2026-05-25

log/2026-05-25 — ad-hoc daily entries

Sub-file of log — see parent for index. Holds full content for one-line pointers in log.md.

[2026-05-25] ingest | chronic venous disease (varicose veins / CVI) + veins tissue

• added: phenotypes/chronic-venous-disease.md (type: phenotype; varicose veins / CVI / CVD; verified: false, banner; literature-checked-through 2026-05-25)
• added: tissues/veins.md (type: tissue; venous wall + valves + calf-pump + venous aging; verified: false, banner)
• updated: phenotypes/cardiovascular-aging.md — added “Venous aging — chronic venous disease” subsection + 2 footnotes (filled a genuine omission: page covered only arterial stiffening + endothelial dysfunction on the vascular side)
• updated: phenotypes/arterial-stiffening.md — sibling pointer to chronic-venous-disease
• updated: tissues/arteries.md — reciprocal pointer to veins / chronic-venous-disease (page already scoped out veins)
• context: ad-hoc user-requested seed — per ad-hoc-seed convention, NOT added to ROADMAP unseeded queue
• sources: live-retrieved PMIDs/DOIs via PubMed/Europe PMC/Crossref — Edinburgh Vein Study (Evans 1999 / Robertson 2013 / Lee 2015), Bonn (Maurins 2008), San Diego (Criqui 2003), mechanism (Bergan 2006 NEJM, Eberhardt & Raffetto 2014 Circulation, Raffetto & Khalil 2021/2008, Lim 2011), GWAS (Fukaya 2018 Circulation — height causal via MR), interventions (Cochrane: compression Shingler 2021, phlebotonics Martínez-Zapata 2020, horse chestnut Pittler 2012; RCTs: CLASS Brittenden 2014/2019, EVRA Gohel 2018, VeClose Morrison 2017; ESVS 2022 + SVS/AVF/AVLS 2023 guidelines)
• gaps surfaced: (1) no verified primary identifier for age-related venous-valve-number decline needs-replication; (2) senescence-specific causal data in human varicose veins thin no-mechanism; (3) no RCT that treating C2 prevents progression to CVI/ulcer contradictory-evidence; (4) MOCA RCTs (LAMA/MARADONA), CEAP-definition paper (Eklöf 2004), NICE CG168 referenced generically — identifiers unverified
• next: wiki-verifier pass against full PDFs to flip verified flags (both new pages verified: false)

[2026-05-25] ingest | venous valve deep-dive + artificial venous valves

• updated: tissues/veins.md — added 3 deep sections (venous valve microanatomy + developmental program; valve failure cellular mechanisms; comparison to cardiac/heart valves incl. genetic correlation) + 24 new footnotes; verified-scope carve-out flags new sections as pending (inline ⚠️); verifier re-dispatched
• added: interventions/procedural/venous-valve-reconstruction.md (type: intervention, mode: procedural — FIRST page in procedural/; surgical repair + bioprosthetic VenoValve + percutaneous BlueLeaf + tissue-engineered; verified: false, banner)
• updated: phenotypes/chronic-venous-disease.md — pointer to venous-valve-reconstruction (deep-system/PTS niche) + veins valve-biology
• updated: tissues/heart.md — cardiac-vs-venous-valve cross-link callout (shared NFATc1/Notch/BMP/EndMT program; PROX1 protects mitral; divergent failure modes)
• context: ad-hoc user-requested deep-dive — not added to ROADMAP queue
• KEY FINDINGS: (1) venous + cardiac + lymphatic valves share a developmental program (PROX1/FOXC2/NFATc1-calcineurin, connexin-37, EndMT); (2) GENETIC BRIDGE — varicose-vein GWAS (Fukaya 2018) implicates PPP3R1 (calcineurin B), FBN2 (fibrillin-2), PIEZO1, CASZ1 — the calcineurin/NFAT + connective-tissue machinery shared with cardiac valves; (3) PROX1 (venous/lymphatic valve TF) protects against myxomatous mitral degeneration (Ho 2023); (4) NO FDA-approved artificial venous valve as of 2026-05 — VenoValve rejected (not-approvable Aug 2025, appeal denied Nov 2025); transcatheter enVVe got FDA IDE Apr 2026; BlueLeaf suspended
• sources: live PubMed/Europe PMC/ClinicalTrials.gov — biology: Phillips 2004, Banjo 1987, Bovill 2011, Mackman 2012, Welsh 2019, Sabine 2012, Munger 2013, Bazigou 2009, Murtomaki 2014, Lange 2006, Saxon 2017, Raffetto 2008 (Phlebology), Bergan 2008 (JVS), Takase 2004, Chen 2017, Lyons 2021, Mellor 2007, Ahalya 2025, Absi 2018, Rajamannan 2003, Garg 2005, Fukaya 2018, Kühne 2013, Ho 2023; devices: Zervides 2021, Raju 1985, Verma 2014, Maleti 2006/2023, Ochoa Chaar 2026 (SAVVE NCT04943172), Vasudevan 2021 (BlueLeaf), Brountzos 2003, Kuna 2015, Lopera Higuita 2020
• gaps surfaced: gap venous leaflet tri-layer ultrastructure (extrapolated from cardiac); age-related venous-valve-number decline (#gap/unsourced — no clean primary); VIC-analogue resident cell in venous valves uncharacterized; varicose-veins↔MVP clinical co-occurrence (#gap/needs-replication — mechanistically motivated only); clinical-rVCSS-vs-reflux-time discordance in VenoValve+BlueLeaf (#gap/contradictory-evidence)
• next: background wiki-verifier pass running on both (full-PDF/PMC cross-check; FDA-status independent confirmation; R25 device-literature supersession)

