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Unveiling nonischemic cardiomyopathies with cardiac magnetic resonance Expert Rev. Cardiovasc. Ther. 12(2), 217–239 (2014)
Niti R Aggarwal*1, Tyler J Peterson1, Phillip M Young2, Philip A Araoz2, James Glockner2, Sunil V Mankad1 and Eric E Williamson2 1 Department of Internal, Division of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA 2 Department of Radiology, Division of Cardiovascular Radiology, Mayo Clinic, Rochester, MN, USA *Author for correspondence: Tel.: +1 507 284 3545 Fax: +1 507 266 7929 [email protected]
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Cardiomyopathy is defined as a heterogeneous group of myocardial disorders with mechanical or electrical dysfunction. Identification of the etiology is important for accurate diagnosis, treatment and prognosis, but continues to be challenging. The ability of cardiac MRI to non-invasively obtain 3D-images of unparalleled resolution without radiation exposure and to provide tissue characterization gives it a distinct advantage over any other diagnostic tool used for evaluation of cardiomyopathies. Cardiac MRI can accurately visualize cardiac morphology and function and also help identify myocardial edema, infiltration and fibrosis. It has emerged as an important diagnostic and prognostic tool in tertiary care centers for work up of patients with non-ischemic cardiomyopathies. This review covers the role of cardiac MRI in evaluation of nonischemic cardiomyopathies, particularly in the context of other diagnostic and prognostic imaging modalities. KEYWORDS: cardiac magnetic resonance . cardiovascular imaging . dilated cardiomyopathy . hypertrophic cardiomyopathy
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infiltrative cardiomyopathy . late gadolinium enhancement
Non-ischemic cardiomyopathies consist of a heterogeneous group of disorders with progressive myocardial dysfunction resulting from various etiologies. The American Heart Association proposed a classification scheme dividing cardiomyopathies into two major categories based on the predominant organ involved [1]. Primary cardiomyopathies are solely or predominantly confined to the heart, and may be genetic, acquired or mixed in origin (TABLE 1). In comparison, secondary cardiomyopathies are generalized systemic disorders, where the heart is one of the multiple organs involved (TABLE 1). Given that many cardiomyopathies may predominantly involve the heart, but may also involve other organs, the distinction between primary and secondary cardiomyopathies may be tenuous. Given this challenge, the European Society of Cardiology took a different approach to classifying cardiomyopathies. While the American Heart Association grouped the cardiomyopathies based on the mechanism of myocardial dysfunction, the European Society of Cardiology took a more clinical approach and grouped them differently based on ventricular morphology and function as hypertrophic, arrhythmogenic right ventricle,
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non-ischemic cardiomyopathy
restrictive, dilated and unclassified [2]. Each phenotype is then further subclassified as familial or non-familial (FIGURE 1). Differentiating one cardiomyopathy from another is important for tailoring of medical therapy, risk stratification and establishing prognosis. Currently, the first-line imaging modality of choice for cardiomyopathies is echocardiography owing to its high temporal resolution, widespread availability and portability. However, echocardiographic images are suboptimal in up to 20% of patients due to inadequate acoustic windows, associated with chest deformity, obesity or underlying lung disease [3]. Additionally, although an endomyocardial biopsy is considered the gold standard, given its invasive nature, associated risks and often lack of disease-specific treatments, it is not commonly indicated for evaluation of myocardial disease [4]. Endomyocardial biopsy may be indispensable in establishing etiology of unexplainable cardiomyopathies, particularly of new onset and with intractable heart failure or arrhythmias. Compared with echocardiography, cardiac MRI is not limited by poor acoustic windows, allows imaging of the heart in any plane with
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Table 1. Classification of cardiomyopathies based on the American Heart Association guidelines. Primary cardiomyopathies Genetic
Hypertrophic cardiomyopathy Arrhythmogenic right ventricular cardiomyopathy Left ventricular noncompaction
Mixed
Dilated cardiomyopathy
Primary genetic cardiomyopathies Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy with a prevalence of 1 in 500 in the general population [6]. It results from mutations in genes encoding the proteins of cardiac sarcomere and is inherited in an autosomal dominant pattern. Histologically, HCM is characterized by myofiber disarray, myocyte hypertrophy and variSecondary cardiomyopathies able amount of interstitial fibrosis. Presence of left ventricular Infiltrative Amyloidosis (LV) wall thickness ‡15 mm in the absence of another cause Hurlers and Hunters disease of LV hypertrophy such as hypertension or valve disease is conStorage Iron overload including hemochromatosis sistent with a diagnosis of HCM. The vast majority of patients Fabry disease remain asymptomatic with a normal life expectancy. However, Danon disease a small number of patients are at increased risk of complicaInflammatory Sarcoidosis tions. Sudden cardiac death may be the first manifestation of HCM in asymptomatic patients [7]. It is the leading cause of Endocrine Thyroid dysfunction Diabetes death in young athletes [7]. Symptoms of dyspnea, exertional Pheochromocytoma chest discomfort, palpitations and syncope may occur due to multiple mechanisms including dynamic left ventricular outEndomyocardial Hypereosinophilic syndromes, flow tract (LVOT) obstruction, systolic and diastolic dysfuncLoeffler endocarditis Carcinoid heart disease tion, arrhythmias and mitral regurgitation. Dynamic LVOT obstruction is present in nearly three of every four patients Neuromuscular Muscular dystrophies with HCM either at rest or with provocation [7]. Friedreich’s ataxia While echocardiography serves as a good screening tool, it Other Chemotherapy-induced cardiomyopathy can underestimate LV wall thickness and may miss up to 6% Radiation-induced heart disease of HCM cases compared with cardiac MRI [8]. Owing to its ability to image the heart in any plane without being dependant a wide field of view. Furthermore, cardiac MRI is able to char- on the acoustic windows, cardiac MRI is being increasingly utiacterize tissue using unique image sequences and tissue lized to image patients with HCM. In addition to better estienhancement [5]. TABLE 2 summarizes the advantage of commonly mating the presence and magnitude of LV hypertrophy used MRI sequences in nonischemic cardiomyopathies. Given compared with echocardiography [8], cardiac MRI may also prothese advantages, as well as technological advances allowing for vide a better assessment of right ventricular (RV) hypertrophy, shorter scan times, cardiac MRI is being increasingly used to seen in 18% of cases with HCM [9]. HCM has a wide variety image patients with cardiomyopathies. Various cardiomyopa- of morphologic expressions with uniform wall thickening in thies often have a unique MRI fingerprint that helps in its some cases, and focal hypertrophy involving the anteroseptal LV diagnosis (TABLE 3). Cardiac MRI has emerged as an important or apex in others. On cardiac MRI, LV wall thickness is measured on short axis steady-state free precession (SSFP) sequences at end-diastole. Cardiomyopathies SSFP imaging in the LVOT view may demonstrate systolic anterior motion of Arrhythmogenic the mitral valve and a posteriorly directed Restrictive Dilated Hypertrophic Unclassified right ventricular cardiomyopathy cardiomyopathy cardiomyopathy cardiomyopathy mitral regurgitation jet (FIGURE 2). Velocitycardiomyopathy encoded phase-contrast imaging performed in the same plane can permit quantitative assessment of the LVOT graFamilial/genetic Non-familial/non-genetic dient and mitral regurgitation severity Figure 1. Schematic of proposed classification of cardiomyopathies by the which have been correlated with worse European Society of Cardiology. prognosis [10]. The repetitive contact Acquired
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diagnostic and prognostic tool for anatomic and functional assessment as well as characterization of myocardial edema and fibrosis in patients with cardiomyopathies. In this manuscript, we review the current clinical applications of cardiac MRI in non-ischemic cardiomyopathies and highlight its advantages over conventional imaging.
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Myocarditis Stress-induced cardiomyopathy Peripartum cardiomyopathy Tachycardia-induced cardiomyopathy Transplant cardiomyopathy
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Unveiling nonischemic cardiomyopathies with cardiac magnetic resonance
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Table 2. Characteristics of cardiac MRI pulse sequences. MRI sequence
Sequence description
Information obtained
Steady-state free precession sequences
T1/T2-weighted bright blood imaging typically as a cine acquisition
Biventricular volume and function, myocardial mass
Myocardial tagging
Apply slice-selective magnetization saturated planes orthogonal to the imaging slice
Diastolic function, myocardial strain
Phase contrast
Velocity encoded flow sequence for flow quantitation
Myocardial diastolic function, valvular stenosis or regurgitation
T1-weighted
T1-weighted inversion recovery sequence
Anatomic evaluation of the heart and great vessels
Native T1 mapping
Multiple images with different T1 sensitivity that follow a T1 decay curve
May quantify diffuse myocardial fibrosis in HCM, DCM, edema in post-infarct patients, and amyloid infiltration in amyloidosis
T2-weighted
T2 weighted inversion recovery sequence with fat saturation
Myocardial edema and inflammation
T2-mapping
Multiple images are acquired with different T2 sensitivity that follow a T2 decay curve
Quantify myocardial edema
T2*-mapping
Multiple images with different T2* sensitivities are acquired
Hemorrhage in acute myocardial infarction, iron deposition in hemochromatosis
Myocardial perfusion
T1-weighted inversion recovery sequence immediately after gadolinium administration
Perfusion abnormalities and mural thrombus
Late gadolinium enhancement
T1-weighted inversion recovery sequence 5-20 minutes after gadolinium administration
Assess perfusion abnormalities and mural thrombus
DCM: Dilated cardiomyopathy; HCM: Hypertrophic cardiomyopathy.
