Heart in Diabetes: Not Only a Macrovascular Disease

D I A B E T E S & C A R D I O V A S C U L A R D I S E A S E Heart in Diabetes: Not Only a Marovasular Disease BERND STRATMANN, PHD DIETHELM TSCHOEPE, MD EPIDEMIOLOGY The importane of diabetes as a ause of mortality and morbidity is well known. The number of patients inreases alongside aging of the population, raising the prevalene of obesity and a sedentary lifestyle. As a disease that is strongly assoiated with both miro- and marovasular ompliations, diabetes results in organ and tissue damage. Cardiovasular disease (CVD) auses up to 70% of all deaths in people with diabetes. The epidemi of diabetes will thus be followed by an epidemi of diabetesrelated vasular diseases. Almost two of three patients who present with symptomati hroni heart disease have abnormal gluose homeostasis. Although the mortality from oronary artery disease (CAD) in patients without diabetes has delined over the past 20 years, the mortality in men with type 2 diabetes has not hanged signifiantly. Moreover, diabetes is an independent risk fator for heart failure, and there are a substantial number of patients with diabetes and heart failure. The main marovasular ompliations, for whih diabetes has been a well-established risk fator throughout the ardiovasular system, are CAD, peripheral vasular disease, inreased intima-media thikness, and stroke. Ishemi heart disease and stroke aount for the highest proportion of omorbid diseases assoiated with diabetes. The joint guidelines of the European Soiety of Cardiology and the European Assoiation of Diabetes take into aount the lose reiproal relationship between diagnostis and therapeutis in ardiology and diabetology. Patients with diabetes and CVD have an unfavorable prognosis (1). Mortality rates due to heart disease are two to four times higher among people with diabetes ompared with those without diabetes after orretion for traditional risk fators for CVD suh as age, obesity, smoking, dyslipidemia, and hypertension. It appears, however, that the presene of even one of these risk fators leads to poorer outomes among people with diabetes ompared with those without diabetes. People with diabetes have an up to fivefold-higher risk for a first myoardial infartion (MI) and a twofold-greater risk for a reurrent MI than people who previously had an MI but do not suffer from diabetes. Patients with diabetes with prior MI have the worst prognosis (2). Furthermore, people with diabetes have a poorer long-term prognosis after MI, inluding an inreased risk for ongestive heart failure and death. People with diabetes are two to four times more likely to develop stroke than people without diabetes. Diabetes aounted for a signifiant perentage of patients with a diagnosis of heart failure in numerous epidemiologi studies suh as The Framingham Study, UK Prospetive Diabetes Study (UKPDS), Cardiovasular Health Study, and Euro Heart Failure Surveys. Data from UKPDS regarding the adjusted rate of heart failure demonstrate a rise from 2.3 events per 100 person-years in people with HbA 1 levels,6% to 11.9 events per 100 personyears in those presenting with HbA 1 levels.10% (3). An inrease in HbA 1 From the Heart and Diabetes Center NRW, Ruhr University of Bohum, Bad Oeynhausen, Germany. Corresponding author: Diethelm Tshoepe, dtshoepe@hdz-nrw.de. This publiation is based on the presentations at the 3rd World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy). The Congress and the publiation of this supplement were made possible in part by unrestrited eduational grants from AstraZenea, Boehringer Ingelheim, Bristol- Myers Squibb, Daiihi Sankyo, Eli Lilly, Ethion Endo-Surgery, Generex Biotehnology, F. Hoffmann-La Rohe, Janssen-Cilag, Johnson & Johnson, Novo Nordisk, Medtroni, and Pfizer. DOI: 10.2337/d11-s208 2011 by the Amerian Diabetes Assoiation. Readers may use this artile as long as the work is properly ited, the use is eduational and not for profit, and the work is not altered. See http://reativeommons.org/ lienses/by-n-nd/3.0/ for details. of 1% orrelates to an inrement of 8% in heart failure (3,4). Diabetes is a powerful preditor of ardiovasular morbidity and mortality and is an independent risk fator for death in patients with established heart failure. In addition, the prevalene of heart failure in elderly diabeti patients was up to 30% (5). Diabeti women are more likely to develop heart failure than men if ompared with age-mathed ontrol subjets (5.1-fold vs. 2.1-fold inrease) (6). The reason for this differene is not