{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T20:49:56Z","timestamp":1784666996144,"version":"3.55.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2024,4,2]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">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\u20105 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction) trial, we examined (1) cross\u2010sectional correlates of circulating NT\u2010proBNP (N\u2010terminal pro\u2010B\u2010type natriuretic peptide)\/cGMP ratio, (2) whether selective phosphodiesterase\u20105 inhibition by sildenafil changed the ratio, and (3) whether the effect of sildenafil on 24\u2010week outcomes varied by baseline ratio.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              In 212 subjects, NT\u2010proBNP\/cGMP ratio was calculated at randomization and 24\u2009weeks. 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\u2010proBNP\/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\u2009weeks (\n              <jats:italic>P<\/jats:italic>\n              =0.17). The effect of sildenafil on 24\u2010week change in peak oxygen consumption, left ventricular mass, or clinical composite outcome was not modified by baseline NT\u2010proBNP\/cGMP ratio (\n              <jats:italic>P<\/jats:italic>\n              \u2010interaction &gt;0.30 for all).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">Among patients with heart failure with preserved ejection fraction, higher NT\u2010proBNP\/cGMP ratio associated with an adverse cardiorenal phenotype, which was not improved by selective phosphodiesterase\u20105 inhibition. Other phosphodiesterases may be greater contributors than phosphodiesterase\u20105 to the adverse phenotype associated with a high natriuretic peptide\/cGMP ratio in HFpEF.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Registration Information<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/clinicaltrials.gov\">clinicaltrials.gov<\/jats:ext-link>\n              . Identifier:\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT00763867\">NCT00763867<\/jats:ext-link>\n              .\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.123.031796","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T12:01:05Z","timestamp":1711540865000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Correlates of Plasma NT\u2010proBNP\/Cyclic GMP Ratio in Heart Failure With Preserved Ejection Fraction: An Analysis of the RELAX Trial"],"prefix":"10.1161","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7803-7052","authenticated-orcid":false,"given":"Leonard","family":"Chiu","sequence":"first","affiliation":[{"name":"Department of Medicine Vanderbilt University Medical Center Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8457-6722","authenticated-orcid":false,"given":"Vineet","family":"Agrawal","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine and Vanderbilt Translational and Clinical Cardiovascular Research Center Vanderbilt University Medical Center Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3198-7277","authenticated-orcid":false,"given":"David","family":"Armstrong","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine and Vanderbilt Translational and Clinical Cardiovascular Research Center Vanderbilt University Medical Center Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5843-3392","authenticated-orcid":false,"given":"Evan","family":"Brittain","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine and Vanderbilt Translational and Clinical Cardiovascular Research Center Vanderbilt University Medical Center Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila","family":"Collins","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine and Vanderbilt Translational and Clinical Cardiovascular Research Center Vanderbilt University Medical Center Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2755-5845","authenticated-orcid":false,"given":"Anna R.","family":"Hemnes","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Medicine Vanderbilt University Medical Center Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5379-1614","authenticated-orcid":false,"given":"Joseph A.","family":"Hill","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Cardiology) University of Texas Southwestern Medical Center Dallas TX USA"},{"name":"Department of Molecular Biology University of Texas Southwestern Medical Center Dallas TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9207-3634","authenticated-orcid":false,"given":"JoAnn","family":"Lindenfeld","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine and Vanderbilt Translational and Clinical Cardiovascular Research Center Vanderbilt University Medical Center Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5655-8201","authenticated-orcid":false,"given":"Sanjiv J.","family":"Shah","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine and Bluhm Cardiovascular Institute Northwestern University Feinberg School of Medicine Chicago IL 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