Current Heart Failure Reports

, Volume 9, Issue 4, pp 293–302 | Cite as

Molecular and Cellular Basis for Diastolic Dysfunction

  • Loek van Heerebeek
  • Constantijn P. M. Franssen
  • Nazha Hamdani
  • Freek W. A. Verheugt
  • G. Aernout Somsen
  • Walter J. Paulus
Prevention of Heart Failure After Myocardial Infarction (M St. John Sutton, Section Editor)


Heart failure with preserved ejection fraction (HFpEF) is highly prevalent and is frequently associated with metabolic risk factors. Patients with HFpEF have only a slightly lower mortality than patients with HF and reduced EF. The pathophysiology of HFpEF is currently incompletely understood, which precludes specific therapy. Both HF phenotypes demonstrate distinct cardiac remodeling processes at the macroscopic, microscopic, and ultrastructural levels. Increased diastolic left-ventricular (LV) stiffness and impaired LV relaxation are important features of HFpEF, which can be explained by changes in the extracellular matrix and the cardiomyocytes. In HFpEF, elevated intrinsic cardiomyocyte stiffness contributes to high diastolic LV stiffness. Posttranslational changes in the sarcomeric protein titin, affecting titin isoform expression and phosphorylation, contribute to elevated cardiomyocyte stiffness. Increased nitrosative/oxidative stress, impaired nitric oxide bioavailability, and down-regulation of myocardial cyclic guanosine monophosphate and protein kinase G signaling could trigger posttranslational modifications of titin, thereby augmenting cardiomyocyte and LV diastolic stiffness.


Cardiomyocytes Cyclic guanosine monophosphate Diabetes mellitus Diastole Diastolic dysfunction Extracellular matrix Fibrosis Guanylate cyclase Heart failure Hypertrophy Inflammation Metabolic risk factors Metabolic syndrome Nitric oxide Natriuretic peptides Obesity Oxidative stress Protein Kinase G Phosphodiesterase Titin 


Heart failure with preserved ejection fraction (HFpEF) currently accounts for 50 % of all HF patients, and its prevalence relative to HF with reduced EF (HFrEF) is rising at a rate of approximately 1 % per year [1]. Patients with HFpEF have a dismal prognosis, with only slightly lower mortality rates than patients with HFrEF [1, 2]. As a result of evidence-based HF therapy, the prognosis of patients with HFrEF improved progressively over the past 3 decades. Conversely, despite frequent use of similar pharmacological agents, the prognosis of patients with HFpEF remained unaltered over the same time period [1]. Indeed, most trials testing modern HF therapy in patients with HFpEF had a neutral outcome, in contrast to the positive outcome observed with similar pharmacotherapy in patients with HFrEF [3]. The main reason for this discrepancy is failure of modern HF therapy to sufficiently address pathophysiological mechanisms driving left-ventricular (LV) remodeling in HFpEF [3, 4•]. LV remodeling substantially differs between HFpEF and HFrEF. In HFpEF, the left ventricle is concentrically remodeled with normal LV cavity size, increased wall thickness, and increased LV mass/volume ratio, whereas in HFrEF, the left ventricle is eccentrically remodeled with LV dilatation, normal or decreased wall thickness, and low LV mass/volume ratio [5, 6]. Similar findings are also observed at the microscopic and ultrastructural levels, with concentrically thickened, stiff cardiomyocytes in HFpEF and eccentrically enlarged, more compliant cardiomyocytes in HFrEF [5, 6]. In addition to disparate responses to similar pharmacotherapy and different patterns of chamber and myocellular remodeling in HFpEF and HFrEF, distinct differences are also observed in demographic and cardiovascular risk factor profiles [1, 2, 7, 8], supporting HFpEF and HFrEF as two separate HF phenotypes. The pathophysiology of HFpEF is incompletely understood, which precludes development of specific therapeutic strategies.

LV Diastolic Dysfunction in HFpEF

According to current criteria, HFpEF is diagnosed in the presence of signs and/or symptoms of HF, preserved systolic LV function with an EF of >50 %, and LV end-diastolic volume index of <97 ml/m2, as well as evidence of diastolic LV dysfunction [9]. The importance of diastolic LV dysfunction for HFpEF was recently reappraised by invasive studies that showed slow LV relaxation and elevated diastolic LV stiffness at rest [10, 11]. In addition, elevated diastolic LV stiffness limited cardiac performance during atrial pacing and exercise [11, 12]. Reduced LV distensibility and increased diastolic stiffness in HFpEF can be explained by the left and upward shift of the LV end-diastolic pressure–volume relation (LV EDPVR), with an increased slope of the LV EDPV curve [6, 10]. Hence, each LV end-diastolic volume is associated with a high end-diastolic pressure. In HFpEF, the steep LV EDPVR seems the most important determinant for impaired exercise tolerance, with deficient early diastolic LV recoil, blunted LV lusitropic or chronotropic response, vasodilator incompetence, and deranged ventriculovascular coupling serving contributory roles [13]. In the absence of endocardial or pericardial disease, the steep LV EDPVR results from increased myocardial stiffness, which is regulated by the extracellular matrix (ECM) and the cardiomyocytes [14].

Regulation of Diastolic Stiffness by the ECM

The ECM contributes to passive stiffness in diastole and prevents overstretch, myocyte slippage, and tissue deformation during ventricular filling, while ECM components also serve as modulators of growth and tissue differentiation [15]. Chronic pressure overload, as occurs in hypertensive heart disease, is associated with excessive forms of collagen deposition, which increases myocardial stiffness [16]. Collagen importantly determines ECM-based stiffness, through regulation of its total amount, expression of collagen type I, and degree of collagen cross-linking [15, 16], which are increased and linked to diastolic LV dysfunction in patients with HFpEF [17, 18•]. In a recent substudy from the landmark HFpEF I-PRESERVE (The Irbesartan in Heart Failure with Preserved Systolic Function) trial, which had a neutral overall outcome [19], increased baseline plasma levels of collagen markers were not independently associated with adverse outcome on multivariable analysis but were on single-variable analysis [20]. Hence, this study partially supports the hypothesis that pathological fibrosis contributes to adverse prognosis in patients with HFpEF [20]. Myocardial collagen turnover is dynamically modulated by the local renin-angiotensin-aldosterone system (RAAS) and transforming growth factor β(TGF-β) [15, 16] and through modulation of collagen synthesis and degradation by matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) [21]. In HFpEF, matrix degradation is decreased because of altered expression of MMPs and up-regulation of TIMPs [22, 23, 24, 25]. Previously, serological markers of collagen turnover significantly predicted diastolic dysfunction and HFpEF, with MMP2 representing the most sensitive and specific biomarker for the identification of HFpEF [23]. Plasma levels of TIMP-1 also predicted diastolic LV dysfunction [24] and have recently been proposed as a potential biomarker of HFpEF in hypertensive patients [25]. In patients with dilated cardiomyopathy, matrix degradation is increased because of up-regulation of MMPs [26]. Distinct expression profiles of MMPs and TIMPs also correspond with unequal patterns of myocardial collagen deposition, with mainly interstitial fibrosis in HFpEF and both replacement and interstitial fibrosis in dilated cardiomyopathy [4•].

