N Varzeshi MD; M Hansen MBBS, FRANZCR; A Rezaee MD; N Dixon MBBS; E Duhig MBBS, FRCPA; R Slaughter MBBS, FRACR.
Radiology and pathology correlation in common infiltrative cardiomyopathies
Article first published online: 5 DEC 2012
© 2012 The Authors. Journal of Medical Imaging and Radiation Oncology © 2012 The Royal Australian and New Zealand College of Radiologists
Journal of Medical Imaging and Radiation Oncology
Volume 56, Issue 6, pages 628–635, December 2012
How to Cite
Varzeshi, N., Hansen, M., Rezaee, A., Dixon, N., Duhig, E. and Slaughter, R. (2012), Radiology and pathology correlation in common infiltrative cardiomyopathies. Journal of Medical Imaging and Radiation Oncology, 56: 628–635. doi: 10.1111/j.1754-9485.2012.02431.x
Conflict of interest: None declared.
- Issue published online: 5 DEC 2012
- Article first published online: 5 DEC 2012
- Manuscript Accepted: 8 DEC 2011
- Manuscript Received: 20 SEP 2011
- endomyocardial biopsy;
- late gadolinium enhancement;
- magnetic resonance imaging;
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.
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.
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. 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 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.
Amyloidosis refers to a pathological process rather than a specific disease entity. 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.
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.
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. 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.
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. Pleural and pericardial effusions are also common findings in particularly Amyloid L patients; 59% and 68%, respectively.
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 (Fig. 3).
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.
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.
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).
Approximately 20% to 30% of patients with sarcoidosis demonstrate cardiac involvement at autopsy but less than 5% manifest cardiac symptoms during life.
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. Granulomas can be present in the epicardium and endocardium including the valves.
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).
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.
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 (Fig. 5).
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.
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. Atrial involvement is a less common feature of cardiac sarcoid with involvement of right atrium, 11%, and left atrium, 7% (Fig. 6).
It has been shown that extent of gadolinium-delayed enhancement correlates with the severity of ventricular dysfunction and therefore possibility of ventricular arrhythmias.
The mortality from sarcoidosis is about 1% to 5% per year and around 85% of deaths from sarcoidosis are the result of cardiac involvement. 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. 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 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. 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. 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.
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.
Myocyte lipid storage results in characteristic cytoplasmic vacuolisation, creating a lace-like appearance (Fig. 8). Electron microscopy shows electron-dense deposits consistent of parallel or concentric lamellae with periodic spacing in the cytoplasm. This finding is not specific, and definitive diagnosis requires biochemical assay for alpha-galactosidase.
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. Moon et al. reported delayed enhancement typically within mid-wall and basal inferolateral segment in 50% and 92% of cases, respectively (Fig. 9).
The diagnosis of Fabry's disease has relevant therapeutic implications as early enzyme replacement and enhancement therapy have been shown to improve prognosis.
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.
- 2Endomyocardial biopsy – when and how? Cardiovasc Pathol 2011. DOI: 10.1016/j.carpath.2010.08.005. (Epub ahead of print)..
- 3Cardiovascular causes of sudden cardiac death. In: Silver MD , Gotlieb AI , Schoen FJ (eds). Cardiovascular Pathology, 3rd edn. Churchill Livingstone, New York, 2001; 326–374., , .
- 11Cardiac sarcoidosis: a pathology-focused review. Arch Pathol Lab Med 2010; 134: 1039–1046., , .
- 16A case of left atrial involvement of cardiac sarcoidosis manifesting as atrial flutter treated with corticosteroids. J Cardiol Cases 2010; 1: e71–74., , et al.
- 23End-stage cardiac manifestations and autopsy findings in patients with cardiac Fabry disease. J Cardiol 2004; 43: 98–99., , et al.
- 24MRI features of cardiac manifestations and Fabry's disease. SCMR. Poster presentation. 2005., , , .