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aortic-stenosis

README.md

Calcific Aortic Valve Stenosis (CAVD / AS) — QSP Model

Disease category: Chronic Cardiovascular Disease
Abbreviation: AS / CAVD
Directory: aortic-stenosis/
Model date: 2026-06-28

Overview

Calcific Aortic Valve Disease (CAVD) leading to Aortic Stenosis (AS) is the most common valvular heart disease in adults over 65, affecting ~2.5% of the population and rising sharply with age. The disease progresses through a stereotyped sequence:

  1. Valve endothelial injury → lipid infiltration → inflammation initiation
  2. Valve Interstitial Cell (VIC) osteogenic transformation via BMP/Wnt/RANKL signaling
  3. Microcalcification → macrocalcification → leaflet stiffening
  4. AVA reduction → transvalvular gradient ↑ → LV pressure overload
  5. Concentric LV hypertrophy → diastolic dysfunction → eventual systolic failure
  6. Symptom onset (angina, syncope, dyspnea) → clinical decompensation → death

Without aortic valve replacement (TAVR/SAVR), median survival after symptom onset is 2–3 years. Current pharmacotherapy has not demonstrated efficacy in halting calcification progression (SEAS/ASTRONOMER trials for statins), but novel targets (RANKL/OPG, Lp(a), MGP) are under active investigation.

Mechanistic Map

File Description
as_qsp_model.dot Full Graphviz mechanistic map (~110+ nodes, 12 subgraphs)
as_qsp_model.svg Vector SVG (scalable)
as_qsp_model.png Raster PNG (150 dpi)

Map Structure (12 Subgraphs)

# Subgraph Key Nodes
1 Risk Factors & Initiating Stimuli Age, LPA, LDL, BAV, NOTCH1, HTN, DM, CKD
2 Valve Endothelium & Initiating Injury VEC injury, shear stress, oxLDL, eNOS, ROS
3 Inflammation & Immune Pathways Macrophage, IL-1β, TNF-α, IL-6, MMP, complement
4 VIC Osteogenic Transformation Runx2, Osterix, ALP, RANKL, OPG, Wnt/LRP5, MGP
5 Valve Calcification Progression Ca score, AVA, leaflet mobility, macrocalcification
6 Hemodynamic Consequences Mean gradient, Vmax, cardiac output, afterload
7 LV Remodeling LVH, fibrosis, LVEF, diastolic dysfunction, BNP
8 Biomarkers & Clinical Endpoints NYHA, 6MWD, MACE, survival, BNP, Troponin
9 Drug PK — Statin & PCSK9i 2-compartment statin, 1-comp SC evolocumab
10 Drug PD Effects LDL↓, Lp(a)↓, RANKL↓, MGP activation, anti-fibrosis
11 Interventional (TAVR/SAVR) AVA restoration, reverse remodeling, complications
12 Systemic Consequences HF, AF, pulmonary HTN, cardiorenal syndrome

mrgsolve ODE Model

File: as_mrgsolve_model.R

Compartments (20 state variables)

Category Compartments
Statin PK STATIN_GUT, STATIN_CENTRAL, STATIN_PERIPH
PCSK9i PK PCSK9I_DEPOT, PCSK9I_CENTRAL
Denosumab PK DENO_DEPOT, DENO_CENTRAL
Vitamin K2 PK VK2_DEPOT, VK2_CENTRAL
ACEi PK ACEI_DEPOT, ACEI_CENTRAL
Valve calcification CS (calcium score), RANKL, MGP_carbox
Lipid biomarkers LDL_C, LPA
Inflammation IL6
Neurohormonal AngII
LV remodeling LVMI, COLLAGEN, LVEF
Clinical NTproBNP

Key Equations

Valve Calcium Score:

dCS/dt = k_calc × calc_driver × (1 - calc_inhibit) × CS × (1 - CS/CS_max)
calc_driver = 0.3×(LDL/LDL₀) + 0.4×(RANKL/RANKL₀) + 0.3×(Lp(a)/LPA₀)

AVA from Calcium Score (sigmoidal):

AVA = AVA_min + (AVA₀ - AVA_min) / (1 + (CS/CS₅₀)^hill)

Mean Transvalvular Gradient (Bernoulli):

Vmax = CO / (AVA × 60 × 0.785)
ΔP_mean = 2.4 × Vmax²

LV Fibrosis:

dCOLLAGEN/dt = k_form × (AngII/AngII₀) × wall_stress × (1 - E_ACEi) - k_deg × COLLAGEN

LVEF Decline:

dLVEF/dt = -k_loss × (Collagen/Collagen_max) × max(afterload - 130, 0)/50 × LVEF

Treatment Scenarios Simulated

# Scenario Key Drugs
1 No Treatment —
2 Statin Rosuvastatin 20mg QD
3 Statin + PCSK9i + Evolocumab 140mg Q2W
4 Statin + Denosumab* + Denosumab 60mg Q6M
5 Statin + Vitamin K2 + MK-7 180μg QD
6 Max Medical Therapy Statin + PCSK9i + VK2 + ACEi

