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Abstract

Infiltrative cardiomyopathies comprise a broad spectrum of inherited or acquired conditions caused by deposition of abnormal substances within the myocardium. Increased wall thickness, inflammation, microvascular dysfunction, and fibrosis are the common pathological processes that lead to abnormal myocardial filling, chamber dilation, and disruption of conduction system. Advanced disease presents as heart failure and cardiac arrhythmias conferring poor prognosis. Infiltrative cardiomyopathies are often diagnosed late or misclassified as other more common conditions, such as hypertrophic cardiomyopathy, hypertensive heart disease, ischemic or other forms of nonischemic cardiomyopathies. Accurate diagnosis is also critical because clinical features, testing methodologies, and approach to treatment vary significantly even within the different types of infiltrative cardiomyopathies on the basis of the type of substance deposited. Substantial advances in noninvasive cardiac imaging have enabled accurate and early diagnosis. thereby eliminating the need for endomyocardial biopsy in most cases. This scientific statement discusses the role of contemporary multimodality imaging of infiltrative cardiomyopathies, including echocardiography, nuclear and cardiac magnetic resonance imaging in the diagnosis, prognostication, and assessment of response to treatment.

Infiltrative cardiomyopathies are a unique group of myocardial diseases characterized by deposition of abnormal substances within the myocardium. Myocardial infiltration can be extracellular or intracellular, the latter of which is more accurately termed as a myocardial storage disorder. Infiltrative cardiomyopathies cause systolic dysfunction, diastolic dysfunction, or both, and can lead to heart failure and premature death. Within the broad group of infiltrative cardiomyopathies, significant differences in clinical features, diagnostic techniques, and treatment strategies exist, and are unique to the type of substance infiltrating the myocardium. Endomyocardial biopsy historically was considered the gold standard for diagnosis. However, due to its associated risks and limited sensitivity in diseases with patchy involvement, biopsy has been gradually replaced by cardiac imaging for the initial diagnosis, risk stratification, and guidance of therapeutic decisions.1 This review will highlight the role of cardiac imaging, including echocardiography, cardiac magnetic resonance imaging (CMR), and nuclear imaging in the diagnosis and management of infiltrative cardiomyopathies.

PATHOPHYSIOLOGY

Myocardial infiltration typically generates an inflammatory response that can progress to fibrosis.2 Infiltrative diseases frequently result in increased wall thickness, although not always.3 Increased wall thickness, along with inflammation and fibrosis eventually lead to impaired systolic and diastolic function, increased mechanical stress, microvascular dysfunction, and decreased coronary flow reserve, thereby perpetuating irreversible tissue damage.4 Reduced ventricular compliance causes significantly elevated left ventricular (LV) filling pressure, atrial dilation, and pulmonary and systemic venous congestion. Infiltration is not necessarily limited to the ventricular myocardium but can also involve the atrial wall and valves, thereby causing atrial stiffness and valvular dysfunction, respectively.5

Diagnosis of infiltrative cardiomyopathies is often delayed after several years of subclinical myocardial injury. Appropriate use of cardiac imaging aids in establishing a diagnosis early, characterizing disease burden, and assessing response to medical therapy while also evaluating other causes of cardiomyopathy such as coronary artery disease or valvular dysfunction. Assessment of cardiac morphology and function is often performed using echocardiography as the preliminary test. Myocardial inflammation, fibrosis, and microvascular dysfunction can be assessed with positron emission tomography (PET), single photon emission computed tomography (SPECT) imaging, and CMR. CMR also has the unique ability to characterize tissue properties using parametric mapping and to quantify extracellular volume.

GENERAL IMAGING FEATURES

Echocardiography is often the first-line evaluation for the assessment of cardiac structure and function given the high temporal and spatial resolution, portability, cost-effectiveness, and lack of ionizing radiation. In addition to wall thickness and systolic function, echocardiography can evaluate diastolic function and assess for restrictive physiology.5 Advances in image-based analysis of local myocardial dynamics, including tissue Doppler imaging and speckle-tracking echocardiography, allow for the quantitative assessment of subclinical myocardial dysfunction.6 Myocardial deformation, measured by strain and strain rate using tissue Doppler imaging and speckle-tracking echocardiography, demonstrates early decreases in radial and longitudinal strain and strain rate that often precede decreases in ejection fraction.6 In patients with subclinical myocardial infiltration, abnormal global average longitudinal strain is shown to predict future adverse cardiovascular outcomes.7

Abnormal diastolic function identified on echocardiography is often the first finding in infiltrative cardiomyopathies.5 The left atrium gradually enlarges due to a burden of elevated LV filling pressure and diastolic dysfunction.8 Atrial enlargement with nondilated ventricles with normal or near-normal systolic function is an early finding in most infiltrative disorders. In addition, abnormal diastolic function can be assessed by evaluation of mitral, tricuspid, pulmonary, and hepatic flow patterns.9 Tissue Doppler echocardiography e′ and a′ annular velocities are typically low, indicating abnormal LV relaxation.

CMR is an important noninvasive imaging modality for the diagnosis, follow-up, and risk stratification of patients with infiltrative cardiomyopathies. A key strength of CMR over other cardiac imaging modalities is the ability to characterize myocardial tissue changes and to quantify the extent of myocardial abnormalities. In the setting of suspected or known infiltrative cardiomyopathies, the CMR protocol should include short- and long-axis cine sequences for assessment of ventricular volumes, function, and mass; late gadolinium enhancement (LGE) imaging (unless there is a contraindication to administration of intravenous contrast); and T1 mapping for assessment of native T1 and the extracellular volume (ECV) fraction. Additional sequences that should be considered depending on the clinical history include T2-based imaging (black blood T2-weighted imaging or T2 maps) for assessment of edema, T2* imaging for assessment of myocardial iron, early gadolinium enhancement for hyperemia, and first-pass perfusion. Gadolinium-based contrast agents are distributed in the extracellular space and are useful to detect expansion of the extracellular space in the setting of infiltrative cardiomyopathies. CMR parametric mapping has high diagnostic utility in patients with infiltrative cardiomyopathies, particularly in those with amyloidosis, compared with CMR protocols without mapping.10