yet fully understood, but may be in part due to a worse omorbid risk fator profile, and the permissive effet upon outome, partiularly in diabeti women (7). The ombination of hyperglyemia, insulin resistane, dyslipidemia, hypertension, and hroni inflammation injures the vasular endothelium, resulting in mirovasular damage (alterations in apillary density and vasular permeability), marovasulopathy, and CVD. Most importantly, more than 70% of people with diabetes have high blood pressure or are being treated with mediations for hypertension. Beause prediabeti subjets often present with multiple CVD risk fators suh as insulin resistane, obesity, entral obesity, elevated blood pressure, elevated total triglyerides, and low HDL holesterol, the onset of ardiovasular damage is not losely related to hyperglyemia alone, but has to be seen in the onert of metaboli derangement (8). The ardia risk in diabeti patients is not only with respet to type 1 or type 2 diabeti patients, but also to several pathophysiologial mehanisms and features suh as CAD, heart failure, and autonomi neuropathy. HISTORY AND DIAGNOSIS Despite deades of basi and linial investigations, diabeti ardiomyopathy as a linial entity remains elusive. A diagnosti method for the identifiation of diabeti ardiomyopathy is still not available. Sine the first report in 1972 by Rubler et al. (9) who analyzed autopsy data from four patients with diabeti renal miroangiopathy and dilated left ventriles in the absene of other ommon auses, evidene and aeptane of diabeti ardiomyopathy as a linial entity has been rising. S138 DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 are.diabetesjournals.org

Looking deades bak, it was in 1881 that Leyden (10) ommented that heart failure was a frequent and noteworthy ompliation of diabetes and Mayer (11) stated that heart disease in diabetes an be traed to an abnormality in metabolism. Diabeti ardiomyopathy desribes diabetes-assoiated hanges in the struture and funtion of the myoardium that are not diretly linked to other onfounding fators suh as CAD or hypertension. As a multifatorial disease entity, it is linially haraterized by an initial inrease in left ventriular stiffness and sublinial diastoli dysfuntion. However, this may advane to ompromised left ventriular systoli funtion with loss of ontratile funtion and progress into an overt ongestive heart failure. Diabeti ardiomyopathy is known to be assoiated with hanges in ardia struture suh as myoardial hypertrophy, fibrosis, and fat deposition. In many patients, partiularly those with type 2 diabetes, the diabetes-assoiated linial findings are amplified by the existene of these omorbidities, augmenting the development of left ventriular hypertrophy, inreasing the suseptibility of the heart to ishemi injury, and inreasing the overall likelihood of developing heart failure. The use of appropriate diagnosti strategies, whih may help orretly identify the disease at early asymptomati stages and lead to the implementation of suitable orretive therapies, is imperative. Diabetes-assoiated vasular alterations inlude anatomi, strutural, and funtional hanges leading to organ dysfuntion (12). Early hanges in ardia funtion are typially manifested as abnormal diastoli funtion that onseutively progresses to loss of ontratile funtion. In its progression, diabeti ardiomyopathy may advane to ompromised left ventriular systoli funtion that with time leads to loss of ontratile funtion and results in an overt ongestive heart failure (13). Ehoardiographybased methods urrently stand as the preferred diagnosti approah for diabeti ardiomyopathy. Newer ehoardiographi methods suh as tissue-doppler imaging have been developed for early and very disrete detetion of ardia dysfuntion before manifest symptoms are present (14). Diastoli dysfuntion preedes the development of systoli dysfuntion. The use of flow and tissue-doppler tehniques suggests a prevalene of diastoli dysfuntion as high as 40 75% in individuals with type 1 and type 2 diabetes without overt CAD (15). In addition to onventional tehniques, magneti resonane imaging and spetrosopy along with ontrast agents are now leading new approahes in the diagnosis of myoardial fibrosis and ardia and hepati metaboli hanges. The measurements of metaboli flux via positron emission tomography are useful to demonstrate loal metaboli maladaption of the myoardium. By assessing the myoardial funtion through the evaluation of myoardial substrate metabolism in asymptomati men with well-ontrolled unompliated type 2 diabetes