Effect of ramipril on progression of nonculprit lesions in patients with ST-elevation myocardial infarction after primary percutaneous coronary intervention.

OBJECTIVE: To investigate the effect of ramipril on progression of nonculprit lesions in patients with ST-elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (PPCI).
METHODS: A total of 200 patients (60.1 ± 11.3 years) with STEMI who underwent successful PPCI from January 2010 to December 2013 were enrolled in this study. All patients underwent PPCI as treatment for culprit lesions. Patients were divided into two groups according to the dosage of ramipril used at hospital discharge as follows: high dosage group (2.5-10 mg, q.d.) and low dosage group (1.25-2.5 mg, q.d.). Clinical and angiographic follow-up was performed for 12 months. The primary endpoint was clinically-driven percutaneous coronary intervention (PCI) for nonculprit lesions. The clinical and angiographic features were analyzed.
RESULTS: Clinical and angiographic follow-up was performed with 87 patients in the high dosage group and 113 patients in the low dosage group. The numbers of patients who underwent additional PCI were six and 20 in the high and low dosage groups, respectively. The rate of having additional PCI performed was lower in the high dosage group than in the low dosage group (6.90% vs. 17.70%, P = 0.03).
CONCLUSIONS: A high dosage of ramipril may prevent progression of nonculprit lesions, which could be the major cause of recurrent PCI in patients with STEMI after PPCI. Institute of Geriatric Cardiology.

Introduction

Primary percutaneous coronary intervention (PPCI) can salvage dying myocardium, reduce cardiovascular events, and improve prognosis in patients with ST-elevation myocardial infarction (STEMI). However, our recent clinical studies have shown that nonculprit lesions may progress after PPCI and progression of nonculprit lesions could be the most significant factor that affects the prognosis after PPCI.[1] We have recently shown that progression of nonculprit lesions can be affected by many factors, such as increased levels of catecholamines and the angiotensin II–MAPK–Cx43 pathway (Figure 1).[2] However, the effect of ramipril on progression of nonculprit lesions has not been studied. In this study, we investigate the effect of ramipril on progression of nonculprit lesions in patients with STEMI after PPCI.

Figure 1.

Flow chart of a hypothetical pharmacological and biochemical mechanism of atherosclerotic progression.

Methods

Study design and participants

All participants or their family members were informed about the potential publication of their identities and images, and all of them completed consent forms. All procedures and protocols were approved by the ethics committee of Capital Medical University, and the experiments were conducted according to the Helsinki declaration (1975 and subsequent revisions).

From January 2010 to December 2013, 200 patients (127 men and 73 women) with acute STEMI who underwent PPCI treatment were enrolled in this retrospective study. Clinical and angiographic follow-up was performed in all patients for 12 months. The inclusion criteria were as follows. (1) Acute myocardial infarction lasted for < 12 h and only one nonculprit lesion was found in the setting of STEMI. Acute myocardial infarction was defined as follows: evidence of ischemic chest pain lasting for > 30 min, and new ST-segment elevation of ≥ 2 mm in two or more contiguous electrocardiographic leads; a de novo lesion; single-vessel treatment in a native vessel ≥ 2.5 mm in diameter and occluded, thrombus-containing; thrombolysis in myocardial infarction (TIMI) flow grade of 0 to 2 in the culprit artery; and the grade of stenosis of nonculprit lesions was < 50%. (2) There was no contraindication for anticoagulation and antiplatelet therapy.

The main exclusion criteria included the following: previous percutaneous coronary intervention (PCI) in an infarction-related artery (IRA) (n = 3), Killip class ≥ 3 (n = 3), left or right bundle branch block (n = 4), IRA with excessive proximal tortuosity or severe calcification (n = 5), left ventricular ejection fraction < 35% (n = 5), lack of clinical and angiographic follow-up (n = 10), in-hospital death after PPCI (n = 4), myocardial infarction within two weeks of PPCI to exclude potential subacute stent thrombosis of the intervened arterial segment (n = 3), and repeated PCI of culprit coronary lesions for restenosis or progression (n = 17). A total of 38 patients had to use angiotensin receptor blockers instead of angiotensin-converting enzyme inhibitors for angiotensin-converting enzyme inhibitor-related cough and were excluded from this study.

