{"id":"5ff6d9b5-bf24-5e6a-8d5a-40e64fd55e83","stable_key":"252872b9-233f-5692-b72b-c8930ba0cfb7:sil-preclinical-cardiac-promise","predicate":"limits","statement":"Cyclic GMP and its primary signalling kinase protein kinase G play a role in counterbalancing stress remodelling in the heart, growing evidence supports a positive impact on a variety of cardiac disease conditions from suppression of cyclic GMP hydrolysis which is regulated by phosphodiesterase family members of which cyclic-GMP-selective PDE5 has been best studied, and inhibitors such as sildenafil and tadalafil ameliorate cardiac pressure and volume overload, ischaemic injury and cardiotoxicity, with clinical trials begun to explore dilated cardiomyopathy and heart failure with preserved ejection fraction.","claim_class":"observational","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"733e3a12-f3ed-569a-ad8b-a51788268024","mechanism_event_label":"In animal hearts under strain, blocking this enzyme helped, and that is what the trials set out to confirm.","subject":{"id":"0be8b435-6b8a-592c-bd4c-c0efd9481a97","slug":"pde5-family","display_name":"Phosphodiesterase 5 family","entity_type_key":"protein_family"},"object":{"id":"6d2f509b-3a5b-5a38-b3e7-b148581edec9","slug":"cgmp","display_name":"Cyclic guanosine monophosphate","entity_type_key":"small_molecule"},"evidence_count":1,"mechanism_event":{"id":"733e3a12-f3ed-569a-ad8b-a51788268024","stable_key":"252872b9-233f-5692-b72b-c8930ba0cfb7:sil-preclinical-cardiac-promise-event","event_type":"observed_intervention","label":"In animal hearts under strain, blocking this enzyme helped, and that is what the trials set out to confirm.","description":"Cyclic GMP and its primary signalling kinase protein kinase G play a role in counterbalancing stress remodelling in the heart, growing evidence supports a positive impact on a variety of cardiac disease conditions from suppression of cyclic GMP hydrolysis which is regulated by phosphodiesterase family members of which cyclic-GMP-selective PDE5 has been best studied, and inhibitors such as sildenafil and tadalafil ameliorate cardiac pressure and volume overload, ischaemic injury and cardiotoxicity, with clinical trials begun to explore dilated cardiomyopathy and heart failure with preserved ejection fraction.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"4c288678-9116-5460-a9a9-8f7e1f253430","slug":"prkg1","display_name":"cGMP-dependent protein kinase I","entity_type_key":"protein"},"role":"downstream_kinase","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"9820ebfe-515d-50cc-9b44-2bd2be220325","slug":"tadalafil","display_name":"Tadalafil","entity_type_key":"drug"},"role":"co_studied_drug","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"3d39054f-649d-5b50-ba42-92d743e23824","slug":"cgmp-hydrolysis","display_name":"Hydrolysis of cyclic GMP to 5-guanosine monophosphate","entity_type_key":"cellular_process"},"role":"suppressed_reaction","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"e99b16fb-beee-5eca-8528-a13763fca75e","slug":"hfpef","display_name":"Heart failure with preserved ejection fraction","entity_type_key":"cellular_process"},"role":"target_condition","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"0be8b435-6b8a-592c-bd4c-c0efd9481a97","slug":"pde5-family","display_name":"Phosphodiesterase 5 family","entity_type_key":"protein_family"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"6d2f509b-3a5b-5a38-b3e7-b148581edec9","slug":"cgmp","display_name":"Cyclic guanosine monophosphate","entity_type_key":"small_molecule"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/sildenafil-research/22798047.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"5456b43dcdb907d5a82ca9999cc94cb6c584589d0b454e1cdbf44fb3ee40941f\", \"start_char\": 0, \"end_char\": 799, \"text_sha256\": \"5456b43dcdb907d5a82ca9999cc94cb6c584589d0b454e1cdbf44fb3ee40941f\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Review of cyclic GMP and protein kinase G signalling in cardiac stress remodelling","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Phosphodiesterase type 5 inhibition across models of pressure and volume overload, ischaemic injury and cardiotoxicity","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"A review summarising preclinical work and stating the clinical trials as ongoing. It reports the expectation that the trial in the next record went on to test.