Myocardial Blood Flow and Innervation Measures from a Single Scan: An Appealing Concept but a Challenging Paradigm
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* Vasken Dilsizian
* William C. Eckelman

The importance of neuronal dysfunction in the progression of heart failure and the utility of cardiac sympathetic imaging for identifying ischemic cardiomyopathy patients who are at high risk of sudden cardiac death is well established. On the basis of the results of the ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) multicenter trial, 123I-*meta-*iodobenzylguanidine (123I-MIBG) has received Food and Drug Administration approval for imaging cardiac sympathetic innervation of the heart in the United States (1,2). The results validated the independent and incremental prognostic value of delayed heart-to-mediastinum ratio of 123I-MIBG in patients with heart failure beyond left ventricular ejection fraction. Whether cardiac sympathetic imaging will also play an important role in identifying or predicting sustained ventricular tachyarrhythmias in patients with cardiomyopathy and determining those who may benefit from cardioverter-defibrillator implantation is currently under investigation (3,4).

See page [1706](http://jnm.snmjournals.org/lookup/volpage/56/1706?iss=11)

The synthesis of molecular and neuronal radioligands in parallel with recent advances in hybrid PET/CT imaging have made it possible to study and characterize cardiac innervation with position-emitting radiotracers such as 11C-*meta*-hydroxyephedrine (11C-HED) (5–7). 11C-HED is taken up by cardiac presynaptic neurons but not metabolized by synaptic degradation enzymes. Similar to the 123I-MIBG planar and SPECT data, decreased 11C-HED PET retention in patients with heart failure has been associated with increased cardiac mortality and the need for cardiac transplantation (8,9). Although PET imaging of the cardiac nervous system is advantageous over planar and SPECT techniques because of its superior spatial and temporal resolution, 11C-HED is not Food and Drug Administration–approved. Moreover, widespread clinical use of 11C-HED is limited by its relatively short 20-min half-life and complex production requiring an onsite cyclotron, which makes the entire production costly. Reduced cardiac neural regeneration after myocardial infarction has been theorized to be associated with arrhythmia risk. This was tested in a swine model, in which perfusion was assessed by 13N-ammonia and innervation by 11C-epinephrine 4–12 wk after myocardial infarction induced by balloon occlusion of the left anterior descending artery. Inducible ventricular tachycardia was present in 7 of the 11 animals studied, and in those with inducible ventricular tachycardia, a significantly larger area of perfusion–innervation mismatch was present (10). These findings led to the PARAPET (Prediction of Arrhythmic Events with PET) study, which was a prospective, observational clinical trial showing that patients developing sudden cardiac arrest had a significantly larger area of viable but denervated myocardium (11).

In this issue of *The Journal of Nuclear Medicine,* Harms et al. explore the possibility of using a single-scan 11C-HED protocol for defining myocardial blood flow (MBF)–innervation mismatch areas in patients with ischemic cardiomyopathy by taking advantage of the underlying tracer kinetic model of 11C-HED (12). They hypothesized that the rate of influx of 11C-HED from blood to myocardium (*K*1) is proportional to MBF. To study this, they measured MBF with 15O-water and multiplied it by perfusable tissue fraction to mathematically derive transmural MBF (MBFT), which represents MBF in both infarcted and perfusable tissue. As the authors point out in the “Discussion” section of their paper, direct comparison between *K*1 and MBFT showed that *K*1 significantly underestimated MBFT, and the limited extraction of 11C-HED rules out use of 11C-HED as a tracer of absolute MBF (12). This essentially negative study brings up important concepts of radiotracer kinetics and the effect of changes in MBF and biochemistry on radiopharmaceutical biodistribution. Given the fact that blood flow influences in vivo studies but not in vitro studies, it is important to have a measurement of flow changes in each study of biochemistry.

