Pathogenesis Of Heart Failure With Preserved Ejection Fraction Research Articles

The effect of sodium-glucose cotransporter type 2 inhibitors on left ventricular diastolic function: current status and prospects

Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) or gliflozins, are a new class of cardiovascular drugs with a proven clinical efficacy and a beneficial effect on prognosis in patients with heart failure with preserved ejection fraction (HFpEF). Impaired left ventricular (LV) diastolic function (DF) is an important element in the pathogenesis of HFpEF. Experimental studies have found intracellular mechanisms for the so-called diastolic effects in gliflozins. Studies using laboratory models of experimental HFpEF have demonstrated a positive effect of dapagliflozin and empagliflozin on the elastic properties of cardiomyocyte myofilaments, the dynamics of myocardial fibrosis, and intracellular sodium and calcium homeostasis. The significance of anti-inflammatory, antioxidant properties of gliflozins in improving the cardiomyocyte DF has been experimentally established. The effect of SGLT2 inhibitors on LV DF in patients at high risk for cardiovascular diseases and their complications, that has been demonstrated in relatively small clinical studies, is due to primary cardiac and secondary effects. Results of individual studies confirmed the protective (in relation to myocardial relaxation) properties of gliflozins in the conditions of a diastolic stress test. The regression of LV diastolic dysfunction associated with the SGLT2 inhibitor treatment found in small observational studies is important in the context of the significant beneficial effect of empagliflozin and dapagliflozin on the prognosis of cardiovascular diseases that has been demonstrated in large randomized clinical trials in patients with HFpEF.

Empagliflozin protects against heart failure with preserved ejection fraction partly by inhibiting the senescence-associated STAT1–STING axis

Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies. Empagliflozin (EMPA) improves cardiovascular outcomes in HFpEF patients, but the underlying mechanism remains elusive. Here, mice were fed a high-fat diet (HFD) supplemented with L-NAME for 12 weeks and subsequently intraperitoneally injected with EMPA for another 4 weeks. A 4D-DIA proteomic assay was performed to detect protein changes in the failing hearts. We identified 310 differentially expressed proteins (DEPs) (ctrl vs. HFpEF group) and 173 DEPs (HFpEF vs. EMPA group). The regulation of immune system processes was enriched in all groups and the interferon response genes (STAT1, Ifit1, Ifi35 and Ifi47) were upregulated in HFpEF mice but downregulated after EMPA administration. In addition, EMPA treatment suppressed the increase in the levels of aging markers (p16 and p21) in HFpEF hearts. Further bioinformatics analysis verified STAT1 as the hub transcription factor during pathological changes in HFpEF mice. We next treated H9C2 cells with IFN-γ, a primary agonist of STAT1 phosphorylation, to investigate whether EMPA plays a beneficial role by blocking STAT1 activation. Our results showed that IFN-γ treatment caused cardiomyocyte senescence and STAT1 activation, which were inhibited by EMPA administration. Notably, STAT1 inhibition significantly reduced cellular senescence possibly by regulating STING expression. Our findings revealed that EMPA mitigates cardiac inflammation and aging in HFpEF mice by inhibiting STAT1 activation. The STAT1–STING axis may act as a pivotal mechanism in the pathogenesis of HFpEF, especially under inflammatory and aging conditions.Graphical abstractThe schematic figure depicts a mechanism model of the STAT1–STING axis in HFpEF (this figure was drawn using FigDraw software).

