Iron overload cardiomyopathy

In patients on regular blood transfusions who are not adequately chelated because of the lack of compliance with, or access to, iron chelation regimens, iron overload cardiomyopathy constitutes the main form of heart disease (Kremastinos & Farmakis, 2011; Kremastinos et al., 2010; Aessopos et al., 2004). The pathophysiology of iron overload cardiomyopathy has been reviewed elsewhere (Figure 2) (Kremastinos & Farmakis, 2011). This form of cardiomyopathy may be manifested as two different phenotypes, either as hypokinetic cardiomyopathy with reduced left ventricular (LV) contractility, with or without LV dilatation, leading to heart failure with reduced LV ejection fraction (HFrEF), or as restrictive cardiomyopathy with severely impaired LV diastolic function and preserved contractility, leading to heart failure with preserved LV ejection fraction (HFpEF). Many patients with severe iron loading persist with normal or near normal systolic LV function, sometimes for prolonged periods, but are at risk of acute decompensation, which may be rapid and often precipitated by intercurrent illness. Reduction in systolic function in the presence of significant myocardial iron overload (T2* <20ms), from the often supra-normal ejection fraction (EF) associated with thalassaemia (EF >60%), have a potentially dire prognosis.

Figure 2

Pathophysiology of iron overload cardiomyopathy (from Kremastinos et al., Circulation 2011;124: 2253-2263).

Rhythm disorders, including conduction abnormalities and ventricular arrhythmias have also been associated with severe myocardial iron overload. The risk of LV ejection fraction decline, heart failure and arrhythmias increases with the severity of cardiac iron overload, as evaluated by MRI T2* (Figure 3) (Kremastinos & Farmakis, 2011; Kirk et al., 2009). Although the prevalence of cardiac abnormalities is very low in well-treated patient populations (Aessopos et al., 2004), the global prevalence of cardiac iron overload remains high, affecting 25% of TM globally (Koohi, Kazemi & Miri-Moghaddam, 2019). Importantly, iron overload cardiomyopathy may be reversed by intensive iron chelation therapy (Tanner et al., 2007, 2008).

Figure 3

Schematic representation of the relationship among cardiac iron overload, as estimated by magnetic resonance imaging T2*, left ventricular ejection fraction and the risk of heart failure in patients with thalassaemia (from Kremastinos et al., Circulation (more...)

High-output failure

In the absence of regular transfusions able to maintain an adequate pre-transfusional haemoglobin concentration, chronic anaemia leads to a compensatory increase in cardiac output (Aessopos, Kati & Farmakis, 2007). High-output failure was actually the single leading cause of death in thalassaemia patients before the era of regular transfusion therapy (Engle, Erlandson & Smith, 1964). In addition, high-output state also contributes to heart disease in contemporary thalassaemia populations, including TI or sub-optimally transfused TM patients, to an extent that is directly related to the severity of residual chronic anaemia (Aessopos et al., 2004, 2005).

Pulmonary hypertension

In non-regularly treated patients with TI, age-related pulmonary hypertension, leading to HFpEF, has been reported as the main form of heart disease, accounting for up to 60% of these patients in previous cohorts (Aessopos et al., 2005, 2001; Farmakis & Aessopos, 2011). In contrast, the prevalence of pulmonary hypertension in contemporary regularly treated thalassaemia populations is considerably lower approximating 2% (Derchi et al., 2014). The pathophysiology of pulmonary hypertension is multifactorial and summarised in Figure 4. In non-transfused TI patients, particularly those with previous splenectomy, a high occurrence of thromboembolic complications is also observed, including deep vein thrombosis, pulmonary embolism, stroke, portal vein thrombosis and others (Taher et al., 2006; Cappellini et al., 2000). The prevalence of thromboembolic disease is reported to be considerably lower in regularly treated TM patients (5%) compared to TI patients with a history of splenectomy (29%) (Cappellini et al., 2000).

Figure 4

Pathophysiology of pulmonary hypertension in thalassaemia. LA, left atrium.

