Ischemic heart disease is a leading cause of heart failure, which often develops as a complication of acute myocardial infarction (AMI).¹ The treatment of AMI has improved dramatically in recent decades with the advent of early reperfusion strategies, including percutaneous coronary intervention and evidence-based pharmacotherapies.^2-4

Left ventricular ejection fraction (LVEF) is a significant parameter that determines early- and long-term prognosis after AMI.^{5, 6} In addition to revascularization, morbidity and mortality advantages have been achieved with medical treatments such as beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB), mineralocorticoid receptor antagonists, sodium-glucose cotransporter 2 inhibitors, and statins. Current guidelines differentiate heart failure into 3 groups: reduced ejection fraction, mildly reduced ejection fraction (HFmrEF), and preserved ejection fraction.⁷ While recent studies in patients with AMI and heart failure with low LVEF are promising, the expected results of studies about heart failure with mildly reduced and preserved LVEF have yet to be achieved.^{8, 9} New research and evaluation of the effects of treatment methods are especially necessary for HFmrEF.

It is well known that ticagrelor is one of the most important antiplatelet agents for AMI.¹⁰ Although it is known that ticagrelor increased survival after AMI and was associated with an increase in LVEF, its effect on patients with HFmrEF is unknown. Ticagrelor has cardioprotective effects by increasing the level of adenosine in the blood, and it has been shown to reduce the infarct area and improve LVEF in animal models.^3,11,12 In addition, in the literature, patients with HFmrEF after AMI have been investigated for in-hospital and long-term prognosis, but there is no study investigating the effect of antiplatelet agents on LVEF in patients with HFmrEF.^13,14 For these reasons, we aimed to investigate the effect of ticagrelor on left ventricular function in patients with HFmrEF after AMI.

Initially, 810 patients with AMI were screened for successful ad-hoc revascularization of the culprit vessel and in-hospital staged complete revascularization. We included 251 patients with LVEF of 40% to 50% evaluated by echocardiography before discharge (48 to 72 hours after admission) in the analysis (Figure 1). The intraclass correlation coefficient between 2 echocardiographers was 0.91 (95% confidence interval 0.86 to 0.93) for LVEF.

Figure 1 CABG: coronary artery bypass graft; LVEF: left ventricular ejection fraction; tPA tissue plasminogen activator.

All patients were treated with in-hospital staged complete revascularization. Baseline demographic, clinical, laboratory, and echocardiographic findings are shown in Table 1. The mean age of the patients was 61.5 ± 11.2 years. Type 2 diabetes, hypertension, body mass index, and use rates of ACEI/ARB and beta-blockers were similar between both groups.

Table 1

Characteristic	Overall n = 251	Clopidogrel treatment group n = 85	Ticagrelor treatment group n = 166	P value
Age (years)	61.5±11.2	61±11.9	61.9±10.6	0.08
Female sex (n, %)	72 (28.7)	27 (31.8)	45 (27.1)	0.440
Medical history (n, %)
Diabetes mellitus	80 (31.9)	31 (36.5)	49 (29.5)	0.263
Hypertension	121 (48.2)	45 (52.9)	76 (45.8)	0.283
Coronary artery disease	73 (29.1)	33 (38.7)	40 (24.1)	0.015
Smoker	129 (51.4)	34 (40)	95 (57.2)	0.01
Heart rate (beats/min)	76.8±14.2	77.8±14	76±14.3	0.419
Systolic blood pressure (mmHg)	133.2±27.8	129.1±27.9	135.5±27.7	0.098
Diastolic blood pressure (mmHg)	78.5±14.3	77±14.3	79.3±14.3	0.233
Body mass index† (kg/m2)	27.8±4.6	27.8±4.2	27.8±4.8	0.925
Fasting plasma glucose (mg/dl)	125 (101-170)	118 (97-172)	128(103-168)	0.037
Hemoglobin (g/dl)	14.4±1.8	14.0±1.9	14.5±1.7	0.035
Leukocyte (103/uL)	10.9±3.5	10.4±3.1	11.3±3.7	0.002
Fasting total cholesterol (mg/dl)	188.3±41.4	192.9±38.2	186.2±42.8	0.449
Serum creatinine (mg/dl)	1.0±0.2	1.1±0.3	1.0±0.2	0.227
Median cardiac troponin level (ng/mL)	15.3 (4.2-43.5)	12.0 (1.4-35.0)	18.5 (5.1-61.7)	<0.001
Median N-terminal pro-B-type natriuretic peptide (pg/ml)	1171 (517-2649)	1812 (682-3807)	998 (469-2231)	0.750
Left ventricular variables
LVEF (%)	46.54±3.6	46.18±3.5	46.7±3.7	0.257
End-diastolic diameter (cm)	5.4±0.3	5.5±0.3	5.5±0.3	0.01
Interventricular septum thickness (cm)	1.1±0.1	1.1±0.2	1.1±0.1	0.540
Posterior wall thickness (cm)	1.0±0.1	1.0±0.1	1.0±0.1	0.464
Left atrium diameter (cm)	3.6±0.3	3.7±0.3	3.6±0.3	<0.004
Clinical features of acute coronary syndrome (n, %)
NSTEMI	83(33.1)	50(58.8)	33(19.9)	<0.001
STEMI	168(66.9)	35(41.2)	133(80.1)

