Independent of the severity of coronary artery disease, diabetic patients have an increased risk of developing heart failure. This clinical entity has been considered to be a distinct disease process referred to as ‘diabetic cardiomyopathy’. Experimental studies suggest that extensive metabolic perturbations may underlie both functional and structural alterations of the diabetic myocardium. Translational studies are, however, limited and only partly explain why diabetic patients are at increased risk of cardiomyopathy and heart failure. Although a range of diagnostic methods may help to characterize alterations in cardiac function in general, none are specific for the alterations in diabetes. Treatment paradigms are very much limited to interpretation and translation from the results of interventions in non-diabetic patients with heart failure. This suggests that there is an urgent need to conduct pathogenetic, diagnostic and therapeutic studies specifically in diabetic patients with cardiomyopathy to better understand the factors which initiate and progress diabetic cardiomyopathy and to develop more effective treatments.

INTRODUCTION

The epidemic of obesity and sedentary lifestyle is projected to result in over 300 million people with diabetes mellitus by 2025 [1]. Cardiovascular disease is responsible for 80% of deaths among diabetic patients much of which has been attributed to CAD (coronary artery disease). However, there is an increasing recognition that diabetic patients suffer from an additional cardiac insult termed ‘diabetic cardiomyopathy’. This entity was originally described in 1972 on the basis of observations in four diabetic patients who presented with HF (heart failure) without evidence of hypertension, CAD, valvular or congenital heart disease [2]. The increasing recognition of this additional cardiac insult is supported by data from epidemiological, molecular and more refined diagnostic studies.

EPIDEMIOLOGY

The Framingham study demonstrated the increased incidence of congestive HF in diabetic males (2.4:1) and females (5:1) independent of age, hypertension, obesity, CAD and hyperlipidaemia [3]. Other prospective studies also show that diabetic patients have a significantly increased lifetime risk of developing HF [4], and increased mortality from both Q-wave and non-Q-wave MI (myocardial infarction) [5,6]. This suggests that there is an additional insult to diabetic myocardium which predisposes it to more extensive damage and subsequent failure. Bertoni et al. [7] have shown a link between idiopathic cardiomyopathy and diabetes.

In contrast with the 4–6% prevalence of diabetes in the community, the overrepresentation of diabetic patients in HF trials such as SOLVD (Studies Of Left Ventricular Dysfunction; 26%) [8], ATLAS (Assessment Trial of Lisinopril And Survival; 19%) [9] and V-HeFT II (Vasodilator-Heart Failure Trial II; 20%) [10] attests to the increased prevalence of this condition among diabetic patients.

PATHOLOGY

Fatal and non-fatal CAD is increased 2–4-fold in patients with diabetes [1113], and autopsy studies have shown that diabetic patients have more extensive CAD than non-diabetic patients with CHD (coronary heart disease) [14,15]. Angiographic studies show more severe proximal and distal CAD [1619]. Mortality from CHD is increased 3–7-fold in patients [2022] with diabetes mellitus, and 80% of deaths among diabetic patients are from CHD [23]. Immediate and long-term post-MI mortality is increased 1.5–2-fold among diabetic patients. Furthermore, Type II diabetic patients without a previous MI have as high a risk of MI as non-diabetic patients who have already had an MI [24]. Similarly, the OASIS registry results of patients hospitalized for unstable angina suggested that diabetic patients with no previous cardiovascular disease had the same long-term morbidity and mortality as non-diabetic patients with established CAD [25]. Furthermore, despite a comparable infarct size, diabetic patients have a far greater risk of developing HF post-MI compared with non-diabetic patients [2628]. Following MI, the surviving myocardium of non-diabetic patients becomes hyperkinetic to compensate for non-viable infarcted myocardium in an attempt to maintain cardiac output. However, in diabetic patients, these areas of myocardium cannot achieve this compensatory enhancement in function due to a complex set of intra- and extra-myocardial factors superimposed on an already reduced coronary artery flow reserve [2931]. Furthermore, endomyocardial samples from diabetic patients show enhanced thickening of capillary basement membrane, myocellular atrophy and hypertrophy with myocardial and interstitial fibrosis, which further reduce myocardial function [3234].

DEFINITIONS

Diabetic cardiomyopathy refers to a disease process which affects the myocardium in diabetic patients causing a wide range of structural abnormalities eventually leading to LVH [left ventricular (LV) hypertrophy] and diastolic and systolic dysfunction or a combination of these. The concept of diabetic cardiomyopathy is based upon the idea that diabetes is the factor which leads to changes at the cellular level, leading to structural abnormalities as outlined above. We know that diabetic patients are at increased risk of hypertension and CAD; however, the idea of the existence of a diabetic cardiomyopathy suggests that changes can occur and be detected without the presence of these other factors. Therefore patients with hypertension and CAD may well have myocardial changes related to these disease processes, but a specific cardiomyopathy may also affect the myocardium secondary to diabetes causing a synergistic adverse effect as seen with a combination of diabetes and hypertension [32]. Diabetic cardiomyopathy can be subclinical or apparent depending on the presence of symptoms and signs. There appears to be a long subclinical course in most patients before the development of symptoms.

STRUCTURAL CHANGES

It is important to understand what is meant by LVH and systolic and diastolic dysfunction and the prognostic implications in the context of diabetic cardiomyopathy.

LVH

As LV mass is a continuous variable, the threshold value for LVH is arbitrary; however, LVH is often defined as the upper 5% of the distribution of LV mass in the population. Although there is no clear consensus on the cut-off values used to define LVH, the 2003 ESC (European Society of Cardiology) guidelines proposed that LVH on echocardiography should be defined by an LV mass >125 g/m2 for men and 110 g/m2 for women (Figure 1). Alternatively, the 12-lead ECG remains a useful qualitative screening technique for LVH. Among the most accurate criteria are the QRS voltage duration product [men: (RaVL+SV3)×QRS duration >2440 mm×ms; women: (RaVL+SV3+8)×QRS]. The presence of LVH on the ECG is a poor prognostic indicator as seen by the results of the Framingham study [35]. Similarly, echocardiographic assessment of LVH in 3222 subjects enrolled in the Framingham study showed that the risk-factor-adjusted relative risk of cardiovascular disease was 1.49 for each increment of 50 g/m in LV mass for men and 1.57 for women [35]. The presence of LVH has been linked with increased markers of systemic inflammation [fibrinogen and CRP (C-reactive protein)] and microalbuminuria and, in a study of 1299 Type II diabetic patients, increased albuminuria was a marker of endothelial damage and increased atherothrombotic risk [36].

Parasternal short-axis view in systole (a) and diastole (b) and parasternal long-axis view (c) in a patient with severe concentric LVH

Figure 1
Parasternal short-axis view in systole (a) and diastole (b) and parasternal long-axis view (c) in a patient with severe concentric LVH
Figure 1
Parasternal short-axis view in systole (a) and diastole (b) and parasternal long-axis view (c) in a patient with severe concentric LVH

FUNCTIONAL CHANGES

Systolic dysfunction

The definition of systolic dysfunction is an impairment in the ability of the heart to eject blood; this is different from systolic HF where symptoms and signs of HF are developed secondary to systolic dysfunction. Although the principle hallmark of systolic dysfunction is a depressed LV ejection fraction, recent studies have shown that standard 2D (two-dimensional) echocardiography may actually miss subtle LV dysfunction, since circumferential LV function is assessed and longitudinal function overlooked [37]. In the context of diabetic cardiomyopathy, systolic dysfunction occurs late, often when patients have already developed significant diastolic dysfunction. The prognosis in patients with depressed systolic dysfunction is poor with an annual mortality of 15–20%.

Diastolic dysfunction

Traditionally diastole is defined as the period in the cardiac cycle from the end of aortic ejection until the onset of ventricular tension and development of the succeeding beat [38]. A more accurate definition as described by Brutsaert et al. [39] is that diastole is the time period where the myocardium is no longer generating force and subsequently returns to an unstressed length and force. Diastolic dysfunction occurs when there is prolongation and slowing of this process. Diastolic function can be assessed using cardiac catheterization where LV relaxation rate and timing of diastolic filling can be assessed [40]; however, this is an invasive technique and not without risk. Alternative non-invasive methods include standard echocardiography and tissue Doppler echocardiography. Diastolic function can be defined by examining trans-mitral and trans-pulmonary flow rates [41]. An important limitation in using trans-mitral flow alone as a marker of diastolic dysfunction is related to the rise in left atrial pressure which occurs with diastolic dysfunction, leading to a pseudo-normalization of the mitral inflow pattern. Thus, although there is progressive diastolic dysfunction, the mitral inflow pattern appears normal. Furthermore, it has been shown that diastolic dysfunction is not just a defect in active relaxation, but also in passive stiffness of the left ventricle [42]. Thus diastolic dysfunction alone refers to echocardiographic features of an abnormal LV relaxation pattern without clinical HF. Diastolic HF refers to a clinical syndrome of HF with a preserved LV ejection fraction. Little work has been done to assess the prognosis of asymptomatic isolated diastolic dysfunction, but there is one study [43] which shows that echocardiographic evidence of subclinical contractile dysfunction and diastolic filling abnormalities are both predictive of subsequent CHF (chronic HF). Furthermore, patients with diastolic HF have a significantly increased mortality of 5–8% annually compared with 1% for aged-matched controls [44]. The underlying cause is important with regard to mortality since, if CAD is excluded, then mortality is reduced to 2–3% [45,46]. The outcomes from systolic dysfunction are much worse in terms of mortality but comparable for morbidity [47,48]. In the course of diabetic cardiomyopathy, a spectrum of myocardial abnormalities develop and progress which include LVH and diastolic and systolic dysfunction. It is thus incumbent upon clinicians to identify these abnormalities, since early detection and appropriate treatment can prevent worsening of this condition to overt HF.

MOLECULAR BASIS FOR DIABETIC CARDIOMYOPATHY

Hyperglycaemia, hyperlipidaemia and increased ROS (reactive oxygen species) induce alterations in downstream transcription factors which result in changes in gene expression, myocardial substrate utilization, myocyte growth, endothelial function and myocardial compliance. These effects are summarized in Table 1.

Table 1
Summary of the major molecular abnormalities and their consequence in the pathogenesis of diabetic cardiomyopathy
CauseMechanism
Hyperglycaemia Excess AGE and ROS formation with deactivation of NO, myocardial collagen deposition and fibrosis [4955]. 
Fatty acids Impaired glycolysis, pyruvate oxidation, lactate uptake results in apoptosis [63], and perturbation of myocardial bioenergetics and contraction/relaxation coupling [62,64]. 
PKC Activation of DAG/PKC signal transduction pathway leads to reduction in tissue blood flow, increased vascular permeability, alterations in neovascularization and enhanced extracellular matrix deposition [67]. 
RAS Cardiomyocyte hypertrophy and apoptosis [6971]. 
Aldosterone-induced fibrosis Myofibroblast growth with interstitial and focal perivascular accumulation of collagen. 
HIF-1/VEGF HIF-1α activation via hypoxia/free radicals [84] induces angiopoietin, PGF, PDGF-β and VEGF [85,86] but, in diabetes, VEGF and its receptors, VEGF-R1 and VEGF-R2, are decreased significantly [89], leading to impaired angiogenesis. 
Endothelial dysfunction Impaired endothelial NO production and increased vasoconstrictor prostaglandins, glycated proteins, endothelium adhesion molecules and platelet and vascular growth factors enhance vasomotor tone and vascular permeability and limit growth and remodelling [100102]. 
Arterial stiffness Increased central aortic pressure and left ventricular afterload and lowered central diastolic and coronary perfusion pressures, leading to subendocardial ischaemia and interstitial fibrosis [104106]. 
Autonomic neuropathy Decreased sympathetic/parasympathetic myocardial innervation with impaired coronary resistance vessel vasodilator response and impaired ventricular diastolic filling [107113]. 
CauseMechanism
Hyperglycaemia Excess AGE and ROS formation with deactivation of NO, myocardial collagen deposition and fibrosis [4955]. 
Fatty acids Impaired glycolysis, pyruvate oxidation, lactate uptake results in apoptosis [63], and perturbation of myocardial bioenergetics and contraction/relaxation coupling [62,64]. 
PKC Activation of DAG/PKC signal transduction pathway leads to reduction in tissue blood flow, increased vascular permeability, alterations in neovascularization and enhanced extracellular matrix deposition [67]. 
RAS Cardiomyocyte hypertrophy and apoptosis [6971]. 
Aldosterone-induced fibrosis Myofibroblast growth with interstitial and focal perivascular accumulation of collagen. 
HIF-1/VEGF HIF-1α activation via hypoxia/free radicals [84] induces angiopoietin, PGF, PDGF-β and VEGF [85,86] but, in diabetes, VEGF and its receptors, VEGF-R1 and VEGF-R2, are decreased significantly [89], leading to impaired angiogenesis. 
Endothelial dysfunction Impaired endothelial NO production and increased vasoconstrictor prostaglandins, glycated proteins, endothelium adhesion molecules and platelet and vascular growth factors enhance vasomotor tone and vascular permeability and limit growth and remodelling [100102]. 
Arterial stiffness Increased central aortic pressure and left ventricular afterload and lowered central diastolic and coronary perfusion pressures, leading to subendocardial ischaemia and interstitial fibrosis [104106]. 
Autonomic neuropathy Decreased sympathetic/parasympathetic myocardial innervation with impaired coronary resistance vessel vasodilator response and impaired ventricular diastolic filling [107113]. 