Glucagon Receptor Antagonist for Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is an emerging major unmet need and one of the most significant clinic challenges in cardiology. The pathogenesis of HFpEF is associated with multiple risk factors. Hypertension and metabolic disorders associated with obesity are the 2 most prominent comorbidities observed in patients with HFpEF. Although hypertension-induced mechanical overload has long been recognized as a potent contributor to heart failure with reduced ejection fraction, the synergistic interaction between mechanical overload and metabolic disorders in the pathogenesis of HFpEF remains poorly characterized. We investigated the functional outcome and the underlying mechanisms from concurrent mechanic and metabolic stresses in the heart by applying transverse aortic constriction in lean C57Bl/6J or obese/diabetic B6.Cg-Lepob/J (ob/ob) mice, followed by single-nuclei RNA-seq and targeted manipulation of a top-ranked signaling pathway differentially affected in the 2 experimental cohorts. In contrast to the post-trans-aortic constriction C57Bl/6J lean mice, which developed pathological features of heart failure with reduced ejection fraction over time, the post-trans-aortic constriction ob/ob mice showed no significant changes in ejection fraction but developed characteristic pathological features of HFpEF, including diastolic dysfunction, worsened cardiac hypertrophy, and pathological remodeling, along with further deterioration of exercise intolerance. Single-nuclei RNA-seq analysis revealed significant transcriptome reprogramming in the cardiomyocytes stressed by both pressure overload and obesity/diabetes, markedly distinct from the cardiomyocytes singularly stressed by pressure overload or obesity/diabetes. Furthermore, glucagon signaling was identified as the top-ranked signaling pathway affected in the cardiomyocytes associated with HFpEF. Treatment with a glucagon receptor antagonist significantly ameliorated the progression of HFpEF-related pathological features in 2 independent preclinical models. Importantly, cardiomyocyte-specific genetic deletion of the glucagon receptor also significantly improved cardiac function in response to pressure overload and metabolic stress. These findings identify glucagon receptor signaling in cardiomyocytes as a critical determinant of HFpEF progression and provide proof-of-concept support for glucagon receptor antagonism as a potential therapy for the disease.

Серцева недостатність зі збереженою фракцією викиду: основні молекулярні і клітинні механізми розвитку

Heart failure with preserved ejection fraction (HFpEF) is characterized by signs and symptoms of heart failure in the presence of a normal left ventricular ejection fraction. HFpEF is a heterogeneous syndrome with diverse etiology and pathophysiological factors. HFpEF is a disease that develops by several pathophysiological mechanisms, although many of them remain unclear due to limited access to human heart tissue. At the heart of the mechanisms of HFpEF pathogenesis are disturbances in the handling of calcium ions in cardiomyocytes and endothelial dysfunction, which occurs as a result of numerous factors. Endothelial defects usually include impaired vasodilation, increased vasoconstriction, arterial stiffness, and atherogenesis. Endothelial dysfunction, the main consequence of which is insufficient NO availability, is associated with adverse events in patients with HFpEF. Compared with HFpEF patients without coronary endothelial dysfunction, patients with impaired endothelial function are characterized by more severe clinical outcomes, especially those associated with type 2 diabetes and obesity.In the heart tissue of an adult, there are mixed populations of macrophages. The ratio of macrophages of different origins changes with aging and the progression of various CVDs, depending on gender and type of cardiovascular dysfunction. Macrophages play important roles in the development and progression of СН. The role of macrophages in the pathogenesis of hypertension, obesity, diabetes, renal dysfunction, which are risk factors leading to СН, is crucial.Analysis of human endomyocardial biopsies has shown that HFpEF patients exhibit a gene expression profile distinct from HfrEF patients and normal controls.The study of these and other mechanisms of the pathogenesis of HFpEF will reveal new promising therapeutic targets for the treatment of heart failure.

Non-coding RNAs in the pathophysiology of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is the largest unmet clinical need in cardiovascular medicine. Despite decades of research, the treatment option for HFpEF is still limited, indicating our ongoing incomplete understanding on the underlying molecular mechanisms. Non-coding RNAs, comprising of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), are non-protein coding RNA transcripts, which are implicated in various cardiovascular diseases. However, their role in the pathogenesis of HFpEF is unknown. Here, we discuss the role of miRNAs, lncRNAs and circRNAs that are involved in the pathophysiology of HFpEF, namely microvascular dysfunction, inflammation, diastolic dysfunction and cardiac fibrosis. We interrogated clinical evidence and dissected the molecular mechanisms of the ncRNAs by looking at the relevant in vivo and in vitro models that mimic the co-morbidities in patients with HFpEF. Finally, we discuss the potential of ncRNAs as biomarkers and potential novel therapeutic targets for future HFpEF treatment.