[2026-05-25] ingest | CVD genetics section (ad-hoc)

• updated: phenotypes/chronic-venous-disease.md — added “Genetics and heritability” section (polygenic ~17% heritability; Fukaya 2018 30 loci + 2022 Nat Commun 810k GWAS + Soh 2026 review; FOXC2/EPHB4 rare-Mendelian forms; genetic-testing utility — SNP array vs WES/WGS vs PRS, PGS Catalog has 6 VV scores; not clinically actionable) + 7 footnotes; inline ⚠️ + verified-scope carve-out; verifier dispatched to nail “to verify” citations (2022 GWAS author/PMID, Soh 2026, FOXC2 papers)
• sources added: 2022 Nat Commun VV GWAS (doi:10.1038/s41467-022-30765-y), Soh 2026 (PMID 41391741), FOXC2 papers (PMC3946558, PMID 15744037/PMC1736007, FOXC2-truncating-mutation), PGS Catalog (HP_0002619, 6 scores), Lyons 2021 EPHB4 (PMID 34403370)
• key answer: varicose veins are polygenic (no single maternal-line mutation expected unless rare FOXC2/EPHB4 Mendelian form w/ early-onset/syndromic flags); 23andMe raw data → research-grade PRS only; sequencing finds rare Mendelian variants but low yield for isolated VV; genotype does not change phenotype-driven management

[2026-05-25] ingest | exercise-for-CVD RCT evidence (ad-hoc)

• updated: phenotypes/chronic-venous-disease.md — expanded Interventions § exercise bullet with actual RCT evidence: Padberg 2004 RCT (PMID 14718821; calf-pump ejection fraction ↑ but REFLUX UNCHANGED — pump improves, valve disease not corrected); exercise-for-ulcer-healing meta-analysis (PMID 36202303; 8 RCTs n=270; healing RR 1.38) + 2 footnotes; inline ⚠️ + scope carve-out; verifier dispatched
• key answer: NO RCT shows exercise slows structural progression of varicose veins/CVD (no incidence/CEAP-progression endpoints; trials small/short/surrogate). RCT evidence DOES show exercise improves calf-pump hemodynamics + ulcer healing (adjunct to compression). Consistent with broader theme: no intervention (incl. ablation) has RCT proof of preventing early-stage progression

[2026-05-25] ingest | CVD progression hypotheses + experiment proposal (ad-hoc)

• updated: phenotypes/chronic-venous-disease.md — added “Hypothesized progression-slowing strategies (open question)” section (3-tier framework: hemodynamic / wall-remodeling repurposing / aging-biology frontier) — flagged mechanism-grounded HYPOTHESIS not verified evidence; reuses verified mechanism footnotes; new anchors (doxycycline-AAA, sulodexide, senolytic→PWV) tagged needs-verification; verified-scope note added

