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Keywords:

  • amyloid;
  • endomyocardial biopsy;
  • Fabry's;
  • late gadolinium enhancement;
  • magnetic resonance imaging;
  • sarcoidosis.

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Amyloidosis
  5. Sarcoidosis
  6. Fabry's disease
  7. Conclusion
  8. References

Infiltrative cardiomyopathies generally pose a diagnostic dilemma as current diagnostic tools are imprecise. Invasive endomyocardial biopsy is considered as the gold standard however it has some limitations. Recently cardiovascular magnetic resonance (CMR) is emerging as an excellent technique in diagnosing infiltrative cardiomyopathies and is increasingly being used. Characteristic pathologic and radiologic findings in most common infiltrative cardiomyopathies (amyloid, sarcoid and Fabry's) are discussed and correlated with relative CMR and histologic examples. There is fairly good correlation between the non-invasive radiologic and the invasive histologic findings in common infiltrative cardiomyopathies. Non-invasive CMR with its high sensitivity and specificity has an excellent role in establishing the diagnosis and improving the prognosis of common infiltrative cardiomyopathies.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Amyloidosis
  5. Sarcoidosis
  6. Fabry's disease
  7. Conclusion
  8. References

Infiltrative cardiomyopathies are characterised by abnormal myocardial deposits that may result in ventricular wall stiffness. While some cause heart failure with a restrictive filling pattern, others present with dilated ventricles and wall motion abnormalities resembling ischemic cardiomyopathies.[1]

Cardiomyopathies in general often pose a diagnostic dilemma. Once ischaemia is excluded, patients often require endomyocardial biopsy. This is considered the gold standard test but is an invasive diagnostic method with some limitations, not the least of which is sampling error.[2] Cardiovascular magnetic resonance (CMR) is increasingly being used in the assessment of cardiomyopathies. In this essay, we aim to discuss the pathology and relatively unique MRI findings of the most common infiltrative cardiomyopathies that present to our institution (amyloid, sarcoid and Fabry's) with illustrated examples of histologically proven infiltrative cardiac diseases.

Amyloidosis

  1. Top of page
  2. Summary
  3. Introduction
  4. Amyloidosis
  5. Sarcoidosis
  6. Fabry's disease
  7. Conclusion
  8. References

Amyloidosis is the extracellular accumulation of an insoluble fibrillary protein with a non-branching cross-β-pleated sheet structure. It appears as amorphous eosinophilic material by light microscopy (Fig. 1) and has an apple-green birefringence by Congo red staining.[3]

figure

Figure 1. A classical case of cardiac amyloid deposition. This is a section of left ventricle from an autopsy specimen. The deposition of the eosinophilic material is more extensive and it encircles individual atrophic myocytes (arrow).

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Amyloidosis refers to a pathological process rather than a specific disease entity.[4] Amyloid fibrils can be composed of many disparate precursor proteins, which can form amyloid in a wide variety of clinical scenarios. Those associated with deposition in the cardiovascular system include serum Amyloid A protein in chronic inflammatory conditions, kappa and lambda in plasma cell dyscrasias, transthyretin in systemic senile amyloidosis and familial amyloid with polyneuropathy, β-2-microglobulin in chronic haemodialysis and atrial natriuretic factor in isolated atrial amyloid.[3]

Macroscopically, amyloid deposits can be occult or manifest as waxy, opaque nodules of variable size or diffuse, waxy stiffening of the tissues. Brown waxy amyloid deposits may also be seen in the epicardium, heart valves and rarely the pericardium.[3]

Microscopically, amyloid deposits are usually seen within the endocardium, myocardium and blood vessel walls. Myocardial deposits can form nodular aggregates and encircle individual cardiac myocytes.[3] Large epicardial arteries are less likely to be involved than small-calibre intramural vessels (Fig. 2). No practical distinction can be made on light microscopy regarding the type of amyloid protein. Immunohistochemical techniques can facilitate the identification and classification of certain amyloid types including Amyloid A, transthyretin and kappa and lambda light chains.[3]

figure

Figure 2. In this case, the endomyocardial biopsies were very small and the deposition of amyloid was relatively subtle. A small vessel (top central field) is surrounded by a rim of eosinophilic material which has a ‘cracked’ appearance (arrow), typical of amyloid.