Hyperglycaemia

Hyperglycaemia may mediate its damaging effects through a series of secondary transducers. One of the principle abnormalities is the excess generation of AGEs (advanced glycation end-products), which deactivate NO (nitric oxide) and impair coronary vasodilation. Sustained hyperglycaemia causes excess formation of mitochondrial ROS [49], which affects transcription, leading to contractile dysfunction [50]. An increase in ROS decreases NO levels, which leads to myocardial inflammation and endothelial dysfunction via PARP [poly (ADP-ribose) polymerase]), inhibition of which has been shown to reverse diabetic endothelial dysfunction [51]. The severity of diastolic dysfunction correlates with HbA1c (glycated haemoglobin) levels [52] and the likely cause is AGE-induced [53] formation of ROS, resulting in myocardial collagen deposition and fibrosis [54,55]. Enhanced expression of metallothionein, a potent antioxidant, limits the development of diabetic cardiomyopathy [56], and breaking collagen cross-links improves diastolic function [57,58]. Recently, the process of advanced glycation has been related directly to alterations in myocardial calcium handling and hence contractility [59,60]. SERCA2a (sarcoplasmic/endoplasmic-reticulum Ca2+-ATPase 2a) is responsible for replenishing intracellular calcium stores following release; this results in the termination of contraction thus playing an integral part in cardiac relaxation. SERCA2a is a P-type ATPase that utilizes energy from the hydrolysis of the terminal phosphate bond of ATP to pump calcium against its electrochemical gradient [59,60]. The turnover rate of SERC2a is low, which makes it susceptible to post-translational modification, especially in a chronic condition like diabetes. Thus advanced glycation of SERCA2a has been shown to lead to a decrease in its activity and a prolongation of cardiac relaxation [61].

Fatty acids

Independent of the effects of hyperlipidaemia on coronary artery endothelial function, the increase in and dependence of diabetic myocardium on fatty acid supply results in several major cellular metabolic perturbations. Thus there is increased β-oxidation and mitochondrial accumulation of long-chain acyl carnitines, leading to uncoupling of oxidative phosphorylation [62]. Enhanced fatty acid oxidation decreases glucose and pyruvate utilization by inhibiting pyruvate dehydrogenase. Pyruvate oxidation is reduced further by pdk4 and activated by PPAR (peroxisome-proliferator-activated receptor). The net result is an excess of glycolytic intermediates and increased synthesis of ceramide leading to apoptosis, which can be prevented by the PPAR-α and -γ agonist troglitazone [63].

Thus impaired glycolysis, pyruvate oxidation, lactate uptake and a greater dependence on fatty acids as a source of acetyl CoA leads to a perturbation of myocardial bioenergetics and contraction/relaxation coupling [64]. Classic pharmacotherapy is aimed at restoring the balance between ATP synthesis and breakdown by increasing oxygen delivery (i.e. long-acting nitrates or Ca2+ channel antagonist) or by decreasing cardiac power by reducing blood pressure and heart rate (Ca2+ channel antagonist or β-blocker). An alternative agent which may readdress the altered bioenergetics of diabetic cardiomyopathy is trimetazidine [1-(2,3,4-trimethoxibenzyl)-piperazine], as it partially inhibits myocardial fatty acid oxidation, increases carbohydrate oxidation and reduces lactate production [65]. Recently, in 32 Type II diabetic patients with ischaemic cardiomyopathy randomized to receive either trimetazidine or placebo for 6 months, a beneficial effect was observed on LV volumes and LV ejection fraction [66].

PKC (protein kinase C)

Increased activation of the DAG (diacylglycerol)-activated PKC signal transduction pathway has been identified in vascular tissues from diabetic animals and in vascular cells exposed to elevated glucose [67]. This has been shown to induce many of the changes in diabetic cardiomyopathy which include a reduction in tissue blood flow, enhanced extracellular matrix deposition, capillary basement membrane thickening and increased vascular permeability with alterations in neovascularization. LY333531, a PKCβ isoform-specific inhibitor, has been shown to be efficacious in a number of phase II clinical trials in diabetic retinopathy, nephropathy, neuropathy and cardiac dysfunction. Phase III clinical trials are currently underway for a number of indications, including diabetic cardiomyopathy, and are expected to report in 2006.

RAS (renin–angiotensin system)

The activation of stretch receptors in the heart activates RAS and the SNS (sympathetic nervous system), leading to changes in myocardial structure and remodelling, which impairs cardiac performance. In diabetes an up-regulation of RAS occurs despite minimal changes in myocardial loading [68]. An increased expression of angiotensin II in diabetic rats has been related to cardiomyocyte hypertrophy and apoptosis. IGF-1 (insulin-like growth factor-1) has been shown to down-regulate the binding of p53 DNA, leading to a reduction in the transcription of angiotensinogen and, thereby, angiotensin II, resulting in a reduction in cardiomyocyte apoptosis [69]. Similarly overexpression of the IGF-1 gene down-regulates the RAS system and inhibits the development of diabetic cardiomyopathy [70,71]. These findings provide a molecular platform for the increased benefits of ACE (angiotensin-converting enzyme) inhibition in diabetic patients in preventing and reversing diabetic cardiomyopathy.

Aldosterone-induced fibrosis

Clinical studies which have included small numbers of diabetic patients have demonstrated a reduction in cardiovascular mortality in patients with HF treated with aldosterone antagonists. In the RALES (Randomized Aldactone Evaluation Study) trial, patients with congestive HF treated with spironolactone added to standard therapy (ACE inhibitors, loop diuretics, digoxin, etc.) demonstrated a 30% reduction in mortality [72]. This effect was only significant in patients with elevated serum levels of collagen synthesis markers, suggesting limitation of excessive extracellular matrix turnover as one mechanism contributing to the beneficial effect of spironolactone [72]. It is known that angiotensin II and aldosterone are able to induce cardiac fibrosis, which is characterized by enhanced accumulation of collagen and increased fibroblast proliferation in vivo [7375]. In vitro, angiotensin II and aldosterone increase the synthesis of collagen by human cardiac fibroblasts in a dose-dependent manner [76]. In addition, angiotensin II also stimulates the proliferation of human cardiac fibroblasts [77]. The existence of a local cardiac renin–angiotensin–aldosterone system comprising all components, including enzymes and receptors, has been demonstrated [78]. In addition, local aldosterone production has been demonstrated in the hearts of 2-month-old rats [79] and in the human foetus. Diffuse areas of fibrosis have been described throughout the myocardium as a result of alterations in the microvasculature of the heart in diabetic patients: changes defined as diabetic cardiomyopathy. Analysis of cardiac tissue, at post mortem, from diabetic patients demonstrated interstitial and focal perivascular accumulation of collagen, indicating fibrosis [80]. It has been suggested that aldosterone and glucose mediate cardiac fibrosis through stimulation of myofibroblast growth in patients with a dysregulated renin–angiotensin–aldosterone system especially with concomitant hyperglycaemia [81].

HIF-1 (hypoxia-inducible factor-1)/VEGF (vascular endothelial growth factor)

An inadequate angiogenic response to ischaemia in the myocardium of diabetic patients could result in poor collateral formation and hence an increased propensity to infarction with a reduced reparative response. Normally, vascular cells are quiescent, but are activated by various stimuli, particularly hypoxia, as occurs in ischaemia/infarction. The hypoxic stimulus is mediated chiefly through HIF-1, a transcriptional regulator complex which operates through a specific promoter motif [HRE (hypoxia response element)] present in many gene promoters, including VEGF [82]. Normally rapidly degraded through the proteasome machinery [83], HIF-1α is stabilized by hypoxia and also by free radicals [84] and, thus, becomes transcriptionally active. It controls the expression of multiple angiogenic growth factors, including angiopoietin-1,-2 and -4, PGF (placental growth factor), PDGF-β (platelet-derived growth factor-β) and VEGF [85,86]. Several observations suggest that VEGF may play an important role in the response to cardiac injury. Thus, after MI, the expression of VEGF mRNA is increased markedly in the cardiac myocytes, arteriolar smooth muscle cells and infiltrating macrophages [87]. HIF-1α mRNA is up-regulated in patients with acute ischaemia or early infarction, whereas VEGF transcripts are seen at a later stage in patients with evidence of evolving infarction [88]. In contrast, in diabetes, the expression of mRNA and protein for VEGF and its receptors, VEGF-R1 and VEGF-R2, has been shown to be decreased significantly (40–70%) in the myocardium of both diabetic and insulin-resistant non-diabetic rats, together with a 2-fold reduction in VEGF and VEGF-R2 in ventricles from diabetic patients compared with non-diabetic donors [89]. This suggests that, in diabetic patients, the normal molecular processes which regulate angiogenesis are impaired. Interestingly, TZDs (thiazolidinediones) have been shown to produce a 4-fold increase in circulating VEGF levels in diabetic patients and a 3-fold increase in VEGF mRNA in adipocytes [90]. Given that these compounds are now licensed to improve glycaemic control, they may also form a means of enhancing VEGF in myocardium and hence ‘therapeutic angiogenesis’.

Gene expression

An alteration in gene expression has been observed for a number of key inducer or transducer molecules in diabetic cardiomyopathy. Enhanced myocardial gene expression for muscle carnitine palmitoyltransferase 1–8 and additional novel sequences predicted to play a role in signal conduction has been observed after 6 weeks of moderate hyperglycaemia in STZ (streptozotocin-induced) diabetic rats [91]. Oxidative damage to cardiomyocytes from diabetic animals has recently been attributed to de novo methylation of the p53-inducible p21 (WAF1/CIP1) gene encoding a protein which binds to and inhibits a broad range of cyclin–CDK (cyclin-dependent kinase) complexes [92]. Sarcolemmal membrane abnormalities in Na+/K+ ATPase, Na+/Ca2+ exchange and Ca2+ pump activity have been proposed to lead to an overload of intracellular Ca2+ during the development of diabetic cardiomyopathy. A significant depression of the Na+/K+ ATPase α1-subunit mRNA and an increase in Na+/Ca2+ exchanger mRNA has been observed in the ventricular myocardium of alloxan-induced diabetic rats [93]. A key electrophysiological abnormality in diabetic cardiomyopathy is enhanced arrhythmogenicity, which may be associated with a decrease of repolarizing K+ currents. RNase protection assay and Western blot analysis have demonstrated a reduction in mRNA expression and protein density of key cardiac K+ channel (Kv2.1, Kv4.2, and Kv4.3) genes in LV myocytes within 14 days of Type I diabetes in the rat [94].

Diabetic rats also show an induction of the foetal gene programme [95,96]. This refers to the re-expression of genes which were utilized during foetal life and down-regulated after birth. Members of this group include the contractile proteins βMHC (β-myosin heavy chain), atrial light chain 1 and α-skeletal actin, all of which are increased in cardiac failure and hypertrophy. There is also a down-regulation of αMHC (fast) isoform (contains 3–4 times enzymic activity of βMHC). These changes lead to contractile dysfunction in diabetic animals, resulting in cardiac hypertrophy and atrophy [96]. Thus it appears that diabetes induces the same pattern of gene expression as that seen in failing hearts, which could explain the link between diabetes and HF. It is interesting to note that β-blockers can reverse foetal gene expression [55]. Similarly, etomoxir, an inhibitor of fatty acid metabolism and promoter of glucose metabolism, has been shown to reverse foetal gene expression in animals [97], and a single clinical study in patients with HF showed an improvement in systolic function [98].

Endothelial dysfunction

Endothelial dysfunction is a precursor to and an effect of atherosclerosis. Anatomical and functional abnormalities of the vascular endothelium are commonly associated with diabetes [99]. Both chronic hyperglycaemia and dyslipidaemia are known to contribute to endothelial dysfunction. Hyperglycaemia results in impairment of endothelial cell NO production [100], increased production of vasoconstrictor prostaglandins, glycated proteins, endothelium adhesion molecules and platelet and vascular growth factors, which cumulatively enhance vasomotor tone and vascular permeability, growth and remodelling. Endothelial dysfunction also includes the accelerated disappearance of capillary endothelium [101], weakening of intercellular junctions, altered protein synthesis and altered expression/production of adhesion glycoproteins on endothelial cells promoting attachment of monocytes and leucocytes, as well as their transendothelial migration. Furthermore, hyperglycaemia enhances endothelial cell matrix production, which may contribute to basement membrane thickening [102]. The clinical implications of endothelial dysfunction are not limited to increased atherosclerosis. Endothelial cells also help form collateral circulation, which is reduced in patients with diabetes, and may explain the increased infarct extension and congestive HF after MI in these patients.

Arterial stiffness

It is well known that hypertension and diabetes lead to a rise in arterial stiffness [54,103] through endothelial-dysfunction-mediated fibrosis. Vinereanu et al. [104] demonstrated an association between conduit arterial stiffness and impaired LV function. Their results suggest that subendocardial function of the left ventricle may be depressed in patients with stiff and relatively non-compliant conduit arteries. Reduced compliance of the large arteries modifies the timing of wave reflections and thus is a factor affecting ventricular load. Ventricular ejection creates a forward pressure wave which is then reflected back by the arterial tree as a wave travelling back towards the heart. In patients with increased arterial stiffness, the reflected wave returns early during LV ejection which leads to an increase in central systolic pressure and LV afterload, resulting in decreased central diastolic and coronary perfusion pressures [105]. The net effect of these haemodynamic changes is ischaemia, especially in the subendocardium, which, if chronic, can lead to interstitial fibrosis and the development of HF [106].

Autonomic neuropathy

CAN (cardiac autonomic neuropathy) may contribute to impaired diastolic function and is associated with an increased cardiovascular risk in diabetic patients. Diabetic autonomic neuropathy was associated with an impaired vasodilator response of coronary resistance vessels to increased sympathetic stimulation [107]. Twenty-one percent of patients with Type I diabetes without ischaemic heart disease have abnormal diastolic filling which is associated with the severity of CAN [108]. Similarly ventricular filling abnormalities are most prominent in patients with autonomic neuropathy [109]. Mustonen et al. [110] have shown a correlation between myocardial sympathetic innervation derived from scintigraphy and the E/A ratio (ratio of early to late peak mitral filling wave velocities) in Doppler echocardiography, providing evidence that an abnormal sympathetic innervation of the heart may contribute to a disturbance in LV filling. Sympathetic dysfunction has been related to both systolic and diastolic dysfunction in Type II diabetes [111]. An abnormal systolic blood pressure response to standing was correlated significantly with a reduced mitral E/A ratio. Studies also reflect an association between parasympathetic and cardiac dysfunction as evidenced by the association between significantly lower mean heart rate variation during deep breathing and abnormal diastolic peak filling rate in diabetic patients [112]. The mitral E/A ratio has been shown to be significantly reduced in patients with autonomic neuropathy and a significant correlation was observed between the E/A ratio and autonomic neuropathy [113].

