The role of cardiovascular multimodality imaging in the evaluation of Anderson–Fabry disease: from early diagnosis to therapy monitoring: A clinical consensus statement of the ESC Working Group on Myocardial and Pericardial Diseases and the European Association of Cardiovascular Imaging of the ESC

Abstract

Graphical Abstract

Clinical evaluation and multimodality imaging to assess cardiac involvement in Fabry disease. AF, atrial fibrillation; CFR, coronary flow reserve; E/E′, early diastolic wave by pulsed-wave Doppler/average E′ wave by tissue Doppler imaging; ECV, extracellular volume; EF, ejection fraction; GLS, global longitudinal strain; LA, left atrial; LAVi, left atrial volume index; LGE, late gadolinium enhancement; LV, left ventricular; NTproBNP, N-terminal-pro-brain natriuretic peptide; RV, right ventricular; SVT, supraventricular tachycardia; TAPSE, tricuspid annular plane systolic excursion; VT, ventricular tachycardia.

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Introduction

Anderson-Fabry disease (AFD) is a pan-ethnic X-linked rare genetic disorder that affects glycosphingolipid metabolism, primarily in young adults. Specifically, the defect resides in the gene for the enzyme alpha-galactosidase A (alpha-GAL), leading to the pathological accumulation of globotriaosylceramide (Gb3) within lysosomes that results in cellular hypertrophy and dysfunction.¹ The reported incidence, between 1 in 40 000 and 1 in 117,000, may be underestimated as recent newborn screening suggests a prevalence of up to 1 in 8800.²

The classic phenotype of AFD is caused by severe genetic defects in the GLA gene resulting in zero or very low enzyme activity, is observed in male patients, and is characterized by a paediatric onset and a multisystem disease that mainly affects the renal, cardiac, vascular, and nervous systems.³ In male patients with specific genetic variants associated with residual alpha-GAL activity, clinical manifestations are often confined to the heart and manifest during adulthood (so-called later-onset phenotype or cardiac variant). In female patients, variable inactivation of the X chromosome causes variable severity of cardiac involvement, usually presenting later in adulthood and with some specific features. In both classic and later-onset phenotypes, cardiac involvement, including heart failure and arrhythmias, represents the leading cause of impaired quality of life and mortality in patients with AFD.⁴ It is estimated that the prevalence of AFD in patients with unexplained left ventricular hypertrophy (LVH) ranges from 0.5 to 1% in adults.⁵ Cardiac damage develops slowly and remains subclinical for many years before symptom onset. To suspect AFD in its early stages, clinicians should consider clinical red flags and instrumental findings. In classic phenotype, early extracardiac manifestations⁶ may suggest diagnosis. In the later-onset cardiac variant, the differential diagnosis may be more complex, relying on the recognition of electrocardiographic and imaging red flags. The electrocardiogram (ECG) can show early indicators such as short PQ interval and repolarization abnormalities.⁷ Still, in most cases, clinical suspicion is raised by imaging findings, commonly at bidimensional (2D) echocardiography⁸ and cardiac magnetic resonance (CMR).⁹ Then, α-galactosidase A/LysoGb3 tests in male and genetic test in female are required to confirm the diagnosis.¹⁰

Multimodality imaging is also central in cardiac involvement staging and prognostic stratification.

This clinical consensus statement aims to describe the role of basic and advanced multimodality imaging in the diagnosing, staging, and monitoring cardiac damage in AFD, together with an insight into current gaps and future directions.

