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Heart 99:204-213 doi:10.1136/heartjnl-2012-301793
  • Education in Heart
  • MYOCARDIAL DISEASE

Recent advances in the imaging assessment of infiltrative cardiomyopathies

  1. Joseph B Selvanayagam
  1. Department of Medicine, Flinders University, Flinders Medical Centre, Adelaide, Australia
  1. Correspondence to Professor Joseph B Selvanayagam, Department of Medicine, Flinders University, Flinders Medical Centre, Adelaide 5042, Australia; joseph.selvanayagam{at}flinders.edu.au

Infiltrative cardiomyopathy can result from a wide spectrum of both inherited and acquired conditions with varying systemic manifestations. They usually portend an adverse prognosis, although in rare instances (eg, Fabry disease) early diagnosis can result in potentially curative treatment. Cardiac amyloid remains the archetypal infiltrative cardiomyopathy and is discussed in most detail in this article. Non-invasive imaging—principally echocardiogram and cardiovascular MRI—plays a pivotal role in the early diagnosis and follow-up of all types of infiltrative cardiomyopathy. This article  focuses on the use of these modalities in infiltrative cardiomyopathy, with special emphasis on the most recent advances in imaging assessment.

Amyloidosis

Amyloidosis is a clinical disorder caused by extracellular deposition of insoluble abnormal fibrils, derived from aggregation of misfolded, normally soluble, protein.1 ,2 About 20 different unrelated proteins are known to form amyloid fibrils in vivo, which share a pathognomonic ultrastructure. Systemic amyloidosis, in which amyloid deposits are present in the viscera, blood vessel walls and connective tissues, is usually fatal and is the cause of about 1/1000 deaths in developed countries. There are also various localised forms of amyloidosis in which the deposits are confined to specific foci or to a particular organ or tissue. ‘Cardiac amyloidosis’ describes involvement of the heart by amyloid deposition, whether as part of systemic amyloidosis (as is most commonly the case) or as a localised phenomenon.

Amyloid subtype classification

Systemic AA amyloidosis, formerly known as secondary amyloidosis, rarely involves the heart (table 1). Systemic AL amyloidosis, previously known as primary amyloidosis, is the most commonly diagnosed form of clinical amyloid disease in developed countries. AL fibrils are derived from monoclonal immunoglobulin light chains and consist of the whole or part of the variable (VL) domain. The heart is affected pathologically in up to 90% of AL patients, in 50% of whom diastolic heart failure with physical signs of right heart failure is a presenting feature. Conversely, <5% of patients with AL amyloidosis involving the heart have clinically isolated cardiac disease. Death in more than half of these patients is due to either heart failure or arrhythmia.

Table 1

Subtypes of amyloid and their characteristics

Rapezzi et al conducted a longitudinal study on 233 patients with cardiac amyloidosis in two large tertiary Italian centres.3 They found significant differences in pathophysiology and courses in the three types of amyloidosis that affect the heart. AL cardiomyopathy seems to be associated with only slightly increased wall thickness, but shows the highest frequency of haemodynamic derangement and low QRS voltage on ECG, and its clinical course is aggressive. The transthyretin (TTR) related cardiomyopathies, especially senile systemic amyloidosis (SSA), are associated with notably increased left ventricular (LV) wall thickness but less frequently with haemodynamic alterations. Their clinical course is less aggressive than in the AL type patients, despite the patients' average higher age and greater morphological abnormalities. It has been postulated that the circulating free light chains in AL amyloid have direct toxic effects on the myocardium and the TTR related amyloid is predominantly an infiltrative cardiomyopathy.w1

Echocardiography

Echocardiography can show several features that are suggestive of cardiac amyloidosis, although the classical features are commonly only present in the later stages of disease, and there is a wide spectrum of echocardiographic findings. It cannot confirm diagnosis in isolation and the images should be interpreted in the context of the clinical picture and other investigations. AA amyloid very rarely affects the heart, and the common types that do—that is, AL and variant/wild-type TTR types—cannot be distinguished by echo. Although extremely rare, hereditary apolipoprotein A-I amyloidosis can involve the heart, again producing similar echocardiographic abnormalities.

