There is a general consensus that cardiac sympathetic neuronal function plays an important role for the pathogenesis of HF [
2]. It is also known that an elevated circulating norepinephrine is a marker of poor outcome [
17]. Using imaging techniques with radio-labeled norepinephrine analogs such as
123I-MIBG, there are a number of studies showing the prognostic value of cardiac sympathetic neuronal imaging, where the patients with low myocardial
123I-MIBG uptake as measured by semi-quantitative heart-to-mediastinum (H/M) uptake ratio are associated with poor prognosis [
8,
9,
16,
18‐
20]. As compared to the aforementioned
123I-MIBG imaging,
11C-HED PET is considered to be a more sophisticated technique with higher image quality and opportunity of quantification of absolute tracer uptake. Additionally, an advantage of
11C-HED PET over
123I-MIBG imaging is that it provides higher tomographic image quality and, therefore, is more suitable for regional assessment, as demonstrated in our previous study [
10]. However, there are only two studies that have systemically investigated the prognostic value of
11C-HED PET due to its limited availability. A retrospective study by Pietila et al. [
11] of 46 patients with chronic heart failure (CHF) indicated that CHF patients had significantly lower global
11C-HED retention than healthy subjects, and that patients with poor prognosis (death or transplantation) had even lower retention. More recently, Fallavollita et al. [
12] have demonstrated that regional myocardial sympathetic denervation assessed by
11C-HED PET was predictive for the risk of sudden cardiac arrest in 204 ischemic HF patients who had undergone implantable cardioverter defibrillator therapy. Our results demonstrated that age and low global
11C-HED retention were independent predictors of all-cause mortality, which remained true when multivariate analysis was performed, indicating that cardiac sympathetic dysinnervation as measured by
11C-HED PET is related to poor survival in patients with LV dysfunction independent of age. Regional parameters such as
11C-HED defect size were not significant predictors of all-cause mortality in this study, although there was a trend toward larger perfusion/
11C-HED mismatch size in patients with death as compared to those without death. This indicates that global rather than regional sympathetic dysinnervation is a better marker of overall mortality. An issue that needs to be addressed is that all-cause mortality includes patients died of non-cardiac disease, including those of malignancy, traffic accident, and unknown cause. Although the exact mechanisms are not clear, it could be possible that the presence of severe HF as reflected by low global
11C-HED retention may have unfavorably affected overall survival even in such patients.
Although all-cause mortality is considered to be an objective and unbiased clinical endpoint, the selection of endpoint is still a matter of debate [
13]. Therefore, we additionally assessed other endpoints such as cardiac death and composite endpoint. Cardiac death is a cause-specific and commonly used endpoint in clinical studies in patients with heart disease [
8,
9,
16,
18‐
20]. The results showed that, although the patients with cardiac death tended to be associated with a larger
11C-HED defect than those without death, the PET derived parameters failed to show predictive power for cardiac death. The small sample size as well as potential misclassification of patients who actually died of cardiac cause as non-cardiac may explain the results. However, serum BNP level, a conventional parameter for HF severity, was still a significant predictor of cardiac death despite the small sample size, indicating that
11C-HED parameters have less significant predictive power than serum BNP in this setting. Thus, the prognostic value of
11C-HED PET may differ depending on what endpoint is chosen.
For the composite endpoint including any cardiac event and any death, the patients with events were associated with a lower global 11C-HED retention and higher serum BNP level than those without event. However, in multivariate analysis, only serum BNP survived as a significant predictor of the endpoint. Whether 11C-HED PET parameters would provide incremental prognostic value to serum BNP needs to be addressed in larger trials in future.
A potential advantage of employing
11C-HED PET instead of serum BNP would be that regional abnormalities can be assessed using PET technique. As aforementioned, a study by Fallavollita et al. [
12] has demonstrated that regional but not global denervation is a predictor of sudden cardiac death. In our study, however, the prognostic value of regional parameters such as HED defect size was not clear mainly because of the limited sample size. Thus, our data have demonstrated that measuring serum BNP is still convenient and useful tool for prediction of cardiac event in any underlying causes.