Clinical evaluation and interaction with biomarkers, imaging, and genetics

AFD is an X-linked phenocopy of hypertrophic cardiomyopathy caused by pathogenic variants in the GLA gene. Hundreds of different variants have been linked with the disease, most of which are missense. The product of the GLA gene, α-galactosidase A, is the enzyme that cleaves galactose from oligosaccharides, glycoproteins, and glycolipids that have been internalized in lysosomes via endocytosis. Gb3 is the main enzymatic substrate that accumulates in AFD in numerous tissues, including the heart, kidneys, skin, and vascular endothelium.¹¹

Examination of genotype–phenotype relations in AFD is difficult because of the high prevalence of a large number of private mutations. Still, the available data indicate that variable expression is common within and between families. Nevertheless, pathogenic variants retaining residual α-galactosidase A activity, which may be measured and estimated for diagnosis (Figure 1), are generally associated with a milder phenotype than mutations that result in complete loss of function.^11,12

Figure 1

Proposed algorithm for diagnosis and monitoring of AFD using clinical evaluation and multimodality cardiac imaging. *Cardiac amyloidosis, glycogenosis, hypertrophic cardiomyopathy, and mitochondriopathy. α-GalA act., alpha-galactosidase A activity; CMP, cardiomyopathies; CMR, cardiac magnetic resonance; ECG, electrocardiogram; EF, ejection fraction; ERT, enzyme replacement therapy; LS, longitudinal strain; LVH, left ventricular hypertrophy; LysoGb3, lysosomial globotriaosylceramide; PET, positron emission tomography; RV, right ventricular; SPECT, single-photon emission computed tomography.

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Identifying the specific pathogenic variant is essential for selecting the most appropriate treatment, as not all variants can be treated with chaperone therapy.¹³

The systemic involvement of AFD has many typical signs which are encountered as ‘AFD extra-cardiac red flags’: renal dysfunction, neuropathic pain, angiokeratomas, albuminuria, cornea verticillata, hypohidrosis, heat/cold and exercise intolerance, gastrointestinal symptoms (nausea, vomiting, non-specific abdominal pain, constipation, and diarrhoea), hearing loss, tinnitus, and vertigo.¹⁰

Gender differences in AFD

Female AFD patients usually have later manifestations and a less severe course of the disease even if skewed inactivation of the X chromosome may lead to a phenotype as severe as in hemizygous males. A gender-specific panel of plasmatic biomarkers has been described suggesting gender differences at the proteomic level.¹⁴ Severe LVH in female patients usually develops later in life compared with men, even if replacement fibrosis can be suggested by advanced modalities, like strain echocardiography and identified by CMR, before hypertrophy appears.¹⁵ In the Fabry Outcome Survey,¹⁶ about 46% of female AFD patients developed cardiac symptoms, among which angina, dyspnoea, and palpitations. Generally, heart failure onset in women occurs later than in men and life expectancy is higher.¹⁷ No significant differences have been described between the two genders regarding severe valvular regurgitation or stenosis.¹⁸

Diagnostic evaluation in patients with suspect or known cardiac involvement in AFD

Basic echocardiography

Left ventricular morphology

Cardiomyopathy is a major manifestation of AFD. In the more common late-onset form of the disease, cardiomyopathy is the predominant and often the only manifestation. Echocardiography is indicated because of cardiomyopathy-related symptoms, including exertional dyspnoea, atrial fibrillation, atrioventricular conduction defects, abnormal ECG, or family history of AFD.⁷ Unexplained LVH, in the context of suggestive clinical features, raises suspicion of AFD. Fabry cardiomyopathy (FC) is characterized by LVH [left ventricular (LV) maximum wall thickness ≥ 12 mm), which is a typical finding on echocardiography in middle-aged and elderly subjects with AFD. LVH is often concentric, but septal hypertrophy indistinguishable from cardiomyopathy caused by sarcomere gene defects is also common. FC is progressive, and LVH worsens with age. Although diffuse concentric LVH is the most prevalent abnormality, regional LVH involving the septum may cause dynamic LV outflow tract obstruction (LVOTO) with systolic anterior motion of the mitral leaflet in up to 45% of the cases.¹⁹ Some patients may present only mid-ventricular or papillary muscle hypertrophy and mid-ventricular obstruction rather than LVOTO, while others may present distal LVH.^20,21 Papillary muscles are considered hypertrophic if the vertical or horizontal diameter of at least 1 of the papillary muscles exceeds 11 mm in the short-axis view, in diastole²² (Figure 2). Papillary muscle hypertrophy may precede LVH but is not specific to AFD.^22,23 The left atrium is often enlarged. Hypertrophy of the right ventricle and aortic root dilatation are other AFD-related findings on echocardiography (Table 1).⁶ The main imaging characteristics of AFD compared with other cardiomyopathies are summarized in Table 2.