* Denosumab for CAVD is investigational (hypothesis-generating)

Key Simulation Findings

  • Statin alone: Minimal effect on calcification progression (consistent with negative SEAS/ASTRONOMER/SALTIRE trials)
  • PCSK9i addition: Meaningful LDL-C and modest Lp(a) reduction; clinically meaningful delay in calcification
  • Denosumab: Largest hypothetical calcification reduction via RANKL blockade in VIC; awaiting clinical trial validation
  • Vitamin K2 (MK-7): Moderate benefit via restoration of carboxylated MGP, natural calcification inhibitor
  • Max medical therapy: ~15-20% delay in severe AS onset estimated; AVR still required

Shiny App

File: as_shiny_app.R

6 Interactive Tabs

Tab Content
Patient Profile AS severity gauge (AVA, gradient, LVEF, NYHA), risk factors, prognosis
Drug PK Time-concentration plots for statin, PCSK9i, denosumab; PK summary table
PD Key Metrics LDL-C response, Lp(a), RANKL, IL-6, MGP carboxylation trajectories
Clinical Endpoints AVA, mean gradient, LVEF, LVMI, NT-proBNP over time; time-to-severe prediction
Scenario Comparison 6-scenario side-by-side comparison with summary table at year 10
Biomarker Panel Calcium score trajectory, collagen fraction, biomarker heatmap, AngII-LV axis

Interactive Controls

  • Patient sliders: Age, LDL-C, Lp(a), LVEF, baseline AVA, baseline calcium score, simulation duration
  • Drug toggles: Statin (dose), PCSK9i (dose, frequency), Denosumab (dose, frequency), Vitamin K2 (dose), ACEi/ARB (dose)
  • Auto-running simulation with "Run Simulation" button

Clinical Context

AS Severity Classification (AHA/ACC 2021)

Grade AVA (cm²) Mean PG (mmHg) Vmax (m/s)
Mild >1.5 <25 <3.0
Moderate 1.0–1.5 25–40 3.0–4.0
Severe <1.0 >40 >4.0
Very Severe <0.6 >60 >5.0

Typical Natural History (Untreated)

  • Asymptomatic severe AS: ~50% develop symptoms within 5 years
  • After symptom onset (triad: angina, syncope, HF):
    • Mean survival with angina: 5 years
    • Mean survival with syncope: 3 years
    • Mean survival with HF symptoms: 1-2 years

Key Molecular Targets

Target Rationale Drug Trial Status
HMG-CoA LDL ↓ Statin Tested/Failed (SEAS)
PCSK9 LDL+Lp(a) ↓ Evolocumab Phase III pending
RANK/RANKL VIC osteogenesis ↓ Denosumab Phase II (SALTIRE-II)
MGP Calcification inhibitor Vitamin K2 Observational
Lp(a) oxPL-mediated calcification Pelacarsen, Olpasiran Phase III
ACE/AT1R LV fibrosis ↓ Ramipril Supportive
IL-6 Inflammation ↓ Ziltivekimab Hypothesis

References

See as_references.md for 50 curated PubMed-linked references organized by:

  • Epidemiology & Natural History
  • Pathophysiology
  • RANKL/OPG/VIC transformation
  • BMP/Notch/Wnt signaling
  • Lp(a) and lipid-mediated calcification
  • Matrix Gla Protein & Vitamin K
  • Statin trials (SEAS, ASTRONOMER, SALTIRE)
  • Novel targets (PCSK9i, Denosumab)
  • TAVR/SAVR evidence (PARTNER, Evolut)
  • LV remodeling & neurohormonal
  • Hemodynamics & echocardiography
  • CT calcium scoring
  • QSP modeling

Files Summary

File Description Size
as_qsp_model.dot Graphviz mechanistic map (12 subgraphs, 110+ nodes) ~35KB
as_qsp_model.svg Rendered vector image ~150KB
as_qsp_model.png Rendered raster image (150 DPI) ~2.5MB
as_mrgsolve_model.R ODE model (20 compartments, 6 scenarios) ~15KB
as_shiny_app.R Interactive Shiny dashboard (6 tabs) ~20KB
as_references.md 50 curated PubMed references ~8KB
README.md This file ~8KB

Acknowledgments

Model parameters calibrated against:

  • SEAS trial data (Rossebø et al., NEJM 2008)
  • PARTNER / Evolut trial outcomes
  • CT calcium score progression studies (Marechaux et al., Heart 2010)
  • Echocardiographic valve area natural history (Pellikka et al., Circulation 2005)
  • ESC/AHA AS management guidelines (2017/2021)

This model is intended for research/educational purposes only and does not constitute clinical guidance.