Klaus KA Witte and Andrew L Clark

CONTENTS

6.1

Introduction

6.2

Minerals

6.2.1

Calcium

6.2.2

Magnesium

6.2.3

Zinc

6.2.4

Copper

6.2.5

Selenium

6.3

Vitamins

6.3.1

Vitamin A

6.3.2

Thiamine (B1)

6.3.3

Riboflavin (B2)

6.3.4

Niacin

6.3.5

Pantothenic acid (B5)

6.3.6

Vitamin B6

6.3.7

Folate

6.3.8

Vitamin B12

6.3.9

Vitamin C

6.3.10 Vitamin E

6.3.11

Vitamin D

6.4

Other Compounds

6.4.1

Ubiquinone (Coenzyme Q10)

6.4.2

Carnitine

6.4.3

Creatine Phosphate

6.5

Oxidative Stress

6.6

Homocysteine and Heart Disease

6.7

References

6.1 INTRODUCTION

Cardiovascular disease is the greatest cause of mortality in developed countries and diet plays an important role in contributing to the development and progression of ischemic heart disease (IHD). The influences of general nutrition and micronutrients such as vitamins and minerals on the progression of IHD are poorly understood and recent studies have done little to clarify the situation.

A micronutrient can be regarded as any essential dietary component present in trace amounts. Micronutrients have multiple roles both as participants in many important metabolic processes throughout the body and to counter the oxidative stress resulting from normal metabolism and daily exposure to environmental agents. They can also serve to facilitate communications, aid muscle contraction, and maintain stable tissue environments.

The most common cause of micronutrient deficiency is a consequence of reduced dietary intake and the role of a particular micronutrient is often uncovered when the consequences of dietary deficiencies such as selenium deficiency (Keshan disease) in China and iodine deficiency (thyroid disease) in the U.K. manifest themselves. (Table 6.1 provides a summary of particular micronutrient deficiencies and their possible contribution to cardiovascular disease.) However, micronutrient deficiency in cardiovascular disease could also be a product of increased losses resulting from the condition, medical therapy, or increased requirements, for example, due to greater levels of oxidative stress. Acute supplementation of individual agents in patients with established coronary disease or at high risk of future events has generally been unsuccessful in randomised trials. This chapter reviews the potential cardiovascular benefits of individual micronutrient supplementation using animal and in vitro studies, and examines studies aimed at prevention and treatment of cardiovascular disease in humans.

6.2 MINERALS 6.2.1 Calcium

Ninety-nine percent of the body's calcium is stored as hydroxyapatite [Ca10(OH)2(PO4)6] in the skeleton. Plasma calcium increases under the influence of vitamin D and its metabolites and parathormone. Calcitonin, a thyroid hormone, lowers plasma calcium by inhibiting bone resorption.

Dietary salt, protein, and caffeine all increase urinary calcium loss. Calcium absorption is reduced in individuals over 70 because the gut may become less sensitive to vitamin D and also because of lower renal vitamin D synthesis. Vitamin D3 or cholecalciferol is derived from the effect of ultraviolet radiation on 7-dehy-drocholesterol. Elderly patients in temperate climates who tend to have less exposure to sunlight also have less 7-dehyrocholesterol in their skin and therefore produce less vitamin D after exposure to ultraviolet light.1

Postmenopausal women with low intakes of calcium have higher mortality from IHD.2 Intriguing evidence from an experiment using chick embryos incubated without their shells, i.e., without their usual sources of calcium, suggests that severe calcium deficiency accelerates smooth muscle hypertrophy and cardiomyocyte proliferation

TABLE 6.1

Potential Contribution of Micronutrient Deficiency to Cardiovascular Disease (CVD)