Radionuclide imaging with PET and SPECT tracers are increasingly being used for evaluation of specific infiltrative cardiomyopathies. 18F-fluorodeoxyglucose (FDG) PET imaging after suppression of myocardial glucose uptake helps detect areas of inflammation. Metabolic imaging, when combined with myocardial perfusion imaging using either PET or SPECT tracers, enables differentiation of active inflammation, myocardial scar, and normal myocardium in infiltrative cardiomyopathies, including cardiac sarcoidosis and Fabry disease. Perfusion defects in the absence of coronary artery disease or scar could represent areas of microvascular dysfunction. Quantification of metabolic activity helps in serial assessment of inflammatory activity and response to treatment. Myocardial planar and SPECT imaging using bone-avid radiotracers such as Technetium (Tc) 99m pyrophosphate (PYP) is now being routinely used for the evaluation of transthyretin amyloidosis due to its high sensitivity and specificity. Novel PET radiotracers such as 11C-Pittsburgh Compound-B, 18F-NaF, and 18F-florbetapir are currently being studied for the diagnosis of cardiac amyloidosis.

Although cardiac computed tomography is not a routine modality of testing in the diagnostic algorithm of infiltrative cardiomyopathies, awareness of clinical features and general morphological characteristics of infiltrative cardiomyopathies may trigger a diagnosis during routine coronary angiographic evaluation. In addition, emerging data on contrast-enhanced CT–based myocardial delayed enhancement using lower energy, dual-source CT scanners appears comparable to LGE on CMR and may potentially serve as an alternative test in those with contraindications to CMR.11 However, the paucity of standardized protocols for CT-based late iodine enhancement and lower signal-to-noise ratio are some of the drawbacks limiting CT as a form of mainstream testing for infiltrative cardiomyopathies. Cardiac CT is also useful in evaluating coronary anatomy if ischemic cardiomyopathy represents an alternative or confounding diagnosis.12

COMMON INFILTRATIVE CARDIOMYOPATHIES

Cardiac Amyloidosis

Amyloidosis is a group of hereditary or acquired diseases characterized by extracellular deposition of misfolded or misassembled proteins.13 Several types of amyloids can involve the heart, including light-chain amyloid (AL) and transthyretin amyloid (ATTR). Treatment is dictated by the type of amyloid and the degree of involvement, and therefore early detection and accurate classification are essential.14 There is increasing recognition that a substantial number of patients with heart failure with preserved ejection fraction have undiagnosed cardiac amyloidosis (CA).15

Light-chain amyloid can present with plasma dyscrasia, nephrotic syndrome, or as connective tissue disorder.16 Other symptoms typical in AL amyloid include postural syncope, angina, skin bruising, peripheral neuropathy, periorbital purpura, and macroglossia.

Familial (ATTRv) or wild-type (ATTRwt) transthyretin amyloidosis typically has a more indolent course. Although the majority of patients with ATTR present in their middle age or later with heart failure with preserved ejection fraction, certain familial variants such as ATTRV30M may manifest as polyneuropathy at a younger age.17 Cardiac features include new-onset diastolic dysfunction,15 rapidly worsening valvular disease,18 and unexplained cardiac hypertrophy. Extracardiac features include carpal tunnel syndrome, biceps tendinopathy, arthropathy, and degenerative disk disease.19

Myocardial amyloid deposition results in elevated natriuretic peptides and troponin.19 Increase in free light chain levels and the presence of κ or λ monoclonal protein on serum or urine immunofixation electrophoresis identify patients with AL amyloidosis. Genetic screening helps differentiate ATTRv and ATTRwt. The 2 most common mutations are Val122Ile, which is prevalent in 3.4% of the US Black population, and Val30Met found across the world.20

Advanced stages of CA usually present as restrictive cardiomyopathy, typified by dyspnea on exertion, elevated jugular venous pressure, hepatomegaly, ascites, and peripheral edema.21

Echocardiography

Increased LV wall thickness with concentric remodeling or hypertrophy and normal LV chamber size is a hallmark of CA.16 Right ventricular hypertrophy, biatrial enlargement, increased thickness of the interatrial septum, atria and valves, and small pericardial effusions, as well, are other common structural abnormalities identified by echocardiography in patients with CA22,23 (Figure 1: IA and IB). Left ventricular diastolic dysfunction is the predominant abnormality even early in the course of disease. Impaired LV relaxation with increased dependence on atrial contraction will initially result in a mitral inflow filling pattern with decreased early diastolic flow across the mitral valve (E wave) relative to the atrial wave (A). As myocardial infiltration progresses, LV wall compliance decreases, left atrial pressure increases, and mitral inflow exhibits a pseudonormal pattern (E/A >1) and then a restrictive filling pattern (E/A >2 and deceleration time <150 ms) with more advanced disease24,25 (Figure 1: IIA, IIB, IIC). Pulsed-wave tissue Doppler velocities at the septal and lateral mitral valve annulus are reduced (typically <8 cm/s) and the ratio of early diastolic mitral flow (E) to early diastolic mitral annular (e′) tissue Doppler velocity (E/e′) progressively increases as CA advances, indicative of increasing left atrial pressure. Although LV ejection fraction is often normal until late in the course, subclinical LV dysfunction can be detected with longitudinal strain imaging.26 The loss of global longitudinal function is secondary to a predominance of amyloid fibril deposition in the subendocardial region, which is primarily responsible for longitudinal deformation.27 Regional diminution of longitudinal strain in the basal and mid-LV segments with preservation at the apex, or “apical-sparing” pattern, is characteristic of amyloidosis (Figure 1: IC). This characteristic regional strain pattern has high sensitivity (93%) and specificity (82%) and may help to distinguish CA from other disorders with increased wall thickness.28 In patients with AL amyloidosis with and without clinical heart failure, a basal strain value of <–4.6% and <–13.0%, respectively, predicts decreased survival.29 Right ventricular dilation is occasionally seen in advanced disease and is a marker of poor prognosis.22

Figure 1.

