Secondary Hypertension

Question 1

Determinants of secondary
hypertension
(< 10% of cases with high blood pressure) (6)

Answer 1

• Renal diseases (e.g. Glomerulonephritis, diabetic nephropathy)
• Vascular causes (e.g. Renal artery stenosis)
• Hormonal abnormalities (e.g. Conn’s syndrome, Cushing’s
  syndrome, Pheochromocytoma)
• Drugs (Contraceptive pill; liquorice)
• Pregnancy (Pre-eclampsia)
• Genetic disorder

Question 2

Glomerulonephritis

Answer 2

Inflammation of
glomeruli

Question 3

Endocrine Hypertension (6)

Answer 3

• Adrenal cortex:
  – Adrenal adenoma producing aldosterone
  (Conn’s syndrome)
  – Adrenal hyperplasia
  – Cushing’s syndrome excess cortisol increasing adrenalin’s vasoconstrictive effect
• Adrenal medulla
  – Pheochromocytoma (adrenalin secreting
  tumour)

Question 4

Drug-induced hypertension (11)

Answer 4

NSAIDs
Oral contraceptives
Alcohol
Cocaine
Cyclosporin, tarcolimus (immunosuppressive)
Erythropoietin
Glucocorticoids
Liquorice (↓K+), Carbenoxolone
Ginseng, yohimbin
Tyramine and MAO inhibitors (antidepressants)
Angiogenesis inhibitors

Question 5

Kidney cancer

Answer 5

highly angiogenic + metastatic tumour

Question 6

Angiogenesis (2)

Answer 6

formation of new blood vessels is essential for solid tumour growth and metastasis

Regulated by proangiogenic soluble mediators such as vascular endothelial growth factor (VEGF)

Question 7

Anti-angiogenic-induced hypertension (2)

Answer 7

• Antiangiogenic drugs that block the VEGF signalling pathway prolong progression free survival in several cancers and are now in broad clinical use
• Hypertension is the most common CVS toxicity of this therapeutic class affecting between 19-67% of patients

Question 8

What is the evidence that VEGF is involved
in maintaining vascular tone (2)

Answer 8

Hypertension: low VEGF (dec. chances)
vs
Hypotension: High VEGF (inc. chances)

Question 9

VEGF signalling (4)

Answer 9

image
* VEGF (VEGF-A) is the main component binds VEGFR-1
(FLT-1) and VEGFR-2 (FLK-1) with VEGFR-2 having predominant role in cell signalling

• Neuropilins (NRP1, NRP2) are VEGF co-receptors but can
  also signal independently
• VEGF-B has restricted angiogenic activity e.g. in heart
• VEGF-C and VEGF-D involved in vasculogenesis and
  lymphangiogenesis

Question 10

Comparison of hemodynamic effects of Flt-SM, KDR-SM, and VEGF in conscious rats

Question 11

VEGF signalling pathways

Question 12

Anti-angiogenic therapy - 3 ways (3)

Answer 12

Anti-VEGF - Avastin

Receptor Tyrosine Kinase Inhib - Sunitinib/ Sorafenib

mTOR - Everolimus/Temsirolimus

Question 13

Anti-angiogenic therapy: site of action

Question 14

Anti-angiogenic-induced hypertension
(6)

Answer 14

• High potency VEGFIs e.g. axitinib – 90%
  incidence of hypertension
• On-target effect (as opposed to off target side effect)

Mechanism-dependent on-target toxicity

• Removal of anti-angiogenic leads to rapid decrease of BP
• Led to idea that hypertension may be a
  biomarker for anti-cancer response –
  predictive of superior outcomes?
• Hypertension still needs to be managed in
  these patients!

Question 15

Management of anti-angiogenic therapy-induced
hypertension

Question 16

Mechanisms of anti-angiogenic-induced
hypertension (4)

Answer 16

Not yet known!!!!

Possibly:
Downregulation of NOS/NO: dec. vasodilation

Increase ET-1: incr. vasoconstriction

Increase bioavailability of ROS incr.
vasoconstriction, vascular remodeling

EC dysfunction/apoptosis/rarefaction incr. peripheral resistance

Question 17

Pregnancy related hypertension facts (6)

Answer 17

Most common complication of pregnancy

Leading cause of morbidity and maternal mortality

• Chronic hypertension
• Gestational hypertension or pregnancy-induced hypertension (PIH)
  New onset without the presence of protein in the urine
• Preeclampsia
  Hypertension and proteinuria
• Eclampsia
  Hypertension induced onset of seizures

Question 18

Nail bed capillaroscopy (2)

Answer 18

Capillary density as a measurement
of vascular rarefaction

normal vs avascular

Question 19

Capillary rarefaction in preeclampsia (4)

Answer 19

• Capillary rarefaction is associated with
  preeclampsia
• Can it be used as a predictor of
  preeclampsia in pregnancy?
• Not yet clear whether it is cause or effect
• Associated with soluble circulating decoy receptors for VEGF (sFLT-1) and others
  (e.g. sENG)

Question 20

VEGF normal and abnormal homeostasis (2)

Answer 20

VEGF is required for maintenance of normal vascular homeostasis

Impaired VEGF signalling mediated by presence of antiangiogenic factors leads to EC dysfunction

Question 21

Summary: role of VEGF in vessel tone (3)

Answer 21

• Hypertension occurs in the vast majority of
  patients treated with anti-angiogenic therapy with VEGF inhibitors
• A reduction in the density of capillaries, likely due to diminished VEGF signalling, is also strongly associated with women who
  subsequently develop preeclampsia
• These two pieces of clinical evidence suggest that VEGF is involved in the maintenance of vessel tone in the adult