Ethnic Influence on the Development of Aortic Stenosis in Patients with Diabetes: A Two-Hit Model of Myocardial Fibrosis and an Integrated Framework for Personalised Management

Diabetes mellitus (DM) affects approximately one-third of patients undergoing aortic valve intervention and is an active modifier of calcific aortic valve disease (CAVD), procedural risk and bioprosthetic durability rather than a passive comorbidity. Because its effects vary with glycaemic exposure, sex, ethnicity and myocardial phenotype, diabetic aortic stenosis (AS) is a model condition for personalised cardiovascular medicine. DM is associated with valvular advanced glycation end-product (AGE) accumulation, NF-κB/BMP-2 upregulation and chronic valvular inflammation, and independently promotes diffuse myocardial fibrosis via profibrotic signalling, myocardial inflammation and microvascular dysfunction. This metabolic fibrosis is superimposed on the pressure-overload fibrosis intrinsic to AS, producing a “two-hit” myocardial substrate that may predispose to earlier ventricular decompensation and impaired reverse remodelling after valve replacement. Ethnicity further modulates this relationship: despite a higher burden of diabetes, Black and East Asian populations develop calcific aortic valve disease less often than White populations, and South Asian populations no more often; in South Asians, however, the effect of diabetes may fall more heavily on the myocardium, raising the hypothesis that the metabolic and haemodynamic ‘hits’ are differentially weighted across ethnic groups. Cardiac magnetic resonance markers, such as late gadolinium enhancement (LGE) and extracellular volume fraction (ECV), together with echocardiographic global longitudinal strain (GLS), predict adverse outcomes. In observational data, DM is associated with higher 30-day mortality after surgical but not transcatheter replacement and with earlier haemodynamic deterioration of surgical bioprosthetic valves. Observational and experimental data suggest that sodium–glucose cotransporter-2 inhibitors may slow AS progression, although randomised evidence is lacking. A personalised, multi-layer framework is proposed that integrates glycaemic phenotype (HbA1c and glycaemic variability), sex, ethnicity, lipoprotein(a) and emerging genomic risk, advanced myocardial imaging, procedural timing, valve selection and pharmacotherapy; its imaging and HbA1c-based elements are untested proposals that should not, at present, alter guideline intervention thresholds. Prospective, ethnically diverse trials enrolling diabetic patients and incorporating myocardial-fibrosis endpoints are needed. This synthesis is intended as evidence-informed expert opinion rather than a guideline-level recommendation.