Myocardial expression of <i>ADGRL4</i> and <i>AQP7</i> is related to regression of left ventricular hypertrophy after aortic valve replacement in a sex-dependent manner

Aortic stenosis (AS) may lead to left ventricular (LV) hypertrophy (LVH). After aortic valve replacement (AVR), LVH often does not regress fully. This has been associated with a worse prognosis. This study aimed at comparing LVH regression between male and female patients and to discover cardiac molecular factors associated with it. Myocardial samples were collected from 18 patients (50% female) that underwent surgical AVR. Preoperative and postoperative LV mass indices (LVMi) were compared between male and female patients. Expression of ADGRL4 and AQP7 was quantified using PCR and assessed with relative regression of LVMi. High-depth RNA-sequencing data of LV free-wall tissues from subjects with heart failure were employed for RNA editing analysis. Male patients had significant LVH regression ( P &lt; 0.05) after AVR, while female patients did not ( P = 0.116). In male patients, a significant relationship was found between the expression of ADGRL4 ( P &lt; 0.05, R 2 = 0.497) and AQP7 ( P &lt; 0.05, R 2 = 0.576) and LVMi regression after AVR. This relationship was insignificant for ADGRL4 ( P = 0.704, R 2 = 0.0220) and AQP7 ( P = 0.860, R 2 = 0.00477) in female patients. RNA editing analysis revealed significant sex-biased differences in intronic A-to-I editing of AQP7, with five positions, particularly within Alu elements, along with sex-biased predicted RBP binding motifs. Recognizing patients at risk of defective LVH regression using molecular factors could lead to more intensive postoperative follow-up and earlier treatment, consequently improving reverse remodeling and prognosis. The present findings warrant further research in a larger study.