between the anterior mitral valve leaflet and the basal interventricular septum can result in fibrosis of the septum and thickening of anterior mitral valve leaflets and chordae. Diastolic dysfunction may often precede LV hypertrophy, and may be an important marker of LV wall stress in patients with HCM. The role of cardiac MRI to characterize diastolic function is still emerging. Measurement of mitral inflow velocities (early filling ‘E’ and atrial systolic filling ‘A’ wave), pulmonary vein flow (systolic ‘S’ and diastolic ‘D’) velocities and myocardial motion velocity (E´) is feasible by phase-contrast MRI imaging, and comparable with measurements obtained by Doppler echocardiography [11,12]. In a study of 18 patients with hypertensive heart disease, E/E´ ratio measured by cardiac MRI had good correlation with invasively measured pulmonary capillary wedge pressure [12]. Additionally, myocardial tagging, which is unique to MRI, may provide 3D assessment of myocardial systolic and diastolic deformation, and strain rate along the circumferential, radial and longitudinal directions. Young et al. demonstrated reduced 3D strain in seven patients with HCM compared with normal controls (-0.18 vs -0.22, p < 0.05) [13]. LV wall stress measured by cardiac MRI was shown to precede LV hypertrophy in 502 patients with non-ischemic cardiomyopathy [14]. In another study, Kim et al. evaluated 25 patients with HCM and reported significantly impaired circumferential shortening in regions of late gadolinium enhancement (LGE), regardless of the degree of myocardial hypertrophy (FIGURE 3) [15]. However, at present, these sequences are not currently routinely performed at most cardiac centers, and additional larger studies www.expert-reviews.com
are needed to explore their feasibility, and diagnostic and prognostic utility in this patient population. Despite our growing knowledge about HCM, our ability to risk stratify patients at risk for sudden cardiac death is still limited. Depending on the selection of patients, presence of LGE on cardiac MRI has been reported in 50–80% of patients with HCM [16], and correlates well with areas of fibrosis on histologic studies. LGE is typically patchy and in a non-vascular distribution (FIGURE 2). It is commonly confined to the RV insertion points and to areas of maximal LV hypertrophy [16]. Besides its diagnostic value, the extent of LGE in HCM was inversely proportional to the LVEF and directly proportional to the incidence of heart failure [17,18]. Additionally, presence of LGE conferred a sevenfold increased risk for lethal ventricular arrhythmias on ambulatory 24-hour ECG monitoring compared with those without LGE (FIGURE 4) [19]. Presence of LGE has also been associated with sudden cardiac death. In a metaanalysis combining the 4 published studies on the topic and comprising 1063 patients with HCM, the presence of LGE was associated with a threefold increased risk of cardiac death (95% CI: 1.01–8.42; p = 0.047) and a twofold increased risk of sudden cardiac death or aborted sudden cardiac death (95% CI: 0.87–6.58; p = 0.091) [20]. However, committee members that wrote the HCM guideline believe the association between LGE and risk of sudden cardiac death was weak and did not support the need to implant an implantable cardioverterdefibrillator (ICD) solely for the presence of LGE, but it can still influence decision-making in borderline cases. 219
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Table 3. Cardiac MRI features of different cardiomyopathies. Cardiomyopathy
Useful MRI sequences
MRI finding
LGE
Hypertrophic cardiomyopathy
SSFP, myocardial tagging, T1 mapping, T2 mapping
Increased wall thickness especially in anterior septum, LVOT obstruction, systolic anterior motion ofmitral valve
Patchy, mid-wall Often at RV insertion points and segments with maximal hypertrophy
Arrhythmogenic right ventricular cardiomyopathy
SSFP, T1 mapping, T2 mapping
RV enlargement, with outpouching and dyskinesis
Patchy LGE in RV wall
Left ventricular noncompaction
SSFP
Prominent ventricular trabeculations and recesses. Noncompacted to compacted myocardium >2.3
Subendocardial LGE
Dilated cardiomyopathy
SSFP, T1 mapping, T2 mapping
Dilated left ventricle with global or regional hypokinesis
Mid-myocardial stripe, or no LGE
Myocarditis
SSFP, T1 mapping, T2 mapping,
Global or regional hypokinesis, pericardial effusion Myocardium/ skeletal muscle >2 on T2 imaging Myocardium/ skeletal muscle >4 on T1 imaging
Subepicardial LGE particularlyin inferolateral region with sparing of subendocardium
Stress-induced cardiomyopathy
SSFP
Regional LV dysfunction, especially in apex. Increased T2 signal (edema)
Typically none or low intensity, patchy LGE
Peripartum cardiomyopathy
SSFP
Dilated cardiomyopathy. Increased T2 signal (edema)
None or diffuse LGE
Amyloidosis
SSFP, T1 mapping
Atrial, ventricular and valvular thickening Pleural and pericardial effusions Prolonged T1 relaxation time (>1020 ms)
Diffuse LGE, often subendocardial
Iron overload
SSFP, T2* mapping
Reduced T2* relaxation time (2.3 in end-diastole is a commonly accepted criterion (FIGURE 9) and results in a sensitivity of 86% and specificity of 99% [45]. LVNC often affects the apical and mid-ventricularlateral segments with sparing of the basal-septal wall [43,45]. Subendocardial LGE, reflective of fibrosis, may be seen in up to 70% of studies and may be present in both the compacted and noncompacted segments [43]. The extent of LGE A
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Mixed primary cardiomyopathies Idiopathic dilated cardiomyopathy
With a prevalence of 1 in 2500, idiopathic dilated cardiomyopathy (DCM) is a common cause of heart failure and the leading referral for cardiac transplantation [1]. DCM is characterized as a mixed cardiomyopathy due to the influence of both genetic and exogenous factors that play an important role in the phenotypic expression of the disease. It is categorized as idiopathic after exclusion of various secondary etiologies including ischemia, myocarditis, iron overload, neuromuscular disorders, chemotherapy toxicity, infectious and metabolic disorders. DCM may be either sporadic or familial in origin. Patients are often asymptomatic during early stages of the disease, and can present with symptoms of advanced heart failure or sudden cardiac death as the first manifestation.
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Figure 7. A 15-year-old with Danon disease. Short-axis cine steady-state free precession images in end-diastole at (A) base, (B) mid and (C) apex demonstrating markedly thickened left ventricular walls. Normal systolic function was seen. (D) Multifocal areas of mid-myocardial late gadolinium enhancement (arrows) were also seen reflective of myocardial inflammation and possible fibrosis.
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Unveiling nonischemic cardiomyopathies with cardiac magnetic resonance
DCM morphologically appears as ventricular enlargement and systolic dysfunction of one or both ventricles. LV dysfunction may be either global or regional in nature. Mural thrombi may be seen in the LV and sometimes in the left atrium. LV mass is increased, despite normal wall thickness due to chamber dilatation. These features can usually be well visualized on both echocardiography and MRI. However, MRI offers incremental diagnostic and prognostic value and may help exclude other causes of DCM. T2* and T2-weighted MRI sequences may help exclude iron overload and myocarditis, respectively (discussed in detail later). Native T1 mapping values were markedly elevated in 27 patients with DCM compared with normal volunteers (1239 vs 1070 ms; p < 0.01) Similar results have also been reported in other studies. While native T1 mapping may be able to reliably distinguish between normal and abnormal myocardial tissue, its role in differentiating DCM from other causes of heart failure is not well understood. LGE may demonstrate mid-myocardial fibrosis (FIGURE 10), which helps exclude ischemic and infiltrative etiologies. In a prospective study of 472 patients with non-ischemic DCM, Gulati et al. demonstrated that the presence of mid-wall fibrosis by LGE was associated with a 2.5-fold increased risk of all-cause mortality even after adjusting for LV ejection fraction (95% CI: 1.87–4.69; p < 0.001) [48]. In another study, Wu and colleagues demonstrated that in 65 patients with non-ischemic DCM presence of LGE was associated with a ninefold increased composite risk of heart failure hospitalization, appropriate ICD firings and cardiac death at 17 months even after adjusting for age, gender, LV size and functional class (95% CI: 2.4–35.1; p = 0.001) (FIGURE 11) [49]. Additional larger studies regarding presence of LGE in patients with DCM may help better risk stratify patients who would benefit from a defibrillator. Acquired primary cardiomyopathies
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Figure 8. Patient with arrhythmogenic right ventricular cardiomyopathy. Short-axis cine steady-state free precession images in (A) end-diastole and (B) end-systole. Right ventricle was dilated with an end-diastolic volume of 187 ml. Right ventricular function was reduced globally with an ejection fraction of 37%, and focal outpouching of the right ventricular free wall (arrow). The left ventricular size and function were preserved.
systemic diseases, drugs and transplant rejection. Endomyocardial biopsy is considered the gold standard for diagnosis, but is limited by sampling bias, poor sensitivity (55–63%) and a high rate of complication [51]. Its limited sensitivity can be explained by the focal and patchy nature of the inflammation involving the left ventricle, while the biopsy sample is typically obtained from the right ventricle. Although not specific, the location and pattern of LGE may also suggest the viral etiology of myocarditis [52]. Epicardial LGE is commonly associated with parvovirus myocarditis, compared with mid-wall LGE seen in herpes virus infection. While different cardiac MRI parameters may suggest a potential etiology, endomyocardial biopsy is only test that can B
Myocarditis
Myocarditis refers to acute or chronic inflammation of the myocardium. It should be suspected when a young patient presents with new onset heart failure, chest pain, arrhythmia or conduction disturbances without an identifiable etiology. The clinical and electrocardiographic presentation of myocarditis can sometimes mimic acute coronary syndrome. In a study by Sarda et al., 78% of patients presenting with acute coronary syndrome and normal coronary angiography had evidence of myocarditis [50]. While often asymptomatic, it may also be a leading cause of sudden cardiac death, particularly in young patients [51]. Patients often have a preceding history of upper respiratory tract infection. Besides post-viral infection, myocarditis may also be triggered by www.expert-reviews.com
Figure 9. Patient with left ventricular noncompaction. 4-chamber (A) cine steadystate free precession images in end-diastole at the mid-ventricular level demonstrating marked increase in ratio of the noncompacted to compacted myocardium, hypertrabeculation (or circumferential left ventricular trabeculation) and deep intertrabecular recesses. On cine imaging, there was mild global decrease in systolic function (ejection fraction 40%), and akinesis of part of the septum. (B) Subendocardial late gadolinium myocardial enhancement is seen in the apical and mid-ventricular inferoseptal segments.
