In this report, we detail the unexpected detection of myocardial binding of the epichaperome tracer 124I-PU-H71 in all members of our study population of cancer patients. Our group coined the term epichaperome in a prior monograph [1]. We were surprised to visualize avid-binding of 124I-PU-H71 to myocardium, as intracellular epichaperome formations are indicative of cellular stress, as occurs in cancer cells [1, 2, 5, 8] or brain resident cells undergoing a neurodegenerative process [3, 4], and we had not observed myocardial avidity for the tracer in animal models [1, 5, 8, 15]. All our study patients, including the patients who had prior exposure to potentially cardiotoxic agents demonstrated similar myocardial avidity for the epichaperome-tracer and none of our patients had known cardiovascular disease, nor suffered any cardiovascular events during the limited follow-up period.
It is worth noting the observations in transgenic mouse models of tauopathies, such as Alzheimer’s disease, epichaperome formation was observed early in the disease spectrum and preceded the appearance of other biomarkers and measurements of brain function decline such as tau pathology, microglial activation (imaged with [11C]-AC-5216, TSPO tracer as a surrogate), MRI-measurable regional atrophies, and impairments of cerebral glucose metabolism (imaged with [18F]-FDG) [3, 16–18]. These clinical and preclinical studies support the plausible hypothesis that epichaperomes as detected by epichaperome imaging, may be indicative of subclinical myocardial dysfunction and precede and perhaps may foretell the clinical presentation of disease. It is now recognized that cardiac dysfunction, similarly to Alzheimer’s disease and cancer, begins with changes decades before clinical symptom onset. Genetic risk factors, inflammation-inducing insults, gender- and age-related changes damage vulnerable cells over decades [19–22]. Diverse environmental factors may precipitate and modify the disease threshold and alter disease course in concert with these risk factors [23]. Recognition of early pathologic cardiac stress is therefore of importance as it may offer clinicians an opportunity for early intervention and potentially prevention of symptomatic cardiovascular disease.
With regards to cancer patients, recent work by Sturgeon et al. showed that cancer patients have an average 2–6 times higher cardiovascular disease mortality risk than the general population [24–25]. For some cancers, like breast, prostate, endometrial, and thyroid cancer, the study found that half of the patients will die from cardiovascular disease, including heart disease, stroke, aneurysm, high blood pressure and damage to blood vessels. Among cancer survivors diagnosed before the age of 55 years, the risk of cardiovascular death was more than ten-fold greater than in the general population. Importantly, whereas the risk of death from cardiovascular diseases was high in the first year of diagnosis, for most cancer patients this risk increased as survivors were followed for ten years or more [24].
Cardiac dysfunction manifesting after cancer may be due to several mechanisms such as shared risk factors, inflammatory states associated with cancers and cardiotoxic effects of cancer therapy, including not only chemotherapy and radiation, but also novel approaches such as immunotherapy, tyrosine kinase inhibitors and others [11, 26–27]. Cancer treatment may increase the risk of cardiovascular diseases either directly by damaging critical structures of the heart or indirectly through systemic or local inflammatory insults [28]. Estimating cardiovascular risk by using advanced imaging and monitoring cardiac biomarkers are therefore active areas of biomedical research for early detection and treatment of subclinical cardiac dysfunction [29]. The hope is that a better knowledge of early and late cardiac effects in cancer patients may help prevent or manage long-term treatment complications in cancer survivors.
We observed myocardial uptake, rapidly achieved peak uptake (within 2 minutes post-injection) and persistence of myocardial tracer-concentrations in the subsequent 4 hours, consistent with true tracer target-binding. PU-H71 binds its epichaperome target for days, dissociating very slowly in vivo [1, 5, 30]. This rapid myocardial extraction kinetics, including rapid blood pool clearance affording excellent myocardial delineation, meet some of the basic criteria for a myocardial perfusion tracer as proposed by Sapirstein [12]. Our resting data encourages further testing of 124I-PU-H71 in healthy patients as well, under conditions of physiologic or pharmacologic induced stress; because 124I-PU-H71 tracer is injected as a bolus, demonstrates promising myocardial kinetics, and offers a half-life suitable for delayed imaging.
Our study lacks confirmatory histologic evidence and tissue assays, to confirm epichaperome formations in myocardium, but prior publications have extensively elaborated on selective binding of epichaperome-targeted PET tracer in tumor cells and neurodegenerative brain cells [1–4], and the ubiquitous myocardial epichaperome tracer-avidity invites the hypothesis that subclinical cardiomyocyte stress might be commonplace. This is also suggested in a population-based study by Ravassa et al. [31], opening new avenues for basic research and potential therapeutic drug development, for which 124I-PU-H71 PET offers a clinical biomarker assay. The study also lacked long-term follow-up data in our patient population to evaluate delayed cardiac-related adverse events. These are important subjects for further research.