Micronutrient

Thiamine

Riboflavin

Magnesium

Deficiency State

Beri beri

Arrhythmias

Calcium/Vitamin D Osteoporosis

Zinc

Copper

Selenium

Vitamin A

Niacin Vitamin B6

Pantothenic acid

(vitamin B5) Folate

Vitamin B12 Vitamin C

Vitamin E Ubiquinone

Pellagra

Macrocytic anemia

Pernicious anemia Scurvy

Possible Relevance to CVD

Specific cardiomyopathy and frusemide-induced thiamine deficiency worsening heart failure and renal failure

Increased prevalence in children with chronic heart failure; possible abnormal lipid metabolism Arrythmogenic, particularly with digoxin; can worsen heart failure and increase symptoms of fatigue; may accelerate atherosclerosis Hypertension, smooth muscle hypertrophy, and increased effects of endothelin; arrythmogenesis, long QT, torsades de pointes, and ventricular fibrillation; osteoporosis common in CHF patients; hypocalcemia-induced cardiomyopathy Contractile dysfunction, particularly in combination with ethanol; increased oxidative stress Myocyte damage; myofibrillar disarray; copper-

deficient cardiomyopathy Decreased antioxidant capacity; reduced smooth muscle relaxation; increased myocyte electrical vulnerability; Keshan disease; peripartum cardiomyopathy Impaired cell-mediated immunity; reduced antioxidant capacity Unknown

Can lead to impaired immunity; elevation of homocysteine levels None

Common in the elderly; homocysteine levels raised; increased risk of symptomatic coronary disease; impaired endothelial function Homocysteine levels raised Increased risk of stroke; impaired endothelial function; reduced antioxidant capacity Increased susceptibility to free radicals; reduced platelet aggregation; inhibition of smooth muscle proliferation

Associated with increased mortality and increased oxidative stress in CHF

(accelerated heart weight gain), decelerates sarcomeric protein expression, and induces atherogenic disorders (higher blood pressure) in vivo?

Hypocalcemia is potentially proarrhythmogenic. It is associated with QT prolongation4 and torsades de pointes5 and hypocalcemic-associated ventricular fibrillation has been reported.6 Patients with heart failure demonstrated increased bone turnover and a higher incidence of osteoporosis.7 Hypocalcemia can lead to cardiomyopathy, usually in young children with congenital causes for the hypocal-cemia, but the response to calcium supplementation can often be dramatic.8-10

6.2.2 Magnesium

Magnesium, the major intercellular divalent cation, is a cofactor in reactions utilizing adenosine triphosphate (ATP) and is essential for deoxyribonucleic acid (DNA) replication and ribonucleic acid (RNA) and protein synthesis. Magnesium is absorbed from the small intestine and excreted in the urine. Loop and thiazide diuretics increase magnesium loss.

Magnesium deficiency is associated with an increase in the rate of ventricular ectopic beats, both in the presence of left ventricular dysfunction11 and normal cardiac function.12 In rats, magnesium deficiency can increase the rate of adrenaline-induced ventricular tachycardia.13 Hypomagnesemia may potentiate the contractile response of smooth muscle to oxidizing agents, thereby accelerating atherosclero-sis.14 In animal studies, hypomagnesemia leads to hypertension, heart failure, and myocardial fibrosis.15-17 More than 30% of patients with CHF are magnesium-deficient,19 which is associated with a worse prognosis in CHF.19-21 The deficiency is a particular problem in patients with heart failure and atrial fibrillation; it can precipitate digoxin toxicity.22,23 Hypomagnesemic heart failure is described in anorexia nervosa and correction of the electrolyte imbalance leads to improvement in left ventricular function.24 Muscular magnesium deficiency, which often follows prolonged serum deficiency, may contribute to symptoms of fatigue and also causes positive sodium and negative potassium balances.25

Magnesium supplementation is associated with a fall in the rate of ventricular arrhythmias in patients with chronic heart failure,26,27 atrial fibrillation,28-30 and digoxin toxicity.30 It may also be useful in the management of atrial fibrillation in patients with Wolff-Parkinson-White syndrome.32 Torsades de pointes also often responds to magnesium,33-35 even if there is no overt biochemical deficiency. Two randomised studies have demonstrated no benefit of intravenous magnesium in acute myocardial infarction in humans.36,37