Importance of Inflammation in HFpEF

Myocardial inflammation was shown to contribute to ECM changes and diastolic dysfunction in HFpEF [27•]. In an endomyocardial biopsy study, when compared with controls, HFpEF patients had increased inflammatory cell TGF-β expression, which induces transdifferentiation of fibroblasts into myofibroblasts, with high production of collagen and low expression of MMP1, whereas both myocardial collagen and the amount of inflammatory cells correlated with diastolic LV dysfunction [27•]. As compared with asymptomatic hypertensives, HFpEF patients had increased circulating biomarkers of inflammation (interleukin 6 [IL6], IL8, monocyte chemoattractant protein 1), of collagen metabolism (aminoterminal propeptide of collagen III, carboxy-terminal telopeptide of collagen I), and of ECM turnover (MMP2 and MMP9) [28]. In addition, MMP9, TIMP1, and the ratio of MMP9/TIMP1 correctly identified patients with a high left atrial volume index, which reflects chronic diastolic LV dysfunction [28]. Moreover, the Health ABC study reported inflammatory biomarkers such as IL6 and tumour necrosis factor α to be strongly associated with the propability of HFpEF development in elderly patients [29].

Interestingly, LV endomyocardial biopsy studies demonstrated that one third of HFpEF patients had a normal myocardial collagen volume fraction (CVF), despite similarly elevated LV end-systolic wall stress and LV stiffness modulus, as compared with HFpEF patients with raised CVF [30]. Numerous subsequent studies unequivocally attributed high diastolic LV stiffness to elevated intrinsic cardiomyocyte stiffness (Fpassive) in HFpEF patients [4•, 30, 31, 32••].

Regulation of Diastolic Stiffness by the Cardiomyocytes

Cardiomyocyte Fpassive is mainly determined by the giant elastic sarcomeric protein titin, which regulates myocardial passive tension, stiffness, and biomechanical stress/stretch signaling [33•]. Titin spans a half sarcomere, running from the Z-disk to the M-band, and functions as a bidirectional spring responsible for early diastolic recoil and late diastolic resistance to stretch [33•]. Within physiological volumes at a sarcomere length (SL) range of 1.8–2.2 μm, titin was identified as the dominant determinant of LV passive pressure, contributing approximately 80 % to LV passive stiffness, while the contribution of the ECM appeared more important at an SL higher than 2.2 μm [34]. Cardiomyocyte titin-based elasticity can be adjusted through transcriptional and posttranslational modifications. At the transcriptional level, titin modulates stiffness through shifts in expression of its compliant N2BA (3.2–3.7 MDa) and stiff N2B (3.0 MDa) isoforms, which are co-expressed in the sarcomere at a N2BA:N2B ratio of approximately 35:65 in the normal heart [33•]. In eccentrically remodeled hearts from dilated [4•, 35, 36] or ischemic cardiomyopathy [37] patients, the N2BA:N2B expression ratio was increased, resulting in reduced myocardial stiffness. In contrast, the N2BA:N2B expression ratio was decreased in LV endomyocardial biopsies from HFpEF patients, as compared with patients with HFrEF [4•].

Titin-based stiffness is posttranslationally modified by a variety of mechanisms. Protein kinase A (PKA) and protein kinase G (PKG) mediated phosphorylation of the stiff N2B segment of titin acutely lowers Fpassive in skinned human LV muscle strips [38, 39••], in isolated human LV myofibrils [39••], and in isolated cardiomyocytes from HFpEF and HFrEF patients [4•, 30, 31, 32••]. Two additional posttranslational modifications of titin, both increasing titin-based stiffness, include protein kinase C α (PKCα) mediated phosphorylation of titin’s PEVK segment (rich in proline, glutamic acid, valine, and lysine) [40] and oxidative stress-induced formation of disulfide bridges in the N2B segment [41]. Contribution by other myofilamentary proteins, such as myosin heavy chain, desmin, actin, troponin T, troponin I, and myosin light chain 1 and 2 was recently ruled out [30, 32••], suggesting that phosphorylation-mediated posttranslational modification of titin represents the most likely mechanism for acute modulation of cardiomyocyte Fpassive. Acute lowering of cardiomyocyte Fpassive by PKA and PKG suggests a myofilamentary protein phosphorylation deficit in HF. In HFpEF, slow LV relaxation and high diastolic LV stiffness have been shown to react favorably to raised PKG activity following in vivo administration of sildenafil, which raises myocardial PKG activity through inhibited breakdown of cyclic guanosine monophosphate (cGMP) by phosphodiesterase type 5A (PDE5A) [42•]. Sildenafil restored LV relaxation kinetics in mice exposed to transverse aortic constriction (TAC) [43] and reduced diastolic LV stiffness in an old hypertensive dog model [44••], in patients with HFrEF [45•], and in HFpEF patients with pulmonary hypertension [46••]. Administration of sildenafil to elderly hypertensive dogs lowered diastolic LV stiffness through restored phosphorylation of the titin N2B segment [44••], which was recently shown to be hypophosphorylated in HF patients [32••] and to have PKG phosphorylation sites [39••]. We recently measured PKG activity, upstream control of PKG activity, and downstream effects of PKG activity in LV myocardial biopsies of HFpEF patients [47••]. To discern altered control by PKG of the myocardial remodeling process in HFpEF, measurements were compared with measurements obtained from LV myocardium remodeled concentrically by severe aortic stenosis (AS) or eccentrically by nonischemic HFrEF. Our study showed that relative to both AS and HFrEF, HFpEF patients had reduced myocardial PKG activity and lower cGMP concentration, which related to higher cardiomyocyte Fpassive and increased myocardial nitrotyrosine levels, indicative of raised nitrosative/oxidative stress. In all groups, cardiomyocyte Fpassive was acutely lowered by in vitro administration of PKG, whereas cardiomyocytes from HFpEF patients demonstrated the largest PKG-induced fall in Fpassive [47••]. Reduced PKG activity and lower myocardial cGMP concentration in HFpEF did not result from altered myocardial soluble guanylate cyclase (sGC) or PDE5A expression, which were similar in all groups, or from unequal natriuretic peptide (NP) expression, which was comparable in HFpEF and AS. Downregulation of cGMP-PKG signaling in HFpEF was therefore most likely related to low myocardial nitric oxide (NO) bioavailability because of high nitrosative/oxidative stress, which was almost fourfold higher in HFpEF than in both HFrEF and AS [47••]. Oxidative stress is known to lower NO bioavailability and down-regulate cGMP-PKG signaling [48, 49].

