Effect of Chronic Pretreatment of Angiotensin-Converting Receptor Blocker on No-Reflow Phenomenon in Patients with Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention
Ling Tao, M.D., Ph.D., Department of Cardiology, Xijing Hospital, Fourth Military Medical University, No.15 Changle West Road, Xi’an 710032, China.
Aims: Angiotensin receptor blockers (ARBs) exert favorable effects on the vascular system, which are not directly related to hypertension lowering function. The no-reflow phenomenon determines the prognosis in patients after acute myocardial infarction (AMI). Early ARB treatment has many beneficial effects on the prognosis after AMI. In this study, we tested the hypothesis that ARB treatment before admission would have beneficial effects on the development of the no-reflow phenomenon after infarction. Methods: We investigated 276 consecutive patients with AMI undergoing successful primary percutaneous coronary intervention (PCI). No-reflow was defined as thrombolysis in myocardial infarction (TIMI) flow grade <3, which was determined by the TIMI frame count method using angiographic images obtained just after PCI and stenting. Results: Compared with patients without ARB treatment, patients with ARB had more frequently hypertension and ST resolution (P < 0.05), but no significant difference was found in the other clinical characteristics (age, sex, Hyperlipidaemia, Diabetes mellitus, etc) between the two groups. A total of 51 patients receiving chronic ARB treatment before admission have lower incidence of the no-reflow phenomenon than those without chronic ARB treatment (8.7% and 26.7%, P= 0.003). However, the incidence of the no-reflow phenomenon between the patients with and without hypertension had no significant difference. Multivariable logistic regression analysis revealed that ARB pretreatment was a significant predictor of the no-reflow phenomenon, whereas blood pressure was found to be insignificant. Conclusion: Chronic pretreatment of ARB is associated with the reduction of the no-reflow phenomenon in patients with reperfused AMI and could preserve microvascular integrity after AMI independent of blood pressure lowering, which may contribute to better functional recovery.
Primary percutaneous coronary intervention (PCI) is the current preferred treatment for acute myocardial infarction (AMI) . Although shown to be extremely important in maintaining epicardial artery patency in AMI, the attention has shifted recently from epicardial artery patency to the status of the microvasculature . Previous studies have shown that 5–30% of patients treated with primary PCI fail to achieve thrombolysis in myocardial infarction (TIMI) flow grade 3 after successful opening of the artery without angiographic evidence of the mechanical obstruction. This phenomenon is deemed as no-reflow, which determines the prognosis in patients after AMI . Several mechanisms responsible for no-reflow have been identified in experimental models, including extravascular compression, microvascular vasoconstriction, and platelet/leukocyte capillary plugging .
Previous evidence suggests that angiotensin receptor blockers (ARBs) have multiple favorable effects on the vascular system not directly related to their effect on blood pressure . However, to the best of our knowledge, there is insufficient data regarding the effects of prior ARB use on coronary blood flow after primary PCI in patients with AMI. Accordingly, this study aims to evaluate the impact of prior ARB use on coronary blood flow after PCI in patients with AMI.
Material and Methods
The study population consisted of 276 consecutive patients with first AMI. The patients were selected from those eligible for this study and treated by primary PCI from January 2004 to December 2008 at Xijing Hospital, China. AMI diagnosis was based on prolonged chest pain (>30 min), ST-segment elevation of ≥1 mm in at least two contiguous electrocardiography leads, and greater than 2-fold increase in serum creatine kinase levels, which was established using the American College of Cardiology/European Society of Cardiology criteria. Patients with previous coronary artery bypass surgery and angioplasty were excluded. In addition, patients undergoing PCI of SVGs, left main disease, severe chronic heart failure, severe valvular heart disease, cardiogenic shock, thrombolytic therapy before angioplasty, pain to balloon time over 12 h, acute or chronic renal impairment (serum creatinine >2 mg/dL), and known malignancy were not included. All clinical data were collected prospectively. The study population was divided into two groups, according to ARB use for at least for 6 months before primary PCI. ARB use was assessed by talking to the patients and examining their outpatient follow-up charts. A clinical history of risk factors, echocardiography, and blood chemistry results were determined from the detailed interview or medical records. This study was approved by the Local Ethics Committee of Xijing Hospital, Fourth Military Medical University, China. Written informed consent was obtained from all participants.
