Role of advanced glycation end products in cardiovascular disease
Impact Factor:
Level of Evidence: 1
Study type: review article
Sample size: N/A
Methods: N/A
Statistical tests: N/A
Results: Many of the studies reviewed in this article provided experimental evidence that supports a link between serum AGE levels and the onset and progression of heart failure (HF). Given this correlation, the development of therapeutic regimes that target and reduce AGE levels may ultimately be beneficial in treating patients with HF.
Discussion: The negative impact of AGEs on cellular functioning is likely associated with their ability to cross link intracellular and extracellular proteins, which ultimately alters the function of affected cells/tissues. With regards to the pathogenesis of HF, AGEs might have a significant role in its development and progression either via indirect mechanisms mediated through enhancing coronary artery disease or directly by inducing myocardial damage independent of vascular effects. Preliminary data suggests that targeting AGEs therapeutically may represent a novel treatment strategy in the management of DM and its cardiovascular complications.
Hegab Z, Gibbons S, Neyses L, Mamas MA. Role of advanced glycation end products in cardiovascular disease. World J Cardiol. 2012 Apr 26;4(4):90-102. doi: 10.4330/wjc.v4.i4.90. PMID: 22558488; PMCID: PMC3342583.
Do Advanced Glycation End Products and Its Receptor Play a Role in Pathophysiology of Hypertension?
Impact Factor:
Level of Evidence: 1
Study type: review article
Sample size: N/A
Methods: To establish a well-documented relationship between AGE levels and arterial stiffness, Prasad et al. reviewed a number of studies, with methodologies ranging from animal models to human clinical trials.
Statistical tests: N/A
Results: The reviewed studies provide evidential support for a positive correlation between plasma AGE levels and arterial stiffness. Additionally, the reviewed evidence also suggests a negative correlation between levels of soluble RAGE (sRAGE)/endogenous secretory RAGE (esRAGE) and hypertension (HTN). Because sRAGE and esRAGE act as decoys for RAGE, their presence reduces AGE-RAGE binding and, as such, decreases the production of ROS (radial oxygen species) associated with AGE-RAGE interactions. In other words, it appears that sRAGE and esRAGE may have protective effects against the development and progression of arterial stiffness commonly seen in patients with HTN.
Discussion: Given these two correlations, therapeutic strategies that reduce plasma AGE levels and/or increase expression of sRAGE are likely to be beneficial in reducing arterial stiffness and, consequently, blood pressure. More specifically, drugs commonly used to treat cardiovascular diseases like HTN and diabetes mellitus (angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor blockers, statins, and metformin) appear to inhibit AGE formation. Results from animal studies have also revealed that systemic administration of sRAGE is correlated with AGE inhibition, suggesting that exogenous administration of recombinant sRAGE may be beneficial in patients with HTN. However, it should be noted that there is currently little to no data available on the effects of exogenous administration of sRAGE in individuals with HTN.
Prasad K, Mishra M. Do Advanced Glycation End Products and Its Receptor Play a Role in Pathophysiology of Hypertension? Int J Angiol. 2017 Mar;26(1):1-11. doi: 10.1055/s-0037-1598183. Epub 2017 Feb 3. PMID: 28255209; PMCID: PMC5330762.
High serum advanced glycation end-products predict coronary artery disease irrespective of arterial stiffness in diabetic patients
Impact Factor:
Level of Evidence: IV
Study type: retrospective/case-control
Sample size: 145 consecutive patients (63±9 years, 58% men) who received a coronary angiogram for evaluation of CAD
Methods: 44 diabetic patients and 101 non-diabetics were divided into 3 groups based on the findings of their coronary angiograms. More specifically, each participant was classified into the one of the three following groups: those with zero obstructive diseased vessels, those with 1 diseased vessel, and those with 2 or more diseased vessels. AGE serum levels and brachial-ankle pulse wave velocities (baPWV) were then obtained for all participants.
Statistical tests: Unpaired t-tests and one-way ANOVAs were used to compare continuous variables between subgroups and a chi-square test was used to compare categorical variables between subgroups. Pearson’s correlation test was used to assess correlations and multiple regression analysis was used to assess the presence of obstructive CAD and the associations with the number of diseased vessels.
