DeCure's autonomous Cardio AI scientist is researching a drug-repurposing hypothesis for aortic valve insufficiency — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleAortic valve insufficiency maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for aortic valve insufficiency is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
fibrillin 1 (FBN1) — FBN1 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1UZK · 1.35 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
A 1980 case report describes one 54-year-old woman with chronic severe aortic insufficiency who received oral hydralazine 125 mg twice a day. After 14 months she had sustained relief of heart failure symptoms, and repeat catheterisation showed haemodynamic improvement, reduction in left ventricular chamber size and muscle mass, and recovery of systolic pump function. The authors suggested arteriolar dilators might be a useful alternative to valve replacement in selected patients. No controlled trial data exist for any drug in aortic insufficiency.
Transcriptional profiling of five normal, five stenotic, and five regurgitant human aortic valves found 4994 differentially expressed genes in aortic insufficiency versus normal controls, and 2771 genes distinguishing insufficiency from stenosis. Among 21 genes of interest, APCDD1L, CDH6, COL10A1, HBB, IBSP, KRT14, PLEKHS1, PRSS35, and TDO2 were upregulated in both disease states, while ALDH1L1, EPHB1, GPX3, HIF3A, and KCNT1 were downregulated. The functional network for insufficiency clustered around ERK1/2 regulation, whereas stenosis clustered around ion regulation, immune regulation, and lipid homeostasis. The authors proposed these data as a roadmap for novel therapeutics, but no drug candidates have been tested based on these signatures.
A 2022 study on aortic valve stenosis found that the anti-angiogenic protein sFlt1 is constitutively expressed in non-diseased valves but significantly reduced in stenotic valves, with hypoxia markers simultaneously increased. In cultured valve interstitial cells, hypoxia decreased sFlt1 expression, and siRNA knockdown of sFlt1 created a pro-angiogenic environment. Incubation of aortic valves with sphingosine 1-phosphate increased sFlt1 expression and inhibited angiogenesis within valve tissue. This work was done in stenosis, not insufficiency, and no clinical intervention has been tested.
A 2017 review summarises genetic advances in bicuspid aortic valve and calcific aortic valve disease, noting the link between NOTCH1 mutations and both conditions, and describing mouse models that implicate endothelial Notch1 in valve morphogenesis. A 2010 review emphasises that aortic valves are not passive structures and that understanding cellular and molecular mechanisms is essential for elucidating valve disease. Neither review reports any drug therapy for aortic insufficiency.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Advanced Research · 2010 · 46 citations · open access
Cellular regulation of the structure and function of aortic valves
AbstractThe aortic valve was long considered a passive structure that opens and closes in response to changes in transvalvular pressure. Recent evidence suggests that the aortic valve performs highly sophisticated functions as a result of its unique microscopic structure. These functions allow it to adapt to its hemodynamic and mechanical environment. Understanding the cellular and molecular mechanisms involved in normal valve physiology is essential to elucidate the mechanisms behind valve disease. We here review the structure and developmental biology of aortic valves; we examine the role of its cellular parts in regulating its function and describe potential pathophysiological and clinical implications.
Long-Term Vasodilator Therapy in Aortic Insufficiency
AbstractAlthough the beneficial effects of acute therapy with arteriolar dilators in aortic insufficiency have been shown, the results of long-term therapy are uncertain. The administration of oral hydralazine, 125 mg twice a day, to a 54-year-old woman with chronic severe aortic insufficiency resulted in sustained relief of heart failure symptoms. Repeat catheterization after 14 months showed hemodynamic improvement, substantial reduction in left ventricular chamber size and muscle mass, and recovery of systolic pump function. Chronic therapy with arteriolar dilators may be a useful alternative to valve replacement in selected patients with aortic insufficiency.
Transcriptional Profiling of Normal, Stenotic, and Regurgitant Human Aortic Valves
AbstractThe genetic mechanisms underlying aortic stenosis (AS) and aortic insufficiency (AI) disease progression remain unclear. We hypothesized that normal aortic valves and those with AS or AI all exhibit unique transcriptional profiles. Normal control (NC) aortic valves were collected from non-matched donor hearts that were otherwise acceptable for transplantation (n = 5). Valves with AS or AI (n = 5, each) were collected from patients undergoing surgical aortic valve replacement. High-throughput sequencing of total RNA revealed 6438 differentially expressed genes (DEGs) for AS vs. NC, 4994 DEGs for AI vs. NC, and 2771 DEGs for AS vs. AI. Among 21 DEGs of interest, APCDD1L, CDH6, COL10A1, HBB, IBSP, KRT14, PLEKHS1, PRSS35, and TDO2 were upregulated in both AS and AI compared to NC, whereas ALDH1L1, EPHB1, GPX3, HIF3A, and KCNT1 were downregulated in both AS and AI (p < 0.05). COL11A1, H19, HIF1A, KCNJ6, PRND, and SPP1 were upregulated only in AS, and NPY was downregulated only in AS (p < 0.05). The functional network for AS clustered around ion regulation, immune regulation, and lipid homeostasis, and that for AI clustered around ERK1/2 regulation. Overall, we report transcriptional profiling data for normal human aortic valves from non-matched donor hearts that were acceptable for transplantation and demonstrated that valves with AS and AI possess unique genetic signatures. These data create a roadmap for the development of novel therapeutics to treat AS and AI.
