Endothelial Dysfunction in Heart Failure With Preserved Ejection Fraction: What are the Experimental Proofs?

Cornuault, Lauriane; Rouault, Paul; Duplàa, C.; Couffinhal, Thierry; Renault, Marie-Ange

doi:10.3389/fphys.2022.906272

Cited by 31 publications

(26 citation statements)

References 220 publications

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“…However, endothelial dysfunction represents an important mechanism underlying heart failure with preserved ejection fraction (HFpEF) [ 53 ]. Impaired coronary microvascular function is strongly associated with the severity of heart failure [ 54 ]. Even though published data do not completely support a causative role for monocytes and heart failure, their role in atrial fibrillation (AF) has been postulated [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

The Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitor Empagliflozin Reverses Hyperglycemia-Induced Monocyte and Endothelial Dysfunction Primarily through Glucose Transport-Independent but Redox-Dependent Mechanisms

Semo

Obergassel

Dorenkamp

et al. 2023

JCM

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Purpose: Hyperglycaemia-induced oxidative stress and inflammation contribute to vascular cell dysfunction and subsequent cardiovascular events in T2DM. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin significantly improves cardiovascular mortality in T2DM patients (EMPA-REG trial). Since SGLT-2 is known to be expressed on cells other than the kidney cells, we investigated the potential ability of empagliflozin to regulate glucose transport and alleviate hyperglycaemia-induced dysfunction of these cells. Methods: Primary human monocytes were isolated from the peripheral blood of T2DM patients and healthy individuals. Primary human umbilical vein endothelial cells (HUVECs) and primary human coronary artery endothelial cells (HCAECs), and fetoplacental endothelial cells (HPECs) were used as the EC model cells. Cells were exposed to hyperglycaemic conditions in vitro in 40 ng/mL or 100 ng/mL empagliflozin. The expression levels of the relevant molecules were analysed by RT-qPCR and confirmed by FACS. Glucose uptake assays were carried out with a fluorescent derivative of glucose, 2-NBDG. Reactive oxygen species (ROS) accumulation was measured using the H2DFFDA method. Monocyte and endothelial cell chemotaxis were measured using modified Boyden chamber assays. Results: Both primary human monocytes and endothelial cells express SGLT-2. Hyperglycaemic conditions did not significantly alter the SGLT-2 levels in monocytes and ECs in vitro or in T2DM conditions. Glucose uptake assays carried out in the presence of GLUT inhibitors revealed that SGLT-2 inhibition very mildly, but not significantly, suppressed glucose uptake by monocytes and endothelial cells. However, we detected the significant suppression of hyperglycaemia-induced ROS accumulation in monocytes and ECs when empagliflozin was used to inhibit SGLT-2 function. Hyperglycaemic monocytes and endothelial cells readily exhibited impaired chemotaxis behaviour. The co-treatment with empagliflozin reversed the PlGF-1 resistance phenotype of hyperglycaemic monocytes. Similarly, the blunted VEGF-A responses of hyperglycaemic ECs were also restored by empagliflozin, which could be attributed to the restoration of the VEGFR-2 receptor levels on the EC surface. The induction of oxidative stress completely recapitulated most of the aberrant phenotypes exhibited by hyperglycaemic monocytes and endothelial cells, and a general antioxidant N-acetyl-L-cysteine (NAC) was able to mimic the effects of empagliflozin. Conclusions: This study provides data indicating the beneficial role of empagliflozin in reversing hyperglycaemia-induced vascular cell dysfunction. Even though both monocytes and endothelial cells express functional SGLT-2, SGLT-2 is not the primary glucose transporter in these cells. Therefore, it seems likely that empagliflozin does not directly prevent hyperglycaemia-mediated enhanced glucotoxicity in these cells by inhibiting glucose uptake. We identified the reduction of oxidative stress by empagliflozin as a primary reason for the improved function of monocytes and endothelial cells in hyperglycaemic conditions. In conclusion, empagliflozin reverses vascular cell dysfunction independent of glucose transport but could partially contribute to its beneficial cardiovascular effects.

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Section: Discussionmentioning

confidence: 99%

The Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitor Empagliflozin Reverses Hyperglycemia-Induced Monocyte and Endothelial Dysfunction Primarily through Glucose Transport-Independent but Redox-Dependent Mechanisms

Semo

Obergassel

Dorenkamp

et al. 2023

JCM

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“…Importantly the causal role of endothelial dysfunction in the pathophysiology of HFpEF has not been yet excluded since endothelial dysfunction may affect cardiomyocyte biology and cardiac function in many ways 11 . Notably, ECs are essential cell components of blood vessels which are necessary to bring nutriments and oxygen to cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

“…However, considering HFpEF is an heterogeneous disease with multiple pheno-groups 28 , these results needs to be verified in other animal models of HFpEF. Indeed, even though endothelial dysfunction does not seem to be necessary for diastolic dysfunction to develop upon a HFD + L-NAME regimen, EC protection was previously shown to prevent the occurrence of both diastolic and systolic dysfunction in other setting including pressure overload and hypertension 11 . Besides, modification of some EC properties was shown to be sufficient to induced diastolic dysfunction in the absence of any other cardiovascular risk factor 6,[8][9][10] .…”

Section: Discussionmentioning

confidence: 99%

“…However, it is still actually not known whether EC dysfunction is responsible for diastolic dysfunction in patients or animal models with HFpEF 11 . Notably, WJ Paulus’s group proposed that decreased NOS3 activity in ECs would decrease NO available to activate soluble guanylate cyclase (sGC) in cardiomyocyte leading to decreased cGMP production, protein kinase cGMP-dependent 1 (PRKG1) activity and subsequently Titin phosphorylation, ultimately leading to cardiomyocyte stiffening 5 .…”

