CARTIZ Registry: Cartilage, Arthropathy and Imaging Under Tirzepatide in Zone-stratified Cohorts - A Four-Institute Mexican Observational Registry

Background and rationale. Tirzepatide, a dual agonist of the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, has demonstrated unprecedented cardiometabolic potency in registration trials (SURPASS, SURMOUNT, SYNERGY-NASH, SUMMIT). Recent evidence has extended the mechanistic reach of the molecule beyond glycemia and weight to specific tissue compartments. The SUMMIT cardiac magnetic resonance substudy demonstrated reduction of left ventricular mass and paracardiac adipose tissue at 52 weeks in heart failure with preserved ejection fraction with obesity. A prespecified diabetes-stratification analysis of SUMMIT established that these structural effects are partially independent of weight change. The SURPASS cardiovascular outcomes trial established cardiovascular superiority of tirzepatide over GLP-1 monoagonism. A recent randomized clinical trial in psoriatic arthritis with overweight or obesity demonstrated articular response at Week 4 when dual incretin agonism was added to IL-17A inhibition, prior to substantial weight loss. The "multi-nutrient-stimulated-hormone" (multi-NuSH) framework now organizing the field articulates the conceptual reach of dual and multi-incretin agonism beyond glycemia. Mechanistic work on human and murine adipocytes establishes direct GIP receptor effects on visceral adipose depots that are biologically distinct from weight-mediated effects. Bibliographic support for each of these statements is provided in the Citations field of this record. The Mexican off-label access asset. Access to tirzepatide in the United States and Europe is restricted by payer prior-authorization to narrow on-label indications. In Mexico, out-of-pocket access permits a phenotypic breadth of clinical exposure not replicable in sponsor-led trials, including patients who receive tirzepatide for insulin resistance, metabolic hypertension, renal protection, and off-label metabolic indications. This pharmacological natural experiment allows the registry to capture the articular, cardiac, compositional, and aging-biology response to dual GIP/GLP-1 agonism across a clinical breadth sponsor trials cannot access. The window is finite: as label expansion advances, the uniqueness of Mexican off-label exposure attenuates. The registry is positioned to capture this window. Four-institute architecture. CARTIZ operates through four specialized cores, each led by a qualified investigator at an independent institution, producing endpoints of differentiated resolution and relevance. Core 1 - Knee Cartilage Imaging Core (Level 3A). Bilateral 3T knee MRI with quantitative T2 mapping at Week 0 and Week 52, performed at Ci3M UAM-Iztapalapa (CONACYT National Laboratory) under Dr. Andres Moron and Dr. Luis Jimenez Angelez departamento de ingenieria en sistemas biomedicos, Facultad de Ingenieria UNAM. All imaging at a single Philips 3T platform with harmonized pulse-sequence parameters. Central overread. 60 evaluable knees at n=30. Core 2 - Cardiac Imaging Core (Level 3B). Non-contrast cardiac computed tomography with prospective electrocardiographic gating at Week 0 and Week 52, performed at the Instituto Nacional de Cardiología Ignacio Chávez under cardiovascular Co-Principal Investigator Dr. Erick Alexánderson Rosas, Chief of the Departamento de Cardiología Nuclear e Imagen Cardiovascular Molecular. Radiomic phenotyping of epicardial adipose tissue (EAT) following the Imaging Biomarker Standardization Initiative (IBSI) specifications using PyRadiomics, with quantification of EAT volume, mean attenuation (Hounsfield units), attenuation distribution (standard deviation, skewness, kurtosis), and texture features (first-order, gray-level co-occurrence matrix, gray-level run-length matrix, gray-level size-zone matrix, neighborhood gray-tone difference matrix). Fat Attenuation Index (FAI) quantification in the adventitia of proximal left anterior descending, circumflex, and right coronary artery territories per published perivascular FAI methodology. 