Optimization of Myocardial Perfusion after Primary Coronary Angioplasty following an Acute Myocardial Infarction. Beyond TIMI 3

Primary angioplasty has become the preferred therapeutic modality in patients with acute myocardial infarction (AMI). Despite a rapid and sustained restoration of flow through a previously occluded epicardial coronary artery, perfusion at the myocardial level is inadequate in about 25–30% of cases.¹ The exact mechanisms underlying the microvascular dysfunction are not fully understood, but more recent evidence suggests that vasospasm in the myocardial vascular bed, due to platelet-derived vasoconstrictors and/or systemic release of agents such as endothelin, play a central role.² Thus, despite restoration of antegrade epicardial flow by mechanical reperfusion therapy, the angiographically assessed myocardial perfusion, or myocardial blush, allows stratification of patients with epicardial TIMI 3 flow into different strata of survival, with significant impact on mortality.3 Since the recognition of the important role of this type of microvascular dysfunction in patients with AMI, an efficacious treatment has not yet been established. There have been no systematic studies comparing the efficacy of different agents acting on the attenuation of microvascular dysfunction in patients with AMI in whom an epicardial TIMI 3 flow was achieved by primary percutaneous coronary intervention (PCI). We sought to determine the efficacy of 3 different vasodilatory agents on myocardial perfusion (angiographic blush) in patients with AMI undergoing primary PCI. Methods Study population. From August 2003 to December 2003, a cohort of 40 patients, mean age 62 years, presenting within 12 hours of symptom onset, typical chest pain lasting more than 30 minutes, ST-segment elevation > 0.2 mV in at least two consecutive electrocardiographic leads, were treated with primary PCI in our center. Included were all patients in whom TIMI 3 flow in the epicardial infarct-related artery (IRA) evaluated by the TIMI corrected frame count (cTIMI fc) was achieved, but had suboptimal angiographic myocardial blush. Patients requiring multivessel PCI, those with a history of prior MI in the same territory, those referred for rescue PCI after failed thrombolysis, patients in whom it was not possible to establish an open IRA, and patients needing PCI on saphenous vein grafts, were excluded. Study design. The study is a single-blind, open label, prospective, randomized, single-center pilot study of intracoronary (IC) treatment with 1 of 4 agents: nitroglycerin, adenosine, verapamil and nitroprusside. A total of 40 patients undergoing primary PCI for AMI were enrolled. Ten patients were assigned to each of the treatment groups. Angiographic TIMI myocardial perfusion grade (TMP), or myocardial blush scoring. Angiographic myocardial blush was graded densitometrically based on visual assessment of relative contrast opacification of the myocardial territory subtended by the infarct vessel in relation to epicardial density, as described by van’t Hof A. and Suryapranata H.⁴Blush score 0: absence of contrast opacification in the myocardial zone; Blush score 1: minimal contrast opacification or persistent stain without washout. The dye staining is present on the next injection (approximately 30 seconds between injections), meaning failure to exit the microvasculature; Blush score 2: reduced but clearly evident blush in the infarct zone compared to the contralateral noninvolved epicardial vessel(s); Blush score 3: normal entry and exit of dye from the microvasculature. The opacification of the myocardium clears normally at the end of the washout phase, similar to that in the noninvolved territory. From multiple orthogonal projections, the single best view was chosen, isolating the myocardial zone in question, most commonly the right anterior oblique (RAO) view with cranial angulation for the left anterior descending artery (LAD) distribution, the RAO with caudal angulation for the left circumflex artery (LCx), and either the left anterior oblique (LAO) or RAO projections for the right coronary artery (RCA) distribution. For this analysis, blush grades were scored by a physician not involved in the TIMI flow analysis. Treatment groups. The study was approved by our Institutional Review Board. Once informed consent was obtained (from the patient or an authorized surrogate), and a TIMI 3 epicardial flow was achieved by primary PCI, eligible patients showing a TMP grade Standard therapy. All patients were treated with upstream administration of glycoprotein (GP) IIb/IIIa inhibitors, and intravenous administration of unfractionated heparin, 60–70 units/Kg, to achieve an activated clotting time between 250–300 seconds. Patients also received oral aspirin 325 mg and oral clopidogrel in a loading dose of 300 mg. Hemodynamic support, when needed at the cath lab, involved repeated injections of norepinephrine