*Pilus-minus values are means ± standard deviation. †The body mass index is the weight in kilograms divided by the square of the height in meters. LVEF: Left ventricular ejection fraction. STEMI: ST-elevation myocardial infarction; NSTEMI: Non-ST-elevation myocardial infaction

Demographic characteristics, AMI type, and distribution ratio of antiplatelet therapy types did not differ significantly in patients whose LVEF decreased, remained unchanged, and increased at 12 months (Table 2). The mean LVEF before discharge was 46.5% ± 3.6% in both groups, and no difference was observed between the ticagrelor and clopidogrel groups. At the end of the first year, the mean LVEF of the patients increased to 49.8% ± 7.6% in both groups. During follow-up, LVEF fell below 40% in 14 (5.6%) patients, remained between 40% and 50% in 141 (56.2%), and increased to over 50% in 96 (38.2%). In the ticagrelor group, LVEF was decreased in 10 patients (6%) and increased in 69 (41.6%). In the clopidogrel group, LVEF was decreased in 4 patients (4.7%) and increased in 27 (31.8%) (Table 3; Figures 2 and 3).

Table 2

Variables	LVEF at 12 months of follow-up			p
	Worsened n = 14	Unchanged n = 141	Improved n = 96
Age (years), mean±SD	66.2±13.7	62.8±11.2	61.6±11	0.328
Female sex (n, %)	7 (50.0)	39 (27.7)	26 (27.1)	0.220
Diabetes mellitus (n, %)	3 (21.4)	47 (33.3)	30 (31.3)	0.710
Hypertension (n, %)	8 (57.1)	64 (45.4)	49 (51.0)	0.533
Coronary artery disease (n, %)	5 (35.7)	47 (33.3)	21 (21.9)	0.125
Smoker (n, %)	7 (50.0)	71 (50.4)	51 (53.1)	0.911
Heart rate (bpm), mean ± SD	81±11.7	78.7±13.7	73.5±14.7	0.012*
Body mass index (kg/m2), mean ± SD	26.9±4.9	28±4.6	27.7±4.7	0.620
Serum creatinine (mg/dl), mean ± SD	1.3±0.4	1.1±0.3	0.9±0.2	0.004*
Antiplatelet (n, %)
Clopidogrel	4 (28.6)	54 (38.3)	27 (28.1)	0.245
Ticagrelor	10 (71.4)	87 (61.7)	69 (71.9)
AMI (n, %)
NSTEMI	4 (28.6)	44 (31.2)	35 (36.5)	0.660
STEMI	10 (71.4)	97 (68.8)	61 (63.5)

AMI: acute nyocardial infarciton; LVEF: left ventricular ejection fraction; NSTEMI: non-ST-elevation myocardial infarction; SD: standard deviation; STEMI: ST-elevation myocardial infarction.

Table 3

	Overall n = 251	Clopidogrel group n = 85		Ticagrelor group n = 166
Baseline LVEF (%)	46.5±3.6	46.2±3.5	p = 0.4	46.7±3.7	p = 0.09
Final LVEF (%)	49.8±7.6	48.1±7.5		51.0±7.6
LVEF variable
Worsened	14(5.6%)	4(4.7%)		10(6.0%)
Unchanged	141(56.2%)	54(63.5%)		87(52.4%)
Improved	96(38.2%)	27(31.8%)		69(41.6%)

*Changes in LVEF were categorized as follows: worsened: < 40%; unchanged: 40% to 50%; and improved ≥ 50%. LVEF: left ventricular ejection fraction

Figure 2 LVEF: left ventricular ejection fraction; EF: ejection fraction.

Figure 3 ΔLVEF: final LVEF (%) − baseline LVEF (%); LVEF: left ventricular ejection fraction.

The relationship between the change in LVEF after follow-up compared to the LVEF before discharge (ΔEF) and the demographic and clinical characteristics of the patients are shown in Table 4. The following factors were correlated with increased ΔEF: increased age, use of ticagrelor low creatinine level, low troponin level, low heart rate, and decreased diameter of the left atrium. No other demographic and clinical findings were found to be correlated with ΔEF.

