Health Improvements by Understanding the Determinants of Residual Risk in Coronary Artery Disease and New Targets for Prevention and Treatment

NCT ID: NCT06601153

Last Updated: 2024-09-19

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 961 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2023-07-07
• Study Completion Date: 2025-12-31

Brief Summary

Current medical treatments, in patients with stable coronary artery disease (CAD), mainly target established risk factors and are able to reduce morbidity and mortality but still leave a substantial residual risk of coronary artery disease progression and events. The main hypothesis of this study is that metabolic derangement, including pre-diabetes, elevated levels of triglycerides, low levels and functionality of high-density lipoprotein cholesterol, often associated with a chronic inflammatory state, is a currently unrecognized and undertreated conditon which could be the most relevant determinant of residual risk.

The goal of HURRICANE observational study is to discover specific individual genetic/molecular profiles subtending emerging cardiometabolic and vascular risk patterns and associating with a more severe and progressive coronary artery disease. We will thus develop and preliminary validate new predictive models for the recognition of high-risk patients and explore possible new targets for individualized preventive treatment.

The severity, extent and progression of coronary plaques will be assessed by qualitative and quantitative analysis of cardiac computed tomography (CCT) performed in retrospective and prospective cohorts of patients with stable coronary disease.

Detailed Description

HURRICANE is an observational clinical study, performed in retrospective and prospective cohorts of patients with stable CAD, to assess the role of emerging cardiometabolic and vascular risk determinants to predict severe and progressive coronary atherosclerosis documented by advanced CCT imaging.

The population of the retrospective study consists of two parallel, independent groups of patients enrolled in previous clinical trials focused on blood and CCT biomarkers of CAD. All participants are assessed for eligibility to the current study which includes in particular availability of blood samples in bio-bank and of interpretable CCT exams. For each cohort and for the whole retrospective population (561 patients) clinical variables (demographic data, cardiovascular risk factors, history of previous CAD, symptoms and medications) and conventional circulating biomarkers (lipid and glucose metabolism, systemic inflammation, liver and kidney function) are recorded. The coronary imaging variables which will provide the disease presence and severity end-points will be derived from qualitative and semiquantitative analyses of CCT exams according to CAD-RADS 2.0 classification system.

The population of the prospective longitudinal study will include 400 patients referred at IRCCS SYNLAB SDN in Naples and FTGM in Pisa, over a 12 months period, to a clinically indicated CCT for suspected CAD, signing a written informed consent and fulfilling Inclusion and exclusion criteria. At baseline, patients will be characterized as in the retrospective study (same clinical variables, conventional circulating biomarkers and CCT imaging variables) and blood samples will be collected and stored in the dedicated Bio-Bank for advanced genetic/molecular analyses. They will be submitted to monitoring visits and a last follow-up visit at 12 months when compliance to medical treatment and events will be registered. A second blood sample will be collected and stored in dedicated Bio-Bank for advanced molecular analyses. A second CCT scan will be performed at 12 months with the same scanner, at the same institution, by the use of a state-of-the art CCT technology with high spatial and temporal resolution to provide quantitative measurements of coronary plaque volumes and coronary plaque composition which will be used to define the disease progression end-points.

Qualitative and semiquantitative analyses of CCT exams will be performed by radiologists according to CAD-RADS 2.0 classification systemin both the retrospective and prospective populations. In the prospective population, CCT images at enrollment and follow-up will also be quantitatively analyzed to define evolving CAD phenotypes. Quantitative analysis will be performed on visually identified plaques using a dedicated software package (QAngio CT Research Edition version 3.1.2.0, Medis Medical Imaging Systems, Leiden, the Netherlands) to generate detailed output on the lumen and plaque statistics, including the degree of stenosis, lesion length, vessel volume, plaque burden, plaque volume, and plaque components (according to the virtual histology classification: dense calcium, necrotic core, fibrous-fatty, fibrous, and media). Additional CT-derived parameters will also be assessed, in particular epicardial and perivascular adipose tissue, to be tested in the predictive models of CAD evolution and to be entered in a Machine Learning data analysis as potential variables of the pathophysiologic CAD network.