6.2.3 Zinc

Zinc is absorbed mainly through the duodenum, and although absorption is unaffected by age, it is reduced by low protein diets. Elderly patients may show a 5% incidence of frank biochemical deficiency, with 20% displaying symptoms suggestive of moderate deficiency such as loss of taste acuity.38

Zinc is a powerful site-specific antioxidant.39 Deficiency leads to elevated oxi-dative stress and cholesterol levels in rats.40,41 A combination of zinc deficiency and ethanol can lead to contractile dysfunction in pre-ischemic conditions in the rat model.42 Zinc deficiency has been noted in patients using angiotensin-converting enzyme inhibitors (ACEi) for hypertension.43

6.2.4 Copper

Copper is absorbed through active processes from the stomach and duodenum. Excretion occurs mainly via the gastrointestinal tract. Deficiency is rare but has been seen in patients receiving total parenteral nutrition (TPN) and premature infants. Copper is also a powerful antioxidant and is involved in the acute phase reaction. As such it is involved in the regulation of oxidative free radicals and deficiency increases lipoprotein peroxidation.44 Copper-deficient cardiomyopathy has been described in patients on TPN.45 This may be due to decreased cytochrome C oxidase activity46 that causes a reduction in mitochondrial activity. Experimental copper deficiency in rats leads to increased risk of myocyte oxidative damage47 and long-term copper restriction can lead to myofibrillar disarray and mitochondrial fragmentation.48 Copper deficiency in humans is associated with elevated cholesterol levels.4950

6.2.5 Selenium

Selenium is absorbed principally in the duodenum. Its main function is as an antioxidant in glutathione peroxidase (GSHPx) — an enzyme and major intracellular antioxidant. Selenoprotein P is postulated to serve as a major extracellular antioxidant.51 Selenium is a powerful antioxidant in its own right and also supports other antioxidant processes.52 Pure selenium deficiency is rare, but symptoms may occur in cases of additional oxidative stress due to deficiency of other antioxidant systems such as vitamin E. Selenium may preserve the ability of myocardial cells to produce ubiquinone, another powerful antioxidant, and also reduce its breakdown53,54 (see Section 6.4.2).

Low selenium levels may predispose an individual to ischemic heart disease and peripheral vascular disease.55 Selenium given to pigs during induced acute myocar-dial infarction suppressed the electrical vulnerability of myocardial cell mem-branes.55 Selenium also causes smooth muscle relaxation and may therefore become useful in the therapy of hypertension.56

Selenium deficiency correlates with clinical assessments of severity of chronic heart failure (n = 21).57 Selenium deficiency impairs the ability of rat sarcoplasmic reticulum to take up calcium58 and leads to ultrastructural changes such as loss of cristae in the mitochondria.59 Selenium deficiency is the cause of an endemic car-diomyopathy known as Keshan disease in China; selenium replacement improved the cardiomyopathy.60 Cardiomyopathies induced by selenium deficiency have also been described in patients on long-term TPN in Western countries.61 Selenium deficiency is also a risk factor for peripartum cardiomyopathy.62

6.3 VITAMINS 6.3.1 Vitamin A

Vitamin A originates from two classes of compounds: pre-formed vitamin A (retinol and related compounds) and carotenoids. Vitamin A is involved in cellular differentiation, morphogenesis, glycoprotein synthesis, gene expression, immunity, and growth. Its deficiency reduces cell-mediated immunity63 and leads to increased susceptibility to infection and increased morbidity from respiratory diseases. Vitamin A deficiency mediates its effects on the cardiovascular system through reduced antioxidant activity.64 Low vitamin A intake is associated with an increase in the risk of acute myocardial infarction.64 Some studies, but not all,66 suggest that vitamin A supplementation may reduce overall cardiovascular mortality. Little clear evidence supports its routine supplementation in patients with heart failure,67 in combination with vitamin E and selenium68 or alone.69

Although thiamine is readily absorbed, its turnover is rapid and body stores are small. Thiamine is lost in the urine, and dietary deficiency can lead to low plasma thiamine within 30 days. Thiamine is a coenzyme for several decarboxylation steps in carbohydrate metabolism. Deficiency leads to impaired tissue oxygenation through inhibition of both the citric acid cycle and hexose monophosphate shunt.

