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)

Abstract

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.

Keywords

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 

Introduction

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.

Conclusion

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.

Notes

Acknowledgments

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).

Disclosure

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

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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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