The present study analyzed IR in the acute phase of STEMI in non-diabetic patients treated by pPCI. First, it confirms that IR in the early post pPCI period is common even in non-diabetic patients and changeable. Second, IR was related to the degree of myocardial reperfusion and correlated well with the CMF after mechanical revascularization, independently of other variables. Third, IR at the end of the first week after pPCI was an independent predictor of the final infarct size.
IR in the acute phase of STEMI is predominately part of acute glycometabolic response to stress. The term acute IR implies its presence during acute (early) phase of STEMI. Although we included only patients without diabetes mellitus, we cannot strictly exclude the presence of IR before and/or after the first STEMI week, since evaluation of IR status was not done before or after this period. Generally, in critically ill patients acute IR is related to more severe acute illness and warrants poor clinical outcome[42, 43]. By traditional concept, acute IR is induced by acute stress, with a small possibility to be further directly involved in the development or aggravation of acute illness. However, recent studies[18–21] challenge this concept to a certain extent.
Few studies have analyzed time dependent changes of acute IR and/or insulin sensitivity and have related it to clinical outcomes[22, 43]. Nishio et al. performed serial HOMA index measurements among patients going to pPCI and identified those with transient IR, in whom HOMA index correlated with stress hormones and patients with persistent IR, in whom HOMA index during the 4 months follow-up correlated with leptin and contributed to stent restenosis. In the current study acute IR was present in 55% of patients on the 2nd day and in 58% of patients on the 7th day. The HOMA index slightly, but statistically significantly increased from day 2 to day 7, mainly due to the increment in insulin concentration. Similar increment in insulinemia in the early post PCI period in non-diabetic patients was previously reported. The potential mechanisms are not clear. Effects of prolonged cardiovascular (hemodynamic) stress and inflammation induced by STEMI could be the reasons. In our study the 7th day HOMA index correlated better than the 2nd day HOMA index with the peak values of NT-proBNP and hs-CRP. Nutritional status might also influence the IR increment. In our study the majority of patients were on regular nutrition on the 7th day as opposed to the 2nd day, with a higher fat intake and potentially higher free fatty acids effects on the insulin sensitivity[45, 46]. However, a comprehensive nutrition data analysis was not done. The effect of drugs should not be neglected, including those of thiazide diuretics, beta blockers and some statins[47–49], reported to have potential impact on insulin sensitivity. However, in the current study we could not find significant differences between HOMA positive and HOMA negative patients regarding the drug regime. None of the patients reached the glycaemic threshold of 11 mmol/l to get insulin.
One of the main findings in the current study is that acute IR was related to more impaired CMF after pPCI, independently of other potential covariates. CFR is a sensitive parameter of CMF. CMF after STEMI is important for the clinical outcome independently of epicardial flow. Although the inverse relationship between HOMA index and CFR was described in different states[51–53], to the best of our knowledge the current study is the first to link acute IR assessed by the HOMA index and CFR in non-diabetic STEMI patients. Acute hyperglycemia per se predicted impaired epicardial flow before pPCI and impaired CMF after pPCI in unselected, mixed diabetic and non-diabetic patients. It is related to increased oxidative stress in STEMI, increases vascular cell apoptosis and induces acute endothelial dysfunction[56, 24, 57]. Insulin is under healthy condition coronary vasodilatator and in the dose-dependent manner increases myocardial blood flow[58, 59]. However, these effects are abolished in chronic, obesity related IR[60, 61]. Only one study evaluated acute insulinemia and coronary flow in acute coronary syndrome. In 60 patients admitted to the emergency department for suspected acute coronary syndrome acute hyperinsulinemia was present in half of them, and closely correlated with TIMI coronary flow score. In the current study CFR better correlated to the HOMA index than to acute glycaemia and/or insulinemia and in the multivariable model including admission glycaemia, the HOMA index remained an independent CFR predictor. These data might suggest that acute IR as a phenomenon per se could be related to the development of CMF impairment after pPCI.
The relationship between acute IR and ST-E resolution was not previously evaluated. Acute hyperglycemia was related to limited ST-E recovery in mixed diabetic and non-diabetic STEMI population after thrombolytic therapy and after pPCI. Metabolic syndrome (chronic IR) was a predictor of ST-E resolution after pPCI. In the current study in patients without diabetes, incomplete ST-E resolution was significantly more frequent among those with acute IR. However, only the 2nd day HOMA index was independently associated with the residual ST-E.
The relationship between acute IR in non-diabetic STEMI patients and myocardial damage in terms of peak enzymes was previously reported[18, 19]. In our study both HOMA indices correlated well with the peak TnI. However, only the 7th day HOMA index was an independent predictor of the final infarct size on SPECT-MPI. It could be speculated that prolonged IR during acute phase is important. Furthermore, the 7th day HOMA index might not only be a part of acute glycolmetabolic response to stress, but also part of chronic or prolonged intermittent IR that might influence formation of final infarct size in the following weeks after STEMI.
From the clinical standpoint, in the current study HOMA index on day 2 better correlated with myocardial reperfusion, both HOMA indices well correlated with the CMF, whereas HOMA index on day 7 predicted final infarct size. Both data might be clinically valuable: HOMA index on day 2 for the in-hospital course, HOMA index on day 7 for the long-term processes such as formation of the final infarct size. Although our data do not unambiguously demonstrate cause and effect relationship between acute IR and CMF, they strengthen the need for attention to be paid to IR during and after STEMI. Taking in mind that IR could be potentially modified, its regulation might become a therapeutic target both in acute STEMI and afterwards.
Study results should be interpreted with some limitations. First, our study is a single centre experience with a relatively small sample size. Second, CMF was measured by echocardiography without invasive or magnetic resonance imaging. However, this approach has been previously validated in our laboratory or elsewhere[39–41] and compared to positron emission tomography imaging. Third, IR assessment was based on the HOMA index and EGIR classification, which was primarily defined for chronic states. Whether different cut-offs for acute IR should be used in the acute phase of myocardial infarction, as suggested by some authors, remains an open question. In the current study the "area at risk" was not determined by SPECT-MPI. However, there were no significant differences between patients with IR vs. without IR regarding the infarct related artery, the position of the culprit lesion and collateral circulation.