Upon admission, all patients received 300 mg oral aspirin daily, a starting dose of 300 mg or 600 mg of clopidogrel, and 75 mg as maintenance dose. Primary PCI was performed as quickly as possible. The use of other medications, including tirofiban, was at the discretion of the attending operator.
Coronary Intervention and Angiographic Analysis
After intravenous heparin (100 U/kg) administration, coronary angiography (GE Healthcare, New York, USA) was performed using the right radial/femoral approach to determine the culprit lesion and collateral channels in multiple orthogonal projections using Judkins’ technique. Thrombectomy or distal embolic protection was not used.
Stenting following coronary intervention with angioplasty using appropriately sized balloon catheters was accomplished by standard techniques, no including aspiration thrombectomy. The technical aspects of the procedure, duration, and pressure of inflation were determined by individual operators. To achieve maximal dilatation, each coronary angiogram was preceded by 200 μg nitroglycerine intracoronary injection. No-reflow was defined as a TIMI flow of <3 in the absence of evident vessel dissection, obstruction or distal vessel embolic cutoff . The rate of direct stenting was approximately 20%. All angiographic analyses were performed offline in chronological order by the same experienced group. The administering group was unaware of the patients’ data.
A 12-lead ECG was recorded from all patients before and after each PCI procedure. The sum of ST elevation was assessed in three contiguous leads in the infarct zone, 60 ms from the J point. To minimize the effect of the different number of leads involved, the sum was divided by the number of leads presenting ST-segment elevation (∑ST index ∑STI). The extent of the ST segment resolution was assessed after primary PCI and expressed as a percentage of the ST elevation (at least 50% decrease, compared with the baseline ∑STI) measured on the ECG recorded before primary PCI. All ECGs were analyzed in a blinded fashion by the same experienced group.
A pilot trial was done to determine the sample size for the study. Categorical data are presented as absolute values and percentages, whereas continuous data are described as mean ± standard deviation (SD). Differences in the metric variables between groups were analyzed using Student's t-test. Analysis of covariance (ANCOVA) was used to analyze the confounding effects of variables on comparisons of the groups according to ARB use before primary PCI. The ANCOVA variables included age, blood pressure, serum total cholesterol, LDL cholesterol, heart rate, pain to balloon time, left ventricular ejection fraction, residual percentage stenosis, lesion length, vessel diameter, and vessel type. The prediction power of ARB pretreatment for the no-reflow phenomenon was calculated using the multivariate logistic regression analysis. All statistical processes were performed using SPSS 13.0 Statistical Package Program for Windows (SPSS-PC Inc., Chicago, IL, USA). Differences and correlations were considered significant at P < 0.05.
A total of 276 patients (mean age, 61 ± 10) were enrolled in this study. The median of the time from the symptomatic onset to coronary reperfusion was 6.5 ± 4.4 h. The study population was divided into two groups according to ARB use for at least 6 months before primary PCI. Comparison of the baseline clinical characteristics (such as age, gender, initial TIMI flow grade, time from symptom onset to restoration, heart rate on admission, coronary risk factors, global left ventricular systolic function, renal function, distribution of target vessel, use of intravenous or intracoronary tirofiban, physical findings on admission, and baseline ∑STI) of patients in group 1 with those in group 2 showed no statistically significant difference (Table 1).
