Keywords
INTRODUCTION
Coronary artery disease is the most frequent cause of cardiovascular mortality in Europe, with almost 2 million deaths per year.1 Within this context, ischemic heart disease with moderately or severely decreased systolic function (ejection fraction ≤35%-40%), ie, ischemic cardiomyopathy (IC), involves very high rates of cardiac mortality (CM): nineteen percent during an average follow-up of 22 (14) months.2 Contractile dysfunction may be caused by necrosis or by so-called viable myocardium. This term refers to living myocardium in the presence of severe contractile abnormalities and can indicate myocardial stunning or hibernation. Stunning is a form of myocardial contractile dysfunction caused by a transitory ischemic episode or reperfusion injury. Such contractile dysfunction can persist for hours or days, but, providing reperfusion recovers, then contractile activity recovers. Myocardial hibernation is another type of contractile dysfunction, but is found within the framework of chronic ischemic heart disease. Unlike stunned myocardium, in which contractile activity spontaneously reverts, myocardial hibernation requires coronary revascularization (CR) to recover ventricular function.
In our experience,3,4 patients with IC present a history of infarction in 84% of cases and multivessel disease has a prevalence of 78%. Around 70% of the patients have scintigraphic criteria of myocardial viability (MV) in 3 or more of the segments with severe contractile abnormalities. This corresponds to 17.6% of the 17 segments into which the left ventricle (LV) is divided for the purposes of imaging techniques, as recommended. When a challenge test can be performed, using exercise or drugs, scintigraphic ischemia can be observed in more than half of the cases.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of IC basically focuses on idiopathic dilated myocardiopathy. The definitive technique for differential diagnosis continues to be coronary angiography, but despite this, different noninvasive techniques, such as echocardiography, radionuclide angiography, magnetic resonance imaging, and computed tomography, can provide orientative criteria for one type of myocardiopathy or another.5-18
In gated myocardial perfusion Single-Photon Emission Computed Tomography (SPECT) studies using thallium 201 (201Tl) or technetium compounds (99mTc-tetrofosmin and 99mTc-methoxyisobutyl isonitrile), different variables have been observed that are hallmarks of IC, such as the presence of extensive myocardial perfusion abnormalities at rest,6-8 the complete absence of segmental uptake,9 abnormalities in segmental wall motion,10 summed stress perfusion score,11 the extent of stress perfusion defect,12,13 and the presence of myocardial ischemia.12,14 In our opinion, when using gated myocardial perfusion SPECT with technetium compounds, the most specific criteria (although having low sensitivity) for IC are the presence of at least 1 wall segment with grade 4 perfusion (absence of uptake) at rest and a divergent pattern of the LV (apical transverse diameter > transverse diameter) (Figure 1).
Figure. 1. Left: divergent left ventricular pattern (transversal diameter at the apical level > transversal diameter at the basal level in vertical long-axis view) and absence of anteroapical uptake in myocardial perfusion SPECT at rest in a patient with anterior infarction. These criteria are highly specific for myocardial nonviability. Right: gated-SPECT of the same patient in whom anterior akinesia and septal and apical dyskinesia can be observed. End-diastolic volume, 248 mL; end-systolic volume, 203 mL; ejection fraction, 18%. Ant indicates anterior; Inf, inferior; SPECT, Single-Photon Emission Computed Tomography.
In magnetic resonance imaging studies, the presence of late gadolinium enhancement at subendocardiac or transmural levels strongly indicates IC.19,20 Cardiac catheterization,21,22 and more recently, coronary angiography by multidetector computed tomography,23,24 which has a very high negative predictive value, are the techniques of choice for differential diagnosis.
