Diabetic cardiomyopathy: pathophysiology and clinical features
- 7.9k Downloads
Since diabetic cardiomyopathy was first reported four decades ago, substantial information on its pathogenesis and clinical features has accumulated. In the heart, diabetes enhances fatty acid metabolism, suppresses glucose oxidation, and modifies intracellular signaling, leading to impairments in multiple steps of excitation–contraction coupling, inefficient energy production, and increased susceptibility to ischemia/reperfusion injury. Loss of normal microvessels and remodeling of the extracellular matrix are also involved in contractile dysfunction of diabetic hearts. Use of sensitive echocardiographic techniques (tissue Doppler imaging and strain rate imaging) and magnetic resonance spectroscopy enables detection of diabetic cardiomyopathy at an early stage, and a combination of the modalities allows differentiation of this type of cardiomyopathy from other organic heart diseases. Circumstantial evidence to date indicates that diabetic cardiomyopathy is a common but frequently unrecognized pathological process in asymptomatic diabetic patients. However, a strategy for prevention or treatment of diabetic cardiomyopathy to improve its prognosis has not yet been established. Here, we review both basic and clinical studies on diabetic cardiomyopathy and summarize problems remaining to be solved for improving management of this type of cardiomyopathy.
KeywordsDiabetes mellitus Heart failure Pathophysiology Infarct size Signal transduction Therapy
The number of patients with diabetes has been increasing worldwide in the past two decade, and these patients are predisposed to serious cardiovascular morbidity and mortality . The impacts of diabetes on the development of atherosclerotic vascular diseases have been established, and results of recent clinical trials have indicated that not only hyperglycemia but also other risk factors need to be controlled for preventing atherosclerotic vascular events in diabetic patients [2, 3]. On the other hand, non-ischemic heart failure associated with diabetes has received much less attention than coronary and cerebral vascular events.
Definition and clinical phenotype of diabetic cardiomyopathy
Definition of diabetic cardiomyopathy
“Diabetic cardiomyopathy” is a concept that was introduced in 1972 by Rubler et al. , who examined pathology of four autopsy cases with diabetic glomerulosclerosis and no known cause of heart failure. The current typical definition of diabetic cardiomyopathy comprises structural and functional abnormalities of the myocardium in diabetic patients without coronary artery disease or hypertension . Obviously, however, this type of cardiomyopathy should be present also in diabetics with coronary artery disease and/or hypertension, though it is difficult to separately assess the contribution of diabetic cardiomyopathy to overall ventricular dysfunction in such cases.
Interstitial and perivascular fibrosis is a histological hallmark of diabetic cardiomyopathy [12, 14, 15], and the extent of fibrosis correlates with heart weight . In addition to the increase in collagen deposition, cross-linking of collagen fibers may be increased by diabetes, contributing to reduction in ventricular compliance . Clinical evidence to support this notion is actually sparse, but some studies [17, 18, 19] indicated that glycation of collagen fibers is indeed increased in hearts of diabetic patients.
“Cardiomyocyte hypertrophy” in diabetic cardiomyopathy is referred to in some earlier reviews, but its contribution to “ventricular hypertrophy” is not clear. Human myocardium biopsied at the time of coronary bypass surgery showed an increased cross-sectional area (CSA) of cardiomyocytes and interstitial fibrosis in diabetic patients compared with those in non-diabetics . However, human biopsy studies by Yarom et al.  and Kawaguchi et al.  showed that the average myocyte diameter was not significantly increased by diabetes alone. Photographs of the histology of autopsy cases presented in earlier reports [12, 14, 15] show hypertrophic cardiomyocytes mixed with atrophic ones in diabetic cardiomyopathy. Increase in the CSA of cardiomyocytes with or without interstitial fibrosis has been reported for different animal models of T1DM and T2DM [23, 24, 25], but significant reduction in the CSA of cardiomyocyte was observed in a model of T1DM, Akita (Ins 2WT/C96Y) mouse . Taken together, cardiomyocyte hypertrophy appears to be a frequently observed feature but not a requisite of diabetic cardiomyopathy. We speculate that long-standing metabolic derangements and modification of microcirculation (see section “Abnormalities in microvasculature” below) by diabetes induce different levels of hypertrophy, atrophy, and loss of cardiomyocytes in the myocardium depending on the duration of diabetes and/or co-morbidities such as hypertension.
Although it has not been included in the definition, increased susceptibility to ischemia/reperfusion injury may be an important feature of diabetic cardiomyopathy. Two clinical studies showed that myocardial infarct size after coronary reperfusion therapy was larger by 30–80 % in diabetic patients than in non-diabetic patients [27, 28]. The difference was observed even though coronary blood flow was similarly restored by percutaneous coronary intervention in the diabetic and non-diabetic groups .
Clinical phenotype of diabetic cardiomyopathy
Previous studies using transthoracic echocardiography (TTE) has indicated that diabetes (mostly T2DM) is associated with left ventricular (LV) hypertrophy or concentric LV remodeling (i.e., increased LV mass [LVM]-to-LV end-diastolic volume ratio) in females but not consistently in males [29, 30, 31, 32, 33, 34]. However, TTE is not always suitable for elderly and/or obese patients, in whom image quality is frequently low. Magnetic resonance imaging (MRI) does not have such a disadvantage, and a recent study using this modality demonstrated significant association of insulin resistance and hyperglycemia with increase in LVM and LVM-to-LV end-diastolic volume ratio regardless of age and gender [35, 36]. Compared with studies on T2DM, few studies on T1DM have shown an increase in LV mass [37, 38, 39, 40, 41, 42] possibly due to the younger age and lower incidence of hypertension in T1DM patients recruited to those studies.
Interstitial fibrosis in diabetic hearts can be assessed by integrated backscatter (myocardial ultrasound reflectivity) in two-dimensional echocardiography [43, 44, 45] and by late gadolinium (Gd) enhancement in cardiac MRI . Two-dimensional echocardiography indicated an increased integrated backscatter index in the ventricular septum by 55 % and posterior wall by 15 % in diabetic patients as compared with that in non-diabetic controls . Kwong et al.  reported that late Gd-enhancement in MRI was present in 28 % of diabetic patients without clinical evidence of myocardial infarction. Which of the two clinical methods is more sensitive for the detection of ventricular fibrosis in diabetic hearts remains unclear.
LV diastolic and systolic dysfunction
The most frequent echocardiographic finding in asymptomatic T1DM and T2DM patients is LV diastolic dysfunction with normal LVEF. Diastolic dysfunction is detectable in diabetic hearts without hypertrophy [37, 47, 48], indicating that hypertrophy is not a requisite of diabetes-induced ventricular dysfunction. It is difficult to rigorously characterize differences, if any, in ventricular dysfunction between T1DM and T2DM since age and co-morbidities in study subjects are not comparable between the studies on T2DM and those on T1DM.
