Abstract 3543: Myocardial Phosphodiesterase 5 Expression Contributes to Left Ventricular Dysfunction in the Pressure-Overloaded Heart
Background - Growing evidence supports an important role for phosphodiesterase 5 (PDE5) in heart failure. We hypothesized that PDE5 gene expression is increased in patients with severe aortic stenosis (AS) and impairs functional and structural adaptation to transverse aortic constriction (TAC) in mice with cardiomyocyte-specific overexpression of PDE5 (PDE5-TG).
Methods - We performed echocardiography in 12 AS patients and 10 controls and measured myocardial PDE5 mRNA levels in surgical biopsies using qRT-PCR. We compared the effect of enhanced PDE5 expression on TAC-induced LV remodeling in male 23–30 g PDE5-TG (n=48) and wild-type (WT; n=47) mice. Ten weeks after TAC, we measured LV dimensions (echocardiography), transaortic pressure gradient (ΔP), LV systolic and diastolic function (Millar), heart to body weight ratio (HW/BW), cardiomyocyte width (laminin immunohistochemistry), myocardial ANP and BNP mRNA levels (qRT-PCR), and myocardial cGMP content (enzyme immunoassay).
Results - Patients with AS had aortic valve area <0.8 cm2 and concentric hypertrophy, and myocardial PDE5 mRNA levels were 2-fold higher in AS patients than in controls (P<0.05). Ten weeks after TAC, PDE5-TG and WT mice had similar HW/BW (7.7± 0.4 vs 8.5± 0.5 mg/g; P>0.05) and cardiomyocyte width (15.0± 0.2 vs 16.0± 0.4 μ m; P>0.05). Wild-type mice developed a higher ΔP than did PDE5-TG (78±5 vs 49± 10 mmHg; P=0.03) associated with better preserved LV systolic function (dP/dtmax 9514± 535 vs 6721± 570 mmHg/s; P=0.0002) and diastolic function (dP/dtmin −9640±550 vs −7067±596 mmHg/s; P=0.0009) and a smaller increase in LV end-systolic and end-diastolic volumes with increasing HW/BW (P=0.006 and P=0.01, respectively). Compared with WT, PDE5-TG had ~3-fold higher ANP and BNP transcript levels (P<0.05 for both), but lower myocardial cGMP concentrations (0.06±0.01 vs 0.12±0.02 pmol/mg protein; P=0.02).
Conclusions - Increased cardiac PDE5 gene expression impairs LV function in mouse hearts after TAC and may contribute to LV dysfunction in AS patients. PDE5 represents a potential target for prevention/treatment of LV dysfunction due to pressure overload.