Figure 2

Representative case of echocardiographic findings in Fabry disease: LV diastolic dysfunction (upper and lower, left and upper middle), LVOTO (upper, right), and LVH (lower, right and middle).

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LV systolic and diastolic function

Ejection fraction is usually preserved, and LV dimensions are normal. Thickening of aortic and mitral valves and associated mild valve regurgitations often accompany the LVH. Reduction of LV global longitudinal strain (GLS) may be an early sign of FC. LV diastolic dysfunction and abnormal longitudinal strain with preserved LV ejection fraction are the earliest findings of AFD rather than prominent LVH that progresses with age and relates to symptoms.²⁴ LV diastolic dysfunction progresses with increasing LVH.²⁵ In some patients, the mid-to-basal inferolateral wall may appear hypokinetic or akinetic, reflecting regional myocardial fibrosis. Abnormal LV contractile reserve with blunted stroke volume augmentation on exertion is reported in those with advanced cardiac involvement.²⁶

Valvular heart disease and study of the aorta

Significant heart valve involvement in AFD is generally uncommon. The first descriptions date back to the mid-1970s when remodelling of the mitral and tricuspid valves, including thickening of the leaflets and interchordal hooding, was described on biopsy cardiac specimens of two homozygous patients.²⁷ Regurgitation is more common than stenosis, but only in a minority of the cases it reaches a severe grade (about 10%), mostly related to increasing age and worsening kidney function.¹⁸ A comprehensive assessment of LV geometry and remodelling is needed to describe the possible mechanisms of functional mitral regurgitation, including chordal tethering and annulus distortion.¹⁸ Aortic root dilatation is also possible, developing since a young age in male patients, mainly at the level of the sinuses of Valsalva and ascending aorta level¹⁷ with a possible associated aortic regurgitation. Less frequently, the aortic valve is involved due to glycosphingolipid deposition (Figure 3A). Few cases of severe aortic stenosis treated surgically²⁸ or with transcatheter intervention²⁹ have been described, requiring a multimodality imaging approach in the preoperative work-up to improve the morpho-functional characterization of left ventricle and aorta, not only focusing on aortic valve and flow dynamics.

Figure 3

Aortic valve with accumulation of small bodies containing Gb3 (A, toluidine blue staining). Endomyocardial biopsy reveals interstitial fibrosis and hypertrophic myocytes with myofibrillar loss and extensive vacuolization. Most myocytes appear empty due to tissue processing (B). In some cardiomyocytes, clusters of round bodies are found consisting of Gb3 deposits (C). Masson trichrome staining.

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Increased aortic diameter is a common finding in patients with AFD, mostly mild or moderate dilatation.^30,31 The prevalence of aortic dilatation increases with age and is significantly higher in male than in female patients. In the larger study that explored aortic remodelling in a cohort of 106 patients with AFD, dilatation of the aortic root and ascending aorta were observed in 32.7% and 29.6% of men, respectively, vs. 5.6% and 21.1% of women, respectively.³⁰

The development of aortic dilatation in AFD has been attributed to degenerative changes of the aortic media caused by the glycolipid accumulation in the vascular endothelium, as demonstrated by post-mortem biochemical studies.³² An aortic root diameter > 40 mm has been associated with echocardiographic signs of advanced cardiac involvement, including severe LVH.³¹ However, the need for surgery or complications, including rupture or dissection of aortic aneurysm, has not been reported in this population.

