Original ArticlePrototype device for endoventricular beta-emitting radiotracer detection and molecularly-guided intervention
Introduction
Catheter-based delivery of therapeutics such as cells, pharmaceuticals, genetic material, and polymers is being explored for the treatment of ischemic and non-ischemic heart disease.1, 2, 3, 4, 5, 6, 7, 8, 9 While these therapies present intriguing possibilities for the protection, repair, and even regeneration of injured or infarcted myocardium, clinical translation has been slowed by limited success in initial clinical trials.10,11 Potential high-yield areas to improve therapeutic efficacy include further development of catheter-based technologies to enhance therapeutic delivery and retention, and diagnostic technologies to optimize patient selection and the timing and location of interventions.
Successful delivery of therapeutics to the heart depends on proper myocardial characterization and anatomical guidance to ensure that therapies are delivered to appropriately selected patients and anatomic locations. Several current catheter-based technologies for endoventricular delivery rely on 2D fluoroscopy and angiography to characterize tissues and guide intervention (e.g., Helical Infusion SystemTM, BioCardia, Inc., San Carlos, CA; C-Cath®, Celyad, Inc., Belgium).12,13 An alternative system combines catheter-based electromechanical tissue characterization with 3D electromagnetic mapping and navigation (MyostarTM catheter with NOGA® electromechanical mapping, Biosense Webster, Diamond Bar, CA).14 The potential benefit of this online electromechanical diagnostic feature is that the information may be utilized to direct interventions to locations most likely to benefit (e.g., viable myocardium—particularly at the infarct border zone) and to avoid those least likely to benefit (e.g., dense scar).
Signals from molecularly-targeted radiotracers provide additional biological information about cardiac tissue that is potentially valuable in guiding the delivery of therapeutics.15 Numerous radiotracers have been developed for preclinical and clinical use that provide information on the intensity and spatial distribution of specific myocardial processes, including inflammation, angiogenesis, apoptosis, metabolism, neuronal activation, and matrix metalloproteinase activity.15, 16, 17 In many cases, the molecular targets of these tracers also represent potential therapeutic targets. As such, the information provided by these sensitive tracers is useful for diagnosis, risk stratification, patient selection, interventional guidance, and finally, the monitoring of therapeutic responses.
Myocardial inflammation and viability in the post-infarction setting are molecular targets that present particularly intriguing possibilities for improving patient selection and guiding catheter-based interventions. Following coronary occlusion, ischemic injury and myocyte necrosis activate an intense inflammatory reaction that helps to clear cell and matrix debris from the injured region and prepare it for repair and collagen scar formation.18 This response is an essential part of the natural post-myocardial infarction (MI) reparative process, although excessive or prolonged inflammation can be destructive and contribute to adverse left ventricular remodeling and heart failure.19, 20, 2118F-fluorodeoxyglucose (18F-FDG) is a positron-emitting glucose analog that, depending on dietary preparation, can be used to measure either myocardial inflammation or viability.22,23 A recent study utilizing 18F-FDG positron emission tomography/magnetic resonance imaging (PET/MRI) in the setting of acute MI demonstrated that the intensity of the post-MI 18F-FDG PET inflammatory signal correlates inversely with MRI-based left ventricular function 6 months later, even after multivariate correction for infarct size and peripheral blood laboratory markers.24 Thus, the post-MI 18F-FDG inflammatory signal has predictive value for functional outcomes and may be an effective signal for improving risk stratification and directing the timing and location of personalized interventions to modulate the local inflammatory response.
We have set out to develop a catheter-based theranostic system that: (a) identifies diseased and at-risk myocardium via endocardial detection of systemically delivered β-emitting radiotracers and (b) utilizes molecular signals to guide the delivery of therapeutics to appropriate tissue locations via direct intramyocardial injection. The prototype device that we present here consists of a miniature β-radiation detector contained within the tip of a flexible intravascular catheter. Importantly, the catheter can be modified to accommodate an injection port and retractable 27 G needle for therapeutic delivery. The combined β-detector and delivery system potentially allows for direct, localized intramyocardial delivery of therapeutics to specific regions identified by their uptake of systemically delivered molecularly-targeted radiotracers. In this paper, we present the characterization of our prototype β-detector devices and demonstrate efficacy in detecting ex vivo post-MI myocardial 18F-FDG uptake.