The most common echocardiographic feature is increased thickness of the LV wall, particularly in the absence of hypertension (figure 1A), referred to incorrectly as ‘hypertrophy’ as the pathological process is infiltration, not myocyte hypertrophy. This feature has poor specificity for amyloidosis due to its occurrence in other conditions (eg, hypertensive heart disease, hypertrophic cardiomyopathy and other infiltrative cardiac diseases such as glycogen storage diseases, sarcoidosis and haemochromatosis) (figure 2). The combination of increased LV mass in the absence of high ECG voltages may be more specific for infiltrative diseases, of which amyloid is the most common. High sensitivity (72–79%) and specificity (91–100%) have been reported for this combination,w2 though some study sizes are small and may be influenced by referral bias.

Figure 1

(A) Apical four chamber 2D echocardiogram in a patient with cardiac amyloid, showing thickened left ventricular walls with increased echogenicity (thick white arrows). (B) Apical four chamber 2D echocardiogram in the same patient, showing left ventricular hypertrophy with enlarged atria and small pericardial effusion (white arrows). LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

Figure 2

Apical four chamber 2D echocardiogram of the left ventricle (LV) in hypertrophic cardiomyopathy (A), cardiac amyloid (B), Fabry disease (C), and hypertension (D). 2D echocardiography cannot distinguish the different types of infiltrative cardiomyopathies.

Increased echogenicity of the myocardium, particularly with a granular or ‘sparkling’ appearance, has been reported in several studies4 (figure 1A). This can occur in other causes of LV hypertrophy (LVH) and, although high specificity rates are quoted (71–81%),w2 the populations studied were those referred with suspected amyloid, and this specificity may not be reflective of ‘real life’ practice. Moreover, sensitivity tends to be low, with this pattern seen in 26–36% of cardiac amyloid (CA) cases, apart from a single study suggesting a sensitivity of 87%. It should be noted that this granular pattern only applies to standard echocardiographic imaging, without tissue harmonics being applied, as this increases myocardial echogenicity in general. Newer echocardiographic image processing techniques may also reduce the granular appearance. Thus, although increased echogenicity is common in amyloid, its usefulness as a discriminating factor is limited.

LV systolic function is usually normal until the late stages of the disease process. Systolic function can in some cases be hyperdynamic (hence can be mistaken for hypertrophic or hypertensive cardiomyopathy) in initial stages, but in advanced stages systolic function can be depressed without cavity dilation, resulting in a pronounced reduction in stroke volume and cardiac output.

Diastolic dysfunction, however, is the fundamental abnormality in cardiac amyloidosis and is abnormal before systolic dysfunction, which is often normal even with advanced symptoms. Early in the disease process, there may be an abnormal relaxation pattern with progression to a restrictive pattern in advanced and symptomatic disease (figure 3). Not only do diastolic parameters correlate with severity of symptoms but they are prognostic with a restrictive filling pattern (deceleration time (DT)<150 ms) associated with a mortality of 50% at 1 year. Atrial enlargement is a common finding in amyloid heart disease and reflects the abnormal diastolic function (figure 1B).

Figure 3

(A) Spectral Doppler of mitral inflow demonstrating shortened deceleration time (DT) (white arrows) and increased E:A ratio, suggestive of restrictive physiology. (B) Tissue Doppler recording at mitral septal annulus of the same patient demonstrating significantly reduced E’ velocity and elevated E/E′ corresponding to pronounced reduction in myocardial longitudinal function and elevated left sided filling pressures, respectively.

Tissue Doppler imaging measures regional myocardial motion and velocity and can detect changes in systolic and diastolic function before more conventional measurements of cardiac dysfunction. However, tissue Doppler velocity imaging suffers from the confounding effects of tethering and translation and hence newer techniques which assess regional longitudinal myocardial deformation, such as strain and strain rate, may be more sensitive. These tissue myocardial changes may be present before increased LV wall thickness and symptoms, and hence may have a role in preclinical detection. In a study of 97 biopsy proven AL amyloid patients, Koyama and colleagues demonstrated that, in contrast to standard echocardiography, strain and strain rate imaging were more sensitive in the detection of a subtle impairment in longitudinal contraction early in the clinical course of cardiac amyloidosis.5 The same authors have subsequently shown that systolic basal strain is a predictor of clinical outcome in patients with AL amyloidosis, more so in the presence of heart failure.6

