Respiratory disease according to Harrison with pathophysiology

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Excellent. I now have comprehensive, authoritative content from Robbins Pathology, Katzung Pharmacology, Goodman & Gilman, and Brenner & Rector's Kidney. Here is the full synthesis:

Vascular Endothelial Growth Factor (VEGF)

1. The VEGF Family

VEGF is a family of homodimeric glycoproteins with five major members:

Member	Primary Role
VEGF-A	The dominant angiogenic factor; simply called "VEGF"
VEGF-B	Embryonic vessel development
VEGF-C	Angiogenesis + lymphangiogenesis
VEGF-D	Angiogenesis + lymphangiogenesis
PlGF (Placental Growth Factor)	Embryonic vessel development, preeclampsia

— Robbins, Cotran & Kumar Pathologic Basis of Disease

2. Receptors

VEGFs bind to a family of transmembrane receptor tyrosine kinases:

Receptor	Alias	Key Function
VEGFR-1	FLT1	Modulates VEGF bioavailability; role in embryogenesis
VEGFR-2	KDR	Main signaling receptor — mediates virtually all angiogenic effects
VEGFR-3	FLT4	Lymphangiogenesis

Binding of VEGF to VEGFR activates intracellular tyrosine kinase activity, initiating:

Mitogenic signaling → endothelial cell proliferation
Antiapoptotic signaling → endothelial cell survival
PI3K → AKT pathway → cell growth and proliferation

— Goodman & Gilman's Pharmacological Basis of Therapeutics

3. Physiological Functions

Angiogenesis — endothelial cell migration, proliferation, capillary sprouting, and vascular lumen formation
Vascular permeability — VEGF was originally named vascular permeability factor (VPF) for its potent ability to increase vessel leakiness
Normal endothelial maintenance — highest expression in epithelial cells adjacent to fenestrated endothelium:
- Kidney podocytes
- Retinal pigment epithelium
- Choroid plexus
Lymphangiogenesis (via VEGF-C and VEGF-D)
Embryonic vasculogenesis (VEGF-B, PlGF)

4. Regulation: The HIF-1 / Hypoxia Axis

The single most important inducer of VEGF is hypoxia, acting via:

Low O₂ → stabilization of HIF-1α → HIF-1 transcription factor → VEGF gene transcription → angiogenesis

The VHL (von Hippel-Lindau) tumor suppressor normally targets HIF-1α for proteasomal degradation. Loss of VHL (e.g., in clear cell renal carcinoma) → constitutive HIF-1 activation → massive VEGF overproduction → hypervascular tumors.

Other inducers at sites of injury and inflammation:

PDGF
TGF-α
Oncogenes (RAS, MYC)

— Robbins Pathologic Basis of Disease; Brenner & Rector's The Kidney

5. VEGF in Pathology

Tumour Angiogenesis

All solid tumours >1–2 mm require new vasculature to sustain growth. Tumour cells secrete VEGF to recruit vessels from the surrounding stroma — the angiogenic switch. Anti-VEGF therapy was developed directly from this insight.

Preeclampsia

Elevated soluble sFLT-1 (soluble VEGFR-1) in pregnant women acts as a decoy receptor, sequestering circulating VEGF and PlGF → reduced VEGF bioavailability → endothelial dysfunction → hypertension and proteinuria, mirroring the pathophysiology of VEGF inhibitor toxicity.

Diabetic Macular Edema & Wet AMD

Retinal ischaemia → upregulation of VEGF → pathological choroidal/retinal neovascularisation and vascular leakage → vision loss.

Psoriasis

Prominent angiogenesis within plaques; increased VEGF expression contributes to the characteristic dermal vascularity. Anti-VEGF therapy reduces inflammation in mouse psoriasis models.

6. VEGF-Targeted Therapies

6a. Antibodies Against VEGF Ligand

Drug	Type	Key Approvals
Bevacizumab	Humanized IgG1 mAb vs. VEGF-A	mCRC, NSCLC (non-squamous), glioblastoma, RCC, cervical Ca, ovarian Ca
Ziv-aflibercept	Recombinant decoy receptor (VEGFR1+2 domains fused to IgG1 Fc); binds VEGF-A, VEGF-B, PlGF with higher affinity than bevacizumab	mCRC after oxaliplatin failure
Ranibizumab / Brolucizumab / Faricimab	Engineered humanized Ab fragments vs. VEGF-A	Wet AMD, diabetic macular edema (intravitreal)
Pegaptanib	Pegylated oligonucleotide binding extracellular VEGF	Wet AMD (intravitreal)