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Figure 10. Patient with dilated cardiomyopathy. Late gadolinium enhancement image at mid-ventricular level demonstrating a mid-myocardial stripe pattern of hyperenhancement of the septum (arrows) in keeping with non-ischemic dilated cardiomyopathy.
reliably confirm or refute the hypothesis. Biopsy is not usually necessary given the risk of the procedure, and lack of specific pathogen-directed treatment for most cases of viral myocarditis. It is nevertheless recommended in patients with intractable arrhythmias and heart failure despite optimal medical management to rule out giant cell myocarditis, where mortality may be high without prompt treatment with steroids [4]. Cardiac MRI is emerging as a promising non-invasive tool to image several aspects of myocarditis. Cine SSFP images may reveal global or regional wall motion abnormalities that typically do not follow a vascular territory. In contrast to myocardial infarction, first-pass perfusion is normal in patients with myocarditis. Increased focal or global signal intensity in the myocardium compared with skeletal muscle (ratio ‡2) on T2-weighted black blood imaging is consistent with myocardial edema. Patients with myositis may have diffuse skeletal muscle 1.00 Event-free survival
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Hyperenhancement absent
0.75 Hyperenhancement present 0.50 0.25 p < 0.001 0.00 0
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Figure 11. Kaplan–Meier event-free survival curve for occurrence of composite event of heart failure hospitalization, appropriate implantable cardioverter defibrillator firings and cardiac death. Patients are grouped by presence or absence of late gadolinium enhancement. Reproduced with permission from [49].
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inflammation which decreases the sensitivity of this criterion. Additionally, increased blood flow in inflamed myocardium leads to early uptake of contrast agents. On early enhancement imaging, a myocardial to skeletal muscle ratio ‡4.0 or an absolute myocardial signal intensity increase between the pre- and post-gadolinium of ‡45% on T1-weighted images is consistent with myocarditis [51,53]. In addition to early gadolinium enhancement, LGE may be present in up to 88% of patients with myocarditis [54]. It is most commonly present in the inferolateral segment of the LV [51,54]. LGE in myocarditis often involves the subepicardium with sparing of the subendocardium (FIGURE 12), which helps distinguish it from infarction. After review of the current cardiac MRI literature, a large consensus group published the Lake-Louise criteria in 2009 [51]. It recommended use of cardiac MRI for assessment of myocardial edema (T2-weighted images), hyperemia (early T1-weighted images after gadolinium administration) and fibrosis (late T1-weighted images after gadolinium administration). Presence of two or more of the above findings was suggestive for myocarditis. These criteria provide a sensitivity of 81% and specificity of 71% compared with endomyocardial biopsy [55]. In another study, Zagrosek and colleagues evaluated 36 patients with biopsy-proven myocarditis and found MRI evidence of edema, hyperemia and fibrosis in 86, 80 and 63% of cases, respectively [56]. Similar to the Lake-Louise criteria, they also suggested a combined approach of multiple MRI sequences for evaluation was superior to use of an individual sequence alone. However, meta-analysis of published MRI literature in human myocarditis has not shown any advantage of using the combined approach compared with individual sequences [57]. In addition to the more conventional sequences, role of native T1 and T2 mapping sequences have also been explored in myocarditis. Early studies on T1 and T2 mapping have suggested a high diagnostic accuracy for detection of myocarditis [58,59], and suggest they may be superior to the more conventionally used T1- and T2-weighted imaging sequences. One of the biggest limitations of the literature is the small direct correlation between MRI findings and endomyocardial biopsies. Inflammation may extend beyond the myocardium to involve the pericardium, and result in perimyocarditis [60,61]. Perimyocarditis may manifest as pleuritic chest pain, new S3 on auscultation, pericardial rub, elevated serum biomarkers and regional or global myocardial dysfunction [61]. Specific MRI features include increased signal in the pericardium on T2-weighted and LGE images consistent with inflammation. The pericardium may appear thickened (>4 mm), particularly on T1-weighted images [62]. While not a specific finding of myocarditis, the presence of a pericardial effusion (seen in 32–57% of patients) may reflect active inflammation [51]. Chronic inflammation of the pericardium may result in constrictive pericarditis that often mimics restrictive cardiomyopathy. Assessment of early diastolic annulus velocity and tissue Doppler analysis using echocardiography allows one to distinguish between the two. However in patients with limited acoustic windows, MRI imaging may be pivotal for accurate diagnosis. MRI features of constrictive Expert Rev. Cardiovasc. Ther. 12(2), (2014)
Unveiling nonischemic cardiomyopathies with cardiac magnetic resonance
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pericarditis include marked pericardial thickening, septal bounce, enhanced interventricular dependence, atrial enlargement, dilated vena cava and LGE of pericardium. Although the inflammation typically resolves spontaneously or with mild anti-inflammatory agents, etiologyspecific treatments are often necessary and include immunosuppression, intravenous immunoglobulins and interferon therapy.
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Chagas disease is a common form of C D DCM in Latin America as a result of infection with the protozoan parasite Trypanosoma cruzi. It is currently estimated to affect 8–10 million people globally [63]. Chagas disease classically presents in three stages (acute, indeterminate and chronic). During the acute phase, patients are often asymptomatic or have mild nonspecific symptoms. Symptoms resolve spontaneously in 4–8 weeks. Patients may progress to the indeterminate stage and have a latent form of infection without any overt symptoms. Cardiac involvement Figure 12. Patient with acute myocarditis with short axis views. (A) Dark-blood may only be detected as regional wall T2-weighted images demonstrating increased signal intensity in the mid-lateral wall motion abnormalities or fibrosis on cardiac (arrows). (B) Native T1 mapping images showing increased T1 value in the lateral wall MRI [64]. Subsequently one to three deca(arrows). (C) Late gadolinium enhancement imaging with increased mid-wall signal in des after the acute infection, 30% of the lateral wall (arrows). (D) Late gadolinium enhancement image with enhancement in the anteroseptal and anterior regions in a mid-myocardial pattern, and inferolateral and untreated patients may progress to the inferior segments epicardially concordant with myocarditis. chronic phase, often with cardiac involveAdapted from [58]. ment. Symptoms arise from heart failure, cardiac arrhythmias and thromboembolism. Cardiac MRI may provide incremental value over echo- systolic dysfunction of the apex and sometimes mid-left ventricardiography, particularly in patients with suboptimal cle triggered by intense emotional or physical distress. Howechocardiographic window. Biventricular hypokinesis and ever, the stressful event cannot always be identified [66]. Patients dilatation, mitral and tricuspid regurgitation, wall thinning, commonly present with substernal chest pain or dyspnea, apical aneurysms and mural thrombus are commonly which can mimic the presentation of an acute myocardial present – all of which are well visualized on cine bright blood infarction. However, coronary angiography reveals only nonMRI imaging. Rochitte and colleagues demonstrated that the obstructive coronary artery disease. Post-menopausal women presence and extent of myocardial fibrosis seen as LGE on are disproportionately affected [66–69]. The exact pathophysiocardiac MRI was present in 35 of 51 patients with Chagas logic basis of stress-induced cardiomyopathy remains to be disease, and correlated with disease severity and prognosis [64]. elucidated. Proposed mechanisms include multi-vessel coronary The pattern of LGE in Chagas disease is heterogeneous, often vasospasm, endothelial dysfunction, catecholamine excess and involving the subendocardium, and may mimic the MRI myocarditis [68,70]. appearance of ischemic cardiomyopathy [65]. Regional wall On cardiac MRI, regional LV dysfunction often involving motion abnormalities and fibrosis often have a predilection the apex and mid-wall is present, typically in a non-coronary for the apex and basal inferolateral walls [65]. Cardiac MRI distribution (FIGURE 13). Mid-wall LV dysfunction with sparing of may serve as an important imaging tool to screen and follow the apex has also been reported. Compensatory hyperkinesis of patients with Chagas cardiomyopathy. the basal LV walls may be present leading to LV outflow tract obstruction. In a series of 256 patients with stress-induced cardiomyopathy, the right ventricle was involved in approximately Stress-induced cardiomyopathy Stress-induced cardiomyopathy, also called apical ballooning or 35% of cases [67]. Myocardial edema may be seen as high signal takotsubo cardiomyopathy, is characterized by acute transient intensity on T2-weighted images corresponding to the regions www.expert-reviews.com
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Figure 13. Stress-induced cardiomyopathy in an 81-year-old woman admitted with chest pain and ST elevations, after emotional stress. Coronary angiography did not reveal any occluded vessels. 4-chamber steady-state free precessions image in (A) systole and (B) diastole show apical akinesis of the left and right ventricles along with normal contractility in the basal segments. (C) Late gadolinium enhancement images show absence of enhancement or fibrosis, excluding the diagnosis of myocardial infarction.