With two dimensional (2D) speckle tracking echocardiography it is possible to assess the LV torsional deformation around its longitudinal axis which is described as twisting (torsion) and untwisting. Twisting/untwisting motion involves both systolic and diastolic function and therefore would be altered in thickened ventricle as in cardiac amyloidosis. This was assessed in a study by Porciani and colleagues in 45 patients with AL amyloid and 26 control subjects.7 The AL patients were subgrouped into CA if LV wall thickness was ≥12 mm and non-CA (NCA) if LV thickness was ≤12 mm. Both AL patients and controls had standard echocardiograms, and 2D speckle tracking, LV rotation in basal and apical planes, twisting, twisting rate and longitudinal strain were measured. The LV twist and untwisting rate was increased in the NCA group compared to the CA and the control groups. The increase is a compensatory mechanism to impaired relaxation seen early in the disease and fails as the disease progresses. Similar findings were noted by the same group in patients with hypertension without any LVH.8

Therefore, newer 2D echocardiography techniques of strain, strain rate and 2D speckle tracking imaging are promising in the preclinical detection of cardiac amyloidosis.

Other echocardiographic features are the result of diffuse infiltration with resultant increased wall thickness of the right ventricle, cardiac valves and interatrial septum. Although cardiac valves may be focally or diffusely thickened, significant dysfunction is not common. Interatrial septal thickening along with speckling is a distinctive sign of amyloid with high specificity. The atria are enlarged and often immobile, giving an ‘owl's eyes’ appearance. Abnormal atrial function can be demonstrable using strain echocardiography and may be contributory to cardiac symptoms in primary amyloidosis. Right ventricular (RV) abnormalities are common and may manifest as systolic or more commonly diastolic dysfunction. RV dilatation, if present, may reflect a more advanced disease process and is associated with a more adverse prognosis. Small to moderate sized pericardial effusion due to pericardial involvement is also common, particularly in end stage disease (figure 1B). A high frequency of intracardiac thrombosis has been noted in patients with cardiac amyloidosis, especially those with the AL type, despite the presence of sinus rhythm and preserved LV ejection fraction.9

Despite the number of echocardiographic features found in amyloid heart disease, none, taken individually, are diagnostic and they can be seen in other cardiac diseases. The diagnosis is still based on the combination of various echocardiographic findings with the integration of clinical findings and (where available) further imaging with cardiovascular magnetic resonance (CMR) (see below). However, pronounced myocardial hypertrophy along with valvular thickening, abnormality of diastolic function (particularly restrictive physiology), and the presence of pericardial effusion in combination with characteristic ECG findings makes amyloid disease an important diagnostic consideration.

CMR imaging

A strength of CMR using the late gadolinium enhancement (LGE) technique is the ability to ‘phenotype’ various forms of cardiomyopathy with high spatial resolution and reproducibility. Maceira et al studied 29 patients with systemic amyloidosis and 16 hypertensive controls using gadolinium enhanced CMR.10 Amyloidosis was associated with qualitative global and subendocardial gadolinium enhancement of the myocardium (figure 4B). Subendocardial longitudinal relaxation time (T1) in amyloid patients was shorter than in controls, and was correlated with markers of increased myocardial amyloid load, such as LV mass, wall thickness, interatrial septal thickness, and diastolic function. Global subendocardial LGE was found in approximately two thirds of patients. Based on pathological correlates in a patient from this study, the CMR hyper-enhancement probably represents interstitial expansion from amyloid infiltration.

Figure 4

(A) Cardiovascular magnetic resonance (CMR) steady state free precession image in a horizontal long axis view demonstrating increased left ventricle (LV), atrial wall thickness (thin white arrows) and bilateral pleural effusions (thick white arrows), in a patient with cardiac amyloid (CA). (B) CMR late gadolinium imaging in vertical long axis view. There is global sub-endocardial hyperenhancement (arrows) in the LV and right ventricle, typical of CA. LA, left atrium.