The major challenge in moving from in vitro studies to in vivo imaging is separating the relative importance of delivery, metabolism, and biochemistry to the biodistribution over time. To measure flow, microspheres (considered the gold standard) are replaced by more clinically useful radiotracers whose ideal biodistribution is heavily weighted by flow and therefore not significantly weighted by biochemistry or metabolism (13). This requires an extraction fraction close to 1 over the relevant range of MBF so that the blood flow is linear with flow changes, with a slope of 1. The radioligand most often mentioned is 15O-water. Certainly a diffusible tracer such as 15O-water is ideal, given it does not have possible confounding biochemistry. On the other hand, the interplay between blood flow and metabolism in the extraction and retention of 13N-ammonia is complex. The radioactivity in the tissue after a 13N-ammonia injection is a combination of interstitial and free cellular space and ammonia converted to glutamine. The early extraction phase of freely diffusible 13N-ammonia reflects blood flow, whereas the later slow-turnover phase reflects metabolic trapping of 13N-ammonia, involving predominantly the conversion of 13N-ammonia and glutamic acid to 13N-glutamine mediated by adenosine triphosphate and glutamine synthetase (14).

If changes in the biochemistry are the critical metric, and the pharmacokinetics can be determined in a patient-friendly imaging study, the biochemistry can often be measured with a dynamic study or a postvalidation single late scan. This is the case in diseases involving cardiac autonomic dysfunction, such as is known to occur in sudden cardiac death, heart failure, diabetic autonomic neuropathy, and cardiac arrhythmias (9). Norepinephrine analogs such as 11C-HED and 123I-MIBG have a rapid uptake in the myocardium but do not bind as irreversibly as the receptor-binding radiotracers. Radioligands for the muscarinic receptor and the β-adrenoceptor designed to measure receptor density are taken up rapidly and retained in the myocardium. They have a microsphere-like biodistribution, although the extraction fraction has not been reported. The β-adrenoceptor ligand CGP 12177 ((−)-4-((*S*)-3-tert-butylamino-2-hydroxypropoxy)−1,3-dihydrobenzo-imidazol-2-one) has rapid uptake in the heart and a slow efflux, with an average off-rate of 0.02 min−1 (15). Since distribution of this ligand in the myocardium is heavily weighted by delivery, in vivo competition studies with high– and medium–specific activity radioligands were required to determine the binding potential and maximum number of binding sites. Delayed images with 11C-HED (30–40 min after injection) and 123I-MIBG (∼4 h after injection) showed decreased retention of radioactivity after injection of 11C-HED and 123I-MIBG in heart failure patients. One group has taken the approach of further reducing the rate of delivery and thereby increasing the weighting of the biodistribution compared with that of MBF (16). The lead compound, 4-18F-fluoro-*m*-hydroxyphenethylguanidine, has a weaker Michaelis constant with about the same maximum velocity, which was the design goal.

Given that both delivery and biochemistry are key metrics in myocardial innervation, the concept of using a single isotope and a single scanning session to derive both parameters may be appealing but is rather challenging. In the case of 11C-HED, its low extraction fraction in the 40%–50% range limits its use as a tracer of absolute MBF. In the future, the most challenging paradigm will be to develop a radioligand that has maximal sensitivity to flow changes and to biochemical changes. In the meantime, the accuracy of clinical data should not be compromised for the convenience of acquiring single-isotope, single-scan imaging with 11C-HED.

## DISCLOSURE

No potential conflict of interest relevant to this article was reported.

## Footnotes

*   Published online Aug. 27, 2015.