of abnormal contractile function [67]. In contrast to myocardial infarction and myocarditis, stress-induced cardiomyopathy does not typically have high-intensity LGE (FIGURE 13). However, subtle patchy LGE may be seen, with signal intensity lower than that observed in myocardial infarction [67]. Use of T1 mapping sequences demonstrated larger area under the curve compared with T2-weighted sequences in differentiating 21 patients with stress-induced cardiomyopathy without LGE compared with normal controls [71]. Although the in-hospital mortality is 2% [69], most patients recover function in 1–4 weeks [66,67]. Followup MRI imaging shows complete normalization of the ejection fraction and regional wall motion abnormalities. Management of stress-induced cardiomyopathy is largely supportive with resolution of underlying physical and emotional stress. Although these patients commonly have recurrence of chest discomfort, recurrence of stress-induced cardiomyopathy is relatively uncommon and involves approximately 10% of cases [69]. Peripartum cardiomyopathy
Peripartum cardiomyopathy is a rare form of DCM with an incidence of 1 in 400 births [72]. It is characterized by the development of heart failure within the last month of pregnancy and up to 5 months postpartum without an identifiable etiology. Although the pathogenesis of peripartum cardiomyopathy is poorly understood, several risk factors have been identified including maternal age >30 years, African descent, multiparity, pregnancy with multiple fetuses and history of eclampsia [73]. There have been a few small case series and case reports on use of cardiac MRI in patients with peripartum cardiomyopathy. SSFP sequences on MRI predominantly demonstrate a dilated left ventricle with reduced contractile function (FIGURE 14). RV dilatation and dysfunction may also be seen. Increased signal intensity may be seen on T2-weighted images representing edema. In some cases, areas of edema on T2-weighted images may be associated with increased signal on LGE sequences [74,75]. By contrast, in one series of eight women with peripartum cardiomyopathy, no evidence of LGE was visualized [76]. Additionally, the 228
authors found no MRI finding that was able to differentiate between patients who had complete LV recovery at 50 months and those with permanent LV dysfunction. Although 50% of patients with peripartum cardiomyopathy recover ventricular function, some can have a deleterious course with high mortality and may require cardiac transplantation. Transplant cardiomyopathy
Despite advances in immunosuppressive therapy, rejection after cardiac transplant continues to be a common problem. Rejection is estimated to account for 18% of deaths before the first year and 10% between 1 and 3 years after cardiac transplantation [77]. Histologically, it is characterized by lymphocyte infiltration and inflammation. The diagnosis of cellular rejection is typically established by endomyocardial biopsies which are performed as part of routine surveillance. However, biopsies are limited by sampling bias and are invasive. Cardiac MRI has the potential to be an important non-invasive tool for early detection of transplant rejection. Increased signal intensity on T2-weighted images may be seen, reflective of myocardial edema. Using this technique, Muehling and colleagues have demonstrated a sensitivity of 89% and specificity of 70% to detect acute rejection compared with endomyocardial biopsy [78]. However, additional prognostic studies are needed prior to widespread use of cardiac MRI for management of transplant cardiomyopathy. Secondary cardiomyopathies Amyloidosis
Amyloidosis is a multisystem disease characterized by deposition of insoluble b-pleated fibrils of amyloid glycoproteins. Primary (AL) amyloidosis is the most common subtype, and results from plasmacytosis, multiple myeloma and plasma cell dyscrasias. It results in deposition of monoclonal light chain immunoglobulins in the myocardial interstitium. Cardiac involvement is common and may be the cause of death in up to 50% of cases [79]. Secondary amyloidosis occurs due to Expert Rev. Cardiovasc. Ther. 12(2), (2014)
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Figure 14. Peripartum cardiomyopathy in a 36-year-old woman 1 month after delivery. Short-axis steady-state free precession image of the mid-left ventricle at (A) end-diastole and (B) end-systole, demonstrating marked dilatation of the left ventricular cavity. On cine images, the left ventricular ejection fraction was 33%. (C) A small focal area of late gadolinium enhancement was seen in the inferolateral left ventricular wall (arrow).
excess acute phase protein produced in response to inflammatory states. Less common forms of amyloidosis include the familial form, an autosomal dominant disorder with transthyretin gene mutation and senile amyloidosis. The latter is very common in the elderly, with one of every four autopsied patients over the age of 90 years reported to have histologic evidence in the myocardium [79]. However, amyloidosis is often clinically silent and isolated to the heart. Irrespective of the etiology, cardiac amyloidosis presents predominantly as diastolic heart failure and restrictive cardiomyopathy. Deposition of amyloid fibrils in the myocardial interstitium leads to thickened wall, restrictive cardiomyopathy and interruption of the conduction system. As the disease progresses, biventricular systolic dysfunction may develop. While echocardiography may demonstrate mural thickening and other morphologic features of amyloidosis, it is limited by its ability to differentiate amyloidosis from other forms of LV hypertrophy. Adjunctive use of strain echocardiography may be promising, and typically demonstrates decreased myocardial strain at the base, with sparing of the apex. In comparison, cardiac MRI allows tissue characterization and visualization of the heart, pericardium and pleura, all in one imaging study. Cardiac MRI features of cardiac amyloidosis seen on SSFP sequences include diffuse biventricular wall thickening, atrial wall thickening, especially involving the interatrial septum, atrial enlargement due to diastolic dysfunction and multivalvular leaflet thickening, particularly in late stages of the disease (FIGURE 15). High signal intensity on T2-weighted spin echo images may be seen within the left atrial chamber due to decreased atrial contractility and resultant stasis of blood in the left atrium [80]. Pericardial and pleural involvement is common, and manifest as effusions (FIGURE 15). The amyloid protein deposits asymmetrically, with greater deposition in the subendocardium compared with the subepicardium. The increased interstitial volume from amyloid deposition leads to increased retention of gadolinium in the www.expert-reviews.com
subendocardium. In contrast to patients with myocardial infarction, LGE in amyloidosis is due to increase in non-fibrotic interstitial space, rather than diffuse fibrosis. In 29 patients with cardiac amyloidosis, 69% demonstrated diffuse global subendocardial LGE (FIGURE 15) [81]. Focal and patchy LGE may also occur. Compared with normal subjects, gadolinium clears rapidly from the blood pool reflecting high myocardial uptake, resulting in a very dark blood pool [81]. Diffuse gadolinium uptake by the myocardium characteristically results in nulling of the blood pool before the myocardium. This also leads to shorter and often difficult to identify inversion recovery time, a finding that is highly suggestive of amyloidosis. Presence of LGE was found to be superior to other echocardiographic and clinical parameters for diagnosing amyloidosis and reported to have a sensitivity and specificity of 88 and 95%, respectively [82]. The prognostic utility of LGE in patients with amyloidosis is somewhat conflicting. In a study of 47 patients with amyloidosis, presence of LGE conferred a worse 1-year mortality (Wald chi-square statistic 4.91, p = 0.03) [82]. By contrast, in 29 patients with amyloidosis, Maceira et al. did not find the presence of LGE to be predictive of mortality at 623 days; however, they found the intramyocardial T1 gradient (gradient between the epicardium and endocardium 2 min post-contrast injection) predicted mortality with 85% accuracy [83]. Cardiac MRI may be useful not just for its role in diagnosis and prognosis of patients with amyloidosis, but also for serial assessment of disease regression with treatment [84]. Patients with amyloidosis have a prolonged myocardial T1 relaxation time on native T1 mapping sequences compared with normal subjects (FIGURE 16) [80,85]. Karamitsos and colleagues demonstrated that using a cut-off value of 1020 ms resulted in a 92% diagnostic accuracy for identification of cardiac amyloidosis, which may be a superior diagnostic technique compared with assessment of LGE [85]. However, additional validation studies are needed prior to the clinical use of this imaging sequence. While cardiac MRI has significantly changed the diagnostic evaluation of 229
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*
**
B
*
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Figure 15. A 56-year-old male with primary amyloidosis. 4-chamber cine steady-state free precession images in (A) end-systole and (B) end-diastole. Normal left and right ventricular sizes, with severe concentric wall thickening involving both ventricular walls and interatrial septum was seen. Severe left ventricular systolic dysfunction (ejection fraction 31%) was present. Right ventricular function was also decreased with ejection fraction 31%. Marked biatrial enlargement present. Small pericardial effusion (*) and large pleural effusion (**) noted. (C) On late gadolinium enhancement images, blood pool nulled prior to the myocardium, with diffuse transmural late gadolinium enhancement of both the left and right ventricles, characteristic of cardiac amyloidosis.