Importance of Myocardial NO for Diastolic LV Function

NO is crucially important for diastolic function, since it potently enhances LV relaxation and distensibility through cGMP-PKG dependent and independent mechanisms, including reduction of myofilament calcium (Ca2+) sensitivity by troponin I phosphorylation and enhancing phospholamban-mediated sarcoplasmic reticular (SR) Ca2+ reuptake, respectively [50]. NO is an ubiquitous intra- and intercellular signaling molecule generated in a temporally and spatially restricted manner by a family of NO synthases (NOSs), including endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS), which vary in their subcellular localization [42•, 51, 52•]. The myocardial autocrine and paracrine effects of NO depend on where and by which NOS isoform NO is produced [51]. Myocardial eNOS-derived NO was demonstrated to enhance LV relaxation and distensibility [53, 54, 55] and to modulate cardiac β-adrenergic responsiveness [56]. Stimulation of eNOS activity by intracoronary administration of NO donors instantaneously hastened LV relaxation, accelerated LV pressure decline, and increased diastolic LV distensibility in the normal human heart [53], as well as in patients with dilated cardiomyopathy [54] and severe AS [55].

NO- and NP-Mediated Activation of cGMP-PKG Signaling

NO activates sGC, which is present predominantly in the cytosol and in smaller amounts at the plasma membrane, via a complex interplay between binding of NO to both heme and nonheme sites of sGC [42•, 52•]. Stimulated sGC subsequently enhances cGMP generation, which modulates phosphodiesterase (PDE) enzyme activity and activates its primary effector kinase PKG [42•, 52•]. In turn, PKG phosphorylates a vast number of target proteins, exerting a wide range of downstream effects like enhanced reuptake of Ca2+ into the SR, inhibition of Ca2+ influx, and suppression of hypertrophic and fibrotic signaling, as well as stimulation of LV relaxation and LV distensibility by phosphorylation of troponin I and the stiff titin N2B segment [39••, 42•, 52•].

Because NO diffusion distances in cardiomyocytes are limited, NO-sGC-cGMP signaling is compartmentalized into functional signalosomes, coupling NO synthesis to downstream sGC-cGMP signals [52•]. For instance, in cardiomyoyctes and endothelial cells, eNOS, sGC, and PKG colocalize with caveolin at plasma membrane invaginations, called caveolae, which may serve as microdomains for optimized NO-sGC-cGMP signaling [52•, 57].

In addition, NP-mediated activation of cGMP-PKG signaling is spatially confined to a distinct subcellular compartment. Natriuretic peptides stimulate the NP receptor at the plasma membrane, resulting in activation of particulate GC (pGC). Activated pGC subsequently stimulates cGMP generation and PKG activation confined to a subsarcoplasmic membrane compartment [52•, 57].

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are released by atrial and ventricular cardiomyocytes, respectively, in response to increased myocardial wall stress due to volume- or pressure-overload conditions [52•, 58]. Both NPs stimulate natriuresis, vasorelaxation, and myocardial relaxation, while they inhibit neurohumoral activation, fibrosis, and hypertrophy [58, 59]. We recently observed myocardial proBNP-108 expression to be similar in HFpEF and AS and higher in HFrEF than in both HFpEF and AS [47••]. These observations are consistent with BNP expression being predominantly regulated by diastolic LV wall stress, which is higher in HFrEF because of eccentric LV remodeling and similar in HFpEF and AS because of concentric LV remodeling [60]. Because of comparable proBNP-108 expression in HFpEF and AS, BNP is unlikely to account for the widely different PKG activities and cGMP concentrations observed in both conditions, which were therefore attributed to higher nitrosative/oxidative stress in HFpEF than in AS [47••]. Lower proBNP-108 expression in HFpEF than in HFrEF also explains the low positive predictive value of BNP for the diagnosis of HFpEF [61]. Acute BNP administration was recently reported to lower diastolic LV stiffness and to increase myocardial titin phosphorylation in an old hypertensive HFpEF dog model [44••] but failed to improve clinical endpoints in acutely decompensated HF patients with LVEF ≥ 40 % [62].

Compartmentalization of cGMP-PKG Signaling and Cross Talk With cAMP Signaling

Particulate GC and sGC generate spatially and functionally distinct cellular pools of cGMP, with NP-pGC-cGMP signals regulated by PDE type 2 (PDE2) and NO-sGC-cGMP signals regulated by PDE5A [63•]. Functionally distinct compartmentalization of NP-pGC-cGMP and NO-sGC-cGMP pathways was shown in rodent cardiomyocytes, in which the PDE5A inhibitor sildenafil suppressed cardiac β-adrenergic receptor (β-AR) responsiveness, which was abrogated by NOS inhibition, whereas activation of pGC by ANP had no effect, despite higher myocardial cGMP elevations [56]. Importantly, considerable cross talk exists between both NO- and NP-mediated cGMP-PKG signaling and the β-AR-cAMP-PKA signaling pathway, which importantly regulates excitation–contraction coupling, relaxation, and myofilament Ca2+ sensitivity [64].

Recently, it was demonstrated that activation of a signalosome consisting of the beta3-adrenergic receptor (β3-AR) and eNOS-NO-sGC-cGMP counteracts myocardial β1-AR- and β2-AR-mediated cardiac stimulation. This inhibition occurred both through cGMP-induced activation of PDE2, which subsequently inhibited cAMP, and through PKG-mediated phosphorylation of troponin I [65, 66]. In rat cardiomyocytes, it was demonstrated that NP-pGC-mediated cGMP generation elicits a strong feed-forward mechanism that further enhances cGMP production in the subsarcolemmal pool [63•]. In contrast, increased cGMP production by NO-sGC activates a negative feedback regulation through PKG-mediated activation of PDE5A, which subsequently inhibits further cGMP generation [63•].

The beneficial clinical and experimental effects of PDE5A inhibitors on diastolic LV stiffness and cardiac remodeling [43, 44••, 45•, 46••] might be explained by PDE5A inhibitors interfering with the negative feedback regulation mediated by PKG, finally resulting in enhanced PKG signaling.

Importance of cGMP-PKG Signaling in Myocardial Remodeling

Cardiac remodeling in HFpEF is characterized by concentric LV and cardiomyocyte hypertrophy and interstitial fibrosis [4•, 5, 17, 18•]. The Framingham Heart Study determined that LV hypertrophy follows aging as an independent risk factor for cardiovascular morbidity and mortality [67]. Stimuli for LV hypertrophy activate an array of membrane-bound receptors coupled to multiple intracellular signaling cascades, which ultimately stimulate prohypertrophic gene expression [59]. Important upstream triggers for cardiac hypertrophy include mechanical stretch, pressure overload, cytokines, activation of RAAS, endothelin, and catecholamines, whereas cGMP-PKG signaling exerts prominent antihypertrophic and antifibrotic effects [42•, 59]. Indeed, modulation of the sGC-PKG-PDE5A axis affected myocardial remodeling with less cardiomyocyte hypertrophy and interstitial fibrosis in TAC mice exposed to sildenafil [43]. Despite similar levels of LV and cardiomyocyte hypertrophy in patients with HFpEF and AS, HFpEF patients demonstrated higher cardiomyocyte Fpassive and lower myocardial PKG activity than did AS patients [47••]. The finding in AS, of higher PKG activity corresponding with low Fpassive but not with cardiomyocyte diameter, suggests that cardiomyocyte diastolic stiffness evolves independently of cardiomyocyte hypertrophy. This concept also emerged from the VALIDD trial, in which only 3 % of hypertensives had significant LV hypertrophy, despite all having diastolic LV dysfunction [68]. External myocardial force signals imposed during hemodynamic load are transmitted to ECM components and the cardiomyocytes [69]. Mechanical stimuli sensed at the outer cardiomyocyte cell membrane can activate cytoskeletal and sarcomeric signaling cascades, which subsequently trigger prohypertrophic factors [69]. In addition to its prominent role in regulating cardiomyocyte stiffness, titin also acts as a dominant signaling protein, which integrates both internally generated sarcomeric forces and externally sensed biomechanical stretch/stress signals to hypertrophy regulation [70•]. Thus, one could speculate that increased cardiomyocyte stiffness sensed by titin precedes titin-mediated stimulation of prohypertrophic signaling.