Right ventricular structure and function

Right ventricle hypertrophy (RVH) defined as right ventricular (RV) wall thickness > 5 mm is a common finding in AFD. The prevalence of RVH typically ranges between 31 and 40%.^30–32 However, in a study published by Niemann et al.³³ evaluating 53 patients with AFD indicated for enzymatic replacement therapy, a rate of RVH up to 71% was reported. The presence of RVH increases with age, and unlike LVH, it appears to affect females and males similarly.³⁴ RVH correlates with the disease severity, and it is present in approximately two-thirds of individuals with LVH. Isolated RVH is rare in patients without significant pulmonary hypertension.³⁵ RV size, as assessed by RV end-diastolic diameter, is typically within the normal range.³⁵

Discordant data exist regarding RV systolic function in AFD. Kampmann et al.³⁴ described that RVH might be accompanied by systolic dysfunction. In this study, severely depressed systolic function [tricuspid annular plane systolic excursion (TAPSE) < 10 mm] was found in 28% of patients with RVH. However, much lower incidences of RV systolic dysfunction were reported in subsequent studies. Palecek et al.³⁵ noted RV systolic dysfunction (TAPSE < 19 mm) in only 1 of the 58 (2%) patients with AFD. Graziani et al.³⁶ found that all 45 patients with AFD had normal TAPSE and RV fractional area change. In this study, only one had a decreased systolic pulsed spectral Doppler velocity (<9.5 cm/s).

RV diastolic dysfunction is reported in about half of the cases with AFD, but severe RV diastolic dysfunction seems to be very rare.³⁷

Advanced echocardiography

Speckle tracking echocardiography

The accumulation of glycosphingolipids within myocardial tissue in patients with AFD is replaced in later stages by fibrosis, typically localized in the basal segment of the posterolateral wall. The development of myocardial fibrosis may be non-invasively suspected using speckle tracking echocardiography.³⁸ Indeed, in AFD, LV longitudinal strain is typically decreased in the basal posterolateral segment,³⁹ which is consistent with the CMR findings (Figure 4). In addition, the loss of normal circumferential strain base-to-apex gradient represents an early marker of cardiac involvement in patients with AFD.^10,40 A reduced LV GLS has been included in AFD red flags, without a specific cut-off value, in the latest European Society of Cardiology (ESC) guidelines for the management of cardiomyopathies.¹⁰ Furthermore, RV strain has been demonstrated to be a useful marker for the differential diagnosis with hypertrophic cardiomyopathy: in fact, AFD patients show a greater impairment of free wall RV strain (<23%) and a lower difference between free wall and global RV strain (defined as ΔRV strain), in comparison with patients with hypertrophic cardiomyopathy.^41,42 Finally, since AFD is mainly characterized by LV diastolic dysfunction and causes heart failure with preserved ejection fraction (HFpEF), the use of left atrial reservoir strain may be considered as a marker of diastolic function and LV filling pressures in HF, as advised in the latest EACVI consensus for the evaluation of HFpEF by multimodality imaging.^43,44 This may be useful for early diagnosis of cardiac alterations in these patients, ensuring early treatment, and for therapy monitoring as well.

Figure 4

Representative case of Fabry disease analysed by multimodality imaging: standard and speckle tracking echocardiography and cardiac magnetic resonance. PL, posterolateral.

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Figure 5

Early signs of cardiac involvement by 2D and 3D echocardiography in a 57-year-old patient with a family history of FC.