Other forms of cardiovascular disease

A high prevalence of pericarditis of nearly 50% has been reported in a historical cohort of young, poorly treated thalassaemia patients, before the era of any regular treatment (Engle, Erlandson & Smith, 1964). The reported prevalence has been considerably lower in more recent cohorts, including 5% in well-treated TM patients (Aessopos et al., 2004), and 8% in TI patients not receiving transfusion therapy (Aessopos et al., 2001).

A 4% prevalence of clinically suspected myocarditis has been reported by a large study in thalassaemia, with half of these cases having histologically confirmed myocarditis according to Dallas criteria (Kremastinos et al., 1995). Myocarditis was associated with acute or chronic heart failure and arrhythmias in these patients.

Valvular heart disease concerns an increasing prevalence of mainly mild to moderate disorders including mitral valve prolapse, mitral and aortic valve regurgitation and some sporadic cases of severe aortic stenosis (Aessopos et al., 2004, 2005, 2001; Farmakis et al., 2006). These lesions have been partly related to cardiac remodelling in the context of a high output state and, interestingly, to a coexisting disorder of elastic tissue resembling hereditary pseudoxanthoma elasticum (PXE) (Aessopos, Farmakis & Loukopoulos, 2002). This disorder is primarily seen in middle-aged or elderly patients, usually with non-regularly treated TI, and is followed by cutaneous, ocular, vascular and valvular lesions.

Cerebrovascular disease in the form of either ischaemic or haemorrhagic stroke has been reported in patients with thalassaemia (Aessopos et al., 1997). Ischaemic strokes have been associated with underlying atrial fibrillation in patients with TM, while haemorrhagic strokes with the aforementioned PXE-like elastic tissue disorder in patients with TI, with PXE-related vascular lesions comprising calcification and increased risk of rupture and bleeding (Aessopos, Farmakis & Loukopoulos, 2002).

As previously stated, ageing in combination with coexisting CV risk factors such as diabetes mellitus, which may arise by suboptimal iron chelation, and smoking, may modify the clinical spectrum of the disease with the increasing occurrence of age-related CV complications, including atrial fibrillation, diastolic LV dysfunction, aortic valve stenosis, and perhaps vascular diseases such as systemic hypertension and coronary and cerebrovascular disease that have hitherto been uncommon in thalassaemia (Farmakis et al., 2020). In addition, already known disease-related complications such as pulmonary hypertension, endothelial dysfunction, increased vascular stiffness and PXE-like lesions also increase with age (Aessopos et al., 2001; Aessopos, Farmakis & Loukopoulos, 2002; Aessopos et al., 2007a).

When to refer?

The burden and prognostic impact of CV disease have imposed the regular CV assessment of thalassaemia patients as an indispensable part of the multidisciplinary monitoring programs. Regular CV monitoring should be performed on an annual basis in all thalassaemia patients, regardless of the presence of history or symptoms of CV disease. In the presence of CV disease, the frequency and content of CV assessment should be tailored to meet each patient’s needs and shorter intervals (e.g., 3 or 6 monthly) may be applied according to severity.

In addition, the development of new symptoms potentially suggestive of CV disease, such as dyspnoea, chest discomfort, frequent palpitations, syncope or fainting, lower limb oedema, fatigue or exercise intolerance should prompt immediate referral for CV evaluation. Importantly, symptoms such as fatigue, exercise intolerance or palpitations may also result from the anaemia caused by the main disease, while hepatic congestion due to right heart failure may be confused with disease-related hepatomegaly or other causes of abdominal discomfort. In these cases, the diagnosis of CV disease may be overlooked or delayed. Given the particularities of CV disease in thalassaemia, CV assessment and monitoring should ideally be performed either in a specialised cardiac clinic for haemoglobinopathies or in close consultation with such a clinic or a cardiologist with experience in thalassaemia heart disease.

How to assess?

The regular annual basic CV assessment consists of (Figure 5):

Figure 5

Basic algorithm for the cardiac evaluation of patients with thalassaemia (modified from Farmakis et al, Eur J Heart Fail 2017;19:479-489). DFO, deferoxamine; DFP, deferiprone; HfrEF, heart failure with reduced left ventricular ejection fraction; MRA, (more...)

