Response to Letter Regarding Article, “Diastolic Stiffness of the Failing Diabetic Heart: Importance of Fibrosis, Advanced Glycation End Products, and Myocyte Resting Tension”

Heerebeek, Loek van; Hamdani, Nazha; Handoko, M. Louis; Falcão-Pires, Inês; Musters, René J.P.; Borbély, Attila; Velden, Jolanda van der; Stienen, Ger J; Paulus, Walter J.; Bronzwaer, Jean G.F.; Diamant, Michaëla; Kupreishvili, Koba; Niessen, Hans W.M.; Schalkwijk, Casper G.; Ijsselmuiden, Alexander; Laarman, Gerrit J.

doi:10.1161/circulationaha.108.778167

Cited by 195 publications

(265 citation statements)

References 5 publications

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“…Despite the assumption that AGEs accumulated in the heart [9] might be released from the myocardial tissue during the damage induced by either ischemia or reperfusion or both, no temporary rise of AGEs was found. However, as sampling and monitoring were not continuous, a short increase during the period between the samplings cannot be excluded completely.…”

Section: Discussionmentioning

confidence: 83%

“…Beyond diabetes mellitus, higher AGE levels are caused by liver diseases [3], renal failure [4], Alzheimer's disease [5] and the aging process [6]. Numerous studies have indicated the importance of AGEs in the pathogenesis of cardiovascular diseases, especially in diabetic patients [7][8][9][10]. Little is known about their role in ischemic heart disease in non-diabetic patients.…”

Section: Introductionmentioning

confidence: 99%

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Advanced glycation end products in myocardial reperfusion injury

Celec

Hodosy

Jani³

et al. 2011

Heart Vessels

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Advanced glycation end products (AGEs) are associated with cardiovascular diseases. Whether the AGE levels change during myocardial reperfusion injury is currently unknown. The aim of our study was to investigate the dynamics of AGEs in myocardial reperfusion injury and to discuss potential reasons for these changes. The dynamics of AGEs, pentosidine and neopterin in the plasma of patients with acute myocardial infarction (AMI) treated using thrombolysis (n = 40) were analyzed. In addition, AGEs were measured in patients with open heart surgery (n = 12) and rabbits with induced AMI (n = 9). In all three studies of myocardial reperfusion injury, a significant decrease of AGEs was observed (by 26 ± 19% in patients with AMI, by 23 ± 14% in patients with open heart surgery and by 39 ± 10% in rabbits with AMI within 1 day of reperfusion; p < 0.05 in all studies). In additional studies, an association between lower AGEs and an activated immune system (R (2) = 0.09; p < 0.01) and fasting (decrease by 38%; p < 0.01) was shown. AGEs decrease in reperfusion injury of the heart. Indices pointing towards the involvement of immune system activation and fasting are presented. Further studies focusing on the underlying mechanism and on the clinical value of the observed dynamics of AGEs are needed.

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Section: Discussionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Advanced glycation end products in myocardial reperfusion injury

Celec

Hodosy

Jani³

et al. 2011

Heart Vessels

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show abstract

“…However, a recent study has shown that mechanisms responsible for the increased diastolic stiffness of the diabetic heart are different in systolic and diastolic HF: in diabetic patients with systolic HF, fibrosis and deposition of advanced glycation end-products (AGEs) are the most important contributors to high LV diastolic stiffness, whereas in diabetic patients with diastolic HF, elevated resting tension of hypertrophied cardiomyocytes is the most important contributor to high LV diastolic stiffness [209].…”

