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Cappellini MD, Cohen A, Porter J, et al., editors. Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT) [Internet]. 3rd edition. Nicosia (CY): Thalassaemia International Federation; 2014.
This publication is provided for historical reference only and the information may be out of date.
The quality and duration of life of transfusion-dependent patients with thalassaemia has been transformed over the last decade (Borgna-Pignatti 2010, Modell 2008, Telfer 2006). It should now be expected that with well organized care a patient with thalassaemia will live a good quality life into middle age and beyond, including the possibility of raising a family of their own. Although historically the major complication affecting the heart was heart failure due to accumulation of iron within heart muscle cells (myocytes), with increased survival other manifestations of thalassaemia have become apparent. Thus the cardiovascular complications of thalassaemia can be considered in two major clinical categories:
An important consensus document on cardiac management in thalassaemia was recently published (Pennell 2013). Previously published consensus documents (Cogliandro 2008) and review articles (Walker 2012, Wood 2005) may also serve as valuable references.
Key commentary: Iron-related heart complications of thalassaemia were once the leading cause of death and remain one of the leading causes of morbidity.
Cardiac iron accumulation is the single greatest risk factor for cardiac dysfunction in thalassaemia. Cardiac iron loading occurs when the heart is exposed to high circulating non-transferrin bound iron species for long periods of time. The exact transport mechanisms remain controversial, although animal studies suggest a role for L and T-type calcium channels. The duration of chelator exposure appears to be an important determinant of cardiac iron accumulation, independent of total body iron balance. As a result chelation strategies that deliver high drug doses, sporadically, should be avoided, even if this strategy can successfully control liver iron and serum ferritin.
Once inside the heart, labile iron is quickly bound to ferritin and degraded to hemosiderin. This buffering mechanism is vital to survival and creates a clinically-silent condition where cardiac iron stores are increased but toxic labile iron species are not present (Anderson 2001). MRI assessment of cardiac T2* can identify and quantitate cardiac iron stores (Carpenter 2011), allowing modification of iron chelation before cardiac symptoms develop.
Eventually, iron buffering mechanisms in the heart fail. The greater the stored iron, the higher the probability this will occur (Kirk 2009). Once labile iron levels rise in the myocyte, they produce oxidative damage to membranes, iron transporters, and DNA, triggering cardiac dysfunction, arrhythmias and if not reversed, eventual fibrosis. Dysregulation of calcium homeostasis, particularly the ryanodine channel, is believed to play an important role in iron cardiomyopathy.
From the clinical point of view, the key feature of iron overload complications, even when severe, is that with intensive chelation therapy they may be reversible. However, prevention of excessive iron overload remains the primary responsibility of the clinicians in charge of thalassaemia patients, since, once symptomatic heart failure occurs there is a high immediate risk of death.
Despite undoubted improvements in care, cardiovascular disorders remain crucially important and their early recognition mandates intensified chelation therapy, with specific cardiac interventions and medication taking second place in priority. Prevention of early life iron load will also impact on at least some of the more troublesome “non-iron overload” complications in later life, such as atrial fibrillation (AF).
Although iron is the most important cause of cardiac dysfunction, deficiencies in carnitine, thiamine, vitamin D, and selenium can worsen cardiac function; these nutrients are commonly deficient in thalassaemia (Claster 2009, Wood 2008). Hypothyroidism, hypoparathyroidism (DeSanctis 2008), and hypogonadism can also exacerbate cardiac dysfunction. Acute myocarditis can precipitate severe heart failure, arrhythmias and heart block (Kremastinos 1995), although this complication is not commonly seen in many countries.
Iron-negative cardiac dysfunction is also encountered in older thalassaemia patients from the Mediterranean region. Patchy delayed hyperenhancement, consistent with fibrosis, has also been described in the same study population (Pepe 2009), raising the possibility that longstanding hepatitis C infection may produce smoldering myocarditis and myocardial dysfunction (Matsumori 2006).
Key commentary: Even after significant toxic effects on heart muscle have prevailed, aggressive iron chelation can restore myocardial function to normality.