Three studies using TDI [52, 54, 55] showed that the peak systolic velocity (S′) was 11–20 % lower in normotensive T2DM patients than in non-diabetic subjects, though LVEFs were similar. SRI enables quantitative measurement of regional LV function independent of cardiac rotational motion and tethering effect. Two-dimensional speckle tracking, by which strain rate in all three directions (longitudinal, circumferential and radial) can be determined without angle dependency, has been employed in recent studies for assessment of LV systolic and diastolic dysfunctions in T2DM patients [57, 58]. Ng et al.  reported that longitudinal strain was reduced with preserved radial/circumferential strains in asymptomatic patients with uncomplicated diabetes mellitus. More recently, Ernande et al.  showed that both longitudinal and radial strains were reduced after adjustment for blood pressure, age, and body mass index in asymptomatic diabetic patients. Significant LV dysfunction was also detected in T1DM by TDI [38, 40, 41]. Taken together, the findings by TDI and SRI suggest that impaired longitudinal LV shortening, reflecting subendocardial dysfunction, is one of earliest signs in diabetic cardiomyopathy.
Response to stress tests
Emerging evidence indicates the presence of latent LV dysfunction in diabetic hearts. Ha et al.  showed that S′ and E′ during an exercise test were significantly lower by 10–15 % in T2DM than in non-diabetic controls, though both S′ and E′ were within normal ranges at rest in the two groups. In a study by Jellis et al. , who defined abnormal E′ (septal E′) at rest as <2SD of normal for age and abnormal E′ at peak exercise stress as <−9.9 cm/s, E′ at stress was abnormally low in 49 % of the T2DM patients with normal E′ at rest. Palmieri et al.  reported that peak exercise stroke volume index and cardiac index were significantly lower in patients with uncomplicated T1DM than in non-diabetic normotensive controls, though LV TDI parameters were comparable in the two groups. Hence, it is likely that prevalence of diabetic cardiomyopathy is much higher than that previously thought in both types of diabetes. Furthermore, latent LV dysfunction caused by diabetes does not appear to be a trivial problem since blunted increase in systolic blood pressure/end-systolic LV volume ratio (SP/ESV) by exercise is associated with poor prognosis .
Mechanism of contractile dysfunction of diabetic myocardium
Different animal models of T1DM (e.g., streptozotocin [STZ]-treated and alloxan-treated animals) and T2DM (e.g., Goto-Kakizaki rat, Otsuka-Long-Evans-Fatty rat [OLETF], ob/ob mouse) have been used for investigation of mechanisms by which diabetes impairs contractile function of the heart. In the following sections, we primarily discuss the findings commonly observed in both T1DM and T2DM models, unless otherwise stated.
Impairments in excitation–contraction coupling
Diabetes significantly modifies action potential, Ca2+ transient and Ca2+ sensitivity of contractile elements in cardiomyocytes [62, 63, 64, 65, 66]. Prolongation of action potential duration (APD) and slower decay of Ca2+ transient are consistently observed in diabetic cardiomyocytes. It is notable that such changes in the Ca2+ transient were observed before development of systolic ventricular dysfunction. Peak amplitude of Ca2+ transient was reduced in some [64, 65, 67, 68, 69], but not all [70, 71, 72], models of diabetes.
As for prolongation of APD, reduction in transient outward K+ (Ito) current has been shown in most animal models of diabetes [62, 63, 65, 66, 73], though reduced expression of L-type Ca2+ channel was an additional abnormality in some models [64, 74]. The prolongation of APD is potentially a compensatory mechanism for preserving Ca2+ influx in cardiomyocytes with down-regulated L-type Ca2+ channel. However, it could lead to untoward outcomes. A study by Sah et al.  showed that down-regulation of Ito induces enhanced Ca2+ cycling and activation of calcineurin, leading to interstitial fibrosis and ventricular contractile dysfunction.
Down-regulation of Kv4.2 (one of alpha-subunit subfamilies of the voltage-gated K+ channel) expression underlies reduction in Ito current in diabetic hearts. The mechanism of the Kv4.2 down-regulation remains unclear, but inactivation of pyruvate dehydrogenase (PDH) and activation of peroxisome proliferator-activated receptor-α (PPARα) may be involved. In the diabetic myocardium, PDH is inhibited by PDH kinase-4 (PDK4) [76, 77, 78], and inhibition of PDH by 3-bromopyruvate has been shown to reduce the Ito current in normal cardiomyocytes . Conversely, reduced Ito current in postinfarct remodeling hearts was restored by 4–5 h treatment with dicholoroacetate or pyruvate . PDK4 is one of enzymes that are up-regulated by activation of PPARα [80, 81], and chronic cardio-specific activation of PPARα has been shown to down-regulate protein expression of both α-subunit (Kv4.2/KCND2) and β-subunit (KChIP2/KCNIP2) of the Ito channel, reducing Ito current density . Hence, it is possible that PPARα activation by increased fatty acid uptake is upstream of PDH inhibition in the mechanism of Kv4.2 down-regulation by diabetes.
Slowed decay in Ca2+ transient in diabetic cardiomyocytes is theoretically attributable to reduced rate of Ca2+ removal from the cytosol and/or reduced affinity of troponin C, a major Ca2+ buffer in the cytosol, for Ca2+. As for the effect of diabetes on affinity of troponin C to Ca2+, a study by Ishikawa et al. , the only one to our knowledge, showed that Ca2+ affinity of troponin C was similar in STZ-induced diabetic and non-diabetic cardiomyocytes. On the other hand, studies using different animal models of diabetes consistently indicated reduction in protein level of sarcoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) , and phospholamban phosphorylation was enhanced in some of the models [63, 64]. In addition, posttranslational modifications of SERCA2a by diabetes were reported by Bidasee et al. ; they found non-enzymatic glycosylation of SERCA2a (i.e., formation of advanced glycation end products [AGEs] on SERCA—see section “Remodeling of extracellular matrix” for details) in a model of T1DM, which potentially compromises pump activity of SERCA2a. Another Ca2+ handling protein for Ca2+ efflux, Na+–Ca2+ exchanger (NCX), is preserved in the diabetic heart . These findings indicate that down-regulation of SERCA2a is a primary mechanism of delayed decay in Ca2+ transient. The mechanism by which diabetes reduces SERCA2a expression is unclear, though involvement of nuclear O-GlcNAcylation was recently suggested by results of experiments using adenovirus-mediated overexpression of O-GlcNac transferase and O-GlcNAcase [85, 86].
Increased leakage of Ca2+ from the sarcoplasmitc reticulum (SR) has also been reported as an abnormality in diabetic hearts. Belke et al.  showed that Ca2+ leak under blockades of NCX and ryanodine receptors (RYRs) was significantly increased in ob/ob mice and that the increase was associated with reduced expression of FKBP12.6, a regulatory factor of RYRs. In a study that determined local SR Ca2+ release as “Ca2+ sparks” by use of a fluorescent Ca2+ probe, frequency of the Ca2+ sparks was increased by 60 % in association with reduction of both RYR2 and FKBP12.6 by 50 % in the myocardium of rats with STZ-induced diabetes . Interestingly, the increase in local Ca2+ sparks and down-regulation of RYR2 and FKBP12.6 were attenuated by candesartan, indicating involvement of AT1 receptor activation . The Ca2+ leak via dysfunctional RYRs and reduced Ca2+ uptake by SERCA2a appear to be responsible for significant reduction in SR Ca2+ store by diabetes .
Change in Ca2+ sensitivity of contractile proteins by diabetes is controversial. Data are contradictory (i.e., decrease vs. increase in Ca2+ sensitivity) even in the same T1DM model (STZ-induced diabetes) [88, 89]. In a study using cardiomyoytes from T2DM patients undergoing coronary artery bypass surgery, significant reduction of Ca2+ sensitivity was observed . There is no clear explanation for the contradictory results.