Perugini et al studied an Italian population of patients with histologically proven systemic amyloidosis and echocardiographic diagnosis of cardiac involvement.11 Gadolinium enhancement by CMR was detected in 16 of 21 (76%) patients. In contrast to the study of Maciera et al, where the pattern of late enhancement was global and subendocardial, Perugini et al reported a much more variable pattern of late enhancement, that could be localised or diffuse, and subendocardial or transmural. Transmural extension of hyperenhancement (ie, how much of the LV wall thickness was enhanced) within each patient significantly correlated with LV end systolic volume. The number of enhanced segments correlated with LV end diastolic volume, end systolic volume, and left atrial size. An especially unique feature of LGE appearances in this population is the blood pool appearing atypically dark. This reflects the similar myocardial and blood T1 values due to high myocardial uptake and fast blood pool washout of the contrast agent.

Syed et al performed LGE CMR in 120 patients referred to a tertiary centre with confirmed amyloidosis; 97% of the histologically confirmed cardiac amyloidosis (35/120) had abnormal LGE and 91% had increased LV wall thickness on echocardiography.12 The pattern of LGE was global (transmural and subendocardial) in 83%. Of the patients without cardiac histology and a normal echocardiogram, 30% had LGE (patchy focal or global), and the LGE presence was strongly associated with clinical, morphological, functional, and biochemical markers of prognosis. The absence of endomyocardial biopsy data in patients with a normal echocardiogram, however, is a weakness of the study and leaves the findings in this study subset as speculative rather than confirmatory.

Although yet to be proven, imaging with a highly reproducible and quantifiable technique such as CMR may help to estimate the prevalence of cardiac involvement in systemic amyloidosis when cardiac morphological changes are not apparent by echocardiography. Screening of subclinical early cardiac involvement may become possible if delayed enhancement proves to have adequate sensitivity in detecting early amyloid infiltration. Improved non-invasive surveillance may also potentially aid in the evaluation of new chemotherapeutic agents. Figures 4A and B illustrates the typical CMR features of amyloid heart disease.

Gadolinium kinetics on CMR could be a potential prognostic marker in cardiac amyloidosis. Maceira et al prospectively followed the 29 patients from their earlier study for a period of 2 years.13 All patients underwent biopsy, 2D echocardiography and Doppler studies, 123I-serum amyloid P (SAP) scintigraphy, serum N terminal pro B-type natriuretic peptide (NT-proBNP) assay, and CMR with T1 mapping method and LGE. Their results show that the 2 min post-gadolinium intramyocardial T1 difference between the subepicardium and subendocardium predicted mortality with 85% accuracy at a threshold value of 23 ms. The intramyocardial T1 gradient as measured post-gadolinium imaging is a reflection of the burden of amyloid deposition in the myocardium. Lower T1 indicates increased subepicardial involvement. The intramyocardial T1 gradient was a better predictor of survival than free light chain response to chemotherapy or diastolic function.

Radiolabelled SAP component scintigraphy

SAP is a highly conserved, invariant plasma glycoprotein of the pentraxin family that becomes specifically and highly concentrated in amyloid deposits of all types as a result of its calcium dependent binding to all types of amyloid fibril. Following intravenous injection, radiolabelled SAP distributes between the circulating and the amyloid bound SAP pools in proportion to their size and can then be imaged and quantified.w3 This safe, non-invasive method provides unique information on the diagnosis, distribution and extent of amyloid deposits throughout the body, and serial scans monitor progress and response to therapy. Serial SAP scans have unequivocally demonstrated that amyloid deposits of all types regress in a proportion of patients when the supply of the respective amyloid fibril precursor protein is sufficiently reduced. Unfortunately, planar SAP scintigraphy is unable to image amyloid in the moving heart.

Sarcoidosis

Sarcoidosis is a systemic disorder of unknown aetiology involving granulomatous infiltration of various organs, including the heart. The pathophysiology is thought to be related to an excessive cell mediated immune response to an unknown antigen with accumulation of mononuclear inflammatory cells, mostly CD4+ lymphocytes.w4 The resultant inflammatory response produces tissue injury and fibrosis which may be focal or diffuse.