DIAGNOSTIC METHODS

Thus it is clear from the discussion above that a range of molecular changes may underlie the development of diabetic cardiomyopathy. Of clinical relevance is the means by which clinicians diagnose and characterize this problem, perhaps prior to it becoming clinically manifest. This is important as it may allow intervention at a point where significant cardiac dysfunction has not yet ensued.

Echocardiography

Clinically apparent diabetic cardiomyopathy may take several years to develop, but echocardiography can detect significant abnormalities well before the onset of symptomatic HF. There are different types of echocardiography which are used in diagnosing LV dysfunction.

Conventional echocardiography

Early abnormalities are defined by a preserved LV ejection fraction with reduced early diastolic filling, prolongation of isovolumetric relaxation and increased atrial filling, the presence of which confirms diastolic dysfunction (Figure 2). A reduction in LV distensibility is characterized by an increased PEP (pre-ejection period) and shorter LVET (LV ejection time), resulting in an increased PEP/LVET ratio. Such abnormalities have been demonstrated in a group of normotensive diabetic patients without overt microvascular or macrovascular complications [114].

Trans-mitral valve spectral Doppler flow pattern in a normal subject (upper panel), in a patient with mild diastolic dysfunction (abnormal relaxation; middle panel), and in a patient with severe (restrictive) diastolic dysfunction (lower panel)
Figure 2
Trans-mitral valve spectral Doppler flow pattern in a normal subject (upper panel), in a patient with mild diastolic dysfunction (abnormal relaxation; middle panel), and in a patient with severe (restrictive) diastolic dysfunction (lower panel)

In the upper panel, the E/A wave ratio is approx. 1.5 to 1.0, and in the middle panel the E/A wave ratio is <1.0. In the lower panel, the E/A wave ratio is abnormally high and A wave velocity is very low.

Figure 2
Trans-mitral valve spectral Doppler flow pattern in a normal subject (upper panel), in a patient with mild diastolic dysfunction (abnormal relaxation; middle panel), and in a patient with severe (restrictive) diastolic dysfunction (lower panel)

In the upper panel, the E/A wave ratio is approx. 1.5 to 1.0, and in the middle panel the E/A wave ratio is <1.0. In the lower panel, the E/A wave ratio is abnormally high and A wave velocity is very low.

Galderisi et al. [115] found a 22% increase in LV mass in diabetic women and, recently, LVH was demonstrated in one-third of patients with Type II diabetes independent of blood pressure or ACE inhibitor use [116]. Similarly Kimball et al. [117] found increased LV mass and performance in Type I diabetic patients with microalbuminuria. Framingham showed an association between diabetes mellitus and increased LV mass independent of conventional risk factors in women, but not in men [3,4]. A large echocardiography study of American Indians with diabetes found a reduction in LV systolic chamber size and LV function, despite increased LV mass in both sexes [54]. It has been suggested that aortic stiffness may contribute to the development of LVH and diastolic dysfunction in diabetic patients by increasing end-systolic wall stress. Eren et al. [118] also found an association between aortic stiffness and diastolic dysfunction in patients with either hypertension or diabetes or both. Earlier Doppler studies have been criticized for underestimating the degree of diastolic dysfunction since they failed to account for pseudo-normal filling patterns, which have been observed in up to 60% of normotensive diabetic patients. This suggests that up to 50% of patients with diastolic dysfunction could be missed on standard echocardiography. Pseudo-normalized filling patterns can be picked up by asking patients to perform the Valsalva manoeuvre whilst assessing trans-mitral and pulmonary Doppler signals [119,120]. Therefore echocardiography is a useful non-invasive tool to assess for the presence of LVH and systolic and diastolic dysfunction and can provide prognostic information in diabetic patients suspected of having cardiomyopathy.

Tissue Doppler echocardiography

In standard echocardiography, a high-velocity low-amplitude filter looks solely at blood flow through the heart to define valvular function. Newer technologies such as TDI (tissue Doppler echocardiographic imaging) look promising as they apply a high-velocity low-amplitude filter to the myocardium enabling an assessment of myocardial tissue velocities. The advantage over standard Doppler echocardiography is that the results are independent of changes in pre-load. This provides a particularly useful tool for defining subtle systolic and diastolic dysfunction. In a recent study, although there was a significant reduction in resting Sm (peak myocardial systolic velocity) and Em (early diastolic velocity) in diabetic patients, the response to dobutamine stress did not differ from control subjects, suggesting that ischaemia due to small-vessel disease may not be important in early diabetic heart muscle disease [121]. TDI also quantifies both longitudinal and circumferential cardiac contraction. Longitudinal (long-axis) contraction of the left ventricle is dependent on the integrity of longitudinal subendocardial myocardial fibres, whereas radial (short-axis) contraction depends on integrity of the circumferential fibres. The former is more susceptible to ischaemia and fibrosis which may result in a relative increase in short-axis velocity compared with a decrease in long-axis function due to compensatory ventricular remodelling. Thus, in 53 patients with diabetes but no LV hypertrophy, normal ejection fraction and no ischaemia on dobutamine echocardiography, radial contractility was increased and appeared to compensate for reduced longitudinal contractility [122]. In a recent study of 35 patients with Type II diabetes, the presence of regional systolic abnormalities in patients with an apparently normal ejection fraction questions the concept of isolated diastolic dysfunction [123].

TDI does not differentiate between active contraction and passive movement of a myocardial segment. Thus rotation and translation movements of the whole heart, as well as active contraction of segments adjacent to the analysed segment, may affect the determined velocity. Strain and strain rate echocardiography is a technique for assessing myocardial systolic and diastolic function. This modality has improved the quantitative assessment of regional wall motion and the accuracy and reproducibility of test readings. Myocardial strain and strain rate can detect inducible ischaemia and at earlier stages than visual estimation of wall motion or wall thickening parameters. Changes in systolic strain rate and strain have the potential to discriminate between different myocardial viability states. Measurement of the diastolic rate of deformation can differentiate physiological from pathological hypertrophy and restrictive from constrictive cardiomyopathy. Strain rate assessment has also been implemented in 3D (three-dimensional) echocardiography with promising results [124].

Doppler acoustics

Fibrosis alters the acoustic properties of the heart in animals and humans, and the magnitude of cyclic variation of myocardial ultrasound integrated backscatter and its phase delay with respect to the onset of the cardiac cycle can be quantified via defining alteration in Doppler acoustics. In 54 diabetic patients with normal ventricular systolic function, the cyclic variation of backscatter in the septum and posterior wall of the left ventricle was significantly reduced and was related to the presence of neuropathy, retinopathy and nephropathy [125]. This technique has evolved in the form of video-densitometry which uses Doppler echocardiography to digitize images of the septum and posterior wall of the left ventricle and estimates the percentage CVI (cyclic variation index). Subjects with high LV masses and concentric hypertrophy demonstrate an increased CVI [126]. This has not yet been applied to diabetic patients.

Intravenous contrast echocardiography

During the last decade, the use of contrast echocardiography has gained considerable interest because it provides a non-invasive means of assessing integrity of the coronary microcirculation and myocardial perfusion as well as improving assessment of LV function. Contrast echocardiography relies on resonance of microbubble contrast agents when excited by diagnostic ultrasound frequencies, thus producing an increased ultrasound backscatter from the blood [127,128] (Figure 3). These agents are used to enhance visualization of the blood–endocardial interface to assess myocardial perfusion. Furthermore, the proper delineation of the endocardial border observed after contrast administration increases the clarity of the images and improves the results provided by the algorithms orientated to the assessment of ventricular motion [129].

Contrast echocardiographic sequence with microbubble contrast agent defining myocardial perfusion within different myocardial segments
Figure 3
Contrast echocardiographic sequence with microbubble contrast agent defining myocardial perfusion within different myocardial segments

Frame i) is immediately following a high power ultrasound flash which destroys the micro-bubbles within the myocardium. Frames ii)–iv) show replenishment of micro-bubbles in the septum and lateral walls within 2 heartbeats. A clear apical perfusion defect (A) is demonstrated which persists.

Figure 3
Contrast echocardiographic sequence with microbubble contrast agent defining myocardial perfusion within different myocardial segments

Frame i) is immediately following a high power ultrasound flash which destroys the micro-bubbles within the myocardium. Frames ii)–iv) show replenishment of micro-bubbles in the septum and lateral walls within 2 heartbeats. A clear apical perfusion defect (A) is demonstrated which persists.

Direct assessment of myocardial blood flow and flow reserve is possible, as microbubble contrast agents remain entirely within the intravascular space and their presence in any myocardial segment denotes the status of microvascular perfusion within that region [130,131]. In a study by Senior and Swinburn [132], the sensitivity and negative predictive value of dobutamine echocardiography for the prediction of recovery of dysynergistic segments improved significantly from 59% to 79% and 88% to 95% when contrast opacification was observed in the dobutamine non-response segments. Thus contrast LV opacification studies allow more accurate measurements of LV size and mass, and myocardial contrast echocardiography provides an alternative non-invasive assessment of CAD.

3D Echocardiography

Conventional 2D echocardiography only provides partial information about cardiac function. Although multiple studies have validated the superiority of 3D over 2D echocardiography to assess LV function, 3D methods have not been embraced in clinical practice because of the cumbersome methodology used until recently for data acquisition and analysis. In contrast with 2D echocardiography, 3D echocardiography does not rely on geometric assumptions to calculate LV volumes. This constitutes a real advantage in ventricles with odd shapes, wall motion abnormalities and in patients with cardiomyopathy. Similarly, the unique shape of the right ventricle has precluded accurate quantification using traditional echocardiography. Transthoracic 3D echocardiography has the potential to overcome these limitations resulting in precise measurements of right ventricular size and function [133,134]. Real-time 3D echocardiography is based on the design of an ultrasound transducer with a matrix array that instantaneously acquires the image contained in a pyramidal volume. The concurrent display of multiple tomographic images allows the anatomically correct examination of any structure contained within the volumetric image. The development of new software and the use of high-performance computers now allows rapid mapping of the volumetric image, and it is possible to simultaneously visualize multiple superimposed planes in an interactive manner. Real-time 3D echocardiography is being used in conjunction with strain rates to evaluate further both regional LV systolic dysfunction and diastolic dysfunction. An area where it looks especially promising is in predicting the response to biventricular pacing in patients with HF and interventricular conduction delay [135].

CT (computed tomography)

The CAC (coronary artery calcification) score, derived originally from electron-beam CT but more recently from multi-slice CT, has been shown to correlate strongly with the presence and severity of histological and angiographic evidence of coronary atherosclerosis and conventional CHD risk factors, in particular CRP, reflecting stable and unstable plaques [136]. In 10377 asymptomatic patients, coronary calcium has been shown to provide independent incremental information in addition to traditional risk factors in the prediction of all-cause mortality [137]. Of 101 patients aged 17–28 years with Type I diabetes and duration of diabetes over 5 years, 10.9% demonstrated CAC [138]. Similarly CAC was significantly increased in asymptomatic patients with Type II diabetes compared with non-diabetic subjects [139]. Although the CAC score correlates well with CAD, there are no studies to date which show an association with diabetic cardiomyopathy.

MRI (magnetic resonance imaging)

MFR (myocardial flow reserve) is not routinely assessed in MPI (myocardial perfusion imaging) studies, but it has been hypothesized to affect test accuracy when assessing disease severity by coronary vessel lumenography. MRI is an emerging diagnostic technique that can both perform MPI and assess MFR [140]. Furthermore, MRI is also a very useful tool to assess diastolic function accurately without the drawbacks observed with echocardiographic assessment of diastolic function [141].

SPECT (single photon emission CT)

Quantitative myocardial perfusion SPECT has advanced significantly over the last few years providing a competitive advantage to nuclear cardiology compared with other higher-resolution non-invasive imaging modalities for the detection of CAD. In particular, gating has provided both perfusion and functional information and attenuation correction SPECT has improved perfusion information [142,143].

TREATMENT

Glycaemic control

Poor glycaemic control has been associated with an increased risk of cardiovascular mortality, with an increase of 11% for every 1% rise in HbA1c levels [144], and a recent study has shown a link between HbA1c and HF [52]. Thus it has been assumed that improving glycaemic control should have a beneficial effect on cardiovascular morbidity and mortality and that achieving this should be the raison d'etre of every diabetologist. However, the UKPDS (UK Prospective Diabetes Study) failed to show a significant benefit of intensive blood glucose control using either sulphonylureas or insulin on the risk of developing macrovascular disease in patients with Type II diabetes [145].

It is important to note that there were significant methodological limitations in the UKPDS which merit consideration when interpreting the results [146]. These include that the study was unblinded and continued when no difference was observed at the initial agreed time point for analysis, patients in the diet-only group actually received drug treatment if the fasting plasma glucose was >15 mmol/l, and at 9 years only 25% of patients were on monotherapy; however, significant benefits were observed in the subgroup of overweight patients treated with metformin, including diabetes-related mortality (42%), all-cause mortality (36%) and MI (39%). Again these data should be interpreted with caution as they are derived from a highly selected subgroup (patients with overt cardiovascular disease were excluded) of only 753 (342 on metformin compared with 411 on diet only) overweight (>120% ideal body weight) patients. These data have, however, laid to rest the concerns raised by the findings of the NIH (National Institutes of Health)-funded UGDP (University Group Diabetes Program) study which had reported increased cardiovascular mortality with the sulphonylurea, tolbutamide [147]. The clinical relevance of this observation is based on the mechanism of action of sulphonylureas which close K+ ATP channels in β cells to augment insulin release. Paradoxically, they also do this in cardiomyocytes and vascular smooth muscle cells which, at least theoretically, may have a detrimental impact on ischaemic preconditioning and vasodilatation.

In DCCT (Diabetes Control and Complications Trial), 1441 Type I diabetic patients were randomly assigned to conventional or intensive glycaemic control over 6.5 years. The number of combined major macrovascular events was 40 in the conventionally treated group compared with 23 in the intensive-treatment group, but the difference was not statistically significant, despite improvements in the lipid profile [148].