Section snippets
Design of β-Detection and Delivery Catheter
The prototype β-detection catheter and wireless display are shown in Figure 1a. The diameter of the flexible catheter is 2.67 mm, which is equivalent to 8 Fr. The catheter tip detector consists of a 1.2 × 1.2 × 0.5 mm anthracene-doped poly(vinyltoluene) plastic scintillator (BC-412, Saint-Gobain, France) coupled to a 1 mm × 1 mm solid state Si photodiode (Hamamatsu Photonics, Japan) (Figure 1b). The plastic scintillator was selected for its high efficiency β-radiation detection and minimal
In Vitro β-Detection Catheter Measurement of 204Tl and 22Na Emissions
Results of in vitro β-detection catheter-based measurements of sealed sources of 204Tl and 22Na and varying thicknesses of a polymeric attenuating medium (packaging tape) are shown in Figure 2. Overall, the narrow standard deviations demonstrate a high degree of reproducibility in β-detection catheter measurements. The β-detection catheter signal of the pure β--emitter 204Tl progressively decreased with increased thickness of polymeric tape and was nearly completely attenuated at ~3.5 WETs
Discussion
We present here a novel catheter device designed for endocardial detection of systemically administered β-emitting radiotracers and subsequent molecular guidance of intramyocardial interventions. Our findings demonstrate the feasibility of incorporating a miniature plastic scintillator for β-radiation detection into the tip of a flexible, small diameter catheter, with the potential for incorporation of a retractable needle for intramyocardial delivery of therapeutics. Our collective in vitro
Conclusions
Our findings demonstrate the feasibility of incorporating a miniature β-radiation detector and a retractable delivery needle into the tip of a flexible, small diameter catheter. The prototype device demonstrates sensitive and selective in vitro detection of β- and β+ emissions over a wide range of energies, and performs high-fidelity ex vivo characterization of endocardial signals from systemically administered radiotracers. These preliminary results represent significant progress towards the
New Knowledge Gained
This study presents the novel concept of utilizing a catheter-based device to detect endocardial signals from molecularly-targeted radiotracers for the purpose of guiding therapeutic interventions to the heart.
Acknowledgements
Experimental assistance was provided by Christi Hawley, Sharon Wang, Tsa Shelton, Milica Vukmirovic, and Tim Mulnix of Yale University. Image processing assistance was provided by Yihaun Lu of Yale University.
Disclosures
Farhad Daghighian is the President and Chief Scientist of Intramedical Imaging, LLC. John Stendahl, Zhao Liu, Nabil Boutagy, Eliahoo Nataneli, and Albert Sinusas have no disclosures.
Funding
This work was supported by grants from the National Institutes of Health (T32 HL098069 (A.J.S.), R01
References (52)
- et al.
Bioabsorbable intracoronary matrix for prevention of ventricular remodeling after myocardial infarction
J Am Coll Cardiol
(2016) - et al.
Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial
Lancet
(2016) - et al.
Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial
Lancet
(2011) - et al.
Intracoronary cardiosphere-derived cells after myocardial infarction: evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction)
J Am Coll Cardiol
(2014) - et al.
Cardiovascular Gene Therapy: Past, Present, and Future
Mol Ther
(2017) - et al.
Translational Molecular Nuclear Cardiology
Cardiol Clin
(2016) - et al.
Inflammation as a therapeutic target in myocardial infarction: learning from past failures to meet future challenges
Transl Res
(2016) - et al.
Differential roles of cardiac and leukocyte derived macrophage migration inhibitory factor in inflammatory responses and cardiac remodelling post myocardial infarction
J Mol Cell Cardiol
(2014) - et al.
Comparison of carbon-11-acetate with fluorine-18-fluorodeoxyglucose for delineating viable myocardium by positron emission tomography
J Am Coll Cardiol
(1993) Fundamental Limits of Spatial Resolution in PET
Nucl Instrum Methods Phys Res A
(2011)
Increasing benefit from revascularization is associated with increasing amounts of myocardial hibernation: a substudy of the PARR-2 trial
JACC Cardiovasc Imaging
A new F-18 labeled PET tracer for fatty acid imaging
J Nucl Cardiol
Myocardial Inflammation Predicts Remodeling and Neuroinflammation After Myocardial Infarction
J Am Coll Cardiol
Molecular Imaging of the Chemokine Receptor CXCR4 After Acute Myocardial Infarction
JACC Cardiovasc Imaging
Positron emission tomographic imaging of cardiac sympathetic Innervation using 6-[18F]Fluorodopamine: Initial findings in humans
Journal of the American College of Cardiology
Molecular hybrid positron emission tomography/computed tomography imaging of cardiac angiotensin II type 1 receptors
J Am Coll Cardiol
Preparation of cyclotron-produced 186Re and comparison with reactor-produced 186Re and generator-produced 188Re for the labeling of bombesin
Nucl Med Biol
Catheter-based Intramyocardial Injection of FGF1 or NRG1-loaded MPs improves cardiac function in a preclinical model of ischemia-reperfusion
Sci Rep
PreSERVE-AMI: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Intracoronary Administration of Autologous CD34+ Cells in Patients With Left Ventricular Dysfunction Post STEMI
Circ Res
A Phase II Dose-Escalation Study of Allogeneic Mesenchymal Precursor Cells in Patients With Ischemic or Nonischemic Heart Failure
Circ Res
Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: the STOP-HF randomized Phase II trial
Eur Heart J
Adenoviral intramyocardial VEGF-DΔNΔC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up
Eur Heart J
Cell therapy trials for heart regeneration - lessons learned and future directions
Nat Rev Cardiol
Optimized delivery system achieves enhanced endomyocardial stem cell retention
Circ Cardiovasc Interv
Improvement of Local Cell Delivery Using Helix Transendocardial Delivery Catheter in a Porcine Heart
Int Heart J
Diagnostic and prognostic value of 3D NOGA mapping in ischemic heart disease
Nat Rev Cardiol
Cited by (0)
The authors of this article have provided a PowerPoint file, available for download at SpringerLink, which summarises the contents of the paper and is free for re-use at meetings and presentations. Search for the article DOI on SpringerLink.com.
The authors have also provided an audio summary of the article, which is available to download as ESM, or to listen to via the JNC/ASNC Podcast.