Cardiac dysfunction

Cardiac disease is the major cause of death in patients with iron overload. The liver and heart have different rates and mechanisms of iron uptake and elimination. As a result, measurements of ferritin and liver iron do not completely predict cardiac risk; high values are associated with future cardiac iron accumulation, but low values may not necessarily be reassuring. Recently, doctors and scientists using cardiac MRI T2* have developed a means to recognize preclinical cardiac iron accumulation. Although currently available only at a limited number of thalassemia centers, cardiac T2* measurements have transformed chelation and cardiac management in thalassemia.

Improved diagnosis of cardiac iron has led to improved chelation strategies. Deferoxamine does remove cardiac iron but is significantly more effective when given six to seven days a week or continuously.

The oral chelator deferiprone, in combination with deferoxamine, has demonstrated excellent cardiac iron removal, as well as improvements in left ventricular function. It requires weekly ANC assessment to monitor for neutropenia and agranulocytosis.

There is less cardiac data for the oral chelator deferasirox, but available studies are promising and indicate that deferasirox does lower cardiac iron. Several clinical trials are ongoing. It is significant that patients now have many more options for therapy to control cardiac iron.

Cardiac evaluation

Prior to initiation of transfusions, a baseline evaluation should be made. This should include an echocardiogram, to evaluate pulmonary artery pressures, systolic function, and diastolic function, and a baseline electrocardiogram to monitor for ventricular hypertrophy and rhythm abnormalities.

Monthly evaluations should include a cardiac history (palpitations, irregular heart rate, chest pain, dyspnea, exercise intolerance, nocturnal cough, orthopnea, dependent edema, or unexplained fevers) and exam (systemic or pulmonary venous congestion, gallop, and edema). Any positive history of cardiac dysfunction requires evaluation by a cardiologist. Serum ferritin should also be checked monthly.

For patients over eight years of age, an annual evaluation should include an echocardiogram assessment of systolic and diastolic function, as well as pulmonary artery pressure (PI and TR jet velocity). Patients also should have an electrocardiogram—cardiac iron is associated with nonspecific ST-T wave changes, T-wave inversions, left ventricular hypertrophy, bradycardia, and PR prolongation. Readings from a Holter monitor need only be obtained if there is clinical suspicion of arrhythmias. Patients should have their cardiac T2* and left ventricular ejection fraction evaluated with a cardiac MRI, if available.

Echocardiography standards

The following parameters should be included in an echocardiographic evaluation.

1. M-mode: Left ventricular end diastolic and systolic dimensions, wall thickness, left ventricular mass and wall stress, shorting fraction, and corrected mean velocity of circumferential shorting
2. Pulse Doppler: mitral inflow peak velocities (E and A) and mitral deceleration time
3. Tissue Doppler: measurements of E, A, and S from the atrioventricular ring at the right ventricular free wall, left ventricular free wall, and interventricular septum
4. Color and continuous wave Doppler: severity and velocity of tricuspid and pulmonic regurgitant jets (estimation of right ventricular and pulmonary artery pressures)

Treatment of established heart failure

Heart failure is defined as a low ejection fraction with evidence of cardiomyopathy. All patients with heart failure should be assumed to have high levels of cardiac iron, regardless of their liver iron or ferritin, until proven otherwise by cardiac T2* assessment. A cardiac MRI should be performed, if possible, to evaluate the relative cardiac and liver iron loading. All patients with heart failure should be placed on continuous deferoxamine therapy (24 hours per day, 7 days per week) at 50 to 100 mg/kg over 24 hours, administered either intravenously or subcutaneously, depending on the patient’s access and tolerance. Patients with low ferritin and/or low liver iron should still be managed with continuous deferoxamine to deplete intracardiac free iron, but the daily dose will have to be lowered to avoid over-chelation.

Combination therapy with deferiprone and continuous deferoxamine is recommended for patients in heart failure. There is less experience with combination therapy with deferasirox, but this is an alternative option. The introduction of any dual agent should occur after the initiation of continuous deferoxamine.

Patients in heart failure should be screened for thiamine and vitamin D deficiency, hypoparathyroidism, hypothyroidism, diabetes, and adrenal insufficiency. Empiric L-carnitine therapy at 50 mg/kg may be beneficial for cardiac function in some patients. Stress dose steroids should be administered empirically for patients in the intensive care unit.

Patients should be referred to a cardiologist who will generally manage their care with ACE inhibition, beta blockers, digoxin, and diuretics. Cardiac arrhythmias should be treated with amiodarone. Ablation is ineffective. Arrhythmias often reverse with iron chelation therapy.

The placement of automatic intracardiac defibrillators should be strongly discouraged because the cardiomyopathy is generally reversible. Heart transplantation should also be strongly discouraged unless the heart failure persists after cardiac iron depletion (verified by MRI), or the patient will not survive long enough for effective chelation.

Patients in heart failure require more frequent transfusions (at two-week intervals) to maintain a pre-transfusion hemoglobin of around 12.0 gm/dL. Diuretic therapy may be required during transfusions. Frequent evaluation of serum electrolytes, calcium, and magnesium while on diuretic therapy is required.

Pulmonary hypertension

Pulmonary hypertension is a progressive increase in the resistance of blood flow to the lungs. It is caused by the disruption of nitric oxide metabolism secondary to the intravascular release of hemoglobin from red blood cells, direct iron toxicity of the vascular endothelium, and back-pressure from the heart as it stiffens from iron and from aging.

Patients with thalassemia also have vasoactive fragments of platelets and red blood cells that appear to constrict pulmonary vessels. This circulating cellular debris is generally removed by the spleen—thus, patients who have undergone splenectomy appear to be at higher risk.

Unsplenectomized thalassemia major patients who are regularly transfused to maintain their pre-transfusion hemoglobin above 9 to 10 g/dL do not have much circulating free hemoglobin or cellular fragments. Pulmonary hypertension is relatively rare in these patients (less than 10 percent) and is usually responsive to improved iron chelation strategies. In contrast, patients who have thalassemia intermedia or who allow their hemoglobin to fall to lower levels between transfusions are at much higher risk of pulmonary hypertension—nearly 50 to 60 percent in some studies.

Treatment of pulmonary hypertension

Liver iron and ferritin values do not really help discriminate the mechanisms of pulmonary hypertension. Physicians must decide whether the pulmonary hypertension is primary or secondary to iron-mediated cardiomyopathy. The former condition will have elevated circulating free hemoglobin, low haptoglobin, low arginine, elevated platelets, and platelet adhesion markers. Treatment consists of initiating transfusion therapy if the patient is not already on regular transfusions and maintaining pre-transfusion hemoglobin above 9.5 g/dL. The latter condition will exhibit left ventricular systolic and diastolic dysfunction, abnormal cardiac T2*, and cardiac arrhythmias. Treatment of the latter condition consists of treating iron cardiomyopathy.

For patients with pulmonary hypertension, optimize their transfusion program to maximize suppression of all marrow activity. All patients with severe pulmonary hypertension (TR jet greater than 3 m per second) should undergo diagnostic catheterization to assess pulmonary vascular resistance and its responsiveness to nitric oxide and oxygen. Patients should be evaluated for oxygen desaturation, particularly at night. Supplemental oxygen should be administered, as needed, to maintain saturations greater than 95 percent. A complete coagulopathy workup should be performed.

Warfarin should be initiated for patients having persistent pulmonary hypertension. The INR target is 1.5 to 2.0. Patients failing to respond to hematologic management should be started on sildenafil as the first line of therapy.