Eicosanoid and eicosanoid-related inflammatory mediators and exercise intolerance in heart failure with preserved ejection fraction

Systemic inflammation has been implicated in the pathobiology of heart failure with preserved ejection fraction (HFpEF). Here, we examine the association of upstream mediators of inflammation as ascertained by fatty-acid derived eicosanoid and eicosanoid-related metabolites with HFpEF status and exercise manifestations of HFpEF. Among 510 participants with chronic dyspnea and preserved LVEF who underwent invasive cardiopulmonary exercise testing, we find that 70 of 890 eicosanoid and related metabolites are associated with HFpEF status, including 17 named and 53 putative eicosanoids (FDR q-value < 0.1). Prostaglandin (15R-PGF2α, 11ß-dhk-PGF2α) and linoleic acid derivatives (12,13 EpOME) are associated with greater odds of HFpEF, while epoxides (8(9)-EpETE), docosanoids (13,14-DiHDPA), and oxylipins (12-OPDA) are associated with lower odds of HFpEF. Among 70 metabolites, 18 are associated with future development of heart failure in the community. Pro- and anti-inflammatory eicosanoid and related metabolites may contribute to the pathogenesis of HFpEF and serve as potential targets for intervention.

Abstract 12425: Stim1 Deletion in Treg Cell Protects From HFpEF Pathogenesis

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a cardiovascular disease that remains untreatable in its pathogenesis. Therefore, there is a critical need to uncover the cellular and molecular mechanisms underlying HFpEF pathogenesis and identify potential targets for treatment that can enhance cardiac function and restrict disease progression. Previous studies have shown that Treg cells are crucial in hypertension-induced cardiovascular complications and metabolic dysregulation. Moreover, the function of Stromal interaction molecule 1 (STIM1) varies depending on the cell type. Hypothesis: We hypothesize that the deletion of STIM1 in Treg cells can protect against the development of HFpEF and its associated conditions. Methods: Male mice aged eight weeks (Stim1 flx/flx and Treg Stim1-/- ) were divided into four groups: control groups receiving a standard diet and water for five weeks, and HFpEF groups fed a high-fat diet (HFD) and N[w]-nitro-l-arginine methyl ester (L-NAME - 0.5g/L) in the drinking water for five weeks. Various measurements and assessments were conducted, including echocardiography, evaluations of metabolism and hypertension, analysis of heart and kidney injury markers, and assessment of vascular endothelial function. Results: After five weeks, Stim1 flx/flx mice subjected to HFD and L-NAME displayed evidence of HFpEF, including hypertension, metabolic disorders, cardiac hypertrophy with fibrosis, kidney injury with fibrosis, impaired exercise tolerance and vascular endothelial function, increased body weight and E/E' ratio, reduced cardiac index, and unchanged ejection fraction. Interestingly, Treg Stim1-/- mice were protected against HFD and L-NAME-induced HFpEF and its associated pathologies. Conclusions: These findings underscore the significance of targeting STIM1 in Treg cells to protect from the development and pathogenesis of HFpEF.

Abstract 13228: Finerenone Inhibits the Progression of Cardiac Hypertrophy in the HFpEF Mouse Model

Background: The efficacy of mineralocorticoid receptor antagonists (MRA) for heart failure with preserved ejection fraction (HFpEF) has not been established, but there are some reports of MRA being effective for early HFpEF.Furthermore, the FIGARO-DKD trial has demonstrated that finerenone, a nonsteroidal MRA, improves cardiovascular outcomes in patients with type 2 diabetes mellitus.The pathogenesis of HFpEF has yet to be fully elucidated, and further investigation is required to validate the mechanistic role of MRAs based on the distinct pathogenesis of HFpEF. Methods: As an HFpEF mouse model, we used the 15 weeks combined stress model of obesity and hypertension. (Schiattarella et al., Nature 2019). High fat diet ingestion and 0.5 g / L of Nω-nitro-L-arginine methyl ester drinking were loaded. As a drug administration experiment, with combined stress for 10 weeks, placebo or 10 mg/kg/day finerenone was administered for the last two weeks. After loading, body weight, blood pressure, heart weight, myocardial cross-sectional area, and mitochondrial protein acetylation were evaluated. Results: Histological analysis revealed the enlargement of cardiomyocyte cross-sectional areas in the combined stress group. In addition, we found mitochondrial protein acetylation level, adjusted by ubiquinol-cytochrome c reductase, rieske iron-sulfur polypeptide 1 (UQCRFS1) was also enhanced in the combined stress model. Subsequently, finerenone administration did not show remarkable reduction of blood pressure compared to the placebo group. However, echocardiography showed that the finerenone group reduced left ventricular diastolic septal wall thickness. And histological analysis revealed reduction of cardiomyocyte CSAs in the finerenone group. Mitochondrial protein hyperacetylation tended to be reduced with the finerenone group, but the difference was not significant. Conclusion: In the HFpEF murine model, finerenone improved cardiac hypertrophy independent of blood pressure. In addition, mitochondrial protein hyperacetylation, which involves mitochondrial dysfunction, was also alleviated by finerenone administration. Our findings indicate that the cardioprotective effects of finerenone may also affect mitochondrial function.