β-Blockers

Chronic stimulation of the SNS leads to increased heart rate and altered gene expression, resulting in cardiac remodelling in both HF [149] and diabetes [150]. Traditionally, there has been a reluctance to use β-blockers in patients with diabetes for fear of adverse effects on insulin resistance and an unawareness of hypoglycaemia. However, with the recent advances in the understanding of HF and the realization of the importance of the SNS in the release of vasoactive substances, they have become an essential treatment for HF [151]. Thus β-blockers have been shown to prevent and even reverse cardiac remodelling, resulting in improved LV function and a reduction in mortality [151]. Earlier studies of β-blockers recruited patients with advanced HF and, although LV function improved, mortality did not [152,153]. However, CIBIS-II (Cardiac Insufficiency Bisoprolol Study II) and MERIT-HF (Metoprolol Controlled-release Randomised Intervention Trial in Heart Failure) enrolled patients with mild-to-moderate HF and showed significant reductions in mortality of 32% and 34% respectively [154,155]. Carvedilol, a third generation β-blocker which antagonizes both α and β receptors, has been shown to have a highly significant effect on both morbidity and mortality (67% reduction) [156]. In a more recent trial, the COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival) study group showed a significant reduction in mortality in patients with severe HF treated with carvedilol [157]. There has only been one large retrospective study which assessed the benefits of bucindol in diabetic patients with HF. Patients with ischaemic cardiomyopathy had a worse prognosis compared with patients without ischaemic aetiology [158] and both diabetic and non-diabetic patients benefited from β-blockade [158]. A metaanalysis of the six main β-blocker HF trials [CIBIS-II, BEST (β-Blocker Evaluation of Survival Trial), ANZ (Australia and New Zealand)-Carvedilol, Carvedilol U.S. Trials, COPERNICUS and MERIT-HF] [159] has subgroup data available which has enabled analysis of the diabetic cohort. Of 13129 patients with chronic HF, 24.6% had diabetes. The results showed that the presence of diabetes was associated with a significant increase in mortality compared with subjects without diabetes mellitus among all patients studied {pooled RR (relative risk), 1.25; 95% CI (confidence interval), 1.15–1.36; P<0.001 [146]}. In the placebo group only, the RR for mortality in patients with diabetes mellitus was 1.19 (95% CI, 1.06–1.33; P<0.002). Similarly, in patients receiving β-blockers in these studies, there was an increase in mortality among diabetic patients (RR, 1.33; 95% CI, 1.17–1.51; P<0.001) for all patients studied. The pooled RR of mortality in patients with diabetes mellitus and CHF on β-blocker treatment compared with placebo was 0.84 (95% CI, 0.73–0.96; P<0.011). However, the relative risk reduction in non-diabetic patients on β-blockers compared with placebo was much greater (RR, 0.72; 95% CI, 0.65–0.79; P<0.001).

In summary, β-blockers should be given to all diabetic patients with any evidence of HF, unless specifically contra-indicated. This will result in an RR reduction in mortality; however, the effect is not as pronounced as the introduction of β-blockers in non-diabetic patients, but both groups derive significant prognostic benefit.

ACE inhibitors

ACE inhibitors form the cornerstone for treatment of HF. The captopril multi-centre study demonstrated a significant improvement in exercise capacity and symptoms of HF without an effect on mortality [160]. The CONSENSUS study group was the first to show a significant reduction in mortality with enalapril in patients with severe HF [161]. The SOLV-D investigators confirmed these findings [162] and also showed that enalapril was able to prevent onset of new HF [163]. A number of post-MI trials have shown a reduction in mortality and morbidity with ACE inhibitors compared with placebo [164166]. Significant benefits were obtained for both cardiovascular morbidity and mortality in the HOPE (Heart Outcomes Prevention Evaluation) study with ramipril in 9297 high-risk patients [167], but this benefit was even more impressive in the diabetic patients [168] (Table 2). Furthermore, HOPE demonstrated a 33% reduction in the rate of development of new HF [169] and a 44% reduction in the risk of developing Type II diabetes [170].

Table 2
Cardiovascular morbidity and mortality in the HOPE study, illustrating a greater benefit in the diabetic patients
All patientsDiabetic patients
Death from cardiovascular causes 26% 37% 
MI 20% 22% 
Stroke 32% 33% 
All-cause mortality 16% 24% 
Revascularization 15% 17% 
All patientsDiabetic patients
Death from cardiovascular causes 26% 37% 
MI 20% 22% 
Stroke 32% 33% 
All-cause mortality 16% 24% 
Revascularization 15% 17% 

Angiotensin II receptor antagonists

Angiotensin II is considered to be a major player in the development of cardiac dysfunction. The ELITE (Evaluation of Losartan in the Elderly) study compared losartan with captopril in elderly patients with HF and found losartan to be as safe as captopril with a lower secondary end point of combined mortality from hospital admission for HF [171]. However, although the ELITE II study confirmed better tolerability of losartan over captopril, it did show a slightly higher mortality [172]. ARBs (angiotensin II type 1 receptor blockers) have been proposed to have additive effects on haemodynamic measurements, neurohumoral activity and LV remodelling when added to ACE inhibitors in patients with chronic HF. Val-HeFT (Valsartan Heart Failure Trial) was the first study designed to measure morbidity and mortality in patients with HF compared with conventional therapy and as add-on therapy to conventional treatment [173]. Although a benefit was observed in patients not taking ACE inhibitors, an increase in mortality was observed in patients on ACE inhibitors and β-blockers [173]. In the OPTIMAAL (Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan) study, losartan was shown to be slightly less effective than captopril in post-MI patients [174]. The more recent VALIANT (Valsartan in Acute Myocardial Infarction Trial) assessed the use of a combination of ACE inhibitors and the ARB valsartan post-MI, and found no extra benefit in mortality but with a greater number of adverse reactions [175]. This was in contrast with the lack of further benefit observed in Val-HeFT [173] and, more recently, the CHARM (Candesartan in Heart Failure to Affect Reduction in Morbidity and Mortality)-Added trial [176]. Again, candesartan reduced the risk of developing Type II diabetes [176].

Ca2+ channel antagonists

An early animal study demonstrated an improvement in diabetic cardiomyopathy with verapamil [177]; however, trials of verapamil, diltiazem and nifedipine have shown a detrimental effect in HF [178]. Amlodipine and felodipine were investigated in the PRAISE (Prospective Randomized Amlodipine Survival Evaluation) [179] and Val-HeFT III [180] trials respectively, and no significant benefit was observed over conventional treatment. A short-term improvement in ejection fraction was observed with felodipine, but this was not sustained at long-term follow-up. With amlodipine there was a reduction of combined fatal and non-fatal events and decreased risk of death in the non-ischaemic subgroup but, in view of the small numbers of patients, a further study is currently underway (PRAISE II).

Statins (hydroxymethylglutaryl CoA reductase inhibitors)

The ability of statins to lower serum cholesterol and reduce CHD end points has confirmed portions of the lipid hypothesis. However, the time to benefit and increased benefit in overlapping populations, in particular diabetic patients, have suggested that they induce pleiotropic effects. Thus, in addition to the direct effect on cholesterol metabolism, they may have a range of additional benefits, including inhibiting isoprenoid intermediates, modifying GTP-binding proteins such as Rho, augmenting collateral blood flow downstream of activated plaques, enhancing endothelial cell NO synthase activity, preventing AGE-induced NF-κB (nuclear factor κB)-induced protein-1 activation and preventing the up-regulation of VEGF mRNA [181,182]. The landmark 4S (Scandinavian Simvastatin Survival Study) demonstrated a significant reduction in CHD events following intervention with simvastatin, and firmly established the role of these drugs in the secondary prevention of CHD [183]. Moreover, recent analyses of the placebo data from 4S and AFCAPS/TexCAPS (Air Force/Texas Coronary Atherosclerosis Prevention Study) have demonstrated a 1.5- and 1.4-fold increased long-term relative risk of major coronary events in patients who have metabolic syndrome [184]. Thus it is not surprising that even greater benefits have been observed in patients with impaired glucose tolerance and diabetes [185]. In the HPS (Heart Protection Study), among the 5963 diabetic patients there was a 22% reduction in the vascular event rate. Furthermore, among the 2912 diabetic participants who did not have any diagnosed occlusive arterial disease the reduction in event rate was 33%. Alarmingly, it was 27% among the 2426 diabetic patients who had pretreatment LDL (low-density lipoprotein)-cholesterol concentrations below 3.0 mmol/l [186]. This therefore argues for treating all Type II diabetic patients with a statin independent of their LDL levels. One can also envisage eventual clinical paradigms of the use of higher doses of statins to enhance pleiotropic effects and treatment, even when lipid markers are within guidelines.

Although statins have shown highly significant benefits in patients with CHD, there has been little data on the effect of statin therapy in HF. However, results of a recently published study do provide support for the use of statins in non-ischaemic HF. Mozaffarian et al. [187] investigated whether statin therapy was associated with decreased mortality among patients with severe HF enrolled in the PRAISE study, the primary results of which have been published previously [177]. Even following adjustment for age, gender, smoking, HF aetiology, diabetes, NYHA (New York Heart Association) class and ejection fraction, statin therapy was associated with a 62% lower risk of death (RR 0.38; 95% CI, 0.23–0.65). Recently, 551 patients with advanced HF of varying aetiologies (45% with ischaemic HF, 25% with idiopathic HF and 30% with valvular, alcoholic and peripartum HF) were enrolled in an intervention trial with a statin. A proportion (45%) of the cohort were already on a statin, including 73% and 22% of ischaemic and non-ischaemic HF patients respectively. Statin therapy was associated with significantly improved survival free from urgent transplantation (84% in the statin group and 70% in patients not on statins after 1 year). Decreased mortality has been observed in mice and rats treated with statins following the induction of LV dysfunction after coronary artery ligation [188,189]. Trials (CORONA; Controlled Rosuvastatin Multinational Study in Heart Failure) are currently underway to assess the efficacy of statins in HF. The recent analysis of the PRAISE data has demonstrated the safety and efficacy of statin therapy in patients with moderate-to-severe HF [190]. There is a significant reduction in mortality in patients with a non-ischaemic HF, adding further support to the additional effects of statins beyond their reduction in cholesterol and prevention of progression of CAD [190]. There is a need for a large randomized, blinded, placebo-controlled trial to evaluate further the benefits in patients with HF.

TZDs

TZDs are a new class of compounds for treating patients with Type II diabetes mellitus, which act by increasing insulin sensitivity in skeletal muscle and adipose tissue through binding and activation of PPAR-δ, a nuclear receptor that has a regulatory role in differentiation of cells. Additionally they also act on PPAR-α and increase serum HDL (high-density lipoprotein)-cholesterol, decrease serum triacylglycerols (triglycerides) and increase LDL-cholesterol levels marginally (pioglitazone to a lesser extent) [191]. To generate sufficient energy to sustain cardiac contractility, myocardial metabolism utilizes a range of substrates including NEFAs (non-esterified fatty acids), glucose and lactate. However, in Type II diabetes, as a consequence of insulin resistance, glucose is under-utilized and NEFA metabolism, is increased impairing contractility. The TZDs, apart from insulin-sensitizing fat and skeletal muscle, increase the expression and function of glucose transporters in the heart, leading to improved glucose metabolism, and reduce NEFA utilization by the myocardium [192]. The consequences of this are that they protect against myocardial injury associated with ischaemia and improve recovery of function following ischaemia. However, caution should be taken in extrapolating these principally experimental findings to patients with diabetic cardiomyopathy as there are concerns regarding the use of the TZDs in patients with HF [193]. Clinical trials with both rosiglitazone and pioglitazone are currently underway in diabetic patients with HF and are expected to report in 2007.

NEW THERAPEUTIC DIRECTIONS

PARP inhibitors

PARP-1 is a member of the PARP enzyme family and is one of the most abundant nuclear proteins which functions as a DNA-nick-sensor enzyme [194]. Recently in endothelial cells, hyperglycaemia-induced overproduction of mitochondrial superoxide has been shown to cause DNA strand breaks, leading to an activation of PARP which inhibits GAPDH (glyceraldehyde-3-phosphate dehydrogenase). This leads to the accumulation of glucose and other glycolytic intermediates prior to their entry into the Krebs cycle. These intermediaries activate a number of major transducers of hyperglycaemic damage (polyol pathway, AGE formation and PKCβ activation) [195]. In addition to the direct cytotoxic pathway regulated by DNA injury and PARP activation, PARP also modulates the course of cardiovascular inflammation and injury by regulating the activation of NF-κB [194] and inducing over-expression of ET (endothelin)-1 and ET receptors [196]. Blocking PARP activity with two different competitive PARP inhibitors provides a ‘magic bullet’ approach as it blocks activation of all the major pathways thought to mediate tissue damage in diabetes [195]. Thus far, PARP activation has been shown to occur in subjects at risk of developing diabetes as well as in those with Type II diabetes. Furthermore, it has been associated with impaired reactivity in the skin microcirculation of these subjects [197].

CONCLUSIONS

There is a large body of evidence to suggest that diabetic patients are prone to significant perturbations at the cellular level causing functional and structural abnormalities in the myocardium, leading to ‘diabetic cardiomyopathy’. There remains considerable controversy over which are the most relevant cellular and molecular mechanisms underlying this process. In particular, there is a sparsity of clinical/translational studies in diabetic cardiomyopathy. The lack of consensus as to how best to diagnose and monitor this condition limits our understanding of the clinical and physiological characteristics of this condition. Furthermore, clinical trials have only enrolled limited numbers of patients with diabetic cardiomyopathy and much of our clinical practice is based on limited subanalyses. However, the future holds promise, especially from data currently being generated from detailed molecular studies in tissue-specific knockout and transgenic models of cardiomyopathy. These and other more clinically relevant translational studies may help to unravel the mechanisms behind diabetic cardiomyopathy. In so doing this offers a means to provide more precise therapeutics which, together with more advanced diagnostics, may allow effective intervention at much earlier stages of the disease.

