Metabolic imaging: predicting recovery of function in heart failure

Dr Roxy Senior, Dr A. Lahiri
Department of Cardiovascular Medicine, Northwick Park Hospital, Harrow, UK

During the past 20–30 years, coronary heart disease mortality rates have declined steadily in Western countries.[1,2] Despite this trend, which has been attributed to a combination of primary preventive measures and improved disease management,[2,3] heart failure remains an important and increasing public health problem.[4–7] Admissions to hospital because of heart failure seem to be increasing, due partly to ageing populations and to greater survival of patients with coronary heart disease. Substantial health care expenditure is required for heart failure management, of which hospital-related costs account for the largest proportion.[7,8]
Coronary artery disease (CAD) is the commonest cause of heart failure in the Western world accounting for up to 60% of cases.[9] It was demonstrated more than 20 years ago that resting wall motion abnormality in patients with CAD can improve after administration of an inotropic agent, nitroglycerine or after coronary artery bypass.[10–12] The term ‘hibernation’ was first used by Diamond et al.[13] in 1978 to describe chronic wall motion abnormalities in patients with CAD but no previous myocardial infarction and their reversibility after revascularization, and this term was subsequently popularized by Rahimtoola.[14]
Thus for the first time it was realized that patients with heart failure secondary to CAD may have dysfunctional myocardium that may become functional following revascularization.

Pathophysiology of reversible dysfunctional myocardium
Histological studies on bioptic material obtained at the time of surgery have produced evidence of profound structural changes in chronically dysfunctional but viable myocardium.[15,16] These changes comprise: progressive loss of contractile proteins (sarcomeres) without loss of cell volume, distinct from atrophic degeneration; increase in glycogen; loss of sarcoplasmic reticulum; and loss of T-tubules. These changes are suggestive of dedifferentiation because they resemble fetal cardiomyocytes. Myocardial tissue characterized by such changes is not likely to regain function immediately after revascularization but might require time to regain sufficient contractile material. However, the finding that some patients regain function rapidly whereas others have a delayed recovery suggests that the histological pattern cannot be the same in all patients with CAD and chronic left ventricular dysfunction.
Positron emission tomography (PET) with positron-emitting radiopharmaceuticals has made possible the study in vivo of myocardial perfusion and metabolism in man. In this technique, ¹³N-ammonia serves as an indicator of relative regional myocardial blood flow. Relative myocardial glucose utilization is assessed with ¹⁸F-2 fluoro-2-deoxyglucose (FDG) a labelled glucose analogue that undergoes facilitated transport into the cell and phosphorylation by hexokinase. Metabolically chronically dysfunctional myocardium is characterized by increased glucose utilization as shown by increased FDG uptake assessed by PET. These data have been confirmed by two other groups.[19,20] In normal subjects studied after overnight fasting, myocardial FDG uptake is extremely low due to prevailing lipid utilization. In contrast, myocardial blood flow as assessed by ¹³N-ammonia using PET is either normal[22] or reduced in the dysfunctional myocardium. Thus, three scenarios may exist in a patient with heart failure and left ventricular dysfunction due to CAD (Figure 1):
• reduced ¹³N-ammonia uptake and reduced glucose uptake suggestive of necrotic myocardium;
• reduced ¹³N-ammonia but increased FDG uptake (perfusion metabolism mismatch) suggestive of hibernating myocardium;
• normal ¹³N-ammonia uptake with increased FDG uptake suggestive of repetitive stunning.

Figure 1. Short axis slices of the left ventricle using PET scan. (Left) Normal to mildly reduced 13N-ammonia uptake in the anterior wall and absent perfusion in the posterior wall. (Right) Increased FDG uptake in the anterior wall suggestive of hibernating myocardium, and absent uptake in the posterior wall suggestive of necrosis.

Currently PET with FDG is considered one of the most accurate techniques for identifying viable myocardium.

Diagnostic accuracy of predicting regional improvement after revascularization
Many studies have shown that FDG PET is accurate in predicting functional recovery in patients undergoing revascularization.24 The results of these studies are summarized in Table 1. The sensitivity ranged from 71 to 100% with a weighted mean of 88%. The specificity ranged from 38 to 91% with a weighted mean of 73%.

Table 1. Sensitivity and specificity of FDG PET for detection of improved regional contractile function after revascularization. (References to all listed studies can be found in Bax et al.[24])

Table 2. Sensitivity and specificity of different imaging techniques (based on weighted mean values from available studies).[24]

While the sensitivity of FDG PET is higher, the specificity of dobutamine echocardiography is higher for predicting recovery of function following revascularization. This is not surprising. Metabolic activity of viable cells may be present in a severely differentiated myocardial region which might not recover function at all following revascularization and these regions are unlikely to show contractile reserve because of lack of contractile protein.
However, what is not known is the time interval of recovery of function of these regions and the effect of these viable cells on remodelling and hence prognosis. In an elegant study by Melon et al.,[41] the relation between contractile reserve and patterns of perfusion and glucose utilization on PET in chronic ischaemic left ventricular dysfunction was investigated. Six patterns of perfusion and metabolism were identified. These were compared to the presence or absence of contractile reserve (Figure 2). 

Figure 2. Distribution of segments with (yellow portions) and without (green portions) contractile reserve according to the six categories of perfusion and [18F]FDG uptake. Category 1: reduced perfusion and moderate FDG reduction; category 2: proportional reduction of perfusion and FDG; category 3: perfusion metabolism mismatch; category 4: preserved perfusion but moderate reduction of FDG; category 5: preserved perfusion and FDG uptake; category 6: normal perfusion and increased FDG uptake.[41]

In this study, myocardial regions with a traditional mismatch pattern of viability showed contractile reserve in 50% of segments. In segments with moderate reduction of FDG, the contractile response to dobutamine was linked to the level of rest perfusion. Most segments with preserved perfusion and increased FDG uptake have impaired rest function but contractile reserve was still present. Thus there is a heterogeneous existence of contractile reserve, metabolism and perfusion characteristics in patients with chronic ischaemic cardiomyopathy.

Survival and presence of metabolically active myocardium
Di Carli et al.[42] showed that the mere presence of dysfunctional myocardium which was metabolically active as determined by PET had an improved survival following revascularization in comparison with medical therapy. Figure 3 shows the Kaplan-Meier survival curves in the study.

Figure 3. Cumulative survival of patients by presence or absence of PET mismatch and mode of treatment (i.e. medical therapy or revascularization).[42]

In another study by Di Carli et al.,[43] the authors found that PET mismatch of more than 18% was associated with a sensitivity and specificity of 76% and 78%, respectively, for predicting change in functional status after revascularization. Patients with a mismatch greater than 18% achieved a significantly higher functional status compared with those with a minimal or no PET mismatch. 

Conclusion
In patients with heart failure and left ventricular dysfunction due to CAD it is important to assess the presence and extent of viable myocardium. Mortality is high in this group of patients on medical therapy. Mortality is also high in these patients who undergo revascularization. However, the presence and extent of viable myocardium considerably improves survival following revascularization. Although there are no randomized studies supporting this concept, there are numerous non-randomized studies favouring this strategy. It is important, however, to conduct a randomized study in patients with heart failure and CAD to establish the benefit of revascularization in patients with metabolically active but dysfunctional myocardium.

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