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Effects of late REopening of Coronary total Occlusion on micRovascular perfusion and myocarDial function: the RECORD study

Leonarda Galiuto, Sabrina Barchetta, Elisa Fedele, Alberto R. De Caterina, Gabriella Locorotondo, Antonio M. Leone, Francesco Burzotta, Giampaolo Niccoli, Antonio G. Rebuzzi, Filippo Crea,
DOI: http://dx.doi.org/10.1093/ehjci/jes188 487-494 First published online: 3 October 2012

Abstract

Aims The effects of the reopening of a coronary total occlusion (CoTO) on microvascular perfusion in subacute or chronic coronary syndromes are actually unclear. We aimed at evaluating the microvascular perfusion pattern by myocardial contrast echocardiography (MCE), in addition to contractile function, before and after CoTO reopening.

Methods Twenty four patients with subacute and chronic coronary syndromes and CoTO datable >7 days underwent evaluation of microvascular perfusion and left ventricular (LV) function by MCE (Acuson Sequoia, with Sonovue, Bracco) before the reopening of the CoTO and at 9 ± 3 months of follow-up. Microvascular perfusion was semi-quantitatively assessed by the contrast score index (CSI), whereas the endocardial length of the perfusion defect [contrast defect length (CDL)], measured in three apical views and averaged, was expressed as a percentage of the total LV endocardial border. The wall motion score index (WMSI), LV volumes, and ejection fraction were also calculated.

Results At baseline, a mild impairment of LV contractile function was observed, which corresponded to a similar impairment of the coronary microvascular perfusion in the overall study population. At follow-up, a significant reduction of CDL% [8.23 (0–19.63) vs. 0 (0–3.68), P = 0.005], improvement of the CSI (1.41 ± 0.29 vs. 1.12 ± 0.17, P = 0.001) and the WMSI (1.73 ± 0.41 vs. 1.33 ± 0.34, P = 0.0004), and increase in the ejection fraction (47.48% ± 8.66 vs. 55.60% ± 8.29, P = 0.0001) were found.

Conclusion Reopening of a CoTO in patients with clinical indications to myocardial revascularization is associated with the improvement of coronary microvascular perfusion and the recovery of contractile function.

  • Myocardial contrast echocardiography
  • Coronary total occlusion
  • Microvascular dysfunction
  • Myocardial dysfunction

Introduction

A coronary total occlusion (CoTO) is nowadays estimated to be found in ∼15–30% of patients with suspected or known coronary artery disease at the time of diagnostic coronary angiography.1 However, its real prevalence in the general population is unknown because the majority of patients are almost entirely asymptomatic and do not undergo diagnostic procedures.

The real benefits of percutaneous coronary intervention (PCI) in CoTO patients are actually challenging. Large randomized studies, enrolling patients unselected for myocardial viability, have found that PCI of a CoTo is associated with a high risk of re-infarction and heart failure and low benefits in terms of survival.2,3 However, other studies have demonstrated that revascularization might improve prognosis4 and the quality of life, being associated with an absence of angina5 and increased exercise tolerance6 at follow-up, likely due to the improvement of global and regional left ventricular (LV) function over time. Particularly, in patients in whom viability has been assessed by pre-procedural cardiovascular magnetic resonance (CMR), beneficial effects on the recovery of LV function have been observed.7

Since the usefulness of the reopening of a CoTO remains unclear, current guidelines on myocardial revascularization suggests that revascularization of a CoTO can be justified in patients with persistent limiting symptoms despite optimal medical therapy or proven significant ischaemic territory.8 Up to now, no study on CoTO patients has assessed coronary microvascular flow before and after CoTO reopening. Myocardial contrast echocardiography (MCE) is a non-invasive imaging technique able to validly visualize microvascular perfusion, and, consequently, detect any perfusion abnormality.

Thus, in this study, we aimed at: (i) evaluating the contractile function and the microvascular perfusion pattern at MCE in patients with clinical indications to CoTO reopening, presenting with subacute or chronic coronary syndromes; (ii) verifying whether CoTO recanalization modifies contractile function and myocardial perfusion at follow-up.

