Cardiovasc Diabetol. 2023;22(1):30.

Systemic proinflammatory-profibrotic response in aortic stenosis patients with diabetes and its relationship with myocardial remodeling and clinical outcome.

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제1저자 이현정 · 교신저자 이승표

PMID 36765354 PMC9921197 DOI 10.1186/s12933-023-01763-1 IF 15.6 순환기내과

소속 (7)

Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, South Korea.
Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
Division of Cardiology, Department of Medicine, Cardiovascular Imaging Center, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, South Korea. sproll1@snu.ac.kr.
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea. sproll1@snu.ac.kr.
Center for Precision Medicine, Seoul National University Hospital, Seoul, South Korea. sproll1@snu.ac.kr.

Abstract

BACKGROUND Previous studies have mainly focused more on how diabetes affects the valve than the myocardium in aortic stenosis (AS). In the pressure-overloaded heart, myocardial fibrosis is an important driver of the progression from compensated hypertrophy to heart failure. Using comprehensive noninvasive imaging and plasma proteomics, we investigated whether and how diabetes aggravates the remodeling of the myocardium and its relation with prognosis in AS patients.

METHODS Severe AS patients were enrolled in two prospective cohorts for imaging and biomarker analysis. The imaging cohort (n = 253) underwent echocardiography and cardiac magnetic resonance, and the biomarker cohort (n = 100) blood sampling with multiplex proximity extension assay for 92 proteomic biomarkers. The composite outcome of hospitalization for heart failure admissions and death was assessed in the imaging cohort.

RESULTS Diabetic patients were older (70.4 ± 6.8 versus 66.7 ± 10.1 years) with more advanced ventricular diastolic dysfunction and increased replacement and diffuse interstitial fibrosis (late gadolinium enhancement % 0.3 [0.0-1.6] versus 0.0 [0.0-0.5], p = 0.009; extracellular volume fraction % 27.9 [25.7-30.1] versus 26.7 [24.9-28.5], p = 0.025) in the imaging cohort. Plasma proteomics analysis of the biomarker cohort revealed that 9 proteins (E-selectin, interleukin-1 receptor type 1, interleukin-1 receptor type 2, galectin-4, intercellular adhesion molecule 2, integrin beta-2, galectin-3, growth differentiation factor 15, and cathepsin D) were significantly elevated and that pathways related to inflammatory response and extracellular matrix components were enriched in diabetic AS patients. During follow-up (median 6.3 years), there were 53 unexpected heart failure admissions or death in the imaging cohort. Diabetes was a significant predictor of heart failure and death, independent of clinical covariates and aortic valve replacement (HR 1.88, 95% CI 1.06-3.31, p = 0.030).

CONCLUSIONS Plasma proteomic analyses indicate that diabetes potentiates the systemic proinflammatory-profibrotic milieu in AS patients. These systemic biological changes underlie the increase of myocardial fibrosis, diastolic dysfunction, and worse clinical outcomes in severe AS patients with concomitant diabetes.

Keywords

Aortic valve stenosisDiabetes mellitusMagnetic resonance imagingProteome

Figures

**Fig. 1** Myocardial fibrosis and left ventricular diastolic function in aortic stenosis patients according to diabetes and diabetes medication status. a, b Comparison of the degree of diastolic dysfunction in a patients with versus without diabetes and in b patients stratified by the diabetes medication status. c, d Comparison of late gadolinium enhancement (LGE) in c patients with versus without diabetes and in d patients stratified by the diabetes medication status. e, f Comparison of extracellular volume fraction (ECV) in e patients with versus without diabetes and in f patients stratified by the diabetes medication status. g, h Representative LGE and ECV images of cardiac magnetic resonance taken from g a non-diabetic aortic stenosis patient (no LGE; ECV 26.4%) versus h a diabetic aortic stenosis patient on oral hypoglycemic agent (midwall LGE in the septal and lateral wall; ECV 34.5%). DM, diabetes mellitus; ECV, extracellular volume; LGE, late gadolinium enhancement; LVDD, left ventricular diastolic dysfunction; OHA, oral hypoglycemic agents

**Fig. 2** Significantly upregulated plasma proteins in AS patients with diabetes on proteomic analysis. a Volcano plot identifying the significantly upregulated proteins (annotated in red) in the plasma proteome of diabetic AS patients. b Scatter plots comparing the plasma levels of differentially expressed proteins in AS patients with and without diabetes. All comparisons were adjusted for multiple testing with the Benjamini & Hochberg method, with adjusted p-values representing the false discovery rate. The horizontal bars for each group indicate median and interquartile range. adj, adjusted; AS, aortic stenosis; DM, diabetes mellitus; SELE, E-selectin; IL-1RT1, interleukin-1 receptor type 1; CTSD, cathepsin D; Gal-4, galectin-4; Gal-3, galectin-3; IL-1RT2, interleukin-1 receptor type 2; GDF-15, growth differentiation factor 15; ICAM-2, intercellular adhesion molecule 2; ITGB2, integrin beta-2

**Fig. 3** Over-represented pathways in the plasma proteome of AS patients with diabetes. Functional enrichment analyses using the g:Profiler with Gene Ontology terms were performed with the proteomic analysis results and are presented in a Manhattan plot. The sizes of circles signify intersection size. adj, adjusted; AS, aortic stenosis; BP, biological process; CC, cellular component; GO, Gene Ontology domains; MF, molecular function

**Fig. 4** Comparison of event-free survival in AS patients according to diabetes. Kaplan–Meier analysis with p-values by the log-rank test are presented for a the composite outcome of admission for heart failure and all-cause death, and b all-cause death. AS, aortic stenosis; DM, diabetes mellitus

그림 출처: PubMed Central 공개 논문 (PMC9921197)

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could influence the work reported in this paper.

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