Axis 5 : CV, renal and brain imaging for guiding therapies

Pierre-Yves Marie

  • Prof. of Nuclear Medecine, Univ. of Lorraine
  • Chief Scientific Officer, Nancyclotep

Jacques Felblinger

  • Prof. of Radiology, Univ. of Lorraine
  • Director, Diagnostic and Interventional Adaptive Imaging Unit (IADI), CHRU Nancy / INSERM
Specific programs are ongoing and will be further developed on multimodal imaging and especially, MRI, molecular PET imaging and echography, with the aim of enhancing imaging driven therapy in the potentially very large personalized medical area covered by cardiovascular aging and corresponding cardiac, brain and renal diseases.
These imaging programs are conducted with the support of the CIC dedicated to innovation and technology (CIC-IT) and the IADI INSERM unit (UMR_S 1254) and of the Nancyclotep imaging platform of metabolic PET imaging, with the additional participation of CNRS teams for the chemistry of new tracers (“L2CM” UMR7053 team and “LCPM” UMR7375 team). These programs are strongly supported by 2 ANR and 5 French clinical research grants (PHRC) coordinated by our teams.

Magnetic Resonance Imaging (MRI)

(i) New methods are developed for the prediction and catheter treatment of life-threatening arrhythmias in post-infarct patients based on our previous MRI studies (68). Comprehensive MRI and ECG imaging data from retrospective and prospective cohorts (“TVScreen”, “SMARTIS”, and ongoing “ATLAS”, “MATCHA”) will be used as inputs of the risk model, which will be validated against gold standard intracardiac catheter mapping. These imaging data will be used also in combination with our robotic catheter navigation system (Stereotaxis Inc.) to minimize the recurrence rate of VT after ablation and standardize/speed-up the procedure. In addition, myocardial tissue is currently characterized by our teams through the measurement of MR relaxation times for detecting heart transplant rejection (ongoing “DRAGET” national PHRC).
(ii) Functional MRI of the arterial tree are planned with specific 3D or 4D flow-sequences for determining arterial stiffness and resistance indexes and improving our understanding of the ways by which the ventricles remodel in athletes (Young Researcher Grant – CoAtri project), in subjects with definite or at risk of heart failure (69-71), and in pulmonary hypertension (ongoing “EVITA” national PHRC). Vascular treatments have an unpredictable efficiency in such populations, and MRI monitoring of cardiac loading conditions could constitute a helpful therapeutic target for such vascular treatments.
(iii) Combined MRI and echography studies, taking advantage of the precise analyses of myocardial strain provided by echography (i.e. especially with identification of post-systolic shortening and increased mechanical dispersion values) (72), in conjunction with the characterizations of myocardial tissue and cardiac load (73). A special emphasis will be placed on the detection of subclinical functional and structural myocardial dysfunction and the timely identification of patients who are at risk for developing overt heart failure and/or arrhythmogenic diseases (STAMP1 and STAMP2 clinical trials).
(iv) Cerebrovascular MRI for assessing the integrity of both grey- and white-matter areas in older individuals in conjunction with PET brain analyses (74,75) and with a throughput analysis of vascular phenotypes and of biological markers of aging (telomere length, but also selected DNA, RNA, microRNA and protein profiles), as well as for an optimal medical monitoring of stroke patients. These topics will be integrated into the dedicated “Cerebrovascular axis” already detailed above.

Molecular PET Imaging

Imaging of cardiovascular inflammation, healing and thrombosis are additionally developed in the Nancyclotep PET imaging platform, in line with a number of imaging studies already published in the field of cardiovascular inflammation by our teams (76-79), and with the CNRS chemistry teams already mentioned above. The global aim of these programs is to help defining the optimal conditions for patients’ referral to dedicated anti-thrombotic, antifibrotic and antiinflammatory drugs, with certain of these drugs being extensively assessed by other teams of CARTAGE-PROFILES (especially, the antagonists of aldosterone and of TREM-receptors (80)). More precisely, these programs involve the development and/or experimental assessments of several families of new PET tracers:
(i) various RGD compounds labelled with 18F or 68Ga and targeting αvβ3-integrin in order to define the role of this integrin in inflammation, arterial stiffness and thrombin formation (a key research field of the Inserm UMR_S 1116).
(ii) the LR12 peptide, a modulator of TREM-receptors labelled with 18F or 68Ga for pharmacokinetic studies within inflammatory sites,
(iii) various PET tracers, which are tested for providing precise differentiation of acute, subacute and chronic inflammatory phases in a multi-omic PET approach (18F-DPA, 18F-Dotatoc, 18F-FDG…).
(iv) 68Ga-FAPI-46 a promising new tracer targeting activated fibroblasts and sites with increased rates of fibrosis turnover. Up to now, 68Ga-FAPI was developed mainly for oncologic indications but in a large collaborative project it will be tested for the first time by our teams in experimental models of cardiovascular fibrosis.
(v) Three PET clinical trials are also programmed or already in course on: a- whole body quantification of amyloid deposits in patients with cardiac amyloidosis (ongoing “CAPRI” national PHRC), b- identification of cardiac inflammation with 68Ga-Datatoc (ongoing single center clinical trial in myocarditis patients), and c- the 18F-GP1 tracer, targeting glycoprotein IIb/IIIa and activated platelets, in a collaborative initial proof-of-concept study of infective endocarditis (clinical trial elaborated with Life Medical Imaging and expected to start in 2020).
References
68. Codreanu A, Odille F, Aliot E, et al. J Am Coll Cardiol. 2008;52:839-42. 69. Huttin O, Mandry D, Eschalier R, et al. J Cardiovasc Magn Reson. 2017;19:2. 70. Bäck M, Marie PY, et al. Circ Cardiovasc Imaging. 2016;9(3):e004590. 71. Joly L, Perret-Guillaume C, Kearney-Schwartz A, et al. Hypertension. 2009;54:421-6. 72. Lemarié J, Huttin O, Girerd N, et al. J Am Soc Echocardiogr. 2015;28:818-27.e4. 73. Aubert R, Venner C, Huttin O, et al. J Am Soc Echocardiogr. 2018;31:905-5. 74. Chetouani A, Chawki MB, Hossu G et al. Neuroimage Clin. 2017;17:804-10. 75. Verger A, van der Gucht A, Guedj E, et al. J Hypertens. 2015;33:1378-85. 76. Filippetti L, Mandry D, Venner C, et al. JACC Cardiovasc Imaging. 2018;11:1367-9. 77. Marie PY, Plissonnier D, Bravetti S, et al. Eur J Nucl Med Mol Imaging. 2018;45:549-57. 78. Morel O, Mandry D, Micard E, et al. J Nucl Med. 2015;56:1030-5. 79. Joly L, Djaballah W, Koehl G, et al. Eur J Nucl Med Mol Imaging. 2009;36:979-85.