*   © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

## REFERENCES

1.  1.Jacobson AF, Senior R, Cerqueira MD, et al. Myocardial iodine-123 meta-iodobenzylguanidine imaging and cardiac events in heart failure: results of the prospective ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) study. J Am Coll Cardiol. 2010;55:2212–2221.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1016/j.jacc.2010.01.014&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=20188504&link_type=MED&atom=%2Fjnumed%2F56%2F11%2F1645.atom) 
    
    [Web of Science](http://jnm.snmjournals.org/lookup/external-ref?access_num=000277652700005&link_type=ISI) 

2.  2.Dilsizian V, Chandrashekhar Y, Narula J. Introduction of new tests: low are the mountains, high the expectations. JACC Cardiovasc Imaging. 2010;3:117–119.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1016/j.jcmg.2009.12.001&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=20129541&link_type=MED&atom=%2Fjnumed%2F56%2F11%2F1645.atom) 

3.  3.Klein T, Huang R, Smith MF, et al. Three-dimensional 123I-meta-iodobenzylguanidine cardiac innervation maps to assess substrate and successful ablation sites for ventricular tachycardia - a feasibility study for a novel paradigm of innervation imaging. Circ Arrhythm Electrophysiol. 2015;8:583–591.
    
    [Abstract/FREE Full Text](http://jnm.snmjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NjoiY2lyY2FlIjtzOjU6InJlc2lkIjtzOjc6IjgvMy81ODMiO3M6NDoiYXRvbSI7czoyMzoiL2pudW1lZC81Ni8xMS8xNjQ1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

4.  4.Klein T, Dilsizian V, Cao Q, Chen W, Dickfeld TM. The potential role of 123I-mIBG for identifying sustained ventricular tachycardia in patients with cardiomyopathy. Curr Cardiol Rep. 2013;15:359.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1007/s11886-013-0359-1&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=23536110&link_type=MED&atom=%2Fjnumed%2F56%2F11%2F1645.atom) 

5.  5.Schwaiger M, Kalff V, Rosenspire K, et al. Noninvasive evaluation of sympathetic nervous system in human heart by positron emission tomography. Circulation. 1990;82:457–464.
    
    [Abstract/FREE Full Text](http://jnm.snmjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTQ6ImNpcmN1bGF0aW9uYWhhIjtzOjU6InJlc2lkIjtzOjg6IjgyLzIvNDU3IjtzOjQ6ImF0b20iO3M6MjM6Ii9qbnVtZWQvNTYvMTEvMTY0NS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

6.  6.Eckelman WC, Dilsizian V. Chemistry and biology of radiotracers that target changes in sympathetic and parasympathetic nervous system in heart disease. J Nucl Med. 2015;56(suppl):7S–10S.
    
    [Abstract/FREE Full Text](http://jnm.snmjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Njoiam51bWVkIjtzOjU6InJlc2lkIjtzOjE4OiI1Ni9TdXBwbGVtZW50XzQvN1MiO3M6NDoiYXRvbSI7czoyMzoiL2pudW1lZC81Ni8xMS8xNjQ1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

7.  7.Dilsizian V, Narula J. Have imagers aptly or inadvertently overlooked the neuronal myocardial compartment? J Nucl Med. 2015;56(suppl):1S–2S.
    
    [FREE Full Text](http://jnm.snmjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6Njoiam51bWVkIjtzOjU6InJlc2lkIjtzOjE4OiI1Ni9TdXBwbGVtZW50XzQvMVMiO3M6NDoiYXRvbSI7czoyMzoiL2pudW1lZC81Ni8xMS8xNjQ1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

8.  8.Schwaiger M, Hutchins GD, Kalff V, et al. Evidence for regional catecholamine uptake and storage sites in the transplanted human heart by positron emission tomography. J Clin Invest. 1991;87:1681–1690.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1172/JCI115185&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=2022739&link_type=MED&atom=%2Fjnumed%2F56%2F11%2F1645.atom) 
    
    [Web of Science](http://jnm.snmjournals.org/lookup/external-ref?access_num=A1991FK45300029&link_type=ISI) 

9.  9.Pietilä M, Malminiemi K, Ukkonen H, et al. Reduced myocardial carbon-11 hydroxyephedrine retention is associated with poor prognosis in chronic heart failure. Eur J Nucl Med. 2001;28:373–376.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1007/s002590000449&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=11315607&link_type=MED&atom=%2Fjnumed%2F56%2F11%2F1645.atom) 
    
