Quantifying cardiac sympathetic nerve density using ¹⁸F-hydroxyphenethylguanidines: pilot studies in heart failure patients staged for implantable cardioverter defibrillator placement.

Objectives: To perform a head-to-head comparison of two new PET tracers developed for quantifying regional cardiac sympathetic nerve density, 4-[¹⁸F]fluoro-m-hydroxyphenethylguanidine ([¹⁸F]4F-MHPG) and 3-[¹⁸F]fluoro-p-hydroxyphenethylguanidine ([¹⁸F]3F-PHPG), in heart failure patients staged for implantable cardioverter defibrillator (ICD) placement.

Methods: Studies were performed in 8 male subjects with heart failure (57 ± 15 y, range 37-74 y; left ventricular ejection fraction 24 ± 6%, range 18% - 35%) using either a Siemens Biograph mCT or Biograph TruePoint PET/CT scanner. Each subject underwent a resting perfusion scan with [¹³N]ammonia (740 MBq, 20 min, 23 frames) and cardiac innervation PET scans with [¹⁸F]4F-MHPG and [¹⁸F]3F-PHPG (240-260 MBq, 60 min, 24 frames). During each innervation scan, 6 venous blood samples were drawn to measure partitioning of activity between plasma and red blood cells and the fraction of radiometabolites in plasma. PET images were reoriented into orthogonal planes and saved as 4 mm thick short-axis slices. For analysis of [¹⁸F]4F-MHPG and [¹⁸F]3F-PHPG kinetics, custom software was used to define 60 myocardial segments on each of 18 short-axis PET images, covering the left ventricle (LV) from apex to base. Time-activity curves (TAC) were extracted from the dynamic PET data for each of the 1080 LV regions. A region-of-interest was also placed in the base of the LV chamber to extract a whole-blood TAC. Data from the blood samples were used to convert the whole-blood TAC into a plasma input function for Patlak graphical analysis, with the measured Patlak slopes K_pat (mL/min/g) used as metrics of regional sympathetic nerve density.

Results: Similar to previous studies in normal human subjects, the quality of cardiac PET images obtained with [¹⁸F]4F-MHPG and [¹⁸F]3F-PHPG was high, with good heart-to-blood contrast and very low uptake in lungs. Significant regional sympathetic denervation was observed in all 8 subjects, ranging from ~ 25% to 70% of the LV. Patlak analysis of the myocardial kinetics of [¹⁸F]4F-MHPG and [¹⁸F]3F-PHPG was successful in all LV regions for all subjects, suggesting that this is a robust approach to quantifying regional cardiac nerve density in heart failure patients. In most subjects, the maximum regional Patlak slopes observed were comparable to values measured in normal controls (K_pat = 0.105 ± 0.009 mL/min/g for [¹⁸F]4F-MHPG and 0.122 ± 0.008 mL/min/g for [¹⁸F]3F-PHPG; n = 4 each), suggesting that these regions have fully functional sympathetic nerve populations at normal densities. Statistical comparison of regional K_pat values obtained with [¹⁸F]4F-MHPG and [¹⁸F]3F-MHPG within a subject showed very high correlation (r = 0.91 to 0.97). Thus, the two tracers provide comparable metrics of sympathetic nerve density. From an imaging viewpoint, each tracer has an advantage over the other. [¹⁸F]4F-MHPG clears from the liver fairly quickly, providing better final heart-to-liver ratios than [¹⁸F]3F-PHPG. On the other hand, [¹⁸F]3F-PHPG is metabolized more slowly in plasma, leading to higher heart-to-blood ratios. Finally, injections of [¹⁸F]4F-MHPG and [¹⁸F]3F-PHPG (cold masses 0.1 to 1.7 μg) had no effects on heart rate or blood pressure, and did not induce any changes in safety lab measures, demonstrating the safety of these compounds.

Conclusion: Pilot PET imaging studies of [¹⁸F]4F-MHPG and [¹⁸F]3F-PHPG in patients with heart failure have shown that both of these tracers can provide reliable quantitative metrics of regional sympathetic nerve density. These findings strongly suggest that this approach can be used clinically to accurately quantify the extent of regional sympathetic denervation in the heart, which is known to be predictive of the risk of sudden cardiac death in heart failure patients. Research Support: NIH/NHLBI SMARTT Program, University of Michigan MTRAC Midstage Award.