• history taking;
• physical examination;
• resting electrocardiogram (ECG);
• transthoracic echocardiography (TTE).

A typical TTE examination should assess and report cardiac cavity dimensions, LV wall thickness, LV systolic and diastolic function indices, right ventricular systolic function indices, tricuspid regurgitant flow velocity (TRV) to screen for pulmonary arterial hypertension, cardiac valve morphology and function and presence of pericardial fluid or other abnormalities such as shunts or intracavity masses. It should be stressed that increased Doppler velocities may reflect a high-output state due to chronic anaemia and not true heart disease. It is increasingly recognised that newer modalities such as strain measurements may be better at detecting subtle changes in function, predating changes in EF and thus give warning that increased chelation is advised.

Evaluation of cardiac iron content with cardiac MRI T2* should be performed simultaneously with hepatic MRI T2* in time intervals determined by the degree of iron load of the patient and the local protocols. Typically, the first MRI T2* scan is performed 7-10 years after the initiation of blood transfusions and repeated every 2 years thereafter. Although the cardiovascular magnetic resonance (CMR) T2* has developed into the ’gold standard‘ metric for iron assessment there is increasing realisation that newer CMR sequences and parameters may provide advantages in the future by drastically reducing scan times and cost and so increasing availability (Abdel-Gadir et al., 2016).

It should be stressed that, serum ferritin concentration, although widely available and used as a predictor of total iron load, correlates quite poorly with cardiac iron content and should not be used as a surrogate in this regard (Aessopos, Kati & Farmakis, 2007). In the absence of access to MRI T2*, worsening of LV diastolic or systolic function indices by serial echocardiography, may serve as red flags for possible cardiac iron overload (Aessopos et al., 2007b; Maggio et al., 2013). It should be kept in mind, however, that cardiac dysfunction generally lags behind cardiac iron deposition by several years, while cardiac iron clearance is also a very slow process requiring years to complete (Carpenter et al., 2011; Anderson et al., 2004). A proposed algorithm to guide MRI T2* use according to availability is depicted in Figure 6 (Viprakasit et al., 2018).

Figure 6

A proposed algorithm to guide magnetic resonance imaging (MRI) T2* use according to local availability (LIC, liver iron concentration; MRI, magnetic resonance imaging; SF, serum ferritin; modified from Viprakasit et al., Am J Hematol 2018;93: E135-E137). (more...)

Additional CV investigations may be needed in the presence of known CV abnormalities, symptoms suggestive of CV disease or abnormal findings during basic CV assessment. Such investigations may include (but are not limited to):

• ambulatory ECG monitoring for the evaluation of frequent palpitations or known arrhythmias or to assess the arrhythmogenic risk of patients with systolic LV dysfunction or heart failure;
• cardiac biomarkers, including cardiac troponins (e.g., in suspected myocarditis) or natriuretic peptides (e.g., for the evaluation of patients with known or suspected heart failure);
• cardiac magnetic resonance imaging for the more accurate assessment of cardiac cavities, systolic LV function and myocardial tissue characterization;
• exercise testing such as exercise ECG or ergospirometry for the assessment of functional capacity or arrhythmias;
• right cardiac catheterization for the evaluation of pulmonary artery pressure in patients with elevated TRV (e.g., >3 m/s, despite optimal transfusion therapy and a pre-transfusional haemoglobin level close to 100 g/l).
• lung function tests, high-resolution chest computed tomography (CT), CT pulmonary angiography or lung scanning along with careful LV ventricular function evaluation are required for the comprehensive diagnostic assessment of confirmed pulmonary hypertension.

Assessment should always take into consideration the parameters of the main disease, such as blood transfusion and iron chelation programme, pre-transfusional haemoglobin level and serum ferritin concentration, as well as parameters related to other systems such as liver or endocrine disease. In addition, CV assessment should always be performed in close collaboration and communication with the thalassaemia physician who oversees the whole patient’s monitoring and treatment.