Importance of NO-cGMP Signaling in Myocardial Energetics

Another paracrine action of endothelial eNOS-derived NO is regulation of myocardial metabolism through modulation of myocardial substrate utilization and by reduction of myocardial oxygen consumption through inhibition of complexes I and II of the mitochondrial electron transport chain [51, 71]. Interestingly, mitochondrial biogenesis is stimulated in response to increased myocardial NO bioavailability and cGMP levels [72]. Because cross-bridge detachment is an energy-consuming process, slow LV relaxation in HFpEF could therefore also result from a myocardial energy deficit. Indeed, recent 31P-magnetic resonance spectroscopy studies demonstrated reduced myocardial energy reserve both in patients with HFpEF [73] and in asymptomatic, normotensive patients with diabetes mellitus type II (DMII), in whom impaired myocardial bioenergetics correlated with diastolic LV dysfunction [74]. Furthermore, cardiac energetic deficiency relating to diastolic dysfunction was also recently demonstrated in obese, as compared with normal weight, subjects both at rest and during inotropic stress with high-dose intravenous dobutamine administration [75].

Nitrosative/Oxidative Stress Lowers NO Bioavailability and NO Signaling in HFpEF

Reduced NO bioavailability, dysregulation of NO-mediated signaling, and increased nitrosative/oxidative stress are firmly implicated in the pathogenesis of HF [49, 76]. Enhanced nitrosative/oxidative stress impairs NO bioavailability and NO-mediated signaling through a number of mechanisms. First, superoxide rapidly reacts with NO to form peroxynitrite. Peroxynitrite oxidizes the essential eNOS cofactor tetrahydrobiopterin (BH4) and triggers eNOS uncoupling with subsequent generation of superoxide instead of NO, thereby augmenting oxidative stress. Second, by scavenging NO, superoxide reduces NO bioavailability and prevents NO from stimulating sGC-mediated activation of cGMP-PKG signaling [48, 49, 76]. Finally, sGC activity is adversely affected by nitrosative/oxidative stress through several mechanisms, including superoxide- and peroxynitrite-mediated decrease in sGC activity and sGC heme group oxidation converting sGC to its NO-insensitive state [49, 57]. In a TAC mouse model, pressure overload decreased sGC responsiveness to NO through sGC heme oxidation and through a shift of sGC out of caveolae-enriched microdomains [57].

The lower myocardial PKG activity and reduced cGMP concentration in HFpEF patients, which was associated with increased myocardial nitrotyrosine levels [47••], could, therefore, have resulted from upstream nitrosative/oxidative stress-induced impairments of NO bioavailability and reduced NO-mediated activation of sGC-induced cGMP/PKG signaling. Accordingly, a number of recent studies also suggested that oxidative stress is involved in the pathogenesis of diastolic LV dysfunction in HFpEF. In HFpEF rodent models, oxidative stress uncoupled cardiac NOS and induced diastolic LV dysfunction, whereas stimulation of eNOS activity reversed oxidative stress and improved diastolic LV function [77, 78]. Furthermore, high plasma levels of methylated L-arginine metabolites, indicative of increased oxidative stress, were strongly related to diastolic LV dysfunction in patients with HFrEF [79]. Moreover, in patients with HFpEF, myocardial fibrosis and inflammation were associated with diastolic LV dysfunction and with increased oxidative stress in endomyocardial biopsies, as compared with controls [27•].

Abundant evidence demonstrates that reactive oxygen species (ROS) potently activate prohypertrophic and profibrotic signaling, and by interfering with NO-sGC-cGMP-PKG signaling, ROS inhibit antihypertrophic and antifibrotic signaling cascades [59, 76].

In addition, nitrosative/oxidative stress induces a state of NO/redox disequilibrium, which impairs S-nitrosylation signaling (a posttranslational protein modification process through coupling of an NO moiety to a reactive cysteine thiol). S-nitrosylation serves as a major effector of NO bioactivity and an important mode of cellular signal transduction, regulating the activity of numerous metabolic enzymes, kinases, phosphatases, and respiratory proteins, as well as cytoskeletal and structural components and transcription factors [76].

Possible Mechanisms for Enhanced Nitrosative/Oxidative Stress in HFpEF

It was recently suggested that the particularly high prevalence of metabolic risk factors in HFpEF could be associated with increased inflammation and nitrosative/oxidative stress in this condition [47••]. HFpEF patients demonstrate a high prevalence of obesity and DMII [7, 8, 80]. Obesity and DMII are strongly related to insulin resistance (IR) and the metabolic syndrome (a constellation of cardiovascular risk factors, including obesity, hypertension, IR, hyperglycemia, dyslipidemia, microalbuminuria, and hypercoagulability), and the frequent clustering of these metabolic risk factors causes synergistic adverse effects on myocardial structure and function [81]. The prevalence of obesity, DMII, IR, and metabolic syndrome increases rapidly and is expected to reach pandemic proportions in the next few decades [81], while these metabolic risk factors have all been prospectively identified as precursors of incident HF [82, 83, 84, 85] and are independently associated with early development of diastolic LV dysfunction [86•, 87, 88•, 89]. Diabetes increases LV diastolic and cardiomyocyte stiffness in both HFpEF [31] and AS [90] patients. Elevated cardiomyocyte stiffness in diabetic AS patients related to hypophosphorylation of the titin N2B segment, which could be corrected by phosphorylation with PKA [90].

Obesity, DMII, and IR can have direct adverse effects on myocardial structure and function independently of common confounders as hypertension or CAD, which has been referred to as “obesity” [91], “diabetic” [92], or “insulin-resistant” [93] cardiomyopathy. Moreover, metabolic risk factors are strongly associated with endothelial dysfunction, inflammation, oxidative stress, impaired myocardial energetics, abnormal cardiomyocyte Ca2+ handling, reduced NO bioavailability, and maladaptive cardiac remodeling [91, 92, 93].

Metabolic Risk Factors Interfere with NO-cGMP-PKG Signaling

Oxidative stress-mediated down-regulation of NO-cGMP-PKG signaling has been demonstrated in various experimental models of obesity, diabetes, IR, and metabolic syndrome [94, 96•]. Cultured rodent aortic smooth muscle cells subjected to hyperglycaemia demonstrated significantly reduced PKG expression and activity, which occurred through a PKC-dependent activation of NADPH oxidase-derived superoxide production [94]. In this model, high glucose-mediated lowering of PKG levels was inhibited by a superoxide scavenger or NADPH oxidase inhibitors [94]. In addition, in human diabetic cardiomyopathy, sildenafil improved measurements of LV geometry, strain, and torsion determined by magnetic resonance imaging [95]. Furthermore, in a rodent model of diet-induced obesity and IR, signaling through the NO-cGMP pathway was reduced, while vascular inflammation and IR were completely prevented by administration of sildenafil [96•].

