Cardiac Iron Loading and Myocardial T2*


Conditions Associated With Cardiac Iron Loading

There are several conditions that can potentially lead to cardiac iron loading with cardiac complications. Cardiac iron loading can occur via two distinct mechanisms: first, primary disruption of iron regulation (genetic hemochromatosis syndromes) where excess gastrointestinal absorption is slow and symptoms often present in middle age; and, second, via transfusional iron overload where the iron accumulation rate is much faster and children can develop cardiac iron accumulation within a few years of initiating regular transfusion therapy. Excess iron cannot be naturally excreted in humans because of the lack of such a regulatory excretory pathway.

The most common pathology leading to severe iron accumulation is thalassemia major (TM). This is a genetic condition with severe reduction or absent production of the beta-globin chain constituent of hemoglobin A (HbA). Excess alpha-chains result from ineffective erythropoiesis, and there is a life-threatening anemia by 2 years of age. Not only does this require treatment with regular, lifelong, repeated blood transfusions, but it is compounded by a mild increase in gastrointestinal iron uptake related to hepcidin suppression. TM occurs predominantly where malaria is endemic because heterozygote genetic hemoglobin mutations confer resistance. In other parts of the world it occurs primarily through immigration.

The detail of the hemoglobinopathy plays a role in the pattern and pathology of transfusion-dependent iron loading. For example, in the less severe condition of thalassemia intermedia, pulmonary hypertension and thrombosis play a greater clinical role and iron loading occurs at a later age. In sickle cell disease (SCD), the defining clinical features include sickle cell crises (intermittent attacks of severe pain), pulmonary hypertension, thrombosis, and stroke. Even where SCD patients are transfused to prevent cardiovascular complications, extrahepatic iron deposition is lower compared with other transfusional anemias. Conversely, in Diamond-Blackfan anemia, where the intrinsic bone marrow activity is low, patients are very prone to nonhepatic tissue iron accumulation.

Prevalence of Cardiac Iron Overload and Cardiomyopathy

The introduction of chelation therapy in the 1960s with deferoxamine changed the natural progression of TM patients receiving regular transfusions, where the most common cause of death was heart failure at a very young age. Despite initially promising data and an increased life expectancy with the introduction of deferoxamine, cardiac iron overload continued to dominate, accounting for 70% of deaths. However, as shown in a UK cohort, by the year 2000 the median age at death was 35 years because by this time patients had been exposed to regular chelation therapy from a young age. Improving survival with deferoxamine by later birth cohort has been confirmed in other countries. In the current millennium, data using T2* from TM patients across the world show that cardiac iron overload continues to be common, using definitions from T2* cardiovascular magnetic resonance (CMR) of severe cardiac iron loading of <10 ms, and mild-to-moderate cardiac iron loading of 10 to 20 ms ( Table 33.1 ). The prevalence of cardiomyopathy is more difficult to measure. It can be estimated from either the prevalence of clinical heart failure or the presence of detectable left ventricular (LV) dysfunction, with the latter being higher in any given population. Prevalence generally increases with age and decreases with a more recent year of birth. For example, in a cohort of patients born before 1976, 37% had heart disease as defined by need for inotropic or antiarrhythmic medications, but in a survey in 2004 the number of TM patients of all ages receiving cardiac medication was only 10%.

TABLE 33.1
Incidence of Cardiac Iron Overload From Published Data Around the World
Modified from Pennell DJ, Udelson JE, Arai AE, et al; American Heart Association Committee on Heart Failure and Transplantation of the Council on Clinical Cardiology and Council on Cardiovascular Radiology and Imaging. Cardiovascular function and treatment in β-thalassemia major: a consensus statement from the American Heart Association. Circulation. 2013;128:281–308.
Country Sample Size Severe Mild-to-Moderate Normal
T2* <10 ms T2* 10–20 ms T2* >20 ms
United Kingdom 109 20% 43% 37%
Hong Kong 180 26% 24% 50%
Turkey 28 46% 39% 14%
Australia 30 37% 27% 37%
Oman 81 24% 22% 54%
United States of America 141 13% 21% 66%
Italy 167 13% (<8 ms) 52% (8–20 ms) 35%
Italy 220 30% <20 ms 66%
Greece 159 68% <20 ms 32%
Worldwide survey 3445 20% 22% 58%
Egypt 89 25% <20 ms 75%
Pakistan 83 47% 16% 37%
Indonesia 162 5% 10% 85%