Multi-omics approach for identification of molecular alterations of QiShenYiQi dripping pills in heart failure with preserved ejection fraction

Ethnopharmacological relevanceTraditional Chinese medicine theory believes that qi deficiency and blood stasis are the key pathogenesis of heart failure with preserved ejection fraction (HFpEF). As a representative prescription for replenishing qi and activating blood, QiShenYiQi dripping pills (QSYQ) has been used for treating heart diseases. However, the pharmacological mechanism of QSYQ in improving HFpEF is not well understood. Aim of the studyThe objective of the study is to investigate the cardioprotective effect and mechanism of QSYQ in HFpEF using the phenotypic dataset of HFpEF. Materials and methodsHFpEF mouse models established by feeding mice combined high-fat diet and Nω-nitro-L-arginine methyl ester drinking water were treated with QSYQ. To reveal causal genes, we performed a multi-omics study, including integrative analysis of transcriptomics, proteomics, and metabolomics data. Moreover, adeno-associated virus (AAV)-based PKG inhibition confirmed that QSYQ mediated myocardial remodeling through PKG. ResultsComputational systems pharmacological analysis based on human transcriptome data for HFpEF showed that QSYQ could potentially treat HFpEF through multiple signaling pathways. Subsequently, integrative analysis of transcriptome and proteome showed alterations in gene expression in HFpEF. QSYQ regulated genes involved in inflammation, energy metabolism, myocardial hypertrophy, myocardial fibrosis, and cGMP-PKG signaling pathway, confirming its function in the pathogenesis of HFpEF. Metabolomics analysis revealed fatty acid metabolism as the main mechanism by which QSYQ regulates HFpEF myocardial energy metabolism. Importantly, we found that the myocardial protective effect of QSYQ on HFpEF mice was attenuated after RNA interference-mediated knock-down of myocardial PKG. ConclusionThis study provides mechanistic insights into the pathogenesis of HFpEF and molecular mechanisms of QSYQ in HFpEF. We also identified the regulatory role of PKG in myocardial stiffness, making it an ideal therapeutic target for myocardial remodeling.

Linkage of Left Atrial Function to Heart Failure with Preserved Ejection Fraction.

In heart failure with preserved ejection fraction (HFpEF), left atrial enlargement is a surrogate marker reflecting chronic left ventricular diastolic dysfunction. As a result, the left atrial volume is often evaluated in daily clinical practice to determine the presence of left ventricular diastolic dysfunction. However, recent studies have shown that left atrial dysfunction is an important factor contributing to the pathogenesis of HFpEF, and it is expected to become one of the therapeutic targets of HFpEF, rather than just a surrogate marker. Echocardiography plays a central role in the identification of left atrial dysfunction and remodeling in HFpEF. In this review, we describe an approach to the evaluation of left atrial function in HFpEF using echocardiography.

In Search of the Holy Grail: Stem Cell Therapy as a Novel Treatment of Heart Failure with Preserved Ejection Fraction

Heart failure, a leading cause of hospitalizations and deaths, is a major clinical problem. In recent years, the increasing incidence of heart failure with preserved ejection fraction (HFpEF) has been observed. Despite extensive research, there is no efficient treatment for HFpEF available. However, a growing body of evidence suggests stem cell transplantation, due to its immunomodulatory effect, may decrease fibrosis and improve microcirculation and therefore, could be the first etiology-based therapy of the disease. In this review, we explain the complex pathogenesis of HFpEF, delineate the beneficial effects of stem cells in cardiovascular therapy, and summarize the current knowledge concerning cell therapy in diastolic dysfunction. Furthermore, we identify outstanding knowledge gaps that may indicate directions for future clinical studies.

