Effect of ticagrelor combined with nicorandil on endothelial function and coronary blood flow after PCI treatment in STEMI patients

1. Introduction

Myocardial infarction (MI) is the most prevalent type of coronary heart disease and the primary cause of patient death [1, 2]. Clinically, MI is classified as ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation myocardial infarction (NSTEMI) based on the electrocardiograms (ECG) [3]. STEMI morbidity and mortality rates can reach 50% or higher within 1 h of disease onset [4]. Currently, percutaneous coronary intervention (PCI) is a viable method to save myocardium on the verge of necrosis and restore myocardial reperfusion in patients with STEMI. PCI rapidly unblocks occluded or stenotic lumens and restores myocardial blood supply [5]. STEMI can, however, lead to diminished vascular endothelial function, and PCI’s rapid recovery of myocardial blood supply can exacerbate vascular endothelial injury [6]. Meanwhile, PCI itself can cause plaque and thrombus rupture or dislodgement, increasing the risk of in-stent thrombosis and leading to the occurrence of major adverse cardiovascular events (MACE) after the procedure [6]. Consequently, an anticoagulant or endothelial-protective drug should be chosen before PCI to reduce risks. This study aimed to examine the effect of PCI with ticagrelor and nicorandil on endothelial function and coronary blood flow in STEMI patients. As a consequence of this study, we hope to provide a reference for selecting preoperative adjuvant therapeutic agents for PCI.

2. Materials and methods

3. Results

3.2 Comparison of cardiac function indices

At T1, a significant increase in PER and LVEF was found in both groups compared with T0, while LVESVI and LVEDD significantly decreased (p < 0.05, Fig. 1). At T1, the observation group had significantly higher PER and LVEF and significantly lower LVESVI and LVEDD than the control group (p < 0.05, Fig. 1).

Fig. 1.Comparison of cardiac function between the two groups. (A) LVESVI; (B) LVEDD; (C) PER; (D) LVEF. Compared with T0, *p < 0.05; Compared with Control group, ^#p < 0.05. LVESVI, LV end-diastolic volume index; LVEDD, LV end-diastolic internal diameter; PER, peak ejection rate; LVEF, LV ejection fraction.

3.3 Comparison of myocardial injury marker levels

At T1, both groups’ cTnI and CK-MB levels significantly decreased than at T0 (p < 0.05, Fig. 2). Comparing the observation group with the control group at T1, levels of cTnI and CK-MB were significantly lower (p < 0.05, Fig. 2).

Fig. 2.Comparison of myocardial injury marker levels between the two groups. (A) Serum cTnI levels; (B) Serum CK-MB levels. Compared with T0, *p < 0.05; Compared with Control group, ^#p < 0.05. cTnI, cardiac troponin I; CK-MB, creatine kinase myoglobin.

3.4 Comparison of vascular endothelial function

At T1 compared with T0, serum NO levels were significantly higher and ET-1 levels were significantly lower in both groups, respectively (p < 0.05, Fig. 3). In the observation group, there was a significant reduction in ET-1 levels and a significant increase in serum NO than in the control group (p < 0.05, Fig. 3).

Fig. 3.Comparison of vascular endothelial function indices between the two groups. (A) Serum NO levels; (B) Serum ET-1 levels. Compared with T0, *p < 0.05; Compared with Control group, ^#p < 0.05. NO, nitric oxide; ET-1, endothelin-1.

4. Discussion

STEMI is a spontaneous infarction caused by intracoronary thrombosis due to coronary plaque rupture, fissure or entrapment. STEMI is characterized by chest pressure-like pain, which, if left untreated, can result in heart failure or shock. Myocardial perfusion can be significantly improved by PCI by opening narrowed or occluded coronary artery lumen. STEMI is primarily treated with it. Often, antiplatelet aggregation drugs are needed as adjuvant therapy before and after PCI to reduce the risk of MACE [12].