Abbreviations

     
  • 2D

    two-dimensional

  •  
  • 3D

    three-dimensional

  •  
  • AGE

    advanced glycation end-product

  •  
  • ACE

    angiotensin-converting enzyme

  •  
  • ARB

    angiotensin II type 1 receptor blocker

  •  
  • CAC

    coronary artery calcification

  •  
  • CAD

    coronary artery disease

  •  
  • CAN

    cardiac autonomic neuropathy

  •  
  • CHD

    coronary heart disease

  •  
  • CI

    confidence interval

  •  
  • CRP

    C-reactive protein

  •  
  • CT

    computed tomography

  •  
  • CVI

    cyclic variation index

  •  
  • E/A ratio

    ratio of early to late peak mitral filling wave velocities

  •  
  • ET

    endothelin

  •  
  • HbA1c

    glycated haemoglobin

  •  
  • HF

    heart failure

  •  
  • HIF-1

    hypoxia-inducible factor-1

  •  
  • IGF-1

    insulin-like growth factor-1

  •  
  • LDL

    low-density lipoprotein

  •  
  • LV

    left ventricular

  •  
  • LVET

    LV ejection time

  •  
  • LVH

    LV hypertrophy

  •  
  • MFR

    myocardial flow reserve

  •  
  • MHC

    myosin heavy chain

  •  
  • MI

    myocardial infarction

  •  
  • MPI

    myocardial perfusion imaging

  •  
  • MRI

    magnetic resonance imaging

  •  
  • NEFA

    non-esterified fatty acid

  •  
  • NF-κB

    nuclear factor κB

  •  
  • NO

    nitric oxide

  •  
  • PEP

    pre-ejection period

  •  
  • PKC

    protein kinase C

  •  
  • PARP

    poly(ADP-ribose) polymerase

  •  
  • PPAR

    peroxisome-proliferator-activated receptor

  •  
  • RAS

    renin–angiotensin system

  •  
  • ROS

    reactive oxygen species

  •  
  • RR

    relative risk

  •  
  • SERCA2a

    sarcoplasmic/endoplasmic-reticulum Ca2+-ATPase 2a

  •  
  • SPECT

    single photon emission CT

  •  
  • statin

    hydroxymethylglutaryl CoA reductase inhibitor

  •  
  • SNS

    sympathetic nervous system

  •  
  • TDI

    tissue Doppler echocardiographic imaging

  •  
  • TZD

    thiazolidinedione

  •  
  • VEGF

    vascular endothelial growth factor

References

References
1
King
 
H.
Aubert
 
R. E.
Herman
 
W. H.
 
Global burden of diabetes 1995–2025: prevalence, numerical estimates, and projections
Diabetes Care
1998
, vol. 
21
 (pg. 
1414
-
1431
)
2
Rubler
 
S.
Dlugash
 
J.
Yuceoglu
 
Y. Z.
Kumral
 
T.
Branwood
 
A. W.
Grishman
 
A.
 
New type of cardiomyopathy associated with diabetic glomerulosclerosis
Am. J. Cardiol.
1972
, vol. 
30
 (pg. 
595
-
602
)
3
Kannel
 
W. B.
Hjortland
 
M.
Castelli
 
W. P.
 
Role of diabetes in congestive heart failure: The Framingham Study
Am. J. Cardiol.
1976
, vol. 
34
 (pg. 
29
-
34
)
4
Kannel
 
W. B.
McGee
 
D. L.
 
Diabetes and glucose intolerance as risk factors for cardiovascular disease: The Framingham Study
Diabetes Care
1979
, vol. 
2
 (pg. 
120
-
126
)
5
Malmberg
 
K.
Ryden
 
L.
 
Myocardial infarction in patients with diabetes mellitus
Eur. Heart J.
1988
, vol. 
9
 (pg. 
256
-
264
)
6
Herlitz
 
J.
Malmberg
 
K.
Karlsson
 
B.
Ryden
 
L.
Hjalmarson
 
A.
 
Mortality and morbidity during a five year follow up of diabetics with myocardial infarction
Acta Med. Scand.
1988
, vol. 
24
 (pg. 
31
-
38
)
7
Bertoni
 
A. G.
Tsai
 
A.
Kasper
 
E. K.
Brancati
 
F. L.
 
Diabetes and idiopathic cardiomyopathy
Diabetes Care
2003
, vol. 
26
 (pg. 
2791
-
2795
)
8
Shindler
 
D. M.
Kostis
 
J. B.
Yusuf
 
S.
, et al 
Diabetes Mellitus, a predictor of morbidity and mortality in the studies of the left ventricular dysfunction (SOLVD) trials and registry
Am. J. Cardiol.
1996
, vol. 
77
 (pg. 
1017
-
1020
)
9
Ryden
 
L.
Armstrong
 
P. W.
Cleland
 
J. G.
, et al 
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.
2000
, vol. 
21
 (pg. 
1967
-
1978
)
10
Cohn
 
J. N.
Johnson
 
G.
Ziesche
 
S.
, et al 
A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure
N. Engl. J. Med.
1991
, vol. 
325
 (pg. 
303
-
310
)
11
Reaven
 
G.
 
Role of insulin resistance in human disease
Diabetes.
1987
, vol. 
37
 (pg. 
1595
-
1607
)
12
Barratt-Connor
 
E.
Ferrara
 
A.
 
Isolated post challenge hyperglycaemia and the risk of fatal cardiovascular disease in older women and men. The Rancho Bernardo Study
Diabetes Care
1998
, vol. 
21
 (pg. 
1236
-
1239
)
13
Lowe
 
L. P.
Liu
 
K.
Greenland
 
P.
Metzger
 
B. E.
Dyer
 
A. R.
Stamler
 
J.
 
Diabetes, asymptomatic hyperglycaemia, and 22-year mortality in black and white men. The Chicago Heart Association Detection Project in Industry Study
Diabetes Care
1997
, vol. 
20
 (pg. 
163
-
169
)
14
Barzilay
 
J. I.
Kronmal
 
R. A.
Bittner
 
V.
Eaker
 
E.
Evans
 
C.
Foster
 
E. D.
 
Coronary artery disease and coronary artery bypass grafting in diabetic patients aged >65 years (report from coronary artery surgery study [CASS] registry)
Am. J. Cardiol.
1994
, vol. 
74
 (pg. 
334
-
339
)
15
Waller
 
B. F.
Palumbo
 
P. J.
Lie
 
J. T.
Roberts
 
W. C.
 
Status of the coronary arteries at necropsy in diabetes mellitus with onset after age 30 years. Analysis of 229 diabetic patients with and without evidence of coronary heart disease and comparison to 183 control subjects
Am. J. Med.
1980
, vol. 
69
 (pg. 
498
-
506
)
16
Granger
 
C. B.
Califf
 
R. M.
Young
 
S.
, et al 
Outcome of patients with diabetes mellitus and acute myocardial infarction treated with thrombolytic agents. The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group
J. Am. Coll. Cardiol.
1993
, vol. 
21
 (pg. 
920
-
925
)
17
Mueller
 
H. S.
Cohen
 
L. S.
Braunwald
 
E.
, et al 
Predictors of early mortality and morbidity after thrombolytic therapy of acute myocardial infarction. Analyses of patient subgroups in the Thrombolysis in Myocardial Infarction (TIMI) trial, phase II
Circulation
1992
, vol. 
85
 (pg. 
1254
-
1264
)
18
Stein
 
B.
Weintraub
 
W. S.
Gebhart
 
S. P.
, et al 
Influence of diabetes mellitus on early and late outcome after percutaneous transluminal coronary angioplasty
Circulation
1995
, vol. 
91
 (pg. 
979
-
989
)
19
Vigorito
 
C.
Betocchi
 
S.
Bonzani
 
G.
, et al 
Severity of coronary artery disease in patients with diabetes mellitus. Angiographic study of 34 diabetics and 120 nondiabetic patients
Am. Heart J.
1980
, vol. 
100
 (pg. 
782
-
787
)
20
Pekkanen
 
J.
Linn
 
S.
Heiss
 
G.
, et al 
Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without pre-existing cardiovascular disease
N. Engl. J. Med.
1990
, vol. 
322
 (pg. 
1700
-
1707
)
21
Rosengren
 
A.
Hagman
 
M.
Wedel
 
H.
Wilhelmsen
 
L.
 
Serum cholesterol and long-term prognosis in middle-aged men with myocardial infarction and angina pectoris: a 16-year follow-up of the Primary Prevention Study in Goteborg, Sweden
Eur. Heart J.
1997
, vol. 
18
 (pg. 
754
-
761
)
22
Rosengren
 
A.
Welin
 
L.
Tsipogianni
 
A.
Wilheimsen
 
L.
 
Impact of cardiovascular risk factors on coronary heart disease and mortality among middle-aged diabetic men: a general population study
Br. Med. J.
1989
, vol. 
299
 (pg. 
1127
-
1131
)
23
Consensus statement
Role of cardiovascular risk factors in prevention and treatment of macrovascular disease in diabetes. American Diabetes Association
Diabetes Care
1993
, vol. 
16
 (pg. 
72
-
78
)
24
Haffner
 
S. M.
Lehto
 
S.
Ronnemaa
 
T.
Pyorala
 
K.
Laakso
 
M.
 
Mortality from coronary heart disease in subjects with type 2 diabetes and in non-diabetic subjects with and without prior myocardial infarction
N. Engl. J. Med.
1998
, vol. 
339
 (pg. 
229
-
234
)
25
Malmberg
 
K.
Yusuf
 
S.
Gerstein
 
H.
, et al 
Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction. Results of the OASIS (Organisation to Assess Strategies for Ischaemic Syndromes) registry
Circulation
2000
, vol. 
102
 (pg. 
1014
-
1019
)
26
Jaffe
 
A. S.
Spadaro
 
J. J.
Schechtman
 
K.
Roberts
 
R.
Geltman
 
E. M.
Sobel
 
B. E.
 
Increased congestive heart failure after myocardial infarction of modest extent in patients with diabetes mellitus
Am. Heart J.
1984
, vol. 
108
 (pg. 
31
-
37
)
27
Stone
 
P. H.
Muller
 
J. E.
Hartwell
 
T.
, et al 
The effect of diabetes mellitus on prognosis and serial left ventricular function after acute myocardial infarction: contribution of both coronary disease and left ventricular dysfunction to the adverse prognosis. The MILIS Study Group
J. Am. Coll. Cardiol.
1989
, vol. 
14
 (pg. 
49
-
57
)
28
Kouvaras
 
G.
Cokkinos
 
D.
Spyropoulo
 
M.
 
Increased mortality of diabetics after acute myocardial infarction attributed to diffusely impaired left ventricular performance as assessed by echocardiography
Jpn Heart J.
1988
, vol. 
29
 (pg. 
1
-
9
)
29
Nitenberg
 
A.
Valensi
 
P.
Sachs
 
R.
Dali
 
M.
Aptecar
 
E.
Attali
 
J. R.
 
Impairment of coronary vascular reserve and Ach-induced coronary vasodilation in diabetic patients with angiographically normal coronary arteries and normal left ventricular systolic function
Diabetes.
1993
, vol. 
42
 (pg. 
1017
-
1025
)
30
Nitenberg
 
A.
Paycha
 
F.
Ledoux
 
S.
Sachs
 
R.
Attali
 
J. R.
Valensi
 
P.
 
Coronary artery responses to physiological stimuli are improved by desferoxamine but not by L-arginine in non-insulin dependent diabetic patients with angiographically normal coronary arteries and no other risk factors
Circulation
1998
, vol. 
97
 (pg. 
736
-
743
)
31
Nahser
 
P. J.
Brown
 
R. E.
Oskarsson
 
H.
Winniford
 
M. D.
Rossen
 
J. D.
 
Maximal coronary flow reserve and metabolic coronary vasodilation in patients with diabetes mellitus
Circulation
1995
, vol. 
91
 (pg. 
913
-
922
)
32
Factor
 
S. M.
Bhan
 
R.
Minase
 
T.
Wolinsky
 
H.
Sonnenblick
 
E. H.
 
Hypertensive diabetic cardiomyopathy in the rat: an experimental model of human disease
Am. J. Pathol.
1981
, vol. 
102
 (pg. 
219
-
228
)
33
Factor
 
S. M.
Minase
 
T.
Sonnenblick
 
E. H.
 
Clinical and morphological features of human hypertensive-diabetic cardiomyopathy
Am Heart J.
1980
, vol. 
99
 (pg. 
446
-
458
)
34
Kawaguchi
 
M.
Techigawara
 
M.
Ishihata
 
T.
Saito
 
F.
Maehara
 
K.
Maruyama
 
Y.
 
A comparison of ultrastructural changes on endomyocardial biopsy specimens obtained from patients with and without diabetes mellitus with and without hypertension
Heart Vessels
1997
, vol. 
12
 (pg. 
267
-
274
)
35
Levy
 
D.
Garrison
 
R. J.
Savage
 
D. D.
Kannel
 
W. B.
Castelli
 
W. P.
 
Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study
N. Engl. J. Med.
1990
, vol. 
322
 (pg. 
1561
-
1566
)
36
Palmieri
 
V.
Bella
 
J. N.
Tracy
 
R. P.
, et al 
Relationship of left ventricular hypertrophy to inflammation and albuminuria in adults with type 2 diabetes. The Strong Heart Study
Diabetes Care
2003
, vol. 
26
 (pg. 
2764
-
2769
)
37
Petrie
 
M. C.
Caruana
 
L.
Berry
 
C.
McMurray
 
J. J. V.
 
Diastolic heart failure caused by subtle left ventricular systolic dysfunction?
Heart
2002
, vol. 
87
 (pg. 
29
-
31
)
38
Wiggers
 
C. J.
 
Studies on the duration of the consecutive phases of the cardiac cycle. 1 The duration of the consecutive phases of the cardiac cycle and criteria for their precise definition
Am. J. Physiol.
1921
, vol. 
56
 (pg. 
415
-
438
)
39
Brutsaert
 
D. L.
Housmans
 
P. R.
Goethals
 
M. A.
 
Dual control of relaxation. Its role in the ventricular function in the mammalian heart
Circ. Res.
1980
, vol. 
47
 (pg. 
637
-
652
)
40
Mirsky
 
I.
 