Circulating biomarkers will be evaluated by standard methodologies of clinical chemistry laboratories at the two participant clinical centers and specific circulating biomarkers will be analyzed at the IFC-CNR Core-Lab in both the retrospective and the prospective populations. In particular, additional markers of lipid metabolism and adipose tissue function, endothelial function and atherosclerotic burden will be evaluated by dedicated immunoassays, while markers of myocardial damage/function will be evaluated by automatized immunoassays. The inflammatory profile will be assessed by multiplex cytokine screens."Omics" analyses, in both populations, will include lipidomic, with the assessment of circulating lipid species using mass spectrometry, and genetic profiling by GWAS (Genome-Wide Association Study) performed by an external provider (Genomix4Life) using new generation microarray technology to genotype single-nucleotide variants (SNVs). In representative extreme groups of patients from the prospective population, a specific panel of 88 candidate genes involved in lipid/glucose homeostasis, endothelial/vascular function and systemic inflammation, together with other relevant genes emerging from the GWAS analysis, will be sequenced for known and unknown variants at FTGM by NGS (Next Generation Sequencing) approach. The library preparation for NGS will be performed using the Illumina DNA Prep with Enrichment Kit. Base-Space Variant Interpreter software will be used to annotate, filter and interpret the variants. The degree of pathogenicity will be also assessed on VarSome (https://varsome.com) and GWAS Catalog (https://www.ebi.ac.uk/gwas/), search engines and impact analysis tools for human genetic variation. The variants identified as pathogenetically relevant, in the subjects with extreme phenotypes will then be assessed in the rest of the population. Moreover, miRNAs, putatively associated with relevant gene variants and screened by in silico bioinformatic analysis, will be assessed by qPCR.

Conditions

Coronary Arterial Disease (CAD)

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: OTHER

Study Groups

Retrospective cohort of 561 patients with suspected CAD

All patients with suspected CAD with available blood samples stored in bio-banks and interpretable CCT stored in imaging repositories.

Cardiac CT

Intervention Type: DIAGNOSTIC_TEST

Cardiac CT to characterize coronary atherosclerosis

Prospective cohort od 400 patients with suspected CAD

All patients with suspected CAD in whom with blood samples will be collected and stored in bio-banks and CCT will be acquired and stored in imaging repositories.

Cardiac CT

Intervention Type: DIAGNOSTIC_TEST

Cardiac CT to characterize coronary atherosclerosis

Interventions

Cardiac CT

Cardiac CT to characterize coronary atherosclerosis

Intervention Type: DIAGNOSTIC_TEST

Other Intervention Names

Computed Tomography Coronary Angiography

Eligibility Criteria

Inclusion Criteria

• patients with known or suspected stable CAD who underwent CCT for the registered studies "SMARTool" or "Studio di biomarcatori in vivo ed in vitro"
• fully accessible CCT image files and whole blood and plasma/serum aliquots stored in BioBank
• written informed consent

• patients with suspected stable CAD clinically referred for a first diagnostic CCT
• fully accessible CCT image files and whole blood and plasma/serum aliquots stored in BioBank
• written informed consent

Exclusion Criteria

• overt heart failure (NYHA Class III-IV) and/or reduced systolic LV function (LVEF<40%)
• relevant comorbid conditions limiting expected survival to less than 1 year
• CCT exam of suboptimal quality

PROSPECTIVE STUDY

• history of previous CAD or major cardiovascular events
• overt heart failure (NYHA Class III-IV) and/or reduced systolic LV function (LVEF<40%)
• relevant comorbid conditions limiting expected survival to less than 1 year
• CCT exam of suboptimal quality

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

CNR Institute of Clinical Physiology, Pisa, Italy

UNKNOWN

Sponsor Role: collaborator

IRCCS SYNLAB SDN, Naples, Italy

UNKNOWN

Sponsor Role: collaborator

Fondazione Toscana Gabriele Monasterio

OTHER

Sponsor Role: lead

Responsible Party

Danilo Neglia

MD, PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Danilo Neglia, MD, PhD

Role: STUDY_CHAIR

Fondazione Toscana Gabriele Monasterio

Locations

Fondazione Toscana Gabriele Monasterio

Pisa, Italy, Italy

Site Status: RECRUITING

Irccs Synlab Sdn

Napoli, , Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Danilo Neglia, MD, PhD

Role: CONTACT

dneglia@ftgm.it

+393355857594

Maria Sole Morelli, PhD

Role: CONTACT

msmorelli@ftgm.it

+393498337562

Facility Contacts

Danilo Neglia, MD, PhD

Role: primary

dneglia@ftgm.it

+393355857594

Alessia Gimelli, MD

Role: backup

alessia.gimelli@ftgm.it

+393487831405

Carlo Cavaliere, MD

Role: primary

carlo.cavaliere@synlab.it

+393387484984

Katia Pane, PhD

Role: backup

katia.pane@synlab.it

+393341363000

References

Cademartiri F, Meloni A, Pistoia L, Degiorgi G, Clemente A, Gori C, Positano V, Celi S, Berti S, Emdin M, Panetta D, Menichetti L, Punzo B, Cavaliere C, Bossone E, Saba L, Cau R, Grutta L, Maffei E. Dual-Source Photon-Counting Computed Tomography-Part I: Clinical Overview of Cardiac CT and Coronary CT Angiography Applications. J Clin Med. 2023 May 23;12(11):3627. doi: 10.3390/jcm12113627.

