Pathological cardiac hypertrophy, a major contributor to heart failure, is characterized by an abnormal increase in the size of atria and ventricles. In the context of ventricular hypertrophy, the right ventricle (RV) exhibits less resistance to hypertrophy than the left one (LV). Insulin-like growth factors (IGF-1 and IGF-2) are critical for cell growth and provide cardioprotective effects. Pregnancy-associated plasma protein-A (PAPP-A) is a protease that cleaves insulin-like growth factor-binding protein-4 (IGFBP-4) and enhances IGF bioavailability. This study investigated PAPP-A-mediated IGFBP-4 proteolysis—one possible mechanism of IGF release regulation in rat models of right ventricular (RVH) and left ventricular (LVH) hypertrophy. RVH was induced with monocrotaline, and LVH via renovascular hypertension (1 Kidney 1 Clip (1K1C) model). Systolic blood pressure was measured using tail-cuff plethysmography. Heart morphometry was used to assess the mass of cardiac chambers. Cardiomyocyte purity was confirmed via troponin I immunocytochemistry. Plasma natriuretic type-B peptide (BNP) and C-terminal IGFBP-4 (CT-IGFBP-4) concentrations were quantified by fluoroimmunoassay. RVH and LVH were successfully modelled, with 1.6-fold and 1.3-fold increases in RV (p < 0.0001) and LV masses (p < 0.05), respectively. Plasma BNP was 2–3 times higher in LVH versus control rats. Hypertrophied cardiomyocytes secreted significantly more BNP than controls, showing 3.3-fold and 4.1-fold increases in LVH and RVH, respectively. PAPP-A-mediated IGFBP-4 proteolysis was 4-fold higher in RVH compared to control, but unaffected in LVH. These findings suggest that PAPP-A-specific elevation of IGFBP-4 proteolysis occurs predominantly in RVH, suggesting a differential IGF bioavailability in both ventricles and highlighting PAPP-A as a potential target to increase RVH resistance to hypertrophy.