Turnover of ATP (up to 35 kg/day) is many times of its pool, and extraction of energy from substrates is not very large (~25 %) in the myocardium [91, 92, 93]. Thus, a small reduction in the efficiency of ATP synthesis could significantly compromise cellular functions, including contraction and relaxation. Diabetes reduces the efficiency of energy production by increase in fatty acid uptake and suppression of glucose oxidation. Fatty acid oxidation is augmented not only by elevation of plasma level of fatty acid but also by activation of PPARα. PPARα is activated by intracellular fatty acids and up-regulates multiple enzymes relevant to fatty acid metabolism [94, 95]. PPARα contributes also to suppression of glucose oxidation by up-regulation of PDK4 transcription . Most of the cytosolic long-chain acyl-CoAs are used for β-oxidation in mitochondria, and approximately 80 % of acetyl-CoA in the heart of a model of T2DM, db/db mouse, was found to be fatty acid-derived both when perfused with low glucose/low fatty acid buffer and when perfused with high glucose/high fatty acid buffer .
Glucose oxidation is inhibited at multiple steps in diabetic hearts. Uptake of glucose is impaired in diabetic hearts by down-regulated expression of GLUT4/GLUT1 and by blunted sarcolemmal translocation of GLUT4 in response to insulin [98, 99]. Impaired tyrosine phosphorylation of the insulin receptor and insulin receptor substrates and blunted activation of PI3K-Akt signaling are involved in the deficient response of diabetic hearts to insulin. In addition, activities of hexokinase, phosphofructokinase, and PDH are inhibited by long-chain acyl-CoA, citrate, and PDK4 in the diabetic myocardium [96, 100, 101].
Mitochondrial dysfunction is also responsible for reduced efficiency in energy production in the diabetic heart as recently reviewed by Bugger and Able . Production of cytotoxic reactive oxygen species (ROS) was augmented in mitochondria in different types of diabetes. Increased fatty acid oxidation, which has higher oxygen cost than glucose, and increased activity of uncoupling proteins (UCPs) in mitochondria appear to underlie the augmented ROS production. ROS can directly activate UCP3 and further reduce efficiency of ATP production in mitochondria [103, 104].
Extra-mitochondrial ROS level is also increased in a model of T2DM (obese Zucker rat). In this model, increased metabolic flux to the pentose phosphate pathway augments generation of Nox-derived ROS by the elevation of NADPH level due to up-regulated activity of glucose-6-phophate dehydrogenase (G6PD) . Protein kinase C (PKC) contributes to the up-regulation of G6PD. However, such up-regulation of G6PD activity in the myocardium was not detected in a model of T1DM (STZ-induced diabetes) .
An important question is whether supply of ATP is indeed insufficient for its demand in diabetic cardiomyocytes. A clue to the answer to this question is change in the phosphocreatine (PCr)/ATP ratio. Reduction of PCr/ATP ratio indicates suppressed ATP production and/or suppressed production of PCr from ATP by the creatine kinase (CK) system. Determination of PCr and ATP in the human myocardium by magnetic resonance spectroscopy (MRS) showed that the PCr/ATP ratio is significantly reduced by diabetes and that the ratio negatively correlates with plasma free fatty acid level or live triglyceride level [107, 108]. These observations support the notion that supply of ATP in response to intracellular demand is compromised in diabetic hearts. It is notable that the cardiac metabolic derangement indicated by PCr/ATP precedes ventricular dysfunction detectable at rest in the diabetic heart but possibly underlies the dysfunction unmasked by stress tests (section “Response to stress tests”).
Remodeling of extracellular matrix
Distinguishing from enzymatic glycosylation of proteins, non-enzymatic formation of stable glycosylation product by Amadori rearrangement (Amadori product) is called glycation. Glycated proteins undergo a series of chemical rearrangements to form complex compounds with cross-links, which are referred to as advanced glycation end products (AGEs). AGEs have been shown to be increased in plasma by hyperglycemia, aging, and renal failure [16, 109, 110, 111]. Accumulation of AGE in collagen was associated with reduced collagen turnover, indicating the possibility that cross-linking of collagen makes collagen resistant to hydrolytic turnover . Such AGE-mediated cross-linking of collagen is thought to be responsible for increased stiffness of arteries and the myocardium. In fact, AGE in the myocardium increases in T1DM and T2DM, and positive correlations of serum level of AGEs with ventricular isovolumetric relaxation time, arterial stiffness, and carotid intimal thickness have been shown in diabetics [109, 110, 113]. Furthermore, treatment with an inhibitor of AGE formation (aminoguanidine) prevented ventricular dysfunction in diabetic rats [114, 115]. Treatment with alagebrium (ALT-711), an “AGE cross-link breaker”, restored the LV function and reduced myocardial collagens in a canine model of diabetes , and its beneficial effect on LV diastolic function was suggested in heart failure patients with preserved ejection fraction .
Fibrosis in the cardiac interstitium and perivascular space in diabetic patients is reproducible in animal models at the late stage of diabetes. Contribution of the AT1 receptor to fibrosis is supported in the models of diabetes by three lines of evidence. AT1 receptor activity was up-regulated in diabetic hearts [118, 119], and this receptor is coupled with transforming growth factor-β1 (TGF-β1) signaling, which stimulates collagen production [120, 121]. Inhibition of AT1 receptor activity by AT1 receptor blockers (ARBs) or angiotensin converting enzyme (ACE) inhibitors ameliorated interstitial fibrosis and significantly improved LV function . It should be noted that extent of interstitial fibrosis and that of glycation of proteins do not necessarily change in parallel .
Abnormalities in microvasculature
“Microangiopathy” has been demonstrated in the myocardium of diabetic patients, and it was reproducible in a rat model of diabetes [12, 14, 21, 22, 122, 123]. Thickening of the capillary basement membrane, medial thickening of the arteriole, and perivascular fibrosis were observed in autopsy samples of the ventricular myocardium by conventional histology [12, 14, 21, 22]. Visualization of three-dimensional morphology of microvessels by use of the microfill technique showed microaneurysms, spasm, and spiral deformation of microvessels in the myocardium of T1DM and T2DM . These vascular changes are reproducible in rat hearts by STZ-induced diabetes and hypertension .
In addition to morphology, density of the microvessels is modified in the heart by diabetes. Yoon et al.  showed that expression of vascular endothelial cell growth factor (VEGF) in the heart is down-regulated by diabetes and that the down-regulation is closely associated with reduction in capillary density, apoptosis of endothelial cells and interstitial fibrosis. Since insulin induces VEGF expression via PI3K-Akt signaling , impairment of this signaling in the diabetic heart may be responsible for the down-regulation of VEGF expression. Furthermore, restoration of VEGF by intramyocardial injection of plasmid DNA encoding VEGF prevented loss of capillaries in diabetic mice . Unfortunately, data on VEGF expression in the human diabetic myocardium are contradictory in the literature [126, 127, 128]. VEGF mRNA level in ventricular biopsy samples from diabetic patients was reportedly reduced , not changed in the non-ischemic area and reduced in the ischemic area  or increased  as compared with non-diabetic patients. Difference between clinical backgrounds in study subjects might be involved in the contradictory results in human studies.
