Heart failure with preserved ejection fraction: molecular mechanisms & dependencies

How nutrients influence it

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What it does

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Recorded relationships

Where it participates (unsigned role)

Among 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.
Sildenafil → Peak oxygen consumption source_derived_draftungraded
Experimental context and source evidence
evidence_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"}
experimental_model
Multicentre double-blind placebo-controlled randomised trial in 216 outpatients with heart failure and preserved ejection fraction
exposure
Sildenafil 20 milligrams three times daily for 12 weeks then 60 milligrams three times daily for 12 weeks
limitations
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.
nutrient_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. · Sildenafil
organism
Human
plain_language
In a proper trial in the condition the animal work pointed at, the drug did nothing at all.
primary_references
[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
tissue_or_cell_type
Cardiopulmonary exercise capacity
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) · lines 626–637
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Multicentre double-blind placebo-controlled randomised trial in 216 outpatients with heart failure and preserved ejection fraction · source_derived_draft · unverified_draft
### sil-no-benefit-in-hfpef Among 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. Condition category: normal nutrient_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. plain_language: In a proper trial in the condition the animal work pointed at, the drug did nothing at all. organism: Human tissue_or_cell_type: Cardiopulmonary exercise capacity experimental_model: Multicentre double-blind placebo-controlled randomised trial in 216 outpatients with heart failure and preserved ejection fraction limitations: 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. exposure: Sildenafil 20 milligrams three times daily for 12 weeks then 60 milligrams three times daily for 12 weeks evidence_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"} [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
Complete structured claim and evidence
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.
Phosphodiesterase 5 family → Cyclic guanosine monophosphate source_derived_draftungraded
Experimental context and source evidence
evidence_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"}
experimental_model
Review of cyclic GMP and protein kinase G signalling in cardiac stress remodelling
exposure
Phosphodiesterase type 5 inhibition across models of pressure and volume overload, ischaemic injury and cardiotoxicity
limitations
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.
nutrient_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. · Sildenafil
organism
Animal and human
plain_language
In animal hearts under strain, blocking this enzyme helped, and that is what the trials set out to confirm.
primary_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
tissue_or_cell_type
Myocardium
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) · lines 600–611
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of cyclic GMP and protein kinase G signalling in cardiac stress remodelling · source_derived_draft · unverified_draft
### sil-preclinical-cardiac-promise 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. Condition category: normal nutrient_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. plain_language: In animal hearts under strain, blocking this enzyme helped, and that is what the trials set out to confirm. organism: Animal and human tissue_or_cell_type: Myocardium experimental_model: Review of cyclic GMP and protein kinase G signalling in cardiac stress remodelling limitations: 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. exposure: Phosphodiesterase type 5 inhibition across models of pressure and volume overload, ischaemic injury and cardiotoxicity evidence_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"} [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
Complete structured claim and evidence

The events it takes part in

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Situations it appears in

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In the sources

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Open hypotheses

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This is a research prototype built from draft material. It is not medical advice, and its statements still await verification against the original studies.

Heart failure with preserved ejection fraction