Secondary Hypertension

Question 1

Definition of Secondary Hypertension

Answer 1

sustained elevation of systolic and diastolic blood pressure > 140/90 mmHg

Question 2

Causes of Secondary Hypertension

Answer 2

primary (idiopathic/essential)
No identifiable cause

secondary to:
renal disease (salt/H2O imbalance)
adrenal tumours (aldosterone)
Can be a source of hormones that induce vasoconstriction
aortic coarctation (narrowing of aorta)
Steroids, Rx

Question 3

Determinants

Answer 3

Around 90 of hypertension is due to primary hypertension. SO < 10% of cases with high blood pressure are secondary causes.

These are underlying diseases that we can identify and hopefully cure, by removing the underlying cause:

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 disorders

Question 4

Glomerulonephritis- renal disease

Answer 4

It essentially is Inflammation of glomeruli

There is acute infectioin. But can also have chronic infection – some autoimmune disease can induce this inflammatory disease.

The gross features:
It is a contracted granular type of pathology of the kidney
The kidney is shrunk in size, but also has a granular morphology due to cortical atrophy of the kidney.
There will be disease mechanisms that induce this atrophy

Ultimately this will cause fluid balance issues
There will be swelling in the lower limbs

This is due to infection and inflammation of the glomeruli within the kidney.

Question 5

Endocrine Hypertension (adrenal cortex)

Answer 5

Within the adrenal cortex there can be:

Adrenal adenoma producing aldosterone (Conn’s syndrome)
Mostly benign tumours.
Can increase blood pressure

Adrenal hyperplasia
Another type of benign

Cushing’s syndrome
This is due to a pituitary adenoma
Excess cortisol increasing adrenalin’s vasoconstrictive effect

Question 6

Endocrine Hypertension (adrenal medulla)

Answer 6

Adrenal medulla
Pheochromocytoma (adrenalin secreting tumour)
This is another benign tumour, but because they secrete these hormones they can have adverse effects in inducing secondary hypertension.

So these tumours can be removed and ultimately cure these patients of seconcary hypertension.

Question 7

Drug-induce hypertension

Answer 7

NSAIDs
Oral contraceptives
Alcohol
Cocaine
Cyclosporin, tarcolimus (immunosuppressive)
Erythropoietin – can increase BP level by balance of vasodilators and vasoconstrictors
Glucocorticoids
Liquorice (can ↓K+ levels), Carbenoxolone is the active compound
Ginseng, yohimbin
Tyramine (found in strong cheeses) and monoamine oxidase MAO inhibitors (antidepressants)
Angiogenesis inhibitors – will focus on this
VEGF family has been targeted for cancer patients, a lot of these patients have hypertension. It has informed us about the role of VEGF in regulating vascular tone in vivo.

Question 8

VEGF inhibitors: Kidney cancers

Answer 8

There are certain types of cancer such as kidney cancer/renal cell carcinoma.
These types of tumours are highly angiogenic and metastatic tumours.
They induce new blood vessel growth. These blood vessels allow for increased nutrience and oxygen to reach the tumours. They are also a route by which tumours or cells can escape – metastatic cells can escape from the tumours by new blood vessel growth.

So induction of new blood vessels is an aggressive type of tumour, and is also a way that tumours can increase their size and how to metastasise.

There are drugs that try to inhibit blood vessel growth. These are called anti angiogenic drugs.

Question 9

VEGF inhibitors: anti-angiogenic induced hypertension

Answer 9

Angiogenesis – is the formation of new blood vessels. It is essential for solid tumour growth and metastasis

There are mediators, cytokines and growth factors the induce new blood vessel growth, one is called VEGF.
So angiogenesis regulated by proangiogenic soluble mediators such as vascular endothelial growth factor (VEGF)
So VEGF is a proangiogenic molecule that gets secreted by the tumour, it acts on nearby capillaries causing the capillaries to grow and migrate forming new vessels around the tumour.

So a lot of VEGF secretion can be detrimental to the patient as the cancer can grow and metastasise.

Antiangiogenic drugs that block the VEGF signalling pathway prolong progression free survival in several cancers and are now in broad clinical use
Is not a cure, but extends life.

In these patients, Hypertension is the most common CVS toxicity of this therapeutic class affecting between 19%-67% of patients
This is increasing with the increasing potency of the new VEGF inhibitors.

Question 10

evidence that VEGF is involved in maintaining vascular tone

Answer 10

When VEGF is inhibited, (LOW VEGF) we see cases of hypertension
Have seen this also in patients on anti VEGF drugs
But there is also a study in healthy patients that shows by giving a VEGF inhibitor, it causes an increase in BP -> hypertension

Conversely:

When there is HIGH VEGF
We see a dramatic decrease in blood pressure -> hypotensive effect.
VEGF receptor 2 is predominantly involved in this effect

Question 11

VEGF signalling

Answer 11

The primary receptors for the VEGF family are:
VEGF receptor 1
VEGF receptor 2
There is also a VEGF receptor 3
These receptors sit on the endothelial cell and also have co receptors

There is also not just one ligand, there is not just one VEGF, there are different family members of these growth factors:
Most described protein: VEGFA
There is also VEGFB, VEGFC, VEGFD
They can tissue specific activity
PLGF (placental growth factor) is another family member.