Section: Introductionmentioning

confidence: 99%

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Increased endothelium activation and leakage do not promote diastolic dysfunction in mice fed with a high fat diet and treated with L-NAME

Cornuault

Mora

Rouault

et al. 2023

Preprint

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Coronary microvascular disease has been proposed to be responsible for heart failure with preserved ejection fraction (HFpEF) about 10 years ago. However, to date the role and phenotype of the coronary microvasculature has still been poorly considered and investigated in animal models of HFpEF. Objective: To determine whether endothelial dysfunction participates in the development of diastolic dysfunction in mice fed with a high fat diet (HDF) and treated with L-NAME. Approach and Results: At first, we thoroughly phenotyped the coronary microvasculature in this model in male, female and ovariectomized (OVX) female considering the sexual dimorphism associated with this disease. We found that both OVX and non OVX females but not males display increased endothelial activation, leakage, and arteriole constriction upon the HFD + L-NAME regimen while both male and OVX females but not non OVX females develop diastolic dysfunction. With the aim to investigate the role of endothelial dysfunction in the pathophysiology of diastolic dysfunction in OVX female mice, we used Cdon deficient mice. Indeed, we previously demonstrated that endothelium integrity, upon inflammatory conditions, is preserved in these mice. Both OVX Cdh5-Cre/ERT2-CdonFlox/Flox (CdonECKO) and CdonFlox/Flox (Ctrl) female mice were fed with the HFD + L-NAME regimen to induced diastolic dysfunction. As expected, CdonECKO mice displayed improved endothelium integrity i.e. decreased endothelium permeability, decreased ICAM-1 expression and decreased infiltration of CD45+ leukocytes in comparison to control mice. However, CdonECKO mice displayed cardiac hypertrophy, cardiac fibrosis and increased end diastolic pressure just like control mice. Moreover, we found that cardiac inflammation does not participate in the pathophysiology of HFpEF either by treating OVX female mice with colchicine. Conclusion: Altogether, the data presented in this paper demonstrate that neither endothelium permeability nor endothelial activation or inflammation do participate in the pathophysiology of diastolic dysfunction in mice exposed to HFD+L-NAME.

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“…XDH catalyzes the rate limiting step in purine metabolism producing uric acid(103) and previous literature supports both the role of serum uric acids in heart failure(81) and plasma XDH activity as relevant for adverse clinical outcomes in HFpEF(104). Nitric oxide synthase (NOS) has been proposed to contribute to endothelial dysfunction in HFpEF(82,83) and NOS1 inhibition was recently associated with recovery of diastolic dysfunction in a murine model resembling HFpEF(105).…”

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confidence: 98%

A Network medicine approach to study comorbidities in heart failure with preserved ejection fraction

Lanzer¹,

Valdeolivas²,

Pepin³

et al. 2023

Preprint

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Background Comorbidities are expected to impact pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). However, comorbidity profiles are usually reduced to a few comorbid disorders. Systems medicine approaches can model multiple comorbidities to help to improve our understanding of HFpEF. Methods We retrospectively explored 569 comorbidities documented in 29,074 HF patients, including 8,062 HFpEF and 6,585 heart failure with reduced ejection fraction (HFrEF) patients from a German university hospital. To analyze comorbidity profiles, first we assessed differences between comorbidity profiles by HF subtype. We fit machine learning classifiers to discriminate between HFpEF and HFrEF patients to interpret important comorbidities. Then we built a network to represent comorbid relationships in HF patients (HFnet) and identified main disease clusters. Lastly, we performed novel gene candidate prediction for HFpEF by linking the HFnet to a multi-layer gene network by integrating multiple databases (HFhetnet). To corroborate HFpEF candidate genes, we collected transcriptomic data in a murine HFpEF model. We compared predicted genes with the murine disease signature as well as with the literature. Results We found that comorbidity profiles vary more in association with HFpEF/HFrEF status than with age or sex. The comorbidities present in HFpEF patients were more diverse than those in HFrEF, and included neoplastic, osteologic and rheumatoid disorders, among others. Disease communities in the HFnet captured important comorbidity concepts of HF patients which could be assigned to HF subtypes, age groups and sex. Within the HFhetnet, we predicted novel gene candidates, including genes involved in fibrosis (COL3A1, MMP1, LOX), oxidative stress (NOS1, GSST1, XDH) and endoplasmic reticulum stress (ATF6). Finally, predicted genes were significantly overrepresented in the murine transcriptomic disease signature. Conclusion We applied systems medicine concepts to analyze comorbidity profiles in a HF patient cohort. We were able to identify disease clusters that helped to characterize HF patients. We derived a distinct comorbidity profile for HFpEF, which was leveraged to suggest novel candidate genes via network propagation. The identification of distinctive comorbidity profiles and candidate genes from routine clinical data will provide insights that may be leveraged to improve diagnosis and treatment for HFpEF patients.

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Endothelial Dysfunction in Heart Failure With Preserved Ejection Fraction: What are the Experimental Proofs?

Cited by 31 publications

References 220 publications

The Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitor Empagliflozin Reverses Hyperglycemia-Induced Monocyte and Endothelial Dysfunction Primarily through Glucose Transport-Independent but Redox-Dependent Mechanisms

The Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitor Empagliflozin Reverses Hyperglycemia-Induced Monocyte and Endothelial Dysfunction Primarily through Glucose Transport-Independent but Redox-Dependent Mechanisms

Increased endothelium activation and leakage do not promote diastolic dysfunction in mice fed with a high fat diet and treated with L-NAME

A Network medicine approach to study comorbidities in heart failure with preserved ejection fraction

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