Inflammation and DM in AMI. The involvement of inflammation in atherosclerosis and, consequently, in AMI is well established [4-7], as well as the prognostic usefulness of biomarker surrogates, such as hs-CRP, for predicting the risk of mortality and recurrent events [11-16,22]. Moreover, observational and randomized studies indicated that cardiovascular benefits are more apparent when systemic inflammation is reduced [23,24]. In particular, the Aggrastat-to-Zocor (A to Z) trial demonstrated that the clinical outcome of patients with acute coronary syndromes significantly improves when the hs-CRP levels are lowered below 2 mg/L [16]. Diabetes mellitus is a multifactorial metabolic disease and growing evidence shows that it is characterized by a state of sub-clinical inflammation [5], as reflected by chronic high levels of hs-CRP [6]. In AMI, patients with DM show a more severe inflammatory condition than those without DM [25], and this may, at least in part, explain their higher short-term and long-term mortality risk [26,27]. However, whether hs-CRP during AMI carries a different prognostic relevance in DM and non-DM patients is still a controversial issue. Indeed, on the one hand, previous studies showed that CRP is an independent predictor of mortality after AMI in both DM and non-DM patients [28,29]. On the other hand, Meisinger et al. [28] found no association between CRP and long-term mortality (median 4 years) after AMI in DM patients. However, these studies were retrospective analyses of registries including old study populations (enrolled between 1998 and 2004), they considered patients with an outdated DM definition [28,29], and, in one study [29], traditional CRP was assessed. More recently, Xia et al. [30] found that CRP predicts three-year mortality in both DM and non-DM patients with AMI. Yet, in this study, the prognostic relevance of CRP was analyzed according to the CRP median value (8.9 mg/L), a cutoff that may encompass patients with the highest degree of inflammation [30]. Thus, the possible different prognostic impact of hs-CRP in AMI patients with and without DM remains unclear.
In our study, we confirmed the presence of a close association between inflammation and DM status in AMI. Indeed, DM patients were more likely to have admission hs-CRP levels >2 mg/L and had a higher median hs-CRP value than non-DM patients. Moreover, both inflammation and DM status, considered separately, were predictors of in-hospital outcome and two-year mortality, even after adjustment for major confounders. However, when we investigated the relationship between inflammation and outcomes, hs-CRP showed a different behavior in DM and in non-DM patients. In particular, the adjusted risk of the primary and secondary endpoints increased in parallel with hs-CRP quartiles in both groups, but with a more evident trend in non-DM patients. Notably, in the overall population, an hs-CRP value >2 mg/L was associated with an almost two-fold higher risk of both endpoints. This same risk corresponded to higher hs-CRP values in DM patients, when compared to non-DM patients, thus suggesting that the prognostic relevance of inflammation is maintained also in DM patients but it is shifted towards higher hs-CRP levels. To the best of our knowledge, this is a novel finding, which, if confirmed in future studies, could pave the way for prognostic stratification and intervention strategies tailored according to DM status.
The mechanisms underlying the different prognostic behavior of hs-CRP in DM and non-DM patients are beyond the purpose of the present analysis. However, the following hypothesis can be proposed. In AMI patients, admission hs-CRP level may be considered the result of a variable combination of chronic and acute inflammation. Thus, high hs-CRP levels at hospital admission may not necessarily represent only the inflammatory response associated with AMI severity. Given the well-established association between DM and inflammation, the contribution of chronic inflammation to hs-CRP levels in AMI patients is possibly more relevant in DM than in non-DM patients. Consistently with this theory, a similar hs-TnI peak value, an estimate of myocardial infarct size, was observed in our study in DM and non-DM patients, although the median hs-CRP level was significantly higher in the former group. Moreover, the correlation between hs-CRP levels and hs-TnI peak value was closer in non-DM than in DM patients.