Mechanisms of Cardiac Iron Entry and Toxicity

The mechanism of human cardiac iron loading is incompletely understood. In vitro and animal studies suggest cardiac entry of iron is mediated by calcium channels, and indeed nifedipine hinders iron uptake into cardiac cells. Accumulation of myocardial iron eventually leads to increased levels of intracellular free iron. The toxicity of free iron is mediated via several mechanisms ( Fig. 33.1 ) : (1) membrane damage caused by lipid peroxidation; (2) mitochondrial damage and perturbation of the respiratory enzyme chain ; (3) altered electrical function, including ryanodine release channel interference ; (4) cardiac fibrosis, which was reported as prominent in early autopsy studies ; and (5) changes in gene expression. Iron that is safely stored in ferritin or hemosiderin is nontoxic, yielding hearts with low T2* and normal function. However, high iron stores predispose patients to development of cardiac dysfunction in the future. The result is that the natural history and clinical course in untreated patients is one of a long asymptomatic phase of progressive myocardial iron accumulation with sudden onset of either malignant arrhythmias or acutely impaired myocardial function in early adulthood. There was a significant mortality once symptomatic, and 5-year survival for patients presenting in heart failure was only 48%. One factor behind this is that although evidence suggested that intensive iron chelation therapy could completely restore cardiac function in most patients with asymptomatic cardiac dysfunction and even some clinical heart failure, there was a risk of relapse caused by a lag between the clearance of cardiac iron and improvements in systolic function. Even in asymptomatic patients, treatment of severe cardiac siderosis by aggressive chelation therapy is associated with improvements in ventricular function. Improved life expectancy for TM patients in the United Kingdom has resulted from the increasing availability of T2* CMR and earlier escalation of therapy. Even with modern-day chelation regimens, it is important to avoid stage IV heart failure in thalassemia as in-hospital mortality remains in excess of 50%.

FIG. 33.1, Amelioration of free iron species (labile plasma iron [LPI] and labile cell iron [LCI] ) by iron chelators and antioxidants. LPI is penetrating through the cell membrane with a consequent accumulation of LCI. Both LPI and LCI react with reactive oxygen intermediate (ROI) producing noxious reactive oxygen species (ROS) , for example, OH' radicals, which are highly reactive and oxidize DNA, proteins, and lipid components of the cell. Deferiprone (DFP) chelates LCI alone or in combination with LPI by deferoxamine (DFO) . Deferasirox (DFX) mainly removes LPI.

Of significant clinical interest is that cardiac iron loading is commonly associated with endocrinologic complications including hypothyroidism, diabetes, hypoadrenalism, growth hormone deficiency, and hypoparathyroidism. This suggests a common or similar iron uptake mechanism. In untreated cardiac iron accumulation, historical series also showed more cardiac complications, such as pericarditis and myocarditis, that occurred in addition to heart failure and arrhythmias. Chelation seems to have has altered this, with myocarditis and pericarditis now being unusual. Chelation has also led to a significant reduction in the historical occurrence of dense replacement fibrosis of myocytes, even in those who die from heart failure, although occasional small patches of fibrosis may be present. In the modern era of chelation therapy, dilated cardiomyopathy (with restrictive features) and arrhythmia (predominantly atrial fibrillation) persist. Ventricular arrhythmias are more common in severe cardiac iron loading. Iron deposition throughout the myocardium in TM patients is nonuniform, being preferentially deposited in the subepicardium, but no systematic variation occurs between myocardial regions such that iron deposition in the interventricular septum is highly representative of total cardiac iron. There are other cardiac changes such as decreased left atrial (LA) function, impaired right ventricular (RV) function, impaired diastolic function, and impaired endothelial function.

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