Hyperglycemia, Diabetes, and Coronary Microvascular Dysfunction in INOCA

Pasquale Mone^1*Fahimeh Varzideh²Fabio Minicucci³Maria Luisa D'Onghia¹Giada Sabatelli¹Luigi Savino¹Marco Savino¹Gaetano Mottola⁴Urna Kansakar²Gaetano Santulli²

• ¹University of Molise, Campobasso, Italy
• ²Albert Einstein College of Medicine, New York, United States
• ³Azienda Sanitaria Locale Napoli 3 Sud, Naples, Italy
• ⁴Casa di Cura Privata Montevergine SpA, Mercogliano, Italy

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 [3][4][5].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: <50% diameter reduction and/or fractional flow reserve >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 [14][15][16].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 [35][36][37]. 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 [42][43][44][45]. 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 [47][48][49][50]. Indeed, subjects with diabetic cardiomyopathy often present significant major epicardial coronary disease associated with heart failure with preserved ejection fraction (HFpEF) [51][52][53][54]. Hyperglycemia beyond diabetes is a well-accepted risk factor for adverse events in patients with cardiovascular diseases and cardiovascular risk factors affecting endothelial function [55][56][57][58]. 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 [61][62][63][64]. 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.