Reference Type: BACKGROUND

PMID: 37297822 (View on PubMed)

Neglia D, Liga R, Gimelli A, Podlesnikar T, Cvijic M, Pontone G, Miglioranza MH, Guaricci AI, Seitun S, Clemente A, Sumin A, Vitola J, Saraste A, Paunonen C, Sia CH, Paleev F, Sade LE, Zamorano JL, Maroz-Vadalazhskaya N, Anagnostopoulos C, Macedo F, Knuuti J, Edvardsen T, Cosyns B, Petersen SE, Magne J, Laroche C, Berle C, Popescu BA, Delgado V; EURECA Investigators. Use of cardiac imaging in chronic coronary syndromes: the EURECA Imaging registry. Eur Heart J. 2023 Jan 7;44(2):142-158. doi: 10.1093/eurheartj/ehac640.

Reference Type: BACKGROUND

PMID: 36452988 (View on PubMed)

Neglia D, Caselli C, Maffei E, Cademartiri F, Meloni A, Bossone E, Saba L, Lee SE, Sung JM, Andreini D, Al-Mallah MH, Budoff MJ, Chinnaiyan K, Choi JH, Chun EJ, Conte E, Gottlieb I, Hadamitzky M, Kim YJ, Lee BK, Leipsic JA, Marques H, de Araujo Goncalves P, Pontone G, Shin S, Stone PH, Samady H, Virmani R, Narula J, Shaw LJ, Bax JJ, Lin FY, Min JK, Chang HJ. Rapid Plaque Progression Is Independently Associated With Hyperglycemia and Low HDL Cholesterol in Patients With Stable Coronary Artery Disease: A PARADIGM Study. Circ Cardiovasc Imaging. 2024 Jul;17(7):e016481. doi: 10.1161/CIRCIMAGING.123.016481. Epub 2024 Jul 16.

Reference Type: BACKGROUND

PMID: 39012946 (View on PubMed)

Caselli C, De Caterina R, Smit JM, Campolo J, El Mahdiui M, Ragusa R, Clemente A, Sampietro T, Clerico A, Liga R, Pelosi G, Rocchiccioli S, Parodi O, Scholte A, Knuuti J, Neglia D; EVINCI and SMARTool. Triglycerides and low HDL cholesterol predict coronary heart disease risk in patients with stable angina. Sci Rep. 2021 Oct 20;11(1):20714. doi: 10.1038/s41598-021-00020-3.

Reference Type: BACKGROUND

PMID: 34671067 (View on PubMed)

Neglia D, Aimo A, Lorenzoni V, Caselli C, Gimelli A. Triglyceride-glucose index predicts outcome in patients with chronic coronary syndrome independently of other risk factors and myocardial ischaemia. Eur Heart J Open. 2021 Jul 24;1(1):oeab004. doi: 10.1093/ehjopen/oeab004. eCollection 2021 Aug.

Reference Type: BACKGROUND

PMID: 35919094 (View on PubMed)

Di Giorgi N, Michelucci E, Smit JM, Scholte AJHA, El Mahdiui M, Knuuti J, Buechel RR, Teresinska A, Pizzi MN, Roque A, Poddighe R, Parodi O, Pelosi G, Caselli C, Neglia D, Rocchiccioli S. A specific plasma lipid signature associated with high triglycerides and low HDL cholesterol identifies residual CAD risk in patients with chronic coronary syndrome. Atherosclerosis. 2021 Dec;339:1-11. doi: 10.1016/j.atherosclerosis.2021.11.013. Epub 2021 Nov 11.

Reference Type: BACKGROUND

PMID: 34801858 (View on PubMed)

Caselli C, Occhipinti M, Pane K, De Gori C, Rocchiccioli S, Botto N, Prontera C, Cavaliere C, Ragusa R, Vecoli C, Sansone F, Passaro E, Ceccherini E, Morlando A, Clemente A, Franzese M, Maffei E, Punzo B, Gimelli A, Cademartiri F, Neglia D. Health improvements by understanding residual risk in coronary artery disease and new targets for prevention/treatment: rationale and research protocol of the HURRICANE project. Eur Heart J Open. 2025 Jan 28;5(1):oeaf005. doi: 10.1093/ehjopen/oeaf005. eCollection 2025 Jan.

Reference Type: DERIVED

PMID: 39949422 (View on PubMed)

Other Identifiers

PNRR-MAD-2022-12376550

Identifier Type: -

Identifier Source: org_study_id