Table 4

Characteristic	R	P value
Age	0.278	0.048
Body mass index	0.034	0.590
Female sex	−0.094	0.139
Smoker	0.055	0.383
Diabetes mellitus	0.009	0.888
Hypertension	0.071	0.263
Coronary artery disease	0.121	0.056
Ticagrelor	0.315	0.009
Hemoglobin	0.038	0.552
Fasting total cholesterol	0.197	0.146
Serum creatinine	−0.349	0.001
Troponin	−0.311	0.003
N-terminal pro-B-type natriuretic peptide	−0.302	0.037
STEMI	−0.006	0.926
End-diastolic diameter	0.046	0.514
Heart rate	−0.321	0.001
Systolic blood pressure	−0.070	0.271
Diastolic blood pressure	−0.104	0.102
Interventricular septum thickness	−0.042	0.514
Posterior wall thickness	−0.088	0.170
Left atrium diameter	−0.297	0.015

ΔEF: final LVEF (%) − baseline LVEF (%); LVEF: left ventricular ejection fraction; STEMI: ST-elevation myocardial infarction.

The following independent parameters affected the increase in ΔEF: ticagrelor use, low creatinine level, low troponin level, and low heart rate (Table 4). In the stepwise logistic regression model that included possible risk factors (creatinine, NT-proBNP) affecting the decreased LVEF during follow-up, creatinine and increased NT-proBNP were found to be independent risk factors affecting reduced LVEF (Table 5).

Table 5

Characteristic
	β±SE	95% CI	p
ΔEF (%)
Ticagrelor	2.05±0.93	0.21 to 3.90	0.029
Serum creatinine	−10.44±2.35	−15.09 to 5.80	<0.001
Troponin	−0.38±0.14	−0.66 to 0.11	0.006
Heart rate	−0.98±0.33	−1.62 to 0.33	0.003
	R2=0.283; p=0.017
	OR	95% CI	p
Worsened LVEF
Serum creatinine	1.30	1.06 to 1.58	0.017
N-terminal pro-B-type natriuretic peptide	1.09	1.02 to 1.18	0.045
	Nagelkerke R2=0.225; p=0.001
Improved LVEF
Serum creatinine	0.09	0.02 to 0.53	0.007
N-terminal pro-B-type natriuretic peptide	0.87	0.77 to 0.98	0.020
Heart rate	0.97	0.95 to 0.99	0.006
	Nagelkerke R2=0.331; p<0.001

ΔEF: final LVEF (%) − baseline LVEF (%); CI: confidence interval; LVEF: left ventricular ejection fraction; OR: odds ratio; SE: standard error.

In the stepwise logistic regression model that included the possible risk factors (creatinine, 24-hour troponin, NT-proBNP, heart rate, and left atrium) that affected LVEF increase during follow-up, low creatinine level, NT-proBNP level, and low heart rate were found to be independent risk factors affecting increased LVEF (Table 5).

In our study, we compared the effect of ticagrelor versus clopidogrel on LVEF in the 1-year follow-up of patients with HFmrEF after AMI. The results of this study show that patients receiving ticagrelor had more improvement in LVEF than those receiving clopidogrel. This is the first study in the literature evaluating the effect of antiaggregant therapy on LVEF in patients with HFmrEF after AMI.

Margolis et al.¹⁴ compared in-hospital events and short- and long-term mortality rates of AMI patients with HFmrEF to other groups. The mean follow-up mortality rate of 3.5 years was higher in the HFmrEF group compared to the preserved LVEF group (9.8% versus 7.2%, p < 0.01), but lower than in the low LVEF group (29.8% versus 9.8%, p < 0.001). However, their study did not compare antiaggregant types or evaluate left ventricular function in the follow-up. They showed that patients with HFmrEF after STEMI differed from other groups in terms of mortality and that patients in this group could be evaluated separately.

The most important study demonstrating the clinical utility of ticagrelor is the PLATO trial.¹⁰ At the end of the study, the composite outcome of cardiovascular death, myocardial infarction, and stroke significantly decreased (10.2% vs. 12.3%, p < 0.001) in the ticagrelor group compared to clopidogrel group at 30 days, and the absolute risk reduction achieved in the early period continued during the 1-year treatment. In the PLATO study, the reason why ticagrelor reduces all-cause mortality is not fully elucidated.

