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The Failing Diabetic Heart: Focus on Diastolic Left Ventricular Dysfunction Loek van Heerebeek, MD, Aernout Somsen, MD, PhD, and Walter J. Paulus, MD, PhD Corresponding author Walter J. Paulus, MD, PhD Laboratory of Physiology, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. E-mail: [email protected] Current Diabetes Reports 2009, 9:79–86 Current Medicine Group LLC ISSN 1534-4827 Copyright © 2009 by Current Medicine Group LLC Diabetes mellitus (DM) is highly prevalent and is an important risk factor for congestive heart failure (HF). Increased left ventricular (LV) diastolic stiffness is recognized as the earliest manifestation of DM-induced LV dysfunction, but its pathophysiology remains incompletely understood. Mechanisms whereby DM increases LV diastolic stiffness differ between HF with normal LV ejection fraction (EF) (HFNEF) and HF with reduced LVEF (HFREF). In diabetic HFREF, fibrosis and deposition of advanced glycation end products (AGEs) are the most important contributors to high LV diastolic stiffness, whereas in diabetic HFNEF, elevated resting tension of hypertrophied cardiomyocytes is the most important contributor to high LV diastolic stiffness. As HF mortality remains high in DM despite proven efficacy of current treatments, better understanding of the pathophysiology of high LV diastolic stiffness could be beneficial for novel therapeutic strategies. Introduction The prevalence of diabetes mellitus (DM), especially type 2 DM, is steadily increasing and is expected to reach pandemic proportions in the next few decades [1]. DM is an important risk factor for congestive heart failure (HF). Mortality and hospitalization rates in diabetic patients with HF remain particularly high, and HF patients with DM have a worse prognosis than those without DM, especially when suffering with ischemic heart disease [2,3]. The prevalence of DM in HF approximates 20% to 35% [2], and is higher in patients with HF and normal left ventricular (LV) ejection fraction (HFNEF) [4,5]. Currently, HFNEF is diagnosed in about 50% of HF patients; chang- ing population demographics will increase its prevalence even more [6]. HFNEF and type 2 DM commonly coexist and the two conditions relate to hypertension, obesity, and older age [6]. In a recent study, type 2 DM and hypertension occurred in 57% and 82% of HFNEF patients, whereas no HFNEF patients had type 1 DM. In contrast, in HF patients with reduced ejection fraction (HFREF), 19% had type 2 DM and 8% had type 1 DM, whereas 11% were hypertensive [7•]. Furthermore, type 2 DM commonly associates with the metabolic syndrome, which represents a constellation of cardiovascular risk factors, including obesity, hypertension, insulin resistance, dyslipidemia, microalbuminuria, and hypercoagulability. The metabolic syndrome predicts subsequent development of type 2 DM and is associated with cardiovascular mortality and LV diastolic dysfunction [8]. The increased incidence of HF in DM persists despite correction for common confounders, such as hypertension or coronary artery disease (CAD), because DM directly affects cardiac structure and function, a condition called diabetic cardiomyopathy [9]. Although initially classified as a dilated cardiomyopathy, LV diastolic dysfunction was later recognized as the earliest manifestation of diabetic cardiomyopathy [10]. About 75% of normotensive, wellcontrolled type 2 diabetic patients without CAD show evidence of LV diastolic dysfunction with tissue Doppler imaging [11]. The pathophysiology of LV diastolic dysfunction in diabetic HF remains incompletely understood, which hinders the development of more effective therapeutic strategies. This article therefore focuses on the pathophysiology and possible therapeutic implications of LV diastolic dysfunction in diabetic HF. Mechanisms of LV Diastolic Dysfunction in DM The following paragraphs discuss the mechanisms responsible for increased LV diastolic dysfunction in DM (Table 1). Fibrosis Diabetes changes the myocardial extracellular matrix, as evident from enhanced interstitial and perivascular fibrosis, increased expression of collagen type I, and downregulation of collagen-degrading matrix metallopro- 