Molecular determinants of heart failure with normal left ventricular ejection fraction

Borbély, Attila; Papp, Zoltán; Édes, István; Paulus, Walter J.

doi:10.1016/s1734-1140(09)70016-7

Cited by 46 publications

(38 citation statements)

References 47 publications

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“…Advanced glycation end-products (AGEs), formed when glucose interacts nonenzymatically with proteins, can cause increased stiffness of the ECM directly by cross linking collagen or elastin and indirectly by stimulating the production of collagen and depleting NO thereby increasing oxidative stress (23). The beneficial effects of AGEs breakers in ventricular distensibility and arterial compliance improvement has been studied in recent years.…”

Section: Altered Signaling Pathways In Hfpef As Potential Targets Formentioning

confidence: 99%

Myocardial reverse remodeling: how far can we rewind?

Gonçalves-Rodrigues

Leite‐Moreira

Falcão-Pires

2016

American Journal of Physiology-Heart and Circulatory Physiology

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Heart failure (HF) is a systemic disease that can be divided into HF with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). HFpEF accounts for over 50% of all HF patients and is typically associated with high prevalence of several comorbidities, including hypertension, diabetes mellitus, pulmonary hypertension, obesity, and atrial fibrillation. Myocardial remodeling occurs both in HFrEF and HFpEF and it involves changes in cardiac structure, myocardial composition, and myocyte deformation and multiple biochemical and molecular alterations that impact heart function and its reserve capacity. Understanding the features of myocardial remodeling has become a major objective for limiting or reversing its progression, the latter known as reverse remodeling (RR). Research on HFrEF RR process is broader and has delivered effective therapeutic strategies, which have been employed for some decades. However, the RR process in HFpEF is less clear partly due to the lack of information on HFpEF pathophysiology and to the long list of failed standard HF therapeutics strategies in these patient's outcomes. Nevertheless, new proteins, protein-protein interactions, and signaling pathways are being explored as potential new targets for HFpEF remodeling and RR. Here, we review recent translational and clinical research in HFpEF myocardial remodeling to provide an overview on the most important features of RR, comparing HFpEF with HFrEF conditions.

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Section: Altered Signaling Pathways In Hfpef As Potential Targets Formentioning

confidence: 99%

Myocardial reverse remodeling: how far can we rewind?

Gonçalves-Rodrigues

Leite‐Moreira

Falcão-Pires

2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…ECM accumulation is, in turn, believed to be a major contributor to the impaired cardiac relaxation that is the hallmark of this condition. 4 Clinical evaluation of the presence and magnitude of ECM accumulation in the heart is difficult. The gold standard for such evaluation is myocardial biopsy, but even then, fibrosis may be missed if it is patchy and nonhomogeneously distributed through the heart.…”

Section: Clinical Perspective On P 568mentioning

confidence: 99%

Relation of Peripheral Collagen Markers to Death and Hospitalization in Patients With Heart Failure and Preserved Ejection Fraction

