Abstract Body: Left ventricular (LV) pressure overload (PO), e.g., in aortic stenosis (AS) or hypertension, drives heart failure (HF). Murine PO models (transverse/aortic constriction, TAC/AAC) are widely used to study HF progression, but creating models with chronic pressure gradients and patient-relevant reproducibility remains challenging. The suture-based banding commonly used in this model may lead to inconsistent constriction and potential suture integration into the vessel wall, which limits the PO duration. AAC-induced PO is a more appropriate model of AS-PO without systemic hypertension. However, it is technically difficult with low survival rates during and after surgery, which prevents its use for long-term studies. Therefore, we employed a clip-based AAC technique to induce long-term PO in mice. Eight to ten-week-old male mice (C57BL/6J) were subjected to AAC. The clip (Model# 005200, Teleflex) with different diameters was positioned on the ascending aorta adjacent to the brachiocephalic artery branch. The pressure gradients at the construction site of AAC mice increased depending on the constriction diameters (clip applier was calibrated using 29g vs 34g needles) and remained stable for up to 28 months (Table). The overall survival rate in the severe constriction group was over 70% until the end of 28 months. HF progression was evident by a ~55% EF% reduction and a 1.5-fold LV mass increase (Table and Figure). We also assessed lung function using whole-body plethysmography. AAC mice exhibited a significant reduction in lung tidal volume (sham: 0.391 ± 0.01; AAC: 0.334 ± 0.021 ml) and an increase in Penh, airway constriction index (sham: 0.521 ± 0.02; AAC: 1.398 ± 0.352), reflecting pulmonary dysfunction secondary to congestive HF. Histological assessment confirmed cardiomyocyte hypertrophy and robust cardiac fibrosis. We further validated that the clip-based AAC was equally feasible in older mice (e.g., 6-month-old) to generate PO models with different severities of pathological outcomes. Therefore, the clip-based AAC in mice that exhibited slow but steady progression from compensated cardiac hypertrophy to decompensated HF is a clinically relevant model presenting the natural history of human HF.