Patients with considerable iron overload of the heart may remain free of symptoms. Once myocardial dysfunction develops, symptoms are related to the degree of ventricular impairment. Subtle early signs may be confused with the effects of the underlying condition. For example, breathlessness during exercise may be attributed to anaemia. In more advanced stages of heart failure, clinical presentations are equivalent to those seen with any severe heart muscle disease and may include dyspnoea, peripheral oedema, hepatic congestion and severe exercise limitation.
Clinical presentation of heart failure is variable. Classic left heart failure features, including rales, or crackles, dyspnea on exertion, and orthopnea are a late finding. Right heart failure symptoms, including neck vein distension, hepatomegally, and peripheral edema, often are the first clinical signs (Pennell 2013). Rapid decompensation, with predominant right heart failure features, may mimic an acute abdomen, with tender hepatomegally mistaken for cholangitis or biliary obstruction. The development of the signs of classical heart failure implies advanced disease with a poor prognosis, until the acute situation is resolved, by intensive chelation. It must be emphasised that the patient may require support of the failing circulation for a period of several weeks in order to achieve a recovery.
Key commentary: An important distinguishing feature of heart failure due to iron overload is the capacity of heart function to make a complete recovery with appropriate chelation therapy - a fact that may not be widely appreciated by physicians and cardiologists unaccustomed to dealing with patients with thalassaemia.
Symptoms of palpitations are common in patients with thalassaemia, and are a frequent cause for anxiety - both for patients and their physicians. In brief, the prognostic implications of arrhythmia are related to the degree of myocardial iron-overload and any associated myocardial dysfunction. Thus in the case of a non-iron overloaded patient, the development of an arrhythmia such as atrial fibrillation (AF) deserves simple investigation and possible pharmacological treatment including anti-coagulation, but does not necessarily imply an adverse outcome. The same arrhythmia in a heavily iron overloaded heart, particularly if cardiac dysfunction is present, may be the harbinger of severe decompensation and requires immediate response and probable hospitalisation. Chest pain is uncommon in thalassaemia, but may accompany intercurrent illnesses including pericarditis or myocarditis. The frequency of these complications appears to differ between countries.
Key commentary: Management of the patient with palpitations depends on the clinical situation taken as a whole, including iron loading status and cardiac function.
A thorough medical history and physical examination are required for a basic cardiological assessment, which should also include: 12-lead electrocardiogram and a detailed echocardiogram, undertaken according to published guidelines. Cardiac magnetic resonance imaging (CMR), used to quantitatively estimate cardiac iron overload (T2*), has become an invaluable tool in the estimation of clinical risk for the development of heart complications in thalassaemia. Additional tests may also be valuable for the detailed assessment of individual clinical problems, such as the investigation of cardiac arrhythmia (Holter or 24-hour ECG) or functional assessment by exercise tests.
Key commentary: The regular assessment of cardiac status helps physicians to recognise the early stages of heart disease and allows prompt intervention.
This is not an exhaustive list, but includes most of the parameters, which characterize cardiac function in thalassaemic patients. If collected longitudinally subtle changes in parameters may become evident, highlighting the need to pursue more vigorous investigation with CMR imaging. A recent publication has illustrated the value of simple echocardiographic follow-up in patients with thalassaemia (Maggio 2013). Iron cardiomyopathy presents first with increased end-systolic volumes and borderline ejection fractions; progression to dilated cardiomyopathy is a late and ominous finding. A combination of conventional and tissue Doppler should be used to evaluate diastolic function. Isolated diastolic dysfunction can occur but is relatively rare.
A simple database for each patient can easily be developed for each patient to aid longitudinal follow up. Newer echo methods may also increase the sensitivity of the echo in detecting pre-clinical disease (Vogel 2003).
Key commentary: The important point is that each centre should develop a specified protocol, for their patients that can be used for long term surveillance and early appreciation of change.
Examination by echocardiography of the ventricular response to exercise may also be useful, highlighting individuals with sub-clinical disease in whom the ejection fraction fails to rise, or even falls, in response to exertion or simulated exercise using intravenous (i.v.) dobutamine
Key commentary: The value of the T2* parameter is that it identifies those individuals at risk of developing cardiac complications, before they become evident by changes in function detected by simpler non-invasive methods, such as echocardiography.