Methods

Definition of study group

A consecutive series of patients with subacute or chronic coronary syndromes and angiographic evidence of CoTO, scheduled for reopening, was admitted to our coronary care unit from March 2010 to September 2011 and initially considered for enrolment. Enrolment was performed after obtaining knowledge of the coronary anatomy. Only patients with single-vessel coronary disease corresponding to CoTO, and in whom the duration of coronary occlusion could be dated at least 7 days, according to the clinical presentation and typical occlusion morphology on angiography,9 were considered as eligible. The indication for CoTO reopening was clinically established, based on the presence of typical angina at rest or on exertion and/or severe inducible ischaemia, lasting for >7 days. Severe inducible ischaemia was defined as a 2 mm or larger horizontal or downward sloping ST shift in >1 of the 12 electrocardiographic leads measured 80 ms after the J points at low-load ECG treadmill stress testing. After coronary angiography and prior to PCI, all patients underwent baseline assessment by standard echocardiography and MCE. Subsequently, elective PCI of CoTO was performed. Eligible patients were included in the final study population if they met the following criteria: (i) achievement of the patency [thrombolysis in myocardial infarction (TIMI) 3 flow grade] of CoTO; (ii) no significant residual stenosis (<50%) of other coronary arteries; (iii) technically adequate echocardiogram. Then, standard echocardiography and MCE were repeated at 9 ± 3 months of follow-up [Figure 1].

Figure 1

Flow-chart showing the selection process for patient enrolment and definition of the final study population; CoTO, coronary total occlusion; MCE, myocardial contrast echocardiography; PCI, percutaneous coronary intervention; TIMI, thrombolysis in myocardial infarction.

Patients were treated by acetylsalicylic acid (75–160 mg daily), clopidogrel (600 or 300 mg oral loading dosage according to the subacute or chronic clinical setting, respectively, followed by 75 mg daily), heparin (initial weight-adjusted intravenous bolus and then further boluses administered), anti-ischaemic drugs (beta-blockers, ACE-inhibitors, calcium-channel antagonist, and statins) according to current guidelines. Except for heparin, such therapy was left unchanged also after PCI. The protocol was conducted in agreement with the Declaration of Helsinki and approved by local Ethics Committee. All patients gave their written informed consent.

Standard echocardiography

All patients underwent conventional echocardiography prior to CoTO recanalization and at 9 ± 3 months of follow-up, using a high-resolution ultrasound system (Sequoia Acouson, Siemens, Malvern, PA, USA). The echocardiographic study was based on the acquisition and analysis of images from apical four-, three-, and two-chamber views. The LV end-diastolic volume (EDV) and end-systolic volume (ESV) were calculated from four- and two-chamber views using the modified Simpson biplane method. The ejection fraction (EF) was derived from the formula: ([EDV − ESV]/EDV)%. The regional wall motion was evaluated by a semi-quantitative score system according to the recommendations of the American Society of Echocardiography10 (1 = normal, 2 = hypokinesia, 3 = akinesia, and 4 = dyskinesia) and a wall motion score index (WMSI) was calculated by the sum of the score of all segments divided by the total number of segments.

Myocardial contrast echocardiography

All patients underwent evaluation of the myocardial perfusion pattern by MCE before the reopening of a CoTO and again at 9 ± 3 months of follow-up. The MCE study was performed using real-time contrast pulse sequencing, operating on a Sequoia ultrasound system (Siemens, Acouson, Malvern, PA, USA). Contrast pulse sequencing is able to provide an image with an excellent signal-to-noise ratio and with particular high sensitivity and penetration using a very low mechanical index. A second-generation ultrasound contrast agent Sonovue® (Bracco, Milan, Italy) was administered intravenously at an infusion rate of 1 mL/min. No side effects were observed in all patients studied during and after the administration of Sonovue®. A single perfusion score was assigned to each myocardial segment on the basis of the degree of opacification at the peak contrast effect. Scores were graded as 1 = normal, 2 = reduced, or 3 = absent opacification. The contrast score index (CSI) was calculated by the sum of MCE scores in each segment divided by the total number of segments. The endocardial extent of regions without any opacification (contrast score 3) was considered as the perfusion defect length [contrast defect length (CDL)] and measured in all three apical views (4-, 2-, and 3-chamber). It was then averaged and expressed as a percentage of the total LV endocardial border (CDL%).11

