What Is Cardiac Amyloidosis?

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Amyloidosis is a family of disorders in which abnormal proteins, called amyloid proteins, are deposited in various tissues. These amyloid deposits can seriously disrupt the normal functioning of the body’s organs.

In cardiac amyloidosis, amyloid proteins are deposited in the heart muscle. The amyloid deposits make the muscular walls of the heart stiff, which produces diastolic dysfunction. In diastolic dysfunction, the heart is unable to relax normally in between heart beats, so it fills with blood less efficiently.

In addition, the amyloid deposits weaken the ability of the heart muscle to contract normally.

So with cardiac amyloidosis, cardiac function is affected both during diastole (the relaxation phase of the heartbeat) and systole (the contraction phase of the heartbeat)—part of how the heart beats.

As a consequence of these problems with both diastole and systole, heart failure is common with cardiac amyloidosis. In addition, people with this condition tend to develop rather severe cardiovascular instability. Cardiac amyloidosis is a very serious condition that usually reduces life expectancy significantly.

What Causes Amyloidosis?

Several conditions can cause amyloid proteins to accumulate in the tissues. These include:

  • Primary amyloidosis. The name “primary amyloidosis" originally referred to a type of amyloidosis in which no underlying cause could be identified. Today, primary amyloidosis is known to result from a plasma cell disorder. (Plasma cells are the white blood cells that produce antibodies). Basically, it is a form of multiple myeloma. With primary amyloidosis, the abnormal protein that accumulates is called "amyloid light chain," or AL protein. About 50 percent of people with cardiac amyloidosis have primary amyloidosis, with AL-type amyloid deposits. People with this kind of cardiac amyloidosis usually also develop amyloid deposits in their kidneys, liver and intestines.
  • Secondary amyloidosis Secondary amyloidosis occurs in people who have some form of chronic inflammatory disease, especially lupusinflammatory bowel disease, or rheumatoid arthritis. Because of the chronic inflammation, deposits of "amyloid type A protein" (also called AA protein) can become excessive. Secondary amyloidosis most often involves the kidneys, liver, spleen, and lymph nodes. Secondary amyloidosis does not usually affect the heart, however. Only about 5 percent of cardiac amyloidosis is caused by deposits of AA protein.
  • Senile amyloidosis Senile amyloidosis gets its name from the fact that it is almost always seen in older men, most often in men over 70 years of age. In this condition, excessive deposits occur of an otherwise normal protein, called TTR protein, which is produced in the liver. In senile amyloidosis, the TTR protein deposits often are found exclusively in the heart. Senile amyloidosis accounts for about 45 percent of cases of cardiac amyloidosis.

Symptoms of Cardiac Amyloidosis

As mentioned, cardiac amyloidosis affects both the filling of the heart and the pumping of the heart, so it should not be surprising overall cardiac function tends to deteriorate significantly.

The most prominent result of cardiac amyloidosis is heart failure. In fact, symptoms of heart failure—chiefly marked dyspnea and significant edema (swelling)—is what usually leads to the diagnosis of amyloidosis.

In cardiac amyloidosis caused by AL protein (primary amyloidosis), the abdominal organs are often affected in addition to the heart. So these individuals tend to have gastrointestinal symptoms, such as loss of appetite, early satiety, and weight loss. In addition, AL protein deposits also tend to accumulate in small blood vessels, which can cause easy bruising, angina, or claudication (muscle cramping with exertion).

People with cardiac amyloidosis are especially prone to syncope (episodes of loss of consciousness). With amyloidosis, syncope can be an ominous sign, because it tends to indicate that cardiovascular reserve has been stretched nearly beyond its limits. Specifically, people with amyloidosis affecting their heart and blood vessels may not be able to recover from any event that severely challenges the cardiovascular system, even momentarily. Such an event may include a vasovagal episode that might just cause a few moments of dizziness in another person.

So, when sudden death occurs in people with cardiac amyloidosis, sudden cardiovascular collapse is usually the cause.

This is in stark contrast to people who experience sudden death from other kinds of heart disease, in whom a cardiac arrhythmia (especially ventricular tachycardia or ventricular fibrillation) is almost always the cause. Consequently, inserting an implantable defibrillator in people with cardiac amyloidosis often does not prolong survival. When people with cardiac amyloidosis experience syncope, the risk of sudden death within the next several months is high.

With cardiac amyloidosis, amyloid deposits often occur within the heart's electrical conduction system. (Read about the conduction system.) In senile amyloidosis, the TTR-type of protein deposits often lead to significant bradycardia (slow heart rhythm), and require the implantation of a permanent pacemaker. However, with AL-type amyloidosis bradycardia is uncommon, and usually does not lead to a pacemaker.

People with cardiac amyloidosis often tend to form blood clots easily, both in the blood vessels and in the heart, leading to a greatly increased risk of stroke and thromboembolism.

Peripheral neuropathy is also a frequent problem in people with AL amyloidosis.

How Is Cardiac Amyloidosis Diagnosed?

Doctors should consider the possibility of cardiac amyloidosis whenever a person has heart failure for unexplained reasons, especially if dyspnea and edema are the most prominent symptoms.

In a person with new heart failure, the presence of low blood pressure, an enlarged liver, peripheral neuropathy, or protein in the urine, should also bring to mind the possibility of cardiac amyloidosis.

The electrocardiogram in cardiac amyloidosis may show low voltage (that is, the electrical signal is tinier than usual), but it's usually the echocardiogram that provides the best clues to the correct diagnosis.