6b. Antibodies Against VEGFR

Drug	Target	Key Approvals
Ramucirumab	VEGFR-2 antagonist (blocks VEGF-A/C/D binding)	Gastric/GEJ adenocarcinoma, NSCLC, mCRC, hepatocellular Ca

6c. Small Molecule VEGFR Tyrosine Kinase Inhibitors (TKIs)

Target the intracellular kinase domain of VEGFR (and often PDGFR, RAF, KIT):

Axitinib, Pazopanib, Sorafenib, Sunitinib, Tivozanib, Cabozantinib, Lenvatinib

These are used predominantly in RCC, hepatocellular carcinoma, thyroid cancer, and other solid tumours.

— Katzung Basic & Clinical Pharmacology, 16th ed.; Goodman & Gilman's

7. Adverse Effects of VEGF Inhibition

Because VEGF is essential for normal endothelial maintenance — especially in the kidney glomerulus — inhibiting it produces predictable toxicities:

Toxicity	Mechanism	Frequency
Hypertension	Loss of endothelial VEGF → reduced NO production, vasoconstriction	11–43%
Proteinuria	Disruption of glomerular slit diaphragm integrity (podocyte VEGF loss)	41–63%
Thrombotic microangiopathy	Primary glomerular pathology seen on biopsy	Variable
Arterial thromboembolic events	Endothelial injury	Significant
Wound healing impairment	Angiogenesis required for tissue repair	Must withhold peri-surgically
GI perforation	Microvascular compromise	~1–2% with bevacizumab
Haemorrhage	Endothelial fragility	Variable

Management: ACEIs/ARBs for hypertension and proteinuria; dose reduction or temporary cessation for severe AKI or TMA.

— Brenner & Rector's The Kidney

8. Pathway Diagram

Tumor growth, angiogenesis, immune pathways, and targeted therapy including VEGF/VEGFR, mTOR/HIF-1, and immune checkpoint pathways

Tumour angiogenesis and targeted therapy. VEGF binds VEGFRs on endothelial cells; bevacizumab blocks the ligand while TKIs block the receptor. Upstream, VHL loss → HIF-1 activation → VEGF transcription. mTOR inhibitors (everolimus, temsirolimus) suppress HIF-1 indirectly. — Brenner & Rector's The Kidney

Summary

Aspect	Key Points
Family	VEGF-A/B/C/D, PlGF
Main receptor	VEGFR-2 (KDR) → tyrosine kinase → pro-angiogenic signalling
Primary inducer	Hypoxia via HIF-1 transcription factor
Physiological roles	Angiogenesis, vascular permeability, endothelial maintenance, lymphangiogenesis
Pathological roles	Tumour angiogenesis, wet AMD, diabetic macular edema, preeclampsia, psoriasis
Therapeutic targets	Anti-VEGF mAbs (bevacizumab), VEGFR mAbs (ramucirumab), TKIs (sunitinib, sorafenib…), intravitreal fragments (ranibizumab)
Key toxicities	Hypertension, proteinuria, TMA, thromboembolism, wound healing impairment

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Case Presentation: Pulmonary Hypertension

Patient Profile

Name: S.M. Age: 34-year-old woman Occupation: Schoolteacher Referral: Cardiology → Pulmonary Hypertension Specialty Centre

Chief Complaint

"I have been getting more and more breathless over the past 18 months, even when walking short distances."

History of Present Illness

S.M. is a 34-year-old woman with no prior cardiac or pulmonary history who presents with an 18-month progressive history of exertional dyspnoea, now present on climbing a single flight of stairs (WHO Functional Class III). She initially attributed her symptoms to deconditioning. Over the past 6 months she has developed:

Exertional pre-syncope on two occasions (dizziness on rapid standing, relieved by sitting)
Non-exertional chest tightness, dull and central
Bilateral ankle oedema, worse in the evenings
Fatigue disproportionate to activity level
No orthopnoea, PND, or cough
No haemoptysis

A delay of approximately 22 months elapsed between symptom onset and specialist referral — consistent with the well-documented mean diagnostic delay of up to 2 years in PAH. — Harrison's Principles of Internal Medicine 22E

Past Medical History

Raynaud's phenomenon (diagnosed age 28) — intermittent bilateral finger colour change in the cold
No prior DVT, PE, or cardiac disease
No connective tissue disease formally diagnosed

