Evidence for Pre- to Postsynaptic Mismatch of the Cardiac Sympathetic Nervous System in Ischemic Congestive Heart Failure

Abstract

Pre-and postsynaptic cardiac sympathetic function is altered in ischemic congestive heart failure (CHF). Whether there is a presynaptic-to-postsynaptic mismatch or whether mismatch is related to adverse cardiac events is unknown. Methods: In 13 patients with ischemic CHF and 25 aged-matched healthy volunteers, presynaptic function was measured by PET of 11 Cmeta-hydroxyephedrine ( 11 C-mHED), a norepinephrine (NE) analog. Postsynaptic function, b-adrenergic receptor (BAR) density (B9 max ), was measured by imaging 11 C-CGP12177. Myocardial blood flow (MBF) was measured by imaging 15 O-water. Each heart was analyzed both globally and regionally, excluding infarcted regions, and a mismatch score, defined as the ratio of B9 max to NE uptake (PS nt ) , was used to indicate mismatch of post-and presynaptic function. Results: Global and regional MBF was not different between CHF and healthy subjects. The global measure of PS nt was lower in CHF (0.32 6 0.34) than that in healthy subjects (0.81 6 0.33, P , 0.0001) and in all 12 regions. Global B9 max tended to be lower in CHF than that in healthy subjects (10.0 6 6.4 pmol/mL vs. 13.4 6 4.2, P 5 0.056) and in all 12 regions. The global mismatch score (B9 max :PS nt ) in CHF patients was significantly greater than that in healthy subjects (50.3 6 50.7 vs. 19.3 6 9.7, P 5 0.005) and also greater in 11 of 12 regions. After 1.5 y of follow-up, 4 individuals had an adverse outcome (CHF death, new or recurrent sudden death, or progressive CHF leading to transplantation). Three of the 4 had mismatch scores . 3 times that of the healthy subjects or the CHF patients without an adverse outcome. Conclusion: Mismatch between pre-and postsynaptic left ventricular sympathetic function is present in patients with severe CHF and may be more marked in those with adverse outcomes.

Imaging Targets of the Sympathetic Nervous System of the Heart: Translational Considerations

“…Table 2 provides an overview. Combinations of autonomic imaging agents have, for example, been used to identify an imbalance between presynaptic neuronal integrity and postsynaptic receptor density in progressive heart failure (18), to show that postsynaptic receptor density and downstream signaling may be impaired despite intact presynaptic catecholamine uptake in adriamycin-induced cardiotoxicity (19) or to show that parasympathetic muscarinic receptors may be upregulated after myocardial infarction (20).…”

“…This ability helps to clarify the importance of regional heterogeneity versus globally impaired innervation. Of note, new 18 F-labeled tracers, such as 18 F-LMI1195, are under investigation and may become a commercial product in the future (12).…”

“…Translational efforts in neuronal imaging are setting a precedent for the entire field of cardiovascular molecular imaging. The catecholamine analog 123 I-metaiodobenzylguanidine ( 123 I-MIBG) is likely to become the next Food and Drug Administration-approved radiotracer for nonperfusion cardiac imaging, more than a decade after the approval of 18 F-FDG for viability (4). It is hoped that other molecular agents will follow.…”

Introduction to Cardiac Neuronal Imaging: A Clinical Perspective

“…Research with compounds labeled with tritium ( 3 H), 14 C, and 125 I laid the groundwork for the development of compounds labeled with g-and positron-emitting radioisotopes (6). These latter developments permitted external imaging of living animals with scintillationdetection devices and gave rise to the use of nuclear medicine techniques for neuronal imaging in the second half of the 20th century (7)(8)(9)(10).…”

What future for the myocardial sympathetic innervation imaging?

“…An impaired function of presynaptic sympathetic nerve terminals is considered to reflect impaired reuptake and thus impaired removal of the neurotransmitter from the synaptic cleft [1], resulting in overexposure of the myocardium to catecholamines and in a pre/post-synaptic signaling imbalance [2]. Consistent with this pathophysiologic model, prospective, large-scale clinical trials confirmed an excellent prognostic value of adrenergic imaging in patients with heart failure, both with single photon emission tomography (SPECT) and with positron emission tomography (PET) [3,4].…”