Diabetic cardiomyopathy: A metabolic perspective

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Diabetic Cardiomyopathy: A Metabolic Perspective Angelo Avogaro, MD, PhD, Saula Vigili de Kreutzenberg, MD, PhD, Christian Negut, Antonio Tiengo, MD, and Roldano Scognamiglio, MD


Patients with diabetes mellitus have a >3-fold increased risk of coronary ischemic events and congestive heart failure. Several hypotheses have been provided to explain the increased cardiac vulnerability in individuals with diabetes; among these are the metabolic abnormalities. Diabetes is associated with profound changes in cardiac metabolism, characterized by diminished glucose utilization, diminished rates of lactate oxidation, and increased use of fatty acids. Very few investigations

have focused on amino acid disturbances at the level of the heart. This area of research is potentially relevant because cardiac amino acid alterations may not only result in a reduced energy reserve but could also lead to quantitative and qualitative abnormalities of contractile protein present in the diabetic heart. 䊚2004 by Excerpta Medica, Inc. Am J Cardiol 2004;93(suppl):13A–16A

ortality from cardiovascular diseases (CVDs) is higher in patients with diabetes mellitus than in M those without diabetes. The cause of this accelerated

ics in the small vessels may also be pathogenetically involved in diabetic cardiomyopathy. Clinical and experimental investigations have suggested that in patients with diabetes, increased sympathetic activity, concomitant diabetic autonomic neuropathy, the activated cardiac renin–angiotensin system, myocardial ischemia/functional hypoxia, and elevated levels of glucose all result in oxidative stress.9,10 This condition results in the production of reactive oxygen and nitrogen species, which leads to abnormal gene expression, altered signal transduction, and the activation of pathways leading to programmed myocardial cell death. The resulting myocardial cell loss thus may play a critical role in the development of diabetic cardiomyopathy.11 Diabetes is associated with profound changes in cardiac metabolism; reduced glucose oxidation rates occur after the induction of diabetes, as does impaired transcription of the major cardiac glucose transporter (GLUT)– 4.12 Fatty acid oxidation is an important source of energy in the heart and normally provides most of the ATP necessary to sustain contractile function.13 In diabetes, fatty acid oxidation is dramatically increased and can account for almost 100% of the heart’s energy production.14 Specifically, long-chain fatty acids are an important source of energy for several cell types, particularly the heart muscle cell. Three different proteins—fatty acid translocase/ CD36, fatty acid transport protein, and plasma membrane fatty acid binding protein— have been identified as possible membrane fatty acid transporters.15 Available data indicate that fatty acid translocase/CD36 may have an important role in the etiology of cardiac disease, especially cardiac hypertrophy and diabetic cardiomyopathy16 (Figure 1). These abnormalities contribute to both the development of contractile dysfunction and to increased sensitivity of the heart to injury during an ischemic insult; increased expression of cardiac peroxisome proliferator-activated receptor–␣ (PPAR-␣) and PPAR-␣– controlled genes in hearts from diabetic animals have been implicated in these high rates of fatty acid oxidation.17

CVD is multifactorial and, although atherosclerotic CVD has an influence on morbidity and mortality in persons with diabetes, myocardial dysfunction independent of vascular defects has also been defined as a risk factor.1 Several hypotheses have been provided to explain the specific pathogenesis and progression of heart disease in diabetes. Disturbances in calcium homeostasis— either directly or indirectly through structural and functional subcellular membrane alterations— have been implicated.2 Chronic abnormalities (such as reduced myosin adenosine triphosphatase [ATPase] activity; decreased ability of the sarcoplasmic reticulum to take up calcium; and inhibition of other membrane enzymes, such as Na⫹–K⫹ ATPase and Ca2⫹–ATPase, leading to changes in calcium homeostasis and eventually to cardiac dysfunction) have been documented.3 Enzymatic data have confirmed diminished calcium sensitivity in the regulation of the cardiac actin–myosin system when regulatory protein(s) complex was recombined from diabetic hearts.4 This diminished calcium sensitivity, along with shifts in the cardiac myosin heavy chain isoforms (V1 to V3), could contribute to impaired cardiac function.5 It has also been reported that alterations in sarcomeric proteins such as myosin light chain–2 and troponin I could contribute to depressed myocardial contractility in experimental diabetes.6 In addition to the functional abnormalities of cardiac proteins in diabetes, recent studies have shown that the endothelial function in the coronary bed of the diabetic heart is altered; this supports a role for the microcirculation in diabetes.7,8 Thus, the hemodynamFrom the Division of Metabolic Diseases, Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy. Address for reprints: Angelo Avogaro, Division of Metabolic Diseases, Department of Clinical and Experimental Medicine, University of Padua, via Giustiniani 2, Padua, Italy. E-mail: [email protected] unipd.it. ©2004 by Excerpta Medica, Inc. All rights reserved.