Physiologically, insulin phosphorylates titin through activation of the phosphoinositol-3-kinase (PI3K)/Akt/eNOS pathway, while IR, free fatty acids, and adipokines inhibit insulin-dependent PI3K/Akt signaling, resulting in reduced eNOS activity and impaired NO generation [97, 98]. Inflammation and oxidative stress associated with metabolic risk factors can reduce eNOS activity and NO bioavailability through a number of ways, including RAAS-mediated activation of ROS producing enzymes, increased flux through the hexosamine biosynthesis pathway, mitochondrial uncoupling, activation of the polyol pathway, lipotoxicity, glucose auto-oxidation, and formation of advanced glycation end products [98]. Moreover, obesity, DM, and IR induce activation of multiple PKC isoforms, with PKCs being prominently involved in numerous cellular functions and signal transduction pathways [99]. PKC can hamper myocardial eNOS activity and NO generation by inhibition of PI3K/Akt signaling and stimulation of NADPH oxidase activity [99], whereas PKCα was recently shown to increase titin-based cardiomyocyte stiffness through phosphorylation of the PEVK segment [40]. Interestingly, in a rodent diabetic HFpEF model, PKCβ inhibition improved diastolic distensiblity, contractility, and maladaptive cardiac remodeling [100].

In summary, metabolic risk factors could contribute to diastolic LV dysfunction and elevated myocardial stiffness in HFpEF by provoking myocardial inflammation and nitrosative/oxidative stress, which in turn results in decreased NO bioavailability, down-regulation of cGMP-PKG signaling, impaired myocardial bioenergetics, and maladaptive remodeling. Furthermore, down-regulation of cGMP-PKG signaling could subsequently result in hypophosphorylation of titin, which elevates cardiomyocyte stiffness and possibly triggers cardiomyocyte hypertrophy.


HFpEF is widely prevalent and is associated with a poor prognosis because of the absence of effective therapeutic strategies due to an incomplete understanding of its pathophysiology. In HFpEF, increased diastolic LV stiffness can be explained by maladaptive changes in the ECM and by elevated cardiomyocyte stiffness, which seem to be related to myocardial inflammation and nitrosative/oxidative stress. Patients with HFpEF demonstrate a high prevalence of metabolic disorders, which may contribute to enhanced myocardial inflammation, nitrosative/oxidative stress, and down-regulation of NO bioavailability and NO-mediated cGMP-PKG signaling, thereby triggering diastolic LV dysfunction. Therefore, targeting metabolic risk and improving endothelial function, NO bioactivity and cGMP-PKG signaling can be promising strategies for specific HFpEF treatment.



L. van Heerebeek, C.P.M. Franssen, N. Hamdani, and W.J. Paulus are funded through a grant from European Commission FP7 Health 2010, Large Collaborative Research Project on Diastolic Heart Failure MEDIA (261409).