Statistical analysis

Statistical analysis was performed by using the statistical software package SPSS version 15.0. After checking for normality assumption by the Kolgomorov–Smirnov test, quantitative variables were presented as mean ± standard deviation if they were normally distributed and as the median with inter-quartile range if they were non-parametric, whereas categorical data were expressed as a percentage. Pearson's or Spearman's correlation coefficients were used to assess correlations between parametric and non-parametric echocardiographic data, respectively. Comparisons between baseline and follow-up data within the entire study population were performed by ANOVA (repeated measurement test). All clinical and biochemical parameters presenting a significance P-value ≤0.10 at univariable analysis were included in the multivariable model, using the stepwise method with backward elimination. A P-value ≤0.05 was always required for statistical significance.

Results

Clinical characteristics of the study population

Among 31 initially enrolled patients, 7 were subsequently excluded from the data analysis due to the failure to achieve successful revascularization of the occluded artery, so that 24 patients (63 ± 13 years old, 17 males) represented the final study population. The clinical characteristics are displayed in Table 1. Among patients presenting with subacute coronary syndrome, 10 (42%) had suffered a recent ST-elevation myocardial infarction (STEMI) and 6 (25%) a non-ST elevation myocardial infarction (NSTEMI), whereas among patients with chronic coronary syndrome, 5 (21%) exhibited stable angina, and 3 (12%) silent inducible ischaemia on stress testing.

View this table:
Table 1

Clinical characteristics of the study population (n = 24)

Demographic and clinical characteristics
Age (years) (mean ± SD)63 ± 13
Males, n (%)17 (71)
Smokers, n (%)9 (37)
Hypertension, n (%)16 (67)
Dyslipidaemia, n (%)9 (37)
Diabetes mellitus, n (%)7 (29)
Positive family history of CAD, n (%)6 (25)
CoTO, n (%)
Anterior descending coronary artery12 (50)
Right coronary artery9 (37)
Circumflex coronary artery3 (13)
Time of coronary occlusion, days (mean ± SD)86 ± 56
Subacute coronary syndrome, n (%)16 (66)
Chronic coronary syndrome, n (%)8 (34)
  • CAD, coronary artery disease; CoTO, coronary total occlusion; SD, standard deviation.

Baseline myocardial contractile function and perfusion

On baseline echocardiographic examination, the overall study population presented slightly depressed global and segmental contractile function, as assessed by an EF of 47.48 ± 8.66 and a WMSI of 1.73 ± 0.41. Moreover, an impaired myocardial perfusion was expressed by a CSI of 1.41 ± 0.29 and a CDL% of 8.23 (0–19.63) (Table 2). Baseline CSI and CDL% showed significant direct correlations with the WMSI (r = 0.73, P < 0.001, rho = 0.66, P = 0.001, respectively) (Figure 2), while they inversely correlated with the EF (r = −0.70, rho = −0.70, P < 0.001, respectively) (Figure 3).

View this table:
Table 2

Baseline echocardiographic characteristics of study population (n = 24)

Baseline echocardiographic characteristics
EDV, mL (mean ± SD)153.99 ± 30.23
ESV, mL (mean ± SD)83.32 ± 27.82
EF % (mean ± SD)47.48 ± 8.66
WMSI (mean ± SD)1.73 ± 0.41
CSI (mean ± SD)1.41 ± 0.28
CDL%, median (IQr)8.23 (0–19.63)
  • CDL%, contrast defect length expressed as % of the total endocardial border length; CSI, contrast score index; EDV, end-diastolic volume; ESV, end-systolic volume; EF, ejection fraction; IQr, inter-quartile range; SD, standard deviation; WMSI, wall motion score index.