80 I Macrovascular Complications in Diabetes Table 1. Mechanisms responsible for increased LV diastolic stiffness in diabetic heart failure Mechanisms Myocardial fibrosis Effects Study Increased collagen type I expression [9,12] Increased expression of profibrotic cytokines (TGF-β, IL-1β) Decreased expression of MMPs AGEs Increased collagen production [13,14] Increased collagen and ECM cross-linking Activation of AGE receptor–based signaling Increased oxidative stress Impaired calcium homeostasis Endothelial dysfunction Impaired NO bioavailability Metabolic disturbances FFA oxidation [9,15,16] Lipid accumulation and lipotoxicity Uncoupling of mitochondrial oxidative phosphorylation Impaired calcium homeostasis Endothelial dysfunction Reduced activities of calcium handling proteins (SERCA2, ryanodine receptor, Na2+-Ca2+ exchanger, sarcolemmal Ca2+ ATPase) [9] Increased expression of inflammatory markers (E-selectin, ICAM-1, VCAM-1) [17,18] Microalbuminuria Impaired NO bioavailability Chronic inflammation Increased oxidative stress Myocardial oxidative stress Enhanced ROS production [19–22] Impaired antioxidant defense systems Glucose auto-oxidation; activation of polyol pathways Enhanced formation of AGEs Increased FFA and leptin Impaired NO bioavailability Toxic reactive substances (ie, peroxynitrite) Impaired myocardial NO bioavailability Endothelial NOS uncoupling [20,22,23] Impaired S-nitrosylation–based signaling Increased LV diastolic stiffness Impaired myocardial cGMP signaling Increased cardiomyocyte resting tension Altered titin regulation Impaired PKG activity [24•,25,26•,27–29] Cytoskeletal abnormalities [30,31•,32•,33,34] Increased stiff titin N2B expression [31•,32•,33,34] Titin hypophosphorylation Disruption in titin-based signaling AGE—advanced glycation end product; ECM—extracellular matrix; FFA—free fatty acid; ICAM-1—intercellular adhesion molecule 1; IL-1β—interleukin-1β; LV—left ventricular; MMP—matrix metalloproteinase; NO—nitric oxide; NOS—nitric oxide synthase; PKG—protein kinase G; ROS—reactive oxygen species; SERCA2—sarcoendoplasmatic reticulum Ca 2+ ATPase; TGF-β—transforming growth factor-β; VCAM-1—vascular cell adhesion molecule 1. teinases [12]. These pathologic mechanisms are mediated by hyperglycemia, oxidative stress, and elevated aldoste- rone and angiotensin II levels [12]. Echocardiograms of diabetic patients show abnormal integrated backscatter The Failing Diabetic Heart (a marker of myocardial reflectivity), which confi rms increased collagen deposition [12]. Advanced glycation end products Advanced glycation end products (AGEs) are modifications of proteins or lipids that become nonenzymatically glycated and oxidized after contact with aldose sugars, with creation of nearly irreversible cross-links. Formation and accumulation of AGEs is enhanced by hyperglycemia, oxidative stress, aging, and hypertension [13,14]. Myocardial AGE deposition augments LV diastolic stiffness by direct and indirect mechanisms, including formation of collagen cross-links, stimulation of collagen production, and activation of specific AGE receptors. AGE receptor activation induces profibrotic signaling and impairs calcium homeostasis [13,14]. In addition, AGEs increase oxidative stress and proinflammatory cytokine release [13,14]. Increased serum AGE levels were identified as an independent predictor of cardiac death and rehospitalization and are associated with LV diastolic stiffness, with endothelial dysfunction, with impaired vascular compliance, and with reduced nitric oxide (NO) bioavailability, in type 1 and 2 DM patients [13,14]. AGE deposition results from poor glycemic control, which carries an increased risk of HF. Each 1% increase in hemoglobin A1c level was shown to be associated with an 8% increase in HF prevalence [15]. Metabolic disturbances Substrate metabolism is altered in DM with a shift from glucose utilization to increased free fatty acid oxidation. This leads to myocardial lipotoxicity, uncoupling of mitochondrial oxidative phosphorylation, and disturbed contraction/relaxation coupling [9]. Reduced high-energy phosphate metabolism was shown to parallel LV diastolic dysfunction in well-controlled, normotensive type 2 diabetic patients without