Results: AGE serum levels were significantly higher in diabetic participants with obstructive CAD than in those without obstructive CAD (2.16±0.29 vs. 1.85±0.29 mU/mL, p=0.010). Additionally, AGE serum levels were significantly correlated with the number of diseased vessels in diabetics (r=0.504, p<0.001), but were not significantly correlated with baPWV in diabetics or non-diabetics. In multiple regression analysis, serum AGEs independently predicted obstructive CAD and were associated with the number of diseased vessels in diabetics.
Discussion: Serum AGE levels independently predict obstructive CAD and the severity of coronary atherosclerosis independent of arterial stiffness only in diabetics. Evaluation of PWV and serum AGEs together may be more effective to identify the risk of CAD in diabetic individuals.
Won KB, Chang HJ, Park SH, Hong SY, Jang Y, Chung N. High serum advanced glycation end-products predict coronary artery disease irrespective of arterial stiffness in diabetic patients. Korean Circ J. 2012 May;42(5):335-40. doi: 10.4070/kcj.2012.42.5.335. Epub 2012 May 24. PMID: 22701499; PMCID: PMC3369965.
Advanced glycation end products in isoproterenol-induced acute myocardial infarction
Impact Factor:
Level of Evidence: Level VII
Study: Rat Study
Sample Size: 40 white male rats were randomly divided into 5 groups: sham (L1=11), control 0.9% NaCl (L2=11), and 3 groups of varying experimental analysis of myocardial infarction (L3= 6, 6 hours), (L4=6, 24 hours), and (L5=6, 7 days).
Methods: 100 mg/kg of isoproterenol hydrochloride was injected subcutaneously. The rats were sacrificed at 6 hours, 24 hours, and at 7 days. Sample cardiac tissue was homogenized with a 0.25 M sucrose buffer. Sample was then treated with a 30 microliter Triton X-100. The tissue was placed in the refrigerator for 30 minutes and then centrifuged at 3000 rpm for 10 minutes. Supernatant was kept at -40 degree C. The samples of blood were put into test tubes and centrifuged at 1500 rpm for 10 minutes. Glucose was measured using the ELITech assay kit (France). AGEs were measured using the Sero Luc method.
Stats: Kolmogorov Smirnov and Shapiro-Wilk normality test, Levene’s test, Kruskal-Wallis, Mann-Whitney U-test, Spearman correlation test, p value<0.05 being significant.
Results: All groups showed a significant difference in the serum glucose and the age level. (Glucose p=0.002 and AGE level p=0.018). The trend for serum showed there was a decrease in glucose (4.56) and AGE levels (262.20) in L3 which was 6 hours after. The glucose (7.00) and AGEs (354.30) then increased after 24 hours post-myocardial infarction which was L4. The AGE level (392.50) continued to increase, while the glucose (6.02) decreased slightly. The glucose and AGE in the homogenate (cardiac tissue) showed no significant differences. A positive correlation was found between glucose and AGEs levels in the tissue (p=0.008), however no correlation was found between serum glucose and AGEs level (p=0.283).
Conclusion: There is a correlation between the serum and tissue variations of AGE in isoproterenol-induced ischemia. The decrease in AGE and glucose in the first 24 hours indicated that there was oxidative stress and membrane lesion exacerbation that led to elimination of both. AGE level does directly depend on the degree of oxidative stress. Therefore it does aid in making a diagnosis and identifying risk stratification for a myocardial infarction.
Limitation: Rat Study
Timercan T, Şveţ I, Pantea V, Ambros A, Lîsîi L. Advanced glycation end products in isoproterenol-induced acute myocardial infarction. Med Pharm Rep. 2019 Jul;92(3):235-238. doi: 10.15386/mpr-1348. Epub 2019 Jul 31. PMID: 31460503; PMCID: PMC6709963.
Implications of advanced oxidation protein products (AOPPs), advanced glycation end products (AGEs) and other biomarkers in the development of cardiovascular diseases
Impact Factor: 2.802
Level of Evidence: III
Study: Experimental
Sample Size: 50 cardiovascular patients screened at Punjab Institute of Cardiology, Lahore, Pakistan. 50 healthy individuals that were the controls. Inclusion criteria was ages 20-70 with ischemic heart disease. Individuals with previous addictions and pre-diagnosis medications were not included in the study.
Methods: 5 mL of blood from periphery was acquired and centrifuged. Different variables such as GSH, CAT, SOD, MDA, GPx, GRx, Vit-E, NO, AOPPs and AGEs by commercial kits, e-NOS through Cayman’s e-NOS ELIZA kit, TNF-a through BioVendor Human TNF-a ELIZA Kit, IL-1 a through BioVendor ELIZA kit, MMP-11 through BioVendor Human MMP-11 ELIZA Kit, and all lipid profile (TCh, TG, LDL, and HDL) through commercial Human Diagnostic Kits. The ethical committee of University of Lahore approved the study, and informed consent was acquired according to Helsinki's declaration.