Figure 2

Correlations of baseline CSI (A) and CDL% (B) with baseline WMSI. CDL%, contrast defect length (% of the total endocardial border length); CSI, contrast score index; WMSI, wall motion score index.

Figure 3

Correlations of baseline CSI (A) and CDL% (B) with baseline EF%. CDL%, contrast defect length (% of the total endocardial border length); CSI, contrast score index; EF, ejection fraction.

Temporal evolution of contractile dysfunction and perfusion defect

At follow-up, EDV and ESV were 142.16 ± 26.98 mL and 65.94 ± 20.94 mL, respectively. Both LV volumes were significantly reduced when compared with baseline data (P = 0.0001 and P < 0.001, respectively) (Figure 4). This finding was associated with a significant improvement of LV contractile function as expressed by an increase in the EF (55.60 ± 8.29, P < 0.001 vs. baseline) and a decrease in the WMSI (1.33 ± 0.34, P < 0.001 vs. baseline) (Figure 5). Also improvement of the myocardial perfusion pattern was found at follow-up in the overall study population: it was expressed by a significant reduction of the CSI (1.12 ± 0.17, P < 0.001 vs. baseline) and by an almost complete resolution of CDL%, exhibiting a median value of 0% (0–3.68), P < 0.001 vs. baseline (Figures 6 and 7).

Figure 4

EDV (A) and ESV (B) evaluated at baseline and follow-up in the overall study population: at follow-up a significant decrease of both volumes vs. baseline is displayed EDV, end-diastolic volume; ESV, end-systolic volume.

Figure 5

Evaluation of the EF (A) and the WMSI (B) at baseline and at follow-up: at follow-up, the EF significantly increased and regional wall motion improved, as shown by the reduction of the WMSI. EF, ejection fraction; WMSI, wall motion score index.

Figure 6

Evaluation of the CSI (A) and the CDL% (B) at baseline and at follow-up in the overall study population: at follow-up a significant improvement of myocardial perfusion is demonstrated by the reduction of both CSI and CDL%. CDL%, contrast defect length (% of the total endocardial border length); CSI, contrast score index.

Figure 7

Myocardial contrast echocardiography short-axis images showing myocardial perfusion in the same patient prior to (A) and after recanalization of the anterior descending artery CoTO (B): in (A), a large perfusion defect is shown in the anterior wall (between arrows), which completely disappears at follow-up (B).

As previously reported,12 patients were then differentiated into the group with subacute CoTO and the group with chronic CoTO on the basis of a 3-month cut-off time point. No significant difference has been found between patients with CoTO <3 and CoTO >3 months in terms of LV EDV, EF, WMSI, CSI, and CDL% at baseline and after reopening. In both groups, however, the reopening of CoTO resulted in significant changes of the LV EDV, EF, WMSI, CSI, and CDL%.

Clinical outcome after CoTO reopening

Although the study was not powered for an outcome analysis, no myocardial infarction or death from all causes was observed in our patients at the 12-month follow-up. Only one case needed a subsequent revascularization procedure of the target lesion due to occurrence of unstable angina. Among the remaining patients, none suffered from recurrent angina.

Discussion

The results of our study provide, for the first time, non-invasive characterization of the microvascular perfusion pattern and contractile function in patients with CoTO prior to and after revascularization. At baseline, the overall study population showed LV contractile dysfunction, which correlated with impairment of microvascular perfusion within the territory supplied by an occluded coronary artery in most patients. After CoTO reopening, a significant recovery of the regional and global LV contractile function was observed, which might be explained by a parallel increase in the coronary microvascular flow.

Coronary total occlusion

CoTO is characterized by severe coronary atherosclerosis resulting in the total absence of epicardial anterograde blood flow, defined by TIMI flow grade 0. Currently, CoTO is differentiated into subacute or chronic, based on the presumed duration of occlusion, lasting from 7 days to 3 months and >3 months,12 respectively. The best treatment strategy of patients with CoTO is under debate. Although current European guidelines suggest a revascularization approach of CoTO only in the presence of angina or documented ischaemia in the myocardial territory supplied by the occluded coronary artery branch,8 the real benefit of such a strategy on the outcome is still unknown. The occluded artery trial (OAT) investigated a large group of patients with persistent CoTO at 48 h after an acute myocardial infarction, who were randomized to receive PCI or optimal medical therapy.3 A significant reduction in recurrent angina was observed in the PCI group. However, no differences were found in the incidence of major adverse events, represented by death, re-infarction, or New York Heart Association (NYHA) class IV heart failure. Thus, benefit in the relief of symptoms produced by PCI of CoTO did not translate into an improvement of the long-term prognosis. However, in the OAT trial, success of CoTO reopening was not taken into account in the analysis of the patient outcome. Indeed, it is conceivable that the clinical outcome might be strictly influenced by optimal angiographic result of the recanalization procedure. In the TOAST–GISE trial, the success of PCI was achieved in a high percentage of patients with a CoTO: patients successfully treated showed a reduced 12-month incidence of MI, reduced need for coronary artery bypass surgery, and greater freedom from angina, when compared with patients with an unsuccessful revascularization attempt.9 The higher survival rate at the 5-year follow-up achieved in patients with successful PCI rather than in patients with failed CoTO recanalization indicates that the success of the revascularization procedure represents an independent predictor of prognosis.6 We have elected to enrol only patients with a successful reopening of the CoTO: although only one minor adverse cardiac event was observed and all patients except one had no recurrence of angina within the first year of follow-up, the small sample size did not allow any clinical and outcome analysis.

LV remodelling and perfusion in coronary total occlusion

Despite conflicting results being derived from outcome studies, when the evolution of LV volumes, remodelling, and EF have been taken into account, a tendency to revert the LV remodelling process, associated with a decrease in LV volumes and preservation or improvement of the EF has been generally proved.13 Such findings were mostly ascribed to the presence of hibernating or stunning myocardium.14 On the contrary, in the TOSCA-2 trial, despite the patency of the infarcted artery, CoTO recanalization did not produce a further improvement of cardiac function when compared with optimal medical therapy.2 The lack of benefits from PCI in high-risk patients with a depressed EF was subsequently confirmed.15 In the present study, we focused on subacute and chronic ischaemic populations, characterized by 100% success rate of CoTO reopening: a significant improvement of global and regional LV contractility, associated with a reduction in LV volumes, was found.

Whether the improvement of LV contractility might be sustained by the restoration of adequate microvascular perfusion has never been clearly proved. Myocardial perfusion, assessed by a gated SPECT, in CoTO patients significantly improved at 1 year after PCI, compared with baseline, in all vascular territories: the increase in the myocardial blood flow was proportional to the success of the revascularization procedure.16 MCE is a non-invasive imaging technique, well validated in the assessment of myocardial perfusion, thanks to its capability to identify the presence or absence of the microvascular blood flow, depicted by a microbubble signal. Since microbubbles behave like blood cells, their signal can be detected within the coronary microcirculation if perfusion is preserved and is completely absent if perfusion is impaired, thus leaving myocardial zones mostly not opacified. Despite its widely accepted importance in detecting stable coronary artery disease and post-infarct myocardial perfusion abnormalities, MCE has not yet been used to evaluate the microvascular perfusion pattern in the setting of CoTO. In the present study, two previously described MCE perfusion indexes (CSI and CDL%) were used. At baseline, significant microvascular perfusion impairment within dysfunctional segments was found in the overall population. However, such perfusion abnormalities significantly decreased at the 12-month follow-up and their change paralleled the improvement of the LV global and regional contractile function. The findings of our study firstly suggest that microvascular perfusion abnormalities assessed at baseline by MCE does not necessarily reflect an irreversible damage of coronary microcirculation: in turn, when myocardial perfusion improves over time, as in our study population, the structural and functional integrity of coronary microcirculation despite the CoTO can be postulated. Moreover, if contractile function recovers contemporarily to the restoration of adequate microvascular blood flow, the existence of viable myocardium within the dysfunctional area may be indirectly proved. Although it is incorrect to generalize our findings to all CoTO due to the small sample size, the present study may be considered as pivotal in the characterization of the myocardial and microvascular status in CoTO and larger studies are needed to expand our results.

