PET imaging of cardiac hypoxia: Opportunities and challenges

Abstract

Myocardial hypoxia is a major factor in the pathology of cardiac ischemia and myocardial infarction. Hypoxia also occurs in microvascular disease and cardiac hypertrophy, and is thought to be a prime determinant of the progression to heart failure, as well as the driving force for compensatory angiogenesis. The non-invasive delineation and quantification of hypoxia in cardiac tissue therefore has the potential to be an invaluable experimental, diagnostic and prognostic biomarker for applications in cardiology. However, at this time there are no validated methodologies sufficiently sensitive or reliable for clinical use. PET imaging provides real-time spatial information on the biodistribution of injected radiolabeled tracer molecules. Its inherent high sensitivity allows quantitative imaging of these tracers, even when injected at subpharmacological (≥pM) concentrations, allowing the non-invasive investigation of biological systems without perturbing them. PET is therefore an attractive approach for the delineation and quantification of cardiac hypoxia and ischemia. In this review we discuss the key concepts which must be considered when imaging hypoxia in the heart. We summarize the PET tracers which are currently available, and we look forward to the next generation of hypoxia-specific PET imaging agents currently being developed. We describe their potential advantages and shortcomings compared to existing imaging approaches, and what is needed in terms of validation and characterization before these agents can be exploited clinically.

64Cu-CTS: A Promising Radiopharmaceutical for the Identification of Low-Grade Cardiac Hypoxia by PET

“…In this study, we identified a key hypoxic threshold that induces the major hallmarks of compromised but salvageable myocardium: depressed contractile function, compromised phosphocreatine levels (but stable ATP levels), elevated HIF-1a expression, and increased but not maximal lactate washout (indicating residual oxidative reserve). At this threshold, achieved by perfusion with KHB saturated with 30% O 2 , we demonstrated that 64 Cu-CTS is the only complex among the 4 evaluated that provides a hypoxic-to-normoxic tissue contrast that would be exploitable for PET imaging (9).…”

“…In the one very small (7-patient) cardiac clinical trial that has been performed to date using 62 Cu-ATSM, 62 Cu accumulation was visualized in the myocardium of only 1 patient with unstable angina, despite 4 of those patients exhibiting increased regional 18 F-FDG uptake (12). Thus, whereas 64 Cu-ATSM can be used to selectively identify the extreme acute hypoxia commonly induced in experimental models, it seems insufficiently sensitive to detect the subtle hypoxia characterizing the chronic cardiac ischemic syndromes that are currently difficult to identify (9).…”

“…In hypertrophic myocardium, perfusion is also often "normal," but increased cell size, loss of t-tubules, and scarring mean that increased diffusion distances critically limit oxygen delivery to mitochondria (6,7). To accurately characterize these conditions, imaging disparities between supply and demand for blood flow (ischemia), or O 2 (hypoxia), would be a potentially more useful approach than measuring poor perfusion per se (8), but as yet, there are no methodologies sufficiently sensitive or specific for this purpose (9,10).…”

“…We reason that this target hypoxia threshold would be the point where there remains a degree of metabolic flexibility: a compromised but functional capacity for oxidative metabolism, but with sufficient adenosine triphosphate (ATP) turnover to maintain ionic homeostasis and cellular integrity (9). We have therefore performed a series of hypoxia titrations in the isolated heart to determine where this threshold lies using a panel of biochemical and biophysical assays.…”

Applications of “Hot” and “Cold” Bis(thiosemicarbazonato) Metal Complexes in Multimodal Imaging

“…[94] However, nitroimidazoles present a number of disadvantages for routine use, such as their low lipophilicity, slow pharmacokinetics, low tumor-to-muscle ratios, and limited clearance from normoxic tissue. [95,96] Bis(thiosemicarbazonato) complexes for the imaging of hypoxia were first employed by Fujibayashi et al in 1997 in a rat heart ischemic model.…”