and verified absene of ardia ishemia, Rijzewijk et al. (16) were able to demonstrate that the left ventriular diastoli funtion was impaired and that the myoardial substrate metabolism was altered in patients ompared with age-mathed healthy ontrol subjets. CARDIAC METABOLISM IN GENERAL Metaboli and morphologi defets onern myoardial energy metabolism, redued flow reserve, formation of advaned glyation end produts (AGEs) and strutural alterations that impair ardia funtion (17). The flexibility in myoardial substrate metabolism for energy prodution is fundamental to ardia health. The loss in variability leads to fixation on speial substrates. Predominane in fatty aid metabolism is harateristi of diabeti heart disease and is assoiated with pressure-overload left ventriular hypertrophy. Myoardial metaboli remodeling is entral to the pathogenesis of a variety of ardia disease proesses, suh as left ventriular hypertrophy. It is the proess in whih the heart loses its ability to use different substrates, beoming dependent primarily on the metabolism of a single substrate for energy prodution (18). The most important result of ardia metabolism in diabetes is the swith from arbohydrates and fatty aids as a soure of energy to an exessive use of fatty aids. In animal models of diabetes, ardia dysfuntion oexists with inreased myoardial nonesterified fatty aid use, triglyeride aumulation, and subsequent inreased prodution of toxi intermediates, whih, in the presene of hyperglyemia, ontribute to inreased formation of reative oxygen speies (ROS), mitohondrial unoupling, dereased adenosine triphosphate (ATP) synthesis, mitohondrial dysfuntion, and finally apoptosis. These deleterious proesses are ommonly referred to as lipotoxiity (19). ROLE OF HYPERGLYCEMIA Chroni hyperglyemia plays a major role in the initiation of diabeti vasular ompliations through many metaboli and strutural derangements. Four main hypotheses and pathomehanisms have been proposed to explain how hyperglyemia and the inhibition of glyeraldehyde-3-phosphate dehydrogenase by superoxides an ause all of the diabetes ompliations (20). Stratmann and Tshoepe Inreased polyol pathway flux Inreased hexosamine pathway flux and modifiation of proteins Inreased formation of AGEs Inreased protein kinase C (PKC) isoform expression Inreased levels of the upstream glyolyti metabolite glyeraldehyde-3- phosphate ativate the AGE pathway by forming the major intraellular AGE preursor methylglyoxal from glyeraldehyde- 3-phosphate. The lassi PKC pathway is ativated, too, sine the ativator of PKC, diaylglyerol, is formed from glyeraldehyde-3-phosphate. Further upstream in glyolysis, levels of the glyolyti metabolite frutose-6-phosphate inrease, leading to a pronouned flux through the hexosamine pathway, resulting in the onversion of frutose-6-phosphate to uridine diphosphate N-aetylgluosamine by the enzyme glutamine:frutose-6-phosphate amidotransferase. Finally, inhibition of glyeraldehyde-3-phosphate dehydrogenase inreases intraellular levels of gluose, whih is onverted to frutose during the polyol pathway. Aording to this hypothesis, all these pathogeni mehanisms are linked by a single, unifying, hyperglyemia-indued proess: the overprodution of superoxide by the mitohondrial eletron transport hain resulting in oxidative stress, whih is regarded as the pathomehanism underlying insulin resistane, CVD, diabetes, and diabetes ompliations (20). Besides the diret effets of gluose on the ells, oxidative stress and nonenzymati glyation are of major onern. AGEs are elevated in serum and tissues of diabeti patients and affet the strutural omponents of the extraellular matrix suh as ollagen (21). Hyperglyemia and the assoiated inrease in AGEs results in strutural hanges by the inrease of arterial stiffness and inreased amounts of ROS, whih ontribute to are.diabetesjournals.org DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 S139

