Abstract
BackgroundCurrently there is no reliable medical treatment for aortic regurgitation (AR).MethodsThirty-nine Sprague–Dawley rats underwent creation of AR or sham operation. Treated rats were assigned to early or late institution of sildenafil therapy (100 mg/kg/day) for a total of 10 weeks. Treatment–effects were measured by serial echocardiography, invasive hemodynamic measurements, and tissue analysis.ResultsRats assigned to early treatment developed less remodeling than untreated rats. Thus, left ventricular (LV) dilation was blunted by sildenafil with end–systolic diameter being significantly smaller (6.6 ± 0.4 vs. 7.7 ± 0.4 mm, respectively, p < 0.05). Also, LV wall thickness was significantly decreased in treated rats compared to controls (2.23 ± 0.08 vs. 2.16 ± 0.05 mm, p < 0.01). Fractional shortening was improved by treatment (p < 0.05). Myocardial fibrosis was borderline decreased by treatment (p = 0.09). Akt was increased in treated compared to controls (p < 0.05).ConclusionSildenafil slightly inhibits LV remodeling and improves fractional shortening in rats with AR when treatment is initiated early.
Highlights
There is no reliable medical treatment for aortic regurgitation (AR)
We examined the effects of Phosphodiesterase 5A (PDE5A)-inhibition in a rodent model of chronic AR with respect to left ventricular (LV) remodeling and LV function, clarifying the more clinical applicable question of timing of therapy vis-à-vis disease duration
Morphology and function AR resulted in classic eccentric hypertrophy and led to rightward shift of PV–loops indicating LV remodeling, Fig. 1
Summary
There is no reliable medical treatment for aortic regurgitation (AR). Aortic regurgitation (AR) is a common valvular disease that affects men more than women, and whose incidence increases with age (Maurer 2006). Chronic AR results in a mixed hypertrophy phenotype (eccentric and concentric) resulting from predominantly volume and elements of pressure overload (Opie et al 2006). Phosphodiesterase 5A (PDE5A) inhibition has demonstrated positive cardiac effects in various disease models, including mitral valve regurgitation (Kim et al 2012). PDE5A-inhibition has shown to abrogate cardiac remodeling and deterioration of LV function in pressure overload by inhibiting several pro–hypertrophic signaling pathways (Takimoto et al 2005). We examined the effects of PDE5A-inhibition in a rodent model of chronic AR with respect to LV remodeling and LV function, clarifying the more clinical applicable question of timing of therapy vis-à-vis disease duration. We investigated if the effects on the heart were mediated by molecular mechanisms known to be operative in pressure overload hypertrophy
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