Impact of Chronic Total Coronary Occlusion on Microvascular Reperfusion in Patients With a First Anterior ST-Segment Elevation Myocardial Infarction

Abstract: Background. We investigated an impact of the presence of chronic total coronary occlusion (CTO) in a non-infarct related coronary artery on microvascular reperfusion in patients with a first anterior ST-segment elevation myocardial infarction (STEMI) who underwent percutaneous coronary intervention (PCI). Methods. In accordance with the presence or absence of CTO in a non-infarct related coronary artery, we analyzed Thrombolysis in Myocardial Infarction myocardial perfusion (TMP) grade on a scale of 0 to 3, with higher scores indicating better perfusion, and ST-segment resolution in sum of lead I, aVL, and V1 through V6 to evaluate microvascular reperfusion in a total of 140 consecutive patients with a first anterior STEMI. Results. We identified CTO in 15 patients (11% of total). The incidence of impaired microvascular reperfusion was greater in patients with CTO vs without CTO, defined as TMP grades 0 or 1 together with <30% ST-segment resolution (33% vs 6%, respectively; P=.0006) and the enzymatic infarct was larger (10304 ± 8060 IU/L vs 6804 ± 4959 IU/L; P=.009). Logistic regression analysis revealed that CTO is closely associated with incidental impaired microvascular reperfusion (odds ratio, 6.801; 95% confidence interval, 1.284-36.209; P=.024). Conclusion. The presence of CTO in a non-infarct related coronary artery might confer a considerable disadvantage upon microvascular reperfusion and result in adverse clinical outcomes of PCI for a first anterior STEMI.

J INVASIVE CARDIOL 2012;24(9):428-432

Key words: ST-segment elevation myocardial infarction, percutaneous coronary intervention, microvascular reperfusion, chronic total coronary occlusion

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The reported prevalence of chronic total coronary occlusion (CTO) in the community hospital setting is 15%-30%.^1,2 A recent large cohort study found that CTO has a profoundly adverse impact on the 1-year mortality rates among patients who undergo percutaneous coronary intervention (PCI) to treat ST-segment elevation myocardial infarction (STEMI) with multivessel disease.³ So far, however, it remains unknown why the presence of CTO manifests adverse clinical outcomes in patients undergoing PCI for STEMI.

The level of microvascular reperfusion provides the key role in the determination of clinical features of patients with STEMI who underwent PCI.^4,5 Pathological microvascular changes are starting during ischemia and might  become aggravated during reperfusion.^6,7 Under the presence of CTO condition, a discrepancy between myocardial oxygen supply and demand might arise not only in the CTO territory but also in the remote territory functioning  as a collateral supplement, resulting in chronic myocardial ischemia. Because subclinical chronic ischemia due to CTO might affect microvascular changes before the onset of STEMI,⁸　we speculated that microvascular reperfusion might worsen during PCI for STEMI when CTO was present in a non-infarct related artery.

Methods

Study patients. Based on the notion that early revascularization with PCI might confer significant prognostic advantages, especially in the setting of anterior STEMI,⁹ we studied 140 consecutive patients (112 men, 64 ± 13 years) with a first anterior STEMI who presented within 12 hours of the onset of symptoms of proximal occlusion of the left anterior descending (LAD) coronary artery. All of the patients had ST-segment elevation >1 mm (0.1 mV) in at least two contiguous precordial leads and in leads I and aVL on 12-lead electrocardiogram.

CTO was defined as the presence of total coronary occlusion characterized by complete interruption of antegrade blood flow without any findings suggestive of acute occlusion, such as contrast haziness in the initial coronary angiogram.⁸ No information was available regarding the duration of CTO, while patients who had an obvious medical history of previous myocardial infarction were not presented in the present study. Significant coronary stenosis was defined as >75% coronary diameter narrowing in the right or left circumflex coronary artery, and >50% in the left main coronary artery. Triple-vessel disease was considered when significant coronary stenosis presented in both major coronary arteries or the left main coronary artery in addition to the LAD. Collateral flow was assessed using Rentrop’s grading.¹⁰

