Treatment of Cardiac Amyloidosis

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Treatment of all types of amyloidosis is currently based on the following principles:

  1. Reducing the supply of amyloid forming precursor proteins.
  2. Supporting the function of organs containing amyloid.

SAP scans in thousands of patients with various forms of amyloidosis have shown that when amyloid precursor protein supply is controlled:

  • existing amyloid deposits often regress (become smaller)
  • new amyloid deposits stop appearing
  • organ function is often preserved and may also recover

Amyloid specific treatment

AL amyloid in the heart

Treatment of AL amyloidosis is directed towards the abnormal plasma cells. Some of the drugs must be used cautiously when there are AL amyloid deposits in the heart. Doctors take into account the presence of amyloid deposits in the heart when choosing treatment regimens.

 

ATTR amyloid in the heart

Liver transplantation

Liver transplantation is not a treatment option for patients with senile systemic amyloidosis (wild type ATTR amyloidosis).

Since most of the TTR in the bloodstream is made in the liver,  Liver transplantation may be a treatment option for some patients with FAP. The liver which makes the abnormal “variantTTR is removed and replaced by a donor liver making normal, “wild type” TTR. The aim is to prevent the formation of further amyloid deposits by reducing the supply of the amyloid-forming precursor TTR.
Over the last 20 years, liver transplantation has been performed in hundreds of patients with FAP around the world. In many cases this has been successful, leading to stabilisation of disease. Success is greatest when transplantation is performed:

  • early in the course of disease before there has been too much damage to the nerves or the heart
  • in younger patients
  • in patients with the TTR Val30Met variant

Unfortunately amyloid deposits in the heart sometimes continue to progress even after liver transplantation. It seems that amyloid deposits composed of abnormal (variant) TTR, present before liver transplantation, act as a template encouraging deposition of normal TTR as amyloid. Thus the normal TTR protein (“wild type” TTR) produced by the new liver builds up on top of the existing ‘variantTTR amyloid deposits. This problem has appeared most often in older patients with variants other than TTR Val30Met.

Heart transplantation

Combined heart and liver transplant has been performed in a few dozen patients with FAP around the world. This operation is only an option for a minority of patients, and it carries significant risks.

Most patients with senile systemic amyloidosis are too elderly to undergo a heart transplant. The risk of complications from this major operation is high with advanced age. But heart transplantation may be an option for younger, otherwise healthy patients with this condition. Heart transplantation may very rarely be an option for a patient who presents at an unusually young age (before 60 years) with the disease.

Treatment of the symptoms of cardiac amyloidosis

All types of amyloid deposits in the heart (AL, ATTR and other rare hereditary types) cause the heart to stiffen which can lead to symptoms of heart failure. Patients can benefit from supportive treatment measures for heart failure, as described below. However many standard medications used for heart failure are not helpful for patients with cardiac amyloidosis.

Fluid balance – the 3Ds

Patients with cardiac amyloidosis should limit their fluid intake

This advice is extremely important, but is often overlooked.

drinking

The most important principle of treatment for cardiac amyloidosis is strict fluid balance control. Specialist heart failure nurse involvement may help patients to achieve this.

When there is cardiac amyloidosis, the heart may be too stiff to pump the blood efficiently around the body. This can lead to fluid build- up, causing leg swelling (oedema) and breathlessness due to fluid in the lungs.  This problem is exacerbated if the patient drinks too much fluid.

Fluid excess can be avoided by careful attention to the 3 Ds:

1. Diet
2. Diuretics
3. Daily weights

1. Diet:

saltFluid intake should be steady and should usually not exceed 1.5 litres per day.

Salt intake should be limited. This includes attention not just to salt added to the food from the salt pot, but also to food with high salt content such as crisps, bacon, canned meats, sausages, canned soups and smoked fish. It can be very helpful to meet with a dietician for precise and personalised dietary advice.

2. Diuretics:

Doctors will often prescribe diuretics (water tablets) which increase the amount of urine produced and help the body to lose excess salt and water in the urine. This can help to reduce ankle swelling and breathlessness. Diuretics prescribed may include furosemide and spironolactone.  Taking these drugs is not a substitute for avoidance of excessive dietary salt and water.

Patients should follow their doctor’s advice carefully regarding the dose of diuretic and the time of day when the tablet should be taken.

