A Breaker of Advanced Glycation End Products Attenuates Diabetes-Induced Myocardial Structural Changes

Candido, Riccardo; Forbes, Josephine M.; Thomas, Merlin C.; Thallas, Vicki; Dean, Rachael; Burns, Wendy C.; Tikellis, Christos; Ritchie, Rebecca H; Twigg, Stephen M.; Cooper, Mark E.; Burrell, Louise M.

doi:10.1161/01.res.0000065620.39919.20

Cited by 397 publications

(312 citation statements)

References 60 publications

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“…As to the pathomechanisms involved, we found increased expression of ET-1, ET receptor, TGF-β and collagen IV in untreated STZ diabetic rats, confirming, at least in part, data of other laboratories [30,31,32]. A further finding of potential pathogenetic relevance was increased systolic blood pressure measured by tail plethysmography.…”

Section: Discussionsupporting

confidence: 88%

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ACE-inhibition is superior to endothelin A receptor blockade in preventing abnormal capillary supply and fibrosis of the heart in experimental diabetes

et al. 2004

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Aims/hypothesis. There is little information whether cardiac capillary supply is deranged in diabetes. Hyperglycaemia is a potent stimulus for endothelin-1 (ET-1) production. We therefore hypothesised that increased ET-1 production in Streptozotocin-induced Type 1 diabetes causes abnormalities of cardiac capillaries and the aorta. To this end we compared the effects of an ET receptor A blocker (ET A -RB) with that of an ACE-inhibitor (ACE-i) or their combination in rats with Streptozotocin (STZ) diabetes. Methods. Sprague Dawley rats were injected with 65 mg STZ i.v. and subsequently developed diabetes. Rats were left untreated or received daily either the ACE-i Trandolapril, the ET A -RB Darusentan or a combination of both. After 6 months the experiment was terminated and the heart and the aorta were investigated using quantitative morphological techniques. Results. ACE-i but not ET A -RB lowered blood pressure in STZ Type 1 diabetic rats. Capillary length density was lower in untreated STZ diabetic rats (2932±128 mm/mm 3 ) compared to non-diabetic control rats (3410±252 mm/mm 3 ). Treatment with ACE-i (3568±431 mm/mm 3 ), but not with ET A -RB (2893±192 mm/mm 3 ), prevented the decrease in capillary supply. Volume density of the myocardial interstitium was higher in untreated STZ diabetic rats (0.86±0.04%) compared to non-diabetic control rats (0.36±0.06%). In all three intervention groups the values were lower (ACE-i: 0.53±0.05%, ET A -RB: 0.7±0.08% and combination: 0.69±0.1). Conclusion/interpretation. Our study identifies a capillary defect of the heart in STZ diabetes, i.e. decreased capillary supply. This abnormality was reversed by ACE-i, but not by ET A -R blockade. A similar trend, although not complete normalisation, was seen in cardiac fibrosis. [Diabetologia (2004) 47:316-324]

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Section: Discussionsupporting

confidence: 88%

“…The modification of extracellular matrix components by advanced glycation leads to increased collagen cross linking and increased myocardial stiffness in diabetes [31]. In addition our study showed increased expression for collagen IV in diabetic rats.…”

Section: Discussionsupporting

confidence: 64%

ACE-inhibition is superior to endothelin A receptor blockade in preventing abnormal capillary supply and fibrosis of the heart in experimental diabetes

et al. 2004

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“…Recently, cardiac BNP gene expression was reported to be increased and to improve by intervention with a breaker of advanced glycation endproducts in streptozotocin diabetic rats [28].…”

Section: Discussionmentioning

confidence: 99%

Plasma N-terminal pro-brain natriuretic peptide as an independent predictor of mortality in diabetic nephropathy

et al. 2004

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Aims/hypothesis: Raised N-terminal pro-brain natriuretic peptide (NT-proBNP) is independently associated with an increased risk of death in chronic heart failure and acute coronary syndromes in nondiabetic populations. Diabetic nephropathy is characterised by an increased risk of cardiovascular morbidity and mortality. This study investigated the prognostic value of NT-proBNP in a large cohort of type 1 diabetic patients with and without diabetic nephropathy. Methods: In a prospective observational follow-up study, 198 type 1 diabetic patients with overt diabetic nephropathy (122 men, age [mean±SD] 41±10 years, duration of diabetes 28±8 years, GFR 74±33 ml min −1 ) and a matched control group of 188 patients with longstanding type 1 diabetes and persistent normoalbuminuria (114 men, age 43±10 years, duration of diabetes 27±9 years) were followed for 9.3 (0.0-9.5) years. Plasma NTproBNP concentration was determined by immunoassay at baseline. Results: In patients with diabetic nephropathy, plasma NT-proBNP concentration was elevated to (median [range]) 110 (5-79640) ng l −1 vs. 27 (5-455) ng l −1 in normoalbuminuric patients (p<0.0001). Among patients with nephropathy, 39 (39%) patients with plasma NTproBNP concentrations above the median and 12 (12%) with values below the median died from any cause (unadjusted hazard ratio 3.86 [95% CI 2.02-7.37], p<0.0001; covariate-adjusted hazard ratio 2.28 [1.04-4.99], p=0.04). This lower mortality rate was attributable to fewer cardiovascular deaths: 31 (31%) and 7 (7%) above and below the median NT-proBNP level respectively (unadjusted hazard ratio 5.25 [2.31-11.92], p<0.0001; covariate-adjusted hazard ratio 3.81 [1.46-9.94], p=0.006). Conclusions/interpretation: Elevated circulating NT-proBNP is a new independent predictor of the excess overall and cardiovascular mortality in diabetic nephropathy patients without symptoms of heart failure.

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“…210 Advanced glycation is also related to alterations in myocardial calcium handling and hence contractility. 211 These findings could explain the electrophysiological alterations that serve as a central mechanism of the vulnerability to AF in diabetes. 212 Aggressive treatment of diabetes and adequate glycemic control may prevent or delay the occurrence of AF, despite little direct evidence of the effects of anti-diabetic drugs on AF.…”

Section: Diabetes Mellitusmentioning

confidence: 95%

EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication

et al. 2016

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A Breaker of Advanced Glycation End Products Attenuates Diabetes-Induced Myocardial Structural Changes

Cited by 397 publications

References 60 publications

ACE-inhibition is superior to endothelin A receptor blockade in preventing abnormal capillary supply and fibrosis of the heart in experimental diabetes

ACE-inhibition is superior to endothelin A receptor blockade in preventing abnormal capillary supply and fibrosis of the heart in experimental diabetes

Plasma N-terminal pro-brain natriuretic peptide as an independent predictor of mortality in diabetic nephropathy

EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication

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