The two main forms of thiamine deficiency in humans are beri beri and Wernicke-Korsakoff syndrome. In Western countries, beri beri is occasionally seen in chronic alcoholics. High output cardiac failure is seen with acute beri beri. The features include a bounding pulse with warm extremities. Peripheral edema due to the accumulation of pyruvate and lactate in the tissues leads to intense vasodilation. Skeletal muscle blood flow increases while cerebral and renal blood flows decrease. Response to thiamine is brisk, with diuresis and full recovery. The accumulation of pyruvate and lactate happens with exercise and does not occur in less active patients, where perhaps the first symptom noticed is encephalopathy (Wernicke-Korsakoff syndrome).

Frusemide-induced thiamine deficiency was first described in rats.70 Moderate thiamine deficiency can occur in hospitalized elderly patients71,72 and chronic heart failure patients on loop diuretics.73,74 Thiamine deficiency reduces myocardial contractile performance.75 Thiamine uptake by cardiac myocytes is impaired by both digoxin and frusemide; the drugs have an additive effect if taken together.76 Thiamine supplementation in patients with moderate to severe chronic heart failure can increase left ventricular ejection fraction and improve symptoms (Figure 6.1).77,78 Post-transplant heart failure can also respond to high dose thiamine supplementation.79

6.3.3 Riboflavin (B2)

Riboflavin forms parts of two important coenzymes, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD); both are oxidizing agents. Rats fed riboflavin-deficient diets showed abnormal lipid metabolism and a reduction in the beta-oxidation of fatty acids.80 Children with chronic heart failure due to congenital heart disease have increased risk of riboflavin deficiency.81 It is, however, not known whether riboflavin deficiency has a detrimental effect on cardiac functioning.

0.40

0.35

0.30

0.25

0.20

Baseline

7 Days

7 Weeks

FIGURE 6.1 Left ventricular ejection fraction (mean +/- SEM) at the end of the doubleblind study (week 1) and at the end of the open ambulatory phase (week 7). * = p < 0.05, thiamine versus placebo, end of week 1. ** = p < 0.01, all patients, end of week 7 versus baseline. (From Shimon, I. et al., Am. J. Med, 98, 485, 1995. With permission.)

6.3.4 Niacin

Niacin is a generic term for nicotinic acid and nicotinamide. Nicotinamide is a component of nicotinamide adenine dinucleotide (NAD), nicotinamide adenine dinu-cleotide phosphate (NADP), and the pyridine nucleotides. Deficiency causes pellagra. No evidence suggests a consequence of niacin deficiency on the cardiovascular system, although niacin supplementation reduces cellular apoptosis to oxidative stress.82 Nicotinic acid was used as a lipid lowering agent prior to development of the coenzyme A reductase inhibitors.

6.3.5 Pantothenic acid (B5)

Vitamin B5 is an essential part of coenzyme A and of acyl carrier protein (ACP). Spontaneous pantothenic acid deficiency has never been described because of the ubiquitous nature of the vitamin in foods.

6.3.6 Vitamin B6

Vitamin B6 occurs in three interchangeable forms in the body: pyridoxine, pyridoxal, and pyridoxamine. They all exist as phosphorylated compounds. The principal form is pyridoxal 5'-phosphate (PLP), which is involved in amino acid metabolism. Lack of vitamin B6 alone is rare; deficiencies most commonly occur in conjunction with other vitamin deficiencies.