Another intriguing issue is represented by the mechanisms underlying the association between hs-CRP and in-hospital outcome in AMI. In this regard, there is growing evidence that inflammation in AMI is not only a marker of AMI severity but it may directly exacerbate the cardiac dysfunction [31-33]. Indeed, in conditions characterized by acute systemic inflammation - such as severe burn, trauma, or sepsis - cardiac cell death is rare but reversible cardiac myocyte injury often occurs resulting in a transient depression of myocardial contractility [31-33]. Notably, the most important mediators of the inflammatory process, like tumor necrosis factor-α, interleukin-1β, and interleukin-6, have been shown to have a negative inotropic effect on cardiac contractility [31,32]. Moreover, an association between elevation of inflammatory markers and myocardial reperfusion injury has been reported in AMI [34]. On this account, we considered a combined in-hospital clinical endpoint including acute pulmonary edema, cardiogenic shock, and death, which are clinical equivalents of acute ventricular dysfunction.
Study clinical implications. Our study may have some potential clinical implications. Firstly, in AMI patients, hs-CRP allows physicians to identify high-risk patients. This is true also for DM patients, in whom, however, a higher hs-CRP threshold than that usually considered (2 mg/L) should be identified to improve risk stratification. This concept is further suggested by the fact that, in our study population, a significant interaction was found between DM status and hs-CRP when long-term mortality was considered. Moreover, the RR of two-year mortality was constantly lower in patients with DM than in those without DM at each given hs-CRP level. For instance, the two-year mortality RR of a non-DM patient with hs-CRP level of 2 mg/L was similar to that of a DM patient with hs-CRP level of 14 mg/L (Figure 5). Secondly, as hs-CRP has been recently considered a potential therapeutic target in AMI, DM status should be taken into account when anti-inflammatory therapeutic strategies are investigated. The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial showed that, among patients with prior AMI and hs-CRP ≥2 mg/L, treatment with a monoclonal antibody targeting interleukin-1β is associated with fewer cardiovascular events [23]. However, in the CANTOS trial, the beneficial effects, in terms of cardiovascular endpoints, were mainly observed in non-DM patients, with a non-significant risk reduction in those with DM [24]. This highlights the possible need of a different hs-CRP cutoff value for the identification of high-risk AMI patients with DM who may benefit the most from an anti-inflammatory therapeutic strategy. Novel therapeutic approaches aiming at reducing hs-CRP levels during AMI are also under investigation, and preliminary experimental and clinical data are being reported on the use of apheresis in this clinical setting [35,36]. This strategy demonstrated to rapidly and safely lower hs-CRP levels by about 50%, independently of the initial concentration [35]. Interestingly, this reduction was associated with a smaller infarct size in animal models [36].
Study strengths and limitations. The strengths of our study include its prospective design, a well-characterized population, and a special focus on the relationship between inflammation and DM status in AMI. However, some limitations warrant mention. Firstly, we evaluated an AMI population admitted to a single center and treated, in most cases, with PCI. As this therapeutic strategy may have influenced the results of our study, the overall applicability of our findings to AMI patients not undergoing coronary revascularization needs to be clarified. Moreover, the promptness, extent, and efficacy of myocardial revascularization was not assessed as a confounder event. Secondly, because of the observational nature of the study, a cause-effect relationship between hs-CRP and outcomes cannot be established. Moreover, we did not evaluate the effectiveness of and the adherence to pharmacological treatment, in particular of lipid- and glucose-lowering therapies, during follow-up. Indeed, previous studies reported that the prognostic effect of admission hs-CRP is attenuated in high-intensity statin users [37] and in patients with optimized glycometabolic control [38]. Thirdly, the association between hs-CRP levels at admission and the duration and treatment of DM was not investigated, and it should be considered as a possible bias. Fourthly, we measured only hs-CRP; however, it is possible that other inflammation indexes, such as the CRP to albumin ratio, may be more accurate in predicting outcomes in AMI patients [39,40]. Fifthly, we measured hs-CRP levels only at admission. As the inflammatory response in AMI begins within hours and peaks after several days [41], hs-CRP levels at other time points might better reflect the magnitude of the acute inflammatory process. Finally, several potential confounding factors associated with chronic inflammation, such as thickened epicardial adipose tissue [42] and fibrinogen concentration [43], were not evaluated in our study.