Cardiac remodeling in moderate aortic stenosis

STRUCTURED ABSTRACTO_ST_ABSBackgroundC_ST_ABSAortic stenosis (AS) accounts for substantial global morbidity and premature mortality even in moderate AS (Mod-AS). The mechanisms for this adverse prognosis in Mod-AS, however, remain poorly understood, although the myocardial remodeling response is thought to be critical. We aimed to prospectively assess myocardial remodeling, perfusion and energetics differences in Mod-AS and severe AS (Severe-AS). MethodsFifty-two Severe-AS and 25 Mod-AS patients and 18 demographically-matched controls underwent cardiovascular magnetic resonance and phosphorus-magnetic resonance spectroscopy to define left ventricular (LV) mass and function, global longitudinal shortening (GLS), rest and adenosine-stress myocardial blood flow (MBF), myocardial perfusion reserve (MPR), layer-specific perfusion metrics (subendocardial [Endo], subepicardial [Epi] MBF and MPR, and Endo-to Epi-MBF ratio [Endo/Epi]), myocardial scar on late gadolinium enhancement (LGE) imaging, and myocardial energetics (phosphocreatine:ATP ratio [PCr/ATP]). ResultsCompared to controls, from Mod-AS to Severe-AS there was a progressive increase in LV concentricity (LV-mass/LV-end-diastolic-volume)(controls:0.58[0.54,0.62], Mod-AS:0.74[0.64,0.84], Severe-AS:0.89[0.83,0.95]g/mL; P<0.0001), LV mass-index (controls: 46[40,51], Mod-AS: 58[51,65], Severe-AS: 70[65,75]g/m2; P<0.0001) and stepwise decline in GLS (controls:19.9[17.6,22.2], Mod-AS:17.7[16.6,18.8], Severe-AS:13.4[12.5,14.4]%; P<0.0001) with significant differences between Mod-AS and Severe-AS for all three comparisons. Both stress MBF (controls:2.1[1.9,2.3], Mod-AS:1.9[1.6,2.2], Severe-AS:1.3[1.2,1.5]ml/min/g; P<0.0001) and MPR (controls:3.3[2.8,3.6], Mod-AS:2.8[2.4,3.2], Severe-AS:1.9[1.8,2.1]; P<0.0001) were only significantly reduced in Severe-AS compared to controls, with significant differences also detected between Mod-AS and Severe-AS. However, stress-endo-MBF (controls:2.0[1.8,2.3], Mod-AS:1.7[1.5,2.0], Severe-AS:1.2[1.1,1.3] ml/min/g; P<0.0001), stress-Endo/Epi (controls:1.00[0.93,1.07], Mod-AS:0.87[0.80,0.94], Severe-AS:0.81[0.75,0.82]; P<0.0001), rest-Endo/Epi (controls:1.12[1.10,1.14], Mod-AS:1.06[1.03,1.09], Severe-AS:1.03[1.02,1.06]; P<0.0001) and endo-MPR (controls:3.2[2.7,3.6], Mod-AS:2.5[2.1,2.9], Severe-AS:1.7[1.5,1.8]; P<0.0001) were all significantly reduced in both Mod-AS and Severe-AS. Compared to controls, both AS groups showed significantly lower PCr/ATP (controls:2.2[2.0,2.3], Mod-AS:1.8[1.6,2.0], Severe-AS:1.7[1.6,1.8]; P<0.0001) and shorter 6-minute-walk-distance (controls:525[495,555], Mod-AS:420[375,465]m, Severe-AS:345[248,420]m; P<0.0001). Only the Severe-AS group had evidence of non-ischemic myocardial scarring on LGE (2.9[0.0,6.2]%), which was detected in 65% (n=34) of patients. Neither group had evidence of ischemic scar. The AS severity (peak aortic valve velocity) correlated with the stress-MBF (r=-0.45, P=0.0003), MPR (r=-0.44, P=0.0005) and GLS (r=-0.47, P=0.0001). ConclusionsModerate and severe AS are both associated with cardiac concentric hypertrophy, reductions in myocardial energetics, subendocardial hypoperfusion, and limitations in exercise distance. Patients with Severe-AS exhibit a more pronounced phenotype with worse LV hypertrophy, contractile dysfunction and myocardial scarring compared to patients with Mod-AS. CLINICAL PERSPECTIVESWhat is new: O_LIPatients with moderate aortic stenosis show cardiac concentric hypertrophy, reduction in myocardial energetics, shorter 6-minute walk distance compared to age-and sex-matched controls, but no evidence of myocardial scarring. C_LIO_LIGlobal myocardial perfusion metrics of rest and stress myocardial blood flow or myocardial perfusion reserve do not show significant reductions in patients with moderate aortic stenosis. C_LIO_LIThe perfusion dynamics of the epicardial and endocardial layers differ in the presence of moderate aortic stenosis, with significant reductions in endocardial stress myocardial blood flow, rest and stress endocardial to epicardial myocardial blood flow ratio, and endocardial as well as epicardial myocardial perfusion reserve compared to controls. C_LI What Are the Clinical Implications?O_LIWhile milder compared to that seen in severe aortic stenosis, the degree of adverse myocardial remodeling and subendocardial hypoperfusion associated with moderate aortic stenosis may be clinically important for the cardiovascular clinical outcomes in patients with moderate aortic stenosis. C_LIO_LILarger prospective serial studies and randomized trials are needed to better understand the mechanisms of high cardiovascular and all-cause mortality rates in patients with moderate aortic stenosis. C_LI