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Radiological findings

Characteristic features of cardiac amyloid are concentric left ventricular wall thickening (with occasional right ventricular and atrial wall thickening) with normal size cavity, restriction of diastolic filling, normal or slightly reduced ejection fraction and disproportional biatrial enlargement.[5] Pleural and pericardial effusions are also common findings in particularly Amyloid L patients; 59% and 68%, respectively.[6]

Late gadolinium enhancement (LGE)-CMR in cardiac amyloidosis frequently shows global, diffuse heterogeneous enhancement of thickened myocardium. Previous studies suggest subendocardial enhancement to be the predominant pattern and attribute that mainly to interstitial expansion from amyloid infiltration rather than fibrosis. The histological distribution of amyloid deposits interestingly matched with their imaging findings.[5-7] In slight contrast to this, mid-wall LGE is more frequently observed in our centre[8] (Fig. 3).

figure

Figure 3. Cardiac amyloid. Four-chamber (a) and left ventricle short-axis (b) steady state free precession imaging demonstrates mild diffuse symmetric LV wall thickening. Corresponding delayed inversion recovery imaging post-gadolinium (c, d) shows faint diffuse enhancement of the LV myocardium. This can be mistaken for poor inversion time selection. Note the low level of blood pool enhancement. This is thought to be due to redistribution of gadolinium into the total body amyloid load. Bilateral pleural effusions are commonly seen in these patients (see asterisks in (a) ).

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In some instances, even with the correct selection of optimal inversion time (assisted by the use of multi-longitudinal relaxation time cine fast gradient echo sequence), suppression of signal from normal myocardium can not be achieved as the myocardium is diffusely abnormal; this is referred to as ‘suboptimal nulling’[5, 8] and is a potential downfall when interpreting delayed inversion recovery imaging of the myocardium post gadolinium.

Maceira et al. identified that T1 mapping demonstrates altered gadolinium kinetics in blood and myocardium. They noted subendocardial T1 (cut-off value of 535 ms at four minutes) is markedly low, likely secondary to increased amyloid load in myocardium; on the contrary, blood T1 is prolonged due to faster clearance of gadolinium to the total body amyloid load. This results in unusual pattern of ‘black blood pool’. They also concluded that the difference between subendocardial and blood T1 (T1 threshold of 191 ms at four minutes) in conjunction with demonstration of ‘amyloid LGE pattern’ is a highly accurate (97%) method for detecting cardiac amyloidosis similar to that of endomyocardial biopsy.[7]

In a longitudinal study, Maceira et al. reported positive LGE-CMR is not a statistically significant survival predicator; contrarily transmyocardial T1 gradient (subepicaridium minus subendocardium T1 < 23 ms at two minutes) could predict outcome with 85% accuracy due to its superior discrimination by T1 kinetics for the severity and transmurality of the amyloid burden.[9]

Austin et al., however, reported compared prognostic value of LGE-CMR with electrocardiogram and trans thoracic echocardiogram variables in group of patients underwent similar standard treatment. It showed LGE-CMR is not only an accurate method for diagnosis (sensitivity 88%, specificity 98%) but also a better predicator of one-year survival compared with the other non-invasive parameters (Wald test 4.91, P = 0.03).[10]

Sarcoidosis

  1. Top of page
  2. Summary
  3. Introduction
  4. Amyloidosis
  5. Sarcoidosis
  6. Fabry's disease
  7. Conclusion
  8. References

Approximately 20% to 30% of patients with sarcoidosis demonstrate cardiac involvement at autopsy but less than 5% manifest cardiac symptoms during life.[3]

The degree of cardiac involvement in sarcoidosis is variable, ranging from very focal disease to large confluent zones of scarring and granulomata. The favoured sites include the left ventricular free wall, interventricular septum including the conduction system and atria.[3] Granulomas can be present in the epicardium and endocardium including the valves.[11]

Grossly, the hearts of patients with cardiac sarcoidosis are globally dilated. The granulomata appear as irregular tumour-like infiltrates within the myocardium. They can have a yellow, tan or grey appearance, and there is a sharp interface between the uninvolved myocardium.[3, 11] Old healed lesions appear as patchy or serpiginous zones of fibrosis, which can be associated with aneurysms. The scarring has a random distribution in contrast to old infarcts, which correspond to coronary artery territories.

