Journal of Cardiology 65 (2015) 270–271

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Editorial

Stress hyperglycemia and microvascular obstruction after acute myocardial infarction

Keywords: Hyperglycemia Microvascular dysfunction Cardiac magnetic resonance imaging

In this issue of the Journal of Cardiology, Ota et al. report an important study on the association between plasma glucose level at hospital admission and the development of microvascular obstruction (MVO) after successful percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) [1]. Their study provides a new insight into the harmful mechanisms of stress hyperglycemia after acute myocardial infarction (AMI). Hyperglycemia at admission as a risk factor after AMI A high blood glucose level is often observed at admission in patients with AMI irrespective of a history of diabetes mellitus. Hyperglycemia at admission might be a marker of undiagnosed diabetes or impaired glucose tolerance (IGT) [2], which are common in patients with AMI [3]. On the other hand, hyperglycemia is frequently observed even in patients without diabetes or IGT [4], as stress hyperglycemia. Several studies demonstrated that hyperglycemia at admission is associated with higher mortality after AMI in patients with or without diabetes [4–6]. It is also associated with a large infarct size, high incidence of congestive heart failure, and cardiogenic shock after AMI. In non-diabetic patients with STEMI, both elevated glucose level on admission and glycated hemoglobin (Hb) A1c are associated with adverse outcome [7]. Hyperglycemia at admission was mainly associated with large infarct size and early mortality while HbA1c was associated with long-term mortality [7], suggesting that stress hyperglycemia and HbA1c are associated with poor outcome due to different mechanisms. Several mechanisms have been proposed for the harmful effects of hyperglycemia after AMI. Association of hyperglycemia with the activation of blood coagulation has been well studied; it could induce a shortening of the fibrinogen half-life, increase in fibrinopeptide A, fragments of pro-thrombin in factor VII, and platelet aggregation, all of which could lead to increased activation of thrombosis [8]. Hyperglycemia at admission is associated with increased levels

DOI of original article: http://dx.doi.org/10.1016/j.jjcc.2014.10.013

of inflammatory markers, enhanced expression of cytotoxic T-cells, and reduced expression of cytotoxic T-lymphocyte-associated protein 4, indicating its association with increased inflammatory immune process after AMI [9]. It also could be associated with endothelial dysfunction, oxidative stress, and possibly, abolition of protective ischemic preconditioning [8]. The other possible mechanism of harmful effects of acute hyperglycemia is microvascular dysfunction after coronary revascularization. Coronary microcirculation and acute hyperglycemia Microvascular dysfunction observed after successful PCI is highly associated with large infarct size, reduced systolic function, higher incidence of malignant arrhythmia, heart failure [10], and long-term mortality [11]. Thus, development of microvascular dysfunction after coronary reperfusion, known as no reflow phenomenon or MVO, is thought to be one of the factors determining functional and clinical outcomes after AMI. Several mechanisms are thought to be involved in the development of microvascular dysfunction. Microemboli associated with PCI procedure is definitely a major cause of microvascular dysfunction. Other pathological mechanisms related with its development include microvascular plugging by neutrophils and platelets, interstitial edema, inflammation, endothelial dysfunction, and oxidative stress. As described above, hyperglycemia could enhance these factors related to development of microvascular dysfunction. Indeed, some previous studies demonstrated that hyperglycemia at admission is an independent predictor of microvascular dysfunction after AMI [6,12]. The present study by Ota et al. demonstrated the association between hyperglycemia at admission and development of MVO using late gadolinium enhancement – cardiovascular magnetic resonance imaging (LGECMR) [1], while previous studies used myocardial contrast echocardiography (MCE) or angiography. Ota et al. performed LGE-CMR within 7 days after PCI in 93 patients with first STEMI. MVO was observed in 34 (37%) patients, and they had higher glucose level on admission than others, whereas no differences were observed in HbA1c and prevalence of diabetes between them. Glucose level on admission was an independent predictor of MVO, along with peak creatine kinase-MB and no reflow on angiography. Several imaging modalities have been used to evaluate coronary microvascular dysfunction, including ST-segment changes on electrocardiography, coronary angiography [thrombolysis in myocardial infarction (TIMI) frame count or TIMI perfusion grade], MCE, coronary Doppler flow wire, pressure wire.

http://dx.doi.org/10.1016/j.jjcc.2014.11.012 0914-5087/ß 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Editorial / Journal of Cardiology 65 (2015) 270–271

Among these modalities, CMR is one of the most promising methods with several advantages over others. It is a non-invasive modality and has a high reproducibility. CMR has a high spatial resolution, compared to MCE, to identify the infarct area and to determine infarct size precisely. MVO area is defined as the area with hypointense core within infarct area, although the relation between infarct area and MVO should be investigated. Thus, the present results by Ota et al. added highly reliable new data to the investigation on the relation between stress hyperglycemia and development of microvascular dysfunction. Clinical implications of the present study As described above, microvascular dysfunction after AMI could determine long-term comorbidity and mortality, and its prevention is a critical issue. Thrombus aspiration during primary PCI could reduce the thrombus burden and prevent microembolism. A large-scale, randomized trial, TAPAS (Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study), demonstrated that thrombus aspiration adjunctive to primary PCI reduced the incidence of microvascular dysfunction, evaluated as myocardial blush grade of 0 or 1, from 26.3% to 17.1% [13]. Thrombus aspiration could be a promising method to reduce microvascular dysfunction, but it could not fully prevent it. Other methods are required for its prevention, and modulation of clinical factors associated with its development should be investigated. As demonstrated in the present study, hyperglycemia is one of these clinical factors, and glycemic control immediately after admission might reduce the incidence of microvascular dysfunction. Glucose–insulin–potassium (GIK) infusion as an adjunct to myocardial reperfusion was reported to be having no cardioprotective effects and no improvement in early mortality in patients with AMI [14]. GIK does not always correct blood glucose levels and might worsen hyperglycemia in some cases, which might explain the disappointing results of GIK infusion. A large-scale, prospective study is needed to investigate whether early control of blood glucose could have protective effects on coronary microcirculation, which should be precisely evaluated by LGE-CMR as in the present study.

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Katsuomi Iwakura (MD, FJCC)* Division of Cardiology, Sakurabashi Watanabe Hospital, 2-4-32, Umeda, Kita-ku, Osaka 5300001, Japan

References [1] Ota S, Tanimoto T, Orii M, Hirata K, Shiono Y, Shimamura K, Matsuo Y, Yamano T, Ino Y, Kitabata H, Yamaguchi T, Kubo T, Tanaka A, Imanishi T, Akasaka T, et al. Association between hyperglycemia at admission and microvascular obstruction in patients with ST-segment elevation myocardial infarction. J Cardiol 2015;65:272–7.

*Tel.: +81 6 6341 8651; fax: +81 6 6341 0785 E-mail address: [email protected] (K. Iwakura). 23 November 2014 Available online 29 December 2014

Stress hyperglycemia and microvascular obstruction after acute myocardial infarction.

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