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3D echocardiography

3D echocardiography has the potential to overcome some of the intrinsic limitations of 2D echocardiography for the assessment of the complex LV myocardial mechanics, offering additional deformation parameters (such as 3D area strain) and a more accurate quantitation of LV volumes, mass, and ejection fraction from a single 3D acquisition (Figure 5).⁴⁵

In AFD patients, LV wall thickness and LV mass should be monitored over time.⁴⁶ 2D calculations may overestimate LV mass and maximum wall thickness in the setting of asymmetrical hypertrophy. Moreover, LV mass by 2D echocardiography has lower reproducibility than its measurement by CMR in patients with AFD.⁴⁷ The use of 2D echocardiography instead of CMR has been shown to potentially affect the diagnosis of LVH in 29% of patients, eligibility for disease-specific therapy in 26% of patients, and prognosis.⁴⁸ 3D echocardiography allows the measurement of LV mass without any geometric assumptions, providing values closer to CMR measurements. Moreover, 3D LV mass has less interobserver and test-retest variability than 2D calculations.^49,50

Currently, the feasibility of 3D speckle tracking in everyday practice is lower (63–83%) in comparison with 2D speckle tracking echocardiography (80–97%).⁴⁵ Notably, the reported feasibility of 3D strain in AFD was 76%.⁵¹ 3D strain parameters were inversely related to LV mass. Of these, the 3D GLS component was the most sensitive parameter, associated with heart failure severity [natriuretic peptide levels and New York Heart Association (NYHA) class] and long-term prognosis.⁵¹ On the other hand, decreased regional 3D circumferential strain at LV inferolateral mid and basal segments reflected the presence of typical AFD-related myocardial scar depicted by late gadolinium enhancement (LGE) at CMR. 3D strain may also help identify early subclinical functional impairment of the RV corresponding to the degree of RV hypertrophy.³⁷

However, the accuracy of 3D strain (especially at the regional level) largely depends on optimal image quality and volume rate. Suboptimal tracking predominantly affects the LV basal segments, which are in the far field in the apical 3D data sets.⁵² Tackling these technical aspects requires a sufficient amount of dedicated training and practical skills, and this may significantly limit the number of patients in whom 3D speckle tracking with current technology is feasible in routine clinical practice (Figure 4). Technical improvements in spatial and temporal resolution that can be achieved in single-beat 3D acquisitions and the implementation of artificial intelligence algorithms are likely to foster the adoption of 3D echocardiography in everyday routines. However, the added value of 3D echocardiography over the conventional 2D echocardiographic assessment in AFD patients requires stronger evidence.

Cardiac magnetic resonance

Evaluation of ventricular morphology

Even if echocardiography is sufficient for the diagnosis of FC, CMR, including LGE and T1 mapping, is advised for all patients with cardiomyopathies, including FC, for further characterization of myocardial tissue¹⁰ (Figure 2). CMR provides the reference standard assessment of LV structure and function. Standard CMR protocols include long-axis cine images of the left ventricle (two-chamber, three-chamber, and four-chamber views) to allow morphological assessment. Adjacent short-axis cine images of the ventricles are then acquired from the mitral valve annulus to the LV apex. Contouring of the endocardial and epicardial border then allows precise estimation of LV mass, volumes, and ejection fraction. Cine images also allow precision measurement of LV wall thickness. CMR visualizes accurately the inferolateral wall and anteroseptum, which can sometimes be difficult to image with echocardiography.⁵ Artificial intelligence-based algorithms have been proven to be valuable tools for LV wall thickness quantification, providing better reproducibility and shorter times than experienced observers.⁹

As discussed, the most common finding in AFD is a concentric LVH, usually associated with an increased LV papillary muscle mass.

In addition, CMR may reveal an increased myocardial trabeculation in AFD, described as a very early sign of cardiac involvement. It also precedes the attenuation of myocardial T1 values and the development of LVH.⁵³

Secondary structural changes in AFD, such as left atrial dilatation and RV hypertrophy, can also be identified and precisely quantified with CMR.^7,8 Furthermore, although the LV ejection fraction is usually preserved, CMR strain analysis may reveal an impairment of LV systolic mechanics. In the pre-hypertrophic phase of the disease, LV GLS impairment correlates with native T1 lowering and may help in the diagnosis of early cardiac involvement.⁵⁴

Similarly, an impairment of atrial deformation may be detected since the early phases of the disease, preceding the development of LVH or diastolic dysfunction⁵⁵ This finding supports the concept of an atrial myopathy in patients with AFD, directly caused by Gb3 accumulation that affects atrial compliance.