Table 1. Baseline clinical, lesion, and procedural characteristics of the patients
|Age, years||62 ± 6||61±7||0.13|
|Sex (M) n (%)||196 (84)||35 (85)||0.74|
|Hypertension n (%)||108 (46)||21(51)||0.22|
|Hyperlipidaemia n (%)||129 (55)||21(51)||0.62|
|Diabetes mellitus n (%)||73 (31)||14 (34)||0.78|
|Family history n (%)||26 (11)||5 (12)||0.32|
|Smoking n (%)||143 (61)||27 (66)||0.52|
|Left ventricular ejection fraction (before PCI), %||51 ± 9||48 ±11||0.11|
|Creatinine, mg/dL||0.8 ± 0.2||1.1 ± 0.4||0.63|
|Blood glucose, mg/dL||142 ± 57||221 ± 72||0.001|
|C-reactive protein, mg/dL||1.1 ± 0.4||3.3 ±1.6||0.004|
|Troponin-T, ng/mL||1.3 ± 2.0||4.8 ± 3.5||0.002|
|Creatine kinase-MB, U/L||99 ± 86||103 ± 94||0.87|
|Low density lipoprotein cholesterol, mg/dL||120 ± 31||116 ± 28||0.28|
|Symptom onset-reflow time, h||5.8 ± 4.9||7.1 ± 5.1||0.007|
|Target coronary artery|| || ||0.21|
|Left anterior descending n (%)||92 (39)||17 (42)|| |
|Left circumflex n (%)||38 (16)||5(12)|| |
|Right n (%)||105 (45)||19 (46)|| |
|Tirofiban use n (%)||61 (26)||15 (36)||0.24|
|Initial TIMI flow grade 0 n (%)||161 (69)||37 (90)||0.001|
|Stent diameter, mm||3.1 ± 0.3||3.3 ± 0.2||0.12|
|Stent length, mm||19.9 ± 4.0||21.8 ± 4.8||0.37|
|Number of Q-waves||1.7 ± 1.3||3.1 ±1.8||0.008|
|Baseline ∑STI, mV||0.33 ± 0.19||0.30 ± 0.15||0.73|
|Medication before AMI|| || || |
| ARB pretreatment n (%)||49 (21)||2 (5)||0.003|
| Irbesartan (150 mg)||17||1|| |
| Valsartan (80 mg)||14||1|| |
| Losartan (50 mg)||12|| || |
| Candesartan (8 mg)||6|| || |
|Statin pretreatment n (%)||44 (19)||3 (7)||0.006|
| β-blocker pretreatment n (%)||28 (12)||5 (12)||0.38|
| Aspirin pretreatment n (%)||86 (37)||16 (39)||0.51|
|Single-vessel disease n (%)||163 (69)||26 (63)||0.42|
|Double-vessel disease n (%)||68 (29)||14 (34)||0.49|
|Three-vessel disease n (%)||4 (2)||1 (3)||0.35|
|Time for emergency room presentation, min||20 ± 5.6||60 ± 3.9||0.007|
The ST segment resolution in patients taking ARB before PCI was better than that in patients without ARB (83% vs. 71%; P = 0.006). Furthermore, a statistically significant negative correlation was observed between the no-reflow phenomenon and ST segment resolution (r =−0.59; P < 0.001). Among the patients, 41 (14.9%) showed no-reflow phenomenon. The no-reflow group had higher blood glucose upon admission, higher high-sensitivity C-reactive protein, higher troponin-T, prolonged symptom onset-reflow time, higher number of Q-waves, longer time for emergency room presentation, and more initial TIMI 0 flow than the normal reflow group (Table 1). The incidence of no reflow was significantly lower in patients with ARB than in those without it (6% vs. 17%; P = 0.004; Table 2). Multivariate logistic regression analyses of the association between the angiographic no-reflow phenomenon and multiple parameters are listed in Table 3. The absence of ARB pretreatment was an independent predictor of the no-reflow phenomenon, along with anterior wall infarction, high-burden thrombus, lack of preinfarction angina, initial TIMI 0 flow, absence of statin pretreatment, and the number of Q-waves.