CRITERIA FOR VIABILITY AND DIAGNOSTIC EFFICACY Of GATED-SPECT AND GATED-PET
The most suitable isotopic technique for the study of MV is gated-Positron Emission Tomography (PET), which offers the possibility of assessing contractile function, using ECG synchronization, perfusion and glucose and fatty acid metabolism. The so-called mismatch pattern (or perfusion-metabolism mismatch) is the basic criterion for the diagnosis of MV (Figure 2). Despite this, in the clinical context, and for reasons of cost-efficiency, the most used technique is gated-SPECT which, at present, is more often performed with technetium compounds than with 201Tl, since image quality is superior using the former techinque.25
Figure 2. Example of anteroapical myocardial viability in PET images in vertical long-axis view: mismatch pattern or disagreement between the perfusion image with abnormal rubidium-82 uptake (left) and that of preserved metabolism with 18F-deoxyglucose (right). PET indicates Positron Emission Tomography.
The MV study should be conducted in regions or segments with severe myocardial wall motion abnormalities. The administration of nitrates prior to radionuclide administration is advisable, since it increases test sensitivity. Electrocardiographic synchronization (gated-SPECT) enables the evaluation of myocardial excursion and wall thickening. The criteria for MV using gated-SPECT are based on the degree of uptake of the radionuclide compared to the maximum LV uptake at rest or after reinjection of the radionuclide in the case of 201Tl, when objectifying myocardial thickening and the presence of stress-rest reversibility. When using gated-SPECT and technetium compounds, our experience-based criteria3,4 are perfusion with a score of 0-2 out of a total of 4 (>30%-40% uptake compared to maximum uptake) (Figure 3) and preserved wall thickening (score 0-2) (Figure 4). Whenever possible, a stress test or drug challenge is recommended, because the presence of stress-rest reversibility, ie, ischemia, indicates viability (Figure 5).
Figure 3. SPECT images of myocardial perfusion at rest (vertical long-axis view) of a patient with anterior infarction and criteria of myocardial viability. The apical akinesia region (right) indicates to moderate (grade 2) perfusion uptake defect (left). End-diastolic volume, 123 mL; end-systolic volume, 81 mL; ejection fraction, 34%. Ant indicates anterior; Inf, inferior; SPECT, Single-Photon Emission Computed Tomography.
Figure 4. Images in diastole and systole using gated-myocardial perfusion SPECT at rest (vertical long-axis view) of the same patient referred to in Figure 3. A moderate alteration (degree 2) in thickening can be observed in the anteroapical region. SPECT indicates Single-Photon Emission Computed Tomography.
Figure 5. Residual ischemia after infarction in the anteroapical region in vertical long-axis view myocardial perfusion SPECT images of the same patient referred to in Figures 3 and 4. Reversibility can be observed between the uptake during stress and at rest. SPECT indicates Single-Photon Emission Computed Tomography.
Tables 1-326-65 show the scintigraphic criteria for MV and Table 4 and Figure 6 present a summary of the efficiency of PET, SPECT, echocardiography, and magnetic resonance imaging in predicting improved systolic function after CR.27,28,35,41-44,46,48,51,64,66-73 As can be seen, the negative predictive value of all these tests is higher than the positive predictive value, which means that in clinical practice these may be more reliable when predicting regions that are not going to recover following revascularization.
Figure 6. Total mean percentages of sensitivity (S), specificity (Sp), efficacy (Ef), and predictive values (PV) of different imaging techniques for the diagnosis of myocardial viability.27,28,35,42,41-44,46,48,51,64,66-73 ECHO indicates echocardiogram; MRI, magnetic resonance imaging; PET, Positron Emission Tomography; SPECT, Single-Photon Emission Computed Tomography.