Previous studies^15,16 have shown that ticagrelor may have some pleiotropic effects, unlike clopidogrel. This effect is due to an increase in adenosine levels in patients using ticagrelor, and it has been shown that adenosine levels are higher than in patients receiving clopidogrel. Ticagrelor has an additional mechanism of action that increases local endogenous adenosine levels by inhibiting the balancing nucleoside transporter-1 (ENT-1: sodium-independent equilibrative nucleoside transporter 1). Ticagrelor does not have a significant direct effect on adenosine receptors (A1, A2A, A2B, A3).^17,18 Adenosine has several positive effects, such as vasodilatation, improved endothelial function, cardioprotection, platelet inhibition, ischemic preconditioning, and immune modulation, which may contribute to the clinical profile of ticagrelor.¹⁹

In the Acute Myocardial Infarction Study of Adenosine (AMISTAD) I and AMISTAD II studies, patients with STEMI had additional adenosine infusion after reperfusion, and the infarct area of the myocardium decreased.^20,21 However, in two other large studies, the benefit of intracoronary adenosine given before reperfusion in patients with STEMI was not found.^22,23 The negative result of these studies was attributed to the immediate destruction of adenosine in the circulation due to the short half-life. Cardioprotective effects are thought to occur due to chronic adenosine elevation in patients using ticagrelor.²⁴

In addition to causing a chronic increase in the level of adenosine, ticagrelor also has immunomodulatory regulation properties such as pleiotropic action. In a study conducted on healthy volunteers, ticagrelor has been shown to significantly reduce plasma granulocyte colony-stimulating factor, interleukin-8, and Tumor Necrosis Factor (TNF-α) levels and to increase anti-inflammatory interleukin-10 levels, compared to placebo and clopidogrel.²⁵

The adenosine-mediated pleiotropic effect of ticagrelor has also been demonstrated in animal studies. Nanhwan et al.²⁶ performed 30-minute ligation on ’coronary arteries in rats. They randomized the rats to ticagrelor and clopidogrel groups, and gave different doses of ticagrelor and clopidogrel to examine the area of myocardial infarction. The myocardial infarct area of ticagrelor-treated subjects was less than that of clopidogrel-treated subjects. This effect of ticagrelor has been reported to be associated with the upregulation of nitric oxide release and cyclooxygenase-2 activation from endothelium via adenosine. In the same study, rats receiving ticagrelor had significantly improved LVEF and decreased myocardial infarct area compared to clopidogrel after a 4-week follow-up. This demonstrated that ticagrelor improves LVEF even in non-thrombotic coronary conditions.

In another study on pigs, subjects were randomized to groups of ticagrelor, clopidogrel, placebo, and ticagrelor with adenosine A1/A2 receptor antagonists (8-[p-sulfophenyl] theophylline for purifying the effects of adenosine) after AMI.¹¹ Subjects were examined by cardiac magnetic resonance imaging, and it was found that the use of ticagrelor significantly reduced myocardial infarction area and myocardial edema compared to clopidogrel. However, cardioprotective effects were not observed in the group that used ticagrelor and adenosine antagonists together.

Ticagrelor has been shown to induce the release of adenosine triphosphate (ATP) from human erythrocytes, leading to an increase in extracellular adenosine concentrations. Both adenosine and ATP play pivotal roles in promoting vasodilation.²⁷ Adenosine primarily achieves this by directly relaxing vascular smooth muscle cells, while ATP functions by stimulating the endothelium to release vasodilatory mediators, including nitric oxide, endothelial hyperpolarizing factor, and prostacyclin. This mechanism not only contributes to promoting myocardial perfusion, but also holds particular importance in the context of vessel damage or hypoxia.²⁸

Ndrepepa et al. reported that patients who successfully restored normal blood flow following the no-reflow phenomenon (NRP) experienced an improvement in their LVEF compared to pre-NRP levels.²⁹ Additionally, they found that NRP occurrence could serve as an independent predictor of mortality. The ONSET/OFFSET study demonstrated that platelet inhibition was more rapid and greater with ticagrelor than clopidogrel.³⁰ It is believed that, by reducing platelet adhesion to debris, it may decrease the occurrence of microembolization and improve reperfusion. Several studies have reported that the preoperative administration of a loading dose of ticagrelor can decrease the occurrence of the NRP in the context of primary percutaneous coronary intervention and effectively enhance coronary blood reperfusion.³¹

In our study, we found improvement in left ventricular systolic function in patients with HFmrEF receiving ticagrelor after AMI. This study serves as a starting point, and it is imperative to conduct further comprehensive research to elucidate the intricacies of the topic.

In our study, we found that ticagrelor significantly improved left ventricular systolic function in patients with mildly reduced LVEF after AMI compared to clopidogrel.