The VEGF ligands will bind to the receptors and initiate new blood vessel growth via:
Angiogenesis – new blood vessel formation from pre existing vessels
And also Vasculogenesis – de novo type of blood vessel growth where you see stem cells developing into new vessels, this is in the developing embryo

There is also lymphangiogenesis, VEGFR3 is involved in the signalling for this.

Question 12

What is KDR

Answer 12

VEGF receptor 2

Question 13

Summary of VEGF signalling

Answer 13

VEGF (VEGF-A) is the main component binds VEGFR-1 (sometimes called FLT-1) and VEGFR-2 (sometimes called FLK-1 or KDR)
Note: VEGFR-2 has predominant role in cell signalling
So VEFG-a binds to VEGFR-2

Neuropilins (NRP1, NRP2) are VEGF co-receptors but can also signal independently

VEGF-B has restricted angiogenic activity e.g. is more expressed in the heart

VEGF-C and VEGF-D involved in vasculogenesis and lymphangiogenesis

Question 14

How do we know that VEGF has an effect on BP

Answer 14

When you give VEGF, you have a hypotensive effect. BP drops
Can also duplicate the effect giving soluble receptor

Study in rats:

Administering VEGF-R1 induces a drop in BP
VEGF-R2 induces a drop in BP
VEGF administration induces the largest drop in BP

So this shows that if you add VEGF or its receptor you can induce a drop in BP. The mean arterial pressure will decrease

Also looked at relaxation.
If you add VEGF there is a maximal relaxation of the vessel – this shows that VEGF is involved in relaxation
If you add VEGF-R2 (KDR) – it also a significant relaxation of the vessel
And with VEGF-R1 there is also relaxation

BUT, when you add VEGF and the vessel is denuded (the endothelial cell layer has been removed) all of the relaxation inducing effects of VEGF are completely abolished.
This shows how important the endothelial cell is to this effect, as without it there is no relaxation of the vessel.

Question 15

Likely mechanism by which VEGF regulates vessel tone

Answer 15

VEGF binds to its receptor VEGF receptor 2
The endothelial cell is required to induce the relaxation effect by inducing nitric oxide.
This is one possible mechanism by which VEGF signals to induce NO
NO then exerts its vasodilatory effect on the SMCs

When VEGF binds ot its receptor there is multiple pathways that it regulates:
Inducing NO – can increase permeability
Can also induce angiogenesis through PIP2 Ca signalling
Can also induce the PKB pathway to increase cell survival, so apoptosis is reduced in the presence of VEGF
Can also induce the Ras Raf MEK MAPK signalling pathway which will increase gene expression, transcription and cell proliferation, and can induce angiogenesis

Therefore, by blocking VEGF signalling, a lot of these processes will be switched off, so by blocking VEGF biding you:
Inhibit cell proliferation
Inhibit angiogenesis
Prevent NO induction on the SMC relaxation – will increase vascular tone

Question 16

Anti-angiogenic therapy

Answer 16

Anti-VEGF
There is a drug or antibody that binds to the VEGF molecule itself.
Eg Avastin
This will prevent VEGF from binding to its receptor

Receptor tyrosine kinase inhibitors
Small molecule inhibitors will target the VEGF receptors
Eg: Sunitinib and Sorafenib

mTOR
Can prevent VEGF synthesis
Compounds that inhibit mTOR
mTOR is a protein within a tumour cell that produced VEGF, you can block it with drugs and precent VEGF being synthesised.
Eg: Everolimus and Temsirolimus

These are used to treat cancers.

Question 17

Anti-angiogenic therapy: site of action

Answer 17

When you have a tumour cell and a endothelial cell in close proximity, the tumour cell will produce VEGF (the cytokine) as it has altered signalling, there are alterations in the cell that causes upregulation of VEGF.
The VEGF will be secreted from the tumour and will bind to its receptor on the endothelial cell, mostly VEGF receptor 2.
It then can mediate the effects mentioned above.

Avastin – antibody that binds to VEGF, prevents it from binding to its receptor
Sunitinib and Sorafenib – target the receptors
Everolimus and Temsirolimus work on the mTOR signalling pathway inside the tumour cell and prevents VEGF from being produced.

Question 18

Anti-angiogenic induced hypertension

Answer 18

High potency VEGFIs e.g. axitinib – see a 90% incidence of hypertension
So the high potency VEGF inhibitors induce the greatest hypertensive effect.