Small Peptide, Large Implications: Endotrophin in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF), the most prevalent type of heart failure (HF), is associated with significant morbidity and mortality and a high rate of hospitalizations. HFpEF incidence is projected to continue to rise over the coming decades, primarily due to the increasing prevalence of multiple risk factors that contribute to the development of this syndrome. Obesity, low cardiorespiratory fitness, hypertension, and chronic kidney disease (CKD) have emerged as crucial elements in the pathogenesis of the syndrome. Obesity, in particular, can trigger and potentiate the systemic inflammatory state that is now recognized as central to the pathogenesis of HFpEF. In HFpEF, a range of cardiovascular changes are observed at the cellular and molecular level, including endothelial dysfunction, cardiomyocyte hypertrophy, abnormal calcium handling, microvascular rarefaction, interstitial fibrosis, and excessive collagen deposition (1). A biomarker to assist in diagnosis and risk stratification of HFpEF would improve patient evaluation and management and enable clinical and preclinical research to impact the course of this syndrome. The ideal biomarker would reliably aid in the diagnosis of HFpEF at early stages, guide medical management, and predict disease complications. However, the quest to identify a biomarker with these characteristics has proven elusive as most previous biomarker candidates have fallen short of reaching the clinical stage. Of the biomarkers currently used in the clinic, B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide (NT-proBNP) support the diagnosis of HFpEF in symptomatic individuals and predict adverse outcomes but cannot distinguish HFpEF from heart failure with reduced ejection fraction (HFrEF). Moreover, levels can be normal in up to 30% of patients with HFpEF; are commonly suppressed in patients with high body mass; and are increased substantially in the setting of CKD, pulmonary hypertension, and atrial fibrillation (1). In asymptomatic individuals, small elevations in NT-proBNP and high sensitivity troponin T and I identify individuals at risk for HF but cannot accurately differentiate future risk of HFpEF from HFrEF.

Porcupine inhibitor CGX1321 alleviates heart failure with preserved ejection fraction in mice by blocking WNT signaling.

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, and lacks effective treatment. The aberration of WNT pathway underlies many pathological processes including cardiac fibrosis and hypertrophy, while porcupine is an acyltransferase essential for the secretion of WNT ligands. In this study we investigated the role of WNT signaling pathway in HFpEF as well as whether blocking WNT signaling by a novel porcupine inhibitor CGX1321 alleviated HFpEF. We established two experimental HFpEF mouse models, namely the UNX/DOCA model and high fat diet/L-NAME ("two-hit") model. The UNX/DOCA and "two-hit" mice were treated with CGX1321 (3 mg·kg-1·d-1) for 4 and 10 weeks, respectively. We showed that CGX1321 treatment significantly alleviated cardiac hypertrophy and fibrosis, thereby improving cardiac diastolic function and exercise performance in both models. Furthermore, both canonical and non-canonical WNT signaling pathways were activated, and most WNT proteins, especially WNT3a and WNT5a, were upregulated during the development of HEpEF in mice. CGX1321 treatment inhibited the secretion of WNT ligands and repressed both canonical and non-canonical WNT pathways, evidenced by the reduced phosphorylation of c-Jun and the nuclear translocation of β-catenin and NFATc3. In an in vitro HFpEF model, MCM and ISO-treated cardiomyocytes, knockdown of porcupine by siRNA leads to a similar inhibitory effect on WNT pathways, cardiomyocyte hypertrophy and cardiac fibroblast activation as CGX1321 did, whereas supplementation of WNT3a and WNT5a reversed the anti-hypertrophy and anti-fibrosis effect of CGX1321. We conclude that WNT signaling activation plays an essential role in the pathogenesis of HFpEF, and porcupine inhibitor CGX1321 exerts a therapeutic effect on HFpEF in mice by attenuating cardiac hypertrophy, alleviating cardiac fibrosis and improving cardiac diastolic function.