CAD [16]. Impaired calcium homeostasis Intracellular calcium (Ca 2+) importantly regulates cardiac contractility and calcium influx. Depolarization-activated voltage-dependent L-type Ca 2+ channels trigger excitation/contraction coupling, which is regulated by various calcium-handling proteins [9]. In type 1 and 2 DM, disturbed cardiomyocyte (CM) calcium handling results from reduced activity of calcium-handling proteins, such as sarcoplasmic reticulum adenosine triphosphatase (ATPase; SERCA2a), ryanodine receptor, Na 2+-Ca 2+ exchanger, and sarcolemmal Ca 2+ ATPase. Reduced activities of these calcium-handling proteins impair LV systolic and diastolic function [9]. Endothelial dysfunction Endothelial dysfunction predicts cardiovascular mortality, correlates with functional capacity of chronic HF patients, I van Heerebeek et al. I 81 and plays a central role in the pathophysiology of congestive HF, type 1 and 2 DM, hypertension, and chronic renal failure [17,18]. In DM and HF, endothelial dysfunction results from inflammatory processes and leads to impaired vasodilator responses, reduced NO bioavailability, and a prothrombotic state [17]. Increased markers of endothelial inflammation, such as E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1, were demonstrated in metabolic syndrome and obesity and represent an independent risk factor for subsequent development of type 2 DM [17]. Myocardial oxidative stress Increased oxidative stress underlies endothelial dysfunction, as evident from elevated production of reactive oxygen species (ROS; eg, superoxide, hydrogen peroxide, and the hydroxyl radical) and from impaired activity of antioxidant defense systems [19,20]. Hyperglycemia induces oxidative stress via several mechanisms, which include glucose auto-oxidation, formation of AGEs, activation of the polyol pathway, and increased levels of free fatty acid and leptin [19]. Prominent cardiovascular sources of ROS production include xanthine oxidoreductase, NADPH oxidase, mitochondrial oxidases, and uncoupled NO synthases [19,20]. Increased generation of ROS contributes to cardiac injury, by direct oxidative cellular damage and by diminished NO bioavailability [20]. Superoxide directly reacts with and inactivates NO, with subsequent production of peroxynitrite. Increased peroxynitrite levels contribute to congestive HF and cardiovascular diabetic complications [21]. In addition, peroxynitrite oxidizes tetrahydrobiopterin, which is a necessary cofactor regulating the function of the multicomponent endothelial NO synthase (eNOS). eNOS is the most prominent vascular source of NO. In oxidative environments, diminished tetrahydrobiopterin induces eNOS uncoupling, which leads to production of superoxide instead of NO, thereby amplifying oxidative stress and endothelial dysfunction. Evidence for uncoupling of eNOS has been obtained in patients with DM, hypertension, and hypercholesterolemia [22]. Myocardial NO bioavailability NO exerts favorable effects on LV diastolic distensibility, and low myocardial NO bioavailability was previously demonstrated to raise LV diastolic stiffness and reduce LV preload reserve in HFREF patients [23]. Furthermore, NO and superoxide regulate myocardial signal transduction via post-translational modification of effector proteins through the process of S-nitrosylation [20]. S-nitrosylation comprises the covalent attachment of NO to thiol side chains of cysteine residues and serves as a major effector of NO bioactivity, regulating various proteins, transcription factors, and ion channels. When physiologically present, superoxide facilitates S-nitrosylation, whereas oxidative 82 I Macrovascular Complications in Diabetes stress disrupts these signaling cascades, leading to a state of NO/superoxide redox-disequilibrium [20]. Interestingly, cardiac NO signaling appears highly compartmentalized as evident from the colocalization of NO sources and targets within confined subcellular compartments, which appear to be disrupted in HF [20]. Decreased myocardial NO bioavailability in diabetic HF could thus interfere with vital intracellular NO redox-based signaling and contribute to the observed diastolic LV dysfunction. Myocardial cGMP signaling Another important aspect