No potential conflicts of interest relevant to this article were reported.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355:251–9.PubMedCrossRefGoogle Scholar
  2. 2.
    The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis. Meta-analysis Global Group in Chronic Heart Failure (MAGGIC). Eur Heart J 2011, Aug 6, epub ahead of print.Google Scholar
  3. 3.
    Paulus WJ, van Ballegoij JJ. Treatment of heart failure with normal ejection fraction: an inconvenient truth! J Am Coll Cardiol. 2010;55:526–37.PubMedCrossRefGoogle Scholar
  4. 4.
    • Schwartzenberg S, Redfield MM, From AM, et al. Effects of vasodilation in heart failure with preserved or reduced ejection fraction implications of distinct pathophysiologies on response to therapy. J Am Coll Cardiol. 2012;59:442–51. This article provides evidence that HFpEF and HFrEF represent distinct heart failure phenotypes as hemodynamic responses to acute vasodilator therapy substantially differ between HFpEF and HFrEF patients. PubMedCrossRefGoogle Scholar
  5. 5.
    van Heerebeek L, Borbely A, Niessen HWM, et al. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation. 2006;113:1966–73.PubMedCrossRefGoogle Scholar
  6. 6.
    Aurigemma GP, Zile MR, Gaasch WH. Contractile behavior of the left ventricle in diastolic heart failure: with emphasis on regional systolic function. Circulation. 2006;113:296–304.PubMedCrossRefGoogle Scholar
  7. 7.
    Yancy CW, Lopatin M, Stevenson LW, et al. For the ADHERE Scientific Advisory Committee and Investigators. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function. A Report from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol. 2006;47:76–84.PubMedCrossRefGoogle Scholar
  8. 8.
    Fonorow GC, Stough WG, Abraham WT, et al. OPTIMIZE-HF Investigators and Hospitals. Characteristics, treatments and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol. 2007;50:768–77.CrossRefGoogle Scholar
  9. 9.
    Paulus WJ, Tschope C, Sanderson JE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J. 2007;28:2539–50.PubMedCrossRefGoogle Scholar
  10. 10.
    Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure – abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med. 2004;350:1953–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Westermann D, Kasner M, Steendijk P, et al. Role of left ventricular stiffness in heart failure with normal ejection fraction. Circulation. 2008;117:2051–60.PubMedCrossRefGoogle Scholar
  12. 12.
    Borlaug BA, Nishimura RA, Sorajja P, et al. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail. 2010;3:588–95.PubMedCrossRefGoogle Scholar
  13. 13.
    Paulus WJ. Culprit Mechanism(s) for Exercise Intolerance in Heart Failure With Normal Ejection Fraction. J Am Coll Cardiol. 2010;56:864–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis and treatment. Eur Heart J. 2011;32:670–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Weber KT, Sun Y, Tyagi SC, Cleutjens JP. Collagen network of the myocardium: function, structural remodeling and regulatory mechanisms. J Mol Cell Cardiol. 1994;26:279–92.PubMedCrossRefGoogle Scholar
  16. 16.
    Berk BC, Fujiwara K, Lehoux S. ECM remodeling in hypertensive heart disease. J Clin Invest. 2007;117:568–75.PubMedCrossRefGoogle Scholar
  17. 17.
    Martos R, Baugh J, Ledwidge M, et al. Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation. 2007;115:888–95.PubMedCrossRefGoogle Scholar
  18. 18.
    • Kasner M, Westermann D, Lopez B, et al. Diastolic tissue Doppler indexes correlate with the degree of collagen expression and cross-linking in heart failure and normal ejection fraction. J Am Coll Cardiol. 2011;57:977–85. This study demonstrates that extracellular matrix remodelling correlates with diastolic LV dysfunction and reduced exercise capacity in patients with HFpEF.PubMedCrossRefGoogle Scholar
  19. 19.
    Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456–67.PubMedCrossRefGoogle Scholar
  20. 20.
    Krum H, Elsik M, Schneider HG, et al. Relation of peripheral collagen markers to death and hospitalization in patients with heart failure and preserved ejection fraction: results of the I-PRESERVE collagen substudy. Circ Heart Fail. 2011;4:561–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol Rev. 2007;87:1285–342.PubMedCrossRefGoogle Scholar
  22. 22.
    Ahmed SH, Clark LL, Pennington WR, et al. Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation. 2006;113:2089–96.PubMedCrossRefGoogle Scholar
  23. 23.
    Martos R, Baugh J, Ledwidge M, et al. Diagnosis of heart failure with preserved ejection fraction: improved accuracy with the use of markers of collagen turnover. Eur J Heart Fail. 2009;11:191–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Lindsay MM, Maxwell P, Dunn FG. TIMP-1: a marker of left ventricular diastolic dysfunction and fibrosis in hypertension. Hypertension. 2002;40:136–41.PubMedCrossRefGoogle Scholar
  25. 25.
    González A, López B, Querejeta R, et al. Filling pressures and collagen metabolism in hypertensive patients with heart failure and normal ejection fraction. Hypertension. 2010;55:1418–24.PubMedCrossRefGoogle Scholar
  26. 26.
    Spinale FG, Coker ML, Heung LJ, et al. A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation. 2000;102:1944–9.PubMedCrossRefGoogle Scholar
  27. 27.
    • Westermann D, Lindner D, Kasner M, et al. Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction. Circ Heart Fail. 2011;4:44–52. This study demonstrates that cardiac inflammation contributes to maladaptive cardiac extracellular matrix remodelling and diastolic LV dysfunction in HFpEF. PubMedCrossRefGoogle Scholar
  28. 28.
    Collier P, Watson CJ, Voon V, et al. Can emerging biomarkers of myocardial remodelling identify asymptomatic hypertensive patients at risk for diastolic dysfunction and diastolic heart failure? Eur J Heart Fail. 2011;13:1087–95.PubMedCrossRefGoogle Scholar
  29. 29.
    Kalogeropoulos A, Georgiopoulou V, Psaty BM, et al. Health ABC Study Investigators. Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study. J Am Coll Cardiol. 2010;55:2129–37.PubMedCrossRefGoogle Scholar
  30. 30.
    Borbely A, van der Velden J, Papp Z, et al. Cardiomyocyte stiffness in diastolic heart failure. Circulation. 2005;111:774–81.PubMedCrossRefGoogle Scholar
  31. 31.
    van Heerebeek L, Hamdani N, Handoko ML, et al. Diastolic stiffness of the failing diabetic heart: Importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation. 2008;117:43–51.PubMedCrossRefGoogle Scholar
  32. 32.
    •• Borbely A, Falcao-Pires I, van Heerebeek L, et al. Hypophosphorylation of the stiff N2B titin isoform raises cardiomyocyte resting tension in failing human myocardium. Circ Res. 2009;104:780–6. This study is of major importance as it links increased cardiomyocyte stiffness to posttranslational modifications of the giant elastic sarcomeric protein titin. A specific titin N2B phosphorylation deficit was demonstrated in heart failure patients which was associated with increased cardiomyocyte stiffness. PubMedCrossRefGoogle Scholar
  33. 33.
    • Krüger M, Linke WA. Titin-based mechanical signaling in normal and failing myocardium. J Mol Cell Cardiol. 2009;46:490–8. This review article represents a thorough overview of the important role of titin in determination of cardiomyocyte stiffness and biomechanical signaling. PubMedCrossRefGoogle Scholar
  34. 34.
    Chung CS, Granzier HL. Contribution of titin and extracellular matrix to passive pressure and measurement of sarcomere length in the mouse left ventricle. J Mol Cell Cardiol. 2011;50:731–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Makarenko I, Opitz CA, Leake MC, et al. Passive stiffness changes caused by upregulation of compliant titin isoforms in human dilated cardiomyopathy hearts. Circ Res. 2004;95:708–16.PubMedCrossRefGoogle Scholar
  36. 36.
    Nagueh SF, Shah G, Wu Y, et al. Altered titin expression, myocardial stiffness and left ventricular function in patients with dilated cardiomyopathy. Circulation. 2004;110:155–62.PubMedCrossRefGoogle Scholar