Table 2. Clinical characteristics of patients with or without ARB
|Age, years||61 ± 7||60 ± 5||0.18|
|Sex (M) n (%)||185 (82)||39 (77)||0.52|
|Hypertension n (%)||88 (39)||41 (80)||0.002|
|Hyperlipidaemia n (%)||121 (54)||29 (57)||0.42|
|Diabetes mellitus n (%)||72 (32)||15 (30)||0.74|
|Family history n (%)||25 (11)||6 (12)||0.86|
|Smoking n (%)||141 (63)||29 (57)||0.11|
|Left ventricular ejection fraction, %||53 ± 9||51 ± 11||0.26|
|Creatinine, mg/dL||1.1 ± 0.3||0.9 ± 0.5||0.23|
|Blood glucose (mg/dL)||152 ± 57||163 ± 42||0.75|
|C-Reactive protein, mg/dL||1.2 ± 0.4||1.3 ± 0.6||0.33|
|Troponin-T, ng/mL||1.9 ± 2.0||2.2 ± 3.5||0.34|
|Creatine kinase-MB,U/L||92 ± 83||98 ± 97||0.13|
|Low density lipoprotein cholesterol, mg/dL||117 ± 26||123 ± 31||0.58|
|Symptom onset-reflow time, h||6.1 ± 4.2||6.3 ± 5.3||0.70|
|No-reflow, n (%)||38 (17)||3(6)||0.004|
|ST-segment Resolution n (%)||160 (71)||42 (83)||0.006|
|Tirofiban use n (%)||52 (23)||24 (47)||0.35|
|Initial TIMI flow grade 0 n (%)||163 (72)||35 (69)||0.62|
|Baseline ∑STI, mV||0.35 ± 0.17||0.32 ± 0.15||0.54|
|Medication before AMI|| || || |
| Statin pretreatment n (%)||41 (18)||8 (16)||0.26|
| β-blocker pretreatment n (%)||27 (12)||6 (12)||0.37|
| Aspirin pretreatment n (%)||83 (37)||19 (37)||0.39|
Table 3. Independent predictive factors for no-reflow phenomenon
|Anterior wall infarction||3.65||1.12–17.03||0.03|
|Lack of preinfarction angina||2.76||1.78–6.29||0.02|
|Initial TIMI flow grade 0||3.42||1.98–7.32||0.001|
|Number of Q-waves||1.79||1.54–2.89||0.03|
|Absence of Statin pretreatment||1.62||1.25–2.17||0.021|
|Absence of ARB pretreatment||2.67||1.82–9.79||0.002|
Rapid restoration of coronary flow to the jeopardized myocardium has become an essential part of the therapy after AMI. The no reflow phenomenon, defined as low or no distal perfusion despite the removal of epicardial occlusion, occurs commonly during acute PCI in patients with AMI. This complication is associated with substantial morbidity and mortality after PCI in patients with AMI, and needs to be recognized and treated promptly . The pathophysiological mechanisms leading to the no-reflow state are not completely understood. The possible mechanisms are the embolization of the atheromatous material to the distal vasculature and intense arteriole vasospasm caused by microembolization of platelet-rich thrombi that release vasoactive agents resulting in microvascular obstructions. These mechanisms are characterized by localized and diffused capillary swelling and arteriolar endothelial dysfunction. In addition, leukocytes become activated and attracted to the lumen of the capillaries. They exhibit diapedesis and may contribute to cellular and intracellular edema and clogging of vessels. During perfusion, the sudden rush of leukocytes and distal atheroemboli further contributes to tissue impairment .
Every effort should be taken to reduce the incidence of the abovementioned complication [9,10]. The current prophylaxis and management strategies are derived from limited clinical data. Intracoronary verapamil, adenosine, and nitroprusside have been studied and administered most frequently for angiographic no-reflow during PCI for AMI lesions and have been shown to improve epicardial flow and microvascular perfusion. The use of distal embolic protection devices in saphenous vein graft interventions also provide microvascular protection and improve clinical outcomes, although not in native coronaries. However, by far, the most important measures are the prevention and anticipation during PCI because once the no-reflow phenomenon is established; the situation may not be reversed completely.
