Understanding myocardial infarction evolution

Introduction Primary angioplasty (PPCI) achieves excellent anatomical results in the treatment of ST elevation acute myocardial infarction (STEMI); nonetheless, approximately 40% of patients do not achieve adequate myocardial reperfusion due to persistent microvascular damage.1,2 In these patients, significant impairment in the microcirculation occurs in the ischemic/necrotic myocardial tissue, mostly correlated with the ischemic time, which prevents effective blood flow to the myocardium (‘no-reflow’ phenomenon) negating the advantages of the epicardial vessel reperfusion. The structural damages to the microcirculation of patients with STEMI are mainly due to intramyocardial hemorrhage and embolization of thrombotic material, both determining a microvascular obstruction (MVO). Microvascular dysfunction is a determining factor in the healing process of the infarct area which also affects the remodeling process and the recovery of the left ventricular (LV) function; accordingly, it is associated with increased incidence of cardiac death, heart failure and reinfarction.3,4 Angiographic parameters such as myocardial blush grade or Thrombolysis in Myocardial Infarction (TIMI) flow grade are not accurate in microvascular damage prediction. Cardiac NMR with contrast enhancement (ceNMR) is currently the gold standard for noninvasive definition of MVO. This parameter has been the most powerful indicator of clinical outcome among all other factors derived from NMR.5 Nonetheless, the difficulties in availability and feasibility of this study in the acute patients impair significantly its use in early assessment of patients with STEMI. In recent years, several invasive techniques have been developed to evaluate the presence of microvascular damage by assessing the microcirculatory resistances. Among the latter techniques, the index of microvascular resistance (IMR) (a measure of the minimal achievable microvascular resistance) is a reflection of the health of microcirculation and thus can be used to evaluate the reperfusion damage. High values of IMR are predictive of MVO as assessed with NMR. McGeoch et al.6 demonstrated that higher median IMR was present in patients with MVO (38 vs. 27; P = 0.003). Yoo et al.7 confirmed that higher IMR was correlated with a larger extension of MVO at the 4–7-day post STEMI. Ahn et al.8 demonstrated IMR as an independent predictor of MVO as assessed by ceNMR 7 days after the acute myocardial infarction (AMI), confirming that IMR, as measured immediately after PPCI, is correlated with the noninvasive imaging assessment of microvascular dysfunction. In this study, the evaluation of coronary flow reserve (CFR) did not significantly increase the diagnostic accuracy of IMR. The latter invasive index has the advantage of allowing direct evaluation soon after completion of PPCI and is calculated utilizing a special pressure sensor/thermistor-tipped guidewire, according to the thermodilution principle applied to the coronary arteries.9 IMR is the product of distal coronary pressure multiplied by the mean transit time (in seconds) of 3-ml saline bolus intracoronary injection repeated three times at room temperature during maximal hyperemia (Fig. 1a and b). Calculation of IMR is not affected by variations in hemodynamic conditions, is reproducible and is a specific measure of microcirculatory system, which is not affected by the severity of epicardial vessels stenosis.10,11 IMR is calculated along with the CFR and fractional flow reserve (FFR), thus providing a complete analysis of the epicardial vessels and of the coronary microcirculation (Fig. 2).Fig. 1: (a) Low panel: thermodilution curves at baseline (light blue) and during maximal hyperemia. By multiplying T mn (0.36 s) with Pd (102 mmHg), during hyperemia, index of microvascular resistance (37 U) is calculated. (b) Example of very high index of microvascular resistance: Values above 40 U are indicative of poor prognosis after STEMI.Fig. 2: Invasive assessment of coronary circulation.The normal value of IMR is less than 25 U12 and could double in patients with STEMI according to the degree of microcirculatory functional impairment. Index of microvascular resistance and early prognostic stratification after acute myocardial infarction Fearon et al.9 first described the predictive value of IMR in the assessment of myocardial damage in 29 patients. In their series, IMR was calculated immediately after PPCI and correlated better with the peak creatinine phospho-kinase and wall-motion score index at 3 months than TIMI frame count or myocardial blush grade, CFR or ST segment elevation resolution. IMR with a cutoff value of 32 U was an independent predictor of microvascular damage and recovery of LV function at 3 months. Later, McGeoch et al.6 demonstrated in 57 patients after STEMI that a median IMR value more than 35 U was a good predictor of the infarct size as assessed with NMR at 2 days and restoration of ventricular function at 3 months. Furthermore, IMR values were correlated with the peak troponin, thus confirming data from Fearon's work. Accordingly, IMR as measured at the completion of PPCI is useful in predicting the extension and severity of STEMI. Payne et al.,13 in a larger number of patients (108), confirmed that microcirculatory resistances are predictive of microvascular damage and infarct size. The acute phase IMR was predictive of myocardial salvage and remodeling as assessed with NMR and was predictive of LV ejection fraction after 3 months only for anterior infarcts. In fact, a small infarct has a minor impact on the systolic function despite the microvascular compromise in the territory of the culprit artery. Overall these studies demonstrated that patients with high IMR after PPCI have significant microvascular dysfunction, high cardiac biomarker values and less complete recovery in time of the LV function, thus confirming the key role of the microcirculation in the evolution of AMI and the prognostic value of this index in the early risk stratification of patients after STEMI. Nonetheless, microvascular dysfunction is a dynamic phenomenon varying in time after coronary reperfusion and it is not clear when the optimal time for microcirculatory resistance evaluation is. Cuculi et al.14 compared invasive physiologic parameters (CFR, IMR and FFR) with data from ceNMR obtained immediately after PPCI, 1 day after and