Although the diagnostic criteria for MV are quite clear regarding wall segments, there is no consensus on what quantity of viable tissue is needed such that the LV significantly improves its general function after revascularization. In our series, we considered that a patient has scintigraphic criteria of viability when viable myocardium is found in 3 or more of the segments with severe contractile abnormalities. This corresponds to 18% of the total area of the LV.3,4 This cut-off value is related to those found in PET studies in which a mismatch pattern ≥18% demonstrated significant benefit after a CR procedure.74
COURSE OF LEFT VENTRICULAR SYSTOLIC FUNCTION AFTER REVASCULARIZATION
In IC patients, improved ejection fraction (EF) may often be observed during medical treatment due its anti-ischemic effects, as well as spontaneous improvement if dysfunction is due to myocardial stunning.75-77 After a CR procedure, a significant increase (≥5%) can be observed in 29%42 to 65%78 of patients, although the greatest benefit is found in patients with criteria of viability or myocardial ischemia providing it is associated with a moderate or severe reduction in EF, especially if CR is not delayed.79,80 Between 59% and 92% of IC patients present improved symptoms of heart failure after CR.75,81 Hibernating myocardium is usually associated with alterations in LV volume and shape that can also revert after successful CR.82,83 In gated myocardial perfusion SPECT studies, left ventricular remodeling finds its greatest expression when there is a divergent pattern of the left ventricle.3,84 The greater the interval between acute myocardial infarction and gated-SPECT, the greater the prevalence of LV remodeling.
In IC patients, chronic angina, when present at least 30 days before infarction, can significantly influence the extent of necrosis, the diagnosis of MV and ventricular remodeling. Observational data indicate a prevalence of 21% of chronic angina prior to infarction, offering a protective effect against IC characterized by a smaller necrotic area, less left ventricular remodeling and a greater percentage of patients with scintigraphic criteria of MV.76
VARIABLES PREDICTIVE OF IMPROVED LEFT VENTRICULAR SYSTOLIC FUNCTION AFTER REVASCULARIZATION
Table 5 presents a summary of the predictors of improved LVEF in echocardiographic, magnetic resonance imaging, and radionuclide angiography studies.42,50,58,69,70,79,85-103 These variables are direct or indirect markers of ischemia, viability, and LV remodeling. In our experience,50 patients with a increase of EF ≥5% after surgery are characterized by having a greater prevalence of left main coronary artery disease and, as assessed by scintigraphy, greater ischemic burden. SPECT imaging indicates that a summed differential stress-rest perfusion score ≥4 is predictive of a significant increase of EF. However, left ventricular dilatation (end-systolic volume >145 mL or end-diastolic volume >190 mL) is the most significant variable showing that EF does not undergo improvement in the presence of MV. Other authors have observed that in patients with less than 6 viable segments (35% of the LV) and an end-systolic volume >145 mL, the probability of increasing EF post-CR is very limited.102
In the presence of myocardial hibernation, post-CR contractile recovery usually occurs relatively early.104 Patients who in earlier dobutamine studies present greater contractile reserve recover the function at rest; however, those who do not present recovered function at rest, despite having contractile reserve, tend to present greater myocardial ischemia prior to revascularization. Dobutamine echocardiography studies are very accurate for predicting the recovery of ventricular function, but can underestimate the degree of late recovery.105
PROGNOSTIC VALUE OF GATED-SPECT AND GATED-PET
The prognostic variables that have been described in IC patients are presented in Table 6.24,52,55,106-115 In our experience, the most important variables are age, the inability to perform the stress test, exercise capacity, MV, myocardial ischemia, left ventricular remodeling and CR.3,4,116,117
Myocardial viability is significantly associated with cardiac mortality and its prognostic value increases even more when it is associated with myocardial ischemia. For this reason, it is advisable to adopt, whenever the patient can tolerate it, stress-rest protocols with the aim of preserving information on the presence and severity of myocardial ischemia, either in the same region as the necrosis or at a distance.
