In this single-center, retrospective, observational study, we evaluated the impacts of DAPT with ticagrelor or clopidogrel on CMD and clinical prognosis over 2-year follow-up in AMI patients. We are the first to evaluate changes in coronary microvascular function using angio-IMR, a novel wire-free measurement for CMD, before and after different DAPT regimens. The main findings were as follows: (1) Following an average duration of approximately 12 months of DAPT maintenance treatment, ticagrelor demonstrated a significant reduction in angio-IMR, indicating its superior efficacy in preserving coronary microvascular function compared with clopidogrel in AMI patients. (2) Ticagrelor treatment was related to a lower risk of readmission for heart failure and myocardial reinfarction during 2-year follow-up when compared with clopidogrel treatment, which may be partially attributed to the greater improvements in CMD with ticagrelor. (3) Ticagrelor treatment independently predicted readmission for heart failure. (4) Angio-IMR emerged as a significant predictor for readmission for heart failure and myocardial reinfarction, highlighting the predictive value of CMD for cardiovascular outcomes in AMI patients.

CMD is frequently observed in patients with AMI, particularly following successful revascularization of the culprit vessel. A comprehensive understanding of CMD considered that microembolization, platelet aggregation, endothelial dysfunction, and vasomotion jointly contribute to its development in AMI [21]. Furthermore, CMD has been strongly associated with MACE, including heart failure, myocardial infarction, arrhythmia, and mortality [22]. Recent studies indicated that ticagrelor may exert protective effects on CMD beyond its antiplatelet effect. For instance, ticagrelor has been reported to elevate plasma adenosine concentration by inhibiting its absorption by red blood cells, as well as enhance adenosine-induced coronary vasodilation [9, 11]. Additionally, ticagrelor appears to exert a positive influence on inflammation and oxidative stress, potentially mitigating endothelial dysfunction and related prothrombotic effects [23]. In comparison with other P2Y12 inhibitors, ticagrelor may also inhibit vasoconstriction by preventing ADP-induced contraction of vascular smooth muscle cells [24]. Collectively, these mechanisms potentially contribute to the observed reduction in microvascular resistance. Nonetheless, it is important to acknowledge that the precise mechanisms by which ticagrelor influences CMD remain incompletely understood. Further mechanistic studies still needed to elucidate the pathway of effect of ticagrelor.

However, clinical evidence regarding the impact of ticagrelor on CMD in AMI patients is limited and inconsistent. Xu et al. and Choi et al. indicated that ticagrelor significantly enhanced guidewire-derived IMR following PCI among ACS patients, as compared with clopidogrel [16, 25]. Similarly, another study reported a greater reduction in guidewire-derived IMR following 6-month maintenance therapy with ticagrelor than clopidogrel among ACS patients [15]. However, a recent study found no benefit when comparing ticagrelor to clopidogrel using myocardial contrast echocardiography-derived global myocardial perfusion score index to evaluate CMD in STEMI patients [26]. Our study demonstrated a significant reduction in angio-IMR among AMI patients who received PCI when treated with ticagrelor maintenance therapy, suggesting superior efficacy of ticagrelor in attenuating CMD. The underlying mechanisms for this effect are likely attributed to the aforementioned properties of ticagrelor. However, further research is necessary to clarify the precise underlying mechanisms.

In our retrospective research, we observed that maintenance therapy with ticagrelor was associated with a lower risk of readmission for heart failure and myocardial reinfarction compared with clopidogrel during the 2-year follow-up in AMI patients. These observations align with the results of the PLATO trial, which demonstrated the ticagrelor’s superior efficacy over clopidogrel in improving clinical prognosis including myocardial reinfarction in patients with ACS [8]. Additionally, ticagrelor remained an independent predictor for readmission for heart failure according to multivariable analysis, though it did not show the same predictive value for myocardial reinfarction. This may indicate that ticagrelor has a more pronounced effect on heart failure than myocardial reinfarction in AMI patients. The potential mechanisms underlying these benefits may be partially attributed to improvements in CMD with ticagrelor, as evidenced by the independent predictive value of angio-IMR for both readmission for heart failure and myocardial reinfarction. This aligns with previous research indicating that angio-IMR independently predicts cardiac death or readmission for heart failure among STEMI patients [13]. Furthermore, it has been demonstrated that CMD is prevalent in patients diagnosed with heart failure with preserved ejection fraction (HFpEF), which may explain why either group exhibited significant improvement in LVEF after DAPT, whereas the risk of readmission for heart failure was significantly reduced with ticagrelor [27, 28]. Ticagrelor exhibits the potential to enhance cardiac function and inhibit cardiac remodeling by improving coronary microvascular function and myocardial perfusion, which are critical for the development of heart failure. However, it is imperative to approach these findings with caution. The retrospective nature of our study introduces the possibility of selection bias and confounding factors, which may limit the direct attribution of clinical outcomes to the improvement of CMD by ticagrelor. While our data suggest a correlation, they do not establish causation. Therefore, prospective studies are necessary to confirm these results and to further elucidate the role of ticagrelor in the management of CMD and its impact on clinical prognosis in AMI patients. Additionally, the ticagrelor group exhibited a higher perioperative use of GP IIb/IIIa inhibitors, potentially attributed to the presence of more complex coronary lesions and an increased risk of stent thrombosis. However, considering the lack of a significant difference in baseline angio-IMR between the groups and the negligible impact of GP IIb/IIIa inhibitors in the multivariate analyses, it is plausible that the influence of GP IIb/IIIa inhibitors on coronary microcirculation function and clinical outcomes may be limited.

Moreover, the sensitivity analyses underscore the consistent and robust predictive value of angio-IMR for both outcomes. However, model 5 stands out as the most informative due to its comprehensive adjustment for covariates. The results obtained from this model not only affirm the independent predictive capability of angio-IMR but also highlight its clinical relevance in forecasting adverse cardiac events. The consistency observed across all models reinforces the conclusion drawn from model 5, solidifying angio-IMR’s role as a reliable prognostic tool. Additionally, we observed that ticagrelor treatment may be related to a reduced risk of readmission for heart failure and myocardial reinfarction in several high cardiovascular risk subgroups. While the data indicate potential benefits in specific comorbidities and lesion characteristics, these findings are preliminary and derived from a non-randomized, retrospective analysis. Consequently, the results should not be construed as definitive evidence but rather as hypotheses generating insights that require validation in prospective, randomized studies.

This study leverages a novel, non-invasive approach to measure CMD, characterized by its simplicity in calculation and minimal susceptibility to hemodynamic factors [29]. Additionally, this study excels in its inclusion of a sizable population of AMI patients who received successful PCI, the prospective collection of prognostic data, and long-term follow-up of clinical outcomes. However, certain limitations remained in this study. Firstly, the limited sample size was a result of the exclusion of patients without routine follow-up coronary angiography. Secondly, this was a retrospective observational study and may be susceptible to selection bias, confounding factors, and residual confounding. While our study suggests a correlation between ticagrelor-induced improvement in coronary microvascular function and enhanced clinical outcomes, it does not establish a definitive causal relationship. Therefore, the findings should be interpreted cautiously and validated through prospective randomized trials. Thirdly, our focus was solely on CMD within the culprit vessel territory; thus, the impact of ticagrelor on CMD in the non-culprit vessel territories and its prognostic value remained unclear. Considering the integral role of non-culprit vessel territories in the overall coronary microcirculation, subsequent research is necessary to ascertain their contribution.