There is a striking variance in prevalence, with the disease more common in blacks and Scandinavians.w5 Cardiac involvement occurs in up to 30–40% of cases in postmortem studies14 and is associated with poorer prognosis, particularly if patients exhibit cardiac symptoms. Clinically, cardiac involvement occurs in 5% of patients and its presentation may include rhythm disturbance (particularly heart block), cardiac failure, cor pulmonale, and even sudden death.w6 However, diagnosis of cardiac involvement is difficult due to the numerous different manifestations of the disease process and the lack of sensitivity or specificity of various cardiac imaging tests. The Japanese Ministry of Health and Welfare guidelines (JMHW) for diagnosis of cardiac sarcoid, which incorporates the use of ECG, cardiac imaging and histopathology, is the most well known and is currently the reference standard.15 Mehta et al found that including advanced cardiac imaging with positron emission tomography (PET) scanning or CMR increased sensitivity above the previously established criteria.16

Echocardiography

Sarcoid involvement of the heart is a great masquerader and may present with a variety of echocardiographic abnormalities, including wall motion abnormalities (particularly regional thinning and aneurysms),w7 systolic and diastolic dysfunction, pulmonary hypertension, and pericardial effusions. Case reports have sarcoidosis mimicking coronary artery disease, takotsubo cardiomyopathy, right ventricular cardiomyopathy,w8 hypertrophic cardiomyopathy, and valvular dysfunction. However, in most cases of systemic sarcoidosis there are no distinctive morphological or functional abnormalities of the heart. Tissue Doppler17 and ultrasonic tissue characterisation by myocardial integrated backscatter have demonstrated abnormalities in the absence of other 2D echocardiographic features, and hence may have the ability to diagnose early cardiac involvement.

Nuclear imaging

Thallium-201 scintigraphy in sarcoidosis can be distinctive with a pattern of reverse redistribution in which a resting perfusion defect improves with stress imaging. This can be helpful in differentiating sarcoid heart disease from an ischaemic cause. However, these findings are non-specific, particularly in the absence of cardiac symptoms, and hence are of limited value as a screening test. Gallium-67 scintigraphy has also been used to diagnose cardiac sarcoid as it accumulates in the presence of active inflammation. Hence the absence of uptake may not exclude sarcoid involvement but suggests lack of active disease and has been shown to predict response to corticosteroid therapy.18

(18)F-fluoro-2-deoxyglucose PET (FDG PET) has high diagnostic accuracy in the assessment of cardiac sarcoidosis. A retrospective study by Langah et al, using FDG PET in 30 patients with systemic sarcoidosis and suspected cardiac sarcoidosis, showed a specificity of 90% and sensitivity of 85%.19 The sensitivity and specificity of diagnostic accuracy of FDG-PET against the JMHW in 164 patients in a recent meta-analysis was 89% and 78%, respectively.20 Restricted availability of this modality is a limitation in its wider uptake in the routine assessment of infiltrative cardiomyopathy.

CMR imaging

The superior spatial resolution of CMR is particularly useful in identifying even small areas of myocardial oedema and fibrosis leading to post-inflammatory scarring that is typically seen in cardiac sarcoidosis. Both global and regional contractile dysfunction has been described, although, similar to cardiac amyloidosis, the LGE technique has been most widely evaluated in clinical studies using CMR. Smedma and colleagues evaluated the utility of LGE in 58 patients with biopsy proven pulmonary sarcoidosis, 25% of whom also had symptoms suggestive of cardiac involvement.21 All patients underwent clinical assessment, 12 lead ECG, ambulatory ECG monitoring, transthoracic echocardiography, 201thallium single photon emission CT (SPECT), and CMR (cine and LGE). The modified JMHW criteria were used as the gold standard. CMR revealed LGE, mostly involving the epicardium of the basal and lateral segments, in 73% of patients diagnosed with cardiac involvement by the Japanese criteria (figure 5). In about half of these patients scintigraphy was normal, while patchy LGE was present, underlining the differences in spatial resolution. This study is limited in that only a minority of patients had correlation between LGE-CMR results and endomyocardial biopsy. Other studies have confirmed the predilection of LGE for the basal–lateral segments, although subendocardial or transmural hyperenhancement has been also observed, mimicking the ischaemic pattern.

