Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is a life-threatening condition arising from incomplete resolution of pulmonary emboli, leading to permanent mechanical obstruction of the pulmonary vasculature by organized fibrous thrombi. Superimposed on this fixed obstruction, progressive small-vessel disease driven by endothelin-1 overproduction, nitric oxide deficiency, and abnormal shear stress creates an additional variable component of elevated pulmonary vascular resistance (PVR). The combination causes progressive right ventricular pressure overload, remodeling, and ultimately failure.

CTEPH is classified as Group 4 pulmonary hypertension (ESC/ERS 2022). Diagnosis requires:

• mPAP > 20 mmHg at rest
• Pulmonary capillary wedge pressure ≤ 15 mmHg (pre-capillary)
• Mismatched perfusion defects on V/Q scan after ≥ 3 months of therapeutic anticoagulation
• Confirmation by CT pulmonary angiography or conventional angiography

Acute PE → Incomplete fibrinolysis → Organized thrombus → Fixed PVR obstruction
                 ↓                          ↓
    Thrombophilic state            Secondary vascular remodeling
         + recurrent PE              (ET-1, NO↓, PGI₂↓, SMC proliferation)
                                          ↓
                                   Variable PVR↑
                                          ↓
                                   Total PVR↑ → mPAP↑
                                          ↓
                               RV pressure overload
                                          ↓
                    Adaptive hypertrophy → Dilatation → Failure
                                          ↓
                               CO↓, SaO₂↓, BNP↑, 6MWD↓

12 Subgraph Clusters:

1. Thrombotic Origin & Acute PE — Thrombophilia, platelet activation, recurrent PE
2. Fibrinolysis Dysfunction — tPA deficiency, PAI-1↑, plasmin↓, fibrin cross-linking
3. Pulmonary Vascular Remodeling — ET-1, NO↓, PDGF, TGF-β, SMC proliferation, plexiform lesions
4. Hemodynamics — mPAP, PVR (fixed + variable), CO, TPG, PCWP
5. Right Ventricular Remodeling — Hypertrophy, dilatation, fibrosis, TAPSE, RVEF
6. Gas Exchange — V/Q mismatch, dead space, PaO₂, SaO₂, DLCO
7. Neurohumoral Biomarkers — BNP, RAAS, ET-1, troponin, D-dimer
8. Riociguat PK/PD — sGC stimulation, cGMP↑, vasodilation, anti-proliferative
9. ERA PK/PD — Macitentan/ACT-132577, ETA/ETB blockade, anti-fibrotic
10. Prostacyclin PK/PD — Treprostinil, IP receptor, cAMP↑, platelet inhibition
11. Surgical/Procedural — PEA (≥70% PVR reduction), BPA (staged), anticoagulation
12. Clinical Endpoints — 6MWD, WHO FC, dyspnea, BNP, survival, TTCW

Drug PK (7):

Disease PD (12):

install.packages(c("shiny","shinydashboard","mrgsolve","dplyr","tidyr",
                   "ggplot2","plotly","DT"))
library(shiny)
shiny::runApp("cteph_shiny_app.R")

• Incidence: ~3–5% of acute PE survivors develop CTEPH
• Prevalence: ~3–30 per million (likely underdiagnosed)
• Male:Female ratio ≈ 1:1
• Median survival without treatment: ~2–3 years from diagnosis

Confirmed CTEPH diagnosis
         ↓
Lifelong anticoagulation (essential for all)
         ↓
CTEPH Expert Center multidisciplinary team assessment
         ↓
Is the patient operable? (proximal disease, good cardiopulmonary reserve)
    /           \
  YES            NO
   ↓              ↓
  PEA         Residual/inoperable CTEPH
(curative)         ↓
                Riociguat ± Macitentan
                   ± BPA (if accessible)
                   ± Prostacyclin (severe cases)

60 references covering:

• ESC/ERS clinical guidelines (2022)
• CHEST-1/CHEST-2 (riociguat), SERAPHIN (macitentan), MERIT-1 (combination)
• PEA outcomes (Madani et al., Jamieson et al.)
• BPA technique and results (Mizoguchi, Wiedenroth, Ogawa)
• QSP/PK-PD modeling methodology

See cteph_references.md for the complete reference list.

Built by Claude Code Routine | QSP Disease Model Library | 2026-06-26