• added: experiments/early-ablation-c2-progression-prevention.md (type: experiment, status: proposed) — RCT proposal: early endovenous ablation at C2 vs surveillance, primary endpoint CEAP progression to C3+ at 5–10y; resolves-edges “venous reflux → CEAP progression”; connects to chronic-venous-disease + veins; documents the recurrence/new-segment confound + equipoise tension

• context: answers the question “hypothesize interventions to slow/halt progression” — captured both the reasoning (CVD section) and the single most-testable hypothesis (experiment page)

• key framing: no intervention has RCT progression-prevention proof; strongest testable lever is hemodynamic + early (abolish reflux before the loop amplifies); aging-biology tier (senolytics/EndMT/calcineurin-NFAT) is mechanism-aligned but evidence-free in venous tissue

• 2026-05-25 verify — phenotypes/chronic-venous-disease.md Interventions § exercise bullet verified. 4 corrections: (1) Turner 2022 (PMID 36202303): 8 RCTs→7, n=270→246, CI 1.14–1.66→1.11–1.71; +27/100 progressive-resistance figure removed (not in paper; actual figure is risk difference +18/100 CI 7–30); (2) Padberg 2004 DOI added (10.1016/j.jvs.2003.09.036), compression detail added (30–40 mmHg class II), quantitative EF/RVF values added to body; (3) Zhang 2023 (PMID 36650634, DOI 10.1111/iwj.14020) added as separate [^exerciseulcer2023] footnote — this is the 8 RCTs/n=270/CI 1.14–1.66 paper that the original footnote had mistakenly attributed to Turner 2022; (4) ⚠️ inline warning removed from exercise bullet. R25 recency check: no newer superseding exercise+CVD meta-analysis or large RCT found beyond Turner 2022/Zhang 2023. Padberg 2004 closed-access (not_oa); verified against PubMed abstract only. Turner 2022 full PDF read (downloaded from bronze OA URL). Progress-prevention-by-RCT absence confirmed — no such trial found.

• 2026-05-25 verify — phenotypes/chronic-venous-disease.md Genetics section verified against primary sources. 9 corrections/clarifications: (1) Ahmed 2022 first authors added (Ahmed WU/Kleeman S), PMID 35654884 confirmed, loci count corrected from “confirmed and expanded” to “49 signals at 46 loci”; (2) ~17% heritability qualified — stated as background in 2022 abstract, not a novel finding; Fukaya 2018 LDSC h²=0.28 noted as a different metric; (3) Soh 2026 full citation confirmed (Soh CL et al., PMID 41391741, PMCID PMC12830204; 13 studies, 602,760 VV patients); prose reframed from “adds” loci to “catalogues convergent loci across studies”; (4) foxc2trunc paper confirmed as existing (DOI 10.46300/91011.2020.14.5, NAUN journal, NOT PubMed-indexed, language Greek, low-impact); quality caveat added to footnote and prose; (5) foxc2prom confirmed as Surendran S et al. PLoS One 2014;9(3):e90682, PMID 24608096, PMC3946558; OR 2.08 confirmed; (6) foxc2linkage confirmed as Ng MYM et al. J Med Genet 2005;42(3):235–9, PMID 15744037, PMC1736007; corrected: linkage for hemorrhoids was NEGATIVE in this paper; prose updated accordingly; (7) FOXC2 prose corrected to distinguish hemorrhoid-VV co-occurrence (foxc2trunc 2020 case) from VV-only linkage (Ng 2005); (8) PGS Catalog 6 scores confirmed via REST API; trait description “Enlarged and tortuous veins” added; (9) inline ⚠️ banner removed from Genetics section; verified-scope updated to fold in full Genetics verification details. Unverifiable: the exact original source of the ~17% population heritability figure (stated as background in Ahmed 2022; not a primary GWAS estimate from that paper; Fukaya 2018 reports 28% by LDSC). Downstream: veins.md genetic-bridge section should note the 46-loci correction; also the FOXC2 footnote on veins.md if it repeats the hemorrhoid linkage claim.