Diabetes and marovasular disease ellular dysfuntion and apoptosis (22). In addition to the intraardia deposition of triglyerides and glyogen granules, whih indiate the metaboli derangement in diabeti heart failure, irregularly distributed apillaries and perivasular plaques of ollagen are frequent. Myoytolysis and deterioration as well as myofilament fragmentation are ommon strutural findings. Areas of foal nerosis and ontration an be found regularly. All these observations indiate severe morphologial and strutural alterations ourring in the diabeti heart (19,23). In addition, mitohondria are severely damaged and inreased in diameter, and the number of apoptoti ells was learly inreased in the hearts of type 2 diabeti patients (ardiomyoytes, fibroblasts, endothelial ells) (24). As none of these lesions seem to be speifi for diabetes, onomitant hypertension may play a entral role. This fat underlines the favorable effet of antihypertensive therapy in people with diabetes. Mehanisms leading to inreased diastoli stiffness of the diabeti heart are different in heart failure with redued and normal left ventriular ejetion fration (LVEF). In ases of redued LVEF, fibrosis ours and AGEs are detetable, whereas in hearts with normal LVEF, ardiomyoyte resting tension is more relevant (23,24). Diabeti heart failure patients without symptoms of CAD showed higher diastoli left ventriular stiffness independently of LVEF. Myoardial ollagen volume fration as well as myoardial AGE deposition was inreased in patients with diabetes and redued LVEF (24). In addition to the above desribed mehanisms, hyperglyemia inhibits the prodution of nitri oxide (NO), leads to elevated levels of free fatty aids (FFAs), lipid deposition in the form of lipid droplets, and stimulates the prodution of endothelin-1, whih has diret vasoonstritive effets on the endothelium as well as indiret fluid volume effets by stimulation of water and salt retention and the ativation of the renin-angiotensin system (25). Impaired endothelial funtion haraterized by the loss of vasodilative ation through inhibition of NO is related to the presene of hyperglyemia. The endothelial NO synthase (enos) is inhibited and the prodution of ROS is inreased, whih in turn leads to further inhibition of enos. Upon insulin resistane, the vasular endothelium loses its ability to produe NO-ativated tissue plasminogen ativator (26). These irumstanes rather aount for the effets on the mirovasulature, whereas, regarding the marovasulature, effets on adhesion, inflammation, and blood pressure are of relevane. The formation of AGEs inhibits NO prodution, too, and further impairs the vasodilatory response in diabetes. Hyperglyemia-stimulated PKC pathway effets on NO and ROS generation and diabetes-assoiated impaired fibrinolyti apaity may ontribute to a prothromboti state. Platelet hyperativity is another fator involved in the development and progression of marovasular disease in diabetes, whih ontributes to the risk for atheroslerosis progression and onseutive thrombus formation. The inreased risk of atherosleroti and atherothromboti events in patients with diabetes aounts for most of the CVDs. It is obvious that atheroslerosis of the epiardial arteries and heart failure are independently linked with insulin resistane and the metabolism, suggesting a ausal link between these omorbidities. OTHER FACTORS Impaired insulin ation (insulin resistane) is haraterized by ompensatory hyperinsulinemia, whih is the major metaboli dysfuntion assoiated with the early stages of type 2 diabetes. Elevated plasma insulin levels an lead to numerous metaboli and pathologial derangements in various tissues, inluding the heart (27). Inflammation represents another diabetes-related mehanism for marovasular disease. Inflammatory ells (e.g., monoytes and T ells) enter damaged endothelial ells and migrate into the intima media, ingesting oxidized LDL and as a onsequene forming foam ells. Foam ells are main omponents of atherosleroti fatty streaks and represent an early marker of marovasular disease. In people with diabetes, the levels of adhesion moleules are elevated, failitating the proess of foam ell formation. Furthermore, diabetes is assoiated with smooth musle ell dysfuntion, whih may be assoiated with similar mehanisms for endothelial ell dysfuntion, inluding ativation of the PKC pathway, deposition of AGEs, as well as ativation of their reeptor RAGE and overprodution of growth fators. In the development of atheroslerosis, ativated smooth musle ells in the medial layer of arteries migrate to the atherosleroti fatty streaks in the intimal layer and produe an extensive extraellular matrix. This leads to a solidifying of the streaks and reiproally redues the protetive strengthening funtion in the medial layer, resulting in an unstable atherosleroti plaque being prone to rupture. These hyperglyemiastimulated events at in onjuntion over time to produe atheroslerosis and thrombosis (28). ENERGETIC ASPECTS OF THE FAILING HEART The daily turnover rate of ATP of more than 6 kg exaerbates the available energy pool of the heart. The energy yield of the healthy heart is around 25% of the energy from