Assessing diastolic function: suggested methods and future considerations
Circulation
1984
, vol. 
69
 (pg. 
836
-
841
)
41
Ommen
 
S. R.
Nishimura
 
R. A.
 
A clinical approach to the assessment of left ventricular diastolic function by Doppler echocardiography: update 2003
Heart
2003
, vol. 
89
 (pg. 
18
-
23
)
42
Zile
 
M. R.
Baicu
 
C. F.
Gaasch
 
W. H.
 
Diastolic heart failure: abnormalities in active relaxation and passive stiffness of the left ventricle
N. Engl. J. Med.
2004
, vol. 
350
 (pg. 
1953
-
1959
)
43
Aurigemma
 
G. P.
Gottdiener
 
J. S.
Shemanski
 
L.
Gardin
 
J.
Kitzman
 
D.
 
Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: the Cardiovascular Health Study
J. Am. Coll. Cardiol.
2001
, vol. 
37
 (pg. 
1042
-
1048
)
44
Vasan
 
R.
Larson
 
M. G.
Benjamin
 
E. J.
Evans
 
J. C.
Reiss
 
C. K.
Levy
 
D.
 
Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort
J. Am. Coll. Cardiol.
1999
, vol. 
33
 (pg. 
1948
-
1955
)
45
Judge
 
K. W.
Pawitan
 
Y.
Caldwell
 
J.
Gersh
 
B. J.
Kennedy
 
J. W.
 
Congestive heart failure in patients with preserved left ventricular systolic function: analysis of the CASS registry
J. Am. Coll. Cardiol.
1991
, vol. 
18
 (pg. 
377
-
382
)
46
Brogan
 
W. C.
Hillis
 
L. D.
Flores
 
E. D.
Lange
 
R. A.
 
The natural history of isolated left ventricular diastolic dysfunction
Am. J. Med.
1992
, vol. 
92
 (pg. 
627
-
630
)
47
Philbin
 
E. F.
Rocco
 
T. A.
 
Use of angiotensin-converting enzyme inhibitors in heart failure with preserved left ventricular systolic function
Am. Heart J.
1997
, vol. 
134
 (pg. 
188
-
195
)
48
Dauterman
 
K. W.
Massie
 
B. M.
Gheorghiade
 
M.
 
Heart failure associated with preserved systolic function: a common and costly clinical entity
Am. Heart J.
1998
, vol. 
135
 (pg. 
S310
-
S319
)
49
Singh
 
R.
Barden
 
A.
Mori
 
T.
Beilin
 
L.
 
Advanced glycation end products: a review
Diabetologia
2001
, vol. 
44
 (pg. 
129
-
146
)
50
Rosen
 
P.
Du
 
X.
Tschope
 
D.
 
Role of oxygen derived free radicals for vascular dysfunction in the diabetic heart: prevention by α-tocopherol?
Mol. Cell Biochem.
1998
, vol. 
188
 (pg. 
103
-
111
)
51
Soriano
 
F. G.
Pacher
 
P.
Mabley
 
J.
Liaudet
 
L.
Szabo
 
C.
 
Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly(ADP-ribose) polymerase
Circ. Res.
2001
, vol. 
89
 (pg. 
684
-
691
)
52
Iribarren
 
C.
Karter
 
A. J.
Go
 
A. S.
, et al 
Glycaemic control and heart failure among adult patients with diabetes
Circulation
2001
, vol. 
103
 (pg. 
2668
-
2673
)
53
Avendano
 
G. F.
Agarwal
 
R. K.
Bashey
 
R. I.
, et al 
Effects of glucose intolerance on myocardial function and collagen-linked glycation
Diabetes
1999
, vol. 
48
 (pg. 
1443
-
1447
)
54
Devereux
 
R. B.
Roman
 
M. J.
Paranicas
 
M.
, et al 
Impact of diabetes on cardiac structure and function: The Strong Heart Study
Circulation
2000
, vol. 
101
 (pg. 
2271
-
2276
)
55
Young
 
M. E.
Mcnulty
 
P.
Taegtmeyer
 
H.
 
Adaptation and maladaptation of the heart in Diabetes: part II Potential mechanisms
Circulation
2002
, vol. 
105
 (pg. 
1861
-
1870
)
56
Liang
 
Q.
Carlson
 
E. C.
Donthi
 
R. V.
, et al 
Overexpression of metallothionein reduces diabetic cardiomyopathy
Diabetes
2002
, vol. 
51
 (pg. 
174
-
181
)
57
Asif
 
M.
Egan
 
J.
Vasan
 
S.
, et al 
An advanced gylcation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness
Proc. Natl. Acad. Sci. U.S.A.
2000
, vol. 
97
 (pg. 
2809
-
2813
)
58
Candido
 
R.
Forbes
 
J. M.
Thomas
 
M. C.
, et al 
A breaker of advanced glycation end products attenuates diabetes induced myocardial structural changes
Circ. Res.
2003
, vol. 
92
 (pg. 
785
-
792
)
59
Sweadner
 
K. J.
Donnet
 
C.
 
Structural similarities of Na, K-ATPase and SERCA, the Ca2+-ATPase of the sarcoplasmic reticulum
Biochem. J.
2001
, vol. 
356
 (pg. 
685
-
704
)
60
Lee
 
A. G.
East
 
J. M.
 
What the structure of a calcium pump tells us about its mechanism
Biochem. J.
2001
, vol. 
356
 (pg. 
665
-
683
)
61
Bidasee
 
K. R.
Zhang
 
Y.
Shao
 
C. H.
, et al 
Diabetes increases formation of advanced glycation end products on sarco(endo)plasmic reticulum Ca2+-ATPase
Diabetes
2004
, vol. 
53
 (pg. 
463
-
473
)
62
Stanley
 
W. C.
Lopaschuk
 
G. D.
McCormack
 
J. G.
 
Regulation of energy substrate metabolism in the diabetic heart
Cardiovasc. Res.
1997
, vol. 
34
 (pg. 
25
-
33
)
63
Zhou
 
Y.
Grayburn
 
P.
Karim
 
A.
, et al 
Lipotoxic heart disease in obese rats: implications for human obesity
Proc. Natl. Acad. Sci. U.S.A.
2000
, vol. 
97
 (pg. 
1794
-
1789
)
64
Rodrigues
 
B.
Cam
 
M. C.
McNeill
 
J. H.
 
Metabolic disturbances in diabetic cardiomyopathy
Mol. Cell. Biochem.
1998
, vol. 
180
 (pg. 
53
-
57
)
65
Stanley
 
W. C.
Marzilli
 
M.
 
Metabolic therapy in the treatment of ischaemic heart disease: the pharmacology of trimetazidine
Fundam. Clin. Pharmacol.
2003
, vol. 
17
 (pg. 
133
-
145
)
66
Rosano
 
G. M.
Vitale
 
C.
Sposato
 
B.
Mercuro
 
G.
Fini
 
M.
 
Trimetazidine improves left ventricular function in diabetic patients with coronary artery disease: a double-blind placebo-controlled study
Cardiovasc. Diabetol.
2003
, vol. 
2
 (pg. 
16
-
25
)
67
Way
 
K. J.
Katai
 
N.
King
 
G. L.
 
Protein kinase C and the development of diabetic vascular complications
Diabet. Med.
2001
, vol. 
18
 (pg. 
945
-
959
)
68
Fein
 
F. S.
Sonnenblick
 
E. H.
 
Diabetic cardiomyopathy
Prog. Cardiovasc. Dis.
1985
, vol. 
27
 (pg. 
255
-
270
)
69
Kajstura
 
J.
Fiordaliso
 
F.
Andreoli
 
A. M.
, et al 
IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress
Diabetes
2001
, vol. 
50
 (pg. 
1414
-
1424
)
70
Leri
 
A.
Liu
 
Y.
Wang
 
X.
, et al 
Overexpression of insulin like growth factor-1 attenuates the myocyte renin angiotensin system in transgenic mice
Circ. Res.
1999
, vol. 
84
 (pg. 
752
-
762
)
71
Fiordaliso
 
F.
Li
 
B.
Latini
 
R.
, et al 
Myocyte death in streptozotocin-induced diabetes in rats is angiotensin II-dependent
Lab. Invest.
2000
, vol. 
80
 (pg. 
513
-
527
)
72
Zannad
 
F.
Alla
 
F.
Dousset
 
B.
Perez
 
A.
Pitt
 
B.
 
Limitation of excessive therapy in patients with CHF: insight from the randomized aldactone evaluation study (RALES)
Circulation
2000
, vol. 
102
 (pg. 
2700
-
2706
)
73
Brilla
 
C. G.
Weber
 
K. T.
 
Mineralocorticoid excess, dietary sodium, and myocardial fibrosis
J. Lab. Clin. Med.
1992
, vol. 
120
 (pg. 
893
-
901
)
74
McEwan
 
P. E.
Gray
 
G. A.
Sherry
 
L.
Webb
 
D. J.
Kenyon
 
C. J.
 
Differential effects of angiotensin II on cardiac cell proliferation and intramyocardial perivascular fibrosis in vivo
Circulation
1998
, vol. 
98
 (pg. 
2765
-
2773
)
75
Young
 
M.
Head
 
G.
Funder
 
J. W.
 
Determinants of cardiac fibrosis in experimental hypermineralocorticoid states
Am. J. Physiol.
1995
, vol. 
269
 (pg. 
E657
-
E662
)
76
Funck
 
R. C.
Wilke
 
A.
Rupp
 
H.
Brilla
 
C. G.
 
Regulation and role of myo-cardial collagen matrix remodeling in hypertensive heart disease
Adv. Exp. Med. Biol.
1997
, vol. 
432
 (pg. 
35
-
44
)
77
Agocha
 
A.
Hyeon-Woo
 
L.
Mahboubeh
 
E.-W.
 
Hypoxia regulates basal and induced DNA synthesis and collagen type I production in human cardiac fibroblasts: effects of TGFβ, thyroid hormone, angiotensin II and basic FGF
J. Mol. Cell. Cardiol.
1997
, vol. 
29
 (pg. 
2233
-
2244
)
78
Silvestre
 
J.-S.
Robert
 
V.
Heymes
 
C.
, et al 
Myocardial production of aldosterone and corticosterone in the rat
J. Biol. Chem.
1998
, vol. 
273
 (pg. 
4883
-
4891
)
79
Kayes-Wandover
 
K. M.
White
 
P. C.
 
Steroidogenic enzyme gene expression in the human heart
J. Clin. Endocrinol. Metab.
2000
, vol. 
85
 (pg. 
2519
-
2525
)
80
Factor
 
S. M.
Okun
 
E. M.
Minase
 
T.
 
Capillary microaneurysms in the human diabetic heart
N. Engl. J. Med.
1980
, vol. 
302
 (pg. 
384
-
388
)
81
Neumann
 
S.
Huse
 
K.
Semrau
 
R.
, et al 
Aldosterone and D-glucose stimulate the proliferation of human cardiac myofibroblasts in vitro
Hypertension
2002
, vol. 
39
 (pg. 
756
-
760
)
82
Liu
 
Y.
Cox
 
S. R.
Morita
 
T.
Kourembanas
 
S.
 
Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells
Circ. Res.
1995
, vol. 
77
 (pg. 
638
-
643
)
83
Sutter
 
C. H.
Laughner
 
E.
Semenza
 
G. L.
 
Hypoxia-inducible factor 1a protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations
Proc. Natl. Acad. Sci. U.S.A.
2000
, vol. 
97
 (pg. 
4748
-
4753
)
84
Richard
 
D.
Berra
 
E.
Pouyssegur
 
J.
 
Non hypoxic pathways mediate the induction of hypoxia-inducible factor 1α in vascular smooth muscle cells
J. Biol. Chem.
2000
, vol. 
275
 (pg. 
26765
-
26771
)
85
Kelly
 
B. D.
Hackett
 
S. F.
Hirota
 
K.
, et al 
Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1
Circ. Res.
2003
, vol. 
93
 (pg. 
1074
-
1081
)
86
Yamakawa
 
M.
Liu
 
L. X.
Date
 
T.
, et al 
Hypoxia-inducible factor-1 mediates activation of cultured vascular endothelial cells by inducing multiple angiogenic factors
Circ. Res.
2003
, vol. 
93
 (pg. 
664
-
673
)
87
Shinohara
 
K.
Shinohara
 
T.
Mochizuki
 
N.
, et al 
Expression of vascular endothelial growth factor in human myocardial infarction
Heart Vessels
1996
, vol. 
11
 (pg. 
113
-
122
)
88
Lee
 
S. H.
Wolf
 
P. L.
Escudero
 
R.
Deutsch
 
R.
Jamieson
 
S. W.
Thistlethwaite
 
P. A.
 
Early expression of angiogenesis factors in acute myocardial ischemia and infarction
N. Engl. J. Med.
2000
, vol. 
342
 (pg. 
626
-
633
)
89
Chou
 
E.
Suzuma
 
I.
Way
 
K. J.
, et al 
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
2002
, vol. 
105
 (pg. 
373
-
379
)
90
Emoto
 
M.
Anno
 
T.
Sato
 
Y.
, et al 
Troglitazone treatment increases plasma vascular endothelial growth factor in diabetic patients and its mRNA in 3T3-L1 adipocytes
Diabetes
2001
, vol. 
50
 (pg. 
1166
-
1170
)
91
Zhang
 
F.
Li
 
G.
Ding
 
W.
, et al 
Screening and analysis of early cardiopathology-related gene in type 2 diabetes mellitus
Zhonghua Nei. Ke. Za. Zhi.
2002
, vol. 
41
 (pg. 
530
-
533
)
92
Monkemann
 
H.
De Vriese
 
A. S.
Blom
 
H. J.
, et al 
Early molecular events in the development of the diabetic cardiomyopathy
Amino Acids
2002
, vol. 
23
 (pg. 
331
-
336
)
93
Golfman
 
L.
Dixon
 
I. M.
Takeda
 
N.
Lukas
 
A.
Dakshinamurti
 
K.
Dhalla
 
N. S.
 
Cardiac sarcolemmal Na+-Ca2+ exchange and Na+-K+ ATPase activities and gene expression in alloxan-induced diabetes in rats
Mol. Cell. Biochem.
1998
, vol. 
188
 (pg. 
91
-
101
)
94
Qin
 
D.
Huang
 
B.
Deng
 
L.
, et al 
Down-regulation of K+ channel genes expression in type I diabetic cardiomyopathy
Biochem. Biophys. Res. Commun.
2001
, vol. 
283
 (pg. 
549
-
553
)
95
Depre
 
C.
Young
 
M. E.
Ying
 
J.
, et al 
Streptozotocin-induced changes in cardiac gene expression in the absence of severe contractile dysfunction
J. Mol. Cell. Cardiol.
2000
, vol. 
32
 (pg. 
985
-
996
)
96
Dillmann
 
W.
 