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6.","comparator":null,"unit":null,"notes":"","entity":{"slug":"sildenafil","display_name":"Sildenafil","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Animal and human","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"In animal hearts under strain, blocking this enzyme helped, and that is what the trials set out to confirm.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[sil-p22798047] Cardiac role of cyclic-GMP hydrolyzing phosphodiesterase type 5: from experimental models to clinical trials. (2012). https://pubmed.ncbi.nlm.nih.gov/22798047/ DOI: 10.1007/s11897-012-0101-0","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Myocardium","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"d4cd1fda-3cab-54c4-a7f4-4c9ef266d698","evidence_kind":"source_excerpt","locator":"Lines 600-611","start_line":600,"end_line":611,"excerpt":"### sil-preclinical-cardiac-promise\nCyclic GMP and its primary signalling kinase protein kinase G play a role in counterbalancing stress remodelling in the heart, growing evidence supports a positive impact on a variety of cardiac disease conditions from suppression of cyclic GMP hydrolysis which is regulated by phosphodiesterase family members of which cyclic-GMP-selective PDE5 has been best studied, and inhibitors such as sildenafil and tadalafil ameliorate cardiac pressure and volume overload, ischaemic injury and cardiotoxicity, with clinical trials begun to explore dilated cardiomyopathy and heart failure with preserved ejection fraction.\nCondition category: normal\nnutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6.\nplain_language: In animal hearts under strain, blocking this enzyme helped, and that is what the trials set out to confirm.\norganism: Animal and human\ntissue_or_cell_type: Myocardium\nexperimental_model: Review of cyclic GMP and protein kinase G signalling in cardiac stress remodelling\nlimitations: A review summarising preclinical work and stating the clinical trials as ongoing. It reports the expectation that the trial in the next record went on to test.\nexposure: Phosphodiesterase type 5 inhibition across models of pressure and volume overload, ischaemic injury and cardiotoxicity\nevidence_span: {\"source_cache\": \"artifacts/sildenafil-research/22798047.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"5456b43dcdb907d5a82ca9999cc94cb6c584589d0b454e1cdbf44fb3ee40941f\", \"start_char\": 0, \"end_char\": 799, \"text_sha256\": \"5456b43dcdb907d5a82ca9999cc94cb6c584589d0b454e1cdbf44fb3ee40941f\"}\n[sil-p22798047] Cardiac role of cyclic-GMP hydrolyzing phosphodiesterase type 5: from experimental models to clinical trials. (2012). https://pubmed.ncbi.nlm.nih.gov/22798047/ DOI: 10.1007/s11897-012-0101-0","model_system":"Review of cyclic GMP and protein kinase G signalling in cardiac stress remodelling","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [sil-p22798047] Cardiac role of cyclic-GMP hydrolyzing phosphodiesterase type 5: from experimental models to clinical trials. (2012). https://pubmed.ncbi.nlm.nih.gov/22798047/ DOI: 10.1007/s11897-012-0101-0","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"c6c2a590-1f8f-5fac-b2c7-3aae0440b9fd","stable_key":"import-252872b9-233f-5692-b72b-c8930ba0cfb7","title":"Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"bc81793d20d20d2eaad9cb530b70695d8d8778a3d7136e24715ac3369b939953","revision_id":"301732e1-2446-5b67-b3bd-580164b85b05","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"bf5977d3-6616-5b51-9941-52bb7a8d6286","title":"Does inhibiting this enzyme help the failing heart?","kind":"contradiction","status":"open","why":"Preclinical work across models of pressure and volume overload, ischaemic injury and cardiotoxicity supported a benefit from suppressing cyclic GMP hydrolysis in the heart, and reviews written while trials were running