The physiological role of the renin–angiotensin–aldosterone system is to maintain the integrity of the cardiovascular system. Angiotensin II is deeply involved in the vasoconstriction, oxidative stress, inflammation, thrombosis, vascular remodeling, and sympathetic nerve activity. The effect of angiotensin II is mediated via the angiotensin type I receptor (AT1). ARBs, which specifically inhibit the AT1 receptor, effectively interfere with the renin–angiotensin system and exert various beneficial actions on cardiac and vascular structure and function beyond their blood pressure-lowering effects . Randomized, controlled clinical trials  have shown that ARBs improve endothelial function, and cardiac and vascular remodeling; retard the anatomic progression of atherosclerosis; and reduce the risk of myocardial infarction, stroke, and cardiovascular death. Therefore, the development of ARB as a new class of drugs for the management of hypertension has elicited the attention of many clinicians worldwide with the aim of improving blood pressure control and cardiovascular protection. These properties are coupled with cardioprotective effects and documented by the evidence that the drug: (1) is effective in favoring the regression of cardiac and vascular organ damage, (2) reduces arterial stiffness and improves vascular distensibility, and (3) reverses the endothelial dysfunction typical of the hypertensive state, particularly when complicated by renal failure, diabetes, obesity or metabolic syndrome. The inhibition of the renin–angiotensin–aldosterone system with ARBs after AMI has been shown to reduce cardiovascular morbidity and mortality.
In clinical therapy, ARB is well tolerated as an antihypertensive drug. After AMI and in stable coronary heart disease, ARB has been shown to reduce mortality in a manner independent of hemodynamic alterations. According to the ESC guidelines, ARB should be used in all patients without contraindications who do not tolerate ACE-inhibitors, regardless of blood pressure or LV function (IIa) . As such, the general clinical efficacy of ARB may be because of a positive influence on hemodynamic load, vascular function, myocardial remodeling, and neurohumoral regulation, rather than a direct attenuation of the atherosclerotic process . In our study, we have shown that prior ARB use for at least 6 months before PCI in patients with AMI has some beneficial effects on coronary blood flow, as demonstrated by TIMI flow grade. This finding suggests that prior long-term ARB use in patients with AMI who have undergone PCI may contribute to the adequate perfusion at the myocardial tissue level by preventing or treating microvascular dysfunction. The proposed mechanism of the no-reflow phenomenon after primary angioplasty is multifactorial, including endothelial damage, microvascular spasm, tissue edema, microembolization of thrombotic material, and plaque fragments. These factors determine the damage to the microcirculation during both the ischemic and reperfusion phases. The precise mechanism by which ARB is beneficial in the reduction of the no-reflow phenomenon remains unclear. Several studies demonstrate that endothelial dysfunction could be a cause of the no-reflow phenomenon after infarction. ARB has been shown to be effective in improving endothelial function . Therefore, the restoration of endothelial dysfunction with ARB may be associated with the prevention of the no-reflow phenomenon. These pleiotropic effects could also contribute to the preservation of microvascular function during ischemia and reperfusion.
ST segment resolution seems to reflect not only epicardial flow, but also the restoration of myocardial tissue perfusion. Rapid ST segment resolution within 30–60 min of successful primary PCI has been proven to predict greater improvement in ejection fraction, reduced infarct size, and improved survival, compared with delayed ST segment resolution . The degree of ST segment resolution after reperfusion therapy is a reliable, noninvasive predictor of mortality. Rapid ST segment resolution after successful primary PCI correlates with microvascular reflow. In this study, we found that the ST-segment resolution in patients taking ARB before primary PCI was better than that of patients without ARB. Furthermore, statistically significant negative correlation was observed between the ST-segment resolution and no-reflow phenomenon. We conclude that these clinical findings may support the beneficial effects of prior ARB use before primary PCI on microcirculation. Further large-scale prospective randomized clinical trials are needed to elucidate the underlying mechanisms and clinical importance of these findings.
Conflict of Interest
The authors declare no conflict of interest.