Coronary angiography was performed using the Judkins method, and coronary artery lesion classification was based on the American College of Cardiology/American Heart Association guideline.[3] Thrombus aspiration catheters (DIVER CE, Invatec, Brescia, Italy) were used for thrombotic burden lesions. Stents were implanted using a routine method, and the procedure succeeded with residual stenosis < 20%, TIMI flow grade of 3 and no acute complications (death, myocardial infarction, emergency coronary artery bypass grafting (CABG)), and no major adverse cardiac events (cardiac death, myocardial infarction, target vessel revascularization) in hospital. Clinical and angiography follow-up was performed for 12 months. The levels of serum catecholamines (epinephrine, norepinephrine (NE)) and C-reactive protein (CRP) were assayed.

The culprit coronary lesions were clearly identified by a combination of electrocardiography and coronary angiography. Nonculprit lesions were defined as those with a diameter of stenosis < 50%. All patients underwent PPCI for the culprit lesions.

Quantitative coronary angiography was performed in the first angiography. Follow-up angiography was performed by two independent investigators who were blinded to the results. We categorized the lesions according to the American College of Cardiology/American Heart Association Classification on the basis of morphological characteristics of lesions that cause significant stenosis of the coronary arteries.[3] These included two categories of simple lesions (A or B1 lesions) and complex lesions (B2 or C).

Collected data included demographic information, medical history, coronary artery disease risk factor status, detailed coronary angiographic information, biomarkers associated with coronary atherosclerosis at the time of baseline PCI, and coronary angiographic information at the time of angiographic follow-up.

All clinical, laboratory, and coronary angiographic data were evaluated by two independent investigators who were not involved in the angiographic procedures. According to the registered dosage of ramipril (Tritace; Sanofi Pharmaceuticals Co, Ltd., Bejing, China) at discharge from hospital, all patients were divided into the high dosage group (2.5–10 mg, q.d.) (high dosage control group and high dosage additional PCI group) or the low dosage group (1.25–2.5 mg, q.d.) (low dosage control control group and low dosage additional PCI group) (Figure 1). We chose the dosages of ramipril according to the safety of differential dosages of ramipril in high-risk cardiovascular Chinese patients.[4]

The primary endpoint was clinically-driven PCI for nonculprit lesions (defined as clinically-driven PCI for a previously nonintervened (no balloon angioplasty or stent implantation) vessel segment. In the present study, clinically driven PCI for nonculprit lesions included PCI for progression of preexisting nonculprit lesions that were discovered during PPCI, as well as development of de novo lesions. All patients were also divided into the control group and the additional PCI group (Figure 2).

Figure 2.

Study flow chart.

PCI: percutaneous coronary intervention.

Statistical analysis

The results for normally distributed continuous variables are expressed as the mean ± SD, while categorical variables are expressed as percentages. Continuous variables were tested for a normal distribution with the Kolmogorov–Smirnov test and for homogeneity of variance with Levene's test. Differences in continuous variables were initially evaluated by one-way analysis of variance or the Student's t test, and then by Tukey's post hoc test where appropriate. Categorical data were analyzed using Fisher's exact test or the chi-square test. Pearson's correlation coefficient was used to quantify the degree of stenosis of nonculprit artery lesions between clinically correlated factors. Differences were considered to be statistically significant if the null hypothesis could be rejected with > 95% confidence. The SPSS 20.0 statistical software package (SPSS Inc., Chicago, IL, USA) was used for all calculations.

Results

This study included 87 (56 men and 31 women) and 113 (72 men and 41 women) patients in the high and low dosage groups, respectively. The patients' age ranged from 32–82 years (60.1 ± 11.3 years).

In the high dosage group, six patients (four men and two women) underwent additional clinically-driven PCI for nonculprit lesions.

A total of 20 patients (13 men and 7 women) in the low dosage group underwent additional clinically-driven PCI for nonculprit lesions.

The degree of stenosis in the high dosage group was significantly lower than that in the low dosage group (70.3% ± 14.1% vs. 82.1% ± 15.3%, P < 0.0001). The additional PCI rate in the high dosage group was significantly lower than that in the low dosage group (6.90% vs. 17.70%, P < 0.05).