Current Opinion in Cardiology · 2017 · 24 citations · open access
Genetic basis of aortic valvular disease
AbstractPURPOSE OF REVIEW: Aortic valve disease is relatively common and encompasses both congenital and acquired forms. Bicuspid aortic valve (BAV) is the most common type of cardiac malformation and predisposes to the development of calcific aortic valve disease (CAVD). Since the description of the link between NOTCH1, BAV and CAVD approximately a decade ago, there have been significant advances in the genetic and molecular understanding of these diseases. RECENT FINDINGS: Recent work has defined the congenital cardiac phenotypes linked to mutations in NOTCH1, and in addition, novel etiologic genes for BAV have been discovered using new genetic technologies in humans. Furthermore, several mouse models of BAV have been described defining the role of endothelial Notch1 in aortic valve morphogenesis, whereas others have implicated new genes. These murine models along with other cell-based studies have led to molecular insights in the pathogenesis of CAVD. SUMMARY: These findings provide important insights into the molecular and genetic basis of aortic valve malformations, including BAV, specifically highlighting the etiologic role of endothelial cells. In addition, numerous investigations in to the mechanisms of CAVD demonstrate the importance of developmental origins and signaling pathways as well as communication between valve endothelial cells and the underlying interstitial cells in valve disease onset and progression.
Can the Results of Aortic Valve Repair Equal the Results of a Biologic Aortic Valve Replacement?
AbstractAortic valve replacement (AVR) has been the default procedure for the surgical management of aortic valve disease, with repair techniques heterogeneously and infrequently used. However, surgical aortic valve repair has evolved with improved techniques. Yet many questions remain regarding the ideal techniques and real-world applicability and effectiveness of valve repair. The AORTA Great Debate highlighted and discussed the controversies regarding the surgical management of aortic valve disease.
Journal of Molecular and Cellular Cardiology · 2022 · 7 citations · open access
An endogenous inhibitor of angiogenesis downregulated by hypoxia in human aortic valve stenosis promotes disease pathogenesis
AbstractAortic valve stenosis is the most common valve disease in the western world. Central to the pathogenesis of this disease is the growth of new blood vessels (angiogenesis) within the aortic valve allowing infiltration of immune cells and development of intra-valve inflammation. Identifying the cellular mediators involved in this angiogenesis is important as this may reveal new therapeutic targets which could ultimately prevent the progression of aortic valve stenosis. Aortic valves from patients undergoing surgery for aortic valve replacement or dilation of the aortic arch were examined both ex vivo and in vitro. We now demonstrate that the anti-angiogenic protein, soluble fms-like tyrosine kinase 1 (sFlt1), a non-signalling soluble receptor for vascular endothelial growth factor, is constitutively expressed in non-diseased valves. sFlt-1 expression was, however, significantly reduced in aortic valve tissue from patients with aortic valve stenosis while protein markers of hypoxia were simultaneously increased. Exposure of primary-cultured valve interstitial cells to hypoxia resulted in a decrease in the expression of sFlt-1. We further reveal using a bioassay that siRNA knock-down of sFlt1 in valve interstitial cells directly results in a pro-angiogenic environment. Finally, incubation of aortic valves with sphingosine 1-phosphate, a bioactive lipid-mediator, increased sFlt-1 expression and inhibited angiogenesis within valve tissue. In conclusion, this study demonstrates that sFlt1 expression is directly correlated with angiogenesis in aortic valves and the observed decrease in sFlt-1 expression in aortic valve stenosis could increase valve inflammation, promoting disease progression. This could be a viable therapeutic target in treating this disease.
Leaflet escape in a modern mechanical heart valve: structure and cavitation: Panel A–C
AbstractA 23-year-old lady presented with New York Heart Association class III dyspnoea of 5 days' duration. She had undergone mechanical aortic valve replacement elsewhere 2 years ago and was irregular with oral anticoagulant therapy. Transthoracic echocardiography (not shown) revealed that only one leaflet was moving, and she was diagnosed as having a stuck aortic valve. At surgery, following aortotomy, when the valve was examined, …
European Journal of Cardio-Thoracic Surgery · 2021 · 0 citations · open access
Long-term durability and resilient tissue: ‘the future end of valve in valve!’
AbstractCurrent research focuses on new preservation technologies for xeno-pericardial prostheses with the aim of improving long-term durability, lowering the age threshold for bio-prosthetic valve implantation and thus reducing the side effects of long-lasting anticoagulation [1]. The increasing shift of an indicated age threshold for bio-prosthetic valve implantation towards younger patients may also lead to new long-term complementary treatment concepts, especially in times of success of the transcatheter aortic valve implantation (TAVI). We read with great interest the article ‘Final 5-year outcomes following aortic valve replacement with a RESILIA™ tissue bioprosthesis’ by Bartus et al., the authors present a prospective, non-randomized, single-arm study of 133 patients implanted with a RESILIA aortic with clinical outcomes and haemodynamic performance assessed annually for 5 years post-implant [2]. This study concluded that the bioprosthesis with RESILIA tissue demonstrated a good safety profile with excellent haemodynamic performance over 5 years of follow-up [3]. Aortic valve-in-valve is a less-invasive alternative to surgical redo in the treatment of failed bioprosthetic valves. In this context, we present our reflection, if the long-term results on RESILIA tissue continue to be promising in the next studies, it could be legitimate to think of a RESILIA treatment on TAVI; this would change the paradigm by extinguishing the valve-in-valve approach in degenerative processes on surgical bio-prosthetic valves and TAVI. Conflict of interest: none declared.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
