Hyperglycemia, diabetes, and coronary microvascular dysfunction in INOCA

Ischemia with no obstructive coronary artery (INOCA) is a common condition in patients admitted for coronary angiography for angina and/or positive stress test, increasing the risk of hospitalizations and adverse events 1,2. Approximately 70% of subjects undergoing coronary angiography for angina have no coronary obstruction with signs of ischemia 345.Previous papers evidenced that older age, hypertension, smoking, dyslipidemia, obesity, female sex, and diabetes mellitus were potential determinants of adverse outcomes in nonobstructive coronary artery disease (CAD) 6,7.The exact mechanism underlying the pathophysiology of INOCA is still lacking; however, currently there are two main hypotheses that seem to prevail: coronary microvascular dysfunction with microvascular angina and epicardial coronary artery spasm 8. In particular, stress hyperglycemia has been advocated as a marker of adverse events in patients with cardiovascular diseases 9,10.We believe that hyperglycemia and diabetes may be pivotal in the onset of coronary microvascular dysfunction and, as such, we summarized the literature accordingly.INOCA is commonly defined by the following criteria 1,11:-Symptoms and objective evidence of myocardial ischemia; -Non-obstructive coronary artery stenosis defined as: 0.80; -Impaired coronary microvascular function defined as: impaired coronary flow reserve (≤2.0), abnormal coronary microvascular resistance (i.e. index of microcirculatory resistance, IMR, ≥25), coronary microvascular spasm (defined as reproduction of symptoms, ischemic ECG shifts but no epicardial spasm during acetylcholine testing).Comorbidities may drive an early CMD impairing microcirculation 12,13. There are currently two endotypes of CMD leading to microvascular angina (MVA): structural microcirculatory remodeling and functional arteriolar dysregulation 141516.A structural remodeling of the coronary microvasculature could decrease in microcirculatory conductance and worsening oxygen delivery capacity 17. This condition is linked to the inward remodeling of coronary arterioles, with an increase in wall to lumen ratio, loss of myocardial capillary density (capillary rarefaction) or both conditions 18. Afterwards, there is a classic remodeling due to traditional comorbidities, atherosclerosis, left ventricular hypertrophy, or cardiomyopathies 7,19,20. As a result, there is a reduction of the vasodilatory range of the coronary microcirculation, limiting maximal blood and oxygen supply to the myocardium, as remodeled arterioles are hypersensitive to vasoconstricting stimuli 21. Finally, in response to adenosine, there are two characteristics of microcirculation: 1) a reduced coronary flow reserve (CFR)2) an increase in minimal (hyperemic) microcirculatory resistance.Stress hyperglycemia is a common condition in hospitalized patients and is defined as a transient hyperglycemia during illness due to inflammation, cortisol, and catecholamines activation 10,22.Stress hyperglycemia is typical in coronary artery disease (CAD) 23 and stress hyperglycemia ratio (SHR) is currently used as a marker in coronary patients 24. A recent investigation has demonstrated that elevated SHR is significantly associated with 1-year and long-term all-cause mortality, especially in subjects without diabetes 25. Furthermore, SHR was a significant predictor for adverse cardiovascular outcomes in patients with or without diabetes and three vessels CAD 26. Consistent with the aforementioned study, a recent paper correlated SHR with the severity of CAD in both prediabetic and diabetic individuals 27. Intriguingly, SHR has been associated to CAD even in patients with acute coronary syndrome and may be a useful marker of risk stratification 28. A recent study highlighted an impact of SHR in myocardial infarction with no-obstructive coronary artery (MINOCA) 29. SHR has been linked to adverse events even in coronary artery bypass grafting (CABG) 40317204 30,31 like in multivessel CAD based on brain natriuretic peptide levels 32.Finally, SHR could be a marker after percutaneous coronary intervention 33.Coronary microcirculation plays a seminal role in the regulation and homeostasis of myocardial perfusion, regulating blood flow, fulfilling myocardial metabolic needs and managing peripheral vascular resistance 34. Diabetes impairs coronary microcirculatory function as insulin resistance drives acute vascular responses during postprandial hyperglycemia 353637. The effect of insulin resistance on microvascular dysfunction may not be due to diabetes and/or hyperglycemia 38,39.Moreover, diabetes negatively impacts endothelial function driving coronary microvascular dysfunction 40,41 with myocardial fibrosis, dysfunctional remodeling driving alterations in left ventricular filling until diastolic dysfunction 42434445. In this scenario, diabetic patients have an increased risk of cardiovascular events than nondiabetic patients 46. Intriguingly, there is an increased risk of heart failure due to "Diabetic Cardiomyopathy" which may be due to coronary dysfunction 47484950. Indeed, subjects with diabetic cardiomyopathy often present significant major epicardial coronary disease associated with heart failure with preserved ejection fraction (HFpEF) 51525354.Hyperglycemia beyond diabetes is a well-accepted risk factor for adverse events in patients with cardiovascular diseases and cardiovascular risk factors affecting endothelial function 55565758. Our group has published a recent paper in which we evidenced the role of stress hyperglycemia in the onset of hospitalization for chest pain in INOCA patients 59. Still, we showed a significant effect of metformin treatment in the reduction of hospitalizations in hyperglycemic INOCA patients with a reduction of oxidative stress in human coronary artery smooth muscle cells and endothelial cells 60.These results should open a reflection because stress hyperglycemia should be considered a consequence of myocardial ischemia probably generated by coronary microvascular dysfunction 61626364.We speculate that hyperglycemia beyond diabetes may be a marker of coronary microvascular dysfunction in INOCA. Of note, several studies are necessary to confirm our hypothesis. However, the detrimental effects of hyperglycemia on endothelium are well known. In this scenario, hyperglycemic patients should be treated before the onset of diabetes to reduce cardiovascular risk and preserve endothelial and coronary microvascular function. Metformin is an old drug that could be pivotal in the treatment of hyperglycemic patients with INOCA. Of note, treating all the risk factors with statins, ACE-Inhibithors, and Beta-Blockers may be crucial in improving the quality of life in INOCA.