There were no significant differences in age, sex, history of diabetes mellitus, HbA1c (%), rates of hypertension, hyperlipidemia, smoking, myocardial infarction, PCI, and CABG, body mass index, heart rate, systolic arterial pressure, left ventricular ejection fractions (LVEF), low-density lipoprotein cholesterol (LDL-C), C reactive protein (CRP), cardiac troponin I (cTnI) peak value, time from heart attack to reperfusion, myocardial blush grade (MBG) of 0–1 in the culprit artery, predilation rate, thrombotic lesion rate, rate of ≥ two-vessel lesions, collateral circulation rate, culprit lesion length, complex lesion rate, and degree of baseline stenosis between the two groups (all P > 0.05). There were significant differences in the degree of follow-up stenosis and the additional PCI rate between the two groups (P < 0.0001, P < 0.05, respectively) (Table 1).

Table 1.

Baseline clinical and angiographic characteristics (n = 200).

	High dosage group (n = 87)	Low dosage group (n = 113)	P
Age, yrs	57.21 ± 12.13	56.34 ± 12.18	NS
Male	56 (64%)	72 (64%)	NS
Diabetes mellitus	35 (40%)	45 (40%)	NS
HbA1C	6.3% ± 1.5%	6.4% ± 1.7%	NS
Hypertension	46 (53%)	59 (52%)	NS
Hyperlipidemia	23 (26%)	30 (27%)	NS
Current smoking	29 (33%)	38 (34%)	NS
Prior myocardium infarction	5 (6%)	6 (5%)	NS
Prior PCI	7 (8%)	8 (7%)	NS
Prior CABG	0	0	NS
BMI	26.87 ± 1.21	25.32 ± 1.33	NS
β-blockers	54 (62%)	73 (65%)	NS
Calcium antagonists	26 (30%)	32 (28%)	NS
Statins	80 (92%)	102 (90%)	NS
Heart rate, beats/min	83 ± 11	82 ± 15	NS
Systolic arterial pressure, mmHg	133 ± 23	131 ± 23	NS
LVEF, %	53 ± 12	53 ± 10	NS
E, pg/mL	268.54 ± 76.41	256.13 ± 77.33	NS
NE, pg/mL	2617.32 ± 732.53	2542.24 ± 769.46	NS
LDL-C, mg/dL	124 ± 39	124 ± 42	NS
CRP, mg/dL	3.36 ± 1.29	3.42 ± 1.28	NS
cTnI peak value, ng/mL	20.89 ± 3.78	23.12 ± 3.65	NS
Time from attack to reperfusion, min	370 ± 174	373 ± 180	NS
MBG 0-1	35 (40.23%)	47 (41.59%)	NS
Predilation rate	29 (33.33%)	36 (31.86%)	NS
Thrombotic lesion rate	21 (24.14%)	30 (26.55%)	NS
≥ 2 vessel lesion rate	41 (47.13%)	58 (51.33%)	NS
Collateral circulation rate	23 (26.44%)	30 (26.55%)	NS
Culprit lesion length, mm	29.2 ± 13.5	29.8 ± 13.4	NS
Complex lesion rate	35 (40.23%)	46 (40.71%)	NS
Baseline stenosis degree	32.8% ± 11.4%	34.5% ± 13.7%	NS
Folow-up stenosis degree	70.3% ± 14.1%	82.1% ± 15.3%	< 0.0001
Additional PCI rate	6.90%	17.70%	< 0.05

Data are presented as n (%) or mean ± SD unless other indicated. BMI: body mass index; CABG: coronary artery bypass grafting; CRP: C reactive protein; cTnI: cardiac troponin I; E: epinephrine; HbA1C: hemoglobin A1C; LDL-C: low-density lipoprotein cholesterol; LVEF: left ventricular ejection fractions; MBG: myocardial blush grade; NE: norepinephrine; NS: not significant; PCI: percutaneous coronary intervention.

For medications, patients received a similar amount of β-blockers (62% vs. 65%), calcium antagonists (30% vs. 28%), and statins (92% vs. 90%) in each group (all P < 0.05). There was no significant difference in epinephrine levels between the two groups (268.54 ± 76.41 vs. 256.13 ± 77.33 pg/mL, P > 0.05). There was no significant difference in NE levels between the two groups (Table 1). The percentage of patients with hyperlipidemia was low for more than 90% of patients who received statin treatment. All patients with diabetes received either metformin and/or a sulfonylurea. If the HbA1c value exceeded 7%, despite maximum doses of oral hypoglycemic agents, addition of insulin was recommended. In this study, hypertension was associated with ramipril treatment and the ramipril dosage. Calcium channel blockers were used apart from β-blockers and ramipril.