Reduction in coronary blood flow reserve (CFR) by diabetes has been demonstrated in both clinical and experimental studies [129, 130, 131]. In diabetic patients, CFR was inversely correlated with an index of LV relaxation (time from R-wave on the electrocardiogram to the onset of relaxation) . In a rat model of obese T2DM (OLETF), CFR was reduced and inversely correlated with wall-to-lumen ratio of arterioles (<100 μm in diameter) and with extent of perivascular fibrosis . Activation of the receptor for AGE (RAGE) in the endothelium by AGE inhibits production of nitric oxide (NO) and up-regulates expression of cell adhesion molecules . Use of an AGE cross-link breaker, alagebrium, significantly improved flow-mediated dilatation in hypertensive patients . Taken together, blunted NO production, AGE-mediated stiffening of coronary media, reduced angiogenesis, and perivascular fibrosis are possibly responsible for the reduction of CFR in diabetic hearts.
Myocardial tolerance against ischemia/reperfusion-induced necrosis
Changes in myocardial susceptibility to infarction by diabetes
Effects of diabetes and hyperglycemia on infarct size
Infarct size enlargement
ob/ob mouse: Ref. 
Infarct size reduction
Zucker rat: Ref. 
No change in infarct size
ob/ob mice: Ref. 
Infarct size enlargement
No change in infarct size
Infarct size enlargement
Rat (Western diet): Ref. 
No change in infarct size
Diabetes-induced defects in intracellular protective signaling
Effects of diabetes and hyperglycemia on cardioprotection afforded by pre- and postconditioning and their mimetics
PDE 3 inhibitor (rat): Ref. 
PPAR-α agonist (rat): Ref. 
Metformin (rat): Ref. 
Ischemic PC (SWOP) (rabbit): Ref. 
KATP channel opener (dog): Ref. 
Ischemic PostC (rat): Ref. 
Like animal models of diabetes, diabetic human hearts have defects in cytoprotective mechanisms. Ishihara et al.  showed that preinfarct angina pectoris, a clinical counterpart of IPC, reduced CK release and improved recovery of cardiac function and in-hospital survival after acute myocardial infarction in non-diabetic patients but not in diabetics. Impairment of IPC in human diabetes was also shown during angioplasty  and during a treadmill exercise test  by use of electrocardiographic severity of ischemia as an endpoint. Direct evidence for diabetes-induced loss of IPC protection in human hearts was provided by an in vitro experiment using atrial trabeculae obtained at open heart surgery. IPC failed to suppress CK release and contractile dysfunction after hypoxia/reoxygenation in vitro in atrial trabeculae from diabetic patients [186, 187].
Multiple defects in cytoprotective signal pathways have been indicated in diabetic hearts. Our recent studies have shown that Jak2, being upstream of PI3K-Akt signaling, is inhibited by enhanced calcineurin activity and that phosphorylation of GSK-3β by ERK is lost by an endoplasmic reticulum stress-dependent mechanism in a rat model of T2DM [119, 143]. Furthermore, protein level of active GSK-3β, a pro-necrotic and pro-apoptotic kinase, was increased in mitochondria, leading to increase in susceptibility of mitochondrial permeability transition in response to calcium overload . On the other hand, a protective mechanism downstream of GSK-3β phosphorylation appears to be intact in diabetic hearts, since direct inhibitors of GSK-3β limit infarct size similarly in diabetic and non-diabetic animals [119, 143, 161, 162, 182].
There is limited information on whether glycemia control repairs defects in protective signaling in diabetic hearts. Acute hyperglycemia induced by dextrose infusion impaired infarct size limitation by IPC, a mitochondrial KATP channel opener and anesthetic agents [158, 170, 172, 174, 175, 176, 177, 178], indicating a primary role of hyperglycemia in impairment of protective signaling. Recently, Przyklenk et al.  reported that the cardioprotective effect of IPost was re-established in STZ-induced diabetic mice by pancreas islet cell transplantation. Transplantation of islet cells in diabetic mice normalized blood glucose level and also ERK signaling activated by IPost. Since dyslipidemia reportedly attenuates the infarct size-limiting effect of IPC [188, 189, 190], restoration of the protective effect of IPost in the diabetic heart by islet cell transplantation could have been a result of normalization of both plasma glucose and lipid profile. Nevertheless, circumstantial evidence to date supports the notion that normalization of the metabolic profile restores protective signaling mechanisms in the diabetic heart.
Clinical diagnosis of diabetic cardiomyopathy
Diagnostic clues of diabetic cardiomyopathy
LV hypertrophy assessed by 2D echocardiography or CMR
Increased integrated backscatter in the LV (septal and posterior wall)
Late Gd-enhancement of the myocardium in CMR
LV diastolic dysfunction assessed by pulsed Doppler echocardiography and TDI
LV systolic dysfunction demonstrated by TDI/SRI
Limited systolic and/or diastolic functional reserve assessed by exercise TDI
Reduced cardiac PCr/ATP detected by 31P-MRS
Elevated myocardial triglyceride content detected by 1H-MRS
Left ventricular diastolic dysfunction detectable by TDI (and possible also by SRI) at exercise stress may be the earliest sign of diabetes-induced LV dysfunction as discussed in section “Clinical phenotype of diabetic cardiomyopathy”. Thus, normal echocardiographic findings at rest do not exclude presence of diabetic cardiomyopathy. Studies to date support the notion that diastolic dysfunction develops earlier than systolic dysfunction in diabetic hearts. However, Ernande et al.  recently reported that systolic longitudinal strain rate was abnormal in 28 % of diabetic patients with normal diastolic function and in 35 % of those with diastolic dysfunction. Assessment of interstitial fibrosis by integrated backscatter or Gd-enhancement of cardiac MRI is possible [43, 44, 45, 46], but its diagnostic value has not yet been established.
A promising novel approach to diagnosis of diabetic myopathy is characterization of metabolic changes in the myocardium by 31P-MRS and by1H-MRS. As discussed in section “Metabolic derangements”, the PCr/ATP ratio, an index of energy charge, is reduced in the myocardium of diabetic patients compared with that in control subjects. Recent studies using 1H-MRS have demonstrated that increase in myocardial triglyceride content (i.e., myocardial steatosis) was associated with LV diastolic dysfunction in diabetic patients [192, 193]. Furthermore, Ng et al.  showed that myocardial steatosis was independently correlated with LV longitudinal strain and with systolic and diastolic strain rates determined by two-dimensional speckle tracking imaging in patients with uncomplicated diabetes mellitus. The possibility that myocardial steatosis is a specific marker of the diabetic cardiomyopathy warrants further investigation.
Prevention and treatment of diabetic cardiomyopathy
Prevention of diabetic cardiomyopathy
Although high prevalence of subclinical myocardial dysfunction has been reported in the early stage of T1DM, clinically relevant heart failure is relatively rare in this type of diabetes. In an observational study, 462 T1DM patients without a previous history of heart disease were followed up, and it found that only 17 patients (3.7 %) developed heart failure during a 12-year follow-up period . The patients who developed heart failure in this cohort were older and had longer diabetes durations (35 ± 9 years), higher blood pressure, and higher prevalence of albuminuria and retinopathy than those in patients without heart failure. In contrast, heart failure develops more frequently in patients with T2DM [4, 5], which is frequently associated with other co-morbidities, such as hypertension, predisposing to heart failure. Hence, it is unlikely that glycemic control alone is sufficient for the prevention of diabetic cardiomyopathy.