substrates, mainly fatty aids and to a lesser extent gluose and latate. Thus, the metaboli disarrangement omprising disturbanes in ellular uptake of energy omponents as well as generation of metabolites found in insulin resistane mainly aounts for the ardia energy starvation (29). Cardia energy metabolism omprises three omponents. Besides the use of substrates derived from gluose and FFAs via the Krebs yle, the oxidative phosphorylation for the generation of ATP and finally the use of ATP are main parts of ardia energy yle. Myoardial energy and lipid metabolism are essential for heart struture and funtion. Energy surplus as well as energy starvation may lead to disarrangement in myoardial tissue. Seventy perent of ardia ATP are derived from fatty aid oxidation; gluose and latate aount for 30% of the energy (30). Gluose is the preferred substrate under hypoxi onditions like ishemia and inreased workload, beause the glyolyti ATP prodution through onversion of gluose to latate is independent from oxygen. The healthy heart is able to swith rapidly between different energy soures to aommodate to different physiologial and pathologial onditions involving altered extraellular hormones, substrate availability, and energy demand (31). The onept of energy starvation as a main reason for myoardial failing was disussed long ago and deteted by redued amounts of reatine phosphate ontent (rev. in 29). Creatine is produed by the liver and kidneys and transported to the heart where it is taken up by a speifi plasma-membrane reatine transporter. Creatine kinase atalyzes the phosphorylation of about twothirds of the total reatine pool in the heart to phosphoreatine, whereas the other one-third remains as free reatine (32). The reatine kinase system ats as an energy buffer, when high energy demands S140 DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 are.diabetesjournals.org

exeed the energy supply. In this ase the phosphoreatine level dereases, whih keeps ATP at a normal level but inreases thefreeadplevel(33).theaugmented level of free ADP inhibits the funtion of many intraellular enzymes, ausing failure of the musle ontration mehanism that relay on intraellular signaling. Thus, a metaboli derangement in the ardia myoyte an our when phosphoreatine levels fall and free ADP levels rise, even if ATP levels remain unhanged. Obviously, the level of phosphoreatine orrelate to the stage of the disease (16). In ases where ATP demand exeeds ATP synthesis, phosphoreatine levels deline first and ATP dereases only when phosphoreatine is substantially depleted beause the reatine kinase reation equilibrium favors ATP synthesis over phosphoreatine. In hroni heart failure, the total reatine level falls leading to a further redution of the phosphoreatine-to-atp ratio (34). Myoardial phosphoreatineto-atp ratios are redued in heart failure, and they are in orrelation with New York Heart Assoiation lasses and with systoli and diastoli funtion (rev. in 29). Thus, the phosphoreatine-to-atp ratio may be a strong preditor of both total mortality and mortality in CVD (35). SUBSTRATE METABOLISM: A LOOK AT THE DETAILS Cardia gluose uptake depends on the transmembrane gluose gradient and the ontent of sarolemmal gluose transporter GLUT1 and GLUT4. GLUT1 is primarily loated in the membrane and GLUT4 is loalized predominantly intraellularly and is transloated to the membrane by insulin stimulation (36). Upon binding of insulin to the ell surfae reeptor, the intraellular tyrosine kinase domain is ativated. Besides the insulin reeptor, insulin reeptor substrates are phoshorylated (37). As a onsequene, lipid kinase phosphatidylinositol 3 -kinase (PI3K) is ativated. After binding to PI3K, Akt is phosphorylated and ativated. The ativation of the PI3K/Akt pathway is of importane in the regulation of fatty aid metabolism and gluose metabolism, as well as gene expression and ell survival (37). In addition to the effet on GLUT4 stimulation, gluose uptake and promotion of glyolysis through ativation of 6-phosphofruto-2-kinase, insulin inreases the myoardial blood flow through the Akt arranged phosphorylation of enos (38). Besides the effets on gluose uptake, insulin promotes the formation of glyogen by inhibiting the glyogen synthase kinase 3b (39). In aerobi onditions,,10% of total ATP generated is derived by glyolysis. Following glyolysis, the generated pyruvate an be further metabolized by three pathways: arboxylation to oxalaetate or malate, redution to latate, or dearboxylation to aetyl- CoA. The diabeti heart relies on