Figure 5

Late gadolinium imaging in left ventricular short axis view demonstrating subepicardial hyperenhancement in the basal septum (thick arrows) and inferior (thin arrows) segments in a patient with biopsy proven cardiac sarcoidosis.

More recently, Patel and colleagues prospectively studied 81 patients with biopsy proven extracardiac sarcoidosis for a parallel and masked comparison of cardiac involvement between LGE CMR and standard clinical evaluation, with the use of consensus criteria based on JMHW guidelines.22 Obstructive coronary disease was excluded by x-ray angiography in the LGE CMR positive patients. They found that LGE CMR identified myocardial abnormalities in significantly more patients than a standard clinical evaluation based on JMHW guidelines (26% vs 12%). LGE CMR positive patients had a higher rate of adverse events, including cardiac death, during a 21 month follow-up, compared to LGE CMR negative patients. Myocardial damage detected by LGE CMR appears to be associated with future adverse events including cardiac death, but there were few events in this small cohort and therefore a large scale study is required.

Apart from LGE, both functional and anatomical (‘white blood’ and ‘black blood’) CMR sequences can help in detecting cardiac sarcoid by demonstrating some of its characteristic features—septal thinning, LV/RV dilatation and systolic dysfunction, and pericardial effusion.w9 w10 T2 weighted sequences may also help in identifying myocardial oedema.23 CMR also identifies pulmonary features of sarcoid, such as enlarged hilar lymph nodes and lung fibrosis.

Anderson-Fabry disease

Fabry disease is an X-linked condition with systemic and cardiac manifestations. It is an enzyme deficiency of ∝-galactosidase,w11 which results in accumulation of glycosphingoplipids in the lysosomes of various cells and organs including the heart. Cardiac involvement is frequent24 and results in myocyte vacuolation, hypertrophy, and regional fibrosis.25 ,26 This can result in heart failure and conduction abnormalities and is an important cause of death in these patients.w12 Currently, the diagnosis is based on one or more of biochemical testing, genetic mapping and endomyocardial biopsy. However, imaging of the myocardium has been explored as a non-invasive way of early screening and diagnosing patients. Correct diagnosis is of vital importance as, unlike many other forms of infiltrative cardiomyopathy, the condition is potentially reversible with treatment by enzyme replacement therapy.27 Fabry cardiomyopathy is not as rare as initially thought and can be difficult to distinguish from other forms of infiltrative or hypertrophic cardiomyopathies. A recent study discovered that 6% of male patients diagnosed with hypertrophic cardiomyopathy in fact have Fabry disease on biochemical and genetic testing.w13 Another study found that Fabry disease was present in 10% of patients referred to their cardiac unit with unexplained hypertrophy.w14

Echocardiography

The principal echocardiographic finding is concentric LVH with often initially preserved systolic function and without cavity dilatation. The main functional abnormality, like in other infiltrative cardiomyopathies, is abnormal diastology, though restrictive physiology is also possible, but not as common. Cardiac valves may be thickened, but severe valve dysfunction is rare. There is also increased incidence of aortic root dilatation.w15

Recent studies using tissue Doppler imaging have shown a reduction in both relaxation and contraction tissue Doppler velocities in patients. These findings are detectable before the onset of LVH and other morphological changes.28 Strain and strain rate imaging reflect regional myocardial function and contractility, respectively. They are also reduced early in the disease process and can be reversed with treatment.27 Strain imaging has the advantage over tissue Doppler velocity in that it can detect regional heterogeneity in myocardial function, which is characteristic of Fabry disease with strain abnormalities being most pronounced in the inferolateral wall.w16 Interestingly, this is also the area where LGE CMR abnormalities are most pronounced.

More recently, Pieroni et al29 have described the so-called binary sign, which is an abnormal appearance of the LV endocardial border thought to be related to glycosphingolipid compartmentalisation. They found this to be both a specific and sensitive marker for Fabry disease. However, other authors have disputed this finding and suggested this binary appearance is non-specific and affected by instrumental settings.w17

As with other infiltrative and storage cardiomyopathies, the progression and spectrum of disease are not static. In the initial stages, standard morphological and functional changes may not be apparent and hence these newer tissue imaging techniques could provide earlier diagnosis with prompt consideration for enzyme replacement. Regardless, the higher than expected incidence of Fabry disease should alert the imaging clinician to this diagnosis in anyone with unexplained LVH.

