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Coronary Artery Disease and Type 2 Diabetes: a Proteomic Study

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Coronary Artery Disease and Type 2 Diabetes: a Proteomic Study Diabetes Care Volume 43, April 2020 843 Coronary Artery Disease and Giulia Ferrannini,1,2 Maria Laura Manca,3 Marco Magnoni,4 Felicita Andreotti,5 Type 2 Diabetes: A Proteomic Daniele Andreini,6,7 Roberto Latini,8 Attilio Maseri,9 Aldo P. Maggioni,10 Study Rachel M. Ostroff,11 Stephen A. Williams,11 and Ele Ferrannini12 Diabetes Care 2020;43:843–851 | https://doi.org/10.2337/dc19-1902 OBJECTIVE Coronary artery disease (CAD) is a major challenge in patients with type 2 diabetes (T2D). Coronary computed tomography angiography (CCTA) provides a detailed anatomic map of the coronary circulation. Proteomics are increasingly used to improve diagnostic and therapeutic algorithms. We hypothesized that the protein panel is differentially associated with T2D and CAD. RESEARCH DESIGN AND METHODS In CAPIRE (Coronary Atherosclerosis in Outlier Subjects: Protective and Novel 1Department of Medical Sciences, Postgraduate Individual Risk Factors Evaluationda cohort of 528 individuals with no previous School of Internal Medicine, University of Turin, 2 Turin, Italy cardiovascular event undergoing CCTA), participants were grouped into CAD 2 1 Department of Medicine Solna, Karolinska (clean coronaries) and CAD (diffuse lumen narrowing or plaques). Plasma proteins Institutet, Stockholm, Sweden were screened by aptamer analysis. Two-way partial least squares was used to 3Department of Clinical and Experimental Med- simultaneously rank proteins by diabetes status and CAD. icine, University of Pisa, Pisa, Italy 4IRCCS Ospedale San Raffaele and Universita` Vita-Salute San Raffaele, Milan, Italy RESULTS 5 1 Institute of Cardiology, FPG IRCCS, Catholic Uni- CARDIOVASCULAR AND METABOLIC RISK Though CAD was more prevalent among participants with T2D (HbA1c 6.7 6 1.1%) versity Medical School, Rome, Italy than those without diabetes (56 vs. 30%, P < 0.0001), CCTA-based atherosclerosis 6CentroCardiologicoMonzino,IRCCS,Milan,Italy 7 burden did not differ. Of the 20 top-ranking proteins, 15 were associated with both Cardiovascular Section, Department of Clinical Sciences and Community Health, University of T2D and CAD, and 3 (osteomodulin, cartilage intermediate-layer protein 2, and Milan, Milan, Italy HTRA1) were selectively associated with T2D only and 2 (epidermal growth factor 8Mario Negri Institute of Pharmacological Research- receptor and contactin-1) with CAD only. Elevated renin and GDF15, and lower IRCCS, Milan, Italy 9 adiponectin, were independently associated with both T2D and CAD. In multivariate Heart Care Foundation, Florence, Italy 10ANMCO Research Center, Heart Care Founda- analysis adjusting for the Framingham risk panel, patients with T2D were “pro- tion, Florence, Italy tected” from CAD if female (P 5 0.007), younger (P 5 0.021), and with lower renin 11Clinical Research and Development, SomaLogic levels (P 5 0.02). Inc., Boulder, CO 12CNR Institute of Clinical Physiology, Pisa, Italy CONCLUSIONS Corresponding author: Ele Ferrannini, ferranni@ We concluded that 1) CAD severity and quality do not differ between participants ifc.cnr.it with T2D and without diabetes; 2) renin, GDF15, and adiponectin are shared Received 24 September 2019 and accepted 31 December 2019 markers by T2D and CAD; 3) several proteins are specifically associated with T2D or 4 This article contains Supplementary Data online CAD; and ) in T2D, lower renin levels may protect against CAD. at https://care.diabetesjournals.org/lookup/suppl/ doi:10.2337/dc19-1902/-/DC1. Cardiovascular (CV) disease has steadily represented the leading cause of death in the © 2020 by the American Diabetes Association. world for the past 15 years, with coronary artery disease (CAD) and stroke being Readers may use this article as long as the work is properly cited, the use is educational and not responsible for a combined 15 million deaths in 2016 (1). Morbidity and mortality of for profit, and the work is not altered. More infor- patients with CAD is considerably higher in the presence of diabetes, accounting for mation is available at https://www.diabetesjournals ;50% of deaths in this population (2). Therefore, detection of CAD and its risk factors .org/content/license. 