fatty aid oxidation and is less able to swith to the use of gluose as a proess with lower oxygen onsumption; substrate fixation is a hallmark of diabeti ardiomyopathy. The aumulation of FFAs leads to the phenomenon of lipotoxiity, whih in turn results in impaired b-oxidation, thereby generating even more FFAs (40). The heart relies on a ontinuous and well organized supply of energy ompounds. Triglyeride-rih lipoproteins like VLDLs and hylomikrons are the main soure for fatty aids and are hydrolyzed by lipoprotein lipase (LPL) (41). LPL therefore plays a entral role in the regulation of fatty aid delivery, on the surfae of ardiomyoytes LPL inreases lipid uptake and produes ardiomyopathy (42). Our own results indiate that LPL levels are upregulated in heart failure, supporting the hypothesis that in heart failure exessive uptake of fatty aids leads to the deposition of exessive fatty aids as lipid droplets and to the prodution of eramides, ayl-coa, and arnitines, whih aount for ROS prodution and apoptosis as well as derangements of the oxidative phosphorylation. The oxidation of long-hain fatty aids (LCFAs) is the major soure of energy for the healthy heart. The uptake of LCFAs is dependent on the energy demand and is regulated by transporting systems suh as fatty aid transloase (CD36), plasmalemmal fatty aid binding protein, and fatty aid transport proteins (FATPs), mainly FATP1 and FATP6 (43). Overexpression of CD36 or FATP has been found to dramatially inrease fatty aid metabolism (44,45), suggesting a entral role of these transporters in fatty aid uptake. Following uptake, LCFAs are bound to soluble fatty aid binding proteins, whih transport LCFAs to the outer mitohondrial membrane where they are onverted to ayl-coa to enter the proess of b-oxidation. Peroxisome proliferator ativated reeptors (PPARs) are transription fators Stratmann and Tshoepe ativated by fatty aids. Their target genes partiipate in lipid metabolism, and therefore PPARs are involved in ardia lipid metabolism. PPARa is a key regulator of fatty aid metabolism. This ligandativated transription fator is highly expressed in tissues that derive most of their energy from fatty aid oxidation, inluding liver, heart, kidney, and skeletal musle. Target genes of PPARa partiipate in lipid metabolism, for example the genes of heart type fatty aid binding protein, LPL, CD36, arnitine-palmitoyltransferase 1, and unoupling protein-3. Knok-out of PPARa abolishes fasting-indued overexpression of fatty aid metaboli genes and swithes substrate seletion from fatty aids to gluose whereas fatty aid uptake and oxidation are inreased by the overexpression of ardia PPARa (46). As FFAs ativate PPARa, the expression of genes involved in fatty aid oxidation and uptake aumulation of fatty aid in the ardiomyoyte is promoted. Inreased uptake and metabolism of fatty aids not only leads to aumulation of fatty aids and triglyerides but also inreases oxygen onsumption and generation of ROS. Augmented fatty aid uptake through overexpression of LPL or fatty aid transporters, or by stimulating PPARa expression or long-hain CoA synthase results in a ardia phenotype resembling diabeti ardiomyopathy (42,44). Diabeti alterations of myoardial metabolism result mainly from malfuntions of aetyl-coa arboxylase, arnitinepalmitoyl transferase 1, whih imports the ayl-coa into the mitohondrium, and pyruvate dehydrogenase. This indues an overflow of fatty aid oxidation and inhibits gluose oxidation. The regulation of ardia energy substrate handling ours at the level of substrate uptake at the sarolemmal membrane as well as at the level of mitohondrial oxidation (Randle yle) (47). The aumulation of fatty aids impairs insulin-mediated uptake of gluose through inhibition of insulin reeptor substrate and protein kinase B (Akt) (48). The amounts of intraellular fatty aids derivatives like fatty ayl-coa, diaylglyerol, and eramide inrease with augmenting intraellular fatty aid ontent. Although there is an overflow ofsubstrates, the heart resembles an engine running out of fuel; mainly disturbanes in the key signal pathways aount for the disbalane between energy demand and ardia effiieny. are.diabetesjournals.org DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 S141

