Abstract 3155: Phosphodiesterase Type 5 is Highly Expressed in the Hypertrophied Human Right Ventricle: Direct Implications for Patients with Pulmonary Hypertension
Sildenafil, a phopshodiesterase-5 (PD5) inhibitor, was recently approved for the treatment of Pulmonary Arterial Hypertension (PAH). Based on early reports showing a lack of significant PD5 expression in the normal heart, the beneficial effects of sildenafil in PAH are thought to result from relatively selective vasodilatory and anti-proliferative effects on the pulmonary vasculature, while sparing the myocardium. We hypothesized that PD5 expression is increased in the myocardium of the hypertrophied right ventricle (RVH). We studied surgical specimens from 9 patients: 2 normal RVs (nRV) and 7 RVH. We used immunohistochemistry, confocal microscopy, laser-capture microdissection and qRT-PCR to show that PD5 protein and mRNA was expressed in the coronaries (co-localized with smooth muscle actin) of both nRV and RVH. However, PD5 was expressed in the myocardium of RVH (co-localized with myosin heavy chain) but not nRV. Brain Natriuretic Peptide, a marker of hypertrophy, was expressed in all RVH but not nRV myocardium. We also studied rat nRV (n=7) versus RVH (n=11, monocrotaline-induced PAH model). As in humans, PD5 was upregulated in RVH hearts. We used a modified Langendorff perfused rat heart model, where RV pressure was recorded by a balloon-transducer. The afterload and preload were kept constant with pulmonary artery ligation and constant balloon volume. Both the nRV and RVH had similar developed pressure in response to isoproterenol. However, a selective PD5 inhibitor (MY-5445) significantly increased contractility (developed pressure and dP/dt) in RVH hearts in a dose-dependent manner (10−5, −6, −7M), yet not in nRV (e.g. developed pressure for the 10−5M dose, in RVH=13.4 ± 1.6 and nRV=0.3 ± 0.6 mmHg, p<0.001). Other rats were given a single dose of sildenafil (50mg per os, 90min before excising the heart), where baseline developed pressure was improved in RVH (+12.3 ± 3.1mmHg) but not in nRV. MY-5445 had no additive effect in these hearts, compared to rats not receiving sildenafil. We show for the first time that PD5 is significantly upregulated in RVH of both human and rat hearts. Our findings have direct clinical implications for patients currently receiving therapy with PD5 inhibitors, and suggest a new means of selectively enhancing RV function.