30 paired cardiac CT studies. Core 3 - HLA Typing Core (Level 2). Class I (A, B, C) and Class II (DRB1, DQB1, DPB1) HLA typing by PCR-SSO Reverse Luminex at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ) Transplant Department under Dr. Mario Vilatoba. Anonymized archival for population comparison and kinship-linkage analysis. Core 4 - Body Composition Core (Level 4). Multi-frequency bioelectrical impedance analysis (seca mBCA) at six longitudinal timepoints (Week 0, 2, 4, 12, 24, 52) at Universidad La Salle México, capturing visceral adipose tissue trajectory, phase-angle trajectory (an established aging-biology biomarker), appendicular skeletal muscle mass, total body water, extracellular water, and hydration ratios. Available at zero marginal cost to the registry. Five-level endpoint structure. Endpoints are organized in five levels of differentiated resolution: Level 1 - mechanistic deconvolution (PI-executed, primary); Level 2 - biomarker and HLA stratification (sponsor-executed under MTA, hypothesis-generating); Level 3A - knee structural imaging (Ci3M, PI-executed); Level 3B - cardiac structural imaging (INCar, PI-executed); and Level 4 - body composition and aging biology (La Salle, PI-executed). Primary co-endpoints. (1) ACR20 response rate at Week 4 in the Mechanistic Analysis Set (MAS), defined as patients with tirzepatide exposure ≤16 weeks at Week 0 and delta-BMI \<1.0 kg/m² through Week 4. (2) Proportion of Week-4 ACR20 response mediated by the combined biomarker panel (high-sensitivity C-reactive protein, SERPINB2, dipeptidyl peptidase-4 activity) in the MAS, assessed by the MacKinnon product-of-coefficients method with 10,000 bias-corrected and accelerated bootstrap iterations. Surgical Tissue Subcohort (prespecified secondary arm). A subset of enrolled participants who undergo clinically indicated cardiac surgery at INCar during registry follow-up (coronary artery bypass grafting, valve replacement, or combined procedures) will be invited to provide specific informed consent for collection of epicardial adipose tissue fragments routinely excised during operative access to the heart (e.g., during aortic root exposure for AVR, coronary target exposure for CABG, or mitral annular exposure for MVR). These fragments are ordinarily discarded as surgical waste. Under this subcohort they are collected intraoperatively, divided into fresh-frozen aliquots (RNAlater, OCT) and formalin-fixed aliquots (10% neutral-buffered formalin), and processed for bulk and/or single-nucleus RNA sequencing, histological characterization, and biobanking for prespecified future analyses. Tissue acquisition does not modify the surgical procedure. Operational launch is contingent on favorable opinion of the INCar Comité de Investigación and Comité de Ética en Investigación for the tissue-specific protocol, formal operational agreement with the INCar Servicio de Cirugía Cardiovascular, and PRS record amendment. This subcohort is declared at initial registration to establish scientific priority for direct human epicardial adipose tissue transcriptomic characterization under dual GIP/GLP-1 receptor agonism - a gap explicitly identified in the multi-NuSH framework and not filled by any currently published or registered study. Governance and oversight. Independent Scientific Advisory Board (ISAB) with advisory competence over the Statistical Analysis Plan, publication policy, and database lock. Cryptographic provenance infrastructure: SHA-256 hash chain for every biospecimen manifest entry, every DICOM series, and every database snapshot, anchored to an append-only audit log under version control, with three-server email timestamping. Informed consent is modular: each attestation (prospective participation, serum biobanking, HLA typing, knee MRI, cardiac CT, body composition, medical record review, and - for the surgical subcohort - tissue collection) is consented separately within a single document. All data transferred to sponsors is de-identified to HIPAA Safe Harbor and LFPDPPP Mexican standards, with cryptographic separation between re-identification key and transferred dataset. Intellectual property status. Four United States Provisional Patent Applications are active, filed pro se by the Principal Investigator as micro entity: PROV-001 (64/019,134, 27 March 2026, DPP4-Incretin-SERPIN axis for chondroprotection); PROV-002 (64/031,635, 7 April 2026, BMP/ROCK/DPP4/Mechanosensory axis); PROV-003 (64/039,918, 15 April 2026, cartilage companion biomarkers); PROV-004 (64/043,606, 19 April 2026, HLA-guided GIPR companion diagnostics). All four are referenced as Secondary IDs in this registration.