of NO-based signaling involves NO-mediated activation of soluble guanylate cyclase, which generates cGMP. The second major pathway for cGMP synthesis involves natriuretic peptide (NP)–mediated membrane guanylate cyclase stimulation [24•]. cGMP is a key regulatory second messenger and modulates cardiac inotropic and metabolic responses via activation of its downstream effectors, including protein kinase G (PKG). PKG stimulation results in decreased myofi lament calcium sensitivity, attenuation of CM hypertrophy, and protection against ischemia-reperfusion injury. Therefore, PKG has anti-hypertrophic, anti-remodeling, and antiinflammatory actions [25]. Termination of cGMP action and PKG signaling is induced through hydrolyzation by phosphodiesterases (PDEs), of which 11 different primary isoenzymes have been described [24•]. In the cardiovascular system, PDE type 5 (PDE5) is particularly important as it becomes upregulated in pathologic conditions, such as congestive HF, pulmonary arterial hypertension, and right ventricular and LV hypertrophy [24•,25,26•]. Recent studies demonstrated that NO-cGMP and NP-cGMP pathways are also compartmentalized and differentially regulated by PDEs, as PDE5 closely interacts with NO-stimulated cGMP, but not with NP-stimulated cGMP [24•]. PDE5 normally appears in a striated pattern colocalizing with α-actinin at the sarcomeric Z-disc. This striated pattern is important for effective β-adrenergic signaling and is lost in failing myocardium [24•]. Downregulation of NO-cGMP-PKG signaling was demonstrated in DM and contributed to diabetic vascular complications [27]. Hyperglycemia reduced PKG expression and activity through PKC-dependent activation of NAD(P)H oxidase-mediated ROS production [27]. PKG activity can be indirectly measured using antibodies against the specific PKG substrate vasodilator-stimulated phosphoprotein (VASP), of which the phosphorylated isoform serine-239 (P-VASP) is a specific marker for PKG activity [28]. Decreased PKG activity was found in hypertrophied LV myocardium [29]; recently, we also demonstrated decreased P-VASP/VASP ratios and, therefore, downregulated PKG activity in endomyocardial biopsies of HFNEF patients without CAD. Thus, cGMP-PKG-PDE signaling is an important and complex regulatory mechanism that underlies fundamental myo- cardial contractile processes. This mechanism is adversely affected by DM, and impaired cGMP-PKG-PDE signaling could be an important contributor to the high LV diastolic stiffness of the failing diabetic heart. CM resting tension and titin Increased CM resting tension (Fpassive) was previously shown to significantly contribute to the high LV diastolic stiffness observed in HFNEF patients [30,31•]. In vitro–determined CM Fpassive correlated with LV diastolic stiffness, LV end-diastolic wall stress, and LV end-diastolic pressure [30,31•]. In these studies, Fpassive was determined in skinned CM (ie, in CMs with all sarcoplasmic and sarcolemmal membrane structures removed by prior submersion in a detergent). CMs were isolated from LV endomyocardial biopsies. Interestingly, increased CM Fpassive in HFNEF was lowered to control values after administration of protein kinase A (PKA); a phosphorylation deficit of myofi lamentary or cytoskeletal proteins was therefore inferred to account for the high Fpassive [30,31•]. The giant sarcomeric elastic protein titin contains PKA phosphorylation sites and is an important determinant of CM Fpassive and elasticity [32•]. Titin spans half a sarcomere from the Z-disc to the M-line and functions as a sarcomeric stretch/stress sensor protein involved in mediation and transmission of external force signals from the extracellular matrix to the CM cytoskeleton. Titin alters CM Fpassive through isoform shifts from a stiff N2B isoform to a more compliant N2BA isoform and through phosphorylation status. Phosphorylation of titin’s N2B region by PKA reduces myofibrillar Fpassive in human myocardium and in isolated rat CM [32•]. Recently, increased expression and lower phosphorylation of the stiff N2B titin isoform were demonstrated in CM isolated from HFNEF patients [31•]. Thus, both changes in titin isoform expression and phosphorylation contributed to the increased CM