Stats: analyzed by SPSS (ver 16), Independent student’s t-test, Pearson correlation, p value<0.05 being significant.
Results: There was a significant difference in oxidative stress and biochemical markers between the control group that did not have any cardiovascular disease and the experimental group that did. Mean serum AGE was 2.74 ± 0.25 mg/ml for CVD patients and 0.85 ± 0.04 for the control group. P value was 0.000. CVD patients also have higher AOPP (p value= 0.011), e-NOS (p value 0.004), MDA (p value= 0.018), and NO (p value= 0.011) than the control group. The lipid profile showed that CVD patients had elevated levels of TCh, TG, and LDL, but decreased levels of HDL. Mean IL1-a, TNF-a, and MMP-11 were elevated in the CVD patients. Mean CAT, SOD, GSH, and GRx were decreased in CVD patients. GPx levels were increased in CVD patients, and Vit-E was decreased in CVD patients.
Conclusion: AOPP has been useful in determining the oxidative damage because AOPP and AGE both induce major cardiovascular complications. AGE works by binding to RAGE receptors and has been proved to be an early sign of atherosclerosis. In addition, e-NOS uncouples and then forms more NO which can result in more peroxynitrite. There was a positive correlation between NO and GSH (r= 0.303), AGEs and NO (r=0.447) and e-NOS anad SOD (r=0.292).
Limitation: Sample Size
Rasool M, Malik A, Butt TT, Ashraf MAB, Rasool R, Zahid A, Waquar S, Asif M, Zaheer A, Jabbar A, Zain M, Mehmood A, Qaisrani TB, Malik IR, Khan SU, Mirza Z, Haque A, Al-Qahtani MH, Karim S. Implications of advanced oxidation protein products (AOPPs), advanced glycation end products (AGEs) and other biomarkers in the development of cardiovascular diseases. Saudi J Biol Sci. 2019 Feb;26(2):334-339. doi: 10.1016/j.sjbs.2018.08.024. Epub 2018 Aug 27. PMID: 31485173; PMCID: PMC6717110.
Cardiac inflammation associated with a Western diet is mediated via activation of RAGE by AGEs.
Impact Factor: 3.469
Level of Evidence: VII
Sample Size/Population: n= 60; 6 different groups with 10 rats each.
Protocol: Diets high in fat represent a major endogenous source of AGEs as a result of interaction between proteins and oxidized lipids in high temperature conditions. The corresponding increase in serum AGEs and their activation of AGE receptors (RAGEs) has been associated with impaired cardiac function through damaged processes such as calcium homeostasis as well as interstitial fibrogenesis. This study compares the AGE related effects of a high-fat diet, specifically a "Western" fast food diet, to that of a standard fat diet, as well as the potentially cardioprotective effects of an AGE-reduced diet in a mouse population. Specifically, the researchers used alagebrium chloride, a known AGE-reducing agent.
Material/Methods: Two different populations of mice were examined in this study, one wildtype group and one RAGE knockout (KO) group. These two groups were further subdivided into a standard diet group, a Western-diet group, and a Western-diet + AL (alagebrium chloride) group. Variables such as cardiac hypertrophy, myocardial fibrosis, and superoxide production were measured. The level of cardiac AGE accumulation was measured through the use of indirect in-house ELISA with a monoclonal AGE antibody specific to nonfluorescent AGE carboxymethyl-lysine (CML). In addition, AGE-R1 and AGE-R3 AGE receptor expressions were assessed with RT-PCR.
Study Type: Rat study.
Statistical Analysis: Student t-test, for 2 groups, and one-way ANOVA, for 3 or more groups, were used for statistical analysis where P<0.05 is considered significant for each. Associations between variables were also measured using Spearman's rank-order correlation. Mann-Whitney rank sum test was used to determine differences between categorical variables.