A number of clinical trials have been conducted to evaluate the impact of glycemic control on the prevention of cardiovascular events in T2DM. However, end-points in the studies were atherosclerotic cardiovascular events and death, leaving non-ischemic heart failure not specifically determined. A recently published meta-analysis including a total of 27,049 subjects in the UKPDS 33 (UK Prospective Diabetes Study 33), ACCORD, ADVANCE, and VADT trials showed that mortality was not affected by intensive glycemic control, with hazard risks of 1.10 for cardiovascular death (95 % confidence interval [CI]; 0.84–1.42) and 1.04 for all-cause death (95 % CI: 0.90–1.20) . These findings may appear to argue against the notion that tight glycemic control is beneficial for prevention of diabetic cardiomyopathy. However, the results do not preclude the possibility that intensive glycemic control commenced at an earlier stage of diabetes together with control of other risk factors prevents heart failure in diabetic patients. This speculation is supported by a few lines, at least, of evidence. First, clinical studies using TDI showed that glycemic control improved LV diastolic function in T2DM [197, 198]. Second, the Steno-2 trial  showed that simultaneous control of glycemia, hypertension, and dyslipidemia significantly reduced cardiovascular events and mortality in T2DM patients. Third, a recent meta-analysis of clinical trials on hypertension indicates that diabetes increases incidence of heart failure by more than fourfold in hypertensive patients .
Whether incidence and/or outcome of heart failure differ depending on the type of hypoglycemic agent selected for hyperglycemia control remains unclear. This issue has not been addressed by a prospective randomized clinical trial. In observational cohort studies and retrospective analyses of registered patients, use of metformin is associated with low incidence of heart failure compared with other glycemia control regimens . Furthermore, clinical outcomes in diabetic patients with heart failure were better in groups treated with metformin [201, 202]. Aguilar et al.  matched metformin-treated and metformin-untreated groups of diabetic patients with heart failure and showed that mortality was lower in the metformin-treated group.
In contrast with metformin, thiazolidinedione (TZD) has been shown to increase incidence of “heart failure” in diabetes compared with sulfonylurea. Unfortunately, it is not clear whether the increase in “heart failure” by TZD indeed reflects worsening of LV function or just retention of fluids [203, 204, 205, 206]. In fact, recent studies have suggested a favorable effect of TZD on cardiac function [207, 208]. Six months of treatment with pioglitazone improved diastolic function assessed by Doppler echocardiography in hypertensive patients in proportion to the amelioration of insulin resistance . The same duration of treatment with pioglitazone was also reported to improve diastolic function and LV compliance assessed by MRI in uncomplicated T2DM patients . It is notable, however, that improvement in the function could not be explained by treatment-related myocardial metabolic change assessed by positron emission tomography and MRS. Nevertheless, prospective clinical trials are necessary to clarify efficacies of hypoglycemic agents in prevention of diabetic cardiomyopathy.
Management of heart failure in diabetic patients
Optimal treatment of heart failure in diabetic patients has not been specifically addressed, and relevant information is limited to effects of diabetes on the efficacy of a heart failure therapy in subgroup analyses of trials. In earlier studies, ACE inhibitor was suggested to be similarly effective in diabetic and non-diabetic patients with heart failure with reduced LVEF [209, 210] and that was the case for ARB as well . In contrast, the benefit of a β-blocker on mortality may be attenuated in diabetic patients, especially in elderly patients [211, 212]. Under the standard treatment with these agents, prognosis of heart failure patients with diabetes is worse than that of heart failure patients without diabetes irrespective of LVEF levels [10, 213]. Heart failure with preserved LVEF is a primary phenotype in diabetes, and therapy to improve prognosis of this type of heart failure in general is still under intensive investigation .
Accumulating evidence obtained by novel imaging techniques (i.e., TDI, SRI, MRS) indicates that these techniques for functional and metabolic analyses of human hearts will make it possible to formulate clinical parameters for diagnosis of diabetic cardiomyopathy. Such diagnostic criteria would facilitate the design of prospective studies to search for optimal therapy for prevention and treatment of this cardiomyopathy. Numerous questions regarding pathogenesis of diabetic cardiomyopathy still remain, but molecular mechanisms of down-regulation of SERCA2a, mitochondrial dysfunction, and defects in cytoprotective signaling appear particularly important issues for designing novel therapies for restoration of contractile function and prevention of progressive heart failure. Novel therapy is in urgent need since even mild diastolic dysfunction in diabetic hearts has been shown to be associated with more than a threefold increase in all-cause mortality .
This work was supported by Japanese Society for the Promotion of Science Grants-in-Aid for Scientific Research (23591085), Tokyo, Japan.
Conflict of interest
Dr. Takayuki Miki has received research funding from Daiichi-Sankyo, Japan, Eisai, Japan, and Pfizer, Japan. Drs. Satoshi Yuda and Hidemichi Kouzu have no conflicts of interest or financial ties to disclose. Dr. Tetsuji Miura has received research funding from Takeda Pharmaceuticals, Japan, Novartis, Japan, Chugai Pharmaceutical, Japan, and Astellas Pharma, Japan.