Abstract 12874: A Novel Mechanism in the Pathogenesis of Heart Failure With Preserved Ejection Fraction Through Hexokinase Mitochondrial Dislocation and Substrate Shuttling Into the O-Glcnacylation Machinery

Introduction: Endothelial cell (EC) dysfunction underlies the pathogenesis of heart failure with preserved ejection fraction (HFpEF), however, the mechanism is unclear. ECs are highly dependent on glycolysis; however, it is not known how their metabolic profile is altered in the setting of HFpEF. Hexokinase 1 (HK1) carries the first step in glycolysis and is mostly bound to the mitochondria in ECs. Objective: We sought to elucidate the role of EC glucose metabolism, and specifically HK1, in the development of HFpEF. Results: We first showed that among glycolytic enzymes, HK1 is highly specific to ECs, suggesting the significance of HK1 in EC physiology. Although HK1 mRNA and protein levels are not changed, we noted increased dislocation of HK1 from the mitochondria in ECs from HFpEF mice. To study the role of HK1 dislocation in the development of HFpEF, we generated mice with mitochondrial-binding domain of the endogenous HK1 replaced with Flag tag (ΔE1HK1). ΔE1HK1mice develop impaired cardiac relaxation at 20 weeks of age and HFpEF by 40 weeks, and ECs from these mice displayed impaired angiogenic potential. Since HK1 is involved in glucose metabolism, we then performed metabolomic studies and demonstrated that intermediates in hexosamine biosynthetic pathway (HBP) are significantly decreased in ECs from ΔE1HK1 mice. To assess the mechanism for the decrease in HBP, we assessed protein modification, and noted reduced protein N-glycosylation and increased O-GlcNAcylation in ECs from ΔE1HK1. We also demonstrated that inhibition of the key enzyme in O-GlcNAcylation (OGT) reverses the EC dysfunction noted in ΔE1HK1 mice, indicating that O-GlcNAcylation is responsible for the angiogenic defect in ECs from ΔE1HK1. Finally, to provide a mechanism for altered protein glycosylation with HK1 mitochondrial dislocation, we showed that HK1 associates with N-glycosylation machinery when it is attached to mitochondria, while it binds to OGT when it is dislocated from mitochondria. Conclusion: Our studies demonstrate a role for HK1 mitochondrial binding and protein O-GlcNAcylation in the pathogenesis of HFpEF, and that HK1 cellular localization plays a major role in the fate of HBP intermediates into either N-glycosylation or O-GlcNAcylation machinery in ECs.

Sex differences and related estrogenic effects in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is an essential subtype of heart failure accounting for 40% of the total. However, the related pathological mechanism and drug therapy research have been stagnant for a long time. The direct cause of this dilemma is the heterogeneity of HFpEF. And some researchers believe that there is no common pathway to reach the origin of HFpEF; others argue that there is an unidentified unified pathophysiological process hidden beneath the ice surface. Aside from the debate, a series of clinical studies have shown that hypertension and obesity play a fundamental role in the pathogenesis of HFpEF. These results imply that there may be two parallel pathological processes interweaved in one disease, manifested as multiple coexistent pathological phenomena, like a shadow. Meanwhile, the prevalence of HFpEF in women is higher than in men in any given age group, especially prominent in elderly patients. These pathological processes and epidemiological data reflect gender differences, reminding us to shift our attention to estrogen. This article will review the parallel pathogenesis of HFpEF, and also introduce sex differences and the potential effect of estrogen in this condition below.

Association of hepatic steatosis with subclinical cardiac dysfunction in asymptomatic people with type 2 diabetes