3. Daily weights:

Some patients benefit from recording their weight regularly, usually daily or weekly. It is important that weight should be measured consistently- using the same scales, at the same time of day. This is usually best done first thing in the morning after passing urine, just wearing underclothes. Several litres of fluid can accumulate in the body without it being very noticeable. An increase in weight can be an early sign of fluid excess. The doctors or nurse can then recommend appropriate measures such as increased diuretic dose, before the patient even feels unwell because of the fluid overload.

Support stockings can be helpful for patients with leg oedema (swelling in ankles and lower legs).

Blood pressure

Careful control of high blood pressure is important in patients with amyloid deposits affecting the kidneys. However, certain blood pressure lowering drugs should be avoided if there is amyloid affecting the heart. The drugs which are most commonly used in heart failure due to other causes may actually lead to a worsening of heart failure due to amyloidosis.

In patients with low blood pressure, drugs such as fludrocortisone or midodrine may help to maintain blood pressure and allow higher diuretic doses.

Some patients  may experience light-headedness, fatigue on minimal exertion or fainting due to drops in blood pressure. They may benefit from instruction in how to change position carefully from lying to sitting, sitting to standing and standing to walking.

Special medication considerations

Some medications reduce the already low blood pressure in patients with cardiac amyloidosis and can actually worsen the symptoms. Others may cause toxicity in the setting of amyloidosis.

The following drugs should be used with caution:

  • calcium channel blockers
  • digoxin
  • angiotensin converting enzyme (ACE) inhibitors
  • angiotensin receptor blockers
  • beta blockers

If you are concerned, ask your doctor whether any of the medicines you are taking interact. Follow your doctor’s advice carefully and take the medicines your doctor prescribes for you.

Under certain circumstances some other treatments may be helpful. For example:

  • Alpha agonist drugs such as midodrine may help to maintain blood pressure and allow higher diuretic doses.
  • In some cases anticoagulation (warfarin) may be recommended.
  • Pacemakers may be recommended if there is a slow heart rate.

Drug interactions

It is very important that patients tell their doctors about any drugs they may be taking, including complementary or alternative medications or supplements. Some drugs may interact inside the body and lead either to toxicity due to raised drug levels, or lack of effect due to reduced drug levels.

If patients with amyloidosis become ill or require any treatment for a different condition or surgery it is important to inform the treating doctors so that, if necessary, the NAC doctors can be informed, in order to maintain co-ordinated care.

Surgery and anaesthesia

It is generally advisable for patients with  amyloidosis to avoid undergoing surgery, anaesthesia and other invasive procedures.

If such procedures are necessary, patients should request that the surgeons, anaesthetists and other doctors involved contact the NAC doctors beforehand, to discuss any special considerations involved. For example, it is very important that great care is taken to monitor and maintain blood pressure and fluid balance throughout such procedures. Care should also be taken because of the tendency of tissues with amyloid in them to bleed and to heal poorly.

Pregnancy and fertility

Thalidomide is prescribed for some patients with AL amyloidosis. It is well known to be particularly harmful to a developing foetus. Before the regulatory authorities allowed thalidomide to be licensed for its current uses, very strict conditions were instituted for prescription of this drug, to ensure that there is no chance that it is taken by a pregnant woman. The drug even reaches the sperm in men, so men taking thalidomide must use condoms at all times, if having intercourse with a woman who could become pregnant. All patients taking this drug must follow the regulatory guidelines for prescription of thalidomide.

Many of the other drugs used to treat AL amyloidosis are also dangerous during pregnancy, so women of child-bearing age should use contraception during treatment. These drugs may also damage fertility. Both men and women of child-bearing age should consider options for freezing sperm or eggs before starting these treatments. Doctors at the NAC can refer patients for appropriate counselling regarding these possibilities.

New drugs for amyloidosis

A number of new drugs that may help patients with cardiac amyloidosis are in various stages of development, both in the Wolfson Drug Discovery Unit and elsewhere around the world.

The treatment approach being developed in the Wolfson Drug Discovery Unit in collaboration with GlaxoSmithKline will be applicable to patients with all types of amyloidosis, if it proves safe and effective in humans. Other new drugs in development for ATTR amyloidosis are discussed in the section on ATTR amyloidosis.

These drugs are not yet available, but they do offer hope for the future.

 

 

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