0002-9149/04/$ – see front matter doi:10.1016/j.amjcard.2003.11.003


FIGURE 1. Glucose and free fatty acid (FFA) metabolism in the heart: possible sites of regulation. AA ⴝ amino acid; ACS ⴝ acyl-CoA synthase; CoA ⴝ coenzyme A; FA ⴝ fatty acid; FAT ⴝ fatty acid translocase; GLUT ⴝ glucose transporter; Lac ⴝ lactate; MCT ⴝ monocarboxylate transporter; PDH ⴝ pyruvate dehydrogenase; PPAR-␣ ⴝ peroxisome proliferator-activated receptor–␣; Pyr ⴝ pyruvate; TCA ⴝ tricarboxylic acid.

ARE THE HEARTS OF PATIENTS WITH TYPE 2 DIABETES INSULIN RESISTANT TO GLUCOSE METABOLISM? Insulin resistance is a principal feature of type 2 diabetes and precedes the clinical development of the disease by 10 to 20 years. Insulin resistance is caused by the decreased ability of peripheral target tissues (especially muscle) to respond to normal circulating concentrations of insulin.18 Defects in muscle glycogen synthesis play a significant role in insulin resistance, and glycogen synthase, hexokinase, and GLUT-4 (3 rate-controlling steps in muscle glucose metabolism) have been implicated in its pathogenesis. These alterations in glucose transport activity are likely the result of decreased insulin-stimulated insulin receptor substrate–1 tyrosine phosphorylation and decreased insulin receptor substrate–1-associated phosphatidylinositol 3-kinase activity, a required step in insulin-stimulated glucose transport into muscle.19 It must be appreciated that insulin resistance may not be limited to glucose but may also apply to lipid and amino acid metabolism.20 In the case of insulin resistance, insulin has reduced effects on the phosphatidylinositol 3-kinase 14A THE AMERICAN JOURNAL OF CARDIOLOGY姞

pathway, whereas mitogen-activated protein kinase activity is maintained. The result is an exaggeration of the mitogenic actions of insulin, leading to vascular wall cell proliferation; this effect plays a critical role in the development of CVD, particularly in patients with type 2 diabetes.21 However, it is not known whether cardiac muscle also shows similar insulin resistance. In the heart, insulin has direct effects on glucose transport, glycolysis, glucose oxidation, glycogen synthesis, and protein synthesis.22 Insulin may also increase cardiac contractility and may have an antiapoptotic effect on cardiomyocytes.23 Data on cardiac insulin resistance in patients with diabetes are subject to debate. As previously outlined, insulin promotes glucose uptake and decreases the use of free fatty acids by the human heart. A decrease in glycolysis has been shown in various animal models of heart failure, and heart failure has also been linked with insulin resistance.24 Researchers using [18F]-2fluoro-2-deoxy-D-glucose and positron emission tomography under normoglycemic hyperinsulinemic conditions in patients with type 2 diabetes have concluded that insulin resistance of the myocardium is not a feature of patients with uncomplicated type 1 and type 2 diabetes.25,26 Paternostro et al27 showed that

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patients with a history of myocardial infarction present a flow-independent insulin resistance at the whole-body level, as well as in skeletal muscle and myocardial muscle, compared with healthy subjects of similar age and body mass. Insulin resistance was also detected in noninfarcted, normally contractile myocardium, which presumably had undergone compensatory hypertrophy.28 Insulin resistance, as a feature of the diabetic heart, has been found by other groups.29,30 This situation contrasts with that of patients with type 1 and type 2 diabetes who have no vascular complications.31 Also, in patients with type 2 diabetes who have overt coronary artery disease (CAD), no insulin resistance at the heart level has been reported.29 As outlined, dissimilar results still exist for cardiac insulin resistance.