Medications

Combined oral contraceptive pill (started age 22)
Nifedipine 10 mg PRN for Raynaud's

Family History

Paternal aunt: died of "heart failure of unknown cause" at age 41

Social History

Non-smoker
Occasional alcohol
No illicit drug use (specifically no appetite suppressants, methamphetamine, or cocaine)

Review of Systems

Arthralgia in small joints of hands — mild, non-deforming
Dry eyes and dry mouth (intermittent)
No skin rash or photosensitivity

Physical Examination

Vital Signs:

Parameter	Value
BP	108/72 mmHg
HR	96 bpm, regular
RR	18/min
SpO₂	94% on room air
Temperature	37.0°C

General: Thin, anxious-appearing woman, not in acute distress at rest

Cardiovascular:

Elevated JVP (4 cm above sternal angle) with prominent a-wave
Left parasternal heave (right ventricular hypertrophy/dilatation)
Loud P₂ (palpable pulmonary component of S₂)
Right ventricular S₄ gallop at left lower sternal border
Pansystolic murmur at left lower sternal border, increasing with inspiration — consistent with tricuspid regurgitation
No peripheral clubbing

Respiratory:

Lungs clear to auscultation bilaterally
No wheeze, crackles, or pleural rub

Abdomen:

Hepatomegaly (liver edge 3 cm below costal margin)
No ascites

Extremities:

Bilateral pitting oedema to mid-shin
Cool peripheries; Raynaud's changes bilaterally

Skin/Joints:

No sclerodactyly, telangiectasiae, or skin thickening
No synovitis

Investigations

Bloods

Test	Result	Reference
FBC	Normal	—
U&E	Normal	—
LFTs	Mildly elevated ALP/bilirubin	—
BNP	820 pg/mL	<100 pg/mL
Anti-nuclear antibody (ANA)	Positive 1:160, speckled	Negative
Anti-centromere antibody	Positive	Negative
dsDNA, Ro/La	Negative	—
HIV serology	Negative	—
LFTs/hepatitis serology	Normal; Hep B/C negative	—
Thyroid function	Normal	—
Thrombophilia screen	Negative	—

The presence of Raynaud's phenomenon + anti-centromere antibody + arthralgia raises strong suspicion for limited systemic sclerosis (lcSSc/CREST syndrome), a major risk factor for PAH (Group 1 PAH — connective tissue disease-associated).

ECG

Sinus tachycardia
Right axis deviation
Right ventricular hypertrophy (R > S in V1; S1Q3T3 pattern)
P pulmonale (tall, peaked P waves in II)

Chest X-Ray

Enlarged main pulmonary artery and bilateral hilar prominence
Oligaemic peripheral lung fields ("pruning" of peripheral vessels)
Mild cardiomegaly — right heart predominant
No parenchymal infiltrates; no pleural effusion

Pulmonary Function Tests

Parameter	Result	% Predicted
FEV₁	2.4 L	88%
FVC	3.0 L	90%
FEV₁/FVC	0.80	Normal
TLC	4.8 L	86%
DLCO	52%	Reduced

Normal spirometry + normal lung volumes + reduced DLCO in isolation — this pattern should always prompt evaluation for pulmonary vascular disease. — Harrison's Principles of Internal Medicine 22E

Transthoracic Echocardiogram (TTE)

Right ventricular dilatation and hypertrophy with reduced systolic function (TAPSE 14 mm)
Interventricular septal flattening ("D-sign") — consistent with right ventricular pressure overload
Estimated RVSP: 72 mmHg (via tricuspid regurgitation jet velocity)
Left ventricular size and function: normal (EF 62%)
No intracardiac shunt on bubble study
Small pericardial effusion

CT Pulmonary Angiography (CTPA)

Enlarged main pulmonary artery (diameter 34 mm; >29 mm is abnormal)
No filling defects — chronic thromboembolic disease excluded
No significant parenchymal lung disease; no honeycombing
No evidence of interstitial fibrosis

Right Heart Catheterisation (RHC) — Gold Standard

Haemodynamic Parameter	Value	Threshold
Mean pulmonary artery pressure (mPAP)	46 mmHg	>20 mmHg = PH
Pulmonary capillary wedge pressure (PCWP)	9 mmHg	≤15 mmHg = precapillary
Pulmonary vascular resistance (PVR)	7.2 Wood units	>2 WU = precapillary PH
Cardiac output (thermodilution)	3.8 L/min	Low-normal
Cardiac index	2.2 L/min/m²	Borderline low