The symptoms of PLP deficiency are general weakness, sleepiness, peripheral neuropathy, personality changes, dermatitis, cheilosis, glossitis, anemia, and impaired immunity. Low PLP is an independent risk factor for coronary artery disease even when homocysteine (see below) is taken into account.83 However, most of its influence is through its effect on homocysteine levels.84,85 Low B6 levels are also associated with increased risk of extracranial carotid artery disease, although the risk, when corrected for homocysteine, is not as significant as first thought.87

6.3.7 Folate

Folate is a generic name for compounds related to pteroylglutamic acid (folic acid). Folic acid deficiency is common in hospitalized patients. Many diseases, especially intestinal, neoplastic, and hematological, increase body requirements for folate. Methotrexate, aminopterin, pyrimethamine, and cotrimoxazole inhibit normal folate metabolism. Tissue levels of vitamin B12, vitamin B6, and folate are not well-related to blood levels and many more elderly patients may be deficient than are recognized.88 Folate deficiency leads to reduced ability of cells to double their nuclear DNA in order to divide because of impaired synthesis of thymidylate. Megaloblastic anemia results with similar changes in leukocytes, platelets, and epithelial cells. Folate deficiency also causes infertility and diarrhea.

Folate is required for the conversion of homocysteine to methionine (Figure 6.2) and a strong inverse relationship exists between folate consumption and homocys-teine levels among patients with and without hyperhomocysteinemia (see Section

Relationship Between Vit And Copper
FIGURE 6.2 Interactions of homocysteine, folate, and vitamin B12. Copyright 2004 by CRC Press LLC
  1. 6).8889 Individuals with low folate intake are at higher risk of coronary heart disease.90-92 Patients with coronary heart disease are more likely to have reduced serum folate and raised homocysteine.93 Folic acid supplementation improves coronary endothelial function in patients with coronary artery disease by an effect on homocysteine94 and also by a homocysteine-independent mechanism.95
  2. 3.8 Vitamin B12

Vitamin B12 (cobalamin) is a generic term for a group of large complex compounds only synthesized by bacteria. Malabsorption due to gastric atrophy or disease of the terminal ileum is the commonest cause of selective B12 deficiency. In the elderly population, the deterioration in gastric production of intrinsic factor due to gastric atrophy leads to pernicious anaemia. This is characterized by megaloblastic anaemia due to the trapping of folate and reduction in DNA synthesis with interruption of normal nuclear division. Vitamin B12 deficiency is associated with elevated homocysteine and consequent elevated risk for coronary artery disease,8485 but no published work has looked at B12 status in patients with heart disease.

6.3.9 Vitamin C

Vitamin C (ascorbic acid) can be synthesized from glucose or galactose in a wide variety of plants and most animal species. The ability to participate in redox reactions is the basis for most of the functions of this antioxidant vitamin. Cigarette smokers have lower plasma and leukocyte levels of vitamin C;96 overt deficiency of vitamin C is rare.

Higher levels of intake of vitamin C correlate with a reduced risk of death from stroke as closely as diastolic blood pressure in otherwise normal elderly subjects.97 Low vitamin C levels increase the risk of stroke, particularly in hypertensive overweight men.98 However, except for one study,99 little correlation was shown between vitamin C levels and death from coronary disease.97,100 High-dose ascorbic acid supplementation might therefore be a useful adjunct in the treatment of hypertension.101 Infusions of vitamin C improved peripheral endothelial function in diabetic patients,102,103 hypercholesterolemic patients,104 hypertensive patients,105 patients with chronic heart failure (Figure 6.3),106 and smokers.107 Coronary artery endothelial function in patients with hypertension and hypercholesterolemia also improves with vitamin C,108 and some benefit on acetylcholine-induced vasospasm may be gained by patients with coronary spastic angina.109