at doses of 8 mcg each, until a systolic blood pressure greater than or equal to 100 mmHg was achieved. A temporary pacemaker electrode was implanted provisionally in the right ventricle in patients requiring primary PCI of an occluded RCA or a dominant LCx. The use of intra-aortic balloon pump counterpulsation was liberal and encouraged. Follow-up. Clinical follow-up was obtained at 30 days after the procedure at the outpatient clinic. Assessment of systolic and diastolic left ventricular (LV) function and LV dimensions was performed by 2-D echocardiography at baseline in the ICCU upon admission and at 30 days. The physician who performed the echocardiography studies was blinded to the assigned treatment group and to the results of the interventional procedure. Primary endpoint. The primary endpoint was the difference in safety and efficacy in achievement of TMP grade 3 between each of the study agents and the IC injection of nitroglycerin (control group) as assessed semiquantitatively by coronary angiography. The study was not powered to compare among the different agents in a head-to-head fashion. Secondary endpoints. Secondary endpoints were the summation of ST-segment resolution up to 30 minutes after the interventional procedure and its correlation with the TMP grade achieved and the changes in LVEF at one month compared to the baseline echocardiography. Statistical analysis. Comparisons were performed between each of the treatment groups and the control group. Continuous variables were expressed as the mean ± SD. Comparison of continuous variables was performed by using the unpaired Student’s t-test. Categorical variables were expressed as frequency (%), and the results were compared by Chi-square statistics. Differences were considered statistically significant at p Demographic characteristics. (Table 1). There were no significant differences in baseline characteristics between each of the treatment groups and the control group (Table 1). The mean age was 62 years, and approximately one-third in each group were diabetics. The majority presented with anterior MI. At admission, only one-third of the patients showed Killip class > 2, with a mean baseline LVEF by echocardiography ranging from 30–35%. Angiographic and procedural characteristics. (Table 2). The LAD was the most frequent target vessel. Taking the 3 investigational groups as a whole and comparing them with the control group (nitroglycerin group), there were no differences in the corrected TIMI frame count, with 35.4 in the control group versus 35.2, representing TIMI 3 antegrade flow in the target vessel in both arms before randomization. No significant differences were noted with respect to GP IIb/IIIa antagonist use or the insertion of an intra-aortic balloon. Primary endpoint. TMP grade scoring. The differences in the TMP grade are shown in Tables 3, 4 and 5. Even in this small sample size, there was a significant difference between the pre- and postprocedure TMP grades in the nitroprusside group compared to the control group (3 versus 1.8; p = 0.023). In the adenosine group, there was a clear trend toward a better TMP grade (2.37 versus 1.8; p = 0.28), but this did not reach statistical significance. In comparison with the control group, verapamil did not show any beneficial effect on the TMP grade. The assessment of the TMP grade is demonstrated in Figures 1 and 2. Secondary endpoints: ST-segment resolution summation. The sum of ST-segment resolution up to 30 minutes after the procedure was 8 mm in the control group, 15 mm with nitroprusside, 12 mm with adenosine and 12.6 mm with verapamil. In regard to this important parameter of procedural effectiveness, a trend in favor of the nitroprusside-treated group was observed, but had no statistical significance. LVEF at one month. Table 6 underlines the statistical significant improvement in LVEF in the nitroprusside group compared with the control group. This interesting finding in the change in global LVEF in this small cohort favoring the nitroprusside-treated group makes this drug an attractive target for future investigation. There were no significant differences in the values of baseline LVEF among groups at admission to the ICCU. Discussion The exact mechanisms underlying microvascular dysfunction leading to impaired myocardial perfusion in the presence of TIMI 3 flow in the epicardial artery in the setting of AMI are not fully understood. Recent data suggest that vasospasm in the vascular bed due to platelet-derived vasoconstrictors and/or systemic release of agents such as endothelin-1 play an important role.⁵ Also, profound vasospasm may be caused by the release of potent vasoconstrictors from cellular elements, like neutrophils contained within the thrombus. In addition, recent studies focused on the critical role of inflammatory mediators leading to microvascular dysfunction and reperfusion injury. The microvascular damage was demonstrated by the elevation of ICAM-1, P-selectin, endothelin-1, release of free radicals and interstitial edema with mechanical compression of involved areas.