Among the groups, 26 patients received additional PCI for progression of nonculprit lesions and the mean degree of stenosis was 87.3% ± 10.5%. However, the degree of stenosis of nonculprit coronary lesions was 32.8% ± 10.4% in the setting of STEMI (87.3% ± 10.5% vs. 32.8% ± 10.4%, P < 0.01). Examination of the baseline morphological characteristics of nonculprit lesions showed that there were no significant differences among the four groups (high dosage control group, high dosage additional PCI group, low dosage control group and low dosage additional PCI group) (Table 2).

Table 2.

Baseline morphological characteristics of nonculprit lesions.

Type of lesion	High dosage control group (n = 81)	High dosage additional PCI group (n = 6 )	Low dosage control group (n = 93)	Low dosage additional PCI group (n = 20)	P
A	45 (56%)	2 (33%)	45 (48%)	7 (35%)	NS
B1	25 (31%)	2 (33%)	28 (30%)	7 (35%)	NS
B2	6 (7%)	1 (17%)	12 (13%)	4 (20%)	NS
C	5 (6%)	1 (17%)	8 (9%)	2 (10%)	NS

NS: not significant; PCI: percutaneous coronary intervention.

Follow-up of clinical characteristics and biomarkers in patients with progression of nonculprit lesions showed that the additional PCI group had higher catecholamine levels (P < 0.0001), CRP levels (P < 0.001), and ramipril dosage (P < 0.0001) than the control group (Table 3). There were no significant differences in systolic arterial pressure, HbA1c, rate of current smoking, BMI, LP (a) levels, LDL-C levels, triglyceride levels, high-density lipoprotein-C levels and the low high-density lipoprotein cholesterol rate between the control group and the additional PCI group. The rate of current smoking declined from 33% (n = 29) in the high dosage group and 34% (n = 38) in the low dosage group to 6% (n = 10) in the control group and 8% (n = 2) in the additional PCI group during follow-up. However, there was no significant difference between the control group and additional PCI group during follow-up (6% vs. 8%, P > 0.05) (Table 3).

Table 3.

Follow-up of clinical characteristics and biomarkers.

	Control group (n = 174)	Additional PCI group (n = 26)	P
E, pg/mL	210.41 ± 50.13	321.36 ± 49.32	< 0.0001
NE, pg/mL	1614.17 ± 324.15	2712.74 ± 401.57	< 0.0001
CRP, mg/dL	1.63 ± 0.54	2.03 ± 0.79	< 0.001
Systolic arterial pressure, mmHg	121 ± 14	124 ± 16	0.32
HbA1C	6.1% ± 1.3%	6.2% ± 1.2%	0.71
Current smoking	10 (6%)	2 (8%)	0.67
BMI	25.13 ± 1.32	25.02 ± 1.23	0.69
LP(a), mg/dL	28 ± 14	32 ± 13	0.17
LDL-C, mg/dL	118 ± 27	114 ± 25	0.48
TG, mg/dL	149 ± 61	162 ± 72	0.32
HDL-C, mg/dL	39 ± 16	44 ± 19	0.15
Low HDL cholesterol (< 40 mg/dL)	83 (48%)	14 (54%)	0.67
Ramipril, mg/day	3.24 ± 0.71	2.01 ± 0.23	< 0.0001

Data are presented as n (%) or mean ± SD unless other indicated. BMI: body mass index; CRP: C reactive protein; E: epinephrine; HbA1C: hemoglobina1c; HDL: high density lipoprotein; HDL-C: high density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; LP(a): lipoprotein a; NE: norepinephrine; TG: triglyceride.

Pairwise correlation analysis was carried out between the degree of stenosis of nonculprit lesions and four individual factors, including serum levels of epinephrine, NE, and CRP, and the dosage of ramipril. We found that serum epinephrine, NE, and CRP levels showed significant positive correlations, while the dosage of ramipril showed a significant negative correlation (correlation coefficients: 0.93, 0.97, 0.81, and −0.95, respectively; all P < 0.0001) (Table 4).

Table 4.

Correlation analysis between the degree of stenosis of nonculprit lesions and clinically correlated factors.

	Pearson correlation analysis
	Pearson Correlation coefficient	P
E, pg/mL	0.93	< 0.0001
NE, pg/mL	0.97	< 0.0001
CRP, mg/dL	0.81	< 0.0001
Ramipril, mg/day	–0.95	< 0.0001

CRP: C reactive protein; E: epinephrine; NE: Norepinephrine.