Results: Wild-type mice fed the high fat Western diet demonstrated increased cross-sectional area of cardiac myocytes, while RAGE KO mice did not demonstrate this cardiac hypertrophy. A similar pattern was observed in regards to myocardial fibrosis, whereby the wild-type high fat diet demonstrated increased gene expression of collagen expression, while the RAGE KO mice did not. High fat diet groups demonstrated a significant increase in myocardial inflammation as compared to normal diet, however RAGE KO mice demonstrated significantly decreased levels of cardiac inflammation on the high fat diet as compared to the wild-type. Mice that were also given AL demonstrated less inflammation in both RAGE KO and wild-type groups as compared to the inflammation in their counterparts that were not given AL. Finally, RAGE KO mice did not experience the same increase in mitochondrial superoxide production that was evident in the wildtype group being fed a high fat diet. AL decreased superoxide production in both wild-type and RAGE KO groups.
The increased AGE intake in both RAGE KO and wild-type groups associated with the high fat diet, showed a small, but significant, increase in cardiac AGE accumulation. While RAGE expression was increased in high fat fed wild-type mice as compared to standard diet, there was no expression of RAGE in RAGE KO mice with any of the experimental manipulations.
Conclusion: A Western-fast food diet represents a significant source of increased AGE-related injurious effects to the heart. AGE-reducing agents such as alagebrium chloride, as well as inhibition of RAGE activation through genetic manipulation practices, are able to prevent the deleterious effects of cardiac inflammation, oxidative stress, and mitochondrial dysfunction that are related to chronic AGE activation of RAGE in mice.
Limitations: Results in rat populations may not necessarily directly translate to humans.
Tikellis C, Thomas MC, Harcourt BE, Coughlan MT, Pete J, Bialkowski K, Tan A, Bierhaus A, Cooper ME, Forbes JM. Cardiac inflammation associated with a Western diet is mediated via activation of RAGE by AGEs. Am J Physiol Endocrinol Metab. 2008 Aug;295(2):E323-30. doi: 10.1152/ajpendo.00024.2008. Epub 2008 May 13. PMID: 18477705; PMCID: PMC2652498.
An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness.
Impact Factor: 9.412
Level of Evidence: VII
Sample Size: 18 dogs.
Material/Methods: Dog subjects were assigned into 3 groups - 1: Young animals. 2: Old animals with treatment. 3: Old animals not receiving treatment. Group 2 received 1mg/kg dose of the ALT-711 drug, which breaks cross-links in AGEs. Subjects from the three groups were followed for 4 weeks. Left ventricular end-diastolic volume (EDV), stroke volume, and decreased end-diastolic pressure (EDP) were measured.
Statistical Tests Ran: Two-way ANOVA with a p<0.05.
Results: Dogs in Groups 2 and 3 were significantly more stiff than the dogs in Group 1. Older dogs had significantly increased EDP and significantly decreased EDV (p<0.01 in both cases). Ejection fraction, heart rate, and systemic pressure were similar among all three groups. Continued hemodynamic studies showed an increase in EDV in Group 2 (p<0.001) without EDP change with ALT-711 use. Stroke volume was significantly increased (p<0.05). LV stiffness decreased from ~57 mmHg⋅m2/mL to 33.1 mmHg⋅m2/mL (p<0.001).
Type of Study: Animal Study - Dog Model
Results/Conclusion: This study showed the effectiveness of ALT-711 in reducing the diastolic stiffness of the left ventricle (LV) by cleaving the AGE cross-link. Over 4 weeks, it was seen that this drug significantly increased EDV. The data presented substantiates the evidence that AGE cross-links have a purpose in aging and cardiovascular state. Administration of ALT-711 demonstrated a reversal in cardiac symptoms, alleviating issues associated with AGEs. There needs to be further testing to determine whether aging in a real world setting would differ.
Asif, M., Egan, J., Vasan, S., Jyothirmayi, G. N., Masurekar, M. R., Lopez, S., Williams, C., Torres, R. L., Wagle, D., Ulrich, P., Cerami, A., Brines, M., & Regan, T. J. (2000). An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. Proceedings of the National Academy of Sciences of the United States of America, 97(6), 2809–2813. https://doi.org/10.1073/pnas.040558497.
Advanced glycation end products in nondiabetic patients with coronary artery disease.
Impact Factor: 7.72
Level of Evidence: IV
Sample Size: 48 nondiabetic patients who received coronary angiography from Nara Medical University in Nara, Japan. 20 with normal glucose tolerance, 28 people with diminished glucose tolerance. 40 of the patients were men and 8 were women (age 26-83 years old). The control group consisted of 25 glucose-tolerant individuals without coronary artery disease (CAD).
