When the Heart Loses Its Nerves…and How Nuclear Imaging Helps to Understand

The first report on the application of radiolabeled catecholamine analogs for nuclear imaging of the presynaptic sympathetic nervous system of the heart now dates back more than 20 years (1). Since then, considerable knowledge on cardiac pathophysiology has been gained using SPECT and PET neurocardiac imaging. Scintigraphic techniques have played a key role in identifying involvement of presynaptic innervation in development and progression of heart failure, in establishing a link between autonomic dysinnervation and arrhythmia, in describing regional patterns and consequences of diabetic cardiac autonomic neuropathy and reinnervation of the transplanted heart, and in identifying the contribution of cardiac presynaptic sympathetic innervation to several other cardiac and noncardiac diseases (2,3).

Because coronary artery disease and its complications still represent the primary cause of morbidity and mortality in industrialized nations, the influence of myocardial ischemia on sympathetic nerve function and integrity has always been of special interest to cardiac neuroscientists. Presynaptic heterogeneity and disturbance of pre- and postsynaptic balance are thought to increase the risk of arrhythmia (4). Additionally, the lack of presynaptic catecholamine reuptake may increase exposure of the myocardium to catecholamines and thereby impair contractile function (5). Through these mechanisms, presynaptic dysinnervation is thought to contribute to adverse outcome in ischemic heart disease (6).

The first mechanistic studies using PET in dogs showed that short periods of ischemia result in sustained regional abnormalities of the presynaptic catecholamine uptake-1 mechanism (7). Subsequent observations of denervation exceeding the area of scarring after myocardial infarction (8,9), and of denervated areas in patients with coronary artery disease but without myocardial infarction (10,11), have corroborated the notion that sympathetic nerve terminals are more sensitive to ischemia than are myocardial cells.

The study by Luisi et al. (12) on pages 1368–1374 of this issue of The Journal of Nuclear Medicine sheds more light on the interrelationship between myocardial ischemia and sympathetic nerve integrity. In a unique pig model of chronic ischemia, which results in hibernating myocardium, the authors describe a persisting regional reduction of PET-determined uptake of the catecholamine analog ¹¹C-hydroxyephedrine (HED) in the absence of myocardial infarction. These data demonstrate that presynaptic sympathetic norepinephrine uptake-1 is impaired in hibernating myocardium. Clinical implications are suggested by the experimental study: In patients with advanced coronary artery disease and left ventricular dysfunction, ischemically compromised but viable (hibernating) myocardium is frequently found and associated with considerable risk of cardiac events (13). Chronic alterations in sympathetic innervation thus seem to contribute to the high mortality seen in the setting of hibernating myocardium.

It is a strength of the study by Luisi et al. (12) that the applied model of chronic ischemically compromised myocardium is well established and characterized so that a clear identification of the effects of chronic hypoperfusion on sympathetic nerve terminals in the absence of confounding factors is possible. At the same time, however, difficulties can be anticipated when one tries to translate knowledge from this pathophysiologic experimental study into a clinical application for imaging. Unlike in the animals, in the typical patient with advanced coronary artery disease and left ventricular dysfunction, regional hibernation will coexist with areas of stunning, nontransmural scars, or transmural scars (14). Also, myocardial hibernation has been described as an unstable process with a continuous transition to myocardial fibrosis and scarring (15). Such heterogeneity will result in a much more complex situation in patients, underlining the fact that identification of a clear clinical role for cardiac neuroimaging in patients with advanced coronary artery disease will be a challenge.

Although cardiac neuroimaging has now been available for decades, it is remarkable that the community has not yet succeeded in establishing a generally accepted clinical indication—neither in ischemic heart disease nor in other heart diseases. Numerous published studies have provided biologic insight into disease mechanisms or into therapy effects, but the patient groups under clinical investigations often have been small, and the studied diseases have sometimes not been common. Ideally, well-designed experimental studies on animal models of clinically relevant disease, such as the study presented by Luisi et al. (12), should be followed by translational efforts and prospective clinical trials that evaluate a clinical role for imaging. In their article, the authors point out that such studies are under way in patients with advanced ischemic heart disease, and results can be eagerly awaited.

Although the clinical usefulness of existing cardiac neuroimaging tools should be pursued consistently, refinement of methodology itself is also desirable. Another important finding of the study by Luisi et al. (12) is the superiority of HED over the single-photon–emitting norepinephrine analog metaiodobenzylguanidine, which they used in a similar setting previously (16). With HED, the authors observed significantly lower nonspecific tracer uptake and thus better signal-to-noise ratios, suggesting that the PET-based approach is preferable. It is tempting to speculate that a PET-based technique, if broadly available, would allow a more rapid establishment of conclusive clinical indications for neurocardiac imaging. Despite the spreading of PET cameras because of their success in oncology, however, the availability of short-lived ¹¹C-labeled tracers such as HED will be limited to the few centers near a cyclotron. Introduction of a reliable ¹⁸F-labeled compound with similar characteristics may thus be of considerable value.

A broader spectrum of different neuronal tracers would also be desirable for the dissection of different aspects of presynaptic autonomic nerve integrity and function. A common limitation of currently used tracers is that a reduction in myocardial uptake may reflect either loss of nerve terminals (structural denervation) or downregulation of the uptake-1 mechanism in dysfunctioning but still present nerve terminals (dysinnervation). Both conditions may differ in their capability to recover during therapy (17). A marker that allows differentiation between true denervation and dysinnervation may thus be of additional clinical value, as may markers of other specific autonomic components such as sympathetic tone, parasympathetic innervation, or receptors. Several such tracers are presently under development (18) and, it is hoped, will contribute to furthering the growth of cardiac neuroimaging.

The heart seems to lose its nerves easily. Undoubtedly, nuclear imaging techniques have great value in helping to understand the reasons and consequences. But the key for an even brighter future will be to find clinically accepted indications and, thus, ways for imaging to help in keeping or regaining the nerves.