Ticagrelor is a clinically used antiplatelet agent that inhibits adenosine diphosphate (ADP)-mediated platelet activation and aggregation through its interaction with the P₂Y₁₂ receptor [13]. Ticagrelor has been widely used to treat myocardial infarction, stroke and peripheral arterial disease. The combination of multiple single agents is shown to be more helpful in preserving cardiac function in STEMI patients and improving clinical outcomes [3]. Nicorandil is a nicotinamide derivative that dilates arteries and veins, reducing cardiac load by activating adenosine triphosphate-sensitive potassium channels [14]. In addition, nicorandil improves arterial blood flow, increases vascular smooth muscle relaxation, and reduces coronary artery spasms and dilatation by controlling K⁺ and Ca²⁺ intra- and extracellular flow [15]. Therefore, nicorandil may reduce cardiovascular disease risk, control disease progression, and relieve pain in patients with heart failure. The use of nicorandil monotherapy on symptoms other than coronary artery disease is less effective, however. Combining this drug with other antithrombotic or antiplatelet drugs is effective compared to administering it on its own [16]. Both the observation group and control group of NSTEMI patients showed significant improvement in cardiac function and myocardial injury after surgery. Patients’ cardiac function improved more in the observation group than in the control group. Therefore, the antithrombotic effect of ticagrelor combined with the vasodilator effect of nicorandil is more favorable to the recovery of cardiac function in patients after PCI.

AMI patients who suffer from vascular endothelial dysfunction are at risk of developing MACE after PCI [17]. Vascular endothelial dysfunction is an early manifestation of atherosclerosis and is considered the initiating factor for myocardial infarction pathologic changes. Moreover, PCI can also stimulate the arterial vasculature and aggravate vascular endothelial dysfunction [6]. Prognosis of emergency PCI patients can be improved by protecting vascular endothelial function. Vascular endothelial dysfunction results from an imbalance between endothelium-derived relaxing factors (e.g., NO) and endothelium-derived contracting factors (e.g., ET-1) [18]. NO is converted from L-arginine mainly by activation of nitric oxide synthase (NOS). Cellular function is maintained by NO, which is also important indicator of endothelial cell function. ET-1 acts as a vasoconstrictor peptide that contracts the arterial smooth muscle. Elevated levels of ET-1 correlate positively with vascular resistance and arterial pressure [19]. As a result of combining ticagrelor with nicorandil, NO production was improved and endothelial ET-1 production was inhibited, which improved vasodilatory and contractile factors imbalance, resulting in improved the vascular endothelial function after PCI in STEMI patients.

PCI is often associated with the phenomena of “no flow” and/or “slow flow”, i.e., restoration of epicardial coronary stenosis but loss or significant slowing of distal antegrade blood flow, failing to restore full myocyte perfusion [20]. “No reflow” and “slow flow” are associated with distal thromboembolism, ischemia-reperfusion injury, microvascular spasms, and endothelial dysfunction. Their incidence during PCI is between 5% and 50%, which significantly reduces PCI effectiveness and increases MACE and in-hospital mortality [21]. A key clinical concern is reducing the risk of “no-reflow” and “slow flow” during PCI. In this study, the observation group had a significantly higher percentage of grade 3 TIMI flow following PCI than the control group. In contrast, CTFC, which reflects microcirculatory perfusion, was significantly lower. This suggest that ticagrelor combined with nicorandil improves coronary blood flow significantly better than ticagrelor alone. The vasodilator effect of nicorandil, in addition to its antiplatelet properties, may accelerate the rapid restoration of blood flow in stenotic vessels or infarct sites. Further, observation patients had a significantly lower MACE incidence at 1 month postoperatively than control patients. Therefore, the preoperative combined application of ticagrelor combined with nicorandil before PCI can delay myocardial infarction progression in STEMI patients, reduce MACE incidence and improve the prognosis.

Many limitations remain in this study. It was a one-site study with a limited sample size. Further, the long-term effectiveness following surgery was not evaluated. This necessitates the increase of the sample size and the conduct of multicenter, extended follow-up research.

5. Conclusions

In conclusion, the preoperative combination of ticagrelor and nicorandil in STEMI patients undergoing PCI helped to attenuate vascular endothelial function impairment, improved coronary blood flow, and promoted postoperative cardiac function recovery.

Availability of data and materials

The authors declare that all data supporting the findings of this study are available within the paper and any raw data can be obtained from the corresponding author upon request.

Author contributions

GRL—designed the study and carried them out. GRL, DMY—supervised the data collection, analyzed the data, interpreted the data; prepared the manuscript for publication and reviewed the draft of the manuscript. Both of authors have read and approved the manuscript.

Ethics approval and consent to participate

Ethical approval was obtained from the Ethics Committee of Shanghai university of medicine & health Sciences affiliated Chongming hospital (Approval no. 2020065). Written informed consent was obtained from a legally authorized representative for anonymized patient information to be published in this article.

Acknowledgment

Not applicable.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest.