Long-term prognostic value of inducible myocardial ischemia in patients with severe ventricular dysfunction undergoing coronary artery bypass graft surgery
LUCRECIA MARÍA BURGOS, JOSEFINA BELÉN PARODI,
VICTORIA GALIZIA BRITO, ALAN SIGAL,
MIRTA DIEZ, MARIANO BENZADON,
DANIEL NAVIA, LEONARDO SEOANE
Instituto Cardiovascular de Buenos Aires (ICBA)
(1428) CABA, Argentina E-mail
Recibido 08-JUL-18 – ACEPTADO despues de revisión el 17-AGOSTO-2018.
There are no conflicts of interest to disclose.
The evaluation of inducible myocardial ischemia (IMI) has been used to identify patients in whom revascularization will provide a clinical benefit. This arises largely from studies in patients with normal or slightly reduced left ventricular ejection fraction (LVEF). There is scarce information regarding the search for IMI in patients with severe LVEF undergoing coronary artery bypass graft surgery (CABG) and its relation to long-term survival. Objective: To evaluate the long-term prognostic value of IMI in patients with severe LVEF deterioration under elective isolated CABG. Methods: Comparative retrospective observational study on a database whose information was collected prospectively from 2004 to 2016. Patients with LVEF of less than 35% were included consecutively, with evaluation of IMI by echo stress (ischemia in ≥2 segments) or gated -SPECT (≥4 segments) prior to an isolated non-urgent CABG. As a primary endpoint, mortality from all causes was analyzed in long-term follow-up. As a secondary point, a combination of in-hospital mortality or low cardiac output syndrome (LCOS) was evaluated. Results: Ninety-two patients were included, of whom 59.7% had IMI (71.8% gated-SPECT, and 28.2% through echo stress). The majority were males, and the mean age was 64.4 ± 8.4 years for the IMI group and 65 ± 6.5 years for the group without IMI (P = 0.07). There were no differences in the baseline characteristics and pharmacological treatment of both groups. The median follow-up was 19 months (PCTL 25-75, 1.2-84.5 months). At follow-up, mortality from all causes was 21.8% in the group of patients with IMI, and 37.8% in those without IMI (Log rank test P=0.034), but after a Cox regression analysis, when in-hospital complications were taken into account, IMI was not an independent variable (HR 0.32 (0.22-1.65)). Regarding the secondary endpoint of in-hospital mortality or low cardiac output syndrome (LCOS), it was also significantly more frequent in the group without IMI (24.3% vs. 9.1%, respectively, P = 0.046). Conclusions: The presence of IMI prior to surgery in patients with severe impairment of LVEF undergoing CABG allows the identification of a group of patients with a better prognosis, presenting a lower rate of the composite event of in-hospital mortality or LCOS, and also lower mortality in the follow-up, losing statistical significance when in-hospital complications are taken into account.
Decompensated heart failure (HF) currently constitutes a significant public health problem [1,2]. The estimated population prevalence in the developed world is 1% to 2% , with ischemic heart disease being the most frequent etiology in these countries  (more than 60% of diagnoses). In Argentina, it presents figures close to 35% [5-7].
Necrotic ischemic etiology and severe systolic left ventricular dysfunction are the main high risk markers, and thus, of greater mortality in patients with heart failure [8,9]. This more aggressive course is in part due to the presence of a set of factors like ischemia, myocardial fibrosis and endothelial dysfunction, that overlap the inherent progressive development of ventricular dysfunction, and often associated co-morbidities that accelerate adverse clinical evolution .
The presence of inducible myocardial ischemia (IMI) during stress test in patients with CAD plays a significant role in the decision of myocardial revascularization [10,11], in spite of the invasive treatment corresponding to this ischemic territory in patients with stable chronic angina or silent ischemia not having proved yet to be of benefit as to a reduction of clinical events proper, except in the presence of severe ischemia or high risk from nonrandomized studies . Moreover, this evidence emerges in most studies in patients with normal o mildly reduced systolic left ventricular function (SLVF) [13,14], where prognosis is mainly related to a reduction of the total ischemic amount and the improvement of symptoms . On the contrary, the prognostic value of inducible ischemia has not been proven specifically in patients with depressed LVEF.
It is important to differentiate IMI from myocardial viability, as these are different concepts and phenomena: all myocardial segments that show inducible ischemia are viable, but not all viable segments present ischemia in stress test, and not all segments with inducible ischemia are dysfunctional in rest . The improvement in LVEF after revascularization is to be expected if there is a significant amount of hypocontractile myocardium, but that is still viable; but this concept could not be proven in prospective trials. STITCH substudies both of myocardial viability and ischemia did not show in any of the cases, the existence of a direct relation between the presence of viable myocardium or inducible ischemia, and the effect of myocardial revascularization surgery in comparison to the optimal medical treatment, in terms of clinical results [15,16].
There is scant information about the prognostic value of the presence of IMI in patients with severe ventricular dysfunction in whom surgical revascularization will be practiced, and its relation to long-term survival.
MATERIAL AND METHODS
Comparative, retrospective, observational study on a database, whose information has been periodically gathered prospectively.
All patients were included consecutively since January 2004 to December 2016, who presented LVEF of less than 35% determined by transthoracic echocardiogram, that presented myocardial ischemia evaluation by stress echo or gated-SPECT before undergoing isolated elective myocardial revascularization surgery, and later they were divided into two groups according to the presence or not of IMI.
Positive IMI was considered to be the presence in stress echo functional test, of ischemic response in 2 or more segments in 16, and in the case of gated-SPECT in 4 segments or more in 17.
The exclusion criteria were patients who had underwent urgency or emergency surgery, patients with acute coronary syndromes, severe or congenital valvular heart diseases, and hypertrophic or restrictive cardiomyopathies.
As primary endpoint, all-cause mortality was analyzed in long-term follow-up. As secondary endpoint, a composite of in-hospital mortality and low cardiac output (LCO), defined as the requirement of ventricular assistance and/or inotropic drugs for more than 48 hours to maintain systolic blood pressure at 90 mmHg with signs of peripheral hypoperfusion.
Follow-up was made by ambulatory controls by clinical cardiology and/or heart surgery, and in those with no follow-up, a phone call was made at 180 days. Follow-up information was collected from digitized clinical histories. Pharmacological treatment at discharge when heart surgery was based on the current recommendations of clinical practice guidelines, indicating in all antiaggregants and statins in high doses; and beta blockers, ACEIs, ARBs and aldosterone antagonists, unless there was a contraindication .
Myocardial revascularization surgery (MRS) was conducted by median sternotomy, with priority use of artery bypass grafting, using mammary arteries as first donor, and with no routine use of extracorporeal circulation pump since year 2004.
Medians and interquartile intervals were estimated, to analyze the discrete numerical variables, as well as frequencies and percentages of categorical variables. To evaluate the association between continuous variables, Mann-Whitney U test and T test were used; and for categorical variables, Fisher’s exact test or Chi squared test were used as it corresponded.
Survival analysis between both subgroups (IMI and non-IMI) was constructed using the Kaplan-Meier method, and compared by the log rank test. A multiple regression model by Cox method was conducted to analyze the presence of IMI as long-term mortality predictor, and to analyze the contribution of independent factors, expressed as hazard ratio and its 95% confidence interval. The variables that presented P<0.1 in univariate analysis were included in the variables model.
A two-tailed p value equal or less than 0.05 was considered statistically significant.
For the statistical analysis, the SPSS 23 software was used.
Patients signed their informed consent to participate in the study that was conducted to meet the national law of personal information data 25.326. The study was conducted according to the national ethical regulations (CABA law, 3301) and the national law of clinical investigation in human beings, the Helsinki declaration and had the approval by the Investigation and Ethical committee of our Institution.
There were 92 patients included, from whom 59.7% presented IMI. 71.8% was evaluated by gated-SPECT, and 28.2% by stress echo. The follow-up median was 19 months (PCTL 25-75 1.2-84.5 months).
Most were males, and mean age was 64.4±8.4 years for the IMI group and 65±6.5 years for the group without IMI (P=0.07). There are no statistically significant differences between the basal characteristics of both groups (Table 1). The proportion of symptomatic patients for angina was similar in both groups, representing 40% in the IMI group, and 40.5% in the non-IMI group (P=0.9).
Table 1. Basal characteristics
With IMI (n=55)
W/o IMI (n=37)
Age (Mean ± SD)
Male gender (n; %)
HTN (n; %)
Diabetes (n; %)
Smoking (n; %)
CKD (n; %)
Previous AMI (n; %)
Previous PTCA (n; %)
Previous MRS (n; %)
Previous HF (n; %)
Angina (n; %)
Use of ECC (n; %)
ACEI: Angiotensin-converting-enzyme inhibitors. ARB: Angiotensin II receptor blockers.
In regard to the primary endpoint of mortality in follow-up, it occurred less frequently in patients with IMI, in a statistically significant way (21.8% vs 37.8%. Log Rank test p=0.03) (Figure 1) with hazard ratio of 0.38 (CI 95%, 0.18-0.96; p=0.038).
Figure 1. Survival curve of long-term mortality according to the presence of inducible myocardial ischemia (IMI).
As to the secondary endpoint of in-hospital mortality and low cardiac output, a significant difference was also observed in favor of patients presenting IMI (10.9% vs 27%, p=0,046) although both components, evaluated separately, did not achieve a statistical significance.
