Gated single-photon emission computed tomography myocardial perfusion imaging phase analysis as an imaging biomarker for mortality prediction in heart failure patients undergoing cardiac resynchronization therapy.

OBJECTIVE: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in heart failure patients. The purpose of this study was to assess the value of gated myocardial perfusion single-photon emission computed tomography (GMPS) phase analysis for predicting survival in heart failure patients undergoing CRT. METHODS: This retrospective cohort study evaluated heart failure patients who underwent GMPS prior to CRT. Phase histogram bandwidth (PHB) and phase SD (PSD) were calculated using GMPS data. Cox proportional hazards model was used to identify independent predictors of overall survival (OS). RESULTS: A total of 35 patients (age 65.1 ± 13.3, 27 men and 8 women), who were followed for mean of 4.1 ± 2.9 years, were enrolled in the study. PSD of greater than 45° was found to be an independent predictor of poor OS (hazard ratio = 12.63, P = 0.011) when compared with age (hazard ratio = 1.00, P = 0.922), gender (hazard ratio = 0.31, P = 0.155), NYHA class (hazard ratio = 0.45, P = 0.087), QRS duration greater than 150 ms (hazard ratio = 2.38, P = 0.401), pre-CRT left ventricular ejection fraction (LVEF) (hazard ratio = 0.95, P = 0.175) and etiology of heart failure (hazard ratio = 1.42, P = 0.641). Furthermore, PHB greater than 140° was also found to be an independent predictor of poor OS (hazard ratio = 5.63, P = 0.040) when compared with age, gender, NYHA class, QRS duration greater than 150 ms, pre-CRT LVEF and etiology of heart failure. CONCLUSIONS: PSD and PHB, measured by GMPS, may serve as biomarkers for the prediction of survival in patients undergoing CRT.

[18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity.

Deoxycytidine kinase (dCK), a rate-limiting enzyme in the cytosolic deoxyribonucleoside (dN) salvage pathway, is an important therapeutic and positron emission tomography (PET) imaging target in cancer. PET probes for dCK have been developed and are effective in mice but have suboptimal specificity and sensitivity in humans. To identify a more suitable probe for clinical dCK PET imaging, we compared the selectivity of two candidate compounds-[(18)F]Clofarabine; 2-chloro-2'-deoxy-2'-[(18)F]fluoro-9-ß-d-arabinofuranosyl-adenine ([(18)F]CFA) and 2'-deoxy-2'-[(18)F]fluoro-9-ß-d-arabinofuranosyl-guanine ([(18)F]F-AraG)-for dCK and deoxyguanosine kinase (dGK), a dCK-related mitochondrial enzyme. We demonstrate that, in the tracer concentration range used for PET imaging, [(18)F]CFA is primarily a substrate for dCK, with minimal cross-reactivity. In contrast, [(18)F]F-AraG is a better substrate for dGK than for dCK. [(18)F]CFA accumulation in leukemia cells correlated with dCK expression and was abrogated by treatment with a dCK inhibitor. Although [(18)F]CFA uptake was reduced by deoxycytidine (dC) competition, this inhibition required high dC concentrations present in murine, but not human, plasma. Expression of cytidine deaminase, a dC-catabolizing enzyme, in leukemia cells both in cell culture and in mice reduced the competition between dC and [(18)F]CFA, leading to increased dCK-dependent probe accumulation. First-in-human, to our knowledge, [(18)F]CFA PET/CT studies showed probe accumulation in tissues with high dCK expression: e.g., hematopoietic bone marrow and secondary lymphoid organs. The selectivity of [(18)F]CFA for dCK and its favorable biodistribution in humans justify further studies to validate [(18)F]CFA PET as a new cancer biomarker for treatment stratification and monitoring.