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The most common form of cardiac hemosiderotic injury is congestive cardiomyopathy (1). Currently, it is thought that cardiomyopathy is caused by the direct effect of non-transferrin-bound iron (NTBI) on myocytes, rather than by interstitial iron infiltration (1). Non-transferrin-bound iron (NTBI) is toxic to cardiac myocytes in extremely low concentrations (1).

Other cardiac pathologies linked to excess iron include pericarditis (1), angina (1), and conduction defects when there is iron deposition in the bundle of His and the Purkinje system (2,3).

Gradual onset of symptoms

Cardiac iron accumulation usually occurs after organs such as the liver and spleen have become saturated with iron. Cardiac function may not change significantly until iron levels reach a critical value or duration, after which systolic function rapidly deteriorates, and refractory heart failure occurs (4). Once cardiac dysfunction is detected, the prognosis is poor without intervention, but can be improved if appropriate therapy is given to address the iron overload (5,6).

Severity of cardiac dysfunction

The severity of cardiac dysfunction depends upon the amount of iron deposited in individual myocardial fibers and the number of fibers affected. In patients with mild cardiac dysfunction, iron deposition is usually limited to the perinuclear areas, with only a few fibers involved. In patients with significant cardiac dysfunction, iron deposits occupy large areas of myocardial fibers (1,4).

Types of cardiac injury

The most common form of cardiac hemosiderotic injury is dilated cardiomyopathy, generally manifesting as systolic or diastolic dysfunction (4). Signs of myocardial damage due to iron overload include arrhythmia, angina, cardiomegaly, heart failure, and pericarditis (4). Iron overload can also produce conduction defects when there is iron deposition in the Bundle of His and the Purkinje system (1,2). Sudden death due to arrhythmia can therefore occur among patients with advanced iron overload (2).

Assessing cardiac iron burden

The most useful noninvasive diagnostic techniques for hemosiderotic cardiomyopathy are left ventricular ejection fraction (LVEF) studies performed with radionuclide ventriculography (in adults) or echocardiography (in children). Recent fast MRI techniques have also shown promise in detecting increased myocardial iron deposition in the heart muscle (7,8). The lower the myocardial MRI T2* value, the higher the risk of cardiac dysfunction; T2* values <20 ms are associated with a progressive and significant decline in LVEF.

Learn more about cardiac MRI

Mechanism of cardiac iron uptake

The mechanism of cardiac iron uptake is not as well defined as that of hepatocyte uptake. Low-capacity divalent metal (DMT1) and transferrin-bound transporters are critical regulatory mechanisms under normal physiologic conditions (3) [Schwartz, Schwartz, 2002]. Under conditions of iron overload, these mechanisms are overwhelmed, and NTBI permeates cell membranes outside of normal cell homeostatic mechanisms. DMT1 may play a part in NTBI uptake in the heart, as may the L-type voltage-dependent Ca 2+ channel (LVDCC). DMT1 is present at low levels in heart tissue, while LVDCCs are found in abundance and with great activity in cardiomyocytes. Furthermore, LVDCC currents can be increased when ferrous iron concentrations are elevated, creating a potential mechanism for precipitous iron uptake (9).

Relationship between Liver Iron Concentration (LIC) and cardiac iron overload

It was once thought that liver and cardiac iron levels were directly correlated (10); however, their relationship has proven to be more complex.

The mechanisms of iron uptake and clearance differ in heart and liver tissue, resulting in differing iron transport kinetics (3). Cardiac iron is cleared six-times more slowly than liver iron (9). Patients may therefore develop cardiac dysfunction despite low liver iron levels. Some data suggest a critical liver iron concentration (LIC) above which high myocardial iron levels are present (11). In one longitudinal study of patients with β-thalassemia receiving chelation therapy, an LIC >15 mg/g dry weight was shown to be suggestive of increased risk of cardiac disease and early death (10). Similarly, the maintenance of serum ferritin levels below 2500 mcg/L has been associated with improved cardiac disease-free survival (6).

Relationship between serum ferritin and cardiac disease-free survival

As a marker of iron overload, serum ferritin levels can predict the chances that at-risk patients will develop cardiac disease. Among regularly transfused patients with β-thalassemia, 82% with persistently elevated serum ferritin levels (>2500 mcg/L) developed cardiac disease within a 15-year follow-up period (6). Conversely, 91% of patients whose serum ferritin levels were adequately controlled did not develop cardiac disease during the same 15-year period (6).

Cardiac disease risk and serum ferritin levels in β-thalassemia