described the rationale as growing evidence. A multicentre randomised trial of 216 patients with heart failure and preserved ejection fraction, dosed for 24 weeks and escalated to 60 milligrams three times daily, found no difference whatever in peak oxygen consumption, clinical status or six-minute walk distance. A third record in this collection offers a possible reason that was available before the trial: immunochemical mapping of human tissue found the major phosphodiesterase of the human cardiac ventricle to be the calcium and calmodulin-dependent PDE1, with no detectable PDE5, and found no functional effect of sildenafil on isolated cardiac trabeculae. If the target is not expressed in the human myocardium, a drug against it would not be expected to remodel it, whatever the animal models show. The absence of a target is antibody-based and therefore weaker evidence than its presence would be, and the trial does not exclude benefit in other cardiac conditions. The trial was also contested in print: a letter and an authors' reply followed in the same journal, neither of which carries an abstract through any accessed endpoint, so the exchange is recorded here as existing and unread.","resolution":"Unresolved; needs review. A published letter and authors' reply on the trial exist and have not been obtained.","created_at":"2026-09-22 18:28:26","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/bf5977d3-6616-5b51-9941-52bb7a8d6286","sides":[{"conflict_id":"bf5977d3-6616-5b51-9941-52bb7a8d6286","ordinal":0,"label":"In animal hearts under strain, blocking this enzyme helped, and that is what the trials set out to confirm.","revision_id":"301732e1-2446-5b67-b3bd-580164b85b05","start_line":600,"end_line":611,"quote":"### sil-preclinical-cardiac-promise\nCyclic GMP and its primary signalling kinase protein kinase G play a role in counterbalancing stress remodelling in the heart, growing evidence supports a positive impact on a variety of cardiac disease conditions from suppression of cyclic GMP hydrolysis which is regulated by phosphodiesterase family members of which cyclic-GMP-selective PDE5 has been best studied, and inhibitors such as sildenafil and tadalafil ameliorate cardiac pressure and volume overload, ischaemic injury and cardiotoxicity, with clinical trials begun to explore dilated cardiomyopathy and heart failure with preserved ejection fraction.\nCondition category: normal\nnutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6.\nplain_language: In animal hearts under strain, blocking this enzyme helped, and that is what the trials set out to confirm.\norganism: Animal and human\ntissue_or_cell_type: Myocardium\nexperimental_model: Review of cyclic GMP and protein kinase G signalling in cardiac stress remodelling\nlimitations: A review summarising preclinical work and stating the clinical trials as ongoing. It reports the expectation that the trial in the next record went on to test.\nexposure: Phosphodiesterase type 5 inhibition across models of pressure and volume overload, ischaemic injury and cardiotoxicity\nevidence_span: {\"source_cache\": \"artifacts/sildenafil-research/22798047.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"5456b43dcdb907d5a82ca9999cc94cb6c584589d0b454e1cdbf44fb3ee40941f\", \"start_char\": 0, \"end_char\": 799, \"text_sha256\": \"5456b43dcdb907d5a82ca9999cc94cb6c584589d0b454e1cdbf44fb3ee40941f\"}\n[sil-p22798047] Cardiac role of cyclic-GMP hydrolyzing phosphodiesterase type 5: from experimental models to clinical trials. (2012). https://pubmed.ncbi.nlm.nih.gov/22798047/ DOI: 10.1007/s11897-012-0101-0","source_key":"import-252872b9-233f-5692-b72b-c8930ba0cfb7","source_title":"Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22)","claim_ids":["5ff6d9b5-bf24-5e6a-8d5a-40e64fd55e83"]},{"conflict_id":"bf5977d3-6616-5b51-9941-52bb7a8d6286","ordinal":1,"label":"In a proper trial in the condition the animal work pointed at, the drug did nothing at all.","revision_id":"301732e1-2446-5b67-b3bd-580164b85b05","start_line":626,"end_line":637,"quote":"### sil-no-benefit-in-hfpef\nAmong 216 patients with heart failure and preserved ejection fraction randomised to sildenafil or placebo for 24 weeks, median changes in peak oxygen consumption were not significantly different with a mean between-group difference of 0.01 millilitres per kilogram per minute, the mean clinical status rank score was not significantly different at 95.8 for placebo and 94.2 for sildenafil, and changes in six-minute walk distance were not significantly different, with serious adverse events in 16% of placebo and 22% of sildenafil patients.