Material/Methods: Patients received coronary angiography during the study for chest pain or assumed CAD. Serum AGE levels were measured as well as insulin sensitivity. Coronary angiograms were measured by having a stenosis greater than 50% diameter in one coronary artery.
Statistical Analysis: Unpaired t test or Mann-Whitney U test. Difference in percentages was assessed using the χ2 test. Spearman’s rank correlation test was employed for correlations. p<0.05. Serum concentration of AGE, fasting serum glucose, 2-hr serum glucose, fasting serum insulin, and 2-hr serum insulin were used as independent variables. Stenosed vessels was the dependent variable.
Results/Conclusion: Four groups were created depending on the number of vessels stenosed, ranging from 0, 1, 2, or 3 vessels. Plasma TGs correlated with increased number of stenosed vessels. Serum creatinine concentration increased following an increase in number of stenosed vessels. Area under the curve and 2-hr serum glucose were higher in the group with 3-vessel CAD and also correlated with the number of vessels. Serum AGEs were elevated in all individuals with CAD when compared to the control group. Serum AGEs correlated with the number of stenosed vessels (p<0.001). No correlation of serum AGEs with fasting serum glucose, 2-hr glucose, AUCglu, or the concentration of plasma creatinine.
Kanauchi M, Tsujimoto N, Hashimoto T. Advanced glycation end products in nondiabetic patients with coronary artery disease. Diabetes Care. 2001 Sep;24(9):1620-3. doi: 10.2337/diacare.24.9.1620. PMID: 11522709.
Impact Factor: 6.607 (2016)
Level of Evidence: IV
Sample Size: 1141 (535 Nondiabetic Men, 606 Nondiabetic Women).
Statistical Analysis: SPSSX, SPCC/PC+ and SPSS 11.0.1 programs. Bivariate correlation assessed by Spearman’s relation coefficient. Chi-squared or 2-tailed t test for independent samples. Univariate and multivariate COX regression models and Kaplan-Meier survival curves.
Results: Women had higher BMI and total HDL levels but had lower total triglycerides and fasting plasma glucose. Serum levels of AGE’s were significantly higher in men than women. Subjects in the highest AGE quartile were more often current smokers (P =.009), had higher total cholesterol (P = .048), total triglycerides (P = .032) and had lower HDL cholesterol (P = .023) than those in other quartiles. AGE levels and gender had a significant interaction in effects on total mortality (P = .023) with CHD mortality (P = .012) even after adjustment for confounding variables (separating men and women). Unadjusted serum AGE’s were significantly related to total (P = .007), CVD (P < .001) and CHD (P<.001) mortality in women but not in men. In women, high AGE levels increased mortality from all causes by 1.6 fold (P = .042) and CHD mortality by 4-fold (P = .014) independently of confounding factors. Kaplan-Meier survival analysis, total (P = .032) and CHD mortality (P<.001) were significantly higher in subjects of the highest AGE quartile.
Type of Study: 18 year follow-up study, Random sample with diabetic patients screened out.
Results/Conclusion: Finding of a significant association of AGE serum levels with CHD and CVD mortality in women might indicate an etiologic role of AGEs in atherosclerosis in patients without diabetes. Even after adjustment for hs-CRP, AGE’s probably increased mortality, at least in part, independently of inflammation in the vascular wall. Circulating AGE’s predicted mortality only in women, therefore it is possible (but more evidence is needed) that AGE’s represent an additional risk for CVD only in low-risk individuals. Serum levels of AGE’s did not correlate with fasting plasma glucose, maybe reflecting anti-AGE antibody recognizes the more heavily modified glucose compounds as well as oxidatively modified proteins. Increased AGE levels did not predict atherosclerotic events in men, which may be because of a high frequency of smoking and other risk factors. It was demonstrated that AGE serum levels predict total, CVD and CHD mortality in nondiabetic women. Measurement of serum AGE’s might Identify high-risk individuals in a low-risk population.
Kilhovd BK, Juutilainen A, Lehto S, Rönnemaa T, Torjesen PA, Birkeland KI, Berg TJ, Hanssen KF, Laakso M. High serum levels of advanced glycation end products predict increased coronary heart disease mortality in nondiabetic women but not in nondiabetic men: a population-based 18-year follow-up study. Arterioscler Thromb Vasc Biol. 2005 Apr;25(4):815-20. doi: 10.1161/01.ATV.0000158380.44231.fe. Epub 2005 Feb 3. PMID: 15692098.
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