amyloidosis, the prognostic utility of this technique is yet to be fully elucidated. Iron overload cardiomyopathy
Iron overload cardiomyopathy is a chronic and potentially lethal condition characterized by myocardial dysfunction secondary to accumulation of excess iron in the myocardium. Potential causes include increased intestinal absorption with normal intake seen in chronic liver diseases, porphyria and hemochromatosis, excess dietary intake and chronic red blood cell transfusions such as in hereditary anemias and myelodysplastic syndromes. Myocardial iron infiltration is the leading cause of death in patients receiving chronic blood transfusions, accounting for up to 70% of all deaths [86], with the incidence further increasing as these patients are now surviving longer. Iron accumulation can occur in multiple organs including the myocardium, liver, spleen, pancreas and central nervous system. In the normal physiologic state, iron is bound to transferrin. In iron overloaded state, the iron that exceeds the transferrin binding capacity is transformed into highly reactive free radicals, which in turn cause myocardial cell damage and death. Cardiac iron deposition begins initially in the epicardium and progresses to the endocardium. Patients are often asymptomatic in early stages of the disease. With progressive iron deposition, patients develop diastolic dysfunction and restrictive cardiomyopathy, and eventually progress to a DCM with systolic dysfunction [87]. Iron deposition may also involve the conduction system, resulting in bradycardia, atrioventricular blocks, atrial fibrillation and ventricular arrhythmias and sudden cardiac death [86]. The diagnosis of iron overload cardiomyopathy can be challenging, particularly in the early stages of the disease. Although elevated serum ferritin levels and iron content on liver biopsy are both used as surrogates of disease progression, they are incomplete in cardiac risk assessment. Patients may develop cardiac symptoms despite low overall iron burden [88]. 230
In patients with iron overload cardiomyopathy, myocardial fibrosis is rare, and hence MRI-LGE is typically absent. The development of newer MRI sequences to characterize myocardial iron stores has changed the fundamental management of iron overload cardiomyopathy, and positively impacted survival [89]. In the iron overload state, paramagnetic effects of iron cause variations in the magnetic field which results in shortening of the relaxation time (reduced T2*) and decreased signal intensity (FIGURE 17). T2* correlates inversely with iron deposition, and the effect is concentration dependent. T2* relaxation time measured at the mid-ventricular septum correlates closely with cardiac biopsy and global iron concentration on autopsy studies [90,91]. In a seminal study by Anderson et al., T2* relaxation time
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Unveiling nonischemic cardiomyopathies with cardiac magnetic resonance Expert Rev. Cardiovasc. Ther. 12(2), 217–239 (2014)
Niti R Aggarwal*1, Tyler J Peterson1, Phillip M Young2, Philip A Araoz2, James Glockner2, Sunil V Mankad1 and Eric E Williamson2 1 Department of Internal, Division of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA 2 Department of Radiology, Division of Cardiovascular Radiology, Mayo Clinic, Rochester, MN, USA *Author for correspondence: Tel.: +1 507 284 3545 Fax: +1 507 266 7929 [email protected]
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Cardiomyopathy is defined as a heterogeneous group of myocardial disorders with mechanical or electrical dysfunction. Identification of the etiology is important for accurate diagnosis, treatment and prognosis, but continues to be challenging. The ability of cardiac MRI to non-invasively obtain 3D-images of unparalleled resolution without radiation exposure and to provide tissue characterization gives it a distinct advantage over any other diagnostic tool used for evaluation of cardiomyopathies. Cardiac MRI can accurately visualize cardiac morphology and function and also help identify myocardial edema, infiltration and fibrosis. It has emerged as an important diagnostic and prognostic tool in tertiary care centers for work up of patients with non-ischemic cardiomyopathies. This review covers the role of cardiac MRI in evaluation of nonischemic cardiomyopathies, particularly in the context of other diagnostic and prognostic imaging modalities. KEYWORDS: cardiac magnetic resonance . cardiovascular imaging . dilated cardiomyopathy . hypertrophic cardiomyopathy
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infiltrative cardiomyopathy . late gadolinium enhancement
Non-ischemic cardiomyopathies consist of a heterogeneous group of disorders with progressive myocardial dysfunction resulting from various etiologies. The American Heart Association proposed a classification scheme dividing cardiomyopathies into two major categories based on the predominant organ involved [1]. Primary cardiomyopathies are solely or predominantly confined to the heart, and may be genetic, acquired or mixed in origin (TABLE 1). In comparison, secondary cardiomyopathies are generalized systemic disorders, where the heart is one of the multiple organs involved (TABLE 1). Given that many cardiomyopathies may predominantly involve the heart, but may also involve other organs, the distinction between primary and secondary cardiomyopathies may be tenuous. Given this challenge, the European Society of Cardiology took a different approach to classifying cardiomyopathies. While the American Heart Association grouped the cardiomyopathies based on the mechanism of myocardial dysfunction, the European Society of Cardiology took a more clinical approach and grouped them differently based on ventricular morphology and function as hypertrophic, arrhythmogenic right ventricle,
10.1586/14779072.2014.876900
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non-ischemic cardiomyopathy
restrictive, dilated and unclassified [2]. Each phenotype is then further subclassified as familial or non-familial (FIGURE 1). Differentiating one cardiomyopathy from another is important for tailoring of medical therapy, risk stratification and establishing prognosis. Currently, the first-line imaging modality of choice for cardiomyopathies is echocardiography owing to its high temporal resolution, widespread availability and portability. However, echocardiographic images are suboptimal in up to 20% of patients due to inadequate acoustic windows, associated with chest deformity, obesity or underlying lung disease [3]. Additionally, although an endomyocardial biopsy is considered the gold standard, given its invasive nature, associated risks and often lack of disease-specific treatments, it is not commonly indicated for evaluation of myocardial disease [4]. Endomyocardial biopsy may be indispensable in establishing etiology of unexplainable cardiomyopathies, particularly of new onset and with intractable heart failure or arrhythmias. Compared with echocardiography, cardiac MRI is not limited by poor acoustic windows, allows imaging of the heart in any plane with
2014 Informa UK Ltd
ISSN 1477-9072
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Table 1. Classification of cardiomyopathies based on the American Heart Association guidelines. Primary cardiomyopathies Genetic
Hypertrophic cardiomyopathy Arrhythmogenic right ventricular cardiomyopathy Left ventricular noncompaction
Mixed
Dilated cardiomyopathy
Primary genetic cardiomyopathies Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy with a prevalence of 1 in 500 in the general population [6]. It results from mutations in genes encoding the proteins of cardiac sarcomere and is inherited in an autosomal dominant pattern. Histologically, HCM is characterized by myofiber disarray, myocyte hypertrophy and variSecondary cardiomyopathies able amount of interstitial fibrosis. Presence of left ventricular Infiltrative Amyloidosis (LV) wall thickness ‡15 mm in the absence of another cause Hurlers and Hunters disease of LV hypertrophy such as hypertension or valve disease is conStorage Iron overload including hemochromatosis sistent with a diagnosis of HCM. The vast majority of patients Fabry disease remain asymptomatic with a normal life expectancy. However, Danon disease a small number of patients are at increased risk of complicaInflammatory Sarcoidosis tions. Sudden cardiac death may be the first manifestation of HCM in asymptomatic patients [7]. It is the leading cause of Endocrine Thyroid dysfunction Diabetes death in young athletes [7]. Symptoms of dyspnea, exertional Pheochromocytoma chest discomfort, palpitations and syncope may occur due to multiple mechanisms including dynamic left ventricular outEndomyocardial Hypereosinophilic syndromes, flow tract (LVOT) obstruction, systolic and diastolic dysfuncLoeffler endocarditis Carcinoid heart disease tion, arrhythmias and mitral regurgitation. Dynamic LVOT obstruction is present in nearly three of every four patients Neuromuscular Muscular dystrophies with HCM either at rest or with provocation [7]. Friedreich’s ataxia While echocardiography serves as a good screening tool, it Other Chemotherapy-induced cardiomyopathy can underestimate LV wall thickness and may miss up to 6% Radiation-induced heart disease of HCM cases compared with cardiac MRI [8]. Owing to its ability to image the heart in any plane without being dependant a wide field of view. Furthermore, cardiac MRI is able to char- on the acoustic windows, cardiac MRI is being increasingly utiacterize tissue using unique image sequences and tissue lized to image patients with HCM. In addition to better estienhancement [5]. TABLE 2 summarizes the advantage of commonly mating the presence and magnitude of LV hypertrophy used MRI sequences in nonischemic cardiomyopathies. Given compared with echocardiography [8], cardiac MRI may also prothese advantages, as well as technological advances allowing for vide a better assessment of right ventricular (RV) hypertrophy, shorter scan times, cardiac MRI is being increasingly used to seen in 18% of cases with HCM [9]. HCM has a wide variety image patients with cardiomyopathies. Various cardiomyopa- of morphologic expressions with uniform wall thickening in thies often have a unique MRI fingerprint that helps in its some cases, and focal hypertrophy involving the anteroseptal LV diagnosis (TABLE 3). Cardiac MRI has emerged as an important or apex in others. On cardiac MRI, LV wall thickness is measured on short axis steady-state free precession (SSFP) sequences at end-diastole. Cardiomyopathies SSFP imaging in the LVOT view may demonstrate systolic anterior motion of Arrhythmogenic the mitral valve and a posteriorly directed Restrictive Dilated Hypertrophic Unclassified right ventricular cardiomyopathy cardiomyopathy cardiomyopathy cardiomyopathy mitral regurgitation jet (FIGURE 2). Velocitycardiomyopathy encoded phase-contrast imaging performed in the same plane can permit quantitative assessment of the LVOT graFamilial/genetic Non-familial/non-genetic dient and mitral regurgitation severity Figure 1. Schematic of proposed classification of cardiomyopathies by the which have been correlated with worse European Society of Cardiology. prognosis [10]. The repetitive contact Acquired
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diagnostic and prognostic tool for anatomic and functional assessment as well as characterization of myocardial edema and fibrosis in patients with cardiomyopathies. In this manuscript, we review the current clinical applications of cardiac MRI in non-ischemic cardiomyopathies and highlight its advantages over conventional imaging.
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Myocarditis Stress-induced cardiomyopathy Peripartum cardiomyopathy Tachycardia-induced cardiomyopathy Transplant cardiomyopathy
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Unveiling nonischemic cardiomyopathies with cardiac magnetic resonance
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Table 2. Characteristics of cardiac MRI pulse sequences. MRI sequence
Sequence description
Information obtained
Steady-state free precession sequences
T1/T2-weighted bright blood imaging typically as a cine acquisition
Biventricular volume and function, myocardial mass
Myocardial tagging
Apply slice-selective magnetization saturated planes orthogonal to the imaging slice
Diastolic function, myocardial strain
Phase contrast
Velocity encoded flow sequence for flow quantitation
Myocardial diastolic function, valvular stenosis or regurgitation
T1-weighted
T1-weighted inversion recovery sequence
Anatomic evaluation of the heart and great vessels
Native T1 mapping
Multiple images with different T1 sensitivity that follow a T1 decay curve
May quantify diffuse myocardial fibrosis in HCM, DCM, edema in post-infarct patients, and amyloid infiltration in amyloidosis
T2-weighted
T2 weighted inversion recovery sequence with fat saturation
Myocardial edema and inflammation
T2-mapping
Multiple images are acquired with different T2 sensitivity that follow a T2 decay curve
Quantify myocardial edema
T2*-mapping
Multiple images with different T2* sensitivities are acquired
Hemorrhage in acute myocardial infarction, iron deposition in hemochromatosis
Myocardial perfusion
T1-weighted inversion recovery sequence immediately after gadolinium administration
Perfusion abnormalities and mural thrombus
Late gadolinium enhancement
T1-weighted inversion recovery sequence 5-20 minutes after gadolinium administration
Assess perfusion abnormalities and mural thrombus
DCM: Dilated cardiomyopathy; HCM: Hypertrophic cardiomyopathy.