Diabetes and marovasular disease INSULIN RESISTANCE AND DIABETES The onept of myoardial insulin resistane is based on the fat that even in the absene of CAD a dereased in vivo stimulation of myoardial gluose uptake is detetable. Insulinmediated gluose uptake rates were positively orrelated with peripheral musle insulin sensitivity. ROS may trigger the development of insulin resistane (49). A sustained presene of CD36 in the sarolemmal membrane has been deteted in the insulin-resistant heart, whih is assoiated with higher rates of fatty aid uptake (50). LCFAs are no longer delivered to the heart by fuel demand but onstitutively. Contratile dysfuntion is deteted in these hearts, whih an in part be reversed by antisteatoti therapy (51). At least the indution of apoptosis by FFAs as a mehanism leading to ardia dysfuntion is disussed (52). The hange in myoardial energy preferenes might be a result of adaption/ maladaption to elevated fatty aid onentrations (53,54). Obese diabeti women demonstrate inreased fatty aid use, inreasedoxygenonsumption,anddereased ardia effiieny. In patients without ishemi heart disease, elevated levels of ardia triglyerides and inreased expression of PPARa target genes have been observed. In addition to the stimulatory effets of PPARa, diret or indiret inhibitory effets on genes involved in gluose uptake, glyolysis, and gluose oxidation are observed (55). The normal adaptive response of a failing heart is the shift from fatty aid oxidation to a more effiient and less oxygen-onsuming gluose metabolism mainly by the downregulation of pyruvate dehydrogenase kinase (56). With dereased expression of the PPARa/retinoid X reeptor omplex and enzymes ritial to FFA metabolism, namely arnitinepalmitoyl transferase 1 and mediumhain ayl-coa dehydrogenase, FFA metabolism is dereased (57,58). To further maximize effiieny, unoupling proteins that generate heat rather than energy are downregulated in the failing heart (59). In the ase of insulin resistane, FFA metabolism is upregulated, resulting in an inreased demand of oxygen, dereased ardia effiieny, and lipotoxiity (60). This dysregulation is already obvious in patients with obesity and insulin resistane laking symptoms of heart failure. Figure 1 summarizes the effets on metabolism and its derangement on the development of diabeti ardiomyopathy. CONCLUSIONS The prevalene of diabetes has inreased and will double Figure 1 Orhestra of ontributing fators to the development of diabeti ardiomyopathy onerning fatty aid and gluose metabolism, (adapted from Boudina and Abel [60]). ACC, aetyl-coa arboxylase; ACoA, aetyl-coa; CE, ardia effiieny; CPT1, arnitine-palmitoyltransferase 1; FA, fatty aid; MCD, malonyl-coa dearboxylase; MCoA, malonyl-coa; PDH, pyruvate dehydrogenase; PDK4, pyruvate dehydrogenase kinase 4; TG, triglyerides. S142 DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 are.diabetesjournals.org

until 2030. This dramati inrease has serious impliations from a ardiovasular perspetive, and thus the aggressive management of blood pressure, dyslipidemia, and blood gluose in diabetes is of great importane. Although the inrease in ardiovasular mortality and heart failure is due in part to aelerated atheroslerosis, epidemiologial and linial data indiate that diabetes inreases the risk for ardia dysfuntion and heart failure independently of other risk fators suh as CAD and hypertension. The failing diabeti heart faes omplex strutural marovasular derangements suh as hypertrophy and loss of funtion due to glyation. The metaboli swith in heart failure is omplex and involves signaling mehanisms, altered substrate preferene and finally strutural alterations. The uptake of fatty aids is enhaned by debiting gluose use. Lipotoxiity aounts for fat aumulation in the heart musle as well as the development of ROS. AGEs, as a result of high blood gluose levels, ontribute to strutural impairment and redued ardia power by inreased arterial stiffness and ollagen modifiation. Metaboli disorders like insulin resistane or diabetes aelerate these derangements in heart failure by several insulin-mediated mehanisms that are of relevane for mirovasular events as well. Aknowledgments No potential onflits of interest relevant to this artile were reported. Referenes 1. Fox CS, Coady S, Sorlie PD, et al. Trends in ardiovasular ompliations of diabetes. JAMA 2004;292:2495 2499 2. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from oronary heart disease in subjets with type 2 diabetes and in nondiabeti subjets with and without prior myoardial infartion. N Engl J Med 1998;339:229 234 3. Stratton IM, Adler AI, Neil HA, et al. Assoiation of glyaemia with marovasular and mirovasular ompliations of type 2 diabetes (UKPDS 35): prospetive observational study. BMJ 2000;321:405 412 4. 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