Finally, a recently validated CMR model, based on LV and LA volumetric analysis, may allow a non-invasive estimation of LV filling pressure.⁵⁶ Despite still unexplored in this context, its application may be promising in the assessment and monitoring of AFD patients.

Late gadolinium enhancement

LGE imaging enables the detection of myocardial replacement fibrosis and plays a pivotal role in the diagnostic pathway and management of AFD patients. In AFD, LGE characteristically involves the basal inferolateral area of the LV with a mid-wall distribution. Thereby, this finding in patients presenting unexplained LVH should raise the suspicion of AFD diagnosis.¹⁰ However, atypical patterns have also been reported and the progression to other LV segments is common in the advanced stages of the disease.⁵⁷ The prevalence of LGE ranges between 40 and 65%^58–60 and, in male patients, correlates with the severity of LVH.⁵⁷ Nevertheless, it may also precede the development of LVH, especially in women.^15–62 Importantly, the presence and extent of myocardial fibrosis are crucial prognostic determinants in patients with AFD and portend an increased risk of malignant arrhythmic events.^57,60 In addition, LGE assessment may also provide important information regarding patients’ response to disease-specific treatments. Indeed, in patients starting enzymatic replacement therapy, the presence of LGE is associated with a low likelihood of LVH regression and with a scarce improvement of myocardial function and exercise capacity^63,64 (Figure 6).

Figure 6

Cardiac magnetic resonance imaging in early stage AFD. A 43-year-old male with classic Fabry disease treated with ERT showing mild LVH (MWT 12 mm) at cine sequences (A) with no evidence of LGE in post-contrast sequences (B). Native T1 mapping values are diffusely reduced (C) while there are no segments with increased native T2 mapping values (D). Please note that Siemens colour scale may sometimes be non-diagnostic, while rainbow scale, if available, is better to highlight myocardial changes.

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T1–T2 mapping

Unexplained hypertrophy and typical posterolateral scar can raise suspicion of AFD; but mapping techniques add substantial value.

Mapping is a quantitative technique in which individual image pixels are colour-coded for longitudinal (T1) or transverse (T2) magnetism.

Reduced T1 may be observed in iron overload or lipid accumulation, whereas increased T1 is related to myocardial fibrosis or oedema.⁶⁵ AFD typically lowers myocardial native T1, as result of the intracellular glycosphingolipid storage, particularly with the pattern of concentric lipid membranes in lamella bodies.⁶⁶ T1 attenuation starts in the early phase of the disease, preceding the development of LVH. Reduced T1 is detectable in approximately 40% of LVH-negative patients and correlated with early electrocardiographic changes and disease progression⁶⁴ (Figure 6). In advanced disease, T1 lowering is prominent. However, the signal may become weaker with inflammation and fibrosis and even reverse if there is extensive LGE. Therefore, T1 mapping should be interpreted with caution and the finding of a normal native T1 does not allow the inclusion of an AFD diagnosis.

With this limitation, T1 lowering currently plays a pivotal role in the differential diagnosis of AFD vs. other causes of LVH, including chronic afterload increase (hypertension and aortic stenosis), hypertrophic cardiomyopathy, and cardiac amyloidosis. Indeed, at variance of AFD, they are all characterized by an increase in native T1, that it is typically more prominent for cardiac amyloidosis.