The echocardiogram often shows thickening of the heart muscle of both ventricles. In addition, the amyloid deposits themselves often create on the echo image a distinctive “sparkling” appearance from within the heart muscle. Blood clots in the heart are also seen fairly frequently.

While the echocardiogram usually leads the way to the diagnosis, pinning down the diagnosis of amyloidosis requires a tissue biopsy that shows amyloid deposits. In people with AL amyloidosis, the biopsy can often be obtained from abdominal fat or from a bone marrow biopsy. However, a cardiac biopsy is needed with TTR amyloidosis (and sometimes even with AL amyloidosis). A heart biopsy is usually done relatively non-invasively, using a catheter technique.

How Is Cardiac Amyloidosis Treated?

In general, cardiac amyloidosis has a bad prognosis. However, in recent years new therapeutic approaches have been developed for cardiac amyloidosis, and people with this condition have reason to feel somewhat more hopeful than they might have been a few years ago.

The treatment of cardiac amyloidosis can be considered in two parts: treatment of heart failure, and treatment of the underlying condition that is producing amyloid deposits.

Treatment of Heart Failure

Treating heart failure caused by cardiac amyloidosis is quite different from treating heart failure caused by other conditions. Whereas beta-blockers and ACE inhibitors are mainstays of treating most varieties of heart failure, these drugs (as well as calcium-channel blockers) can make amyloid heart failure worse. These limitations make the medical treatment of heart failure a major challenge in amyloidosis.

Use of the loop diuretics, such as furosemide (Lasix), is the mainstay of medical therapy in cardiac amyloidosis. These drugs are usually quite effective in reducing the rather severe edema that often accompanies this condition, and also can relieve the dyspnea (the other common symptom) substantially. Loop diuretics are often used in high doses, and can be given intravenously if needed.

Beta blockers should not be used in cardiac amyloidosis. The heart’s ability to pump is severely limited in this condition, and at the same time the heart cannot fill with blood very efficiently. As a result, an increased heart rate is necessary to maintain an adequate cardiac output in cardiac amyloidosis. This means that beta blockers, by slowing the heart rate, can cause sudden decompensation in these people. Calcium blockers can also slow the heart rate, and should also be avoided.

In people with AL-type amyloidosis, ACE inhibitors can produce a profound (and possibly fatal) reduction in blood pressure—possibly because deposits of amyloid in the peripheral nerves keeps the vascular system from compensating for the drop in pressure which ACE inhibitors often cause. This severe drop in blood pressure is generally not seen in people with TTR amyloidosis, and in these individuals ACE inhibitors can be tried cautiously.

Heart transplantation is not an option for people with AL-type amyloidosis, because they generally have significant disease in several other organs. While people with TTR-type amyloidosis typically have disease limited to the heart, they are usually too old to be considered as suitable candidates for cardiac transplantation. Transplantation may be an option for the rare younger person who has TTR-type cardiac amyloidosis.

Treatment of the Disorder Causing Amyloidosis

Primary, AL-type Amyloidosis. This type of amyloidosis is usually caused by an abnormal clone of plasma cells that manufactures large quantities of AL-type amyloid. Consequently, in recent years chemotherapeutic regimens have been developed to attempt to kill the abnormal clone of cells. High-dose melphalan followed by bone marrow transplantation is the treatment most commonly recommended. Unfortunately, people with AL amyloidosis who have cardiac involvement are often not healthy enough to tolerate this kind of aggressive therapy. Other chemotherapy regimens can be used in these individuals, however, and at least a partial response is seen in most of them. If AL amyloidosis can be diagnosed and treated before it becomes extensive, an improved outcome is much more likely.

Secondary Amyloidosis. Only a small minority of people with cardiac amyloidosis have this condition. However, aggressive treatment of the underlying inflammatory disorder may slow the progression of the amyloidosis.

Senile Amyloidosis. In people with cardiac amyloidosis caused by TTR amyloid, the excess protein is manufactured in the liver. It turns out that TTR-type amyloidosis is of two types. In one of these types, a rare variety that is seen in younger people, liver transplantation removes the source of the TRR-type amyloid protein and halts the progression of amyloidosis. Unfortunately, in older people who have the more typical, senile TTR-type amyloidosis, liver transplantation does not affect the progression of the disease.

Drugs are under investigation that are aimed at “stabilizing” the TTR protein so that it will no longer accumulate as amyloid deposits. However, it is too early to know whether these drugs will substantially improve the outcome of TTR-type cardiac amyloidosis.

Bottom Line

Cardiac amyloidosis is a very serious condition that causes significant symptoms, and greatly reduces longevity. Several underlying conditions can produce amyloidosis, and optimal treatment—and to a certain extent the prognosis — varies with the type of amyloid protein that is being deposited in the tissues.

Despite these grim facts, substantial progress is being made in understanding the various types of cardiac amyloidosis, and in teasing out optimal treatment strategies for each of them.

Sources:

Careddu L, Zanfi C, Pantaleo A, et al. Combined Heart-liver Transplantation: a Single-center Experience. Transpl Int 2015; 28:828. 

Dubrey SW, Hawkins PN, Falk RH. Amyloid Diseases of the Heart: Assessment, Diagnosis, and Referral. Heart 2011; 97:75. 

Kristen AV, Dengler TJ, Hegenbart U, et al. Prophylactic Implantation of Cardioverter-defibrillator in Patients With Severe Cardiac Amyloidosis and High Risk for Sudden Cardiac Death. Heart Rhythm 2008; 5:235. 

Wechalekar AD, Schonland SO, Kastritis E, et al. A European Collaborative Study of Treatment Outcomes in 346 Patients With Cardiac Stage III AL Amyloidosis. Blood 2013; 121:3420.

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