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Background: We had reported that metabolic syndrome (MetS) was associated with increased prevalence of concentric hypertrophy in patients with aortic stenosis (AS). Insulin resistance could be a mediator of this association. The objective of this substudy from the ASTRONOMER trial was to examine the association between insulin resistance and progression of left ventricular hypertrophy (LVH) and global LV hemodynamic load in AS patients.Methods: Among 269 patients randomized in ASTRONOMER, 253 had an echocardiographic follow-up (mean time: 3.4±1.2 yrs). None had hypercholesterolemia, diabetes or coronary artery disease. However, 30% had hypertension and 27% met MetS. The LV mass was calculated with the modified ASE formula and was indexed to a 2.7 power of height (LVMi). As an estimate of the global LV hemodynamic load, we calculated the valvulo-arterial impedance. The Homeostatic Model Assessment (HOMA) index was used as an index of insulin resistance.Results: There was a significant (p<0.0001) increase in LVMi among patients (n=134) with no LV hypertrophy but not in those with pre-existing LVH (p=0.12). In the former subset, annualized progression rate of LVMi was significantly higher in patients with HOMA>1.25 (median value) compared to those with HOMA<1.25 (2.49±0.53 vs. 0.03±0.53 g.m-2.7/yr, p=0.001). During follow-up, 39% of patients with HOMA>1.25 developed LVH compared to 10% in those with HOMA<1.25 (p=0.0002). On multivariable analysis, after adjustment for age, hypertension, SBP, peak aortic jet velocity and Zva, the independent predictors of faster LVMi progression were degree of aortic valve calcification (p=0.03) and HOMA index (p=0.02). HOMA index was also an independent predictor of the progression of Zva (p=0.003). After further adjustment for the latter variable, HOMA index remained a significant (p=0.02) predictor of LVMi progression. Furthermore, patients with HOMA>1.25 had faster LVMi progression in the arm treated with statin (3.26±0.53 vs. 0.06±0.53g.m-2.7/yr, p=0.003) but not in those treated with placebo (1.74±0.53 vs. −0.12±0.53g.m-2.7/yr, p=NS).Conclusion: This study reports that insulin resistance is an independent predictor of faster progression of global LV hemodynamic load and LVH in AS patients. Given that the most prevalent form of insulin resistance is associated with visceral obesity, the findings provide strong impetus for the elaboration of interventional studies targeting visceral obesity and other conditions predisposing to insulin resistance. The adverse effect of insulin resistance on LVH seems to be exacerbated by statin therapy.