Vitamin C supplementation can reduce oxidative stress-mediated postprandial endothelial dysfunction.110 Oral vitamin C improves endothelial-dependent vasodilation of the brachial artery.111,112 In addition to these acute effects, vitamin C also reduces apoptosis in cardiomyocytes in rats with experimental heart failure, suggesting a potential long-term benefit in CHF patients.113

6.3.10 Vitamin E

Vitamin E (tocopherol) is a powerful antioxidant and is ubiquitous in cell membranes, protecting them from free radical damage. Vitamin E levels predict cardiovascular events and death more accurately in elderly patients (>80 years) than serum cholesterol.114

Normals Chronic Heart Failure

FIGURE 6.3 Change in radial artery diameter (%) during reactive hyperemia (flow-dependent dilation) after wrist occlusion in normal individuals (n = 8) and patients with CHF (n = 10). The filled bars demonstrate the effect of vitamin C infusion prior to occlusion on flow-dependent dilation. (Adapted from Hornig, B. et al., Circulation, 97, 363, 1998. With permission.)

FIGURE 6.3 Change in radial artery diameter (%) during reactive hyperemia (flow-dependent dilation) after wrist occlusion in normal individuals (n = 8) and patients with CHF (n = 10). The filled bars demonstrate the effect of vitamin C infusion prior to occlusion on flow-dependent dilation. (Adapted from Hornig, B. et al., Circulation, 97, 363, 1998. With permission.)

High vitamin E intake is associated with a lower incidence of coronary heart disease in middle-aged subjects.116 Men with high vitamin E intakes have a 40% reduced risk117 and women a 34% reduction.118 This effect is, however, not confined to the middle-aged. Additional reductions in risk were noted in subjects over 65 years of age if they took both vitamin E and vitamin C.118 High-dose vitamin E reduces the oxidation of LDL.119120 Oxidized LDL may enhance the generation of foam cells in the arterial walls, proliferation of smooth muscle cells, and platelet adhesion and aggregation, and trigger thrombosis.121 In healthy volunteers, diabetics, and cardiac transplant patients, vitamin E can lead to a reduction of platelet aggre-gation.122-124 This is a direct effect of vitamin E on platelet activity125 through the inhibition of platelet protein kinase C.126 127 Alpha-tocopherol can also control the proliferation of smooth muscle cells through a similar mechanism.128 A transient reduction in endothelial function that occurs after a high-fat meal is inhibited by pretreatment with high doses of vitamin E.129 Alpha-tocopherol can also improve endothelial function in cholesterol-fed rabbits.130

Leukocyte-endothelium cell interactions are reduced by vitamin E due to attenuated surface expression of adhesion molecules on both cell types.131 In experimental coronary artery occlusion lasting 45 minutes, high-dose vitamin E supplementation prior to ischemia combined with intravenous vitamin C infusion prior to reperfusion led to significantly less myocardial damage in pigs.132 This suggests further that water-soluble vitamin C aids the antioxidant action of lipid-soluble vitamin E. There is strong evidence that vitamin C is able to regenerate vitamin E radicals at the borders of the lipids and aqueous phases in cell membranes.133

Despite these theoretical bases for benefits from vitamin E, few clear data suggest that routine supplementation would benefit patients with ischemic heart disease.66 134 The CHAOS trial showed a significant reduction in nonfatal myo-cardial infarction with vitamin E, but a 22% increase in all-cause mortality was found in the vitamin E group.135 The use of vitamin E in post-acute myocardial infarction also has little supportive evidence.136 137 The GISSI Prevenzione trial showed no benefit from vitamin E on post-infarct mortality.138 The HOPE study demonstrated no benefit from vitamin E in primary prevention of coronary events in patients at high risk of coronary disease.139 140 Vitamin E can reduce oxidative stress in patients with chronic heart failure,141 but no clinical data support its routine use.