Figure 1. Imaging findings in Cardiac Amyloidosis. I, Echocardiography images in a patient with cardiac amyloidosis showing (A and B) severe left ventricular concentric hypertrophy, right ventricular hypertrophy, biatrial enlargement, and mild pericardial effusion. C, Apical-sparing global longitudinal strain pattern. II, A, Doppler parameters demonstrating advanced diastolic dysfunction with severe restrictive physiology in cardiac amyloidosis. Restrictive filling pattern with mitral inflow E/A >2; short deceleration time (118 ms). B, Reduced tissue Doppler velocity at septal mitral valve annulus (e′). C, Reduced tissue Doppler velocity at lateral mitral valve annulus (e′); elevated average E/e′ ratio indicative of elevated left atrial pressure. III, Cardiac magnetic resonance images acquired at 3T in a 60-year-old man with light chain amyloid. A, Midventricular short-axis late gadolinium–enhancement image demonstrates dark blood pool and diffuse myocardial hyperintensity with concentric wall thickening. B, Midventricular short-axis native T1 map (3T) demonstrates high native T1 values (1507 ms). C, Midventricular short-axis extracellular volume map (3T) demonstrates high extracellular volume values, in keeping with expansion of the extracellular space (49%). IV, Cardiac radionuclide imaging showing a negative Tc-99m-PYP study with a H/CL=1.34 at 3-hour incubation with tracer activity limited to the blood pool as demonstrated by SPECT/CT imaging. V, Radionuclide imaging showing: A, Negative Tc-99m-PYP study (grade 0 on planar and SPECT/CT and a H/CL=1.0) for cardiac amyloidosis. B, Positive Tc-99m-PYP scan (grade 3 on planar and SPECT/CT and a H/CL=2.36) for cardiac amyloidosis, which confirms the presence of transthyretin cardiac amyloidosis, assuming the absence of plasma cell dyscrasia. H/CL indicates heart-to-contralateral lung ratio; PYP indicates pyrophosphate; SPECT, single photon emission computed tomography; and Tc, technetium.

Cardiac Magnetic Resonance Imaging

CMR has high specificity for amyloidosis on the basis of the typical morphological appearance, a characteristic pattern of LGE, high T1, and high ECV. Cine steady-state free precession images typically demonstrate concentric wall thickening, biatrial dilation, and biventricular dysfunction. Amyloid deposition markedly alters gadolinium kinetics of the myocardium and blood pool. Increased gadolinium concentration in the extracellular space results in shorter myocardial T1, and rapid gadolinium washout from the blood pool causes prolonged blood pool T1.30 In addition, early infiltration may result in lower subendocardial T1 than subepicardial T1, resulting in a transmural T1 gradient when imaged within 8 minutes of gadolinium injection, giving the appearance of diffuse subendocardial delayed enhancement. Typical findings on LGE imaging include dark blood pool, inversion of the typical blood pool and myocardial pattern of nulling on the TI scout, difficulty nulling the myocardium, and subendocardial to diffuse myocardial enhancement31 (Figure 1: III). As the infiltration becomes diffuse, the transmural T1 gradient shortens. A transmural T1 gradient of <23 ms 2 minutes postgadolinium may predict poor survival in AL amyloidosis.32 Native T1 and ECV values are often dramatically elevated in CA due to expansion of the interstitial space from fibrillar deposits.33 Mean native T1 and ECV values have been shown to differ between subtypes, with higher native T1 in AL and higher ECV in ATTR.34 Total myocyte cell volume, derived from ECV and indexed LV myocardial volume, is higher in ATTR than AL amyloidosis, indicative of concomitant and potentially compensatory myocyte hypertrophy. However, substantial overlap in values precludes differentiation between amyloid types in individual patients.35 Higher values of ECV are noted in areas of LGE, suggesting significant extracellular deposition of amyloid. Albeit to a lesser degree, ECV is also higher in myocardium without LGE, suggesting its role in early diagnosis even before LGE ensues.36 ECV has been shown to be a more robust marker of prognosis compared with native T1 or LGE in cardiac amyloidosis.37 Furthermore, ECV may be useful for tracking disease burden and response to therapy, although some studies have demonstrated lower ECV in AL amyloid after treatment38 while others have not.39 There are also conflicting data on the presence and significance of myocardial edema in cardiac amyloid, with elevated T2 values reported in some studies,40 whereas others have demonstrated normal T2 values both in patients with active amyloidosis and those in remission.38

Radionuclide Imaging

Cardiac scintigraphy using bone-avid radiotracers can establish the diagnosis of ATTR CA, obviating the need for biopsy. Moreover, the development of novel tracers and implementation of quantitative analysis have the potential to improve early detection of CA, enhance discrimination of CA subtypes, and quantify amyloid burden for prognostication and response to therapy.19,23,41 The mechanism behind retention of bone-avid tracers within ATTR amyloid fiber remains unknown. It has been hypothesized that it relates to the presence of microcalcifications that are more common (yet not exclusive) in ATTR amyloidosis.42 Three (Tc)-bisphosphonate derivatives are available: 99mTc-PYP, 99mTc-3,3-disphosphono-1,2-propanodicarboxylic acid, and 99mTc-hydroxymethylene diphosphonate. Although there are no large comparative studies, the diagnostic performance of these tracers is comparable.19,23,41 A novel ATTR cardiomyopathy score comprising clinical and echocardiographic variables may guide appropriate selection of patients with heart failure with preserved ejection fraction for cardiac PYP scintigraphy. A score of ≥6 identifies patients at increased risk for ATTR CA with good sensitivity and negative predictive value.43