Microscopically, the granulomas of sarcoid are classically tight, non-necrotising and epithelioid. There are usually no significant cuff-of lymphocytes (so-called ‘naked granulomas’). Multi-nucleated giant cells are often present and may contain numerous cytoplasmic inclusions including Schaumann bodies or asteroid bodies. A background of fibrosis is present in progressive disease (Fig. 4).

figure

Figure 4. (a) Shows extensive fibrosis of the myocardium with only a small aggregate of residual myocytes (arrow). Non-necrotising granulomas (indicated by asterisks) are scattered throughout the fibrosis. (b) Shows a higher power view of a typical ‘sarcoidal’ granuloma in this case. It is composed of a tight cluster of epithelioid histiocytes. A few giant cells are also present.

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Radiological findings

Studies suggest that CMR with gadolinium has a sensitivity of 100%, specificity of approximately 80% and positive predictive value of approximately 55% in diagnosing cardiac sarcoidosis.[12]

With regional wall motion abnormalities and areas of focal thickening or thinning, sarcoid infiltrates may be visible on MRI as focal intramyocardial areas of increased signal intensity on T2-weighted and early gadolinium-enhanced images caused by oedema associated with inflammation[13] (Fig. 5).

figure

Figure 5. Sarcoid. Focal area of thickening within the basal posteroseptal segment of the left ventricle on four-chamber (a) and short-axis (b) steady state free precession. Corresponding delayed IR imaging post-gadolinium demonstrates intense mid-wall to transmural enhancement (arrows in (c) and (d) ).

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Thickened myocardium that results from granulomatous involvement or oedema can mimic hyperthrophic cardiomyopathy.

Confluent sarcoid granulomata may also be apparent on T2-weighted images as nodules with central, low-signal intensity from hyaline fibrotic tissue and peripheral high-signal intensity secondary to inflammation.[14]

Infiltrative lesions are frequently located in the septum (particularly, the basal portion) and sometimes in the left ventricular free wall, whereas the right ventricle and papillary muscles are less commonly rarely affected.[15] Atrial involvement is a less common feature of cardiac sarcoid with involvement of right atrium, 11%, and left atrium, 7%[16] (Fig. 6).

figure

Figure 6. Atrial sarcoid. Four-chamber views with (a) steady state free precession (SSFP), (b) double inversion recovery fat sat and (c) delayed inversion recovery imaging post-gadolinium. The lesion is noted at the basal atrial septum on the SSFP and DIR fat sat images (see arrows in (a) and (b) ) but enhances with a signal intensity similar to that of the adjacent blood pool (arrow in (c) ). Occasionally, mass lesions can demonstrate signal intensities on SSFP similar to that of the blood pool also, underscoring the value of black blood imaging when imaging masses.

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Delayed gadolinium enhancement occurs because of accumulation of gadolinium in areas of scarring.[14, 15] It is frequently nodular though can be sheet-like in morphology (Fig. 7).

figure

Figure 7. Sarcoid. Vertical long-axis and short-axis delayed imaging of the left ventricle myocardium post-gadolinium demonstrates a thinned area of intense enhancement at the anteroseptal basal segment (arrows). Thinned enhancing myocardium usually occurs in ‘burnt out sarcoid’, though sheet-like areas of enhancement without thinning does occur in more active/acute sarcoid.

