Cardiac remodeling in moderate aortic stenosis

Background Aortic 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). Methods Fifty-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]). Results Compared 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/m[2][1]; 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). Conclusions Moderate 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 PERSPECTIVES What is new: What Are the Clinical Implications? ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial Prospective cohort study, not a clinical trial ### Funding Statement The study was jointly supported by the Wellcome Trust (grant number: 221690/Z/20/Z) and Diabetes UK (grant number:18/0005870). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study complied with the Declaration of Helsinki and was approved by National Research Ethics Committees (ref:18/YH/0168 for the severe AS cohort and ref:18/YH/0168 for the moderate AS cohort and healthy volunteers). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data will be shared on reasonable request to the corresponding author. * ### ABBREVIATIONS View this table: [1]: #ref-2