SPECT imaging is required for the interpretation of cardiac scintigraphy with bone-avid tracers to avoid interpretation pitfalls of planar imaging (eg, blood pool activity mimicking myocardial uptake). A study is considered positive only when there is significant radiotracer uptake localized to the myocardium on SPECT imaging. Planar imaging can be helpful in corroborating and grading findings on SPECT, but a heart-to-contralateral lung ratio (semiquantitative method) or myocardial uptake compared with bone uptake (qualitative or visual grading) on planar images alone is not sufficient to interpret a study as positive or to secure a diagnosis.44 (Supplemental Table S.1). Among these 2 parameters, only the semiquantitative method has demonstrated prognostic value.45 In patients with suspected CA, a positive study with radiotracer uptake localized to the myocardium with a grade ≥2 uptake or a heart-to-contralateral lung ratio ≥1.5 (or ≥1.3 with 3 hour imaging) is highly specific for ATTR CA virtually eliminating the need for biopsy (Figure I: IV and V).46,47 However, because up to 25% of AL CA cases might have grade ≥1 uptake of bone-avid radiotracers, the exclusion of light chain disease is imperative. Alternative causes of false positive testing must also be considered and excluded, including previous focal myocardial infarction or hydroxychloroquine cardiotoxicity.23 Simultaneous dual isotope SPECT imaging with Tc-99m-PYP and low-dose thallium-201 more recently has been shown to improve differentiation of myocardial uptake versus blood pool activity, thereby minimizing equivocal results as opposed to standard visual or quantitative methods of comparison with rib or contralateral lung activity.48 The sensitivity of cardiac bone scintigraphy technique in detecting ATTR CA may also be influenced by the type of amyloid fibril (type A versus type B), subtype of ATTR CA and underlying mutations. For example, those with early-onset ATTRV30M CA and those with type B fibers (full length only) might not demonstrate uptake of bone-avid radiotracers in contrast to those with type A fiber (mixed full and truncated), ATTRwt, non-ATTRV30M, and late-onset ATTRV30M CA.49,50

Several studies have evaluated PET tracers in CA. Despite demonstration of a higher 18F-NaF myocardial uptake with ATTR CA, early experience with this bone-avid PET radiotracer has been disappointing due to low sensitivity and poor myocardial signal.51,52 Further studies are needed to determine the role and added value of PET imaging with 18F-NaF in ATTR CA. Amyloid-targeted PET radiotracers, namely 11C-Pittsburgh Compound-B, 18F-florbetapir, 18F-flutemetamol, and 18F-florbetaben, are thioflavin-T analogs that bind the β-pleated motif of amyloid fibrils irrespective of the precursor protein. PET imaging using these radiotracers holds promise to reliably detect all subtypes of CA, improve early diagnosis, and facilitate quantitation of amyloid burden to improve prognostication and assess response to therapy.23 Positron emission tomography imaging with these amyloid-binding radiotracers reliably discriminates patients with ATTR and AL CA from controls by using quantitative metrics.23 Promising results have been reported on the use of 11C-Pittsburgh Compound-B for the early detection of CA before occurrence of structural changes using quantitative metrics of myocardial uptake.53 Quantitation of amyloid-targeted radiotracer uptake using standardized uptake value (SUV) metrics correlates closely with amyloid burden, even when compared with amyloid deposition on biopsy specimen.54 Higher myocardial uptake of 11C-Pittsburgh Compound-B seems to correlate with performance status, biomarkers, and worse clinical outcomes.54 Thus, quantitative analysis of amyloid-binding PET radiotracers might prove useful for disease monitoring, evaluation of response to treatment, and prognostication. Moreover, 18F-florbetaben, with its unique affinity for AL fibers, has shown persistent high cardiac uptake in AL CA and decreased uptake in ATTR CA on delayed imaging versus early imaging, suggesting its role as a promising discriminatory tool between both the subtypes.55 However, PET imaging in CA is still in the initial stages of development and further studies are warranted to validate its use and value in clinical practice.23

Focal or diffuse subendocardial hypoperfusion suggestive of microvascular dysfunction is prevalent in patients with CA. Myocardial PET perfusion imaging often demonstrates a significant reduction in myocardial blood flow and coronary flow reserve in these patients, despite the absence of epicardial coronary artery disease. In addition, patients with CA are predisposed to cardiac dysautonomia because of amyloid deposition within the myocardium and nerve conduction tissues. Cardiac dysautonomia detected by 123I-metaiodobenzylguanidine imaging, although cannot discriminate between CA subtypes and other cardiomyopathies, provides useful prognostic information. A decreased heart-to-mediastinal ratio at 4 hours from 123I-metaiodobenzylguanidine injection reflects the degree of sympathetic dysautonomia and is associated with an increased rate of ventricular dysrhythmia and arrhythmic death in CA.23

Anderson Fabry Disease

Fabry disease (FD) is a lysosomal storage disorder characterized by accumulation of intracellular glycosphingolipids in different organs, including the heart. Cardiac involvement is the leading cause of mortality and is characterized by progressive myocardial glycosphingolipid deposition, hypertrophy, inflammation, and fibrosis.56 More than 30% of patients experience dyspnea, angina, palpitations, syncope, or peripheral edema.56 Ventricular tachyarrhythmia is common as an initial presentation. Electrocardiographic features include short PR interval, LV hypertrophy (LVH), and intraventricular conduction delay. LVH is often misdiagnosed as hypertrophic obstructive cardiomyopathy (HCM).57 Despite the X-linked inheritance, women may manifest any of the clinical features of FD, including cardiac involvement.58 However, women present later and tend to have milder disease with lower LV mass, suggesting that there are key differences in cardiac remodeling between sexes.59 The diagnosis rests on genetic testing of mutations in α-galactosidase A. The classical variant of FD usually affects men with low or absent levels of serum α-galactosidase A. Cardiac imaging plays an important role in establishing a diagnosis of FD, risk stratifying patients, and monitoring disease progression. Accurate assessment of LV mass and wall thickness is important for early detection of cardiac involvement, assessment for treatment eligibility, and prognostication.60