Abstract Introduction Non-alcoholic fatty liver disease is highly prevalent among people with type 2 diabetes (T2D) and is an emerging risk factor for heart failure with preserved ejection fraction (HFpEF). Whether excess liver adiposity is simply a marker of the coexisting adverse cardiometabolic risk profile or independently contributes to the development of HFpEF is unclear. Purpose To assess the association between liver fat fraction and subclinical cardiac dysfunction in adults with T2D. Methods Prospective cross-sectional study. Two-hundred and thirty-eight adults with T2D (mean age 63±7 years, 62% males, HbA1c 7.2±1.5%, diabetes duration 10±8 years) with no signs, symptoms, or evidence of cardiovascular disease and 40 age-, sex-, and ethnicity-matched non-diabetic controls (mean age 61±8 years, 63% males, HbA1c 5.2±1.2%) underwent comprehensive phenotyping with echocardiography and multiparametric cardiac MRI including adenosine stress and rest perfusion. Volumetric liver fat fraction (VLFF) was measured using a histologically validated, proprietary MRI technique blinded to all participant details. Inter-study reproducibility was assessed in participants (n=28) who underwent a repeat MRI within two weeks. Linear regression analysis was performed to assess any independent associations between VLFF and identified markers of subclinical cardiac dysfunction in subjects with T2D. Results People with T2D had evidence of concentric left ventricular (LV) remodelling (higher LV mass/volume), extracellular matrix expansion (higher ECV fraction), both systolic and diastolic dysfunction (lower global longitudinal systolic strain and E/A ratio, respectively), and coronary microvascular dysfunction (lower myocardial perfusion reserve) (Table 1). VLFF demonstrated excellent inter-study reproducibility with an intra-class correlation coefficient (ICC) of 0.988 (0.974–0.994). T2Ds had higher VLFF compared to controls [7.5 (3.8–13.7)% vs 2.9 (1.7–4.7)%, p&amp;lt;0.001]. In multivariable regression analysis adjusting for age, sex, ethnicity, body mass index, ambulatory systolic blood pressure, HbA1c, and low-density lipoprotein, VLFF (β=−0.161, p=0.027) was independently associated with E/A, but not other imaging measures of subclinical cardiac dysfunction. Conclusion Liver fat fraction is elevated in people with T2D and is independently associated with early LV diastolic dysfunction. These results add to the growing evidence that ectopic fat plays an important role in the pathogenesis of HFpEF and may be a potential target for intervention. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): National Institute for Health Research (NIHR) United Kingdom through a Research Professorship award (RP-2017-08-ST2-007).British Heart Foundation through a Clinical Research Training Fellowship (FS/16/47/32190).

Von Willebrand factor (vWF) in patients with heart failure with preserved ejection fraction (HFpEF): A retrospective observational study.

Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial damage and inflammation. In addition, von Willebrand factor (vWF) has been discovered as a biomarker of endothelial dysfunction. Therefore, the study aims to investigate the association between vWF level and HFpEF. Moreover, we analyzed a potential correlation between vWF and inflammatory factors, such as C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-6.We recruited altogether 272 hospitalized patients from The Fifth Affiliated Hospital of Xinjiang Medical University, 88 of whom were HFpEF patients, 88 were non-heart failure patients, and 96 were healthy controls from the medical examination center of the hospital. Enzyme-linked immunosorbent assay and double antibody sandwich immunochromatography were used for testing vWF, tissue plasminogen activator, galectin-3, nitric oxide, TNF-α, IL-6, and CRP.The HFpEF group’s levels of vWF, IL-6, TNF-α, CRP, tissue plasminogen activator, galectin-3, and nitric oxide were statistically higher than those of non-heart failure and healthy control ones (F = 403.563, 21.825, 20.678, 39.609, 35.411, 86.407, 74.605; all P = .000). the highest level of vWF was observed in class IV (New York Heart Association) of HFpEF patients and the significant difference is <.05 (P < .001). An increasing level of vWF were shown in groups (CRP: CRP >3 mg/L group and CRP ≤3 mg/L group; IL-6: IL-6 <7.0 pg/mL group and IL-6 ≥7.0 pg/mL group; TNF-α: TNF-α <5.5 pg/mL group and TNF-α ≥5.5 pg/mL group) with higher level of IL-6, TNF-α, CRP. A multiple regression analysis regarding the relationship of vWF and inflammation markers was performed among the HFpEF patients. Further, statistical significance of the analysis remained after adjusting variables such as body mass index, low-density lipoprotein cholesterol, total cholesterol, coronary artery disease, and type 2 diabetes mellitus (β = 0.406, t = 4.579, P < .001; β = 0.323, t = 3.218, P < .001; β = 0.581, t = 6.922, P < .001).Our study shows that elevated vWF levels are associated with HFpEF, and it may serve as a potential biomarker for HFpEF severity. We also found that increased vWF levels are positively correlated to IL-6, TNF-α, and CRP, which may provide a clue for further researching the pathogenesis of HFpEF.