This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
- 1.Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ, Lin JK, Farzadfar F, Khang YH, Stevens GA, Rao M, Ali MK, Riley LM, Robinson CA, Ezzati M, Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Blood Glucose) (2011) National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 378:31–40PubMedGoogle Scholar
- 7.Lewis EF, Velazquez EJ, Solomon SD, Hellkamp AS, McMurray JJ, Mathias J, Rouleau JL, Maggioni AP, Swedberg K, Kober L, White H, Dalby AJ, Francis GS, Zannad F, Califf RM, Pfeffer MA (2008) Predictors of the first heart failure hospitalization in patients who are stable survivors of myocardial infarction complicated by pulmonary congestion and/or left ventricular dysfunction: a VALIANT study. Eur Heart J 29:748–756PubMedGoogle Scholar
- 9.Du X, Ninomiya T, de Galan B, Abadir E, Chalmers J, Pillai A, Woodward M, Cooper M, Harrap S, Hamet P, Poulter N, Lip GY, Patel A, ADVANCE Collaborative Group (2009) Risks of cardiovascular events and effects of routine blood pressure lowering among patients with type 2 diabetes and atrial fibrillation: results of the ADVANCE study. Eur Heart J 30:1128–1135PubMedGoogle Scholar
- 10.MacDonald MR, Petrie MC, Varyani F, Ostergren J, Michelson EL, Young JB, Solomon SD, Granger CB, Swedberg K, Yusuf S, Pfeffer MA, McMurray JJ, CHARM Investigators (2008) Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the candesartan in heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J 29:1377–1385PubMedGoogle Scholar
- 11.Shah AM, Uno H, Køber L, Velazquez EJ, Maggioni AP, MacDonald MR, Petrie MC, McMurray JJ, Califf RM, Pfeffer MA, Solomon SD (2010) The inter-relationship of diabetes and left ventricular systolic function on outcome after high-risk myocardial infarction. Eur J Heart Fail 12:1229–1237PubMedGoogle Scholar
- 17.Schalkwijk CG, Baidoshvili A, Stehouwer CD, van Hinsbergh VW, Niessen HW (2004) Increased accumulation of the glycoxidation product Nepsilon-(carboxymethyl)lysine in hearts of diabetic patients: generation and characterisation of a monoclonal anti-CML antibody. Biochim Biophys Acta 1636:82–89PubMedGoogle Scholar
- 18.van Heerebeek L, Hamdani N, Handoko ML, Falcao-Pires I, Musters RJ, Kupreishvili K, Ijsselmuiden AJ, Schalkwijk CG, Bronzwaer JG, Diamant M, Borbély A, van der Velden J, Stienen GJ, Laarman GJ, Niessen HW, Paulus WJ (2008) Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation 117:43–51PubMedGoogle Scholar
- 19.Falcão-Pires I, Hamdani N, Borbély A, Gavina C, Schalkwijk CG, van der Velden J, van Heerebeek L, Stienen GJ, Niessen HW, Leite-Moreira AF, Paulus WJ (2011) Diabetes mellitus worsens diastolic left ventricular dysfunction in aortic stenosis through altered myocardial structure and cardiomyocyte stiffness. Circulation 124:1151–1159PubMedGoogle Scholar
- 20.Fischer VW, Barner HB, Larose LS (1984) Pathomorphologic aspects of muscular tissue in diabetes mellitus. Human Pathol 15:1127–1136Google Scholar
- 23.Sakata S, Lebeche D, Sakata Y, Sakata N, Chemaly ER, Liang L, Nakajima-Takenaka C, Tsuji T, Konishi N, del Monte F, Hajjar RJ, Takaki M (2007) Transcoronary gene transfer of SERCA2a increases coronary blood flow and decreases cardiomyocyte size in a type 2 diabetic rat model. Am J Physiol Heart Circ Physiol 292:H1204–H1207PubMedGoogle Scholar
- 26.Basu R, Oudit GY, Wang X, Zhang L, Ussher JR, Lopaschuk GD, Kassiri Z (2009) Type 1 diabetic cardiomyopathy in the Akita (Ins2WT/C96Y) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function. Am J Physiol Heart Circ Physiol 297:H2096–H2108PubMedGoogle Scholar
- 27.Marso SP, Miller T, Rutherford BD, Gibbons RJ, Qureshi M, Kalynych A, Turco M, Schultheiss HP, Mehran R, Krucoff MW, Lansky AJ, Stone GW (2007) Comparison of myocardial reperfusion in patients undergoing percutaneous coronary intervention in ST-segment elevation acute myocardial infarction with versus without diabetes mellitus (from the EMERALD Trial). Am J Cardiol 100:206–210PubMedGoogle Scholar
- 28.Algeria JR, Miller TD, Gibbons RJ, Yi QL, Yusuf S, Collaborative Organization of RheothRx Evaluation (CORE) Trial Investigators (2007) Infarct size, ejection fraction, and mortality in diabetic patients with acute myocardial infarction treated with thrombolytic therapy. Am Heart J 154:743–750Google Scholar
- 31.Bella JN, Devereux RB, Roman MJ, Palmieri V, Liu JE, Paranicas M, Welty TK, Lee ET, Fabsitz RR, Howard BV (2001) Separate and joint effects of systemic hypertension and diabetes mellitus on left ventricular structure and function in American Indians (the Strong Heart Study). Am J Cardiol 87:1260–1265PubMedGoogle Scholar
- 35.Heckbert SR, Post W, Pearson GD, Arnett DK, Gomes AS, Jerosch-Herold M, Hundley WG, Lima JA, Bluemke DA (2006) Traditional cardiovascular risk factors in relation to left ventricular mass, volume, and systolic function by cardiac magnetic resonance imaging: the Multiethnic Study of Atherosclerosis. J Am Coll Cardiol 48:2285–2292PubMedGoogle Scholar
- 36.Velagaleti RS, Gona P, Chuang ML, Salton CJ, Fox CS, Blease SJ, Yeon SB, Manning WJ, O’Donnell CJ (2010) Relations of insulin resistance and glycemic abnormalities to cardiovascular magnestic resonance measures of cardiac structure and function. The Framingham Heart Study. Circ Cardiovasc Imaging 3:257–263PubMedGoogle Scholar
- 40.Palmieri V, Capaldo B, Russo C, Iaccarino M, Di Minno G, Riccardi G, Celentano A (2006) Left ventricular chamber and myocardial systolic function reserve in patients with type 1 diabetes mellitus: insight from traditional and Doppler tissue imaging echocardiography. J Am Soc Echocardiogr 19:848–856PubMedGoogle Scholar
- 46.Kwong RY, Sattar H, Wu H, Vorobiof G, Gandla V, Steel K, Siu S, Brown KA (2008) Incidence and prognostic implication of unrecognized myocardial scar characterized by cardiac magnetic resonance in diabetic patients without clinical evidence of myocardial infarction. Circulation 118:1011–1020PubMedGoogle Scholar
- 47.Ha JW, Lee HC, Kang ES, Ahn CM, Kim JM, Ahn JA, Lee SW, Choi EY, Rim SJ, Oh JK, Chung N (2007) Abnormal left ventricular longitudinal functional reserve in patients with diabetes mellitus: implication for detecting subclinical myocardial dysfunction using exercise tissue Doppler echocardiograpjhy. Heart 93:1571–1576PubMedGoogle Scholar
- 54.Andersen NH, Poulsen SH, Eiskjaer H, Poulsen PL, Mogensen CE (2003) Decreased left ventricular longitudinal contraction in normotensive and normoalbuminuric patients with type II diabetes mellitus: a Doppler tissue tracking and strain rate echocardiography study. Clin Sci 105:59–66PubMedGoogle Scholar