Echocardiography

Concentric thickening of the LV myocardium is a typical echocardiographic finding in FD. LV ejection fraction is usually preserved. Mild to moderate diastolic dysfunction is frequently present; however, severe restrictive physiology is uncommon. A diagnostic feature of FD is a binary endocardial layer thought to be caused by endomyocardial glycosphingolipid compartmentalization. Identifying a binary endocardial layer has a sensitivity of 94% and specificity of 100% for distinguishing FD from HCM and hypertensive heart disease61 (Figure 2: I). Hypertrophy of the papillary muscles is also characteristic of FD and can mislead to the diagnosis of HCM.62 Speckle-tracking echocardiography may show reduced global longitudinal strain and decreased regional strain in the basal anterolateral and inferolateral walls indicative of myocardial fibrosis that correlates with the location and degree of LGE by CMR.63 Another specific pattern seen in FD is a loss of the normal base-to-apex circumferential strain gradient.64 Echocardiography is also useful for monitoring the response to enzyme replacement therapy, particularly regression of LV wall thickness.65

Figure 2.

Figure 2. Imaging features of Fabry Disease. I, Echocardiography in Fabry disease with concentric thickening of the LV myocardium, binary endocardial layer (A, arrow), and hypertrophied papillary muscles (B, arrow heads). II, Cardiac magnetic resonance images acquired at 1.5 T in a 39-year-old woman with Fabry disease. A, Basal short-axis late gadolinium–enhanced image demonstrates minimal midwall late gadolinium–enhanced image at the basal inferolateral segment. B, Midventricular short-axis native T1 map (1.5 T) demonstrates low native T1 values (918 ms). C, Midventricular short-axis native T2 map (1.5 T) demonstrates normal T2 values (48 ms).

Cardiac Magnetic Resonance Imaging

Typical CMR findings include concentric LVH, midwall basal inferolateral LGE and low native T1.66 LVH and LGE on CMR are strong predictors of adverse cardiac events in FD.67 Although concentric LVH is the most common pattern, FD can also mimic the morphological characteristics of various subtypes of HCM, including asymmetric septal and apical variants.68 Due to intracellular nature of glycosphingolipid accumulation, native T1 values are substantially lower in patients with FD compared with healthy controls and patients with other causes of LVH59,69 (Figure 2: II). In patients who have FD without LVH, lower native T1 values are associated with clinical disease worsening.70 On similar grounds, ECV is often normal in early stages but can be increased in later stages, particularly in areas of fibrosis and LGE.69,71 Other CMR findings include high regional T2 in keeping with inflammation (usually colocalizing with LGE), impaired global and circumferential strain, and increased spread of segmental native T1 values.71,72

Radionuclide Imaging

Mounting evidence demonstrates that inflammation plays a significant role in the early stages of Fabry cardiomyopathy. Lysosomal accumulation of glycosphingolipids might result in the activation of inflammatory pathways contributing to and perpetuating end-organ damage.73 PET 18F-FDG imaging with appropriate patient preparation can detect and quantify myocardial inflammation in FD. Imaging with PET 18F-FDG might provide complementary value to CMR by detecting earlier stages of the disease process, assessing disease activity, evaluating disease progression, and monitoring response to therapy74 (Figure 3). It may also improve disease staging by differentiating dense fibrosis from inflammation as an explanation for myocardial LGE. Pilot experience demonstrated improvement and possible resolution of 18F-FDG uptake with enzyme replacement therapy, which could be interpreted as stabilization of the disease process.75 These results, in combination with the expansion of the therapeutic armamentarium (next-generation enzyme replacement therapy, chaperone therapy, substrate reduction therapy, and gene therapy) have ignited the optimism for monitoring response to therapy and guiding therapeutic strategies.

Figure 3.

Figure 3. Fabry Disease: Cardiac hybrid PET/MRI findings. I, Cardiac hybrid PET/MR short-axis view imaging in a patient with Fabry disease showing LGE (A) and positive STIR MR images in the basal segments of the lateral wall (B) and a focal increase in 18F-FDG uptake in the same myocardial region (C). II, Cardiac hybrid PET/MR short-axis images in a patient with Fabry disease showing LGE in the inferolateral wall (A) and negative STIR MR images (B) without focal 18F-FDG uptake (C) in the same region. FDG indicates fluorodeoxyglucose; LGE, late gadolinium enhancement; MR, magnetic resonance; PET, positron emission tomography; and STIR, short tau inversion recovery. Reproduced with permission from Nappi et al.74 © Copyright 2015 Springer Nature.

Cardiac Sarcoidosis

Sarcoidosis is a multisystem disease characterized by the development and accumulation of noncaseating granulomas in multiple organs including the heart. Cardiac involvement affects at least one-quarter of patients with sarcoidosis. Cardiac sarcoidosis (CS) is associated with poor prognosis, with most deaths due to ventricular arrhythmias, high-degree heart block, or heart failure.76,77 A major challenge with diagnosis is the lack of a reliable reference standard. Endomyocardial biopsy can confirm cardiac involvement, although the sensitivity is low due to patchy involvement.78 Several expert consensus criteria have been proposed but have limited diagnostic accuracy.77 Hence, imaging is frequently relied on for assessment of cardiac involvement.

Echocardiography

There are no specific echocardiography findings in CS, although several findings may raise suspicion. The most characteristic finding is thinning or scarring of the basal portion of the interventricular septum and associated akinesis. Sarcoid infiltration of the papillary muscles can result in valvular incompetence secondary to papillary muscle dysfunction in up to 70% of patients with myocardial involvement.79 LV aneurysms, which may be variable in number and location, in the absence of obstructive coronary artery disease, can raise clinical suspicion (Figure 4: IA and IB). However, these may also be found in other inflammatory conditions, such as Chagas disease.80

Figure 4.

