Abstract 17940: PDEV Inhibition + BNP Administration Enhanced the Cardiac but not the Renal Response to Acute Volume Overload in Human Preclinical Diastolic Dysfunction as Compared to PDEV Inhibition Alone

Abstract

Background: Preclinical diastolic dysfunction (PDD) is defined as subjects with normal systolic function, moderate or severe diastolic dysfunction determined by Doppler criteria but with no symptoms of heart failure (HF). We have previously demonstrated that an impaired cardiorenal endocrine response to stress by acute volume loading (AVL) exists in PDD and that is corrected by acute administration of sq B-type natriuretic peptide (BNP). Type V phosphodiesterase (PDEV) metabolizes cGMP, second messenger of BNP. The objective of the current study is to determine if the combination of PDEV inhibitor (PDEVI) and BNP will result in a greater enhancement of the cardiorenal response to AVL as compared to PDEVI alone in PDD. Methods: Randomized double-blind single placebo-controlled cross-over study in 20 PSD subjects. We determined cardiorenal effects of PDEVI with Tadalafil (T) 5 mg alone and in combination with acute sq BNP (Nesiritide 10 μg/Kg), in response to AVL (normal saline 0.25 ml/kg/min for 1 hour). Each subject had 2 study visits, separated by at least 1 week. At each visit, echocardiogram and renal clearance studies with iothalmate and PAH to measure GFR and renal plasma flow (RPF) were done before and after AVL. Each patient was randomized to receive T at both visits and either placebo or sq-BNP one visit and crossover to the other on the next visit. Results: T+BNP resulted in smaller LA volume index (-4±10 vs 3±7 ml/m 2 , p< 0.05) and lower right ventricular systolic pressure (-4±3 vs 2±6 mmHg, p< 0.05) in response to AVL as compared to T alone. Moreover, T+ BNP resulted in a significant reduction of plasma ANP and LV end-systolic volume in response to AVL while T alone did not. However, the combination to T+BNP did not enhance the renal response to AVL as compared to T alone. Both the change in urine flow (1.7±5 vs 2.4±5 ml/min, p> 0.05) and sodium excretion (129±200 vs 124±270 mEq/min, p>0.05) in response to AVL were similar between T+BNP and T alone. Conclusion: In PDD, the combination of PDEVI and BNP reduced LV filling pressure in response to AVL as compared to PDEVI alone. However, it did not enhance the renal response to AVL. This suggests a differential cardiac versus renal response to the maximization of cGMP system with PDEVI and BNP.