On-target effect (as opposed to off target side effect)
The effect is specific to the target

It is also called Mechanism-dependent on-target toxicity
There is an adverse effect (hypertension) but it is due to the mechanism of action of the drug. So it isn’t a non specific effect

Removal of anti-angiogenic (anti-VEGF drug) leads to rapid decrease of blood pressure
This led to idea that hypertension may be a biomarker for efficacy of anti-cancer response – predictive of superior outcomes?
Hypertension still needs to be managed in these patients!

Question 19

Management of anti-angiogenic therapy induced hypertension

CASE: ASYMPTOMATIC, SUNITINIB-INDUCED HYPERTENSION

Answer 19

56y Male with renal cell carcinoma:

Is in sunitinib – a VEGF receptor inhibitor
Patient is given sunitinib and you see a increase in systolic and diastolic BP
It is managed with classic anti hypertensive medication:
ACE inhibitors
Beta blockers
Thiazides – diuretic

Question 20

Mechanisms of anti-angiogenic-induced hypertension

Answer 20

Not yet known:
Possibly:
It is likely that it is due to downregulation of NOS/NO. So when you inhibit the effects of VEGF on NO, you prevent vasodilation so have increased hypertension/

Could also be: if you inhibit VEGF signalling, then you can have effects on vasoconstrictors. So can alter the balance of vasoconstrictors and vasodilators.
Can increase ET-1 -> vasoconstriction

Could be due to the increase bioavailability of ROS, which increases vasoconstriction and vascular remodelling

Could be: when you significantly inhibit VEGF, as it is important for maintaining endothelial cell survival, if you inhibit it you can induce endothelial cell dysfunction or cell apoptosis which can lead to vessel density reduction, this can increase peripheral resistance -> hypertension.

Question 21

Pregnancy related hypertension

Answer 21

Most common complication of pregnancy
It is significant as it is the leading cause of morbidity and maternal mortality

These patients can have:
Chronic hypertension – already
Or they can have a pregnancy induced hypertension: Gestational hypertension or pregnancy-induced hypertension (PIH)
Diagnosis is characterised by New onset without the presence of protein in the urine

Preeclampsia
Hypertension and proteinuria (protein in urine)
The preeclampsia can lead to eclampsia:
Eclampsia
Hypertension induced onset of seizures
This can be lethal

Question 22

Nail bed capillaroscopy

Answer 22

Capillary rarefaction - Capillary density as a measurement of vascular rarefaction

Capillary density measurement is a potential biomarker, but also mediator of hypertension seen in pregnant women.

Vascular rarefaction – if you see a reduction in vessel density, the resistance will be increased in the vasculature, this can induce increases in BP.

The peripheral vascular density can be measured through nail bed capillaroscopy
Can be normal vascular density or reduced number (avascular)

Question 23

Capillary rarefaction in preeclampsia

Answer 23

We know that capillary rarefaction (a reduction in vessel density) is associated with preeclampsia

Can Nail bed capillaroscopy be used as a predictor of preeclampsia in pregnancy?
BUT not yet clear whether it is cause or effect

We know that this disorder is associated with altered VEGF signalling.
Associated with soluble circulating decoy receptors for VEGF receptor 1 (sFLT-1) and others (e.g. sENG)
We can see that in these patients they have soluble forms of the receptor
Note: you can have receptors that are integrated into the cell membrane, but you can also have cleaved forms of the receptor known as soluble forms of the receptor. They will circulate in the plasma of patients and will bind to VEGF, it is often called a decoy receptor.
It often prevents VEGF from signalling onto the endothelial cell membrane, so they have an inhibitory effect.

SO… it is possible that there are increased levels of soluble VEGF receptor 1 (s-FLT-1)
It will bind to VEGF
Will prevent VEGF signalling
Ultimately will result in an increase BP in these women

Question 24

Pre-eclampsia vs normal

Answer 24

VEGF is required for maintenance
of normal vascular homeostasis. Endothelial health and vascular relaxation.

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

In preeclampsia there is abnormal expression of the soluble VEGF receptor 1 (sFLT-1). This receptor is a decoy, it will bind to circulating VEGF and prevent it from further binding to the cell membrane associated receptor. It is having an anti-angiogenic effect. So when you stop VEGF signalling, you don’t have relaxation and you can have endothelial ysfunction leading to a reduction in cell numbers (cell death) and impaired relaxation. This can lead to increased vasoconstriction and increased blood pressure.

Question 25

why is there abnormal soluble receptors for VEGF increased in the maternal plasma

Answer 25

there are a number of mechanisms, there are mediators that potentially increase the levels of the soluble decoy receptor in the maternal plasma. It potentially comes from the placenta due to placental ischaemia.
Some of the potential mediators for increased expression of the soluble FLT-1 are:
HIF-1a
TNF-a
AT1-AA

So the increase of soluble FLT-1 which has been document in women
It will bind to VEGF in the plasma and prevent VEGF from signalling as it normally would
This results in endothelial cell dysfunction.
There is an imbalance in vasodilators and vasoconstrictors, which can ultimately result in hypertension in these women.

This is a proposed mechanism by which we see hypertension an pre-eclampsia in pregnant women.