How Does Iron Buildup In The Heart Muscles (Hemochromatosis) Cause Cardiomyopathy?

Iron is an essential element responsible for oxygen transport in the blood and many metabolic processes such as DNA synthesis and cellular respiration. It’s also necessary for normal cognitive and immune function. Our bodies developed several regulatory mechanisms that control the level of iron through absorption, transportation, and storage.

When the concentration of iron is below or above its normal value, the body can’t function normally. While low iron levels can lead to anemia, too much iron can also be dangerous. Excess iron accumulates in the liver, spleen, heart, bone marrow, pituitary gland, pancreas, and brain, causing damage to these organs. Iron buildup can sometimes lead to heart and liver failure.

What is hemochromatosis?

Hemochromatosis is the accumulation of iron in the body. The cause can be genetic (primary hemochromatosis) or acquired, as a result of excessive administration of iron (through food or blood transfusion). Primary or hereditary hemochromatosis results from mutations of the genes that encode the proteins involved in iron metabolism, causing increased gastrointestinal absorption. It’s mostly associated with the HFE gene, sometimes called "British gene" or "Irish curse" because it often affects people of Celtic, English, and Scandinavian origin.

Certain conditions can also lead to increased absorption of iron. These include:

• Porphyria cutanea tarda (a condition in which exposure to the sun causes painful blisters on the skin)
• Chronic liver diseases like nonalcoholic fatty liver disease, hepatitis B and C
• Sideroblastic anemia (a type of anemia in which the body produces abnormal red blood cells)
• Thalassemia (a blood disorder characterized by inadequate production of hemoglobin, a protein that carries oxygen in the blood)

Most patients with hemochromatosis don’t have any symptoms, and when the symptoms are present they are usually related to organ damage.

What is cardiomyopathy?

Cardiomyopathy is a group of disorders that affect the heart muscle. These disorders can affect the heart’s size, shape, and the thickness of the muscle walls. Structure and function are correlated, so these changes in the structure of the heart muscle may lead to a decrease in function. The heart’s ability to pump blood becomes reduced, and that can present with symptoms like fatigue, breathlessness, and exhaustion. As the disease progresses, it can lead to arrhythmia (irregular heartbeats), heart valve problems, cardiac arrest, heart failure, and death.

There are many causes of cardiomyopathy. Depending on the cause, cardiomyopathy can be either primary, when the cause is of genetic origin, or secondary. Secondary or acquired cardiomyopathy happens as a result of another (primary) condition. One of the conditions that may lead to cardiomyopathy is hemochromatosis.

The link between cardiomyopathy and iron overload

Iron is transported in the blood through a protein called transferrin. When there is excess iron, transferrin becomes saturated, which means that all of the binding places for iron are already taken and iron is present in the blood in its free form.

As the blood passes through the heart, iron enters heart cells through the calcium channels and begins to accumulate. When a certain dose of iron in the cells is exceeded, it reacts to form dangerous radical species (the Fenton reaction) that damage the membrane of the heart cell.

The damaged membrane leaks hydrolytic enzymes. Hydrolytic enzymes are named for their ability to break chemical bonds using water molecules. Those processes are important and necessary parts of metabolic processes in the cell, but once they are outside of the cell, in the heart tissue, they can cause severe damage. They indicate heart cell damage and the death of these cells, eventually leading to the damage of the whole heart muscle. However, while this mechanism might be a trigger for iron overload cardiomyopathy (IOC), there are also other mechanisms involved, as IOC is not simply a consequence of iron deposition. Genes and the immune system also play an important role.

What is iron overload cardiomyopathy?

The heart consists of four chambers-two upper chambers called atria that collect the blood, and two lower chambers or ventricles that pump the blood. The left ventricle is the heart's main pumping chamber, and this is the part of the heart that is first and most affected in IOC.

This is why the first symptoms of IOC are usually the symptoms of left ventricular dysfunction. Those symptoms can include:

• Breathlessness (due to fluid build-up in the lungs )
• Swelling of the legs, ankles, and feet (due to fluid retention)
• Tiredness and fatigue (due to lack of oxygen)

Iron overload can lead to two types of cardiomyopathy:

• Restrictive cardiomyopathy. In restrictive cardiomyopathy, the walls of the ventricles become stiff. When the walls are rigid, the muscle can’t fully relax. While the heart will continue to work and pump blood, the inability to relax properly means that the ventricles can’t fill with blood. A part of the blood travels back (because the ventricle can’t relax so there is less place for the blood), causing increased pressure in the atria-the chambers above the ventricles.
• Dilated cardiomyopathy. This condition is characterized by enlarged walls of the left ventricle. The walls become thinner and stretched, which means that they can’t pump the blood with the same efficiency. Another part of the heart that can be affected is the mitral valve. Mitral valve is something like a gate between the left atrium and left ventricle that enables the blood to flow only in one direction, from the atrium to the ventricle.

Whether someone gets restricted or dilated cardiomyopathy depends on other factors like your immune system, but the dilated cardiomyopathy usually happens later, as the disease progresses. ​

Hemochromatosis can also disrupt the normal electrical conduction in the heart, leading to arrhythmias. Arrhythmias are irregular heartbeats that you might feel as your heart beating too fast, erratically or too slow. Some arrhythmias like ventricular fibrillation (VF) are extremely dangerous and will lead to death without immediate medical attention. If caught early, IOC can be treated and various new treatment options are emerging. However, in the progressed stages of the disease survival rates are poor, with average life expectancy less than a year.