Secondary Hypertension Flashcards
Determinants of secondary
hypertension
(< 10% of cases with high blood pressure) (6)
- 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
Glomerulonephritis
Inflammation of
glomeruli
Endocrine Hypertension (6)
- 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)
Drug-induced hypertension (11)
NSAIDs
Oral contraceptives
Alcohol
Cocaine
Cyclosporin, tarcolimus (immunosuppressive)
Erythropoietin
Glucocorticoids
Liquorice (↓K+), Carbenoxolone
Ginseng, yohimbin
Tyramine and MAO inhibitors (antidepressants)
Angiogenesis inhibitors
Kidney cancer
highly angiogenic + metastatic tumour
Angiogenesis (2)
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)
Anti-angiogenic-induced hypertension (2)
- 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
What is the evidence that VEGF is involved
in maintaining vascular tone (2)
Hypertension: low VEGF (dec. chances)
vs
Hypotension: High VEGF (inc. chances)
VEGF signalling (4)
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
Comparison of hemodynamic effects of Flt-SM, KDR-SM, and VEGF in conscious rats
VEGF signalling pathways
Anti-angiogenic therapy - 3 ways (3)
Anti-VEGF - Avastin
Receptor Tyrosine Kinase Inhib - Sunitinib/ Sorafenib
mTOR - Everolimus/Temsirolimus
Anti-angiogenic therapy: site of action
Anti-angiogenic-induced hypertension
(6)
- 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!
Management of anti-angiogenic therapy-induced
hypertension
Mechanisms of anti-angiogenic-induced
hypertension (4)
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
Pregnancy related hypertension facts (6)
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
Nail bed capillaroscopy (2)
Capillary density as a measurement
of vascular rarefaction
normal vs avascular
Capillary rarefaction in preeclampsia (4)
- 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)
VEGF normal and abnormal homeostasis (2)
VEGF is required for maintenance of normal vascular homeostasis
Impaired VEGF signalling mediated by presence of antiangiogenic factors leads to EC dysfunction
Summary: role of VEGF in vessel tone (3)
- 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
