Myocardial expression of ADGRL4 and AQP7 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) who underwent surgical AVR. Preoperative and postoperative LV mass indices (LVMi) were compared between male and female patients. Expression of ADGRL4 and AQP7 was quantified by PCR and assessed with relative regression of LVMi. High-depth RNA-sequencing data from LV free-wall tissues of subjects with heart failure were employed for RNA editing analysis. Male patients had significant LVH regression (P < 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 < 0.05, R2 = 0.497) and AQP7 (P < 0.05, R2 = 0.576) and LVMi regression after AVR. This relationship was insignificant for ADGRL4 (P = 0.704, R2 = 0.0220) and AQP7 (P = 0.860, R2 = 0.00477) in female patients. RNA editing analysis revealed significant sex-biased differences in intronic adenosine-to-inosine (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.NEW & NOTEWORTHY Regression of left ventricular hypertrophy is associated with better long-term outcome. This study demonstrates a significant relationship between ADGRL4 and AQP7 gene expression in perioperatively collected myocardial tissues and the regression of left ventricular mass postoperatively in male patients with aortic stenosis only. This could contribute to the development of a sex-based tool to predict the extent of postoperative hypertrophy regression.