Section: Diastolic Dysfunction In Diabetesmentioning

confidence: 99%

Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment

2011

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Diabetes mellitus is an important and prevalent risk factor for congestive heart failure. Diabetic cardiomyopathy has been defined as ventricular dysfunction that occurs in diabetic patients independent of a recognized cause such as coronary artery disease or hypertension. The disease course consists of a hidden subclinical period, during which cellular structural insults and abnormalities lead initially to diastolic dysfunction, later to systolic dysfunction, and eventually to heart failure. Left ventricular hypertrophy, metabolic abnormalities, extracellular matrix changes, small vessel disease, cardiac autonomic neuropathy, insulin resistance, oxidative stress, and apoptosis are the most important contributors to diabetic cardiomyopathy onset and progression. Hyperglycemia is a major etiological factor in the development of diabetic cardiomyopathy. It increases the levels of free fatty acids and growth factors and causes abnormalities in substrate supply and utilization, calcium homeostasis, and lipid metabolism. Furthermore, it promotes excessive production and release of reactive oxygen species, which induces oxidative stress leading to abnormal gene expression, faulty signal transduction, and cardiomyocytes apoptosis. Stimulation of connective tissue growth factor, fibrosis, and the formation of advanced glycation end-products increase the stiffness of the diabetic hearts. Despite all the current information on diabetic cardiomyopathy, translational research is still scarce due to limited human myocardial tissue and most of our knowledge is extrapolated from animals. This paper aims to elucidate some of the molecular and cellular pathophysiologic mechanisms, structural changes, and therapeutic strategies that may help struggle against diabetic cardiomyopathy.

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“…AGEs have been detected in myocardium in animals with experimental DM and are thought to contribute to the various manifestations of DM that comprise diabetic cardiomyopathy (Berg et al 1999;Schafer et al 2006). These include abnormalities of ion pumps and contractile proteins, abnormal energy metabolism and increased passive stiffness due to the aforementioned effects on collagen (van Heerebeek et al 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Three previous studies using light microscopic immunolocalization of the AGE carboxymethyl lysine (CML), two in postmortem specimens and one in LV endomyocardial biopsy material from pts with heart failure, have identified AGEs in small arteries in pts with and without DM, with virtually no localization elsewhere (Nakamura et al 1993;van Heerebeek et al 2008;Yoshida et al 1998). These results are in agreement with a recent light microscopic immunolocalization study in elderly hypertensive canines demonstrating that CML is confined to the vasculature and occurs in the myocardium only in association with arterioles (Shapiro et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Combined immunoelectron microscopic and computer-assisted image analyses to detect advanced glycation end-products in human myocardium

Donaldson

Taatjes

Zile

et al. 2010

Histochem Cell Biol

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Advanced glycation end-products (AGEs) result from oxidation-reduction reactions that ensue when a sugar becomes adducted to a protein. AGEs cause various complications of diabetes mellitus (DM). Experimental and clinical evidence suggest that AGEs also contribute to the complications of hypertension (HTN). Little is known about the abundance and localization of AGEs in human myocardium. In a few light microscopic studies, the AGE carboxymethyl lysine (CML) has been immunolabeled and localized virtually exclusively to the walls of small arteries. To more precisely delineate the abundance and localization of CML, we developed an immunoelectron microscopic (IEM) detection method using anti-CML monoclonal antibody 6D12 in conjunction with computer-assisted image analysis. Antibody was pre-absorbed with purified AGE-bovine serum albumin to assure specificity. Antigen-antibody (ag-ab) complexes were individually identified with protein A-conjugated colloidal gold and counted with an automated system. We applied this method in 21 patients (pts) undergoing epicardial biopsy during coronary bypass grafting (CBG) [20 M, 1 F; mean age 65 +/- 7.4 (+/- SEM) years]. Seven pts had neither DM nor HTN, seven had HTN, and seven had DM + HTN. In contrast to the prior light microscopic studies, we detected CML scattered throughout the cardiomyocyte in all pts, but in widely varying amounts. Ag-ab complexes were abundant in sections through myofilaments (mean count 23.6 +/- 9.2 per microm(2), range 9.4-48) and even more so in mitochondria (mean count 34.4 +/- 11.9 per microm(2), range 14.1-68.2, P < 0.001 vs. myofilaments). CML was also detected in vascular endothelial cells. There were no statistically significant differences based on presence or absence of HTN or DM. In conclusion, our IEM method is the first to provide detailed delineation of the localization and abundance of CML in myocardium. CML is very prevalent in CBG pts, suggesting that AGEs could play a role in abnormal cardiomyocyte function, including altered energy metabolism.

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Response to Letter Regarding Article, “Diastolic Stiffness of the Failing Diabetic Heart: Importance of Fibrosis, Advanced Glycation End Products, and Myocyte Resting Tension”

Cited by 195 publications

References 5 publications

Advanced glycation end products in myocardial reperfusion injury

Advanced glycation end products in myocardial reperfusion injury

Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment

Combined immunoelectron microscopic and computer-assisted image analyses to detect advanced glycation end-products in human myocardium

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