Our study was focused on the interplay between hyperglycemia, inflammation and infarct size in a cohort of patients admitted with acute myocardial infarction, including cases of MINOCA, a still poorly investigated nosological entity.
Hyperglycemia was homogeneously associated with an increase of all inflammatory indices at admission, irrespective of the underlying ischemic pathophysiological mechanism, either obs-AMI or MINOCA. Importantly, hyperglycemia correlated with the detection of large infarct sizes in patients with obs-AMI while no differences were observed between normoglycemic and hyperglycemic MINOCA cases, which exhibited a modest myocardial damage.
Hyperglycemia and inflammation markers in obstructive-AMI
Among our overall study population, hyperglycemia was more frequently observed in patients with obs-AMI. This subgroup of hyperglycemic subjects exhibited an “inflammatory status” as expressed by increased levels of all measured inflammatory markers. High values of NLR, NPR, PLR and CRP had been previously described in this setting, and our results are in line with the existing literature, confirming the relationship between glycemic disorders and inflammation in the context of obs-AMI22,23. Indeed, the activation of inflammatory mediators and pathways is vastly described as a cornerstone of atherosclerosis24, not only in terms of chronic arterial remodelling but also favouring plaque instability and rupture25. Moreover, some studies have identified an association of elevated inflammatory markers, including NPR and NLR, with larger infarct sizes and an increased risk of short-term mortality12,26,27.
Hyperglycemia-mediated alterations may further precipitate the atherosclerotic process28-30. In fact, not only does hyperglycemia amplify the inflammatory cascade, but it is also promoted by the inflammatory process itself throughout the generation of insulin-resistance and gluconeogenesis31-33. As a result, the interplay between hyperglycemia and inflammation triggers a vicious circle, ultimately leading to a heightened atherosclerotic burden and plaque rupture34 with an increased mortality risk1,35,23.
Hyperglycemia and inflammatory markers in MINOCA
The main novelty of our study is that for the first time, we investigated the correlation between glycemic levels inflammatory markers in MINOCA patients. Similarly, to the results observed in obs-AMI, hyperglycemic MINOCA subjects had higher values of NLR, NPR, and PLR than normoglycemic ones.
Shared underlying pathophysiological mechanisms may explain the complex interplay between hyperglycemia, inflammation and MINOCA. In particular, a central role seems to be played by endothelial dysfunction36. In this setting, several studies have identified endothelial dysfunction as a determinant factor towards coronary artery vasoconstriction and vasospasm, resulting in myocardial ischemia37. As abovementioned, inflammation has the possibility of impairing endothelial function throughout the reduction of endothelium-derived vasodilators bioavailability, thereby decreasing the expression of endothelial nitric oxide synthase (eNOS) and nitric oxide synthesis. Another potential mechanism is the cytokine-mediated imbalance of the autonomic nervous system. Specifically, the hypothalamic-pituitary-adrenal axis response to inflammation causes an upregulation of the sympathetic system leading to coronary vasoconstriction, affecting both macro and micro-circulation38.
Although hyperglycemia in the context of MINOCA is still largely unexplored, it seems plausible that the same mechanisms described in obs-AMI may be valid in MINOCA as well. Supposedly, hyperglycemia can further precipitate the endothelial homeostasis and amplify the inflammatory process conferring an unbalanced vascular tone and a prothrombotic state, ultimately increasing the ischemic burden39,40.
Infarct size and hyperglycemia in Obstructive-AMI and MINOCA patients
Hyperglycemic obs-AMI patients showed a larger infarct size than normoglycemic ones while in MINOCA no correlation was observed between admission glucose levels and the extent of myocardial damage, which was overall modest in such cases.
The link between hyperglycemia and large infarct size in the context of obs-AMI is well established, and our results are in line with previously published studies41,42. In fact, several strategies have been adopted to assess the impact of admission hyperglycemia on the extent of myocardial damage, all leading toward the same conclusion43,44.
On the other hand, the impact of hyperglycemia on the magnitude of infarct size in MINOCA patients is still unexplored. Our findings suggest for the first time a negligible correlation between admission glucose levels and myocardial damage among MINOCA cases, who overall exhibited a limited infarct size, especially when compared to hyperglycemic obs-AMI subjects. The explanation to such results might be found in CMR studies specifically focused on the myocardial substrate of MINOCA. In particular, studies showed areas of myocardial oedema either associated with small necrotic regions with a typical patchy distribution or even without necrosis45,46. Since myocardial damage observed in our cohort was minimal, it is difficult to elucidate the actual impact of hyperglycemia in the still hazy world of MINOCA. Keeping in mind that endothelial dysfunction seems to be a key pathophysiological mechanism underlying MINOCA and it is known to be impaired by hyperglycemia as well, it appears plausible that an “hyperglycemic environment” can further alter the endothelial homeostasis and negatively affect the natural history of such patients, often characterized by heart failure with preserved ejection fraction. This hypothesis clearly requires future investigations in order to evaluate whether hyperglycemia may represent a prognostic risk factor for MINOCA subjects, regardless of a concomitant diabetes diagnosis47-52.
Our study had several limitations. First of all, analyses were conducted on a relatively small sample size, especially regarding the MINOCA cohort. Second, not all laboratory parameters were available for each patient. Furthermore, it is not possible to clarify whether admission hyperglycemia has a direct relationship with infarct size and inflammatory markers or simply represents a marker of myocardial ischemia. In fact, the study does not establish causality between hyperglycemia and acute myocardial infarction by the nature of its cross-sectional design.
In patients with suspected DM, no definite rule-out criteria were adopted. However, not all patients can undergo an oral glucose tolerance test in the setting of AMI. Therefore, HbA1c could be a reasonable alternative in this clinical situation. Lastly, in our study we did not evaluate other inflammatory markers such as IL-6, TNF-α, IL-1, and the soluble matricellular protein Cysteine-rich angiogenic inducer, which might reflect the inflammatory status more accurately. Taking into account that a correlation between such parameters and the indices adopted in our study was previously demonstrated11-14,48,49, we chose to use common and widely available inflammatory markers for simplicity.