⁶ Furthermore, it was demonstrated that the activation of coagulation pathways with microthrombi and plugging of the arterioles causes significant obstruction of antegrade flow.⁷ Abnormal postprocedure myocardial perfusion with normal flow at the infarct-related epicardial artery, evaluated by angiographic TMP or myocardial blush, correlates with in-hospital and cumulative mortality. In patients in whom TIMI 3 flow was restored, the degree of myocardial perfusion correlated with early and late survival;⁸ this relationship was especially strong in patients with cardiogenic shock. The recognition of the important role of this microvascular dysfunction on infarct size and outcome led to the development of several approaches, including intracoronary or intragraft injections of verapamil, nitroglycerin, urokinase, papaverin, nitroprusside, high-velocity injections of adenosine and systemic abciximab, with different results.^9–13 Our study shows that only the IC injection of nitroprusside had an advantage in achieving TMP grade 3 as compared with IC injection of nitroglycerin. In addition, in the nitroprusside group, a trend toward better ST resolution at 30 minutes after the interventional procedure was observed. In addition, this arm of the study showed a statistically significant beneficial effect on LVEF at 30 days. The achievement of TMP grade 3 and the benefit in LVEF observed with nitroprusside compared with the standard IC injection of nitroglycerin are of potential importance. A possible explanation for the superiority of nitroprusside, as was shown in our study, is based on the metabolism of the nitric oxide. Nitric oxide is an endothelium-derived compound that has multiple vascular functions, including vasodilatation, inhibition of platelet adhesion and anti-inflammatory activity. As a potent vasodilator in the resistance arteriolar circulation, it plays a significant role in the control of coronary blood flow through the microcirculation.¹⁴ The metabolism of nitroglycerin by the vascular wall is necessary to derive nitric oxide. However, resistance arterioles are unable to convert nitroglycerin into nitric oxide as large nonresistance vessels do.¹⁵ Nitroprusside is a direct donor of nitric oxide and is reported to require no intracellular metabolism to derive nitric oxide, suggesting a potent vasodilatory effect, especially at the microcirculatory level.¹⁶ This fact may account for the greater benefit obtained with nitroprusside in our study. On the other hand, adenosine is a nucleoside that functions by release of nitric oxide from intact vascular endothelial cells, and thus, like nitroglycerin, requires normal intracellular metabolism. This intracellular pathway at the microvascular level is profoundly altered in the setting of AMI, as is also the case with the different pathways of adenosine biosynthesis: the intracellular ATP pathway, the extracellular ATP pathway, the transmethylation pathway, and the cyclic AMP-adenosine pathway at the vascular smooth muscle level.^17,18 In regard to verapamil, Yoshiaki et al.¹⁹ found that verapamil could not totally reverse microvascular dysfunction. The direct effect of verapamil on calcium flux across the sarcolemmal membrane or within intracellular compartments might be attenuated by other factors contributing to no-reflow, such as neutrophil plugging and endothelial blistering, which are not reversed by verapamil.²⁰ In this study, the IC injection of adenosine and verapamil failed to show a beneficial effect on myocardial perfusion compared to nitroglycerin. Study limitations. There area several limitations in this study. First, our findings are derived from a small sample size of patients. Second, this is a single-center study, without the review of a core laboratory. The angiographic TMP grade was evaluated semiquantitatively by visual estimation of the coronary angiography, meaning the possible confounder of the error inherent in the operator’s evaluation. Conclusion Despite these limitations, our results indicate that IC injection of sodium nitroprusside in at least 3 independent doses of 120 µg in the setting of primary coronary angioplasty in AMI, compared with the routine administration of IC nitroglycerin, was more beneficial in reaching a TMP 3 grade score. Also, sodium nitroprusside was the most helpful agent in achieving ST-segment resolution 30 minutes after the procedure. Finally, there appears to be a trend toward a significant improvement in the global LVEF at one month. We can conclude that effective treatment of microvascular dysfunction and of myocardial perfusion beyond the patency of the infarct-related epicardial artery may have a beneficial effect on LVEF, and thereby on acute and long-term outcomes.

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