Pathophysiology
Insulin Resistance ― Beginning of the Road to Coronary Microvascular Dysfunction and Beyond ―
2022 Volume 86 Issue 5 Pages 874-876
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2022 Volume 86 Issue 5 Pages 874-876
The epicardial coronary arteries have a primary conductance function and exhibit minimal resistance to coronary flow when not obstructed. In contrast, the coronary microvascular circulation of pre-arterioles and arterioles comprises most of the resistance circuit of the heart.1–3 The microcirculation has a critical role in the regulation of myocardial blood flow. Because myocardial oxygen extraction is almost maximal even at rest, increased oxygen demand must be met by increased coronary blood flow, not by a further increase in oxygen extraction. Thus, a proportional increase in coronary blood flow is essential to balance an increase in oxygen demand by myocardial metabolic activity and oxygen supply. Stenosis of the epicardial coronary arteries has long been considered as the main predictor of ischemic heart disease. However, emerging evidence has shown that coronary microvascular dysfunction (CMD) is highly relevant in the development of a plethora of cardiovascular diseases, including myocardial infarction, even in the absence of obstruction of the epicardial coronary arteries.1–3 On the other hand, development of CMD has been linked to multiple conditions and diseases including dyslipidemia, hypertension and diabetes mellitus.4 Although chronic persistent hyperglycemia is associated with significantly reduced endothelium-dependent and endothelium-independent coronary vasodilatation,5 glucose fluctuations also contribute to cardiac pathophysiology in patients with diabetes.6 It has already been reported that coronary flow reserve (CFR) measured by intracoronary Doppler flow wire is significantly reduced in diabetic patients with early vascular disease compared with non-diabetic patients.7 However, it has not been clarified whether, and if so how, transient hyperglycemia, which is often observed in patients in the early stage of impaired glucose metabolism, affects coronary microvascular function.
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In this issue of the Journal, Takei et al8 report that CMD indicated by a decline in the coronary flow velocity reserve (CFVR) under the condition of acute hyperglycemia is associated with insulin resistance, but not oxidative stress or sympathetic activity, in patients in the early stage of impaired glucose metabolism. They used transthoracic Doppler echocardiography (TTDE) to measure coronary flow velocity (CFV) and CFVR. Because of its noninvasive nature, this technique is much easier to perform than analyses with an intracoronary Doppler flow wire for repeated assessment of coronary microvascular function (i.e., measurement of CFV under baseline and hyperemic conditions), both before and after an oral glucose tolerance test (Figure). Despite the drawback that TTDE can measure the CFV of only the distal left anterior descending coronary artery, CFVR measured by TTDE has been shown to have an excellent correlation with CFR measured by intracoronary means.9 In the report by Takei et al, the decline in CFVR was attributed to increased basal CFV and decreased maximal hyperemic CFV induced by adenosine infusion (Figure). Although insulin resistance was significantly associated with elevation of baseline CFV and reduction of CFVR, the mechanisms responsible for the reduction in hyperemic CFV were not identified (Figure).
Summary of the results in the report by Takei et al.8 Under the condition of hyperglycemia (1 h after OGTT), baseline CFV increased, while adenosine infusion-induced hyperemic CFV decreased compared with under the condition of normoglycemia (before OGTT). As a result, CFVR under hyperglycemic conditions decreased compared with under normoglycemic conditions. The change in baseline CFV, the change in CFVR and the CFVR value correlated with HOMA-IR, but the change in hyperemic CFV did not correlate with any of the variables tested. CFV, coronary flow velocity; CFVR, coronary flow velocity reserve; DM, diabetes mellitus; HOMA-IR, homeostasis model assessment-insulin resistance; IR, insulin resistance; MI, myocardial infarction; OGTT, oral glucose tolerance test; TBARS, thiobarbituric acid reactive substance; TTDE, transthoracic Doppler echocardiography.
It has been reported that either increased basal coronary flow7 or decreased hyperemic coronary flow10 is responsible for the decline in CFR in diabetic patients, most likely depending on the stage and comorbidities. Adenosine-induced vasodilation and hyperemia mainly involve endothelium-independent mechanisms in which stimulation of both adenosine A1 and A2 receptors and the opening of ATP-sensitive potassium channels on smooth muscle cells play a role.11 Thus, dysfunction of these signaling pathways might be responsible for the reduction in hyperemic coronary blood flow in hearts with impaired glucose metabolism. On the other hand, increased basal coronary flow is likely to be induced by metabolic derangements. Insulin resistance in cardiomyocytes results in decreased glucose uptake and glucose oxidation12 and increased fatty acid oxidation,13 leading to inefficient ATP production per molecule of oxygen consumed. Accordingly, the consequent increase in oxygen requirement by cardiomyocytes is physiologically coupled with an increase in resting coronary blood flow. Being mediated by distinct mechanisms, elevation of basal coronary blood flow and reduction of hyperemic coronary blood flow may lead to distinct pathological consequences and require different therapeutic approaches, though the resultant reduction in CFVR is seemingly the same.
The findings in the report by Takei et al8 demonstrate that patients in the early stage of impaired glucose metabolism with insulin resistance may show CMD and are likely to be susceptible to future development of cardiovascular diseases, including acute coronary syndrome, myocardial infarction, heart failure, stroke and sudden death.14 Interestingly, the presence of CMD may also represent a risk factor for diabetic cardiomyopathy. Recent evidence demonstrated that CMD was independently associated with worsening diastolic dysfunction.15 Furthermore, patients with CMD and diastolic dysfunction showed a >5-fold risk of hospitalization for heart failure with preserved ejection fraction even in the absence of overt structural abnormalities or obstruction of the epicardial coronary arteries,15 which is a hallmark feature of diabetic cardiomyopathy.
An important question raised by the report by Takei et al8 is how the CMD in patients in the early stage of impaired glucose metabolism can be restored and whether therapeutic intervention improves clinical outcomes. In light of the results presented in this report, a reasonable approach would be treatment with insulin sensitivity-improving medications, including biguanides, thiazolidinediones, SGLT2 inhibitors and GLP-1 receptor agonists, even before the development of overt diabetes mellitus. Furthermore, a concurrent therapeutic approach against mechanisms underlying the suppressed increase in hyperemic CFV, if identified in a future investigation, may also be desirable. With TTDE being a noninvasive and reliable method that can be performed repeatedly to assess the effect of treatment on CFVR, identifying an effective treatment to improve CMD in patients with early-stage impaired glucose metabolism will be a promising topic for future clinical research.
