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Abstract：
BACKGROUND: Phosphodiesterases degrade cyclic GMP (cGMP), the second messenger that mediates the cardioprotective effects of natriuretic peptides. High natriuretic peptide/cGMP ratio may reflect, in part, phosphodiesterase activity. Correlates of natriuretic peptide/cGMP in patients with heart failure with preserved ejection fraction are not well understood. Among patients with heart failure with preserved ejection fraction in the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction) trial, we examined (1) cross-sectional correlates of circulating NT-proBNP (N-terminal pro-B-type natriuretic peptide)/cGMP ratio, (2) whether selective phosphodiesterase-5 inhibition by sildenafil changed the ratio, and (3) whether the effect of sildenafil on 24-week outcomes varied by baseline ratio.
RESULTS: In 212 subjects, NT-proBNP/cGMP ratio was calculated at randomization and 24 weeks. Correlates of the ratio and its change were examined in multivariable proportional odds models. Whether baseline ratio modified the sildenafil effect on outcomes was examined by interaction terms. Higher NT-proBNP/cGMP ratio was associated with greater left ventricular mass and troponin, the presence of atrial fibrillation, and lower estimated glomerular filtration rate and peak oxygen consumption. Compared with placebo, sildenafil did not alter the ratio from baseline to 24 weeks (P=0.17). The effect of sildenafil on 24-week change in peak oxygen consumption, left ventricular mass, or clinical composite outcome was not modified by baseline NT-proBNP/cGMP ratio (P-interaction >0.30 for all).
CONCLUSIONS: Among patients with heart failure with preserved ejection fraction, higher NT-proBNP/cGMP ratio associated with an adverse cardiorenal phenotype, which was not improved by selective phosphodiesterase-5 inhibition. Other phosphodiesterases may be greater contributors than phosphodiesterase-5 to the adverse phenotype associated with a high natriuretic peptide/cGMP ratio in HFpEF.
UNASSIGNED: clinicaltrials.gov. Identifier: NCT00763867.
RESULTS: In 212 subjects, NT-proBNP/cGMP ratio was calculated at randomization and 24 weeks. Correlates of the ratio and its change were examined in multivariable proportional odds models. Whether baseline ratio modified the sildenafil effect on outcomes was examined by interaction terms. Higher NT-proBNP/cGMP ratio was associated with greater left ventricular mass and troponin, the presence of atrial fibrillation, and lower estimated glomerular filtration rate and peak oxygen consumption. Compared with placebo, sildenafil did not alter the ratio from baseline to 24 weeks (P=0.17). The effect of sildenafil on 24-week change in peak oxygen consumption, left ventricular mass, or clinical composite outcome was not modified by baseline NT-proBNP/cGMP ratio (P-interaction >0.30 for all).
CONCLUSIONS: Among patients with heart failure with preserved ejection fraction, higher NT-proBNP/cGMP ratio associated with an adverse cardiorenal phenotype, which was not improved by selective phosphodiesterase-5 inhibition. Other phosphodiesterases may be greater contributors than phosphodiesterase-5 to the adverse phenotype associated with a high natriuretic peptide/cGMP ratio in HFpEF.
UNASSIGNED: clinicaltrials.gov. Identifier: NCT00763867.
摘要：
背景：磷酸二酯酶降解环GMP（cGMP），介导利钠肽保护心脏作用的第二信使。高利钠肽/cGMP比值可能反映，在某种程度上,磷酸二酯酶活性。射血分数保留的心力衰竭患者中利钠肽/cGMP的相关性尚不清楚。在RELAX（抑制磷酸二酯酶-5以改善射血分数保留的心力衰竭的临床状态和运动能力）试验中射血分数保留的心力衰竭患者中，我们检查了（1）循环NT-proBNP（N-末端B型利钠肽原）/cGMP比率的横截面相关性，(2)西地那非选择性抑制磷酸二酯酶-5的比例是否改变,(3)西地那非对24周结局的影响是否因基线比率而异.
结果：在212名受试者中，在随机分组和24周时计算NT-proBNP/cGMP比率。在多变量比例赔率模型中检查了该比率及其变化的相关性。基线比率是否改变了西地那非对结果的影响通过相互作用项进行检查。更高的NT-proBNP/cGMP比值与更大的左心室质量和肌钙蛋白相关，心房颤动的存在，和较低的估计肾小球滤过率和峰值耗氧量。与安慰剂相比，从基线到24周,西地那非的比率没有改变(P=0.17).西地那非对24周峰值耗氧量变化的影响，左心室质量,基线NT-proBNP/cGMP比值(均P-交互作用>0.30)未改变临床复合结局.
结论：在射血分数保留的心力衰竭患者中，较高的NT-proBNP/cGMP比率与不良心肾表型相关，选择性磷酸二酯酶-5抑制没有改善。其他磷酸二酯酶可能比磷酸二酯酶-5对与HFpEF中的高利钠肽/cGMP比率相关的不良表型有更大的贡献。
■clinicaltrials.gov.标识符：NCT00763867。
结果：在212名受试者中，在随机分组和24周时计算NT-proBNP/cGMP比率。在多变量比例赔率模型中检查了该比率及其变化的相关性。基线比率是否改变了西地那非对结果的影响通过相互作用项进行检查。更高的NT-proBNP/cGMP比值与更大的左心室质量和肌钙蛋白相关，心房颤动的存在，和较低的估计肾小球滤过率和峰值耗氧量。与安慰剂相比，从基线到24周,西地那非的比率没有改变(P=0.17).西地那非对24周峰值耗氧量变化的影响，左心室质量,基线NT-proBNP/cGMP比值(均P-交互作用>0.30)未改变临床复合结局.
结论：在射血分数保留的心力衰竭患者中，较高的NT-proBNP/cGMP比率与不良心肾表型相关，选择性磷酸二酯酶-5抑制没有改善。其他磷酸二酯酶可能比磷酸二酯酶-5对与HFpEF中的高利钠肽/cGMP比率相关的不良表型有更大的贡献。
■clinicaltrials.gov.标识符：NCT00763867。