Monitoring the effectiveness of chelation in individual patients has proven to be critical in benefiting patient motivation in adhering to demanding treatment programmes and thus to outcomes. Cardiac MRI represents the gold standard for monitoring patients with thalassaemia major, not only because it allows estimation of cardiac iron burden (Carpenter 2011, Kirk 2009), but because it provides consistency in detecting preclinical changes in ejection fraction. Studies are recommended at 24, 12, and 6 month intervals for low, standard, and high risk patients. As a result of chronic anaemia, norms for cardiac volumes and ejection fraction are different for thalassaemia patients and must be taken into account when evaluating results (Westwood 2007).
The therapeutic strategy to diminish the risk of heart complications in patients with thalassaemia involves a number of general measures including the maintenance of a pre-transfusion Hb of at least 10 g/dl, along with particular cardiovascular interventions. The primary emphasis must be to encourage regular chelation therapy and maintenance of a CMR T2* > 20 ms. Monitoring cardiac function can be a useful guide to a patient’s overall prospects. Impaired myocardial function may require specific cardiac treatment, but it also calls attention to the immediate need for much stricter adherence to chelation protocol or the initiation of a more intensive chelation programme, in order to prevent an inexorable progression to severe cardiac dysfunction.
Cardiac dysfunction generally lags cardiac iron deposition by several years (Carpenter 2011). Unfortunately, cardiac iron clearance is an extremely slow process, often requiring 3 or more years to clear severe cardiac iron deposition (Anderson 2004). Therefore, prevention of cardiac iron accumulation and early recognition of preclinical disease (through MRI) have a much greater likelihood of success than waiting for echocardiographic or clinical evidence of heart dysfunction or clinical symptoms to appear (Chouliaras 2010, Modell 2008).
Key commentary: Mild decreases in ventricular function, merit aggressive escalation of iron chelation therapy, even if patients are completely asymptomatic (Davis 2004).
Combined therapy with deferiprone 75-100 mg/kg and deferoxamine 40-50 mg/kg/day represent the best option to clear cardiac iron and stabilize ventricular function (Porter 2013). Deferoxamine should be given continuously, either subcutaneously or through a percutaneous intravenous catheter, until the ventricular function normalizes (Anderson, 2004, Davis 2000, Tanner 2008). An important practical point is that intra-venous lines pose a considerable risk of thrombosis and iatrogenic pulmonary hypertension, through chronic pulmonary thromboembolism and should mandate formal anticoagulation, particularly in chronically implanted lines.
Patients with cardiac T2* values below 6 ms are at high risk for symptomatic heart failure (Kirk 2009) and should be treated with intensive chelation, even if cardiac function remains normal. The presence of symptomatic heart failure should trigger admission to a tertiary hospital with experience in managing thalassaemia patients. If this is not possible, then communication between the treating physician and cardiac consultants with experience in thalassaemia major is strongly advised because of key differences between iron cardiomyopathy and other forms of cardiomyopathy. A summary of recommendations is as follows (Pennell 2013):
Clinical stabilization can occur as soon as 2 weeks but can also take months. Clinical improvement precedes cardiac iron clearance. Removal of longstanding cardiac iron is quite slow, with a half-life of fourteen months (Anderson 2004). The iron chelator, deferasirox, has not been evaluated in heart failure patients and may be ill-advised in patients with marginal renal perfusion. Its use later in the convalescent phase is reasonable (Pennell 2010, Wood 2010).
Over recent years there has been a trend towards treating patients with thalassaemia exhibiting mild ventricular dysfunction with agents known to improve myocardial function in other forms of cardiomyopathy (see published guidelines: (McMurray 2012, Yancy 2013)). All these agents have a tendency to lower blood pressure, making their use in thalassaemia difficult and usually limited by the development of hypotension.
Key commentary: Adjunctive treatment of thalassaemia patients at risk of developing or having ventricular dysfunction with medications known to improve survival in other forms of ventricular dysfunction should be strongly considered.
Treatment of myocardial dysfunction is best undertaken using a group of drugs (see Table 1), including angiotensin converting enzyme inhibitors (ACE inhibitors). In controlled trials, these agents as well as beta-blockers and aldosterone antagonists, have been shown to reduce mortality in patients with cardiomyopathy and to reduce the rate of appearance of heart failure in those with asymptomatic left-ventricular dysfunction.