Disease specific therapy

The management of CV abnormalities in thalassaemia patients should take under consideration the pathophysiology and characteristics of the main underlying disease. As a result, disease-specific therapy, including regular blood transfusions aiming at a pre-transfusional haemoglobin level of 100 g/l and iron chelation regimens aiming at a cardiac T2* value greater than 20 ms, hold the key role for the prevention and management of CV disease (Figure 7). Patients with high levels or serum ferritin or hepatic iron overload with or without cardiac iron overload should be treated with combined chelation therapy (e.g., deferoxamine and deferiprone), (Porter et al., 2013) while those with acute or advanced iron overload-induced heart failure may require continuous intravenous infusion of deferoxamine.(Tanner et al., 2008) It should further be stressed that cardiac dysfunction generally lags cardiac iron deposition by several years, while cardiac iron clearance is also a very slow process requiring several years to complete (Carpenter et al., 2011; Anderson et al., 2004). In the presence of significant cardiac iron overload (T2* <20 ms), patients are at risk of rapid deterioration, even in the presence of normal or near normal systolic LV function, while a drop in LV EF may often carry a dire prognosis, As a result, chelation regimes must be adjusted to ensure a rapid fall in cardiac iron content (Pennell et al., 2013).

Figure 7

A basic algorithm for the management of thalassaemia patients on regular blood transfusions (DFO: deferoxamine; DFP: deferiprone; DFX: deferasirox; Hb: haemoglobin concentration; ACEi: angiotensin converting enzyme inhibitors; ARB: angiotensin II receptor (more...)

CV Prevention

Undertaking a healthy lifestyle, in terms of diet, regular exercise, body weight control and smoking abstinence, in accordance with general guidelines on CV prevention is crucial for the prevention of CV disease in combination with proper disease-specific therapy. In addition, the management of CV risk factors and of complications arising from other systems or organs such as diabetes, thyroid disease, or liver disease, is also of key importance. CV prevention is becoming even more important today in view of the increasing risk of age-related complications in ageing thalassaemia patients.

CV treatment

Diagnosis of a specific form of CV disease will prompt the initiation of the recommended therapeutic modalities, in accordance with the corresponding guidelines published by cardiology societies or associations such as the European Society of Cardiology (ESC) or the American Heart Association (AHA); the description of the management of each form of CV disease falls outside the scope of this guideline. The CV management of patients should take under consideration the following tips:

• CV disease should primarily prompt optimisation of disease-specific therapy, including blood transfusions and iron chelation as well as investigation and treatment of comorbid conditions such as endocrine or metabolic disease.
• Cardiac dysfunction and heart failure due to iron overload may be reversed with intensified iron chelation therapy and this possibility should be considered in decision making regarding more permanent CV interventions such as implantable cardioverter defibrillator (ICD) implantation (using MRI conditional devices), catheter ablation of arrhythmias, permanent ventricular assist device implantation or cardiac transplantation.
• A pacemaker may be need for the management of atrioventricular block, often related to iron overload; in this case leads should be MRI conditional to allow periodic evaluation of iron overload by the T2* technique.
• Thalassaemia patients generally have low blood pressure levels, and therefore use of blood pressure-lowering medications such as renin-angiotensin-aldosterone system inhibitors should be cautious. In addition, the use of vasopressors and other blood support therapies in patients with hypotensive heart failure should rather be targeted to renal perfusion and other surrogates instead of blood pressure values.
  Thalassaemia patients often have restrictive cardiac physiology, usually due to iron overload, and increased vascular stiffness, that may render them sensitive to hypovolaemia during diuresis.
  Anticoagulation in patients with atrial fibrillation may be challenging; non-regularly treated patients with previous splenectomy carry an increased risk of thromboembolism,5 while patients with pseudoxanthoma elasticum-like lesions may carry an increased risk of bleeding (Aessopos, Farmakis & Loukopoulos, 2002). The use of general risk prediction scores such as the CHA2DS2-VASc may be inappropriate for thalassaemia patients, as it may underestimate their potential risk.

Box

Summary and Recommendations.