The focus of most research into myocardial sympathetic neuronal imaging has been on NE
analogues labeled with gamma- or positron-emitting radioisotopes. The most widely studied
conventional nuclear imaging agent is 123I-metaiodobenzylguanidine (123I-mIBG), which
provides effective and well-validated semi-quantitative information. In the pivotal trial
(ADMIRE-HF) on which the US approval of 123I-mIBG for cardiac imaging was based, there
was an increased occurrence of adverse outcomes (composite of HF progression, potentially
fatal arrhythmias, and cardiac death) in HF subjects based upon the heart/mediastinum
(H/M) ratio on late ("delayed") planar 123I-mIBG (AdreView™) images. Analyses of
all-cause mortality in the ADMIRE-HFX extension study confirmed the low risk associated
with H/M ≥1.60 (2-year mortality of 4%). Subsequent analyses specifically focused on
arrhythmic events suggested that sympathetic neuronal imaging could aid in discriminating
between low and higher risk cohorts. However, 123I-mIBG imaging results are heavily
dependent on the imaging equipment and acquisition techniques used, and global
standardization efforts have had limited success. In addition, absolute quantitation of
myocardial uptake and clearance kinetics cannot be effectively achieved using
single-photon emission computed tomography (SPECT), even with use of attenuation and
scatter correction methods. These limitations and the high cost of the procedure have
severely limited its use in clinical practice.
The preferred nuclear technique for high-resolution quantitative imaging of cellular
functional behavior is PET. The present research will utilize a new 18F-labeled
radiopharmaceutical, 18F-meta-fluorobenzylguanidine (18F-mFBG). The greatest advantage of
this agent is its structural equivalence to 123I-mIBG, with the 123I atom in the latter
replaced by a 18F atom.
The vast clinical and research experience with mIBG provides a strong basis for the
expected performance of 18F-mFBG. In addition, animal and limited human experience
suggests that clearance of 18F-mFBG from blood and certain target organs is more rapid
than mIBG, such that target-background ratios (TBRs) for the heart should be superior for
18F-mFBG, improving both image quality and reliability of global and regional myocardial
quantitation. To date, the focus of most research using 18F-mFBG has been on its use as
an imaging agent for neural crest tumors such as neuroblastoma and pheochromocytoma (22).
However, analyses of myocardial 18F-mFBG uptake in patients being evaluated for neural
crest tumors suggested this agent could be effective as a cardiac imaging agent.
Past analyses of cardiac sympathetic imaging results have suggested this method might be
of value for identifying heart disease patients at greater risk for arrhythmic events and
sudden cardiac arrest (SCA). The largest prospective study on this topic enrolled 204
subjects eligible for implantable cardioverter defibrillators (LVEF ≤35%) who underwent
cardiac PET imaging for myocardial sympathetic denervation using
11C-meta-hydroxyephedrine (11C-HED). The results showed that volume of denervated
myocardium had the strongest correlation with SCA (arrhythmic death or defibrillator
discharge). The 33 subjects with SCA had significantly larger denervated volumes than the
171 subjects without SCA (33±10% vs 26±11%; p<0.001). Multivariate analysis revealed that
presence of 2 or more of risk factors of sympathetic denervation >37.6% of LV, LV
end-diastolic index >99 ml/M2, creatinine >1.49 mg/dl, and no anti-angiotensin medication
predicted a nearly 50% event rate over 4 years vs <1% annual rate without these risk
factors (p < 0.0001).
The rationale for the present study is twofold.
Correlate areas of cardiac denervation with accurate measurements of regional
cardiac blood flow (CBF) and inducible ischemia using standardized 82Rb PET.
Determine variables of sympathetic innervation and CBF most strongly related to past
occurrence of arrhythmic events.
With the greater sensitivity and resolution of PET imaging compared to planar and SPECT
techniques, it is expected that 18F -mFBG imaging will detect abnormalities that are
missed with 123I mIBG and provide the reliable and reproducible quantitative accuracy
necessary to support use of this agent for clinical patient studies.