844 Protein Biomarkers for CAD in Diabetes Diabetes Care Volume 43, April 2020 is crucial to improve both treatment and presence of type 2 diabetes (T2D) and 4) previous documented acute or chronic prevention, especially in patients with CCTA-proven CAD by using an expanded peripheral vascular disease (stroke, tran- diabetes. proteomic platform and bivariate anal- sient ischemic attack, previous revascu- Coronary computed tomography an- ysis of associations. larization); 5) claudication at rest or at giography (CCTA) provides a noninvasive, low-grade effort); and 6) active inflam- highly sensitive anatomic investigation RESEARCH DESIGN AND METHODS matory or neoplastic disease. of the epicardial coronary circulation by Study Design visualizing the coronary artery lumen and The Coronary Atherosclerosis in Outlier CVRF Definition wall with an intravenous contrast agent Subjects: Protective and Novel Individual The conventional CVRFs that are based (3). CCTA is highly accurate in the early Risk Factors Evaluation (CAPIRE) study on the Adult Treatment Panel III and the detection of obstructive atherosclerosis, (ClinicalTrials.gov identifier: NCT02157662) 2013 American College of Cardiology/ defined by invasive coronary angiogra- is part of the Gruppo Italiano per lo Studio American Heart Association guidelines phy, and therefore is being increasingly dellaStreptochinasinell’InfartoMiocardico for CV disease prevention were consid- included in international guidelines for (GISSI) Outlier Project, jointly promoted ered in selecting the study population the diagnostic workup of CAD (4,5). The by the Heart Care Foundation Onlus, (18). CVRFs were defined as follows: extent of atherosclerotic burden can be Italian Association of Hospital Cardiol- family history of ischemic heart disease assessed by several CCTA-derived scores, ogists (ANMCO), and Mario Negri In- (history of early manifestations of ische- which have demonstrated independent stitute of Pharmacological Research. mic heart disease in first-degree relatives long-term predictive power for adverse CAPIRE was designed as a prospective, before 55 years of age for men and cardiac events (i.e., the segment involve- observational study aimed at identifying 65 years for women), arterial hyperten- ment score, the segment stenosis score, possible new mechanisms that promote sion (history of arterial hypertension, and the CT-adapted Leaman score [6]). In or protect against atherothrombosis; in ongoing antihypertensive treatment, or patients with diabetes, the prevalence of its longitudinal phase, participants are recent observation of blood pressure obstructive, CCTA-detected CAD is nearly being followed for 5 years or longer [BP] values .140/90 mmHg), hypercho- 25% (i.e., much higher than in the pop- (17). The study enrolled participants 45– lesterolemia (total serum cholesterol ulation without diabetes) (7). Moreover, 75 years of age, without previous clin- .200 mg/dL or ,200 mg/dL with on- CCTA provides long-term prognostic in- ical manifestations of ischemic heart going lipid-lowering medications), diabe- formation for patients with diabetes, disease (acute myocardial infarction, un- tes (fasting plasma glucose levels .126 allowing their risk stratification and show- stable angina, chronic stable angina, pre- mg/dL or a 2-h value $200 mg/dL by oral ing excellent prognosis when no evidence vious percutaneous or surgical coronary glucose tolerance test or isolated eleva- of atherosclerosis is detected (7,8). revascularization, heart failure), who un- tion of glycated hemoglobin [HbA1c] $6.5% Addressing traditional CV risk factors derwent a 64-slice (or superior) CCTA in or current use of insulin or oral glucose- (CVRFs) has proved advantageous in re- the outpatient clinics of the 11 participat- lowering medications), and cigarette smok- ducing CV mortality in the general pop- ingcentersbecauseofsuspectedCAD.The ing (current cigarette smoking habit or ulation as well as in people with diabetes main indications for CCTA were 1)unin- recent abstention within 1 year). (9–11). Nevertheless, the relationship terpretable, equivocal, or contraindicated Source data for defining CVRFs were between the presence of traditional functional stress test (44% of patients); 2) physical examination, medical records, CVRFs and atherosclerosis development new-onset chest pain syndrome at low- and laboratory tests reported by the is hardly linear, and CV events can occur intermediate pretest likelihood of CAD participant or documented before CCTA. independently of traditional CVRF man- (25% of patients); and 3) other indication After enrollment, a centrally performed agement.Thus, substantial improvement (including evaluation before valve or non- biomarker profile, including lipid profile in CAD prevention is still needed, espe- cardiac surgery, elevated risk profile, ar- and metabolic markers, allowed a refined cially in patients with diabetes (12,13). rhythmias, or atypical symptoms) (31% of assessment of CVRFs, such as diabetes Over the past decade, technology has patients). Patients with T2D were further and dyslipidemia. According to data in provided novel tools for the identifica- selected to be eligible for the CCTA pro- the literature, most patients without any tion of protective and susceptibility fac- cedure if they were in good clinical con- CVRFs or one single risk factor belong tors for both CAD and
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