- 56.Muranaka A, Yuda S, Tsuchihashi K, Hashimoto A, Nakata T, Miura T, Tsuzuki M, Wakabayashi C, Watanabe N, Shimamoto K (2009) Quantitative assessment of left ventricular and left atrial functions by strain rate imaging in diabetic patients with and without hypertension. Echocardiography 26:262–271PubMedGoogle Scholar
- 57.Ng AC, Delgado V, Bertini M, van der Meer RW, Rijzewijk LJ, Shanks M, Nucifora G, Smit JW, Diamant M, Romijn JA, de Roos A, Leung DY, Lamb HJ, Bax JJ (2009) Findings from left ventricular strain and strain rate imaging in asymptomatic patients with type 2 diabetes mellitus. Am J Cardiol 104:1398–1401PubMedGoogle Scholar
- 58.Ernande L, Rietzschel ER, Bergerot C, De Buyzere ML, Schnell F, Groisne L, Ovize M, Croisille P, Moulin P, Gillebert TC, Derumeaux G (2010) Impaired myocardial radial function in asymptomatic patients with type 2 diabetes mellitus: a speckle-tracking imaging study. J Am Soc Echocardiogr 23:1266–1272PubMedGoogle Scholar
- 60.Palmieri V, Capaldo B, Russo C, Iaccarino M, Pezzullo S, Quintavalle G, Di Minno G, Riccardi G, Celentano A (2008) Uncomplicated type 1 diabetes and preclinical left ventricular myocardial dysfunction: insights from echocardiography and exercise cardiac performance evaluation. Diabetes Res Clin Pract 79:262–268PubMedGoogle Scholar
- 69.Yaras N, Bilginoglu A, Vassort G, Turan B (2007) Restoration of diabetes-induced abnormal local Ca2+ release in cardiomyocytes by angiontensin II receptor blockade. Am J Phyiol Heart Circ Physiol 292:H912–H920Google Scholar
- 74.Howarth FC, Qureshi MA, Hassan Z, Al Kury LT, Isaev D, Parekh K, Yammahi SR, Oz M, Adrian TE, Adeghate E (2011) Changing pattern of gene expression is associated with ventricular myocyte dysfunction and altered mechanisms of Ca2+ signaling in young type 2 Zucker diabetic fatty rat heart. Exp Physiol 96:325–337PubMedGoogle Scholar
- 89.Falcao-Pires I, Palladini G, Gonçalves N, van der Velden J, Moreira-Gonçalves D, Miranda-Silva D, Salinaro F, Paulus WJ, Niessen HW, Perlini S, Leite-Moreira AF (2011) Distinct mechanisms for diastolic dysfunction in diabetes mellitus and chronic pressure-overload. Basic Res Cardiol 106:801–814PubMedGoogle Scholar
- 91.Taegtmeyer H (1994) Energy metabolism of the heart: from basic concepts to clinical application. Curr Prob Cardiol 19:59–113Google Scholar
- 93.Knaapen P, Germans T, Knuuti J, Paulus WJ, Dijkmans PA, Allaart CP, Lammertsma AA, Visser FC (2007) Myocardial energetics and efficiency: current status of the noninvasive approach. Circulation 15:918–927Google Scholar
- 95.Hafstad AD, Khalid AM, Hagve M, Lund T, Larsen TS, Severson DL, Clarke K, Berge RK, Aasum E (2009) Cardiac peroxisome proliferator-activated receptor-α activation causes increased fatty acid oxidation, reducing efficiency and postischaemic functional loss. Cardiovasc Res 83:519–526PubMedGoogle Scholar
- 96.Buchanan J, Mazumder PK, Hu P, Chakrabarti G, Roberts MW, Yun UJ, Cooksey RC, Litwin SE, Abel ED (2005) Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hypoglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology 146:5341–5349PubMedGoogle Scholar
- 105.Serpillon S, Floyd BC, Gupte RS, George S, Kozicky M, Neito V, Recchia F, Stanley W, Wolin MS, Gupte SA (2009) Superoxide production of NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH. Am J Physiol Heart Circ Physiol 297:H153–H162PubMedGoogle Scholar
- 108.Rijzewijk LJ, Jonker JT, van der Meer RW, Lubberink M, de Jong HW, Romijn JA, Bax JJ, de Roos A, Heine RJ, Twisk JW, Windhorst AD, Lammertsma AA, Smit JW, Diamant M, Lamb HJ (2010) Effects of hepatic triglyceride content on myocardial metabolism in type 2 diabetes. J Am Coll Cardiol 56:225–233PubMedGoogle Scholar
- 109.Berg TJ, Snorgaard O, Faber J, Torjesen PA, Hildebrandt P, Mehlsen J, Hanssen KF (1999) Serum levels of advanced glycation end products are associated with left ventricular diastolic function in patients with type 1 diabetes. Diabetic Care 22:1186–1190Google Scholar
- 119.Hotta H, Miura T, Miki T, Togashi N, Maeda T, Kim SJ, Tanno M, Yano T, Kuno A, Itoh T, Satoh T, Terashima Y, Ishikawa S, Shimamoto K (2010) Angiotensin II type 1 receptor-mediated upregulation of calcineurin activity underlies impairment of cardioprotective signaling in diabetic hearts. Circ Res 106:129–132PubMedGoogle Scholar
- 124.Yoon YS, Uchida S, Masuo O, Cejna M, Park JS, Gwon HC, Kirchmair R, Bahlman F, Walter D, Curry C, Hanley A, Isner JM, Losordo DW (2005) Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy: restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor. Circulation 111:2073–2085PubMedGoogle Scholar
- 125.He Z, Opland DM, Way KJ, Ueki K, Bodyak N, Kang PM, Izumo S, Kulkarni RN, Wang B, Liao R, Kahn CR, King GL (2006) Regulation of vascular endothelial growth factor expression and vascularization in the myocardium by insulin receptor and PI3K/Akt pathways in insulin resistance and ischemia. Arterioscler Thromb Vasc Biol 26:787–793PubMedGoogle Scholar
- 126.Chou E, Suzuma I, Way KJ, Opland D, Clermont AC, Naruse K, Suzuma K, Bowling NL, Vlahos CJ, Aiello LP, King GL (2002) Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic states: a possible explanation for impaired collateral formation in cardiac tissue. Circulation 105:373–379PubMedGoogle Scholar
- 127.Marfella R, Esposito K, Nappo F, Siniscalchi M, Sasso FC, Portoghese M, Di Marino MP, Baldi A, Cuzzocrea S, Di Filippo C, Barboso G, Baldi F, Rossi F, D’Amico M, Giugliano D (2004) Expression of angiogenic factors during acute coronary syndromes in human type 2 diabetes. Diabetes 53:2383–2391PubMedGoogle Scholar
- 128.Sasso FC, Torella D, Carbonara O, Ellison GM, Torella M, Scardone M, Marra C, Nasti R, Marfella R, Cozzolino D, Indolfi C, Cotrufo M, Torella R, Salvatore T (2005) Increased vascular endothelial growth factor expression but impaired vascular endothelial growth factor receptor signaling in the myocardium of type 2 diabetic patients with chronic coronary heart disease. J Am Coll Cardiol 46:827–834PubMedGoogle Scholar
- 135.Marfella R, Di Filippo C, Esposito K, Nappo F, Piegari E, Cuzzocrea S, Berrino L, Rossi F, Giugliano D, D’Amico M (2004) Absence of inducible nitric oxide synthase reduces myocardial damage during ischemia reperfusion in streptozotocin-induced hyperglycemic mice. Diabetes 53:454–462PubMedGoogle Scholar
- 143.Miki T, Miura T, Hotta H, Tanno M, Yano T, Sato T, Terashima Y, Takada A, Ishikawa S, Shimamoto K (2009) Endoplasmic reticulum stress in diabetic hearts abolishes erythropoietin-induced myocardial protection by impairment of phosphor-glycogen synthase kinase-3beta-mediated suppression of mitochondrial permeability transition. Diabetes 58:2863–2872PubMedGoogle Scholar