RHC confirms precapillary pulmonary hypertension: mPAP >20 mmHg + PCWP ≤15 mmHg + PVR >2 WU — consistent with Group 1 PAH (connective tissue disease-associated). Updated 2022 diagnostic thresholds now define PH as mPAP >20 mmHg (previously ≥25 mmHg) to enable earlier detection. — Harrison's 22E

Vasoreactivity Testing (inhaled NO):

mPAP fell by only 4 mmHg → Non-responder (negative test; response requires ≥10 mmHg fall to <40 mmHg with maintained/increased CO)

Diagnosis

Pulmonary Arterial Hypertension (PAH) — Group 1 Associated with limited systemic sclerosis (lcSSc) WHO Functional Class III

Pathophysiology Summary

In this patient, PAH arises from the interplay of immune-mediated endothelial injury (SSc) and intrinsic vascular biology:

Endothelial dysfunction — autoimmune-driven injury to pulmonary arteriolar endothelium disrupts the balance between vasoconstrictors (endothelin-1, thromboxane A₂) and vasodilators (prostacyclin, nitric oxide)
Obliterative arteriopathy — apoptosis resistance + smooth muscle cell and fibroblast proliferation → hypertrophic and plexogenic remodelling of distal pulmonary arterioles → reduced vascular compliance
In situ thrombosis — platelet activation and reduced prostacyclin promote microthrombus formation within remodelled arterioles
Extracellular matrix expansion — integrins, nonfibrillar collagens, and fibronectin further stiffen affected vessels
Genetic predisposition — mutations in BMPR2 (BMP receptor 2, within the TGF-β superfamily) are the most common hereditary driver; the family history of early cardiac death is relevant here. Sporadic BMPR2 mutations account for a significant proportion of apparently idiopathic cases
Right ventricular failure — sustained pressure overload → RV hypertrophy → dilation → reduced cardiac output → systemic venous congestion (elevated JVP, hepatomegaly, peripheral oedema)

"Apoptosis resistance, cell proliferation, dysregulated metabolism, and increased oxidant stress involving pulmonary vascular cells, pericytes, and adventitial fibroblasts underlie the pathogenesis of PAH." — Harrison's 22E

Management

General Measures

Supplemental oxygen to maintain SpO₂ ≥90–92% (hypoxia is a potent pulmonary vasoconstrictor)
Diuretics (furosemide) for RV volume overload — oedema and hepatic congestion
Anticoagulation: warfarin (INR 1.5–2.5) — evidence-based for idiopathic/heritable PAH; more variable in CTD-PAH
Exercise rehabilitation — supervised; avoid strenuous exertion
Vaccination: influenza, pneumococcal, COVID-19, RSV
Avoid pregnancy — carries very high mortality in PAH
Cease oestrogen-containing OCP — oestrogens are a risk factor for PAH

Pharmacologic Treatment

This patient is a vasoreactivity non-responder — calcium channel blockers are not indicated. All 14 FDA-approved PAH therapies target three pathways:

1. Endothelin Receptor Antagonists (ERAs) — Endothelin Pathway

Drug	Route
Ambrisentan	Oral
Bosentan	Oral
Macitentan	Oral

Endothelin-1 is a potent vasoconstrictor and mitogen overproduced in PAH. ERAs block ET_A and/or ET_B receptors.

2. PDE-5 Inhibitors / sGC Stimulators — Nitric Oxide Pathway

Drug	Route
Sildenafil	Oral
Tadalafil	Oral
Riociguat (sGC stimulator)	Oral

Enhance cGMP-mediated vasodilation in pulmonary vasculature.

3. Prostanoids — Prostacyclin Pathway

Drug	Route
Epoprostenol	IV (continuous) — gold standard for severe disease
Treprostinil	IV/SC/inhaled/oral
Iloprost	Inhaled
Selexipag (IP receptor agonist)	Oral

Replaces deficient prostacyclin; produces vasodilation, antiproliferation, and platelet inhibition.

4. Novel: Activin Signal Inhibitor

Sotatercept — rebalances TGF-β/BMPR2 signalling; approved 2024 as add-on therapy

Recommended initial strategy for this patient (WHO FC III, non-vasoreactive):

Dual oral combination therapy: ERA (e.g., macitentan) + PDE-5 inhibitor (e.g., tadalafil) initiated at a PH specialty centre, with planned escalation to triple therapy (adding a prostanoid) if insufficient response at 3–4 months.