\nCondition category: normal\nnutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6.\nplain_language: In a proper trial in the condition the animal work pointed at, the drug did nothing at all.\norganism: Human\ntissue_or_cell_type: Cardiopulmonary exercise capacity\nexperimental_model: Multicentre double-blind placebo-controlled randomised trial in 216 outpatients with heart failure and preserved ejection fraction\nlimitations: An adequately powered randomised trial with an objective primary endpoint, reported as fully negative. Its participants had elevated filling pressures and pulmonary artery systolic pressure of 41 millimetres of mercury, so the target population was appropriate.\nexposure: Sildenafil 20 milligrams three times daily for 12 weeks then 60 milligrams three times daily for 12 weeks\nevidence_span: {\"source_cache\": \"artifacts/sildenafil-research/23478662.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"563c3c4bab090bd15f4627c45776c1b7cba040d7532cd85102d059753df3f8d1\", \"start_char\": 0, \"end_char\": 3109, \"text_sha256\": \"563c3c4bab090bd15f4627c45776c1b7cba040d7532cd85102d059753df3f8d1\"}\n[sil-p23478662] Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. (2013). https://pubmed.ncbi.nlm.nih.gov/23478662/ DOI: 10.1001/jama.2013.2024","source_key":"import-252872b9-233f-5692-b72b-c8930ba0cfb7","source_title":"Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22)","claim_ids":["ef5a9551-70fa-51f9-bcba-76dac5052de7"]},{"conflict_id":"bf5977d3-6616-5b51-9941-52bb7a8d6286","ordinal":2,"label":"The target enzyme is in blood vessels and not detectable in heart muscle, which is where the drug does and does not act.","revision_id":"301732e1-2446-5b67-b3bd-580164b85b05","start_line":314,"end_line":325,"quote":"### sil-no-pde5-in-the-ventricle\nThe major phosphodiesterase activity in the human cardiac ventricle was calcium and calmodulin-dependent PDE1 with no detectable level of PDE5, whereas human saphenous vein contained PDE1, PDE4 and PDE5 and human mesenteric artery contained PDE1, PDE2, PDE3, PDE4 and PDE5, and sildenafil unlike milrinone had no effect on isolated trabeculae carneae, consistent with the lack of PDE5 expression in cardiac myocytes.\nCondition category: normal\nnutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6.\nplain_language: The target enzyme is in blood vessels and not detectable in heart muscle, which is where the drug does and does not act.\norganism: Human, rabbit and dog\ntissue_or_cell_type: Cardiac ventricle, saphenous vein, mesenteric artery, corpus cavernosum and platelets\nexperimental_model: Immunochemical distribution of phosphodiesterase activity across human tissues with isolated organ bath studies and platelet aggregometry\nlimitations: Maps where the target enzyme is and is not, which is what predicts where the drug acts. Antibody-based detection, so absence of signal is weaker evidence than presence.\nexposure: Anti-PDE1 and anti-PDE5 antibodies with functional testing, and sildenafil against sodium nitroprusside on platelets\nevidence_span: {\"source_cache\": \"artifacts/sildenafil-research/10078537.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5\", \"start_char\": 0, \"end_char\": 2610, \"text_sha256\": \"dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5\"}\n[sil-p10078537] Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. (1999). https://pubmed.ncbi.nlm.nih.gov/10078537/ DOI: 10.1016/s0002-9149(99)00042-9","source_key":"import-252872b9-233f-5692-b72b-c8930ba0cfb7","source_title":"Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22)","claim_ids":["e9d8089b-c879-50e2-a8d9-866958b148fd"]}]}],"corrections":[],"research":null}