Figure 4. Imaging features in Cardiac Sarcoidosis. I, Echocardiography in a patient with cardiac sarcoidosis showing characteristic thinning of the basal interventricular septum (arrow, A) or ventricular aneurysms (arrowhead, B). II, Combined cardiac 18F-FDG PET/MRI images acquired at 3T in a 67-year-old man with cardiac sarcoid. A, Short-axis T2 map demonstrates high T2 values (49 ms) at the mid anterior wall in keeping with myocardial edema (green arrow). B, Short-axis LGE image demonstrates midwall LGE at the midanterior wall (red arrow). C, Short-axis fused PET and LGE image demonstrates that focal FDG PET uptake corresponds to the same area as elevated T2 values and LGE (yellow arrow), in keeping with inflammation. III, Whole-body imaging in the evaluation of cardiac sarcoidosis. A, Patchy and multifocal myocardial 18F-FDG uptake including involvement the right ventricle in pattern highly suggestive of cardiac sarcoidosis. B, Demonstrates intense avid 18F-FDG uptake by hilar and mediastinal lymphadenopathy, which increases the likelihood of cardiac sarcoidosis. IV, A, Normal PET 18F-FDG sarcoidosis study showing normal perfusion and absence of 18F-FDG in the myocardium. B, Demonstrates focal/intense18F-FDG uptake involving the basal to mid anterolateral wall (white arrows) matched by minimal resting perfusion defect due to active cardiac sarcoidosis (inflammatory pattern). C, Demonstrates patchy perfusion/metabolism mismatch along anterior and anterolateral walls (arrows) combined with focal areas of 18F-FDG uptake or resting perfusion defects in isolation (mixed pattern). D, Demonstrates resting perfusion defects in noncoronary distribution (arrows) with no or minimal 18F-FDG uptake (scarred pattern). FDG indicates fluorodeoxyglucose; LGE, late gadolinium enhancement; and PET, positron emission tomography.

Cardiac Magnetic Resonance Imaging

Typical imaging findings on CMR include intense nodular or patchy LGE in a nonischemic distribution (Figure 4: II).81 LGE can involve both left and right ventricles, often involving the subepicardial or midmyocardial layers with prominent involvement at the insertion points, and direct and contiguous extension, as well, across the basal interventricular septum into the right ventricle (the hook-sign).82 A recent comparative meta-analysis found that CMR is more sensitive than FDG-PET for the detection of CS with similar specificity.83 Given higher sensitivity, CMR is particularly useful in ruling out CS when negative.

Abnormal enhancement on T2-weighted imaging identifies areas of myocardial edema suggestive of active inflammation.84,85 However, respiratory motion, cardiac arrhythmia, and impaired cardiac output can affect the quality of T2 imaging. Parametric T1 and T2 mapping have diagnostic and prognostic value in CS and provide complementary information when interpreted together. In the setting of active inflammation and edema, T1 and T2 are both elevated.84,85 However, chronic or burnt-out CS without ongoing edema will demonstrate high T1 but normal T2. CMR has the unique strength over FDG-PET of identifying both active and chronic phases of the disease.

CMR findings including LGE, low LV ejection fraction, and high T1 also have prognostic value and are strongly associated with adverse cardiac events.84,86–88 Quantitative parametric mapping may be useful for evaluation of longitudinal changes including response to treatment.85

Radionuclide Imaging

Myocardial PET 18F-FDG combined with resting myocardial perfusion imaging (PET 18F-FDG sarcoidosis imaging) is the radionuclide imaging method of choice in the evaluation of CS.89 The presence of myocardial 18F-FDG uptake in a pattern consistent with CS with evidence of extracardiac sarcoidosis supports CS as a diagnosis of exclusion. Indications for PET 18F-FDG are listed in Supplemental Table S.290 (Supplemental Figure S.1). Gallium-67 scintigraphy, although included in diagnostic algorithms, is not frequently used due to a low diagnostic sensitivity, low contrast resolution, high radiation exposure, and challenges in distinguishing cardiac from adjacent pulmonary or mediastinal uptake.89 The ability of PET 18F-FDG imaging to detect CS relies on the higher metabolic activity and glucose utilization of infiltrating macrophages. Because normal myocardium consumes a combination of fatty acids and glucose as fuel, suppression of myocardial glucose utilization is key to enhancing the specificity for the detection of pathological uptake.89 For this purpose, strict patient preparation with prolonged fasting, dietary manipulation, and intravenous heparin administration, often in combination, is required89 (Supplemental Table S.3). Normalized resting perfusion and 18F-FDG images are typically reviewed in conjunction. CS is associated with various abnormalities in perfusion and 18F-FDG uptake including: (1) patchy or focal on diffuse 18F-FDG uptake with colocalized perfusion defects, which is known as a perfusion/metabolism mismatch; (2) patchy or focal on diffuse 18F-FDG uptake without perfusion defects; or (3) focal or multifocal perfusion defects in a noncoronary distribution without 18F-FDG uptake. The probability of CS depends on the number, location, and type of abnormalities encountered (Figure 4: IV) and is highest in the presence of multiple noncontiguous perfusion/metabolism mismatch defects, particularly when involving the basal anteroseptal, inferior, or inferolateral walls along with associated mediastinal/hilar avid lymph node uptake. Inadequate myocardial suppression presents as low-grade and diffuse myocardial 18F-FDG uptake, whereas a diffuse uptake along the lateral wall is regarded as a nonspecific finding (Supplemental Figure S.2). It is important to note that myocardial 18F-FDG uptake is not specific to CS and is also identified in the setting of other causes of myocardial inflammation, including viral myocarditis and genetic or inflammatory cardiomyopathies.91 These conditions should be considered and excluded before establishing a diagnosis of CS on the sole basis of abnormalities on PET 18F-FDG sarcoidosis imaging.92 It is also imperative that epicardial coronary artery disease is excluded with either CT or invasive coronary angiography in most cases.