• 2026-05-25 verify — tissues/veins.md valve sections + interventions/procedural/venous-valve-reconstruction.md verified; intervention page flipped to verified:true. See corrections summary in agent output 2026-05-25 (veins.md valve sections + intervention page). PDFs read end-to-end: Fukaya 2018 (Circulation, local), Sabine 2012 (Dev Cell, downloaded), Welsh 2019 (JCI, downloaded), Lyons 2021 (JCI Insight, downloaded), Mellor 2007 (Circulation, downloaded), Ochoa Chaar 2026/SAVVE (JVSV, downloaded via PMC12553046), Maleti 2006 (J Vasc Surg, downloaded), Maleti 2023 (JVSV, downloaded). 8 corrections: (1) FBN2 corrected from GWAS locus to eQTL association in the Fukaya 2018 genetic-bridge claim; (2) perivalvular endothelial program corrected from “anticoagulant” to “antithrombotic” per Welsh 2019 exact terminology; (3) Munger 2013 + Sabine 2012 footnotes clarified as primarily lymphatic-valve evidence with extrapolation to venous valves; (4) Welsh 2019 journal issue corrected (129(11)→129(12)); (5) SAVVE CEAP C4b–C6 corrected to C4b/C4c/C5/C6; (6) mean rVCSS −7.9 qualified as responder-cohort mean (all-patient mean −6.7 at 12 months); (7) Maleti 2023 pooled competence body claim corrected from 84% to 87% (internal valvuloplasty subgroup); neovalve subgroup data added; (8) VenoValve device description corrected per paper (stainless-steel frame; enVVeno Medical attribution; Hancock Jaffe name removed). FDA not-approvable/IDE claims remain no-fulltext-access (company URLs returned HTTP 403). Supersession: PMID 41391741 (2026 systematic review of CVD GWAS, JVSV:VLD) identified as covering newer varicose-vein GWAS beyond Fukaya 2018 — flagged as recency-update candidate. literature-checked-through: 2026-05-25.

• 2026-05-25 verify — phenotypes/chronic-venous-disease.md and tissues/veins.md both flipped verified:true. See corrections summary below. PDFs read: Evans 1999 (J Epidemiol Community Health, full 5 pp), Maurins 2008 Bonn Vein Study (J Vasc Surg, full 8 pp), Raffetto 2021 (Vessel Plus, 15 pp of 30 read — introduction through MMP activities sections), Eberhardt 2014 (Circulation, full 5 pp of review). PMC full texts cross-checked: Criqui 2003 (San Diego Population Study), Lim 2011, Fukaya 2018, Pittler 2012 Cochrane. Abstracts verified via PubMed for: Robertson 2013, Lee 2015, Shingler 2021, Martínez-Zapata 2020, CLASS 2014/2019, EVRA 2018, VeClose. ESVS 2022 guideline verified against full PDF (title/TOC). 6 factual corrections across both pages: (1) Criqui 2003 ORs rounded incorrectly: OR 2.2→2.18 (varicose veins), OR 5.4→5.36 (spider veins), OR 0.7→0.65 (trophic changes); added note that CIs are not reported in Table 3. (2) Raffetto 2021 article number: 5:30→5:36 in both pages’ footnotes. (3) MMP list corrected: wiki cited MMP-1, MMP-3, MMP-9 as “notably” elevated; Raffetto 2021 primary text states MMP-1, -2, -3, -7 are elevated and MMP-2 activity is specifically increased; MMP-9 is enriched in specific cell types but not in the primary “elevated” list. Corrected in both pages. (4) Bonn Vein Study analysis n clarified: enrolled 3072 vs analysis n=3016; CEAP distribution percentages derive from n=3016. (5) Evans 1999 exact figures added to footnote: paper reports 39.7% M / 32.2% W (abstract rounds to 40%/32%) for trunk varices; 9.4% M / 6.6% W for CVI (abstract rounds to 9%/7%). Wiki body text (which cites abstract rounding) left unchanged; footnote now carries exact values. (6) Maurins PMID added: 18586443; footnote also expanded with exact superficial and deep reflux CIs. Unverifiable claims: Robertson 2013 and Lee 2015 full texts are not OA; family history OR and DVT OR from Lee 2015 confirmed from abstract only (abstract’s CI for family history OR appears corrupted in the fetched text — CI not propagated; wiki’s body claim of “OR ~1.85” is from the abstract and retained). Fukaya 2018 MR 95% CI: paper does not separately report IVW CI; wiki correctly omits it. Supersession check: R25 run — no new meta-analysis or large RCT (n>100) supersedes the Edinburgh, Bonn, CLASS, EVRA, or Fukaya data. A 2024 10-year RCT (PMID 39162334, BJS, n=206) confirms EVLA superiority over surgery at 10 years, consistent with CLASS framing. literature-checked-through: 2026-05-25.