Fpassive and LV diastolic stiffness in HFNEF. Furthermore, administering PKG to CM isolated from HFNEF patients lowered Fpassive to a level comparable to the level observed after PKA administration [33]. No additional fall was noted in CM Fpassive when PKA was administered after PKG. This suggested that PKG and PKA acted on the same phosphorylation site [33]. PKG phosphorylation sites on titin were recently identified [34]. Combined with the previously discussed downregulation of cGMP-PKG-PDE signaling, these results suggest that PKG-mediated hypophosphorylation of titin could be a major determinant of the high CM Fpassive and the high LV diastolic stiffness observed in HFNEF patients. Relative Importance of Mechanisms of LV Diastolic Dysfunction in DM Recently, we demonstrated that LV myocardial stiffness was higher in diabetic HFREF (DM+HFREF) and diabetic The Failing Diabetic Heart I van Heerebeek et al. I 83 Figure 1. Diabetes mellitus (DM)–related pathways of myocardial damage and resulting clinical phenotypes of the failing diabetic heart in the absence of coronary artery disease. DM impairs left ventricular (LV) function through advanced glycation end product (AGE) deposition-inflammation-fibrosis in patients with heart failure with reduced LV ejection fraction (HFREF). HFREF usually results from previous myocarditis. In DM patients with glomerulosclerosis, AGE deposition-inflammation-fibrosis can occasionally be the only cause of HFREF, as described in the original reports of diabetic cardiomyopathy (CMP) [35]. DM impairs LV function through myocyte hypertrophy–myocyte stiffness in patients with heart failure with normal LV ejection fraction (HFNEF). In most patients, HFNEF results from concomitant arterial hypertension. However, sometimes DM is the only cause of HFNEF, and in these patients a novel HFNEF phenotype of diabetic CMP becomes manifest. HFNEF (DM+HFNEF) patients compared with nondiabetic HFREF (DM-HFREF) and HFNEF (DM-HFNEF) patients [7•]. No significant differences were noted in HF treatment among these patient groups. The mechanisms responsible for the increased LV diastolic stiffness differed in DM+HFREF and in DM+HFNEF, as evident from analysis of structure and function of LV myocardium procured by transvascular LV endomyocardial biopsy technique. In DM+HFREF patients, interstitial fibrosis was significantly higher compared with DM-HFREF, DM-HFNEF, and DM+HFNEF patients in whom levels of interstitial fibrosis were comparable [7•]. In addition, myocardial AGE deposition was exclusively present in the microvasculature and was again significantly higher in DM+HFREF patients compared with DM-HFREF patients. In DM+HFNEF patients, only a nonsignificant trend toward increased microvascular AGE deposition was observed [7•]. In DM+HFREF patients, AGE deposition was paralleled by endothelial E-selectin expression, a marker of inflammatory endothelial activation [7•]. In DM+HFNEF, increased LV diastolic stiffness mainly resulted from elevated Fpassive of hypertrophied CM [7•]. CM Fpassive was similar between DM+HFREF and DM-HFREF patients. The increased CM Fpassive in DM+HFNEF patients was corrected by PKA [7•]. Increased Fpassive in DM+HFNEF patients was paralleled by opening of the CM Z-discs, which appeared wider in DM+HFNEF than in DM-HFNEF [7•]. Z-disc widening had previously been observed in transgenic mice after nebulin or muscle LIM protein knockout [32•] and was thought to result from altered elastic properties of cytoskeletal proteins, which pull at and open up adjacent Z-discs. From the foregoing results, DM appears to impair myocardial function by two distinct pathways, each resulting in a different HF phenotype: the fi rst pathway consists of AGE deposition-inflammation-fibrosis and results in an HFREF phenotype, whereas the second pathway consists of myocyte hypertrophy–myocyte stiffness and results in an HFNEF phenotype (Fig. 1). In DM+HFREF patients, the pathway of AGE deposition-inflammationfibrosis resulted not only in diastolic LV dysfunction but also in systolic LV dysfunction, as evident from LV dilatation and depressed LV ejection fraction. Previous viral or toxic myocarditis is the most likely cause for the dilated cardiomyopathy in most