Concomitant whole-body imaging with a large field of view (base of skull to midthigh) is recommended for the assessment of metabolic-active extracardiac disease (Figure 4: III). The presence of extracardiac activity in a pattern suggestive of sarcoidosis with accompanying cardiac abnormalities increases the likelihood of CS. It could also suggest areas more amenable than the heart for biopsy. Last, the extent and severity of extracardiac disease activity might be factored when considering initiation of therapy.89,92

Serial PET 18F-FDG sarcoidosis imaging is valuable in assessing response to therapy and in guiding therapy adjustments (Supplemental Figure S.3). Quantitative analysis of the myocardial 18F-FDG uptake using several SUV-based metrics provides a more objective and reproducible assessment of burden of myocardial inflammation.93 The severity of inflammation is derived from the peak inflammatory activity or SUVmax (concentration of radiotracer in the region of interest corrected by injected dose and patient’s weight). The extent of inflammation is computed from the volumetric quantification of 18F-FDG–positive voxels over a predefined SUVmax threshold. Inflammation heterogeneity is quantified using the coefficient of variation (SD/mean FDG uptake), whereas the burden of perfusion/metabolism mismatch can be derived from summed scores using the 17-segment model.93–95 Quantitative metrics provide a better assessment of response to therapy than visual assessment. A change in the severity and extent of inflammation in the same direction and by at least 20% is regarded as clinically significant. Pretreatment inflammatory burden is seen to correlate favorably with clinical, echocardiographic, and radiological response to immunosuppressive therapy.96 Moreover, quantitative metrics of inflammation, inflammation heterogeneity, and perfusion/metabolism mismatch seem to be of incremental value in the prediction of adverse cardiovascular events.94,95 Further research is warranted to determine if this change in quantitative metrics in response to therapy is associated with a reduction in cardiovascular events or altered disease prognosis.89,92

Combined evaluation of CS with PET/MRI enables precise spatial colocalization of LGE with FDG activity and provides complementary diagnostic information, differentiates active from chronic sarcoidosis, and predicts major adverse cardiac events although access to hybrid scanners remains limited.88,97–99 In addition, pulmonary arterial wall FDG uptake on PET/MRI may identify patients with pulmonary hypertension and is found in ≈19% of patients with active CS.100

There is growing interest in the use of radiotracers that target somatostatin receptors and DNA synthesis for the assessment of CS.101 Somatostatin receptors are expressed in activated macrophages, epithelioid cells, and multinucleated giant cells, which are the main constituents of sarcoid granuloma. Early experiments with these somatostatin receptor–targeted radiotracers have been promising with the potential to distinguish between active and chronic disease. Gallium-68-DOTA-Tyr3-octreotide is a novel PET radiotracer that targets somatostatin receptors and is under active investigation. On the other hand, cellular proliferation radionuclide imaging targets DNA synthesis using thymidine analogs. These radiotracers accumulate in cells with high turnover such as inflammatory and cancer cells. PET imaging with 18F-fluorothymidine seems to have a sensitivity for the detection of CS comparable to 18F-FDG imaging. These novel tracers hold the promise of better detection of CS over 18F-FDG due to the absence of myocardial uptake. However, further research is warranted to determine the role of these agents in CS.101–103

Iron Overload Cardiomyopathy

Iron overload cardiomyopathy can result from altered iron homeostasis, increased intestinal absorption, and chronic transfusions and is associated with adverse outcomes, including heart failure and arrhythmia.104 Primary iron overload cardiomyopathy is a genetically inherited cardiomyopathy predominantly from HFE gene mutation. Secondary causes are hemoglobinopathies and myelodysplastic syndromes necessitating multiple blood transfusions. Although most of the body iron is in the heme component of hemoglobin in circulating red blood cells, a small portion (≈10%) is stored in intracellular lysosomes of liver, spleen, bone marrow, and skeletal muscle as ferritin (short term) and hemosiderin (long term). Less than 5% of body iron circulates bound to the carrier protein transferrin.105 Although high liver iron concentrations are associated with cardiac iron levels, the iron uptake mechanism and kinetics in cardiac and extrahepatic tissues is different from that of liver. Hence, myocardium may be relatively spared in the early stages of hepatic iron accumulation. Likewise, myocardial iron clearance with iron chelation therapy is a much slower process compared with hepatic clearance. In addition, labile, inorganic free iron species appear in blood once transferrin is saturated and are thought to be responsible for cardiac dysfunction and arrhythmias.106 Cardiac dysfunction typically presents with a nondilated restrictive clinical phenotype, which then advances to systolic dysfunction with LV dilation.

Although serum ferritin levels correlate poorly with myocardial iron content, a markedly elevated level of >2500 ng/mL, in general, suggests an increased risk of heart disease. Genetic testing is recommended to confirm hereditary disorders of hemoglobinopathies or hereditary hemochromatosis. Timely identification of iron overload cardiomyopathy is imperative because it may be reversible when chelation therapy is instituted early.

Echocardiography

Echocardiography detects functional consequences of iron overload in the heart. LV wall thickness is typically normal and the ejection fraction is initially preserved, but moderate to severe systolic dysfunction can occur with heavy iron deposition, leading to dilated cardiomyopathy. Right heart failure can be seen early in the course of disease with progressive dilation of both the right and left ventricles with advanced disease. Diastolic dysfunction is mild early in the disease with enhanced left atrial contraction being the earliest detectable echocardiographic finding of iron overload cardiomyopathy.107 Later in the disease, a restrictive phenotype with severe diastolic dysfunction and pulmonary hypertension can be seen.108 Echocardiography has demonstrated a decrease in LV mass and wall thickness with iron-depleting therapies in idiopathic hemochromatosis.109

Cardiac Magnetic Resonance Imaging

Cardiac iron concentration is inversely related to MRI T1, T2, and T2* values. CMR T2* analysis remains the clinical standard for noninvasive assessment of myocardial hemosiderin (not ferritin or labile iron), with high sensitivity and reproducibility110,111 (Figure 5). Midseptal T2* values <20 ms are considered clinically important, whereas values <10 ms reflect severe iron overload, thereby predicting the risk of heart failure and arrhythmias better than liver T2* or serum ferritin.112 However, native T1 may be more sensitive and reproducible than T2* in the evaluation of myocardial iron, particularly in the setting of severe and mild iron overload where T2* analysis is less reliable.113 Combined use of both segmental native T1 and T2* could improve the sensitivity for detecting myocardial iron.114,115 In patients with severe myocardial iron overload, fibrosis eventually results and is detectable using LGE and ECV.116 Parametric mapping with T1 and T2* is also useful to monitor longitudinal changes, including response to treatment and quantification of hepatic iron. CMR is also useful for evaluation of LV volumes and function in patients receiving iron chelators, because improved function is associated with reduced risk of heart failure.117

Figure 5.