Discussion

PPCI in a culprit artery is the preferred strategy for treating patients with acute STEMI. However, approximately 40%–65% of patients with STEMI present with three-vessel lesions. A clinical follow-up study of patients with three-vessel lesions after successful PCI suggested that nonculprit lesions may be progressing.[1] This may be the most important factor that affects the prognosis of patients with acute myocardial infarction after successful PCI.

However, there have been few studies on progression of nonculprit lesions. Hanratty, et al.[5] demonstrated exaggeration of nonculprit lesions during acute myocardial infarction, and indicated that inflammation and a spasm mechanism may be involved in progression of nonculprit lesions. Tsiamis, et al.[6] performed follow-up angiography for 117 patients with acute coronary syndrome. These authors suggested that nonculprit lesions may have progressed, and acute myocardial infarction may be an independent predictive factor for progression of nonculprit lesions. Our follow-up study on progression of nonculprit lesions suggested that this progression may be the most important prognostic factor in patients with STEMI after successful PCI (Figures 3 & 4).[7] Our data suggested that progression of nonculprit lesions could involve inflammation and a stress mechanism. Using a rabbit ischemia–reperfusion model in our recent study, we showed that progression of nonculprit lesions could involve the angiotensin II–MAPK–Cx43 pathway.[2] Our previous study provided novel insights into the mechanism of progression of nonculprit lesions.

Figure 3.

Primary PCI for the culprit artery (LAD).

(A): Left coronary artery angiography before primary PCI; (B): left coronary artery angiography after primary PCI; and (C): righht coronary artery (nonculprit artery) angiography. The arrow indicates a coronary artery lesion. LAD: left anterior descending artery; PCI: percutaneous coronary intervention.

Figure 4.

Follow-up angiography in 12 months.

(A): Left coronary artery angiography; (B): right coronary artery angiography. The arrow indicates a coronary artery lesion.

In the present study, we investigated the effect of ramipril on progression of nonculprit lesions in patients with STEMI after PPCI. We carried out a 12-month clinical and angiographic follow-up in 200 patients, and found that the rate of additional PCI in the high dosage group was lower than that in the low dosage group. This result indicates that a high dosage of ramipril may inhibit progression of nonculprit lesions, which could be the main cause of revascularization after PPCI for patients with STEMI.

In our study, there were no significant differences in the patients' characteristics and medical history between the high and low dosage groups. Additionally, all patients received comparable medication. There were also no significant differences in baseline morphological characteristics of nonculprit lesions among the four groups (Table 2). In the present study, Follow-up of biomarkers and the dosage of ramipril in patients with progression of nonculprit lesions showed that patients with sustained stress, chronic inflammation, and dosage of ramipril may be involved in additional PCI.[8],[9]

Our recent animal experiments showed that sympathetic nerve—catecholamines—angiotensin II-Cx43 may participate in progression of nonculprit arteries.[8],[9] Angiotensin-converting enzyme inhibitors may inhibit progression of nonculprit arteries. These possibilities may lead to new therapeutic targets for progression of nonculprit arteries.

In our study, we found that that serum level of epinephrine, NE, and CRP, and the dosage of ramipril may be clinical correlation factors of progression of nonculprit lesions. These findings indicated that the renin–angiotensin system was activated because the neuroendocrine axis was activated (serum catecholamine levels were increased) and hemodynamics were altered in patients with acute STEMI after PPCI.[10]–[12] Increased angiotensin II levels may affect signal transduction of the MARK pathway via autocrine, paracrine, and emiocytosis effects (or via microcirculation between the culprit artery and nonculprit artery). This could lead to upregulation of Cx43 expression, smooth muscle cell proliferation and migration, and progression of atherosclerotic lesions. Ramipril may prevent progression of nonculprit lesions by inhibiting the renin–angiotensin system.

Exercise training could play a significant role in progression of atherosclerosis. However, almost all patients in our study did not start formal exercise training because they did not know about formal exercise training and cardiac rehabilitation. Cardiac rehabilitation may be important for patients and further efforts for cardiac rehabilitation are required.

In conclusion, recurrent PCI is mainly due to progression of nonculprit lesions in patients with STEMI after PPCI. Chronic inflammation and sustained stress may be involved in progression of nonculprit lesions in patients with STEMI. Ramipril may prevent progression of nonculprit lesions.