CARDIAC AMINO ACID METABOLISM: IS IT RELEVANT FOR HEART FUNCTION IN PATIENTS WITH DIABETES? Protein degradation and fractional turnover in heart muscle occur at a rate almost 3 times that of peripheral muscle; this implies that amino acid metabolism plays a relevant role in cardiac homeostasis.32 In conscious dogs, it was shown that only leucine and isoleucine are removed significantly by myocardium, with a net branched-chain amino acid uptake; in contrast, glycine, alanine, and glutamine are released.33 The highest net myocardial production was that of glutamine, whereas no net exchange was seen for valine, phenylalanine, tyrosine, cysteine, methionine, glutamate, asparagine, serine, threonine, taurine, and aspartate. There is also a highly significant linear correlation between myocardial uptake and arterial concentration of branched-chain amino acids, which, along with insulin, play an important role in suppressing myocardial protein degradation.34 It has been known since 1980 that diabetes produces an inhibition of protein synthesis in the heart due both to a decrease in RNA concentration and to a decrease in the efficiency of protein synthesis itself; insulin therapy is able to reverse these abnormalities.35 In humans, hyperglycemia is associated with a significant arterial–venous difference of branchedchain amino acids across the myocardium.36 These data strengthen the concept that diabetes is associated with an increased or poorly regulated rate of amino acid catabolism, particularly at the heart level. In fasted, untrained individuals, such as older patients with type 2 diabetes, the amino acids needed to produce muscle proteins at an increased rate after exercise are largely derived from protein breakdown.37 In patients with diabetes, the role of amino acids is further enhanced because a net release of these compounds from the heart was reported, even in the presence of mildly elevated plasma glucose.36 If one assumes that a large proportion of patients with diabetes have both CAD and heart failure, the scenario becomes even bleaker. The perpetual and vigorous nature of heart muscle work requires efficient myocardial energetics. In particular, the failing myocardium

is characterized by reduced catalytic activity of creatine kinase, adenylate kinase, carbonic anhydrase, and glycolytic enzymes, which collectively facilitate ATP delivery and promote removal of adenosine diphosphate, inorganic phosphate, and H⫹ from cellular ATPases.38 Collectively, these data pinpoint the importance of maintaining an adequate metabolism in the failing heart. Thus, the chronically failing heart has been shown to be metabolically abnormal, both in animal models and in humans. For these reasons, several metabolic approaches have been proposed, such as the administration of compounds that improve fatty acid oxidation and the administration of antioxidant agents. There is some indication that patients with compensated New York Heart Association class III heart failure have a significantly greater rate of lipid oxidation and decreased glucose uptake and carbohydrate oxidation compared with healthy agematched individuals; in addition, there is some evidence that therapies that acutely switch the substrate of the heart away from fatty acids result in improvement in left ventricular function.39 These findings suggest that chronic manipulation of myocardial substrate oxidation toward greater carbohydrate oxidation and less fatty acid oxidation may improve ventricular performance and slow the progression of left ventricular dysfunction, especially in people with diabetes. Ischemia and heart failure transform free fatty acids from an effective to a harmful fuel. Thus, amino acid supplementation potentially represents a tool to improve the energetics of both the diabetic heart and the failing diabetic heart. The rationale for their use is that the provision of different metabolic substrates to the failing myocardium is likely to have significant effects in limiting the damage during myocardial ischemia. In patients with CAD, it was shown that branched-chain amino acids have a primary anabolic effect, and they appear to protect the heart against myocardial ischemic injury by enhancing the postischemic pressure recovery and improving postischemic systolic and diastolic myocardial function.40,41 It has also been recently proposed that glutamine may be beneficial in ischemic heart disease; this amino acid is rapidly transported across the cardiac sarcolemma and not only ameliorates cardiac output but also limits the electrocardiographic findings, possibly through an antioxidant effect.42 The observation of a positive effect of glutamate has also been shown in humans.43 Furthermore, the myocardium can survive under ischemic conditions only if it is able to maintain an appropriate redox balance; this step involves the regeneration of nicotinamide adenine dinucleotide (NAD⫹) from its reduced form, which is mainly dependent on lactate dehydrogenase and on the transformation of pyruvate to lactate.44 – 46 Another alternative pathway that allows the generation of NAD⫹ is the conversion of aspartate to succinate; the latter compound could maintain a physiologic redox state without the harmful effect of an exaggerated lactate accumulation within the myocardium. This hypothesis was first supported in 1985.47 Data on the effect of amino acid provision on myocardial function in diabetes and in other patho-



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