Figure 5. Cardiac magnetic resonance images acquired at 1.5T in a 32-year-old woman with β-thalassemia major and cardiac iron overload. A, Midventricular short-axis late gadolinium–enhancement image demonstrates no LGE. B, Midventricular short-axis native T1 map (1.5 T) demonstrates low global native T1 values (820 ms), in keeping with iron overload. C, Midventricular short-axis T2* map (1.5 T) demonstrates low global T2* values (13 ms), in keeping with iron overload.

UNCOMMON INFILTRATIVE CARDIOMYOPATHIES

Danon disease is an X-linked dominant genetic disorder caused by mutations in the gene encoding LAMP2 (lysosome-associated membrane protein-2) and resulting in glycogen accumulation in tissues including cardiac myocytes.118 Men are more severely affected than women and typically present with cardiomyopathy, ventricular preexcitation, skeletal myopathy, and ocular disease with neurobehavioral problems.119 Definitive diagnosis rests on genetic testing for the LAMP2 gene. Typical CMR findings in men with Danon disease include LV wall thickening that is frequently misclassified as sarcomeric HCM. Women can present with either LV wall thickening or dilation. Additional CMR findings include a characteristic pattern of extensive LGE with basal to midseptal sparing, resting perfusion defects, and hyperintensity and hypointensity on T2-weighted imaging120 (Figure 6).

Figure 6.

Figure 6. Cardiac magnetic resonance images acquired at 1.5T in a 31-year-old woman with Danon disease. A, Midentricular short-axis LGE image demonstrates severe concentric wall thickening and extensive, midwall LGE that spares the septum (red arrow). B, Midventricular short-axis native T1 map (1.5 T) demonstrates elevated global native T1 values (1205 ms), suggestive of fibrosis. C, Midventricular short-axis T2 map (1.5 T) demonstrates elevated T2 values (53 ms), in keeping with edema. LGE indicates late gadolinium enhancement.

Friedreich ataxia is a rare early-onset degenerative disease with an autosomal recessive inheritance pattern caused by an insufficient amount of the nuclear-encoded mitochondrial protein frataxin, resulting in iron metabolism dysregulation and mitochondrial dysfunction. Friedreich ataxia presents with neurological and cardiovascular phenotypes.121 Age of onset is between the late first or early second decade of life. The predominant clinical symptom to manifest early is neurological ataxia. Friedreich ataxia is associated with a progressive hypertrophic cardiomyopathy. Often masked by neurological status, cardiac involvement is evident only late in the course of the disease.122 Cardiac arrhythmias trigger decompensated heart failure and are the leading cause of death. Typical imaging findings in Friedreich ataxia include progressive myocardial thickening and declining LV ejection fraction. CMR is useful in quantifying ventricular size, mass, and myocardial iron accumulation using T2* imaging.123

Other rare infiltrative cardiomyopathies such as Pompe Disease, PRKAG2 syndrome, and the various types of mucopolysaccharidosis, which are genetically transmitted, are typically diagnosed, and their outcome determined by their neurological and systemic manifestations (Supplemental Figure S.4). A general diagnostic algorithm and key imaging features of the common infiltrative cardiomyopathies are outlined in Figure 7. As described throughout this scientific statement, various imaging modalities, while serving as discrete imaging tools, can also be combined to provide complimentary information to clinicians in better understanding the underlying pathophysiological process, staging and quantification of disease burden, and in guiding appropriate therapeutic decisions.

Figure 7.

Figure 7. Suggested diagnostic algorithm for suspected infiltrative cardiomyopathy. AL indicates light chain amyloidosis; ATTR, transthyretin amyloidosis; ECV, extracellular volume; 18F-FDG, 18F-fluorodeoxyglucose; GLA, α-galactosidase A; HCM, hypertrophic cardiomyopathy; LGE, late gadolinium enhancement; MRI, magnetic resonance imaging; PET, positron emission tomography; SIEP, serum immunofixation electrophoresis; SPECT, single photon emission computed tomography; Tc 99m PYP, technetium 99m pyrophosphate scan; and UIEP, urine immunofixation electrophoresis.

SUMMARY

Significant advances in cardiac imaging in the past 2 decades have refined our approach to accurate diagnosis of various infiltrative cardiomyopathies, a group of myocardial disorders that was previously often unrecognized or misclassified. The future of multimodality cardiac imaging, with ongoing sophistication in technology, holds promises in increasing our noninvasive diagnostic accuracy and monitoring disease progression with or without treatment.

ARTICLE INFORMATION

Footnotes

Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/HCI.0000000000000081

The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.

This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on June 12, 2023, and the American Heart Association Executive Committee on September 18, 2023. A copy of the document is available at https://professional.heart.org/statements by using either “Search for Guidelines & Statements” or the “Browse by Topic” area. To purchase additional reprints, call 215-356-2721 or email

The American Heart Association requests that this document be cited as follows: Kottam A, Hanneman K, Schenone A, Daubert MA, Sidhu GD, Gropler RJ, Garcia MJ; on behalf of the American Heart Association Committee on Cardiovascular Imaging and Intervention Committee of the Council on Cardiovascular Radiology and Intervention. State-of-the-art imaging of infiltrative cardiomyopathies: a scientific statement from the American Heart Association. Circ Cardiovasc Imaging. 2023;16:e934–e951. doi: 10.1161/HCI.0000000000000081

The expert peer review of AHA-commissioned documents (eg, scientific statements, clinical practice guidelines, systematic reviews) is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit https://professional.heart.org/statements. Select the “Guidelines & Statements” drop-down menu, then click “Publication Development.”

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