    [Web of Science](http://jnm.snmjournals.org/lookup/external-ref?access_num=000167668900017&link_type=ISI) 

10. 10.Sasano T, Abraham MR, Chang KC, et al. Abnormal sympathetic innervation of viable myocardium and the substrate of ventricular tachycardia after myocardial infarction. J Am Coll Cardiol. 2008;51:2266–2275.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1016/j.jacc.2008.02.062&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=18534275&link_type=MED&atom=%2Fjnumed%2F56%2F11%2F1645.atom) 
    
    [Web of Science](http://jnm.snmjournals.org/lookup/external-ref?access_num=000256434200011&link_type=ISI) 

11. 11.Fallavollita JA, Heavey BM, Luisi AJ Jr., et al. Regional myocardial sympathetic denervation predicts the risk of sudden cardiac arrest in ischemic cardiomyopathy. J Am Coll Cardiol. 2014;63:141–149.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1016/j.jacc.2013.07.096&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=24076296&link_type=MED&atom=%2Fjnumed%2F56%2F11%2F1645.atom) 
    
    [Web of Science](http://jnm.snmjournals.org/lookup/external-ref?access_num=000329839200007&link_type=ISI) 

12. 12.Harms HJ, Lubberink M, de Haan S, et al. Use of a single 11C-*meta*-hydroxyephedrine scan for assessing flow–innervation mismatches in patients with ischemic cardiomyopathy. J Nucl Med. 2015;56:1706–1711.
    
    [Abstract/FREE Full Text](http://jnm.snmjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Njoiam51bWVkIjtzOjU6InJlc2lkIjtzOjEwOiI1Ni8xMS8xNzA2IjtzOjQ6ImF0b20iO3M6MjM6Ii9qbnVtZWQvNTYvMTEvMTY0NS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

13. 13.Dilsizian V, Taillefer R. Journey in evolution of nuclear cardiology: will there be another quantum leap with the F-18 labeled myocardial perfusion tracers? JACC Cardiovasc Imaging. 2012;5:1269–1284.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1016/j.jcmg.2012.10.006&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=23236979&link_type=MED&atom=%2Fjnumed%2F56%2F11%2F1645.atom) 

14. 14.Kitsiou AN, Bacharach SL, Bartlett ML, et al. 13N-ammonia myocardial blood flow and uptake: relation to functional outcome of asynergic regions after revascularization. J Am Coll Cardiol. 1999;33:678–686.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1016/S0735-1097(98)00630-5&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=10080468&link_type=MED&atom=%2Fjnumed%2F56%2F11%2F1645.atom) 
    
    [Web of Science](http://jnm.snmjournals.org/lookup/external-ref?access_num=000079179400013&link_type=ISI) 

15. 15.Delforge J, Mesangeau D, Dolle F, et al. In vivo quantification and parametric images of the cardiac β-adrenergic receptor density. J Nucl Med. 2002;43:215–226.
    
    [Abstract/FREE Full Text](http://jnm.snmjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Njoiam51bWVkIjtzOjU6InJlc2lkIjtzOjg6IjQzLzIvMjE1IjtzOjQ6ImF0b20iO3M6MjM6Ii9qbnVtZWQvNTYvMTEvMTY0NS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

16. 16.Jang KS, Jung YW, Gu G, et al. 4-[18F]fluoro-m-hydroxyphenethylguanidine: a radiopharmaceutical for quantifying regional cardiac sympathetic nerve density with positron emission tomography. J Med Chem. 2013;56:7312–7323.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1021/jm400770g&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=23965035&link_type=MED&atom=%2Fjnumed%2F56%2F11%2F1645.atom) 

*   Received for publication August 5, 2015.
*   Accepted for publication August 6, 2015.