DM+HFREF patients because fasting glucose, hemoglobin A1c, and DM duration were all similar in the DM+HFREF and DM+HFNEF groups. Inflammatory myocardial damage is known to facilitate AGE deposition. Furthermore, AGE deposition itself amplifies myocardial inflammation [13,14], as evident from the observed rise of myocardial E-selectin in the DM+HFREF patients. In the presence of longstanding poor glycemia control, these interactions between AGE deposition and myocardial inflammation could eventually induce a diabetic cardiomyopathy without foregoing viral or toxic myocarditis, as observed in the initial reports on diabetic cardiomyopathy [35] and as suggested by the raised DM prevalence in idiopathic dilated cardiomyopathy [36]. In DM+HFNEF, increased CM Fpassive and CM hypertrophy were the most important contributors to the high LV diastolic stiffness. Most of the HFNEF patients suffered from hypertensive heart disease. However, CM hypertrophy observed in the DM+HFNEF patients was unrelated to higher LV pressure overload because LV peak systolic pressure and LV peak systolic wall stress were similar in the DM+HFNEF and DM-HFNEF groups. DM was the unique cause of high LV stiffness in only a small subgroup of the DM+HFNEF patients, who had no arterial hypertension. This subgroup presents with a novel phenotype of diabetic cardiomyopathy, which differs from the original reports [35], as these patients have preserved LV ejection fraction, no LV cavity dilatation, and elevated diastolic LV stiffness. Treatment of High LV Diastolic Stiffness Pathophysiologic mechanisms underlying high LV diastolic stiffness in diabetic HF are multifactorial, involving 84 I Macrovascular Complications in Diabetes myocardial and vascular dysfunction and extracellular and intracellular disturbances. A selective treatment strategy to reduce high LV diastolic stiffness in diabetic HF is therefore also composed of multiple compounds. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers Numerous HF trials demonstrated improved cardiovascular morbidity and mortality by angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), and inhibitors of the renin-angiotensin-aldosterone system have become indispensable drugs for HF treatment [37,38]. The beneficial effects of ACEIs or ARBs in HF and DM are manifold and include improvement of endothelial function, raised vascular and myocardial NO bioavailability, enhanced insulin sensitivity, control of arterial hypertension, prevention of unfavorable LV remodeling, and less vascular inflammation or oxidative stress. ACEIs and ARBs can also prevent end-organ damage in ischemic heart disease, renal disease, hypertension, and DM, and possibly development of type 2 DM [37,38]. Numerous studies demonstrated that angiotensin II and aldosterone stimulate myocardial fibroblast-mediated collagen synthesis and decrease myocardial collagenase activity. These actions result in progressive myocardial fibrosis and high LV diastolic stiffness [39]. Chronic use of ACEIs and ARBs improves echocardiographic parameters of LV diastolic function in patients with hypertensive heart disease and type 2 DM [39,40]. Furthermore, aldosterone inhibitors, such as spironolactone and eplerenone, also reduce myocardial fibrosis as a result of decreased NAD(P)H oxidase–derived ROS generation and increased NO bioavailability [41]. AGE cross-link breakers In congestive HF, administration of the AGE breaking compound 4,5-dimethyl-3-phenacylthiazolium chloride (ALT-711), which cleaves AGE cross-links between proteins and preserves natural carbohydrate modification to proteins, improved arterial compliance and LV diastolic function and decreased pulse pressure, myocardial fibrosis, and LV mass [13,14]. Furthermore, patients with systolic HF treated with ALT-711 demonstrated a trend toward improved LV systolic function [13,14]. Adequate glycemic control, ACEIs, ARBs, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins also reduce AGE accumulation [13,14]. Statins Statins importantly reduce cardiovascular risk in diabetic patients, as evident from numerous primary and secondary prevention studies [3]. Statins lower cholesterol biosynthesis via inhibition of the conversion of HMG-CoA to mevalonic