Diabetes mellitus induces changes in cardiac myosin of the rat
Diabetes.
1980
, vol. 
29
 (pg. 
579
-
582
)
97
Schimdt-Schweda
 
S.
Holubarsch
 
C.
 
First clinical trial with etomoxir in patients with chronic congestive heart failure
Clin. Sci.
2000
, vol. 
99
 (pg. 
27
-
35
)
98
Bristow
 
M.
 
Etomoxir: a new approach to treatment of chronic heart failure
Lancet
2000
, vol. 
356
 (pg. 
1621
-
1622
)
99
Paston
 
L.
Taylor
 
P. D.
 
Endothelium-mediated vascular function in insulin-dependent diabetes mellitus
Circ. Res.
1995
, vol. 
88
 (pg. 
245
-
255
)
100
Tesfamariam
 
B.
Brown
 
M. L.
Cohen
 
R. A.
 
Elevated glucose impaired endothelium-dependent relaxation by activating protein kinase C
J. Clin. Invest.
1991
, vol. 
87
 (pg. 
1643
-
1648
)
101
Tooke
 
J. E.
 
Microvascular function in human diabetes
Diabetes
1995
, vol. 
44
 (pg. 
721
-
726
)
102
Cagliero
 
E.
Roth
 
T.
Roy
 
S.
Lorenzi
 
M.
 
Characteristics and mechanisms of high-glucose-induced over-expression of basement membrane components in cultured human endothelial cells
Diabetes
1991
, vol. 
40
 (pg. 
102
-
110
)
103
Cockroft
 
J. R.
Webb
 
D. J.
Wilkinson
 
I. B.
 
Arterial stiffness, hypertension and diabetes mellitus
J. Hum. Hypertens.
2000
, vol. 
14
 (pg. 
377
-
380
)
104
Vinereanu
 
D.
Nicolaides
 
E.
Boden
 
L.
Payne
 
N.
Jones
 
C. J. H.
Fraser
 
A. G.
 
Conduit arterial stiffness is associated with impaired left ventricular subendocardial function
Heart
2003
, vol. 
89
 (pg. 
449
-
451
)
105
London
 
G. M.
Guerin
 
A.
 
Influence of arterial pulse and reflected waves on blood pressure and cardiac function
Am. Heart J.
1999
, vol. 
138
 (pg. 
220
-
224
)
106
Ohtsuka
 
S.
Kakihana
 
M.
Watanabe
 
H.
, et al 
Alterations in left ventricular wall stress and coronary circulation in patients with isolated systolic hypertension
J. Hypertens.
1996
, vol. 
14
 (pg. 
1349
-
1355
)
107
Di Carli
 
M. F.
Bianco-Batlles
 
D.
Landa
 
M. E.
, et al 
Effects of autonomic neuropathy on coronary blood flow in patients with diabetes mellitus
Circulation
1999
, vol. 
100
 (pg. 
813
-
819
)
108
Kahn
 
K.
Zola
 
B.
Juni
 
J. E.
Vinik
 
A. I.
 
Radionuclide assessment of LV diastolic filling pressures in diabetes mellitus with and without cardiac autonomic neuropathy
J. Am. Coll. Cardiol.
1986
, vol. 
7
 (pg. 
1303
-
1309
)
109
Airaksinen
 
K.
Kostinen
 
J.
Akaheimo
 
M.
Huikuri
 
H.
 
Augmentation of atrial contraction to LV filling in IDDM subjects as assessed by Doppler echocardiograph
Diabetes Care
1989
, vol. 
12
 (pg. 
159
-
161
)
110
Mustonen
 
J.
Mantysaari
 
M.
Kuikka
 
J.
, et al 
Decreased myocardial 123I-metaiodobenzylguanidine uptake is associated with disturbed LV diastolic filling in diabetes
Am. Heart J.
1992
, vol. 
123
 (pg. 
804
-
805
)
111
Annonu
 
A. K.
Fattah
 
A. A.
Mokhtar
 
M. S.
Ghareeb
 
S.
Elhendy
 
A.
 
LV systolic and diastolic functional abnormalities in asymptomatic patients with non-insulin-dependent diabetes mellitus
J. Am. Soc. Echocardiogr.
2001
, vol. 
14
 (pg. 
885
-
891
)
112
Uusitupa
 
M.
Mustonen
 
J.
Laakso
 
M.
, et al 
Impairment of diastolic function in middle aged type 1 and type 2 diabetic patients free of cardiovascular disease
Diabetologia
1988
, vol. 
31
 (pg. 
783
-
791
)
113
Monteagudo
 
P. T.
Moises
 
V. A.
Kohlmann
 
O.
Ribeiro
 
A. B.
Lima
 
V. C.
Zanella
 
M. T.
 
Influence of autonomic neuropathy upon LV dysfunction in insulin-dependent diabetic patients
Clin. Cardiol.
2000
, vol. 
23
 (pg. 
371
-
375
)
114
Ahmed
 
S. S.
Jafer
 
G. A.
Narang
 
R. M.
, et al 
Preclinical abnormality of left ventricular function in diabetes mellitus
Am. Heart J.
1975
, vol. 
89
 (pg. 
153
-
158
)
115
Galderisi
 
M.
Anderson
 
K. M.
Wilson
 
P. W.
Levy
 
D.
 
Echocardiographic evidence for the existence of a distinct diabetic cardiomyopathy (The Framingham Heart Study)
Am. J. Cardiol.
1991
, vol. 
68
 (pg. 
85
-
89
)
116
Struthers
 
A. D.
Morris
 
A. D.
 
Screening for and treating left ventricular abnormalities in diabetes mellitus: a new way of reducing cardiac deaths
Lancet
2002
, vol. 
359
 (pg. 
1430
-
1432
)
117
Kimball
 
T. R.
Daniels
 
S. R.
Khoury
 
P. R.
Magnotti
 
R. A.
Turner
 
A. M.
Dolan
 
L. M.
 
Cardiovascular status in young patients with insulin dependent diabetes mellitus
Circulation
1994
, vol. 
90
 (pg. 
357
-
361
)
118
Eren
 
M.
Gorgulu
 
S.
Uslu
 
N.
Celik
 
S.
Dagdeviren
 
B.
Tezel
 
T.
 
Relationship between aotric stiffness and left ventricular diastolic dysfunction in patients with hypertension, diabetes, or both
Heart
2004
, vol. 
90
 (pg. 
37
-
43
)
119
Poirier
 
P.
Bogaty
 
P.
Marois
 
L.
Dumnesil
 
J. G.
Garneau
 
C.
 
Diastolic dysfunction in normotensive men with well controlled type 2 diabetes mellitus. Importance of manoeuvres in echocardiographic screening for preclinical diabetic cardiomyopathy
Diabetes Care
2001
, vol. 
24
 (pg. 
5
-
10
)
120
Dumnesil
 
J. G.
Gaudreault
 
G.
Honos
 
G. N.
Kingman
 
J. G.
 
Use of valsalva manoeuvre to unmask left ventricular diastolic function abnormalities by Doppler echocardiography in patients with coronary artery disease or systemic hypertension
Am. J. Cardiol.
1991
, vol. 
68
 (pg. 
515
-
519
)
121
Fang
 
Z. Y.
Najos-Valencia
 
O.
Leano
 
R.
, et al 
Patients with early diabetic heart disease demonstrate a normal myocardial response to dobutamine
J. Am. Coll. Cardiol.
2003
, vol. 
42
 (pg. 
A46
-
A53
)
122
Fang
 
Z. Y.
Leano
 
R.
Marwick
 
T. H.
 
Relationship between longitudinal and radial contractility in subclinical diabetic heart disease
Clin. Sci.
2004
, vol. 
106
 (pg. 
53
-
60
)
123
Vinereanu
 
D.
Nicolaides
 
E.
Tweddel
 
A. C.
, et al 
Subclinical left ventricular dysfunction in asymptomatic patients with Type II diabetes mellitus, related to serum lipids and glycated haemoglobin
Clin. Sci.
2003
, vol. 
105
 (pg. 
591
-
599
)
124
Greenberg
 
N. L.
Firstenberg
 
M. S.
Castro
 
P. L.
, et al 
Doppler-derived myocardial systolic strain rate is a strong index of left ventricular contractility
Circulation
2002
, vol. 
105
 (pg. 
99
-
105
)
125
Perez
 
J. E.
McGill
 
J. B.
Santiago
 
J. V.
, et al 
Abnormal myocardial acoustic properties in diabetic patients and their correlation with the severity of disease
J. Am. Coll. Cardiol.
1992
, vol. 
19
 (pg. 
1154
-
1162
)
126
Di Bello
 
V. D.
Pedrinelli
 
R.
Giorgi
 
D.
, et al 
The potential prognostic value of ultrasonic characterization (videodensitometry) of myocardial tissue in essential arterial hypertension
Coron. Artery Dis.
2000
, vol. 
11
 (pg. 
513
-
521
)
127
Burns
 
P. N.
Powers
 
J. E.
Simpson
 
D. H.
, et al 
Harmonic imaging: principles and preliminary results
Clin. Radiol.
1996
, vol. 
51
 (pg. 
50
-
55
)
128
Porter
 
T. R.
Xie
 
F.
Kricsfeld
 
D.
, et al 
Improved myocardial contrast with second harmonic transient ultrasound response imaging in humans using intravenous perfluorocarbon-exposed sonicated dextrose albumin
J. Am. Coll. Cardiol.
1996
, vol. 
27
 (pg. 
1497
-
1501
)
129
Cohen
 
J. L.
Cherif
 
J.
Segar
 
D. S.
, et al 
Improved left ventricular endocardial border delineation and opacification with OPTISON (FS069), a new echocardiographic contrast agent. Results of a phase III Multicenter Trial
J. Am. Coll. Cardiol.
1998
, vol. 
32
 (pg. 
746
-
752
)
130
Palagi
 
C.
Mengozzi
 
G.
Rovai
 
D.
, et al 
Assessment of myocardial perfusion with intravenous contrast echocardiography: comparison with 99Tc-tetrofosmin single photon emission computed tomography and dobutamine echocardiography
Echocardiography
2003
, vol. 
20
 (pg. 
37
-
45
)
131
Kaul
 
S.
Jayaweera
 
A. R.
 
Myocardial contrast echocardiography has the potential for the assessment of coronary microvascular reserve
J. Am. Coll. Cardiol.
1993
, vol. 
21
 (pg. 
356
-
358
)
132
Senior
 
R.
Swinburn
 
J. M.
 
Incremental value of myocardial contrast echocardiography for the prediction of recovery of function in dobutamine non-responsive myocardium early after acute myocardial infarction
Am. J. Cardiol.
2003
, vol. 
91
 (pg. 
397
-
402
)
133
Jiang
 
L.
Levine
 
R. A.
Weyman
 
A. E.
 
Echocardiographic assessment of right ventricular volume and function
Echocardiography
1997
, vol. 
14
 (pg. 
189
-
205
)
134
Vogel
 
M.
Gutberlet
 
M.
Dittrich
 
S.
, et al 
Comparison of transthoracic three dimensional echocardiography with magnetic resonance imaging in the assessment of right ventricular volume and mass
Heart
1997
, vol. 
78
 (pg. 
127
-
130
)
135
Sogaard
 
P.
Egeblad
 
H.
Pedersen
 
A. K.
, et al 
Sequential versus simultaneous biventricular resynchronization for severe heart failure: evaluation by tissue Doppler imaging
Circulation
2002
, vol. 
106
 (pg. 
2078
-
2084
)
136
Thompson
 
G. R.
Partridge
 
J.
 
Coronary calcification score: the coronary-risk impact factor
Lancet
2004
, vol. 
363
 (pg. 
557
-
559
)
137
Shaw
 
L. J.
Raggi
 
P.
Schisterman
 
E.
Berman
 
D. S.
Callister
 
T. Q.
 
Prognostic value of cardiac risk factors and coronary artery calcium screening for all-cause mortality
Radiology
2003
, vol. 
228
 (pg. 
826
-
833
)
138
Starkman
 
H. S.
Cable
 
G.
Hala
 
V.
Hecht
 
H.
Donnelly
 
C. M.
 
Delineation of prevalence and risk factors for early coronary artery disease by electron beam computed tomography in young adults with type 1 diabetes
Diabetes Care
2003
, vol. 
26
 (pg. 
433
-
436
)
139
Wolfe
 
M. L.
Iqbal
 
N.
Gefter
 
W.
Mohler
 
E. R.
Rader
 
D. J.
Reilly
 
M. P.
 
Coronary artery calcification at electron beam computed tomography is increased in asymptomatic type 2 diabetics independent of traditional risk factors
J. Cardiovasc. Risk
2002
, vol. 
9
 (pg. 
369
-
376
)
140
Doyle
 
M.
Fuisz
 
A.
Kortright
 
E.
, et al 
The impact of myocardial flow reserve on the detection of coronary artery disease by perfusion imaging methods: an NHLBI WISE study
J. Cardiovasc. Magn. Reson.
2003
, vol. 
5
 (pg. 
475
-
485
)
141
Ficaro
 
E. P.
Corbett
 
J. R.
 
Advances in quantitative perfusion SPECT imaging
J. Nucl. Cardiol.
2004
, vol. 
11
 (pg. 
62
-
70
)
142
Paelinck
 
B. P.
Lamb
 
H. J.
Bax
 
J. J.
Van der Wall
 
E. E.
de Roos
 
A.
 