- 150.Ma G, Al-Shabrawey M, Johnson JA, Datar R, Tawfik HE, Guo D, Caldwell RB, Caldwell RW (2006) Protection against myocardial ischemia/reperfusion injury by short-term diabetes: enhancement of VEGF formation, capillary density, and activation of cell survival signaling. Naunyn Schmiedebergs Arch Pharmacol 373:415–427PubMedGoogle Scholar
- 154.Kristiansen SB, Løfgren B, Nielsen JM, Støttrup NB, Buhl ES, Nielsen-Kudsk JE, Nielsen TT, Rungby J, Flyvbjerg A, Bøtker HE (2011) Comparison of two sulfonylureas with high and low myocardial KATP channel affinity on myocardial infarct size and metabolism in a rat model of type 2 diabetes. Diabetologia 54:451–458PubMedGoogle Scholar
- 159.Nieszner E, Posa I, Kocsis E, Pogátsa G, Préda I, Koltai MZ (2002) Influence of diabetic state and that of different sulfonylureas on the size of myocardial infarction with and without ischemic preconditioning in rabbits. Exp Clin Endocrionol Diabetes 110:212–218Google Scholar
- 160.Ebel D, Müllenheim J, Frässdorf J, Heinen A, Huhn R, Bohlen T, Ferrari J, Südkamp H, Preckel B, Schlack W, Thämer V (2003) Effect of acute hyperglycemia and diabetes mellitus with and without short-term insulin treatment on myocardial ischaemic late preconditioning in the rabbit heart in vivo. Pflugers Arch 446:175–182PubMedGoogle Scholar
- 162.Ghaboura N, Tamareille S, Ducluzeau PH, Grimaud L, Loufrani L, Croué A, Tourmen Y, Henrion D, Furber A, Prunier F (2011) Diabetes mellitus abrogates erythropoietin-induced cardioprotection against ischemic-reperfusion injury by alteration of the RISK/GSK-3β signaling. Basic Res Cardiol 106:147–162PubMedGoogle Scholar
- 163.Drenger B, Ostrovsky IA, Barak M, Nechemia-Arbely Y, Ziv E, Axelrod JH (2011) Diabetes blockade of sevoflurane postconditioning is not restored by insulin in the rat heart: phosphorylated signal transducer and activator of transcription 3- and phosphatidylinositol 3-kinase-mediated inhibition. Anesthesiology 114:1364–1372PubMedGoogle Scholar
- 169.Matsumoto S, Cho S, Tosaka S, Ureshino H, Maekawa T, Hara T, Sumikawa K (2009) Pharmacological preconditioning in type 2 diabetic rat hearts: the role of mitochondrial ATP-sensitive potassium channels and the phosphatidylinositol 3-kinase-Akt pathway. Cardiovasc Drug Ther 23:263–270Google Scholar
- 177.Amour J, Brzezinska AK, Jager Z, Sullivan C, Weihrauch D, Du J, Vladic N, Shi Y, Warltier DC, Pratt PF Jr, Kersten JR (2010) Hyperglycemia adversely modulates endothelial nitric oxide synthase during anesthetic preconditioning through tetrahydrobiopterin- and heat shock protein 90-mediated mechanisms. Anesthesiology 112:576–585PubMedGoogle Scholar
- 180.Thim T, Bentzon JF, Kristiansen SB, Simonsen U, Andersen HL, Wassermann K, Falk E (2006) Size of myocardial infarction induced by ischaemia/reperfusion is unaltered in rats with metabolic syndrome. Clin Sci (Lond) 110:665–671Google Scholar
- 188.Ueda Y, Kitakaze M, Komamura K, Minamino T, Asanuma H, Sato H, Kuzuya T, Takeda H, Hori M (1999) Pravastatin restored the infarct size-limiting effect of ischemic preconditioning blunted by hypercholesterolemia in the rabbit model of myocardial infarction. J Am Coll Cardiol 34:2120–2125PubMedGoogle Scholar
- 191.Ernande L, Bergerot C, Rietzschel ER, De Buyzere ML, Thibault H, Pignonblanc PG, Croisille P, Ovize M, Groisne L, Moulin P, Gillebert TC, Derumeaux G (2011) Diastolic dysfunction in patients with type 2 diabetes mellitus: is it really the first marker of diabetic cardiomyopathy? J Am Soc Echocardiogr 24:1268–1275PubMedGoogle Scholar
- 194.Ng ACT, Delgado V, Bertini M, van der Meer RW, Rijzewijk LJ, Hooi Ewe S, Siebelink HM, Smit JW, Diamant M, Romijn JA, de Roos A, Leung DY, Lamb HJ, Bax JJ (2010) Myocardial steatosis and biventricular strain and strain rate imaging in patients with type 2 diabetes mellitus. Circulation 122:2538–2544PubMedGoogle Scholar
- 196.Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP, Duckworth WC, Evans GW, Gerstein HC, Holman RR, Moritz TE, Neal BC, Ninomiya T, Patel AA, Paul SK, Travert F, Woodward M (2009) Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 52:2288–2298PubMedGoogle Scholar
- 197.von Bibra H, Hansen A, Dounis V, Bystedt T, Malmberg K, Rydén L (2004) Augmented metabolic control improves myocardial diastolic function and perfusion in patients with non-insulin dependent diabetes. Heart 90:1483–1484Google Scholar
- 200.Eurich DT, McAlister FA, Blackburn D, Majumdar SR, Tsuyuki RT, Varney J, Johnson JA (2007) Benefits and harms of anti-diabetic agents in patients with diabetes and heart failure: systematic review. Br Med J 335:497–586Google Scholar
- 201.Andersson C, Olesen JB, Hansen PR, Weeke P, Norgaard ML, Jørgensen CH, Lange T, Abildstrøm SZ, Schramm TK, Vaag A, Køber L, Torp-Pedersen C, Gislason GH (2010) Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: a retrospective nationwide cohort study. Diabetologia 53:2546–2553PubMedGoogle Scholar
- 208.van der Meer RW, Rijzewijk LJ, de Jong HW, Lamb HJ, Lubberink M, Romijn JA, Bax JJ, de Roos A, Kamp O, Paulus WJ, Heine RJ, Lammertsma AA, Smit JW, Diamant M (2009) Pioglitazone improves cardiac function and alters myocardial substrate metabolism without affecting cardiac triglyceride accumulation and high-energy phosphate metabolism in patients with well-controlled type 2 diabetes mellitus. Circulation 119:2069–2077PubMedGoogle Scholar
- 210.Rydén L, Armstrong PW, Cleland JG, Horowitz JD, Massie BM, Packer M, Poole-Wilson PA (2000) Efficacy and safety of high-dose lisinopril in chronic heart failure patients at high cardiovascular risk, including those with diabetes mellitus. Results from the ATLAS trial. Eur Heart J 21:1967–1978PubMedGoogle Scholar
- 212.de Boer RA, Doehner W, van der Horst IC, Anker SD, Babalis D, Roughton M, Coats AJ, Flather MD, van Veldhuisen DJ, SENIORS Investigators (2010) Influence of diabetes mellitus and hyperglycemia on prognosis in patients > or =70 years old with heart failure and effects of nebivolol (data from the Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with heart failure [SENIORS]). Am J Cardiol 106:78–86PubMedGoogle Scholar
- 213.Komajda M, Carson PE, Hetzel S, McKelvie R, McMurray J, Ptaszynska A, Zile MR, Demets D, Massie BM (2011) Factors associated with outcome in heart failure with preserved ejection fraction: findings from the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE). Circ Heart Fail 4:27–35PubMedGoogle Scholar
- 214.Borlaug BA, Paulus WJ (2011) Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 2:670–679Google Scholar
- 215.Redfiled MM, Jacobsen SJ, Burnett JC, Mahoney DW, Bailey KR, Rodeheffer RJ (2003) Burden of systolic and diastolic ventricular dysfunction in the community. JAMA 289:194–202Google Scholar