Assessment of microvascular reperfusion and enzymatic calculated infarct size. PCI with coronary stent deployment was performed with the conventional technique to eliminate occlusion or sub-occlusion of the proximal LAD. Dual anti-platelet drug therapy with aspirin and either clopidogrel or ticlopidine was initiated in all patients. Glycoprotein IIb/IIIa inhibitors are not available in Japan and thus none of the patients received these drugs before PCI. Stent deployment with predilatation or directly (ie, direct stenting) as well as the use of the aspiration catheter to retrieve culprit coronary thrombus were at the discretion of the physician in charge. In cases of hemodynamic instability, intra-aortic balloon counter pulsation was actively used. Pre- and postprocedural culprit epicardial coronary flow was evaluated by Thrombolysis in Myocardial Infarction (TIMI) flow grade.¹¹ Successful PCI outcome was defined as the adequate restoration of coronary artery patency with postprocedural grade 2 or 3 TIMI flow and <25% postprocedural diameter stenosis in the culprit lesion. Microvascular reperfusion was evaluated based on the filling and clearance of microvascular radio-opacity from coronary angiograms and TIMI myocardial perfusion (TMP) grades 0 (contrast dye does not enter the microvasculature), 1 (dye slowly enters the microvasculature but does not exit), 2 (dye entry into and exit from the microvasculature is delayed compared with non-infarct related areas), and 3 (dye enters and exits the microvasculature normally).¹² Analysis of TMP grade was carried out by 2 physicians who were blinded to patient identity and electrocardiographic data. The interobserver reproducibility of TMP grade analysis was 0.93 (95% confidence interval [CI], 0.86-1.00) and used the worse one for this analysis.

Changes in sum of ST-segment elevation in leads I, aVL, and V1 through V6 at 30 to 60 minutes after PCI compared with values determined by an initial 12-lead electrocardiogram on admission were also evaluated as ST-segment resolution to electrically assess microvascular reperfusion.13 ST-segment elevation was measured manually 20 msec after the end of QRS complex by 2 physicians who were unaware of the clinical and angiographic data. The interobserver reproducibility of calculation of ST-segment resolution was 0.99 (95% CI, 0.98-1.00) and used the lower values in the present analysis.

Well-preserved microvascular perfusion was defined as having both TMP grade 3 and >50% ST-segment resolution, and severely impaired microvascular reperfusion was defined as having TMP grades 0 or 1 together with <30% ST-segment resolution. Values for microvascular reperfusion between severely impaired or well-preserved were assessed as moderately impaired.^14,15

The present study also used a two-compartment model to calculate enzymatic infarct size as the area under the curve of plasma levels of creatine kinase-myocardial band fraction that were measured every 4 hours during the first 48 hours after hospital admission.¹⁵ Our institutional review board approved the study protocol. All patients or an immediate family member provided written informed consent to participate in the present study at the time of admission.

Statistical analysis. Continuous variables are presented as means ± standard deviation. Data between patients with and without CTO were compared using student’s t-test or the Mann-Whitney test for continuous variables and the chi-square test for categorical variables. We identified variables that were independently associated with incidental severely impaired microvascular reperfusion using logistic regression analysis. Statistical significance was set at P<.05.

Results

A total of 15 patients (11% of total) had CTO mainly in the proximal to mid right coronary artery (Table 1). The prevalence of Killip class III or IV was high among patients with CTO who also had a tendency toward a low left ventricular ejection fraction upon admission compared with those without CTO. Triple-vessel disease was more frequent in patients with versus without CTO. The PCI was successful in all patients, and the frequency of thrombus aspiration or direct stenting as well as achieving postprocedural TIMI flow grade 3 did not differ between those with and without CTO. A high prevalence of TMP grade 0 or 1 and quite poor ST-segment resolution indicated a high incidence of severely impaired microvascular reperfusion (Figure 1) in patients with CTO. The enzymatic infarct size was larger in patients with versus without CTO (10304 ± 8060 IU/L vs 6804 ± 4959 IU/L, respectively; P=.009). Two patients each with and without CTO died in hospital (13% vs 2%; P=.01). Logistic multivariate regression analysis showed a close association between CTO and incidental severely impaired microvascular reperfusion (Table 2).

Discussion

How microvascular reperfusion manifests during PCI for STEMI accompanied by CTO in a non-infarct related coronary artery remains unknown. We clearly found a high incidence of severely impaired microvascular reperfusion in patients with anterior STEMI accompanied by CTO in a non-infarct related artery. These patients also had a larger enzymatic infarct and higher in-hospital mortality rates than those without CTO in a non-infarct related artery. Thus, we believe that compromised microvascular reperfusion is a key factor involved in the poor clinical outcomes of patients with CTO irrespective of prompt PCI to treat anterior STEMI.

A large cohort study by van der Schaaf et al discovered that CTO, but not multi-vessel disease per se, is an independent predictor of 1-year mortality in patients treated with PCI for STEMI accompanied by multi-vessel disease.³ Similar to their study in which only a fraction of the patients with CTO had a previous myocardial infarction, the present study included only patients with no obvious medical history of previous myocardial infarction.