acid. In addition, statins exert numerous cholesterol-independent beneficial actions in cardiovascular disease, referred to as the pleiotropic actions of statins. These actions include reduction of inflammation, oxidative stress, and thrombogenicity. Statins thereby improve coronary endothelial function with increased NO bioavailability and enhanced myocardial PKG activity [38,42]. This last effect could be especially beneficial for the high LV diastolic stiffness of diabetic HFNEF patients. Peroxisome proliferator-activated receptor agonists Peroxisome proliferator-activated receptor (PPAR)-α and PPAR-δ are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors, which upon activation bind to DNA (PPAR-response element) to regulate gene transcription [43,44]. PPAR-α (fibrates) and PPAR-γ (thiazolidinediones) agonists were shown to reduce cardiovascular events in high-risk populations with metabolic syndrome, dyslipidemia, or DM and to improve atherogenic dyslipidemia and metabolic control in DM [43,44]. In addition, PPARs also exhibit anti-inflammatory and antioxidative actions with improved endothelial function through restored insulin-dependent endothelial NO release [43,44]. However, a higher prevalence of congestive HF was demonstrated in diabetic patients treated with thiazolidinediones. The latter is probably explained by thiazolidinediones’ favorable effects on myocyte hypertrophy and contractile performance being offset by increased renal sodium reabsorption and plasma volume expansion. Isosorbide-dinitrate The A-Heft (African-American Heart Failure Trial) demonstrated that therapy with a fi xed-dose combination of isosorbide dinitrate (NO donor) and hydralazine (vasodilator and antioxidant) improved cardiovascular morbidity and mortality in African-American patients with advanced HF, when added to conventional HF therapy [45]. Isosorbide-dinitrate/hydralazine therapy improved both cardiovascular hemodynamics as well as LV remodeling and this improvement probably resulted from enhanced NO bioavailability [45]. Natriuretic peptides NPs (ie, atrial natriuretic peptide, brain natriuretic peptide [BNP], and C-type natriuretic peptide) are released from the myocardium in response to increased CM stretch. They stimulate natriuresis, improve myocardial relaxation, reduce ventricular preload, and exert sympathico-inhibitory effects [46]. BNP concentrations are consistently raised in disorders associated with LV diastolic dysfunction, such as aortic stenosis, hypertrophic cardiomyopathy, or restrictive cardiomyopathy [46]. Nesiritide is a recombinant form of human Btype NP and also exhibits vasodilator, natriuretic, and lusitropic activities. Nesiritide administration resulted in reduced pulmonary wedge pressure in patients with acute decompensated HF. However, the recent FUSION The Failing Diabetic Heart II (Follow-Up Serial Infusions of Nesiritide) trial, which evaluated the clinical use of outpatient, intermittent nesiritide infusions in advanced HFREF patients, failed to observe cardiovascular end-point reductions when compared with standard care outpatient management [47]. Whether nesiritide administration could be benefi cial in HFNEF remains unknown. PDE inhibitors PDE5 inhibition with sildenafi l is currently used for treating pulmonary hypertension [26•,48]. In patients with pulmonary hypertension, sildenafi l decreases pulmonary vascular resistance, increases cardiac output, reverses myocardial hypertrophy, and improves endotheliumdependent flow-mediated dilation [26•,48]. This beneficial effect on endothelial dysfunction has also been observed in diabetic men [49] and could therefore be used for treating high diastolic LV stiffness in diabetic HF. Conclusions Even in the absence of CAD, the failing diabetic heart has elevated LV diastolic stiffness. Mechanisms responsible for the elevated LV diastolic stiffness are multifactorial and differ between DM+HFREF and DM+HFNEF patients. Inflammation, deposition of AGEs, and collagen are important determinants of increased LV diastolic stiffness in DM+HFREF, whereas increased Fpassive of hypertrophied CM is the main determinant of increased LV diastolic stiffness in DM+HFNEF. 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