Another variable of prognostic value is the degree of LV remodeling. Gated-PET studies using fluorodeoxyglucose have reported an end-systolic volume ≥200 mL or end-diastolic volume ≥260 mL2 as predictors of cardiac mortality. In the presence of MV, a divergent pattern of the LV as assessed by scintigraphy—a sign of apical aneurysm—is associated with mortality in general and cardiac mortality due to heart failure.3,118,119
In our experience,4 during a follow-up of 2.3 (1.2) years of 167 patients with IC, cardiac mortality was 17.4% and the scintigraphic criterion of MV was an independent predictor of cardiac mortality using gated-SPECT at rest (P=.027; HR=5.1; 95% confidence interval [CI], 1.2-21.4). In the 137 patients who could undergo stress gated-SPECT, the predictors were ischemia + scintigraphic viability (P=.026; HR=3.6; 95% CI, 1.16-11.2) and an exercise duration of ≤5 min (P=.04; HR=2.7; 95% CI, 1.01-7.36). The variables derived from coronary angiography—performed in 111 patients—did not significantly modify the prognosis of the noninvasive variables (Figure 7).
Figure 7. Incremental prognostic value of cardiac death according to the independent variables obtained in the multivariate analysis: clinical characteristics (age >65 years, inability to perform a stress test), of gated-SPECT during stress (duration of exercise <5 min scintigraphic ischemia viability and coronary angiographies proximal stenosis 4 spect indicates single-photon emission computed tomography p
In a metaanalysis which included SPECT, PET, and echocardiographic studies, a close association was observed between MV and a significant improvement in survival after a CR procedure; this was not the case among patients without criteria for MV.120 We obtained similar outcomes in our series of IC patients who were studied using gated myocardial perfusion SPECT, observing greater CM in the patients with criteria for MV who did not undergo revascularization (Figure 8).116,117
Figure 8. Cardiac mortality is significantly higher in the patients with scintigraphic criteria of viability who did not undergo revascularization than in the patients with viability who underwent revascularization and in the patients without criteria for viability.116 CR indicates coronary revascularization; NCR, no coronary revascularization; NV, non-viable; V, viability.
In clinical practice, therapeutic decision-making is based on symptoms, myocardial ischemia, ventricular function, MV, coronary anatomy, and comorbidities. Patients who have undergone coronary angiography are in general more symptomatic, have a more depressed LV systolic function and a greater degree of myocardial ischemia as assessed by gated myocardial perfusion SPECT.
In practice, we believe that the decision to indicate coronary angiography and CR is based more on the demonstration of ischemia in the SPECT images, together with less LV remodeling, than on the presence of MV. The main reason for coronary angiography in the patients without myocardial viability is scintigraphic ischemia in non-necrotic regions, that is, ischemia at a distance. Revascularization procedures are more frequent in patients in whom SPECT is performed prior to cardiac catheterization, probably because coronary angiography is often no longer indicated when no criteria of MV or ischemic criteria are observed according to SPECT or PET.
The other therapeutic option in IC patients is cardiac resynchronization therapy. It has been shown that the phase analysis of ECG-gated SPECT myocardial perfusion imaging and ECG-gated PET myocardial perfusion imaging enables the assessment of LV dyssynchrony and the selection of potential candidates for resynchronization.121-127 Resynchronization therapy does not lead to improved symptoms or ventricular function in approximately 40% of the patients undergoing this procedure.125 It has been observed that patients with lateral scar tissue have a lower probability of response to resynchronization therapy.128-131
CONCLUSIONS
Ischemic cardiomyopathy is a disease with high mortality and whose prognosis is basically influenced by exclusively cardiac variables, such as ischemia and myocardial viability, the degree of ventricular remodeling and exercise tolerance. Gated-SPECT and gated-PET techniques are very suitable tools for studying these patients, as they provide information on perfusion and myocardial metabolism, systolic function, remodeling, and ventricular synchrony.
Correspondence: Dr. J. Candell-Riera.
Servei de Cardiologia. Hospital Universitari Vall d'Hebron. Universitat Autònoma de Barcelona.
Pg. Vall d'Hebron, 119-129. 08035 Barcelona. España.
E-mail: jcandell@vhebron.net