between the anterior mitral valve leaflet and the basal interventricular septum can result in fibrosis of the septum and thickening of anterior mitral valve leaflets and chordae. Diastolic dysfunction may often precede LV hypertrophy, and may be an important marker of LV wall stress in patients with HCM. The role of cardiac MRI to characterize diastolic function is still emerging. Measurement of mitral inflow velocities (early filling ‘E’ and atrial systolic filling ‘A’ wave), pulmonary vein flow (systolic ‘S’ and diastolic ‘D’) velocities and myocardial motion velocity (E´) is feasible by phase-contrast MRI imaging, and comparable with measurements obtained by Doppler echocardiography [11,12]. In a study of 18 patients with hypertensive heart disease, E/E´ ratio measured by cardiac MRI had good correlation with invasively measured pulmonary capillary wedge pressure [12]. Additionally, myocardial tagging, which is unique to MRI, may provide 3D assessment of myocardial systolic and diastolic deformation, and strain rate along the circumferential, radial and longitudinal directions. Young et al. demonstrated reduced 3D strain in seven patients with HCM compared with normal controls (-0.18 vs -0.22, p < 0.05) [13]. LV wall stress measured by cardiac MRI was shown to precede LV hypertrophy in 502 patients with non-ischemic cardiomyopathy [14]. In another study, Kim et al. evaluated 25 patients with HCM and reported significantly impaired circumferential shortening in regions of late gadolinium enhancement (LGE), regardless of the degree of myocardial hypertrophy (FIGURE 3) [15]. However, at present, these sequences are not currently routinely performed at most cardiac centers, and additional larger studies www.expert-reviews.com
are needed to explore their feasibility, and diagnostic and prognostic utility in this patient population. Despite our growing knowledge about HCM, our ability to risk stratify patients at risk for sudden cardiac death is still limited. Depending on the selection of patients, presence of LGE on cardiac MRI has been reported in 50–80% of patients with HCM [16], and correlates well with areas of fibrosis on histologic studies. LGE is typically patchy and in a non-vascular distribution (FIGURE 2). It is commonly confined to the RV insertion points and to areas of maximal LV hypertrophy [16]. Besides its diagnostic value, the extent of LGE in HCM was inversely proportional to the LVEF and directly proportional to the incidence of heart failure [17,18]. Additionally, presence of LGE conferred a sevenfold increased risk for lethal ventricular arrhythmias on ambulatory 24-hour ECG monitoring compared with those without LGE (FIGURE 4) [19]. Presence of LGE has also been associated with sudden cardiac death. In a metaanalysis combining the 4 published studies on the topic and comprising 1063 patients with HCM, the presence of LGE was associated with a threefold increased risk of cardiac death (95% CI: 1.01–8.42; p = 0.047) and a twofold increased risk of sudden cardiac death or aborted sudden cardiac death (95% CI: 0.87–6.58; p = 0.091) [20]. However, committee members that wrote the HCM guideline believe the association between LGE and risk of sudden cardiac death was weak and did not support the need to implant an implantable cardioverterdefibrillator (ICD) solely for the presence of LGE, but it can still influence decision-making in borderline cases. 219
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Table 3. Cardiac MRI features of different cardiomyopathies. Cardiomyopathy
Useful MRI sequences
MRI finding
LGE
Hypertrophic cardiomyopathy
SSFP, myocardial tagging, T1 mapping, T2 mapping
Increased wall thickness especially in anterior septum, LVOT obstruction, systolic anterior motion ofmitral valve
Patchy, mid-wall Often at RV insertion points and segments with maximal hypertrophy
Arrhythmogenic right ventricular cardiomyopathy
SSFP, T1 mapping, T2 mapping
RV enlargement, with outpouching and dyskinesis
Patchy LGE in RV wall
Left ventricular noncompaction
SSFP
Prominent ventricular trabeculations and recesses. Noncompacted to compacted myocardium >2.3
Subendocardial LGE
Dilated cardiomyopathy
SSFP, T1 mapping, T2 mapping
Dilated left ventricle with global or regional hypokinesis
Mid-myocardial stripe, or no LGE
Myocarditis
SSFP, T1 mapping, T2 mapping,
Global or regional hypokinesis, pericardial effusion Myocardium/ skeletal muscle >2 on T2 imaging Myocardium/ skeletal muscle >4 on T1 imaging
Subepicardial LGE particularlyin inferolateral region with sparing of subendocardium
Stress-induced cardiomyopathy
SSFP
Regional LV dysfunction, especially in apex. Increased T2 signal (edema)
Typically none or low intensity, patchy LGE
Peripartum cardiomyopathy
SSFP
Dilated cardiomyopathy. Increased T2 signal (edema)
None or diffuse LGE
Amyloidosis
SSFP, T1 mapping
Atrial, ventricular and valvular thickening Pleural and pericardial effusions Prolonged T1 relaxation time (>1020 ms)
Diffuse LGE, often subendocardial
Iron overload
SSFP, T2* mapping
Reduced T2* relaxation time (2.3 in end-diastole is a commonly accepted criterion (FIGURE 9) and results in a sensitivity of 86% and specificity of 99% [45]. LVNC often affects the apical and mid-ventricularlateral segments with sparing of the basal-septal wall [43,45]. Subendocardial LGE, reflective of fibrosis, may be seen in up to 70% of studies and may be present in both the compacted and noncompacted segments [43]. The extent of LGE A
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Mixed primary cardiomyopathies Idiopathic dilated cardiomyopathy
With a prevalence of 1 in 2500, idiopathic dilated cardiomyopathy (DCM) is a common cause of heart failure and the leading referral for cardiac transplantation [1]. DCM is characterized as a mixed cardiomyopathy due to the influence of both genetic and exogenous factors that play an important role in the phenotypic expression of the disease. It is categorized as idiopathic after exclusion of various secondary etiologies including ischemia, myocarditis, iron overload, neuromuscular disorders, chemotherapy toxicity, infectious and metabolic disorders. DCM may be either sporadic or familial in origin. Patients are often asymptomatic during early stages of the disease, and can present with symptoms of advanced heart failure or sudden cardiac death as the first manifestation.
C
D
Figure 7. A 15-year-old with Danon disease. Short-axis cine steady-state free precession images in end-diastole at (A) base, (B) mid and (C) apex demonstrating markedly thickened left ventricular walls. Normal systolic function was seen. (D) Multifocal areas of mid-myocardial late gadolinium enhancement (arrows) were also seen reflective of myocardial inflammation and possible fibrosis.
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Unveiling nonischemic cardiomyopathies with cardiac magnetic resonance
DCM morphologically appears as ventricular enlargement and systolic dysfunction of one or both ventricles. LV dysfunction may be either global or regional in nature. Mural thrombi may be seen in the LV and sometimes in the left atrium. LV mass is increased, despite normal wall thickness due to chamber dilatation. These features can usually be well visualized on both echocardiography and MRI. However, MRI offers incremental diagnostic and prognostic value and may help exclude other causes of DCM. T2* and T2-weighted MRI sequences may help exclude iron overload and myocarditis, respectively (discussed in detail later). Native T1 mapping values were markedly elevated in 27 patients with DCM compared with normal volunteers (1239 vs 1070 ms; p < 0.01) Similar results have also been reported in other studies. While native T1 mapping may be able to reliably distinguish between normal and abnormal myocardial tissue, its role in differentiating DCM from other causes of heart failure is not well understood. LGE may demonstrate mid-myocardial fibrosis (FIGURE 10), which helps exclude ischemic and infiltrative etiologies. In a prospective study of 472 patients with non-ischemic DCM, Gulati et al. demonstrated that the presence of mid-wall fibrosis by LGE was associated with a 2.5-fold increased risk of all-cause mortality even after adjusting for LV ejection fraction (95% CI: 1.87–4.69; p < 0.001) [48]. In another study, Wu and colleagues demonstrated that in 65 patients with non-ischemic DCM presence of LGE was associated with a ninefold increased composite risk of heart failure hospitalization, appropriate ICD firings and cardiac death at 17 months even after adjusting for age, gender, LV size and functional class (95% CI: 2.4–35.1; p = 0.001) (FIGURE 11) [49]. Additional larger studies regarding presence of LGE in patients with DCM may help better risk stratify patients who would benefit from a defibrillator. Acquired primary cardiomyopathies
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Figure 8. Patient with arrhythmogenic right ventricular cardiomyopathy. Short-axis cine steady-state free precession images in (A) end-diastole and (B) end-systole. Right ventricle was dilated with an end-diastolic volume of 187 ml. Right ventricular function was reduced globally with an ejection fraction of 37%, and focal outpouching of the right ventricular free wall (arrow). The left ventricular size and function were preserved.
systemic diseases, drugs and transplant rejection. Endomyocardial biopsy is considered the gold standard for diagnosis, but is limited by sampling bias, poor sensitivity (55–63%) and a high rate of complication [51]. Its limited sensitivity can be explained by the focal and patchy nature of the inflammation involving the left ventricle, while the biopsy sample is typically obtained from the right ventricle. Although not specific, the location and pattern of LGE may also suggest the viral etiology of myocarditis [52]. Epicardial LGE is commonly associated with parvovirus myocarditis, compared with mid-wall LGE seen in herpes virus infection. While different cardiac MRI parameters may suggest a potential etiology, endomyocardial biopsy is only test that can B
Myocarditis
Myocarditis refers to acute or chronic inflammation of the myocardium. It should be suspected when a young patient presents with new onset heart failure, chest pain, arrhythmia or conduction disturbances without an identifiable etiology. The clinical and electrocardiographic presentation of myocarditis can sometimes mimic acute coronary syndrome. In a study by Sarda et al., 78% of patients presenting with acute coronary syndrome and normal coronary angiography had evidence of myocarditis [50]. While often asymptomatic, it may also be a leading cause of sudden cardiac death, particularly in young patients [51]. Patients often have a preceding history of upper respiratory tract infection. Besides post-viral infection, myocarditis may also be triggered by www.expert-reviews.com
Figure 9. Patient with left ventricular noncompaction. 4-chamber (A) cine steadystate free precession images in end-diastole at the mid-ventricular level demonstrating marked increase in ratio of the noncompacted to compacted myocardium, hypertrabeculation (or circumferential left ventricular trabeculation) and deep intertrabecular recesses. On cine imaging, there was mild global decrease in systolic function (ejection fraction 40%), and akinesis of part of the septum. (B) Subendocardial late gadolinium myocardial enhancement is seen in the apical and mid-ventricular inferoseptal segments.