CMR imaging

Systematic reporting of CMR features in this disease is sparse. Moon et al have reported LGE patterns in a unique distribution involving the basal inferolateral wall, sparing the endocardium, in 50% of affected patients.30 LGE in this respect probably represents interstitial expansion secondary to replacement fibrosis, although why this region of the myocardium is favoured is unclear. The extent of fibrosis on LGE CMR determines the response to enzyme replacement therapy (ERT). Weidemann and colleagues studied 32 Fabry patients over 3 years regarding disease progression and clinical outcome under ERT.31 LGE CMR was used to assess myocardial fibrosis. They found that in patients without myocardial fibrosis, ERT resulted in significant reduction in LV mass, an improvement in myocardial function, and higher exercise capacity. Those with mild or severe fibrosis showed a minor reduction in LVH and no improvement in myocardial function or exercise capacity.

Prolongation of myocardial T2 relaxation time has also been shown in studies of patients with genotype positive Fabry disease, probably related to the pronounced deposition of glycolipid in the myocardium. This has been suggested by some as a useful marker of this disease. However, there is a wide overlap in myocardial T2 values of Fabry disease patients when compared with patients with LVH from other causes, such that T2 times alone are unlikely to be useful in confirming the diagnosis.32

Cardiac siderosis

CMR myocardial T2* assessment has proven to be an important diagnostic tool and prognostic indicator in cardiomyopathy secondary to iron overload.33 Non-invasive determination of the cardiac iron load is possible using CMR by measuring myocardial relaxation time T2*. T2* is a measure of magnetic relaxation and is shortened when particulate hemosiderin storage iron disturbs the magnetic microenvironment. Myocardial T2* correlates well with cardiac iron concentration measured from biopsy specimens in contrast to liver iron concentration and serum ferritin. This direct assessment allows early detection of patients at risk of cardiomyopathy secondary to iron overload, directs chelation therapy effectively, and prevents deaths from a potentially reversible cardiomyopathy. Declining myocardial T2* is associated with increasing risk of LV dysfunction34 ,35 and increased likelihood of cardiac events in transfusion dependent thalassaemia.36 Significantly, Modell et al observed a 60% reduction in mortality in thalassaemia major patients after the introduction CMR T2* guided chelation therapy.37 This is one of the few examples where systemic use of non-invasive imaging modality has led to an improvement in patient outcome.

Alpendurada and colleagues have demonstrated that the RV function mirrors the decrease in LV function with worsening myocardial iron overload.w18

Hereditary haemochromatosis (HH) can also be considered an infiltrative cardiomyopathy, as it is a deposition disease in which iron is deposited intracellularly, causing cell damage with associated cardiac dysfunction. Cardiac siderosis in HH is uncommon. In a retrospective analysis of patients presenting for evaluation of myocardial iron overload on CMR, Grasso et al found cardiac siderosis in six (11%) out of 53 patients with HH.w19 Echocardiography demonstrates features of dilated cardiomyopathy, including LV dilatation and global systolic dysfunction in an advanced stage of cardiac involvement. Cardiac involvement is progressive and in the later stages can manifest restrictive physiology that clinically can mimic constrictive disease. As in secondary causes of cardiac siderosis, CMR T2* imaging plays a vital role in the early detection of myocardial iron overload, consequently eliminating the need for endomyocardial biopsy in the assessment of iron deposition in HH.

Other infiltrative cardiomyopathies

In glycogen storage diseases (GSD), deficiencies in enzymes responsible for metabolising muscle glycogen not only cause systemic diseases, but can involve the myocardium. Many types have been described, most of which can involve the heart, although in a number of cases (eg, GSD type 2a, Pompe disease) the disease is invariably fatal in early infancy, and is unlikely to be encountered by the adult cardiologist. Danon disease (GSD type 2b), characterised by an X-linked dominant inheritance pattern, can present in childhood and early adulthood. Among males, the key features are cardiomyopathy, skeletal myopathy, and intellectual disability ranging from mild learning problems to mental retardation. In a recent seminal study, Arad et al showed that cardiac disease can be the initial and predominant manifestation of defects in human glycogen metabolism.w20 It was found that specific glycogen metabolism mutations, LAMP2 and PRKAG2, cause multisystem glycogen storage disease and can also present as primary cardiomyopathy, mimicking hypertrophic or infiltrative cardiomyopathy.