6.3.11 Vitamin D

Vitamins D2 and D3 are derived from the effects of ultraviolet radiation on the skin. Older individuals produce less vitamin D after exposure to ultraviolet light because their skin contains lower amounts of steroid precursors.1

Vitamin D can reduce the hypertrophic effects of endothelin on rat myocytes.142 The requirement for calcium in myocardial contraction is discussed in Section 6.2.1, and vitamin D also seems to be an essential agent. Rats fed vitamin D-deficient diets with calcium levels maintained by high-dose calcium supplements developed deteriorating myocardial contractile function. The myocardial contraction returned to normal only when vitamin D was supplemented.143

Patients with chronic heart failure have low serum vitamin D metabolites and increased bone turnover with high levels of osteopenia or osteoporosis.7,240

  1. 4 OTHER COMPOUNDS
  2. 4.1 Ubiquinone (Coenzyme Q10)

Coenzyme Q10 (2,3-dimethoxy-5 methyl-6-decaprenyl-1,4-benzoquinone) was first isolated in 1957 in bovine cardiac muscle.144 It is an endogenous fat-soluble quinone found in high concentrations in the mitochondria of myocardium, liver, and kidney. It functions as an electron carrier during the synthesis of adenosine triphosphate (ATP), but also has membrane stabilizing properties and is a powerful antioxidant.

Myocardial biopsies in patients with heart disease have shown mitochondrial ubiquinone depletion, so ubiquinone deficiency may therefore play a role in the pathogenesis of both heart failure and ischemic heart disease.145 Patients with heart failure have lower myocardial levels of ubiquinone than normal individuals,146 and low serum ubiqinone levels are associated with increased mortality in heart fail-ure.147 The production of ubiquinone is reduced by HMG CoA reductase inhibitors (statins) leading to low serum levels148 149 although tissue levels remain stable with short-term statin therapy.150,151

Non-randomised studies in patients with dilated cardiomyopathy and ischemic heart disease-induced systolic dysfunction have shown positive results for ejection fraction, exercise tolerance, and New York Heart Association (NYHA) status with ubiquinone supplementation.152154 Most placebo-controlled trials,155,156 but not all of them,157 support these findings and also show reductions in hospitalizations. Ubiquinone may also be of some benefit in left ventricular diastolic dysfunction.158

6.4.2 Carnitine

Carnitine supplementation improves the utilization of pyruvate in the Krebs cycle,227 and thereby improves muscle metabolism. It has been investigated in patients undergoing cardiac surgery,228 and in those with angina pectoris,229-232 acute myocardial infarction,233,234 shock,235 and peripheral vascular disease.236,237 Some improvement of exercise tolerance in patients with limiting ischemic symptoms was noted, but a lack of strong evidence for the use of carnitine in these situations remains. Oral propionyl-L-carnitine in some studies227 but not all238 has shown improved exercise tolerance (but not hemodynamic variables) in patients with chronic heart failure. The compound may also reduce apoptosis in skeletal muscle cells, suggesting a potential benefit in the myopathy of chronic heart failure.239

6.4.3 Creatine Phosphate

Creatine is used to improve athletic performance. Patients with chronic heart failure develop skeletal myopathies.240 Muscle contraction and relaxation are fueled through the dephosphorylation of ATP, which must be rapidly resynthesized. Creatine serves as a phosphate donor to maintain high levels of intracellular ATP, and creatine supplementation increases the rate of phosphocreatine resynthesis.241 Skeletal muscle strength and endurance were improved in patients with chronic heart failure after short-term oral creatine supplementation, but no effect on cardiac contractility was noted.242 Creatine administered intravenously improved ejection fraction.243,244 The improvements in skeletal muscle function were seen predominantly in patients with low levels of creatine and phosphocreatine in their skeletal muscles.245 This was not a ubiquitous finding in patients with chronic heart failure.245,246

It is possible that creatine is of benefit in some chronic heart failure patients, but long-term safety issues have yet to be addressed, the improvements have not been shown to be sustained, and the patient group most likely to benefit can only be identified by muscle biopsy.