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Figure 10. Patient with dilated cardiomyopathy. Late gadolinium enhancement image at mid-ventricular level demonstrating a mid-myocardial stripe pattern of hyperenhancement of the septum (arrows) in keeping with non-ischemic dilated cardiomyopathy.
reliably confirm or refute the hypothesis. Biopsy is not usually necessary given the risk of the procedure, and lack of specific pathogen-directed treatment for most cases of viral myocarditis. It is nevertheless recommended in patients with intractable arrhythmias and heart failure despite optimal medical management to rule out giant cell myocarditis, where mortality may be high without prompt treatment with steroids [4]. Cardiac MRI is emerging as a promising non-invasive tool to image several aspects of myocarditis. Cine SSFP images may reveal global or regional wall motion abnormalities that typically do not follow a vascular territory. In contrast to myocardial infarction, first-pass perfusion is normal in patients with myocarditis. Increased focal or global signal intensity in the myocardium compared with skeletal muscle (ratio ‡2) on T2-weighted black blood imaging is consistent with myocardial edema. Patients with myositis may have diffuse skeletal muscle 1.00 Event-free survival
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Hyperenhancement absent
0.75 Hyperenhancement present 0.50 0.25 p < 0.001 0.00 0
0.5
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Figure 11. Kaplan–Meier event-free survival curve for occurrence of composite event of heart failure hospitalization, appropriate implantable cardioverter defibrillator firings and cardiac death. Patients are grouped by presence or absence of late gadolinium enhancement. Reproduced with permission from [49].
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inflammation which decreases the sensitivity of this criterion. Additionally, increased blood flow in inflamed myocardium leads to early uptake of contrast agents. On early enhancement imaging, a myocardial to skeletal muscle ratio ‡4.0 or an absolute myocardial signal intensity increase between the pre- and post-gadolinium of ‡45% on T1-weighted images is consistent with myocarditis [51,53]. In addition to early gadolinium enhancement, LGE may be present in up to 88% of patients with myocarditis [54]. It is most commonly present in the inferolateral segment of the LV [51,54]. LGE in myocarditis often involves the subepicardium with sparing of the subendocardium (FIGURE 12), which helps distinguish it from infarction. After review of the current cardiac MRI literature, a large consensus group published the Lake-Louise criteria in 2009 [51]. It recommended use of cardiac MRI for assessment of myocardial edema (T2-weighted images), hyperemia (early T1-weighted images after gadolinium administration) and fibrosis (late T1-weighted images after gadolinium administration). Presence of two or more of the above findings was suggestive for myocarditis. These criteria provide a sensitivity of 81% and specificity of 71% compared with endomyocardial biopsy [55]. In another study, Zagrosek and colleagues evaluated 36 patients with biopsy-proven myocarditis and found MRI evidence of edema, hyperemia and fibrosis in 86, 80 and 63% of cases, respectively [56]. Similar to the Lake-Louise criteria, they also suggested a combined approach of multiple MRI sequences for evaluation was superior to use of an individual sequence alone. However, meta-analysis of published MRI literature in human myocarditis has not shown any advantage of using the combined approach compared with individual sequences [57]. In addition to the more conventional sequences, role of native T1 and T2 mapping sequences have also been explored in myocarditis. Early studies on T1 and T2 mapping have suggested a high diagnostic accuracy for detection of myocarditis [58,59], and suggest they may be superior to the more conventionally used T1- and T2-weighted imaging sequences. One of the biggest limitations of the literature is the small direct correlation between MRI findings and endomyocardial biopsies. Inflammation may extend beyond the myocardium to involve the pericardium, and result in perimyocarditis [60,61]. Perimyocarditis may manifest as pleuritic chest pain, new S3 on auscultation, pericardial rub, elevated serum biomarkers and regional or global myocardial dysfunction [61]. Specific MRI features include increased signal in the pericardium on T2-weighted and LGE images consistent with inflammation. The pericardium may appear thickened (>4 mm), particularly on T1-weighted images [62]. While not a specific finding of myocarditis, the presence of a pericardial effusion (seen in 32–57% of patients) may reflect active inflammation [51]. Chronic inflammation of the pericardium may result in constrictive pericarditis that often mimics restrictive cardiomyopathy. Assessment of early diastolic annulus velocity and tissue Doppler analysis using echocardiography allows one to distinguish between the two. However in patients with limited acoustic windows, MRI imaging may be pivotal for accurate diagnosis. MRI features of constrictive Expert Rev. Cardiovasc. Ther. 12(2), (2014)
Unveiling nonischemic cardiomyopathies with cardiac magnetic resonance
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pericarditis include marked pericardial thickening, septal bounce, enhanced interventricular dependence, atrial enlargement, dilated vena cava and LGE of pericardium. Although the inflammation typically resolves spontaneously or with mild anti-inflammatory agents, etiologyspecific treatments are often necessary and include immunosuppression, intravenous immunoglobulins and interferon therapy.
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2000 ms
1000 ms 500 ms
Chagas disease
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Chagas disease is a common form of C D DCM in Latin America as a result of infection with the protozoan parasite Trypanosoma cruzi. It is currently estimated to affect 8–10 million people globally [63]. Chagas disease classically presents in three stages (acute, indeterminate and chronic). During the acute phase, patients are often asymptomatic or have mild nonspecific symptoms. Symptoms resolve spontaneously in 4–8 weeks. Patients may progress to the indeterminate stage and have a latent form of infection without any overt symptoms. Cardiac involvement Figure 12. Patient with acute myocarditis with short axis views. (A) Dark-blood may only be detected as regional wall T2-weighted images demonstrating increased signal intensity in the mid-lateral wall motion abnormalities or fibrosis on cardiac (arrows). (B) Native T1 mapping images showing increased T1 value in the lateral wall MRI [64]. Subsequently one to three deca(arrows). (C) Late gadolinium enhancement imaging with increased mid-wall signal in des after the acute infection, 30% of the lateral wall (arrows). (D) Late gadolinium enhancement image with enhancement in the anteroseptal and anterior regions in a mid-myocardial pattern, and inferolateral and untreated patients may progress to the inferior segments epicardially concordant with myocarditis. chronic phase, often with cardiac involveAdapted from [58]. ment. Symptoms arise from heart failure, cardiac arrhythmias and thromboembolism. Cardiac MRI may provide incremental value over echo- systolic dysfunction of the apex and sometimes mid-left ventricardiography, particularly in patients with suboptimal cle triggered by intense emotional or physical distress. Howechocardiographic window. Biventricular hypokinesis and ever, the stressful event cannot always be identified [66]. Patients dilatation, mitral and tricuspid regurgitation, wall thinning, commonly present with substernal chest pain or dyspnea, apical aneurysms and mural thrombus are commonly which can mimic the presentation of an acute myocardial present – all of which are well visualized on cine bright blood infarction. However, coronary angiography reveals only nonMRI imaging. Rochitte and colleagues demonstrated that the obstructive coronary artery disease. Post-menopausal women presence and extent of myocardial fibrosis seen as LGE on are disproportionately affected [66–69]. The exact pathophysiocardiac MRI was present in 35 of 51 patients with Chagas logic basis of stress-induced cardiomyopathy remains to be disease, and correlated with disease severity and prognosis [64]. elucidated. Proposed mechanisms include multi-vessel coronary The pattern of LGE in Chagas disease is heterogeneous, often vasospasm, endothelial dysfunction, catecholamine excess and involving the subendocardium, and may mimic the MRI myocarditis [68,70]. appearance of ischemic cardiomyopathy [65]. Regional wall On cardiac MRI, regional LV dysfunction often involving motion abnormalities and fibrosis often have a predilection the apex and mid-wall is present, typically in a non-coronary for the apex and basal inferolateral walls [65]. Cardiac MRI distribution (FIGURE 13). Mid-wall LV dysfunction with sparing of may serve as an important imaging tool to screen and follow the apex has also been reported. Compensatory hyperkinesis of patients with Chagas cardiomyopathy. the basal LV walls may be present leading to LV outflow tract obstruction. In a series of 256 patients with stress-induced cardiomyopathy, the right ventricle was involved in approximately Stress-induced cardiomyopathy Stress-induced cardiomyopathy, also called apical ballooning or 35% of cases [67]. Myocardial edema may be seen as high signal takotsubo cardiomyopathy, is characterized by acute transient intensity on T2-weighted images corresponding to the regions www.expert-reviews.com
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Figure 13. Stress-induced cardiomyopathy in an 81-year-old woman admitted with chest pain and ST elevations, after emotional stress. Coronary angiography did not reveal any occluded vessels. 4-chamber steady-state free precessions image in (A) systole and (B) diastole show apical akinesis of the left and right ventricles along with normal contractility in the basal segments. (C) Late gadolinium enhancement images show absence of enhancement or fibrosis, excluding the diagnosis of myocardial infarction.
