Diabetes and calcific aortic valve disease: controversy of clinical outcomes in diabetes after aortic valve replacement

Abstract

Calcific aortic valve disease (CAVD) is a progressive disease, of which the 2-year mortality is >50% for symptomatic aortic valve stenosis unless transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) is performed promptly. The prevalence of diabetes among CAVD has increased rapidly in recent years. The combination of diabetes with its cardio-renal and metabolic comorbidities, such as hypertension, hyperlipidemia, chronic kidney disease, and ageing, accelerated the progression of CAVD and increased the subsequent needs for aortic valve replacement. Clinical data regarding the impact of diabetes on outcomes of patients undergoing TAVR or SAVR have exhibited inconsistent results. Compared with non-diabetes, the short-term mortality after TAVR was not significant in diabetes, while the mid-term mortality differed from different cohorts. Although there were worse mid-term and long-term mortalities after SAVR in diabetes, the short-term mortality in diabetes was disputable. As for complications, there were common worse manifestations with coronary heart disease, acute kidney injury, heart failure, and systemic inflammatory response syndrome in diabetes undergoing TAVR or SAVR. Moreover, diabetes was one of the risk factors for deterioration of bioprosthetic aortic valves, leading to increased long-term mortality. Based on the efficacy for CAVD and atherosclerotic cardiovascular disease, glucose-lowering medications might have potential to inhibit deterioration of bioprosthetic aortic valves independent of glucose control.

Keywords: calcific aortic valve disease; deterioration of bioprosthetic aortic valve; diabetes; surgical aortic valve replacement; transcatheter aortic valve replacement.

Figure 1

Risk factor and time course of diabetes concomitant to calcific aortic valve disease. Shown is the relationship among disease stage, risk factor, molecular link, valve anatomy, stage of cardiac damage, and the age of the patient. The morbidity of aortic valve stenosis (dashed line) increased rapidly with age. Once in symptomatic stenosis, the mortality of aortic valve stenosis (solid line) increased rapidly. Once with cardiac damage, aortic valve replacement was the only effective treatment. AGEs, advanced glycation end products; RAGE, receptor for AGEs; LV, left ventricle; LA, left atrium; RV, right ventricle; RA, right atrium; LVEF, left ventricular ejection fraction; TAVR, transcatheter aortic valve replacement; SAVR, surgical aortic valve replacement.

Figure 2

Pathway and molecular link between diabetes and calcific aortic valve disease. Pathological mechanism of initiation and progression of CAVD in diabetes was shown as crosstalk of various pathways. Different stimuli induced EndMT and broke the endothelial barrier, resulting in infiltration of lipoproteins and immune cells. This infiltration was accompanied by the overproduction of ROS via dysregulation of eNOS, and accumulation of NOX and MitoROS. Oxidative stress could promote the formation of OxLDL and OxPL, which induced osteogenic differentiation of VICs, and eventual bone formation. Apoptosis of VICs and subsequent diffuse calcification were induced by infiltrated macrophages, T lymphocytes and mast cells via direct interaction, activation of Ang II, and secretion TGFβ, TNFα, IL-1β, and IL-6. Increased circulating AGEs induced the pro-osteogenic reprogramming via RAGE/NF-κB/ATF4/CHOP pathway. Diffuse calcification accounted for approximately 83% of all calcification deposits, while bone formation accounted for the other 17%. LDL, low-density lipoprotein; Lp(a), lipoprotein (a); EndMT, endothelial-to-mesenchymal transition; ROS, reactive oxygen species; eNOS, endothelial nitric oxide synthase; NOX, nicotinamide adenine dinucleotide phosphate oxidase, MitoROS, mitochondria-generated ROS; OxLDL, oxidized LDL; OxPL, oxidized phospholipids; Ang, angiotensin.

Figure 3

Clinical outcome and complication of diabetes in transcatheter aortic valve replacement. Compared with non-diabetes, the impact of diabetes on clinical outcomes and various complications after TAVR.

Figure 4

Clinical outcome and complication of diabetes in surgical aortic valve replacement. Compared with non-diabetes, the impact of diabetes on clinical outcomes and various complications after SAVR.

Figure 5

Glucose-lowering medication option for patients with diabetes and deterioration of bioprosthetic aortic valve based on the efficacy for CAVD and ASCVD. ASCVD, atherosclerotic cardiovascular disease; BAV, bioprosthetic aortic valve; PPARγ, peroxisome proliferator-activated receptor γ; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT-2, sodium–glucose co-transporter-2.