Common drugs and dosing regimens used in the treatment myocardial dysfunction, including heart failure in thalassaemia.
These results are very promising, and while their extension to heart failure in thalassaemia remains conjectural, it is widely applied in clinical practice. The usual precautions for initiating treatment in patients who are well hydrated and starting at low doses are recommended. The dose should be increased to the maximum tolerated, limited by hypotension in patients with thalassaemia. Certain patients are unable to tolerate ACE inhibitors due to the development of chronic cough. These individuals should be treated with angiotensin II receptor antagonists (ARB), such as losartan.
These usually present as palpitations, but sometimes may be asymptomatic. The context within which the arrhythmia occurs generally determines the clinical response and the risk to the patient. Arrhythmias are life-threatening in the presence of heart failure (Mancuso 2009), but can also be ominous harbingers of pending cardiac decompensation in patients with normal cardiac function, but high iron overload. Palpitations must therefore be investigated and treated in the context of the patient as a whole. Ectopic activity, usually supra-ventricular but occasionally ventricular, can produce symptoms requiring prophylactic drug treatment (often with beta-blockers), especially as these transient events can trigger more sustained arrhythmias, particularly AF. Arrhythmias that produce symptoms of haemodynamic compromise (dizziness, syncope or pre-syncope) pose a significant clinical risk and are almost always associated with significant myocardial iron-overload. In the absence of a CMR iron load measurement, clinicians should assume significant arrhythmias are due to iron overload and respond by intensifying chelation therapy, as a matter of urgency if the symptoms include syncope or pre-syncope. Treatment is directed towards the relief of iron overload, with a secondary strategy of symptomatic treatment of the documented arrhythmia. Arrhythmias in thalassaemia major can often be reduced or eliminated by aggressive iron chelation (Anderson 2004). In many instances, the use of drugs to treat relatively benign but symptomatic arrhythmias may produce greater problems than the symptoms deserve. The decision to treat arrhythmias in patients with thalassaemia must therefore be carefully considered, bearing in mind that iron toxicity is the primary cause of this complication. For most supraventricular arrhythmias, reassurance of the patient is generally appropriate; frequent premature ventricular contractions, by themselves, are not suggestive of iron toxicity but couplets and non-sustained ventricular tachycardia are highly specific for iron cardiomyopathy and require urgent attention to address associated high myocardial iron load, via intensified chelation.
In older patients with thalassaemia, even without any evidence of current iron overload, there appears to be a high and increasing incidence of atrial fibrillation (up to 40% of those over 40 years in one large clinic experience). This may pose a future management problem and risk of stroke in this group of individuals who may carry increased thrombotic tendencies (Walker 2013). Sudden death is relatively rare in thalassaemia major, in the modern era, but historical data suggests an association with increased QT dispersion (Russo 2011), consistent with Torsades de Pointes as a possible mechanism.
Key commentary: Any arrhythmia associated with cerebral symptoms or collapse must be considered a medical emergency, until fully characterized.
Since many arrhythmias reverse over time, antiarrhythmic therapy can often be relatively short term (less than one year). Amiodarone is the drug of choice in the acute setting because of its broad spectrum of action and modest compromise of cardiac function (Pennell 2013). Long term amiodarone therapy is associated with an increased risk of hypothyroidism because of pre-existing iron toxicity to the thyroid gland (Mariotti 1999), however therapy can often be terminated after 6-12 months. Beta-blockers are also generally well tolerated, if titrated slowly, and can be useful in controlling ectopic rhythms.
Atrial fibrillation may occur in an acute context, particularly in situations of heavy iron load, where it may precipitate heart failure. Immediate cardioversion by synchronized DC shock should be considered, if the duration of the episode is known to be <48hr, if the patient is already fully anti-coagulated or if a simultaneous trans-oesophageal echocardiogram confirms the absence of atrial clot. Less acute presentations can be conventionally managed with anti-coagulation and introduction of parenteral amiodarone (via a central vein), simultaneously with intensive chelation. Cardioversion should be considered in patients who fail to revert to sinus rhythm with iron chelation therapy and pharmacological intervention. In view of the likelihood of an associated pro-thrombotic tendency, anti-coagulation should be undertaken in all patients with significant episodes of AF.