  37. 37.
    Neagoe C, Kulke M, del Monte F, et al. Titin isoform switch in ischemic human heart disease. Circulation. 2002;106:1333–41.PubMedCrossRefGoogle Scholar
  38. 38.
    Krüger M, Linke WA. Protein kinase-A phosphorylates titin in human heart muscle and reduces myofibrillar passive tension. J Muscle Res Cell Motil. 2006;27:435–44.PubMedCrossRefGoogle Scholar
  39. 39.
    •• Krüger M, Kötter S, Grützner A, et al. Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the titin springs. Circ Res. 2009;104:87–94. This article was the first to demonstrate specific PKG binding sites within the stiff N2B segment of titin and that PKG-mediated phosphorylation of the stiff N2B segment lowers cardiomyocyte stiffness. PubMedCrossRefGoogle Scholar
  40. 40.
    Hidalgo C, Hudson B, Bogomolovas J, et al. PKC phosphorylation of titin’s PEVK element. A novel and conserved pathway for modulating myocardial stiffness. Circ Res. 2009;105:631–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Grützner A, Garcia-Manyes S, Kötter S, et al. Modulation of titin-based stiffness by disulfide bonding in the cardiac titin N2-B unique sequence. Biophys J. 2009;97:825–34.PubMedCrossRefGoogle Scholar
  42. 42.
    • Tsai E, Kass DA. Cyclic GMP signalling in cardiovascular pathology and therapeutics. Pharmacol Ther. 2009;122:216–38. This review article provides comprehensive insight into the importance of cGMP-PKG signaling for cardiovascular physiology and pathophysiology. PubMedCrossRefGoogle Scholar
  43. 43.
    Takimoto E, Champion HC, Li M, et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med. 2005;11:214–22.PubMedCrossRefGoogle Scholar
  44. 44.
    •• Bishu K, Hamdani N, Mohammed SF, et al. Sildenafil and BNP acutely phosphorylate titin and improve diastolic distensbility in vivo. Circulation. 2011;124:2882–91. In an old, hypertensive dog model, enhanced signaling through the cGMP-PKG pathway by either stimulating natriuretic peptide-mediated activation of cGMP-PKG signaling as well as by sildenafil-mediated prevention of cGMP breakdown was shown to increase phosphorylation of titin, which improved diastolic LV distensibility. PubMedCrossRefGoogle Scholar
  45. 45.
    • Guazzi M, Vicenzi M, Arena R, et al. PDE-5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry and clinical status in patients with stable systolic heart failure: results of a 1-year prospective, randomized, placebo controlled trial. Circ Heart Fail. 2011;4:8–17. This study demonstrates that sildenafil improves diastolic function, cardiac remodelling and clinical status in HFrEF patients. PubMedCrossRefGoogle Scholar
  46. 46.
    •• Guazzi M, Vicenzi M, Arena R, et al. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study. Circulation. 2011;124:164–74. This study is the first to demonstrate improvements of diastolic function in HFpEF patients with pulmonary hypertension following sildenafil treatment. PubMedCrossRefGoogle Scholar
  47. 47.
    •• van Heerebeek L, Hamdani N, Falcao-Pires I, et al.: Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation 2012, In press. This study demonstrated reduced myocardial cGMP concentration and PKG activity in HFpEF compared to HFrEF and aortic stenosis patients. The lower myocardial cGMP concentration and reduced PKG acitivity in HFpEF were related to lower myocardial NO bioavailability due to increased nitrosative/oxidative stress. Google Scholar
  48. 48.
    Münzel T, Daiber A, Ullrich V, et al. Vascular consequences of endothelial nitric oxide synthase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase. Arterioscler Thromb Vasc Biol. 2005;25:1551–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Münzel T, Gori T, Bruno RM, Taddei S. Is oxidative stress a therapeutic target in cardiovascular disease? Eur Heart J. 2010;31:2741–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Paulus WJ, Bronzwaer JGF. Nitric oxide’s role in the heart: control of beating or breathing? Am J Physiol Heart Circ Physiol. 2004;287:H8–H13.PubMedCrossRefGoogle Scholar
  51. 51.
    Seddon M, Shah AM, Casadei B. Cardiomyocytes as effectors of nitric oxide signaling. Cardiovasc Res. 2007;75:315–26.PubMedCrossRefGoogle Scholar
  52. 52.
    • Hammond J, Balligand JL. Nitric oxide synthase and cyclic GMP signaling in cardiac myocytes: from contractility to remodeling. J Mol Cell Cardiol. 2012;52:330–40. This review provides comprehensive insight into the importance of NO and cGMP signaling in cardiomyocytes. PubMedCrossRefGoogle Scholar
  53. 53.
    Paulus WJ, Vantrimpont PJ, Shah AM. Acute effects of nitric oxide on left ventricular relaxation and diastolic distensibility in humans. Assessment by bicoronary sodium nitroprusside infusion. Circulation. 1994;89:2070–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Heymes C, Vanderheyden M, Bronzwaer JG, et al. Endomyocardial nitric oxide synthase and left ventricular preload reserve in dilated cardiomyopathy. Circulation. 1999;99:3009–16.PubMedCrossRefGoogle Scholar
  55. 55.
    Matter CM, Mandinov L, Kaufmann PA, et al. Effect of NO donors on LV diastolic function in patients with severe pressure-overload hypertrophy. Circulation. 1999;99:2396–401.PubMedCrossRefGoogle Scholar
  56. 56.
    Takimoto E, Belardi D, Tocchetti CG, et al. Compartmentalization of cardiac beta-adrenergic inotropy modulation by phosphodiesterase type 5. Circulation. 2007;115:2159–67.PubMedCrossRefGoogle Scholar
  57. 57.
    Tsai EJ, Liu Y, Koitabaschi N, et al. Pressure-overload-induced subcellular relocalization/oxidation of soluble guanylate cyclase in the heart modulates enzyme stimulation. Circ Res. 2012;110:295–303.PubMedCrossRefGoogle Scholar
  58. 58.
    Kim HN, Januzzi Jr JL. Natriuretic peptide testing in heart failure. Circulation. 2011;123:2015–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Ritchie RH, Irvine JC, Rosenkranz AC, et al. Exploiting cGMP-based therapies for the prevention of left ventricular hypertrophy: NO* and beyond. Pharmacol Ther. 2009;124:279–300.PubMedCrossRefGoogle Scholar
  60. 60.
    Iwanaga Y, Nishi I, Furuichi S, et al. B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: comparison between systolic and diastolic heart failure. J Am Coll Cardiol. 2006;47:742–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Shuai XX, Chen YY, Lu YX, et al. Diagnosis of heart failure with preserved ejection fraction: which parameters and diagnostic strategies are more valuable? Eur J Heart Fail. 2011;13:737–41.PubMedCrossRefGoogle Scholar
  62. 62.
    O’Connor CM, Starling RC, Hernandez AF, et al. Effect of Nesiritide in patients with acute decompensated heart failure. N Engl J Med. 2011;365:32–43.PubMedCrossRefGoogle Scholar
  63. 63.
    • Castro LRV, Schittl J, Fischmeister R. Feedback control through cGMP-dependent protein kinase contributes to differential regulation and compartmentation of cGMP in rat cardiac myocytes. Circ Res. 2010;107:1232–40. This study demonstrates that cGMP-PKG signaling is subject to complex differential spatiotemporal regulation and distinct compartmentation with the existence of specific cGMP-PKG “signalosomes” for either natriuretic peptide or NO. PubMedCrossRefGoogle Scholar
  64. 64.
    Zaccolo M, Movsesian MA. cAMP and cGMP signaling cross-talk: role of phosphodiesterases and implications for cardiac pathophysiology. Circ Res. 2007;100:1569–78.PubMedCrossRefGoogle Scholar
  65. 65.
    Mongillo M, Tocchetti CG, Terrin A, et al. Compartmentalized phosphodiesterase-2 activity blunts beta-adrenergic cardiac inotropy via an NO/cGMP-dependent pathway. Circ Res. 2006;98:226–34.PubMedCrossRefGoogle Scholar
  66. 66.
    Lee DI, Vahebi S, Tocchetti CG, et al. PDE5A suppression of acute beta-adrenergic activation requires modulation of myocyte beta-3 signaling coupled to PKG-mediated troponin I phosphorylation. Basic Res Cardiol. 2010;105:337–47.PubMedCrossRefGoogle Scholar
  67. 67.