Krum

Elsik

Schneider

et al. 2011

Circ: Heart Failure

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Background-Heart failure with preserved ejection fraction (HFPEF) is a common and increasing public health problem.Myocardial fibrosis is a key pathological feature of HFPEF. Peripheral collagen markers may reflect this excess fibrosis; however, the relation of these markers to prognosis in patients with HFPEF has not as yet been determined. Methods and Results-This substudy of the Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE) trial measured plasma levels of procollagen type I amino-terminal peptide, procollagen type III amino-terminal peptide, and osteopontin in 334 patients with HFPEF. Measurements were performed at baseline and 6 months after randomization to placebo or irbesartan 300 mg/day. The relation of baseline collagen markers to the I-PRESERVE primary end point (all-cause death and hospitalization for prespecified cardiovascular causes) was evaluated by single and multivariable analysis. Similar evaluations were performed for all-cause death alone as well as heart failure events (death or hospitalization because of heart failure). Increased plasma levels of collagen markers at baseline were associated with increased frequency of the study primary end point for all collagen markers. For each 10-g/L increase in procollagen type I amino-terminal peptide, the hazard ratio (HR) for the primary end point was 1.09 (95% CI, 1.052 to 1.13; PϽ0.0001); for each 10-g/L increase in procollagen type III amino-terminal peptide procollagen type I amino-terminal peptide, the HR was 2.47 (95% CI, 0.97 to 6.33; Pϭ0.059); and for each 10-nmol/L increase in osteopontin, the HR was 1.084 (95% CI, 1.026 to 1.15; Pϭ0.004). No variable remained significant as an independent predictor when introduced into a multivariable model. Both treatment groups tended to reduce collagen markers, with the reduction significantly greater for placebo versus irbesartan for procollagen type III amino-terminal peptide only (Pϭ0.0185). Conclusions-Increased peripheral collagen turnover markers were not independently associated with increased mortality and cardiovascular hospitalization in an HFPEF population on multivariable analysis but were associated on single-variable analysis. These findings provide some support to the hypothesis that pathological fibrosis in the heart, and possibly the peripheral vasculature, may be contributory to adverse clinical outcomes in patients with HFPEF. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.(Circ Heart Fail. 2011;4:561-568.)

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“…2,3 For example, AGEs may impair both diastolic and systolic left ventricular (LV) function directly, through extracellular matrix protein cross-linkage and/or altered calcium handling, and/or indirectly, through the interaction with cardiac AGE receptors, which in turn lead to low-grade inflammation, increased oxidative stress and altered gene expression. [2][3][4] Consequently, AGEs may also unfavourably affect the process of LV remodeling. [2][3][4] The impact of AGEs on LV function may be of particular importance in T2DM, as T2DM is characterized by chronic hyperglycaemia and hyperlipidaemia, which in turn can induce the formation of AGEs, as well as oxidative stress and low-grade inflammation, which can further enhance the formation of AGEs.…”

Section: Introductionmentioning

confidence: 99%

Serum advanced glycation endproducts are associated with left ventricular dysfunction in normal glucose metabolism but not in type 2 diabetes: The Hoorn Study

Linssen

Henry

Schalkwijk³

et al. 2016

Diabetes and Vascular Disease Research

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Objective: To investigate whether serum advanced glycation endproducts are associated with left ventricular systolic and diastolic function in participants with normal glucose metabolism, impaired glucose metabolism and type 2 diabetes mellitus. Methods: Participants from a cross-sectional, population-based study (n = 280 with normal glucose metabolism, n = 171 with impaired glucose metabolism, n = 242 with type 2 diabetes mellitus) underwent echocardiography. Serum proteinbound advanced glycation endproducts [i.e. Nε-(carboxymethyl)lysine, pentosidine and Nε-(carboxyethyl)lysine] were measured. Linear regression analyses were used and stratified according to glucose metabolism status. Results: In normal glucose metabolism, higher Nε-(carboxymethyl)lysine and pentosidine levels were associated with worse diastolic function (left atrial volume index and left atrial volume × left ventricular mass index product term) and higher Nε-(carboxymethyl)lysine and Nε-(carboxyethyl)lysine levels with worse systolic function (ejection fraction). In impaired glucose metabolism, a similar pattern emerged, though less consistent. In type 2 diabetes mellitus, these associations were non-existent for diastolic function or even reversed for systolic function. Conclusion: This suggests that serum advanced glycation endproducts are associated with impaired left ventricular function in normal glucose metabolism, but that with deteriorating glucose metabolism status, serum advanced glycation endproducts may not mirror heart failure risk.

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Molecular determinants of heart failure with normal left ventricular ejection fraction

Cited by 46 publications

References 47 publications

Myocardial reverse remodeling: how far can we rewind?

Myocardial reverse remodeling: how far can we rewind?

Relation of Peripheral Collagen Markers to Death and Hospitalization in Patients With Heart Failure and Preserved Ejection Fraction

Serum advanced glycation endproducts are associated with left ventricular dysfunction in normal glucose metabolism but not in type 2 diabetes: The Hoorn Study

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