In vivo imaging of heart failure with preserved ejection fraction by simultaneous monitoring of cardiac nitric oxide and glutathione using a three-channel fluorescent probe

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) remains unclear, making the diagnosis and treatment challenging. Cardiac oxidative and nitrative stress are strongly implicated in the pathogenesis of HFpEF. Herein, we present a unique three-channel fluorescent probe for evaluating cardiac oxidative and nitrative stress in HFpEF by simultaneous detection of NO and GSH. The probe exhibits a native green fluorescence (probe channel), while the presence of GSH and NO can sensitively turn the native green fluorescence into red fluorescence (GSH channel) and near-infrared fluorescence (NO channel), respectively. The probe clearly reveals that both GSH and NO levels are upregulated in cardiomyocytes and heart tissue with HFpEF. Moreover, it uncovers that the enhancement in NO and GSH levels are closely associated with increased level of iNOS (inducible nitric oxide synthase) and activation of the Keap1 (Kelch-like ECH-associated protein 1)/Nrf2 (nuclear factor erythroid 2–related factor 2)/ARE (antioxidant response element) signaling pathway in cardiomyocytes, respectively. This work proposes a promising approach for distinguishing normal heart and HFpEF heart by in vivo noninvasive imaging of both GSH and NO, and greatly contributing to the improvement of the diagnosis and treatment of HFpEF.

Proteomic analysis of epicardial adipose tissue from heart disease patients with concomitant heart failure with preserved ejection fraction

BackgroundAlthough epicardial adipose tissue (EAT) is known to be a major contributor to the pathogenesis of heart failure with preserved ejection fraction (HFpEF), the underlying mechanisms remain incompletely understood. This study aimed to compare the proteomic profiles of EAT from HFpEF patients and patients without HF (non-HF) and to explore candidate molecules characteristic of EAT in HFpEF. MethodsEAT samples were collected from patients who underwent cardiac surgery. Proteins were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and protein–protein interaction network analysis were conducted. The gene expression of one significant differentially expressed protein was examined by quantitative reverse transcription polymerase chain reaction. ResultsA total of 2416 proteins were detected by LC-MS/MS experiments, and expression levels were quantified for 2349 proteins. Among them, 96 proteins (including 71 upregulated proteins and 25 downregulated proteins) were significantly differentially expressed between the HFpEF (n = 5) and non-HF groups (n = 5). GO enrichment and KEGG pathway analyses revealed that these differentially expressed proteins were predominantly involved in HFpEF-related processes, including lipid metabolic disorder, inflammation, and mitochondrial dysfunction. ConclusionsThe results of this comprehensive analysis of the EAT proteome in HFpEF patients offer new insights into the pathogenesis of HFpEF and potential molecular targets in EAT.

What Role do Mitochondria Have in Diastolic Dysfunction? Implications for Diabetic Cardiomyopathy and Heart Failure With Preserved Ejection Function.

Diastolic dysfunction is common to both diabetic cardiomyopathy and heart failure with preserved ejection fraction (HFpEF). Although commonly attributed to increased fibrosis, alterations in mitochondrial function and associated Ca2+ handling may contribute to impaired cardiac function. With mitochondrial dysfunction, increased reactive oxygen species (ROS), inflammation, and decreased adenosine triphosphate/adenosine diphosphate ratio may lead to increased extracellular matrix and diminished contractile relaxation. In this article, we discuss recent research implicating deficient mitochondria-associated endoplasmic reticulum membranes (MAMs) as it relates to impaired metabolic function and what role that may have in diastolic dysfunction in diabetic cardiomyopathy. The contribution of mitochondrial dysfunction to diastolic dysfunction in HFpEF is less established, but equally credible based on preclinical studies. However, there are notable differences between diabetic cardiomyopathy and HFpEF. Recent evidence implicates impaired endoplasmic reticulum signaling, in particular the unfolded protein response (UPR), in the pathogenesis of HFpEF. With HFpEF, enhanced pressure on the mitochondrial "gas pedal" because of increased cytosolic Ca2+ may perturb mitochondrial homeostasis. For diabetic cardiomyopathy and HFpEF, a better understanding of how altered cellular ion and redox status affect mitochondrial function is needed. Finally, we discuss the implications that mitochondrial dysfunction may have in devising novel therapeutic strategies for diabetic cardiomyopathy and HFpEF.