Monitoring

6-minute walk distance (6MWD) — functional status marker
BNP/NT-proBNP — right ventricular stress marker; target normalisation
Echocardiography — RV function, RVSP trend
Repeat RHC at 3–6 months to assess haemodynamic response
WHO functional class reassessment at every visit

Prognosis

Among optimally treated PAH patients:

Timepoint	Survival
1 year	~82%
3 years	~67%
5 years	~58%

Adverse prognostic indicators in this patient: WHO FC III, reduced cardiac index, elevated BNP, pericardial effusion, RV dysfunction.

Escalation / Refractory Disease

Lung transplantation (bilateral) — referral should be considered early given young age and CTD-associated PAH
Atrial septostomy — palliative in refractory RV failure

Clinical Pearls

Key Point	Detail
Diagnostic delay	Mean delay of ~2 years is common; maintain suspicion in young women with unexplained dyspnoea
New mPAP threshold	PH now defined as mPAP >20 mmHg (was ≥25 mmHg) — enables earlier diagnosis
PVR threshold	Precapillary PH: PVR >2 Wood units (was ≥3 WU)
Isolated reduced DLCO	Normal spirometry + normal lung volumes + low DLCO → always investigate pulmonary vasculature
BMPR2	Most common hereditary PAH gene; family history of early cardiac death should raise suspicion
Vasoreactivity	Only ~10–15% of PAH patients are responders; non-responders should NOT receive CCBs
Oestrogens	OCP is a modifiable risk factor — must be stopped

Sources: Harrison's Principles of Internal Medicine 22E (2025), Chapters 294–295

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What's in the Presentation (14 Slides)

#	Slide Title
1	Title Slide — dark blue, branded
2	Patient Profile & Chief Complaint — timeline with diagnostic delay highlight
3	History — HPI, PMH, medications, family/social history
4	Physical Examination — vitals table + key cardiovascular findings
5	Investigations: Bloods & ECG — autoimmune panel, BNP, ECG findings
6	Investigations: Imaging & PFTs — CXR, CTPA, PFT table with DLCO pearl
7	Right Heart Catheterisation — haemodynamics table + updated thresholds
8	Diagnosis — WHO Group classification table
9	Pathophysiology — 5-step cascade diagram + BMPR2 genetics
10	General Management — O₂, diuretics, anticoagulation, lifestyle
11	Pharmacologic Treatment — 3 pathways (ERA / PDE-5i / Prostanoids)
12	Novel Therapy & Prognosis — Sotatercept, lung transplant, survival table
13	Clinical Pearls — 8 key take-home points in card format
14	Case Summary — full domain-by-domain recap table

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Structured tables, bullet boxes, and pathway diagrams
Footer on every slide citing Harrison's 22E

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Vascular Endothelial Growth Factor (VEGF)

1. The VEGF Family

2. Receptors

3. Physiological Functions

4. Regulation: The HIF-1 / Hypoxia Axis

5. VEGF in Pathology

Tumour Angiogenesis

Preeclampsia

Diabetic Macular Edema & Wet AMD

Psoriasis

6. VEGF-Targeted Therapies

6a. Antibodies Against VEGF Ligand

6b. Antibodies Against VEGFR

6c. Small Molecule VEGFR Tyrosine Kinase Inhibitors (TKIs)

7. Adverse Effects of VEGF Inhibition

8. Pathway Diagram

Summary

Case Presentation: Pulmonary Hypertension

Patient Profile

Chief Complaint

History of Present Illness

Past Medical History

Medications

Family History

Social History

Review of Systems

Physical Examination

Investigations

Bloods

ECG

Chest X-Ray

Pulmonary Function Tests

Transthoracic Echocardiogram (TTE)

CT Pulmonary Angiography (CTPA)

Right Heart Catheterisation (RHC) — Gold Standard

Diagnosis

Pathophysiology Summary

Management

General Measures

Pharmacologic Treatment

1. Endothelin Receptor Antagonists (ERAs) — Endothelin Pathway

2. PDE-5 Inhibitors / sGC Stimulators — Nitric Oxide Pathway

3. Prostanoids — Prostacyclin Pathway

4. Novel: Activin Signal Inhibitor

Monitoring

Prognosis

Escalation / Refractory Disease

Clinical Pearls

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What's in the Presentation (14 Slides)

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