Assessment of diastolic function by cardiovascular magnetic resonance
Am. Heart J.
2002
, vol. 
144
 (pg. 
198
-
205
)
143
Schinkel
 
A. F.
Bax
 
J. J.
Valkema
 
R.
, et al 
Effect of diabetes mellitus on myocardial 18F-FDG SPECT using acipimox for the assessment of myocardial viability
J. Nucl. Med.
2003
, vol. 
44
 (pg. 
877
-
883
)
144
Adler
 
A. I.
Neil
 
H. A.
Manley
 
S. E.
Holman
 
R. R.
Turner
 
R. C.
 
Hyperglycemia and hyperinsulinemia at diagnosis of diabetes and their association with subsequent cardiovascular disease in the United Kingdom prospective diabetes study (UKPDS 47)
Am. Heart J.
1999
, vol. 
138
 (pg. 
S353
-
S359
)
145
UK Prospective Diabetes Study (UKPDS) Group
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)
Lancet
1998
, vol. 
352
 (pg. 
837
-
853
)
146
McCormack
 
J.
Greenhalgh
 
T.
 
Seeing what you want to see in randomised controlled trials: versions and perversions of UK PDS data. United Kingdom prospective diabetes study
Br. Med. J.
2000
, vol. 
320
 (pg. 
1720
-
1723
)
147
University Group Diabetes Program
A study of the effects of hypoglycaemic agents on vascular complications in patients with adult-onset diabetes
Diabetes
1970
, vol. 
19
 (pg. 
747
-
830
)
148
Effect of intensive diabetes management on macrovascular events and risk factors in the Diabetes Control and Complications Trial
Am. J. Cardiol.
1995
, vol. 
75
 (pg. 
894
-
903
)
149
Mann
 
D. L.
Kent
 
R. L.
Parsons
 
B.
, et al 
Adrenergic effects on the biology of the adult mammalian cardiocyte
Circulation
2000
, vol. 
85
 (pg. 
624
-
628
)
150
Festa
 
A.
D'Agostino
 
R.
Hales
 
C. N.
Mykkanen
 
L.
Haffner
 
S. M.
 
Heart rate in relation to insulin sensitivity and insulin secretion in non-diabetic subjects
Diabetes Care
2000
, vol. 
23
 (pg. 
624
-
628
)
151
Lowes
 
B. D.
Gill
 
E. A.
Abraham
 
W. T.
 
Effects of carvedilol on left ventricular function mass, chamber geometry, and mitral regurgitation in chronic heart failure
Am. J. Cardiol.
1999
, vol. 
83
 (pg. 
1201
-
1205
)
152
Waagstein
 
F.
Bristow
 
M.
Swedburg
 
K.
 
Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy
Lancet
1993
, vol. 
342
 (pg. 
1441
-
1446
)
153
The Cardiac Insufficiency Bisoprolol Study (CIBIS) Investigators and Committees
A Randomised trial of β-blockade in heart failure: The Cardiac Insufficiency Bisoprolol Study (CIBIS)
Circulation
1994
, vol. 
90
 (pg. 
1765
-
1773
)
154
CIBIS II Investigators and Committees
The Cardiac Insufficiency Bisoprolol Study (CIBIS II): a randomised trial
Lancet
1999
, vol. 
353
 (pg. 
9
-
13
)
155
Merit-HF Study Group
Effect of Metoprolol CR/XL in chronic Heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF)
Lancet
1999
, vol. 
353
 (pg. 
2001
-
2007
)
156
Packer
 
M.
Bristow
 
M.
Cohn
 
J.
 
The effect of carvedilol on morbidity and mortality in patients with chronic heart failure
N. Engl. J. Med.
1996
, vol. 
334
 (pg. 
1349
-
1355
)
157
Packer
 
M.
Coats
 
A.
Fowler
 
M.
, et al 
Effect of carvedilol on survival in severe chronic heart failure
N. Eng J. Med.
2001
, vol. 
344
 (pg. 
1651
-
1658
)
158
Domanski
 
M.
Krause-Steinrauf
 
H.
Deedwania
 
P.
, et al 
The effect of Diabetes on outcomes of patients with advanced heart failure in the BEST Trial
J. Am. Coll. Cardiol.
2003
, vol. 
42
 (pg. 
914
-
922
)
159
Haas
 
S. J.
Vos
 
T.
Gilbert
 
R. E.
Krum
 
H.
 
Are β-blockers as efficacious in patients with diabetes mellitus as in patients without diabetes mellitus who have chronic heart failure? A meta-analysis of large-scale clinical trials
Heart
2003
, vol. 
146
 (pg. 
848
-
853
)
160
Captopril Multicentre Research Group
A placebo controlled trial of captopril in refractory chronic congestive heart failure
J. Am. Coll. Cardiol.
1983
, vol. 
2
 (pg. 
755
-
763
)
161
The CONSENSUS Trial study Group
Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)
N. Engl. J. Med.
1987
, vol. 
316
 (pg. 
1429
-
1435
)
162
The SOLVD Investigators
Effects of enalapril on survival in patients with reduced left ventricular ejection fractions
N. Engl. J. Med.
1991
, vol. 
325
 (pg. 
293
-
302
)
163
The SOLVD Investigators
Effects of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions
N. Engl. J. Med.
1992
, vol. 
327
 (pg. 
669
-
677
)
164
The Acute Ramipril Efficacy (AIRE) Study Investigators
Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure
Lancet
1993
, vol. 
342
 (pg. 
821
-
828
)
165
Gruppo Italiano per lo Studia della Sopravvivenza nell'Infarto Miocardico (GISSI-3)
Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction
Lancet
1994
, vol. 
343
 (pg. 
1115
-
1122
)
166
ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group
A randomized factorial trial assessing early oral Captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction
Lancet
1995
, vol. 
345
 (pg. 
669
-
685
)
167
Yusuf
 
S.
Sleight
 
P.
Pogue
 
J.
Bosch
 
J.
Davies
 
R.
Dagenais
 
G.
 
Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators
N. Engl. J. Med.
2000
, vol. 
342
 (pg. 
145
-
153
)
168
Yusuf
 
S.
Sleight
 
P.
Pogue
 
J.
Bosch
 
J.
Davies
 
R.
Dagenais
 
G.
 
the HOPE Investigators
Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators
Lancet
2000
, vol. 
355
 (pg. 
253
-
259
)
169
Arnold
 
J. M.
Yusuf
 
S.
Young
 
J.
, et al 
the HOPE Investigators
Prevention of Heart Failure in Patients in the Heart Outcomes Prevention Evaluation (HOPE) Study
Circulation
2003
, vol. 
107
 (pg. 
1284
-
1290
)
170
Yusuf
 
S.
Gerstein
 
H.
Hoogwerf
 
B.
, et al 
HOPE Study investigators
Ramipril and the development of diabetes
JAMA, J. Am. Med. Assoc.
2001
, vol. 
286
 (pg. 
1882
-
1885
)
171
Pitt
 
B.
Segal
 
R.
Martinez
 
F. A.
, et al 
Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the elderly study, ELITE)
Lancet
1997
, vol. 
349
 (pg. 
747
-
752
)
172
Pitt
 
B.
Poole-Wilson
 
P. A.
Segal
 
R.
, et al 
Effect of Losartan compared with Captopril on mortality in patients with symptomatic heart failure: randomised trial: the Losartan Heart Failure Survival Study ELITE II
Lancet
2000
, vol. 
355
 (pg. 
1582
-
1587
)
173
Cohn
 
J. N.
Tognoni
 
G.
 
A randomised trial of the angiotensin-receptor blocker valsartan in chronic heart failure
N. Engl. J. Med.
2001
, vol. 
345
 (pg. 
1667
-
1675
)
174
Dickstein
 
K.
Kjekshus
 
J.
 
the OPTIMAAL Steering committee for the OPTIMAAL Study group
Effects of Losartan and Captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial
Lancet
2002
, vol. 
360
 (pg. 
752
-
760
)
175
Pfeffer
 
M. A.
Mcmurray
 
J. J. V.
Velazquez
 
E. J.
, et al 
Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both
N. Engl. J. Med.
2003
, vol. 
349
 (pg. 
1893
-
1906
)
176
McMurray
 
J. J.
Ostergren
 
J.
Swedberg
 
K.
, et al 
Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial
Lancet
2003
, vol. 
362
 (pg. 
767
-
771
)
177
Afzal
 
N.
Ganguly
 
P. K.
Dhalla
 
K. S.
Pierce
 
G. N.
Singal
 
P. K.
Dhalla
 
N. S.
 
Beneficial effects of verapamil in diabetic cardiomyopathy
Diabetes
1988
, vol. 
37
 (pg. 
936
-
942
)
178
Parameshwar
 
J.
Poole-Wilson
 
P.
 
The role of calcium antagonists in the treatment of chronic heart failure
Eur. Heart J.
1993
, vol. 
14
 (pg. 
38
-
44
)
179
Packer
 
M.
O'Connor
 
C.
Ghali
 
J.
, et al 
Effect of amlodipine on morbidity and mortality in severe chronic heart failure: the PRAISE trial
N. Engl. J. Med.
1996
, vol. 
335
 (pg. 
1107
-
1114
)
180
Cohn
 
J.
Ziesche
 
S.
Loss
 
L.
, et al 
Effect of the calcium channel antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril: V-HeFT III
Circulation
1997
, vol. 
96
 (pg. 
856
-
863
)
181
Callahan
 
A. S.
 
Vascular pleiotropy of statins: clinical evidence and biochemical mechanisms
Curr. Atheroscler. Rep.
2003
, vol. 
5
 (pg. 
33
-
37
)
182
Okamoto
 
T.
Yamagishi
 
S. I.
Inagaki
 
Y.
, et al 
Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin
FASEB J.
2002
, vol. 
16
 (pg. 
1928
-
1930
)
183
Scandinavian Simvastatin Survival Study Investigators
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)
Lancet
1994
, vol. 
344
 (pg. 
1383
-
1389
)
184
Girman
 
C. J.
Rhodes
 
T.
Mercuri
 
M.
, et al 
The metabolic syndrome and risk of major coronary events in the Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study
Am. J. Cardiol.
2004
, vol. 
93
 (pg. 
136
-
141
)
185
Haffner
 
S. M.
Alexander
 
C. M.
Cook
 
T. J.
, et al 
Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study
Arch. Intern. Med.
1999
, vol. 
159
 (pg. 
2661
-
2667
)
186
Collins
 
R.
Armitage
 
J.
Parish
 
S.
Sleigh
 
P.
Peto
 
R.
 
MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial
Lancet
2003
, vol. 
361
 (pg. 
2005
-
2016
)
187
Mozaffarian
 
D.
Nye
 
R.
Levy
 
W. C.
 
Statin therapy is associated with lower mortality among patients with severe heart failure
Am. J. Cardiol.
2004
, vol. 
93
 (pg. 
1124
-
1129
)
188
Hayashidani
 
S.
Tsutsui
 
H.
Shiomi
 
T.
, et al 
Fluvastatin, a 3-hydroxy-3 methylglutaryl coenzyme a reductase inhibitor, attenuates left ventricular remodelling and failure after experimental myocardial infarction
Circulation
2002
, vol. 
105
 (pg. 
868
-
873
)
189
Bauersachs
 
J.
Gallupo
 
P.
Fraccarollo
 
D.
Christ
 
M.
Ertl
 
G.
 
Improvement of left ventricular remodelling and function by hydroxymethyl-glutaryl coenzyme a reductase inhibition with cerivastatin in rats with heart failure after myocardial infarction
Circulation
2001
, vol. 
104
 (pg. 
982
-
985
)
190
Horwich
 
T. B.
MacLellan
 
W. R.
Fonarow
 
G. C.
 
Statin therapy is associated with improved survival in ischaemic and non-ischaemic heart failure
J. Am. Coll. Cardiol.
2004
, vol. 
43
 (pg. 
642
-
648
)
191
Florkowski
 
C. M.
 
Management of co-existing diabetes mellitus and dyslipidemia: defining the role of thiazolidinediones
Am. J. Cardiovasc. Drugs
2002
, vol. 
2
 (pg. 
15
-
21
)
192
Young
 
L. H.
 
Insulin resistance and the effects of thiazolidinediones on cardiac metabolism
Am. J. Med.
2003
, vol. 
115
 (pg. 
75S
-
80S
)
193
Hollenberg
 
N. K.
 
Considerations for management of fluid dynamic issues associated with thiazolidinediones
Am. J. Med.
2003
, vol. 
115
 (pg. 
111S
-
115S
)
194
Szabo
 
C.
 
PARP as a drug target for the therapy of diabetic cardiovascular dysfunction
Drug News Perspect.
2002
, vol. 
15
 (pg. 
197
-
205
)
195
Du
 
X.
Matsumura
 
T.
Edelstein
 
D.
, et al 
Inhibition of GAPDH activity by poly (ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells
J. Clin. Invest.
2003
, vol. 
112
 (pg. 
1049
-
1057
)
196
Minchenko
 
A. G.
Stevens
 
M. J.
White
 
L.
, et al 
Diabetes-induced overexpression of endothelin-1 and endothelin receptors in the rat renal cortex is mediated via poly (ADP-ribose) polymerase activation
FASEB J.
2003
, vol. 
17
 (pg. 
1514
-
1516
)
197
Szabo
 
C.
Zanchi
 
A.
Komjati
 
K.
, et al 
Poly(ADP-ribose) polymerase is activated in subjects at risk of developing type 2 diabetes and is associated with impaired vascular reactivity
Circulation
2002
, vol. 
106
 (pg. 
2680
-
2686
)