No differences were shown in other evaluated points individually, as in the rate of use of ventricular assistance devices (2.7% vs 3.6%. P=0.64) or in the duration of the hospital stay (6 days ±1.8 vs 7.1 days ±4.7. P=0.46). The non-IMI group presented greater respiratory failure, defined as requirement for invasive and noninvasive mechanical ventilation (0% vs 8.1%; P=0.032) and also presented a statistically non-significant trend to show during in-hospital evolution, major atrial fibrillation, kidney failure with requirement of hemodialysis and multiple organ failure (Table 3).
In the multivariate analysis using Cox regression, taking into account in-hospital events as the use of intra-aortic balloon counterpulsation, multiple organ failure and low cardiac output of patients with long-term follow-up showed that IMI was not an independent protective factor in the long run (HR 0.61 CI 95% 0.22-1.69; P=0.34) (Table 4) (Figure 2); with intra-aortic balloon counterpulsation in the postoperative period being an independent risk factor, with history of diabetes and the clinical syndrome of low cardiac output being a marked statistically non-significant trend.
Table 4. Univariate and multivariate analysis with in-hospital events for long-term mortality.
Hazard Ratio (CI 95%)
Smoker or former smoker
Post IABP counterpulsation
AF in postsurgical period
Figure 2. Cox multivariate regression analysis with in-hospital event for long-term mortality.
In this study, the absence of inducible myocardial ischemia by stress echo or gated-SPECT in patients with severe deterioration of systolic ventricular function, who underwent myocardial revascularization surgery, was a strong mortality predictor in follow-up. However, when in-hospital events were taken into account in multivariate analysis, the absence of IMI was not an independent predictor of mortality.
The way we see it, there are two main reasons why there is still no clear recommendation on the research about inducible myocardial ischemia to determine a prognosis in the preoperative context of patients with ventricular dysfunction. On the one hand, because most of the ischemia evaluation studies include patients with CAD and stable chronic angina, where the population with severe left ventricular dysfunction is underrepresented, as in general it is a criterion that guides the attending physician toward revascularization, even in the presence of asymptomatic CAD or mild to moderate ischemia. The results of these studies are usually controversial, as the benefit of routine revascularization in patients with stable coronary disease in comparison to optimal pharmacological treatment has still not shown to be beneficial, and in this context it is even more difficult to extrapolate conclusions to patients with ventricular dysfunction.
On the other hand, IMI is not a dichotomic variable, and in turn, there is a wide range of tests to evaluate it, each with different degrees of sensitivity and specificity. Traditionally, stress echo is considered a highly specific test, while PET, gated-SPECT and cardiac nuclear magnetic resonance with gadolinium are considered tests with a greater sensitivity for the diagnosis of inducible ischemia and necrosis , with some differences between them. Currently, there are even more modern methods, not generally used in classical preoperative viability studies such as the STITCH, as cardiac NMR with stress using adenosine or dipyridamole protocols have shown a wide sensitivity and special resolution [19,20]. In this regard, it is possible to understand that there is still no unified concept on which is the best method to study myocardial ischemia, in absence of a study comparing their results in regard to clinical events in follow-up.
In a Spanish multicenter registry , 391 patients with severe systolic left ventricular function deterioration were evaluated prospectively by cardiac NMR with dipyridamole to study the origin of ventricular dysfunction; in 53% of cases, heart disease of ischemic origin was determined, while in the remaining 47% the cause was unknown. In patients in whom at least two segments with perfusion defects were observed in cardiac NMR, the rate of major events, defined as cardiovascular death and non-fatal AMI was significantly greater in follow-up. Even in multivariate analysis, the presence of perfusion defect, and therefore of inducible ischemia, was the only independent predictor of events. To be able to understand this result and the difference with that in our study, where the presence of IMI is a predictor of better evolution, it is important to highlight that revascularized patients were excluded from follow-up because of the cardiac NMR results, which are more likely to have occurred in patients with significant IMI. These results are then to be expected, since if we analyze the results of the PARR-2 study, the patients with myocardial viability that were revascularized, presented a greater number of events in follow-up in regard to non-revascularized patients with no IMI .
On the other hand, a prospective study of Buckert et al, published in 2013, using cardiac NMR with adenosine and late gadolinium enhancement in 1299 patients with stable chronic angina, showed that patients that were revascularized due to having myocardial ischemia presented a greater number of events of death and nonfatal infarction . This leads us again to the discussion of benefits in the revascularization of coronary artery lesions in patients with stable chronic angina, or even with silent ischemia.
