The most important finding of our study was that fluorescent AGE [detectable in plasma by 360/460 nm (exc./em.) fluorescence] is an independent and predictive biomarker for HF development risk after an acute myocardial infarct, whereas glycation precursors such as glycated haemoglobin lost their predictive value after a multivariate statistical adjustment. High AGE levels (over the median value) 5-fold increased the risk of post-infarction HF during the follow-up period, regardless of age, DM presence and glycaemic control, infarct’s seriousness (ventricle dysfunction and troponin elevation) and other biomarkers such as NT-proBNP. Although HbA1c, fructosamine and basal glucose, were significantly associated with a higher post-infarction HF rate in the univariate analysis, they lost their significance after being adjusted with other confounding variables, like AGE, in the multivariate analysis.
Within the last few years it has been reported the relation between hyperglycaemia and HbA1c and a higher risk of HF, both in diabetic and non-diabetic patients [6
]. This suggests that maintained hyperglycaemia plays an important role as a myocardial deleterious agent [11
] and that advanced glycation is one of the main action mechanisms [10
]. The role played by the AGE-RAGE axis in the onset of HF has been studied [12
], laying the foundations for the link between hyperglycaemia and HF.
AGE levels increase in the context of maintained hyperglycaemia [9
] and they trigger intracellular signalling pathways that activate NF-κB transcription factor, promoting oxidative stress [10
], which also contributes to AGE formation [11
]. AGE lead to both diastolic and systolic dysfunction [12
]. There are three reported molecular mechanisms for diastolic dysfunction mediated by AGE: 1) AGE establish cross links between matrix proteins decreasing their flexibility and promoting myocardial stiffness [22
]. 2) Through the activation of their receptors (AGE-RAGE axis), AGE induce fibrosis by up-regulation of transforming growth factor beta [23
]. 3) AGE-RAGE axis activation also may influence intracellular calcium homeostasis in cardiomyocytes, increasing repolarisation period [24
]. Regarding systolic dysfunction, it stands out, by its clinical repercussion, the acceleration of the coronary artery disease progression. AGE-RAGE interaction may induce atherosclerosis, thrombosis and vasoconstriction [12
]. AGE promote endothelial dysfunction secondary to a reduced nitric oxide bioavailability mediated by free radicals [25
] and they have shown to increase endothelial permeability in vitro
]. Endothelial dysfunction is involved in the early stages of atherosclerosis and may trigger endothelium repair by endothelial progenitor cells. However, AGE have demonstrated to promote apoptosis and impair functions of endothelial progenitor cells in culture [27
] and also to reduce growth and migration of mesenchymal stem cells [28
]. AGE can establish cross links with cholesterol-LDL particles resulting in the formation of more atherogenic molecules by increasing their affinity to macrophage receptors and enhancing foam cells formation [29
]. AGE may also induce systolic dysfunction by reducing intracellular calcium levels [24
] which conducts to a reduction of myocardial contractility. Taken all these considerations into account, the AGE-RAGE axis accelerates post-infarct myocardium remodelling, generating a deleterious feedback mechanism. In fact, the relation between the rennin-angiotensin-aldosterone system, a relevant system in ventricular remodelling and with demonstrated pathophysiological implications, with AGE-RAGE axis has been suggested [30
]. So, angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists reduced plasma AGE levels [31
]. In contrast, it has been demonstrated that AGE promote angiotensin II formation [32
]. Other possible ways to regulate AGE-RAGE axis activity have been explored. The most physiological one would be to increase physical activity in an attempt to reduce AGE-RAGE axis activity. A preliminary study has shown a reduction of soluble RAGE levels and an inverse correlation between these levels and paraoxonase-1 activity (an antioxidative enzyme) after an increasing physical activity intervention [33
]. However, alagebrium, an AGE-breaker, has not shown to improve physical exercise tolerance \and other secondary endpoints in patients with heart failure in the BENEFICIAL clinical trial [34
]. Even though, it is clear that AGE can play a role in post-infarction HF, being crucial elements of ventricular remodelling. However, to our knowledge, this is the first study to analyze the relationship between AGE levels and post-infarction HF.
Therefore, it is reasonable to think that all the data relating glycaemic and HbA1c with HF development risk [5
] could be explained based on the AGE-RAGE axis, since the glucose-fructosamine-HbA1c pathway ends in AGE [11
] as pentosidine or carboxymethyl-lysine and these molecules can mediate myocardial remodelling towards cardiac dysfunction. In fact, in this study, glucose, fructosamine and HbA1c were predictors of post-infarction HF in the univariate analysis, but after the adjustment by confounding variables and AGE all of them lost their significance. This result suggests that their predictive value is influenced by some of the other variables (probably AGE).
The higher level of AGE found in patients with post-infarction HF showed the pathophysiological role that these molecules can play in ventricular remodelling. This means that, rather than a simple risk biomarker after an acute myocardial infarction, AGE can be a new etiological way to focus therapeutic research to reduce the harmful effects of remodelling. In fact, there are some blockers of the AGE-RAGE axis that have been studied in animals. The best known are aminoguanidine, an AGE formation inhibitor [35
], and alagebrium (ALT-711), an AGE breaker [36
]. Both molecules have been tested in animals showing an improvement of myocardial compliance [35
] and an enhancement of cardiac function in animals with contractile dysfunction [36
]. The effect of alagebrium on diastolic dysfunction has also been studied in humans [36
]. In the DIAMOND trial 23 stable patients with diastolic dysfunction were treated with alagebrium. After 16 weeks, left ventricle mass was reduced and diastolic function was improved [37
]. The PEDESTAL trial studied the effects of alagebrium in HF patients with depressed systolic function (LVEF < 45%) and the preliminary results showed a tendency to improve systolic function [38
]. Our work opens the field to study the possible role of AGE-RAGE axis blockers in post-infarction HF development prevention.
Despite the impact and enthusiasm that our results can generate, we are aware of the limitations of our study and they should be taken into account for the interpretation of the results. Mainly, we must consider that our study population, which included all patients admitted for acute coronary syndrome in the coronary care unit within 15 months, was subjected to strict inclusion/exclusion criteria to eliminate possible interfering variables, thus limiting the extrapolation of our results to the real world of acute myocardial infarction patients. On the other hand, this meant a significant reduction in our sample size (n=194) and, considering it along with the inclusion of very selective population with a lower cardiovascular risk, it determines the statistical power of the analysis. Furthermore, some analytical parameters were not determined in some of the patients. Hence, AGE were measured in 100% population, whereas HbA1c was measured in 87.2%, fructosamine in 72.7% and NT-proBNP in 79.4%. On the other hand, in our study AGE were measured by Much’s method, which means that an unspecified mixture of different fluorescent AGE were detected in the measurement, but non-fluorescent AGE were not considered. Despite all this, we believe that our results maintain the pathophysiological and clinical implications exposed and open the field to future investigations.