Thalassaemia patients with permanent or persistent AF may respond to radiofrequency isolation of the pulmonary veins but catheter based interventions for intra-atrial reentrant and ventricular tachycardia should be avoided. In thalassaemia, these procedures have a low success rate because the rhythms lack a true anatomic substrate (there is no scar, only functional conduction impairment). Treatment of potentially life threatening ventricular arrhythmias, such as Torsades De Pointes, may pose management problems in thalassaemia because they are often reversible and conventional criteria for device therapy do not apply to this unusual group of patients with a “toxic cardiomyopathy”. Implantable cardio-defibrillators could provide vital rescue shocks while the heart is being de-ironed but their placement permanently precludes future MRI interrogation. External defibrillation vest can provide an important alternative safety net in these situations.
Historically, before the availability of chelation therapy, complete heart block was relatively common in thalassaemia patients, occurring in up to 40% of those aged over 15 years. It is now rare in most communities, but may occasionally be encountered in the context of severe iron load. The heart block generally, but not always, responds to adequate chelation, but the speed of this response may be slow. Thus these patients may require a pacemaker. It is essential that MRI conditional pacemakers and leads be used. Placing the pacemaker on the right may also be advantageous in allowing better unrestricted imaging of the ventricular walls and septum, to allow for continued monitoring of myocardial iron content (T2*).
Pulmonary hypertension is quite common in thalassaemia intermedia syndromes but reports on the prevalence in thalassaemia major vary (Vlahos 2012, Morris 2010,). Local differences in chelation and transfusion practices as well as the use of splenectomy undoubtedly impact reported prevalence rates. Splenectomy, transfusion intensity (frequency and pre-transfusion haemoglogbin), and severity of iron overload appear to be the strongest predictors of pulmonary hypertension (Vlahos 2012, Morris 2011, Musallam 2011).
Pulmonary hypertension represents the interaction of multiple mechanical and biochemical interactions to produce impaired endothelial function, smooth muscle proliferation, and eventual vascular obliteration in the pulmonary vasculature (Morris 2008). Mechanical forces include increase vascular shear stress from high cardiac output as well as increased vascular distending pressures resulting from left ventricular diastolic dysfunction. Biochemical stressors include circulating free haemoglobin, non-transferrin bound iron, vasoactive membrane fractions (Singer 2006) anderythropoeitic stress hormones. Increased arginase activity and low nitric oxide bioavailability has been implicated, demonstrating some overlap with the pulmonary hypertension found in sickle cell disease(Morris 2013, Hagar 2006), but multiple pathways are likely operational. Lung disease and hypoxia likely contribute to pulmonary hypertension in thalassaemia as well, similar to the general population. Chronic pulmonary embolic disease must be considered in all patients, particularly those with implanted central venous lines.
Echocardiographic screening for pulmonary hypertension should be performed annually or biannually. Tricuspid regurgitation (TR) and pulmonary insufficiency jets provide estimates of pulmonary artery systolic and diastolic pressure, respectively. TR velocity below 2.5 m/s represents a negative screening test, 2.5 – 3.0 m/s a borderline finding and TR velocity > 3 m/s a positive finding. Borderline and abnormal TR velocities should prompt a review of transfusion practices to determine whether ineffective erythropoiesis is adequately suppressed. Left ventricular systolic and diastolic function should be carefully evaluated to screen for possible mechanisms of post-capillary pulmonary hypertension. Overnight pulse oximetry is indicated to screen for nocturnal desaturation in all patients. However symptoms of obstructive sleep apnea should provide a formal sleep evaluation. Complete pulmonary function testing, including diffusing capacity, should be obtained to exclude restrictive lung disease. High resolution CT and CT angiogram to exclude pulmonary fibrosis and thromboembolic disease is warranted. Cardiac catheterization is indicated in patients with persistent elevated TR velocity greater than 3 m/s despite optimization of haematologic status. Brain natriuretic peptide and six-minute walk tests are useful for trending response to therapy.
