The role of advanced glycation end-products and their receptor on outcome in heart failure patients with preserved and reduced ejection fraction

Willemsen, Suzan; Hartog, Jasper W. L.; Veldhuisen, Dirk J. van; Meer, Peter van der; Roze, Joline F.; Jaarsma, Tiny; Schalkwijk, Casper G.; Horst, Iwan C. C. van der; Hillege, Hans L.; Voors, Adriaan A.

doi:10.1016/j.ahj.2012.07.027

Cited by 54 publications

(42 citation statements)

References 21 publications

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“…These studies include the use of aminoguanidine (inhibitors), alagebrium chloride; Vitamin B compounds: pyridoxamine, thiamine, benfotiamine; glucose lowering agents: metformin, rosiglitazone, sulphonylureas; Angiotensin receptor blockers and AGEs restricted diets [11,14]. Animal studies have presented beneficial results in reduction of diabetic complications and possible under laying causes of CVD.…”

Section: Mechanisms Of Mitochondrial Regulationmentioning

confidence: 97%

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Targeting advanced glycation endproducts and mitochondrial dysfunction in cardiovascular disease

Ward

Fotheringham

Cooper

et al. 2013

Current Opinion in Pharmacology

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Section: Mechanisms Of Mitochondrial Regulationmentioning

confidence: 97%

“…This evidence provides a possible target for therapeutic intervention. Studies utilising metformin and repaglinide provided a reduction in Amadori albumin linked with a reduction in AGE formation in a non-obese T2D cohort [11].…”

Section: Advanced Glycation and Cardiovascular Diseasementioning

confidence: 99%

Targeting advanced glycation endproducts and mitochondrial dysfunction in cardiovascular disease

Ward

Fotheringham

Cooper

et al. 2013

Current Opinion in Pharmacology

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“…69,70 Plasma levels of two AGEs (N(ε)-(carboxymethyl)lysine (CML) and pentosidine) in HFrEF and HFpEF patients were reported to predict HF-related hospitalization and/or mortality with CML being associated with a higher risk of mortlity. 71 AGEs can cause increased stiffness of the ECM directly by crosslinking collagen or elastin and indirectly by stimulating the production of collagen and depleting NO thereby increasing oxidative stress. 70 Cardiac AGE deposition has been observed in diabetic patients with HFrEF, but whether it occurs to any great extent in HFpEF is unclear.…”

Section: Drugs In the Pipelinementioning

confidence: 99%

Heart Failure with Preserved Ejection Fraction

Zouein

Brás²,

Costa³

et al. 2013

Journal of Cardiovascular Pharmacology

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Approximately half of heart failure patients have a normal ejection fraction, a condition designated as heart failure with preserved ejection fraction (HFpEF). This heart failure subtype disproportionately affects women and the elderly and is commonly associated with other cardiovascular comorbidities, such as hypertension and diabetes. HFpEF is increasing at a steady rate and is predicted to become the leading cause of heart failure within a decade. HFpEF is characterized by impaired diastolic function, thought to be due to concentric remodeling of the heart along with increased stiffness of both the extracellular matrix and myofilaments. In addition, oxidative stress and inflammation are thought to have a role in HFpEF progression, along with endothelial dysfunction and impaired nitric oxide-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling. Surprisingly a number of clinical studies have failed to demonstrate any benefit of drugs effective in heart failure with systolic dysfunction in HFpEF patients. Thus, HFpEF is one of the largest unmet needs in cardiovascular medicine and there is a substantial need for new therapeutic approaches and strategies that target mechanisms specific for HFpEF. This conclusion is underscored by the recently reported disappointing results of the RELAX trial, which assessed the use of phosphodiesterase-5 inhibitor sildenafil for treating HFpEF. In animal models, endothelial nitric oxide synthase (eNOS) activators and If current inhibitors have shown benefit in improving diastolic function and there is a rationale for assessing matrix metalloproteinase-9 (MMP-9) inhibitors and nitroxyl donors. LCZ696, a combination drug of angiotensin II receptor blocker and neprilysin inhibitor, and the aldosterone receptor antagonist spironolactone are currently in clinical trial for treating HFpEF. Here we present an overview of the etiology and diagnosis of HFpEF that segues into a discussion of new therapeutic approaches emerging from basic research, as well as drugs currently in clinical trial, that primarily target diastolic dysfunction or imbalanced ventricular-arterial coupling.

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“…Of note, non-enzymatic cross-link formation can be mediated by advanced glycation end products (AGEs). [64,65] AGEs bind to specific cell membrane receptors that include RAGE (receptor for AGE). The extracellular ligand binding domain of the receptor, soluble RAGE (sRAGE), is released into the ECM and thereby can be released into the vascular compartment.…”

Section: Future Directions For Hfref and Hfpef – Diagnostics And Thermentioning

confidence: 99%

Integrating the Myocardial Matrix Into Heart Failure Recognition and Management

Spinale

Zile

2013

Circulation Research

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In contrast to public perception, the morbidity and mortality as well as the resultant health care costs associated with chronic heart failure (HF) are increasing and arguably reaching epidemic proportions. While basic research efforts have provided unique insights into fundamental processes that govern myocardial extracellular matrix (ECM) growth and function, the translation of these findings to improved diagnostics and therapeutics for HF have not been as forthcoming. The factors that contribute to this relative paucity of new clinical tools for HF are multifactorial but likely include the need to recognize and differentiate HF phenotypes, and to couple the use of biomarkers and multimodality imaging in early translational research studies. Recognizing the classification scheme of HF with a reduced ejection fraction (HFrEF) to that of HF with a preserved ejection fraction (HFpEF)and incorporating unique and differential measurements of ECM remodeling to these specific disease processes are warranted. For example, profiling pathways of ECM degradation such as the matrix metalloproteinases (MMPs) in patients with ischemic heart disease and HFrEF can provide prognostic information in terms of risk of progression to HF. In patients with chronic hypertensive disease and HFpEF, plasma profiling indices of ECM synthesis and turnover, as well as advances in ECM imaging have been shown to provide diagnostic and prognostic utility. In terms of therapeutics, strategies which stabilize the ECM in HFrEF hold potential, whereas in contradistinction, selective antifibrotic agents may hold promise with HFpEF.

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The role of advanced glycation end-products and their receptor on outcome in heart failure patients with preserved and reduced ejection fraction

Cited by 54 publications

References 21 publications

Targeting advanced glycation endproducts and mitochondrial dysfunction in cardiovascular disease

Targeting advanced glycation endproducts and mitochondrial dysfunction in cardiovascular disease

Heart Failure with Preserved Ejection Fraction

Integrating the Myocardial Matrix Into Heart Failure Recognition and Management

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