Summary

The evaluation and management of patients with infiltrative cardiomyopathy remains clinically challenging  (table 2). Cardiac involvement in amyloidosis and sarcoidosis is associated with a more adverse prognosis and hence early identification is warranted. Echocardiography, though able to detect gross morphological and functional abnormalities, lacks specificity and sufficient sensitivity. Newer methods using tissue imaging may prove to have a role in the future by their ability to define focal abnormalities and detect subclinical disease. Nuclear imaging is helpful in differentiating sarcoid from other cardiac diseases when symptoms are present, as well as predicting response to treatment. More recently, cardiac MRI has shown promise for all types of infiltrative cardiomyopathy (figure 6), in not only identifying typical morphological and functional changes, but also in assessing disease activity. However, no imaging technique stands alone, and even the ‘gold standard’ of endomyocardial biopsy may often not be conclusive, given the focal nature of cardiac infiltration in some cases. The integration of clinical assessment, tissue biopsy and cardiac imaging will still need to form the basis of any future diagnostic framework.

Advances in imaging assessment of infiltrative cardiomyopathies: key points

  • Infiltrative cardiomyopathy usually portends an adverse prognosis, although in rare instances (eg, Fabry disease) early diagnosis can result in potentially curative treatment.

  • Echocardiography and CMR are important non-invasive imaging techniques in the assessment of infiltrative cardiomyopathy.

  • Late gadolinium CMR imaging can distinguish the various types of cardiomyopathies, with excellent spatial resolution and reproducibility.

  • Sarcoidosis of the heart mimics most other common cardiac diseases.

  • Cardiac iron overload can be determined by myocardial relaxation time (T2*) on CMR and is a prognostic marker in thalassaemia major.

  • Diagnosis of infiltrative cardiomyopathy requires integration of clinical assessment, multimodality cardiac imaging and endomyocardial biopsy.

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Table 2

Clinical, echocardiographic and CMR features of common infiltrative cardiomyopathies

Figure 6

Cardiovascular magnetic resonance (CMR) based algorithm for the diagnostic evaluation of infiltrative cardiomyopathies. HCM, hypertrophic cardiomyopathy; LGE, late gadolinium enhancement; LVH, left ventricular hypertrophy.

Footnotes

  • Competing interests In compliance with EBAC/EACCME guidelines, all authors participating in Education in Heart have disclosed potential conflicts of interest that might cause a bias in the article. The authors have no competing interests.

  • Provenance and peer review Commissioned; internally peer reviewed.

References

  1. A large review analysing the diagnostic and clinical profiles of the different types of cardiac amyloid.
  2. A recent review on the role of LGE in the assessment of severity and the prognosis in cardiac amyloid.
  3. A recent study demonstrating the role of LGE CMR in identifying cardiac amyloid and its association between clinical, morphological, functional, and biochemical features.
  4. Landmark retrospective study looking at the incidence of antemortem clinical manifestations and postmortem evidence of myocardial lesions in necropsy of patients with cardiac sarcoidosis.
  5. This is the first study to show that advanced cardiac imaging with PET scanning or CMR is more sensitive than established Japanese criteria for identification of cardiac sarcoidosis.
  6. This is the first prospective study evaluating the utility of delayed enhancement CMR imaging in asymptomatic patients with biopsy proven extracardiac sarcoidosis. The study showed increased adverse cardiac events including sudden cardiac death when there was myocardial involvement.
  7. This study demonstrated that enzyme replacement therapy in Fabry disease can decrease LVH and improve regional myocardial function.
  8. This study showed the long term benefits of early detection and treatment in Fabry's disease. This is one of the few examples where non-invasive cardiac imaging has a positive impact on long term outcomes.
  9. First study to validate the role of T2* CMR in non-invasive assessment of myocardial iron overload.
  10. A large study that demonstrated T2* CMR can predict heart failure and arrhythmia in thalassaemia major.

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