Treatment for pulmonary hypertension in thalassaemia is multifaceted and depends upon its severity and etiology. Continuous positive airway pressure should be used in the presence of obstructive sleep apnea. Nasal cannula may be sufficient in the presence of nocturnal desaturation without airway obstruction. Chronic anticoagulation is the treatment of choice in thromboembolic disease and should be considered as prophylaxis against thrombosis in-situ in patients with severe pulmonary hypertension. Early pulmonary hypertension in thalassaemia major patients often responds to shortening transfusion intervals, by suppressing proinflammatory cytokines such as PLGF. Hydroxyurea use in thalassaemia major has never been systematically studied, but has been used with benefit in non-transfused thalassaemia syndromes and is effective in some patient populations (Banan 2013). In patients refractory to more conservative measures, sildenafil has been effective in small series and is generally well tolerated (Morris 2013, Derchi 2005). Successful use of the endothelin 1 blocker, bosentan, has been described in a single thalassaemia intermedia patient but careful consideration must be given to hepatic function in patients with hepatitis C or hepatic iron overload.
Progressive vascular disease is part of normal aging. Many factors contribute, but abnormal free radical signaling is central to the decreased endothelial reactivity, intimal proliferation, increased cellular adhesion, and vascular inflammation observed in senescent vessels. However, many factors in thalassaemia accelerate this process, including iron overload, circulating microparticles, circulating haemoglobin, chronic anaemia, oxidized lipoproteins, and inflammatory cytokines. Insulin resistance and diabetes mellitus also increase vascular oxidative stress. The underlying systemic vessel pathophysiology is similar to that observed in pulmonary hypertension. Thalassaemia patients are also at risk for acquired pseudoxanthoma elasticum (Aessopos 2002), a degenerative process of elastin fibers of unknown mechanism more common in patients who are inadequately transfused or poorly chelated.
No consensus exists for routine screening of systemic vascular disease. Flow mediated dilatation (FMD), while a sensitive marker of endothelial health, is not well suited to clinical practice. Carotid intimal thickness can be performed routinely but norms are laboratory and patient population specific. Furthermore, no clear risk thresholds or identified interventions have been characterized. Oxidized low density lipoprotein correlates with vascular stiffness in thalassaemia (Stakos 2009), but it is not widely available.
Routine surveillance of ascorbate sufficiency is recommended because ascorbate deficiency causes impaired collagen formation in elastic arteries. However, ascorbate replacement in iron overload syndromes must be performed in conjunction with iron chelation therapy to prevent increases in labile iron. Pseudoxanthoma elasticum typically presents with specific cutaneous manifestations. Valvular and pericardial manifestations of this condition can be identified during routine echocardiographic screening. However, computed tomography angiography is advisable to evaluate vascular calcification and possible aneurysm formation in patients with cutaneous lesions.
Prevention of vascular disease in thalassaemia primarily consists of properly controlling transfusion therapy and iron chelation. Splenectomy may be a factor, because of the spleen’s essential role in removing prematurely senescent red blood cells and vasoactive membrane fragments (Morris 2011, Singer 2006). Iron chelation therapy should be aimed at controlling non-transfusion bound iron, as well as lowering mitochondrial oxidative stress. Different chelators have different relative strengths in these regards, however both deferasirox and deferiprone improve endothelial function over time (Cheung 2008, Tanner 2007).
The prospects for patients with thalassaemia have improved with a greater understanding of the disease and with better individualised regimes of management. Close co-operation between the medical disciplines is called for. At the same time, the fundamental treatment aim remains to provide regular, effective iron chelation, in forms that encourage patients to comply with treatment - which must be allied to more precise definition of tissue-specific iron loads, so that patient and physician alike have a better idea of individualised risk. Similar to vascular disease in non thalassaemic patients, lifestyle choices can have a major impact. Obesity is less common in thalassaemia patients than the general population, but no less toxic to the vasculature. Regular exercise improves vascular health by restoring endothelial reactivity and lowering vascular inflammation. While there have been no controlled studies of diet and exercise in the thalassaemia population, there is sufficient shared pathophysiology to extrapolate results from the general population.
Below is a summary of the key recommendations discussed in this chapter. The level of evidence associated with each respective point is included:
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