is a good source. Taurine is very important in the modulation of intracardiocyte calcium concentrations through promotion of calcium release from the sarcoplasmic reticulum and stimulation of the sarcolemmal sodium-calcium exchanger. Taurine also exhibits antioxidant properties and neutralizes toxic aldehydes, including malondialdehyde and acetaldehyde. Taurine is taken up into the myocardial cell by active transport. The taurine transporter is promoted by calmodulin and inhibited by protein kinase C. Reductions in cardiac taurine content in acute myocardial ischemia and CHD coincide with increasing circulating tumor necrosis factor-␣ and interleukin-6 concentrations. Cytokine-induced inhibition of taurine uptake may be reversible with taurine supplementation. Taurine accounts for over one-fourth of the total free amino acid pool in the heart, its concentration being four times that of glutamic acid, the next most abundant cardiac amino acid. Important cardiovascular effects exerted by taurine include maintenance of intracellular calcium concentrations within a range associated with optimal cardiac contractility, with antiarrythmic and positive inotropic effects on cardiac muscle. Taurine inhibits platelet aggregability and may exert a hypotensive effect. Plasma malondialdehyde and lipid peroxide concentrations are significantly increased in CHD and increased oxidative stress is related to disease severity. Because taurine neutralizes malondiadehyde and modulates calcium flux, taurine supplementation could be beneficial in CHD. However, studies of taurine supplementation in CHD are limited. The Heart Failure Research with Taurine Group reported that
Nutrition Volume 18, Number 2, 2002 breathlessness on exertion improved in 39% of patients given 3 g/d of taurine for 1 y, whereas only 15% of patients given placebo exhibited similar improvement. In addition, about 75% of those given taurine exhibited overall clinical improvement compared with about 25% of those given placebo. Patient self-assessments of energy level and edema of extremities favored taurine supplementation over placebo.
CONCLUDING REMARKS The clinical evidence for the use of carnitine therapy in cardiac disease is well documented. Admittedly, there is a lack of definitive clinical evidence that CoQ10 and taurine are as therapeutically effective. However, there is voluminous experimental evidence supporting the use of both agents. There certainly is evidence supporting the use of antioxidants in protecting the myocardium from oxidative stress. It is important to note that supplementation of a single nutrient is less likely to ameliorate the abnormalities that are present in the damaged myocardium than is supplementation with a full complement of nutrients. Consequently, it is even more remarkable that favorable results have occurred when L-carnitine, CoQ10, or taurine has been studied individually. Moreover, de novo synthesis of these conditionally essential nutrients by damaged myocardium is unlikely to be adequate to maintain their physiologic and biochemical functions. Consequently, relatively large daily intakes are likely to be required for therapeutic results. The inclusion of information on the potential therapeutic uses of these nutrients would enhance this otherwise excellent book’s stature as a textbook of truly “preventive cardiology.” Perhaps this deficit will be addressed in future editions.
Barry S. Kendler, PhD, CNS, FACN Manhattan College Bronx, New York, USA PII S0899-9007(01)00789-4
REFERENCES 1. Caponnetto S, Canale C, Masperone A, et al. Efficacy of L-propionyl carnitine treatment in patients with left ventricular dysfunction. Eur Heart J 1994;15:1267 2. van Es A, Henny FC, Kooistra MP, et al. Amelioration of cardiac function by L-carnitine administration in patients on haemodialysis. Contrib Nephrol 1992; 98:28 3. Iliceto S, Scrutinio D, Bruzzi P, et al. Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: The CEDIM Trial. Am Coll Cardiol 1995;26:380 4. Singh RB, Niaz MA, Agarwal P, et al. A randomized, double-blind placebocontrolled trial of L-carnitine in suspected acute myocardial infarction. Postgrad Med J 1996;72:45 5. Hanaki Y, Sugiyama S, Ozawa T, et al. Coenzyme Q10 and coronary artery disease. Clin Invest 1993;71:S112