This prospective observational study investigated the link between aHGL and AMI with a particular focus on prognostic information. Importantly, we evaluated for the first time the impact of hyperglycemia on MINOCA, a quite heterogeneous and still largely unexplored clinical entity. The main findings are: i) aHGL is two times more frequent among MIOCA patients compared to MINOCA (37.6% vs 16.3%); ii) aHGL carries a worse clinical profile in terms of baseline characteristics and hemodynamic instability; iii) the expected clinical and prognostic impact of hyperglycemia on MIOCA patients was similarly observed in the context of MINOCA; iv) aHGL accurately identified a group of high-risk patients for short-term outcomes; v) the prognostic role of hyperglycemia is maintained over time resulting in an adverse long-term outcome, conferring an adjunctive risk to the sole diabetic condition; vi) after AMI, the prognosis is strongly influenced by the gluco-metabolic status independently of the coronary anatomy.
Hyperglycemia and short-termoutcomes
The incidence of aHGL in the context of AMI ranges from 20 to 50%25, depending on the definition of stress hyperglycemia, which varies from 140 to 180mg/dL. By setting the cut-off at 140mg/dl as proposed by the American Heart Association Diabetes Committee2, we found an overall prevalence of 37.6%, ranging from 40% in MIOCA to 16.3% in MINOCA. The latter data is particularly relevant as aHGL was estimated for the first time in a systematically studied MINOCA population. Indeed, such a difference in the glycemic status should not be surprising given that MINOCA subjects are usually females with a lower atherosclerotic burden as expressed by fewer cardiovascular risk factors16. Nevertheless, our study revealed that stress hyperglycemia was homogeneously associated with a worse functional status in all AMI patients, including those falling into the current definition of MINOCA. In particular, hyperglycemic patients were older, overweight, with cardiovascular risk factors and comorbidities, both in MIOCA and MINOCA groups.
Moreover, our results showed that even the clinical conditions at hospital admission in hyperglycemic patients were overall characterized by signs of hemodynamic instability and heart failure, with a higher heart rate and Killip class and a greater prevalence of atrial fibrillation. All these clinical and instrumental indices are paralleled by a higher GRACE score observed in hyperglycemic subjects, both in MIOCA and MINOCA groups. Consequently, it was intriguing to assess the interplay between aHGL and short- and long-term prognosis. Previous studies have demonstrated a hyperglycemia-related mortality risk in AMI patients, both diabetic and non-diabetic, without however distinguishing between MIOCA and MINOCA1. Notably, our data corroborate and support the current knowledge, adding however a crucial piece to the puzzle: hyperglycemia maintains its prognostic relevance independently of coronary stenoses.
From a pathophysiological point of view, in the early stage of AMI, hyperglycemia promotes a prothrombotic state, increases inflammation and sympathetic nervous system activity, worsens endothelium function, and imbalances the oxidative stress releasing reactive oxygen species20,26. As a result, all these changes impair coronary microvascular function with an increased risk of no-reflow phenomenon27,28. Reasonably, this evidence derives mainly from hyperglycemic MIOCA cohorts that exhibit a larger infarct size, potentially explaining the adverse events occurring during hospitalization. Similarly, in the context of MINOCA, a “hyperglycemic environment” can impact both macro and micro-circulation, producing endothelial erosion and plaque disruption, epicardial and microvascular coronary spasm, coronary thrombosis and microvascular dysfunction, overall intensifying the underlying pathophysiologic mechanisms. In our study, MINOCA patients presented a trivial infarct size, and only 2 in-hospital deaths were recorded. Interestingly, a high incidence of intra-hospital arrhythmias was observed among hyperglycemic patients, both in MIOCA and MINOCA. Plausible mechanisms for this occurrence may be related to insulin resistance and catecholamine overproduction, leading to lipolysis and the release of circulating free fatty acids. The latter induces two potential toxic effects on the ischemic myocardium: damage of cardiac-cell membranes and calcium overload, consequently increasing the arrhythmic burden and reducing myocardial contractility29. Notably, in our overall study population, aHGL emerged as the strongest independent predictive factor of short-term mortality, highlighting the utility of such a quick and accessible parameter to identify high-risk patients.
Hyperglycemia and long-termoutcomes
In terms of long-term prognosis, aHGL patients – both in MIOCA and MIOCA groups – exhibited a higher rate of all-cause and cardiovascular mortality. Macrovascular complications (stroke and re-AMI) were recorded in MIOCA more often than in MINOCA patients, reflecting the high burden of atherosclerosis in obstructive ischemic disease. Furthermore, hyperglycemic patients experienced over time more hospitalization for heart failure within the MIOCA cohort, while a trend was observed in MINOCA. These results might ultimately confirm recent data which demonstrated that microvascular dysfunction plays a role in the pathophysiological mechanism of heart failure with preserved ejection fraction30–32. This concept is particularly relevant and underlies useful clinical implications: the approach to AMI should always go beyond coronary stenoses as MINOCA patients might still have an eventful prognosis, potentially characterized either by the recurrence of acute coronary syndromes or by stable angina and episodes of heart failure with preserved ejection fraction. In fact, all these clinical entities supposedly represent different sides of the same “pathophysiological coin”, which is functional coronary dysfunction. Another important aspect of our work was the search for risk factors predicting long-term outcomes. Our analysis showed that both hyperglycemia and T2DM per se have a long-lasting prognostic impact after AMI, regardless of the anatomic substrate - MIOCA or MINOCA. Notably, combining the two conditions seems to confer an adjunctive risk, highlighting the importance of optimal gluco-metabolic control. Although the prognostic role of diabetes is well known, we assessed the long-lasting impact of a simple parameter such as aHGL on all patients admitted for AMI, including for the first time those fulfilling the current diagnostic criteria of MINOCA. Indeed, both diabetes and hyperglycemia directly influence atherosclerotic plaque formation and progression and may induce microvascular dysfunction and microangiopathy. Therefore, the resulting vicious circle might affect the macrovascular and microvascular beds, leading to an adverse long-term prognosis in both MIOCA and MINOCA patients33–35.
Thus, the pivotal issue of our study is that we proved for the first time that in MINOCA patients, a simple measurement of blood glucose levels at hospital admission could impact both short- and long-term prognosis. Therefore, in the setting of AMI, the prognosis is strongly influenced by the gluco-metabolic status independently of the underlying coronary anatomy (Fig. 2). Interestingly enough, in the heterogeneous world of MINOCA, a quick and widely accessible parameter such as aHGL can accurately identify a group of “high-risk” patients who could probably benefit from a proper secondary prevention medical therapy.
Study limitations
Our results should be interpreted in light of some limitations. First of all, analyses were conducted on relatively small sample size, especially regarding the MINOCA cohort, even though all these patients were well characterized aiming to exclude other causes of acute myocardial injury. Secondly, aHGL levels may have been influenced by multiple factors such as last meal composition and timing and day versus night measurements. Moreover, in patients with suspected DM, no definite rule-out criteria were adopted, therefore some diabetes diagnoses may have been missed. However, it should be noted that not all patients admitted for AMI can undergo an oral glucose tolerance test, especially in the acute phase. Lastly, our follow-up data did not include laboratory information regarding the gluco-metabolic status.