The lack of significant differences between patients with CoTO <3 months and patients with CoTO >3 months regarding the pattern of myocardial perfusion and contractile function represents a new finding and apparently it could seem contrary to what is expected. Actually, both groups display a significant improvement of myocardial perfusion and contractile function. Although direct comparison with previous studies, which enrolled patients with different duration of coronary occlusion, is not possible, such findings may be explained by pathophysiological consideration. Firstly, despite the different duration of coronary occlusion, previous studies aimed to evaluate the evolution of LV volumes, remodelling and EF found a general tendency to revert LV remodelling process, to decrease in LV volumes, and to preserve or improve EF, which is most consistent with having the presence of hibernating or stunning myocardium. Our results expand such findings, demonstrating a general improvement of myocardial perfusion as a likely substrate for the improvement of contractile function. Furthermore, most of the previous studies, focusing on the clinical outcome, enrolled stable patients, in which probably myocardial and microvascular damage is as far as already established. The presence of angina and the evidence of inducible ischaemia in our study population led us to suspect that, despite the contractile dysfunction and the perfusion defect at baseline and irrespective of the duration of coronary occlusion, most of the myocardium and coronary microcirculation could be still viable and worthy of being treated.

It is conceivable that a crucial role in the preservation of LV function and myocardial perfusion is sustained by the development of collateral circulation that can adequately supply myocardial blood flow in CoTO territory. However, the direct effect of collateral circulation on LV function remains actually controversial, because Werner et al. 17 have recently demonstrated that the development of collateral circulation appears similar between patients with or without the recovery of dysfunction after recanalization of a CoTO. Furthermore, LV function seems to be not directly dependent on the quality of collateral circulation, but rather on the presence of intact microvasculature within stunning or hibernating but viable myocardium.17

Despite the absence of data on collateral circulation, the recovery of LV function in our study population is directly related to the restoration of the microvascular blood flow detected on MCE. Thus, according to the Werner hypothesis, the presence of coronary microvascular integrity represents a primary requisite for the recovery of contractile function after CoTO reopening. However, such findings need to be confirmed by further clinical studies.

Study limitation

The sample size of our population is quite small, although our findings are characterized by an elevated level of statistical significance. However, they should be validated in larger clinical trials. Moreover, the absence of randomization to PCI or optimal medical therapy, such as in the OAT trial, does not permit one to compare the evolution of contractile function and the myocardial perfusion pattern between these two different approaches, in order to state that PCI is really effective in such patients. On the other hand, there are no reasons to believe that contractile function and the myocardial perfusion pattern might spontaneously improve without an adequate reopening of the CoTO. Finally, because no data regarding myocardial viability were collected by SPECT or CMR, especially in patients with recent STEMI, our results are not comparable with findings of other imaging techniques. However, the significant recovery of contractile function after the restoration of adequate myocardial perfusion allows ruling out the existence of widespread irreversibly damaged myocardium. The present study firstly gives evidence of the possibility of improvement of contractile function and perfusion in CoTO patients, as assessed by widely validated MCE.

Conclusions

The reopening of CoTO based on clinical indications provides significant benefits, represented by the improvement of LV contractile function and myocardial perfusion. Restoration of contractile function and re-establishment of normal myocardial perfusion after the late reopening of subacute or chronic coronary occlusion suggest that in these patients, despite CoTO, the myocardium is still viable and coronary microcirculation is not irreversibly damaged.

Conflict of interest: none declared.

Footnotes

  • RECORD investigators: C. Trani, MD, M. Mazzari, MD, R. Mongiardo, MD, G. Schiavoni, MD.

References

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