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

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.

Impact of diabetes on remodelling, microvascular function and exercise capacity in aortic stenosis

“… 12 Indeed, ECV has been associated with markers of disease severity and all-cause mortality in patients with AS, even after aortic valve replacement. 13 We found a small increase in diffuse fibrosis in the diabetes group with AS which is consistent with a previous study that examined preoperative LV biopsies, although in a much smaller sample size (n=16 with diabetes), 14 as well as in the study by Lee et al 11 In diabetes, the mechanism of cardiac fibrosis is complex but may be related to changes in fibroinflammatory markers (such as transforming growth factor or matrix metalloproteinases) 15 which may lead to the deposition of collagen within the extracellular matrix. This can cause increased myocardial stiffness which could help drive the myocardial hypertrophic response from being adaptive to decompensation 1 and contribute to microvascular dysfunction.…”

“…With a similar length of follow-up (median 6.3 years) compared with our study, Lee et al showed diabetes is significantly associated with outcomes (HR 1.88). 11 Their events, however, were largely driven by all-cause death which would be somewhat consistent with our secondary outcome findings. Other groups have shown that diabetes increases the risk of non-cardiac deaths.…”

“…To our knowledge, only one other study has directly evaluated the impact of diabetes on CV structure/function in AS. Lee et al 11 showed worse diastolic function and more diffuse interstitial fibrosis in their diabetes group compared with non-diabetes. They also demonstrated an elevation of a range of biomarkers involved with inflammation and the modulation of extracellular matrix in diabetes.…”

Haemodynamic and metabolic phenotyping of patients with aortic stenosis and preserved ejection fraction: A specific phenotype of heart failure with preserved ejection fraction?

“…49 We also conducted an exploratory sensitivity analysis in patients with T2DM. Lee et al 6 demonstrated that T2DM in patients with AS is associated with increased serum levels of pro-inflammatory cytokines, more advanced ventricular diastolic dysfunction, deregulated myocardial fibrosis, and increased risk of HF and death. We show that peak VO 2 is significantly impaired in diabetic versus non-diabetic patients in both ASpEF and HFpEF.…”

“…arterial hypertension, type 2 diabetes mellitus [T2DM]) are associated with an increased risk of developing AS 4 and with marked cardiac structural and functional abnormalities (i.e. left ventricular diastolic dysfunction, 5,6 diffuse myocardial fibrosis, 5,6 increased systemic inflammation 6 ) independently of AS severity and left ventricular ejection fraction (LVEF). 7,8 Also, these patients are associated with a worse prognosis in AS, even after AV replacement (AVR).…”