    Levy D, Garrison RJ, Savage DD, et al. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990;322:1561–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Solomon SD, Janardhanan R, Verma A, et al. For the Valsartan In Diastolic Dysfunction (VALIDD) Investigators. Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: a randomised trial. Lancet. 2007;369:2079–87.PubMedCrossRefGoogle Scholar
  69. 69.
    Linke WA. Sense and stretchability: the role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction. Cardiovasc Res. 2008;77:637–48.PubMedGoogle Scholar
  70. 70.
    • Krüger M, Linke WA. The giant protein titin: a regulatory node that integrates myocyte signaling pathways. J Biol Chem. 2011;286:9905–12. This review article shows the importance of titin in biomechanical signaling and regulation of cardiac remodelling. PubMedCrossRefGoogle Scholar
  71. 71.
    Trochu JN, Bouhour JB, Kaley G, Hintze TH. Role of endothelium-derived nitric oxide in the regulation of cardiac oxygen metabolism: implications in health and disease. Circ Res. 2000;87:1108–17.PubMedCrossRefGoogle Scholar
  72. 72.
    Nisoli E, Tonello C, Cardile A, et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science. 2005;310:314–7.PubMedCrossRefGoogle Scholar
  73. 73.
    Smith CS, Bottomley PA, Schulman SP, et al. Altered creatine kinase adenosine triphosphate kinetics in failing hypertrophied human myocardium. Circulation. 2006;114:1151–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Diamant M, Lamb HJ, Groeneveld Y, et al. Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes mellitus. J Am Coll Cardiol. 2003;42:328–35.PubMedCrossRefGoogle Scholar
  75. 75.
    Rider OJ, Francis JM, Ali MK, et al. Effects of catecholamine stress on diastolic function and myocardial energetics in obesity. Circulation. 2012;125:1511–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Nediani C, Raimondi L, Borchi E, Cerbai E. Nitric oxide/reactive oxygen species generation and nitroso/redox imbalance in heart failure: from molecular mechanisms to therapeutic implications. Antiox Redox Signal. 2011;14:289–331.CrossRefGoogle Scholar
  77. 77.
    Silberman GA, Fan THM, Liu H, et al. Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction. Circulation. 2010;121:519–28.PubMedCrossRefGoogle Scholar
  78. 78.
    Westermann D, Riad A, Richter U, et al. Enhancement of the endothelial NO synthase attenuates experimental diastolic heart failure. Basic Res Cardiol. 2009;104:499–509.PubMedCrossRefGoogle Scholar
  79. 79.
    Wilson Tang WH, Tong W, Shrestha K, et al. Differential effects of arginine methylation on diastolic dysfunction and disease progression in patients with chronic systolic heart failure. Eur Heart J. 2008;29:2506–13.PubMedCrossRefGoogle Scholar
  80. 80.
    McMurray JJV, Carson PE, Komajda M, et al. Heart failure with preserved ejection fraction: Clinical characteristics of 4133 patients enrolled in the I-PRESERVE trial. Eur J Heart Fail. 2008;10:149–56.PubMedCrossRefGoogle Scholar
  81. 81.
    Horwich TB, Fonarow GC. Glucose, obesity, metabolic syndrome and diabetes. J Am Coll Cardiol. 2010;55:283–93.PubMedCrossRefGoogle Scholar
  82. 82.
    Kenchaiah S, Evans JC, Levy D, et al. Obesity and the risk of heart failure. N Engl J Med. 2002;347:305–13.PubMedCrossRefGoogle Scholar
  83. 83.
    Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol. 1974;34:29–34.PubMedCrossRefGoogle Scholar
  84. 84.
    Ingelsson E, Sundström J, Ärnlöv J, et al. Insulin resistance and risk of congestive heart failure. JAMA. 2005;294:334–41.PubMedCrossRefGoogle Scholar
  85. 85.
    Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;288:2709–16.PubMedCrossRefGoogle Scholar
  86. 86.
    • Russo C, Jin Z, Homma S, et al. Effect of obesity and overweight on left ventricular diastolic function. A community-based study in an elderly cohort. J Am Coll Cardiol. 2011;57:1368–74. HFpEF patients demonstrate a high prevalence of metabolic risk factors and obesity induces diastolic LV dysfunction independent of other cardiovascular risk factors. PubMedCrossRefGoogle Scholar
  87. 87.
    Boyer JK, Thanigaraj S, Schechtman KB, Pérez JE. Prevalence of ventricular diastolic dysfunction in asymptomatic, normotensive patients with diabetes mellitus. Am J Cardiol. 2004;93:870–5.PubMedCrossRefGoogle Scholar
  88. 88.
    • Dinh W, Lankisch M, Nickl W, et al. Insulin resistance and glycemic abnormalities are associated with deterioration of left ventricular diastolic function: a cross-sectional study. Cardiovasc Diabet. 2010;9:63–76. This study demonstrates that insulin resistance and glycemic abnormalities induce diastolic LV dysfunction. CrossRefGoogle Scholar
  89. 89.
    De las Fuentes L, Brown AL, Mathews SJ, et al. Metabolic syndrome is associated with abnormal left ventricular diastolic function independent of LV mass. Eur Heart J. 2007;28:553–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Falcao-Pires I, Hamdani N, Borbely A, et al. Diabetes mellitus worsens diastolic left ventricular dysfunction in aortic stenosis through altered myocardial structure and cardiomyocyte stiffness. Circulation. 2011;124:1151–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Abel ED, Litwin ES, Sweeney G. Cardiac remodelling in obesity. Physiol Rev. 2008;88:389–419.PubMedCrossRefGoogle Scholar
  92. 92.
    Falcao-Pires I, Leite-Moreira AF. Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment. Heart Fail Rev. 2011;17:325–44.CrossRefGoogle Scholar
  93. 93.
    Witteles RM, Fowler MB. Insulin-resistant cardiomyopathy. J Am Coll Cardiol. 2008;51:93–102.PubMedCrossRefGoogle Scholar
  94. 94.
    Liu S, Ma X, Gong M, et al. Glucose down-regulation of cGMP-dependent protein kinase I expression in vascular smooth muscle cells involves NAD(P)H oxidase-derived reactive oxygen species. Free Radic Biol Med. 2007;42:852–63.PubMedCrossRefGoogle Scholar
  95. 95.
    Giannetta E, Isidori AM, Galea N, et al. Chronic Inhibition of cGMP Phosphodiesterase 5A Improves Diabetic Cardiomyopathy: A Randomized, Controlled Clinical Trial Using Magnetic Resonance Imaging With Myocardial Tagging. Circulation. 2012;125:2323–33.PubMedCrossRefGoogle Scholar
  96. 96.
    • Rizzo NO, Maloney E, Pham M, et al. Reduced NO-cGMP signaling contributes to vascular inflammation and insulin resistance induced by high-fat feeding. Arterioscler Thromb Vasc Biol. 2010;30:758–65. This study links oxidative stress, inflammation and insulin resistance to downregulation of NO-cGMP signaling and vascular dysfunction. Inhibition of cGMP breakdown by sildenafil abrogated the detrimental vascular effects of high fat feeding and prevented vascular inflammation and insulin resistance. PubMedCrossRefGoogle Scholar
  97. 97.
    Krüger M, Babicz K, von Frieling-Salewsky M, Linke WA. Insulin signaling regulates cardiac titin properties in heart development and diabetic cardiomyopathy. J Mol Cell Cardiol. 2010;48:910–6.PubMedCrossRefGoogle Scholar
  98. 98.
    Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation. 2006;113:1888–904.PubMedCrossRefGoogle Scholar
  99. 99.
    Geraldes P, King GL. Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res. 2010;106:1319–31.PubMedCrossRefGoogle Scholar
  100. 100.
    Connelly KA, Kelly DJ, Zhang Y, et al. Inhibition of protein kinase C-beta by ruboxistaurin preserves cardiac function and reduces extracellular matrix production in diabetic cardiomyopathy. Circ Heart Fail. 2009;2:129–37.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Loek van Heerebeek
    • 1
    • 2
  • Constantijn P. M. Franssen
    • 1
  • Nazha Hamdani
    • 1
  • Freek W. A. Verheugt
    • 2
  • G. Aernout Somsen
    • 2
  • Walter J. Paulus
    • 1
    • 3
  1. 1.Department of PhysiologyInstitute for Cardiovascular Research, VU University Medical CenterAmsterdamThe Netherlands
  2. 2.Department of CardiologyOnze Lieve Vrouwe GasthuisAmsterdamThe Netherlands
  3. 3.ICaR-VU, VU University Medical CenterAmsterdamThe Netherlands

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