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It has been shown that extent of gadolinium-delayed enhancement correlates with the severity of ventricular dysfunction and therefore possibility of ventricular arrhythmias.[17]

The mortality from sarcoidosis is about 1% to 5% per year and around 85% of deaths from sarcoidosis are the result of cardiac involvement.[18] Treatment of cardiac sarcoidosis is aimed at controlling inflammation and fibrosis and despite the lack of confirmatory randomised trials, corticosteroid is the cornerstone of treatment for cardiac sarcoidosis, and hence, early detection of cardiac sarcoidosis and early initiation of corticosteroid therapy can improve and possibly reverse cardiac disease secondary to sarcoidosis. In one large retrospective study of 95 patients with cardiac sarcoidosis, patients treated with corticosteroid had a five-year survival of 75% versus 10% for patients treated without corticosteroids.[19] Also, permanent pacemakers, antiarrhythmic therapy and implantable cardioverter defibrillators are indicated in the presence of arrhythmia and advanced cardiac involvement secondary to sarcoidosis.

Fabry's disease

  1. Top of page
  2. Summary
  3. Introduction
  4. Amyloidosis
  5. Sarcoidosis
  6. Fabry's disease
  7. Conclusion
  8. References

Fabry's disease is a rare X-linked recessive genetic disorder caused by the galactosidase A deficiency. It leads to the globotriaosylceramide (Gb3) accumulation in vascular endothelium and other tissues throughout the body causing renal, cerebrovascular or cardiovascular complications with associated premature mortality.[20] A rare cardiac variant is described in which patients had some residual enzyme activity and present in the fifth and sixth decades with left ventricular hypertrophy and conduction abnormalities.[21] In this older onset group, Fabry's disease is reported in 3% of men with left ventricle hypertrophy in tertiary referral centres and in up to 6% of men and 12% of women with late onset hypertropic cardiomyopathy.[22]

Globotriaosylceramide accumulates in all heart cells including myocytes, specialised conduction tissue, valves and endothelium. Deposition of Gb3 within the valves can cause valvular disease. The regurgitant mitral valves show typical fibrotic thickening of the free-edge with hooding. Aortic and coronary artery involvement can also occur.[3]

Myocyte lipid storage results in characteristic cytoplasmic vacuolisation, creating a lace-like appearance[3] (Fig. 8). Electron microscopy shows electron-dense deposits consistent of parallel or concentric lamellae with periodic spacing in the cytoplasm.[23] This finding is not specific, and definitive diagnosis requires biochemical assay for alpha-galactosidase.[3]

figure

Figure 8. The biopsy demonstrated the classic histological features of Fabry's disease. The myocardium has a ‘lace-like’ appearance with marked cytoplasmic clearing of cardiac myocytes (arrow indicating cleared cytoplasm). This clearing effect is due to intracellular accumulation of lipids.

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Radiological findings

Grossly, cardiac involvement in Fabry's often mimics hypertrophic cardiomyopathy with significant left ventricular hypertrophy (20).

CMR is a complementary non-invasive diagnostic tool in Fabry's patients. It is especially helpful by evaluating left ventricle mass, wall thickness and cardiac function; it also assesses the severity of cardiac involvement.[24] Moon et al. reported delayed enhancement typically within mid-wall and basal inferolateral segment in 50% and 92% of cases, respectively[25] (Fig. 9).

figure

Figure 9. Fabry's disease. Four-chamber (a) and left ventricle (LV) short-axis (b) steady state free precession imaging demonstrates diffuse symmetric LV wall thickening. Corresponding delayed inversion recovery imaging post-gadolinium (c, d) shows characteristic mid-wall enhancement within the posterolateral segment of the basal LV myocardium (see arrows).

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The diagnosis of Fabry's disease has relevant therapeutic implications as early enzyme replacement and enhancement therapy have been shown to improve prognosis.[22]

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Amyloidosis
  5. Sarcoidosis
  6. Fabry's disease
  7. Conclusion
  8. References