of abnormal contractile function [67]. In contrast to myocardial infarction and myocarditis, stress-induced cardiomyopathy does not typically have high-intensity LGE (FIGURE 13). However, subtle patchy LGE may be seen, with signal intensity lower than that observed in myocardial infarction [67]. Use of T1 mapping sequences demonstrated larger area under the curve compared with T2-weighted sequences in differentiating 21 patients with stress-induced cardiomyopathy without LGE compared with normal controls [71]. Although the in-hospital mortality is 2% [69], most patients recover function in 1–4 weeks [66,67]. Followup MRI imaging shows complete normalization of the ejection fraction and regional wall motion abnormalities. Management of stress-induced cardiomyopathy is largely supportive with resolution of underlying physical and emotional stress. Although these patients commonly have recurrence of chest discomfort, recurrence of stress-induced cardiomyopathy is relatively uncommon and involves approximately 10% of cases [69]. Peripartum cardiomyopathy
Peripartum cardiomyopathy is a rare form of DCM with an incidence of 1 in 400 births [72]. It is characterized by the development of heart failure within the last month of pregnancy and up to 5 months postpartum without an identifiable etiology. Although the pathogenesis of peripartum cardiomyopathy is poorly understood, several risk factors have been identified including maternal age >30 years, African descent, multiparity, pregnancy with multiple fetuses and history of eclampsia [73]. There have been a few small case series and case reports on use of cardiac MRI in patients with peripartum cardiomyopathy. SSFP sequences on MRI predominantly demonstrate a dilated left ventricle with reduced contractile function (FIGURE 14). RV dilatation and dysfunction may also be seen. Increased signal intensity may be seen on T2-weighted images representing edema. In some cases, areas of edema on T2-weighted images may be associated with increased signal on LGE sequences [74,75]. By contrast, in one series of eight women with peripartum cardiomyopathy, no evidence of LGE was visualized [76]. Additionally, the 228
authors found no MRI finding that was able to differentiate between patients who had complete LV recovery at 50 months and those with permanent LV dysfunction. Although 50% of patients with peripartum cardiomyopathy recover ventricular function, some can have a deleterious course with high mortality and may require cardiac transplantation. Transplant cardiomyopathy
Despite advances in immunosuppressive therapy, rejection after cardiac transplant continues to be a common problem. Rejection is estimated to account for 18% of deaths before the first year and 10% between 1 and 3 years after cardiac transplantation [77]. Histologically, it is characterized by lymphocyte infiltration and inflammation. The diagnosis of cellular rejection is typically established by endomyocardial biopsies which are performed as part of routine surveillance. However, biopsies are limited by sampling bias and are invasive. Cardiac MRI has the potential to be an important non-invasive tool for early detection of transplant rejection. Increased signal intensity on T2-weighted images may be seen, reflective of myocardial edema. Using this technique, Muehling and colleagues have demonstrated a sensitivity of 89% and specificity of 70% to detect acute rejection compared with endomyocardial biopsy [78]. However, additional prognostic studies are needed prior to widespread use of cardiac MRI for management of transplant cardiomyopathy. Secondary cardiomyopathies Amyloidosis
Amyloidosis is a multisystem disease characterized by deposition of insoluble b-pleated fibrils of amyloid glycoproteins. Primary (AL) amyloidosis is the most common subtype, and results from plasmacytosis, multiple myeloma and plasma cell dyscrasias. It results in deposition of monoclonal light chain immunoglobulins in the myocardial interstitium. Cardiac involvement is common and may be the cause of death in up to 50% of cases [79]. Secondary amyloidosis occurs due to Expert Rev. Cardiovasc. Ther. 12(2), (2014)
Unveiling nonischemic cardiomyopathies with cardiac magnetic resonance
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Figure 14. Peripartum cardiomyopathy in a 36-year-old woman 1 month after delivery. Short-axis steady-state free precession image of the mid-left ventricle at (A) end-diastole and (B) end-systole, demonstrating marked dilatation of the left ventricular cavity. On cine images, the left ventricular ejection fraction was 33%. (C) A small focal area of late gadolinium enhancement was seen in the inferolateral left ventricular wall (arrow).
excess acute phase protein produced in response to inflammatory states. Less common forms of amyloidosis include the familial form, an autosomal dominant disorder with transthyretin gene mutation and senile amyloidosis. The latter is very common in the elderly, with one of every four autopsied patients over the age of 90 years reported to have histologic evidence in the myocardium [79]. However, amyloidosis is often clinically silent and isolated to the heart. Irrespective of the etiology, cardiac amyloidosis presents predominantly as diastolic heart failure and restrictive cardiomyopathy. Deposition of amyloid fibrils in the myocardial interstitium leads to thickened wall, restrictive cardiomyopathy and interruption of the conduction system. As the disease progresses, biventricular systolic dysfunction may develop. While echocardiography may demonstrate mural thickening and other morphologic features of amyloidosis, it is limited by its ability to differentiate amyloidosis from other forms of LV hypertrophy. Adjunctive use of strain echocardiography may be promising, and typically demonstrates decreased myocardial strain at the base, with sparing of the apex. In comparison, cardiac MRI allows tissue characterization and visualization of the heart, pericardium and pleura, all in one imaging study. Cardiac MRI features of cardiac amyloidosis seen on SSFP sequences include diffuse biventricular wall thickening, atrial wall thickening, especially involving the interatrial septum, atrial enlargement due to diastolic dysfunction and multivalvular leaflet thickening, particularly in late stages of the disease (FIGURE 15). High signal intensity on T2-weighted spin echo images may be seen within the left atrial chamber due to decreased atrial contractility and resultant stasis of blood in the left atrium [80]. Pericardial and pleural involvement is common, and manifest as effusions (FIGURE 15). The amyloid protein deposits asymmetrically, with greater deposition in the subendocardium compared with the subepicardium. The increased interstitial volume from amyloid deposition leads to increased retention of gadolinium in the www.expert-reviews.com
subendocardium. In contrast to patients with myocardial infarction, LGE in amyloidosis is due to increase in non-fibrotic interstitial space, rather than diffuse fibrosis. In 29 patients with cardiac amyloidosis, 69% demonstrated diffuse global subendocardial LGE (FIGURE 15) [81]. Focal and patchy LGE may also occur. Compared with normal subjects, gadolinium clears rapidly from the blood pool reflecting high myocardial uptake, resulting in a very dark blood pool [81]. Diffuse gadolinium uptake by the myocardium characteristically results in nulling of the blood pool before the myocardium. This also leads to shorter and often difficult to identify inversion recovery time, a finding that is highly suggestive of amyloidosis. Presence of LGE was found to be superior to other echocardiographic and clinical parameters for diagnosing amyloidosis and reported to have a sensitivity and specificity of 88 and 95%, respectively [82]. The prognostic utility of LGE in patients with amyloidosis is somewhat conflicting. In a study of 47 patients with amyloidosis, presence of LGE conferred a worse 1-year mortality (Wald chi-square statistic 4.91, p = 0.03) [82]. By contrast, in 29 patients with amyloidosis, Maceira et al. did not find the presence of LGE to be predictive of mortality at 623 days; however, they found the intramyocardial T1 gradient (gradient between the epicardium and endocardium 2 min post-contrast injection) predicted mortality with 85% accuracy [83]. Cardiac MRI may be useful not just for its role in diagnosis and prognosis of patients with amyloidosis, but also for serial assessment of disease regression with treatment [84]. Patients with amyloidosis have a prolonged myocardial T1 relaxation time on native T1 mapping sequences compared with normal subjects (FIGURE 16) [80,85]. Karamitsos and colleagues demonstrated that using a cut-off value of 1020 ms resulted in a 92% diagnostic accuracy for identification of cardiac amyloidosis, which may be a superior diagnostic technique compared with assessment of LGE [85]. However, additional validation studies are needed prior to the clinical use of this imaging sequence. While cardiac MRI has significantly changed the diagnostic evaluation of 229
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Figure 15. A 56-year-old male with primary amyloidosis. 4-chamber cine steady-state free precession images in (A) end-systole and (B) end-diastole. Normal left and right ventricular sizes, with severe concentric wall thickening involving both ventricular walls and interatrial septum was seen. Severe left ventricular systolic dysfunction (ejection fraction 31%) was present. Right ventricular function was also decreased with ejection fraction 31%. Marked biatrial enlargement present. Small pericardial effusion (*) and large pleural effusion (**) noted. (C) On late gadolinium enhancement images, blood pool nulled prior to the myocardium, with diffuse transmural late gadolinium enhancement of both the left and right ventricles, characteristic of cardiac amyloidosis.
amyloidosis, the prognostic utility of this technique is yet to be fully elucidated. Iron overload cardiomyopathy
Iron overload cardiomyopathy is a chronic and potentially lethal condition characterized by myocardial dysfunction secondary to accumulation of excess iron in the myocardium. Potential causes include increased intestinal absorption with normal intake seen in chronic liver diseases, porphyria and hemochromatosis, excess dietary intake and chronic red blood cell transfusions such as in hereditary anemias and myelodysplastic syndromes. Myocardial iron infiltration is the leading cause of death in patients receiving chronic blood transfusions, accounting for up to 70% of all deaths [86], with the incidence further increasing as these patients are now surviving longer. Iron accumulation can occur in multiple organs including the myocardium, liver, spleen, pancreas and central nervous system. In the normal physiologic state, iron is bound to transferrin. In iron overloaded state, the iron that exceeds the transferrin binding capacity is transformed into highly reactive free radicals, which in turn cause myocardial cell damage and death. Cardiac iron deposition begins initially in the epicardium and progresses to the endocardium. Patients are often asymptomatic in early stages of the disease. With progressive iron deposition, patients develop diastolic dysfunction and restrictive cardiomyopathy, and eventually progress to a DCM with systolic dysfunction [87]. Iron deposition may also involve the conduction system, resulting in bradycardia, atrioventricular blocks, atrial fibrillation and ventricular arrhythmias and sudden cardiac death [86]. The diagnosis of iron overload cardiomyopathy can be challenging, particularly in the early stages of the disease. Although elevated serum ferritin levels and iron content on liver biopsy are both used as surrogates of disease progression, they are incomplete in cardiac risk assessment. Patients may develop cardiac symptoms despite low overall iron burden [88]. 230
In patients with iron overload cardiomyopathy, myocardial fibrosis is rare, and hence MRI-LGE is typically absent. The development of newer MRI sequences to characterize myocardial iron stores has changed the fundamental management of iron overload cardiomyopathy, and positively impacted survival [89]. In the iron overload state, paramagnetic effects of iron cause variations in the magnetic field which results in shortening of the relaxation time (reduced T2*) and decreased signal intensity (FIGURE 17). T2* correlates inversely with iron deposition, and the effect is concentration dependent. T2* relaxation time measured at the mid-ventricular septum correlates closely with cardiac biopsy and global iron concentration on autopsy studies [90,91]. In a seminal study by Anderson et al., T2* relaxation time