at a 6-month follow-up. Data confirmed that the improvement in microcirculatory function begins within the first 24 h after AMI and is progressive during the first 6 months when returned toward normal values (IMR 24 ± 22). MVO was found in 47% of the patients who also had a tendency toward higher IMR values (P = 0.07); however, after 6 months, CFR and IMR did not differ amongst the two groups. Currently, there are few data demonstrating IMR as predictive of clinical outcome. Fearon et al.15 presented 3-year follow-up data of 253 patients after STEMI in whom IMR was measured immediately after PPCI. Mortality and hospital readmission for heart failure were significantly higher with IMR values more than 40 U (20 vs. 11%, P = 0.04). The IMR value of more than 40 U was the only independent predictor of mortality in this study. Furthermore, IMR was useful in predicting the long-term outcome (favorable/unfavorable) of patients after STEMI and PPCI, confirming that microcirculatory dysfunction is the most important factor in determining clinical outcome after revascularization. Fukunaga et al.16 evaluated the predictive value on the clinical outcome, at midterm, of IMR and the pattern of thermodilution curves recorded during maximal hyperemia in 88 patients with STEMI. MVO documented with the ceNMR was associated with higher value of IMR, and a value of more than 37 U was the best predictor of event-free survival. The multivariate analysis did not show IMR as an independent predictor of major adverse cardiovascular event (MACE) at 6 months (composite of cardiac death, nonfatal AMI, hospital readmission for heart failure). On the other hand, the bimodal pattern of the thermodilution curve was an independent predictor of MACE. The latter data gave rise to the hypothesis that the shape of the curve could reflect the dominant physiopathology of microvascular damage: the natural history varies after MVO whether the predominant mechanism is microvascular destruction or microembolization. The bimodal pattern of the thermodilution curve reflects the prevalence of microvascular destruction, which is associated with worst clinical outcome. IMR cannot differentiate among these two causes of microvascular damage; accordingly, it is less specific than the thermodilution curve pattern assessment as a surrogate for microvascular reperfusion. Further studies will be necessary to identify the most relevant prognostic parameter both alone or in combination. The AMICRO Study (NCT 02325973), a prospective, multicenter trial, will evaluate whether IMR could predict 1-year clinical outcome in 242 patients after AMI. Data will be collected regarding the changes of this index in time, as it is measured right after PPCI and 5–7 days after STEMI. Index of microvascular resistance as a target for interventional and pharmacological therapy IMR as an index of microcirculatory function could be used as a guide in clinical practice to improve outcome of patients after AMI. IMR offers the opportunity to evaluate the efficacy of treatment specifically designed to preserve microvascular integrity. To this point, strategies to protect microcirculation during treatment of AMI are mainly focusing on prevention of distal microembolization of thrombotic debris and preservation of distal perfusion. Nonetheless, one major limitation is the lack of objective measures of these treatments. Manual and/or mechanical thrombus aspiration is usually used to prevent distal embolization which is often associated with MVO and no-reflow phenomenon during PPCI. There are contrasting data regarding the routine use of thrombus aspiration: Woo et al.17 evaluated the efficacy of manual thrombus aspiration using IMR in 63 patients with STEMI. Patients were randomized to PPCI or manual thrombus aspiration followed by PPCI. The IMR value in the thrombus aspiration group was significantly lower (23.5 ± 10.2 vs. 34.2 ± 21.7 U, P = 0.018), and the delta of the ejection fraction measured at baseline and at follow-up was significantly better (increase of 3.3 vs. 0.73%, P = 0.005). De Maria et al.18 investigated the variation of IMR before and after stent deployment during PPCI. Stent deployment significantly decreased the value of IMR from 67.7 to 36.7 U (P < 0.01) with an improvement in microvascular function in half of the treated patients. However, the IMR value remained elevated (>40 U) in 32.9% of the patients, a portion of which had an increased IMR value after stent implantation. IMR could also be useful in the evaluation of stents designed specifically for the treatment of AMI, which are conceived with the purpose of reducing distal thrombotic embolization and the consequent no-reflow phenomenon. Theoretically, the synergic effect of specifically designed devices could increase the protective effects on the microcirculation.19 New antithrombotic drugs could also be assessed with IMR as far as their ability to limit microvascular dysfunction. Currently, the study REDUCE-MVI20 will assess whether the adenosine-mediated effect of ticagrelor could better preserve microcirculatory function compared with prasugrel in patients with STEMI. Finally, patients with elevated IMR value immediately after PPCI could be candidates for a more aggressive pharmacological and/or mechanical treatment or enter a follow-up specifically designed to prevent heart failure and sudden cardiac death. Conclusion The integrity of the microvascular circulation affects the recovery of LV function and the prognosis and constitutes the last frontier in the treatment of patients with STEMI. Invasive assessment of microvascular circulation immediately after PPCI is an important focus for future research and represents a unique opportunity to highlight and quantify microvascular impairment and implement therapeutic maneuvers designed to treat it and, if possible, to prevent it. IMR as a surrogate of microvascular integrity could be utilized to predict infarct size and prognosis in patients with STEMI, allowing early recognition of patients with unfavorable outcome for which intensive cardiac care surveillance is necessary. In addition to the important prognostic information, IMR could represent a target to guide interventional and/or pharmacological treatment useful in reducing reperfusion damage (as a reduction of IMR value) and improve the prognosis of patients with STEMI. Acknowledgements Conflicts of interest There are no conflicts of interest.