6.5 OXIDATIVE STRESS

Free radicals are highly active by-products of many metabolic processes that have the potential to damage biomolecules. The presence of these molecules represents oxidative stress. Systems for removing free radicals have evolved and include superoxide dismutase and glutathione peroxidases. Once they have been involved in the reactions to remove the free radicals, however, these enzymes are dependent upon continued antioxidant intake for reconstitution to their active state.

Elevated levels of markers of oxidative stress, such as exhaled pentane159 and plasma or urinary malondialdehyde, have been reported in heart failure patients.160,161 The presence of these markers in CHF patients correlates with functional class and inversely with exercise tolerance, antioxidant levels, and indices of prognosis.162-165 Patients with coronary artery disease also show evidence of greater oxidative stress, which correlates with endothelial dysfunction and predicts cardiac events.166

Free radicals are linked to the gradual progression of myocardial dysfunction that is a hallmark of chronic heart failure.167-169 Some stimuli for free radical production such as catecholamines,170 cardiac sympathetic tone,171 cytokine activation,172 and microvascular reperfusion injury173 are elevated in heart failure. Chronic elevation of angiotensin II in rats can stimulate increases in vascular superoxide production.174 The cytokine-stimulated cardiomyocyte production of free radicals in CHF can be inhibited by antioxidant vitamins.175 Oxidative stress also reduces endothelium-mediated vasodilation in CHF patients,176-178 which leads to an increase in afterload.179

In the presence of free radicals, LDL is oxidized. Oxidized LDL is highly atherogenic and encourages arterial mural thrombus formation,180 perhaps as a consequence of prostacyclin inhibition and nitric oxide synthesis.181 LDL oxidation leads also to the generation of reactive oxygen species (ROS), in particular superoxide anion. The oxidation of LDL can be inhibited by superoxide dismutase and vitamin C,182 which may explain some of the antiatherogenic effects of vitamin C. Vitamin C also prevents leukocyte adhesion to the microvascular endothelium and the formation of leukocyte-platelet aggregates in response to the oxidized LDL.180 This may be due to reduced vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression, which is regulated through an antioxidant-sensitive mechanism.183

Vitamins C and E suppress free radical production in the leukocytes of patients with acute myocardial infarction.133 184 They also retard the progression of transplant-associated coronary arteriosclerosis.185

A study examining the effects of profound lipid lowering and antioxidant vitamin therapy in patients at high risk for cardiovascular events confirmed the results of retrospective studies of reported vitamin intake and the incidence of cardiovascular events.186 In the Heart Protection Society (HPS), which included over 20,000 patients with coronary artery disease, previous myocardial infarction, peripheral vascular disease, diabetes mellitus, and hypertension, no benefit arose from a combination of antioxidant vitamins (vitamin E, vitamin C, and beta-carotene) despite significant increases in plasma levels of these vitamins.187 There was also no benefit from an antioxidant combination on angiographically determined coronary artery progres-sion.188 To date, no data suggest a therapeutic role for specific antioxidant therapy.

6.6 HOMOCYSTEINE AND HEART DISEASE

Several vitamins interact through the metabolism of homocysteine. Most studies189-191 but not all192 demonstrate a link between hyperhomocysteinaemia and increased risk of cardiovascular disease. Levels of only 12% above the upper limit of normal are associated with a three-fold increase in risk of acute myocardial infarction.190 Individuals of Asian Indian origin living in the U.K. who have higher mortality rates from cardiovascular disease also have higher average homocysteine levels.193 A genetic mutation in the methylenetetrahydrofolate reductase gene that causes hyperhomocysteinemia increased the risk for vascular disease in some194 but not all studies.195

A hyperhomocysteinemic state may promote atherosclerosis by (1) alteration of platelet function and coagulation factors to promote coagulation,196-198 (2) endothelial

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