The larger infarct in patients with CTO seems to be associated not only with jeopardized myocardium in the territory of the CTO but also with failed microvascular reperfusion. Several factors could explain the high incidence of severely impaired microvascular reperfusion in patients with anterior STEMI accompanied by CTO. One-third of patients with CTO in the present study had triple-vessel disease, which might cause microvascular reperfusion to fail.¹⁶ The CADILLAC trial found very poor ST-segment resolution among patients with STEMI and multi-vessel disease who underwent PCI compared with those who had single-vessel disease.¹⁶ The CADILLAC trial emphasized multi-vessel disease as a key factor involved in damaged microvascular reperfusion injury, although the mechanistic relationship between the two was not identified.

Complication with overt heart failure and/or cardiogenic shock upon admission is more frequent among patients with versus without CTO. A previous study proposed a role for extensive microvascular damage complicated with heart failure in failed microvascular reperfusion associated with STEMI.¹⁷ We supposed that a high Killip class would be an independent variable for impaired microvascular reperfusion based on the findings of that study. However, multivariate regression analysis including these variables showed that CTO is mostly associated with incidental severely impaired microvascular reperfusion.

The medical history revealed a relatively higher prevalence of diabetes mellitus among the patients with versus without CTO in the present study. Thus, impaired coronary flow reserve due to vascular, especially endothelial, dysfunction which is established in the setting of diabetes¹⁸ might be one cause of impaired microvascular reperfusion. Furthermore, the low frequency of thrombus aspiration and/or direct stenting in the present study would have been somewhat associated with microvascular obstruction due to atherothrombotic plaque embolization.¹⁹ Because platelet activation also contributes to microvascular reperfusion damage,²⁰ glycoprotein IIb/IIIa inhibitors might provide some clinical benefits for patients with STEMI complicated by CTO.²¹

Although the precise mechanisms regarding the role of CTO in impaired microvascular reperfusion could not be further defined in the present study, we also suppose that CTO-related chronic ischemic microvascular damage8 and subsequent lethal reperfusion together with failed microvascular reperfusion might be associated.⁵ One clinical study recently referred to vasomotor dysfunction in the CTO territory as hibernation of the vascular wall that persisted for up to 12 months after recanalization of a CTO.²² However, whether microvascular dysfunction presents in the donor territory as a functioning collateral source possibly because of relative chronic ischemia via an oxygen demand/supply mismatch remains uncertain. Further study is needed to understand the critical details of the pathogenesis of impaired microvascular reperfusion in patients with STEMI complicated with CTO. Patients treated with PCI for STEMI who developed residual CTO in a non-infarct related coronary artery should also undergo long-term follow-up.

The reported potential clinical benefits of PCI for treating CTO include relief of angina pectoris, improved cardiac dysfunction, and a possible reduction in cardiac death rates.^8,23,24 In contrast, routine PCI does not seem to confer any clinical benefit upon patients with stable CTO who are on optimal medication.^25,26 Despite remarkable technical advances in PCI.^27-30 the National Cardiovascular Data Registry has shown that the rate of PCI for CTO has remained rather low and has remained unchanged since 2007.³¹ The present study suggests that CTO is associated with failed microvascular reperfusion in the setting of STEMI even when treated with prompt PCI. Treatment strategies should be very carefully considered to ensure the best possible outcomes for patients diagnosed with CTO.

Study limitations. Our study has several limitations. First, the statistical power was insufficient to address the impact of CTO on in-hospital clinical outcomes because only a few patients died in-hospital among a small cohort of patients with CTO. Therefore, we focused on the potential association between CTO and failed microvascular reperfusion, which is a pivotal surrogate linked to poor clinical outcomes.³² Second, we analyzed microvascular reperfusion using a combination of angiographic TMP grade and ST-segment resolution. Grades generated by such analysis comprise a practical, reliable marker of real-time microvascular reperfusion and the early risk stratification of patients with STEMI who undergo PCI.^5,15 This type of analysis has also revealed a close relationship with precise parameters generated using cardiac MRI,^33,34 which provides a wide range of clinically reliable information regarding not only microvascular pathological processing, but also the condition of the transmural myocardium in STEMI.³⁵ Larger studies using cardiac magnetic resonance imaging are required to precisely assess microvascular reperfusion and confirm the present findings.

Conclusion

The presence of CTO in a non-infarct related coronary artery may provide serious disadvantages on microvascular reperfusion which is associated with adverse clinical outcomes among patients undergoing PCI for a first anterior STEMI.

Acknowledgment. We are greatly indebted to Yui Hayakawa for her expert assistance in the preparation of the manuscript.

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From the ¹Section of Cardiology, Department of Community Emergency Medicine, Ehime University Graduate School of Medicine, and the ²Department of Cardiology, Ehime Prefectural Central Hospital, Ehime, Japan.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted January 16, 2012, provisional acceptance given February 8, 2012, final version accepted April 23, 2012.
Address for correspondence: Makoto Suzuki, MD, Section of Cardiology, Department of Community Emergency Medicine, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan. Email: suzuki-m@m.ehime-u.ac.jp