LGE-CMR has demonstrated high clinical value for tissue characterisation with high sensitivity and specificity in diagnosing infiltrative cardiomyopathies. It can recognise the disease at early stages when clinical cardiac symptoms are not apparent. Early detection can potentially improve prognosis by early initiation of intensive medical treatment. Although CMR is routinely performed in our institution to both rule out ischaemic cardiomyopathy and to further investigate suspected non-ischaemic causes such as infiltrative variants, access to CMR throughout Australia remains limited. This highlights the need for more training in the area and better education as to the utility of CMR in cardiomyopathies.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Amyloidosis
  5. Sarcoidosis
  6. Fabry's disease
  7. Conclusion
  8. References
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    Thiene G, Basso C, Corrado D. Cardiovascular causes of sudden cardiac death. In: Silver MD , Gotlieb AI , Schoen FJ (eds). Cardiovascular Pathology, 3rd edn. Churchill Livingstone, New York, 2001; 326374.
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    Syed IS, Glockner JF, Feng D et al. Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. JACC Cardiovasc Imaging 2010; 3: 155164.
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    Vogelsberg H, Mahrholdt H, Deluigi CC et al. Cardiovascular magnetic resonance in clinically suspected cardiac amyloidosis: noninvasive imaging compared to endomyocardial biopsy. J Am Coll Cardiol 2008; 51: 10221030.
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    Maceira AM, Joshi J, Prasad SK et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2005; 111: 186193.
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    vanden Driesen RI, Slaughter RE, Strugnell WE. MR findings in cardiac amyloidosis. AJR Am J Roentgenol 2006; 186: 16821685.
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    Austin BA, Tang WH, Rodriguez ER et al. Delayed hyper-enhancement magnetic resonance imaging provides incremental diagnostic and prognostic utility in suspected cardiac amyloidosis. JACC Cardiovasc Imaging 2009; 2: 13691377.
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    Lagana SM, Parwani AV, Nichols LC. Cardiac sarcoidosis: a pathology-focused review. Arch Pathol Lab Med 2010; 134: 10391046.
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    Vignaux O, Dhote R, Duboc D et al. Detection of myocardial involvement in patients with sarcoidosis applying T2-weighted, contrast-enhanced, and cine magnetic resonance imaging: initial results of a prospective study. J Comput Assist Tomogr 2002; 26: 762767.
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    Vignaux O. Cardiac sarcoidosis: spectrum of MRI features. AJR Am J Roentgenol 2005; 184: 249254.
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    Ichinose A, Otani H, Oikawa M et al. MRI of cardiac sarcoidosis: basal and subepicardial localization of myocardial lesions and their effect on left ventricular function. AJR Am J Roentgenol 2008; 191: 862869.
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    Shin-ichi Aso AI, Naoyuki A, Hirohiko M et al. A case of left atrial involvement of cardiac sarcoidosis manifesting as atrial flutter treated with corticosteroids. J Cardiol Cases 2010; 1: e7174.
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    Smedema JP, Snoep G, van Kroonenburgh MP et al. The additional value of gadolinium-enhanced MRI to standard assessment for cardiac involvement in patients with pulmonary sarcoidosis. Chest 2005; 128: 16291637.
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    Manins V, Habersberger J, Pfluger H, Taylor AJ. Cardiac magnetic resonance imaging in the evaluation of cardiac sarcoidosis: an Australian single-centre experience. Intern Med J 2009; 39: 7782.
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    Yazaki Y, Isobe M, Hiroe M et al. Prognostic determinants of long-term survival in Japanese patients with cardiac sarcoidosis treated with prednisone. Am J Cardiol 2001; 88: 10061010.
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    Sheppard MN. The heart in Fabry's disease. Cardiovasc Pathol 2011; 20: 814.
  • 21
    von Scheidt W, Eng CM, Fitzmaurice TF et al. An atypical variant of Fabry's disease with manifestations confined to the myocardium. N Engl J Med 1991; 324: 395399.
  • 22
    Hughes SE. The pathology of hypertrophic cardiomyopathy. Histopathology 2004; 44: 412427.
  • 23
    Teraguchi H, Takenaka T, Yoshida A et al. End-stage cardiac manifestations and autopsy findings in patients with cardiac Fabry disease. J Cardiol 2004; 43: 9899.
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    Medoro LRS, Strugnell W, Denaro C, Riley R. MRI features of cardiac manifestations and Fabry's disease. SCMR. Poster presentation. 2005.
  • 25
    Moon JC, Sachdev B, Elkington AG et al. Gadolinium enhanced cardiovascular magnetic resonance in Anderson–Fabry disease. Evidence for a disease specific abnormality of the myocardial interstitium. Eur Heart J 2003; 24: 21512155.