In the ’80s, three studies evaluated the benefit of revascularization over pharmacological treatment in patients with CAD: the CASS , the veterans study  and the ECSS . The patients of these studies noticeably differ from the current practice, mainly because their pharmacological treatment consisted almost exclusively of beta blockers, and because the only method to evaluate ischemia was stress ECG, the sensitivity and specificity of which is less than stress tests with imaging. However, an interesting conclusion of these studies was that those that presented ischemia by these methods showed to have a greater survival after MRS in comparison to pharmacological treatment, and even an analysis of patients with severe LVEF (<35%) that were initially excluded from the CASS study and involved in the registry, showed that patients with angina as myocardial ischemia marker presented better outcomes after revascularization .
Some more recent randomized clinical trials have attempted to establish an association between the presence of ischemia and the benefit of revascularization. In year 2007, the COURAGE study  was published, that evaluated patients with chronic CAD with lesions of at least 70% and evidence of ischemia (defined as T-type or ST-segment changes in the ECG in rest, or tests that develop positive ischemias), or with lesions of 80% or more associated to typical angina, not requiring the presence of ischemia in additional tests. These patients were randomized to optimal pharamacological treatment or revascularization by any method. The primary endpoint of death and nonfatal AMI was not different in the follow-up between groups. Only statistically significant differences were observed in favor of the angioplasty group needing a new revascularization, and initially in the decrease of angina symptoms, but in a 5-year follow-up this difference is lost. Unlike our patients, in the COURAGE study, only a small percentage presented severe systolic left ventricular function impairment. In turn, the BARI-2D study from 2009 , with a design similar to the COURAGE, but exclusively in 2368 diabetic patients, did not show either, differences between revascularization and pharmacological treatment in terms of the primary endpoints of mortality and a composite of death, nonfatal AMI and stroke. In the analysis of subsets, patients that were revascularized by MRS had less major cardiovascular events than those treated exclusively by pharmacological treatment.
In 2012, the FAME-2  was published, where the evaluation of ischemia was functional by FFR (fractional flow reserve) of angiographically stenotic lesions. In this study, the primary endpoint (death, nonfatal AMI and urgency revascularization) occurred in a less frequent way in those in whom functionally severe lesions (FFR<0.80) were revascularized, but when breaking down the individual points, the only one that reached statistical significance was the need for new revascularizations in follow-up.
In a meta-analysis published in JACC of 3088 patients with severe ventricular dysfunction and myocardial ischemia evaluated by PET with FDG, gated-SPECT with thallium or stress echo, revascularization in patients with viable myocardium showed a 76% reduction in mortality in regard to the pharmacological treatment; while in patients with no proven viability, there were no differences between both groups. We should highlight that patients with no viability who underwent revascularization, just as in our experience, had more mortality events than those with viability (7.7 vs 3.2%), and that in the latter group it was observed that the worse SLVF, the greater the benefit. Finally, there were no significant differences observed in terms of diagnostic capacity by any of the three imaging methods .
In brief, currently there is no uniform criterion about the benefit in the revascularization of stable coronary arteries, but there are some clinical scenarios, such as extensive CAD or at the level of the trunk or proximal ADA, the presence of ventricular dysfunction, or co-morbidities as chronic kidney disease, among others, where the consensus seems to indicate a certain benefit with revascularization .
On the other hand, evidence seems to indicate that the presence of ischemia in challenge tests is a poor prognosis marker, and that revascularizing these patients, particularly surgically, may improve it. Nevertheless, in patients with severe ventricular dysfunction, evidence is scarce.
The way we see it, this is the first study evaluating the prognostic value of the presence of IMI in the evolution of patients with severe impairment of SLVF who undergo surgical coronary artery revascularization, suggesting that MRS could yield a greater benefit in those that present inducible ischemia in comparison to those that do not.
The limitations presented in our study are inherent to the retrospective character of the study, including the impossibility of having in all cases, the detailed characteristics of the functional test, as well as the percentage of ischemic amount and ventricular dimensions. On the other hand, variability in follow-up of patients prevents a proper analysis of characteristics such as the percentage of improvement of LVEF and cardiac remodeling, considering this information as additional but relevant to make decisions. Moreover, we should mention the size of the sample in our study, given the scant number of patients presenting the characteristics sought, which could have led to a considerable error number of the Beta type, requiring greater statistical power to find the differences between both arms.
The presence of presurgical inducible myocardial ischemia in patients with severe LVEF impairment who underwent isolated elective myocardial revascularization surgery allows to identify a subgroup of patients with better prognosis, presenting a lower rate of mortality in follow-up, losing statistical significance when taking into account the immediate postoperative period complications. Besides the composite secondary endpoint of in-hospital mortality or presence of low cardiac output was significantly lower in patients with inducible myocardial ischemia.
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