Notably, a slight reduction of native T1 has also been observed in athlete’s heart vs. healthy controls, but with values that typically remain in the normal range.⁶⁷

For the global analysis, a single region of interests should be drawn in the septum on mid-cavity short-axis T1 map, limiting susceptibility artefacts. For the assessment of focal changes, additional regions of interests should be drawn in abnormal segments on visual inspection and particularly in the basal inferolateral wall. Of importance, the use of local reference range of native T1 is advised, depending on the specific scanner and sequence.⁶⁷

T2 also adds value in disease phenotyping as T2 elevation typically reflects oedema. In AFD, T2 is typically elevated in areas of LGE in the basal inferolateral wall and correlates with troponin rise.⁶⁸ T2 elevation supports a pivotal role of inflammation in AFD pathogenesis, in line with the findings by positron emission tomography (PET) and endomyocardial biopsy.⁶⁹ In this regard, immune-mediated myocardial inflammation may be triggered by Gb3 accumulation, which has been detected at the histological examination in up to 56% of patients with AFD.⁶⁹

Importantly, combined LVH, LGE, and T1/T2 mapping can be used to stage cardiac AFD, as extensively described in the following sections.

For therapy monitoring, T1 changes are disappointingly small suggesting a failure of existing therapies to remove lipid from myocytes and a therapeutic opportunity for new approaches.⁶¹

Nuclear imaging

Cardiac single-photon emission computed tomography (SPECT) and PET imaging can provide useful information in patients with AFD and important insights into the underlying pathophysiology. Further research is required to assess how current and future nuclear imaging techniques can help with the clinical assessment and management of these patients.

A feature of AFD is the progressive accumulation of Gb3 within various tissues, including the heart. SPECT imaging, typically performed using radiopharmaceuticals like 99mTc-sestamibi, allows clinicians to visualize and assess myocardial perfusion, which can be altered in AFD due to Gb3 deposition. Perfusion defects observed on SPECT scans can indicate compromised blood flow to specific areas of the heart, a hallmark of AFD-related cardiac involvement. In 2008, Chimenti et al.⁷⁰ investigated the mechanism of chest pain in AFD patients. They found that patients with angina had perfusion defects, slow coronary flow, and narrowing of intramural arteries, suggesting that microvascular disease might make an important contribution to symptom development and progressive myocardial dysfunction in AFD patients, highlighting its clinical relevance.

To exclude microvascular disease in AFD patients with chest pain of LV dysfunction, since this can neither reliably visualized by typical SPECT perfusion nor being excluded by normal coronary computed tomography or invasive angiography unless functional measures are collected, perfusion imaging in these patients should favour quantitative perfusion imaging by PET or coronary flow reserve imaging with new digital SPECT systems or using CMR with flow quantification.

These data were confirmed by Tomberli et al.⁷¹ who demonstrated that a global reduction in coronary flow reserve obtained by PET was an early sign of cardiac involvement in Fabry disease, regardless of sex and LVH. Accordingly, coronary microvascular dysfunction may represent the only sign of cardiac involvement in AFD patients, with potentially important implications for clinical management.

18F-fluorodeoxyglucose-PET (¹⁸F-FDG-PET) is commonly used to assess myocardial inflammation based upon the increased glucose utilization demonstrated by macrophages. ¹⁸F-FDG-PET has also been investigated in AFD. In particular, Spinelli et al.⁷² investigated 24 females carrying an α-galactosidase A mutation. In this study, focal ¹⁸F-FDG uptake was observed as an early sign of disease-related myocardial damage and likely represented an inflammatory response to cardiomyocyte Gb3 storage. Furthermore, the presence of ¹⁸F-FDG uptake correlates with impaired LV longitudinal function at echo and LGE areas on CMR. In particular, Nensa et al.^73,74 prospectively compared ¹⁸F-FDG-PET with LGE and T2-weighted MRI sequences, using hybrid ¹⁸F-FDG-MRI in patients with suspected myocarditis, demonstrating an overall good agreement between MRI findings and increased myocardial ¹⁸F-FDG-PET uptake.

Further data are required to investigate whether focal myocardial ¹⁸F-FDG uptake in young patients carrying AFD-related mutations may serve as a marker of disease activity and predictor of subsequent disease progression.

Progressive glycosphingolipid accumulation in AFD can ultimately lead to myocardial fibrosis as shown in endomyocardial biopsies (Figure 3B and C) and subsequent cardiac sympathetic denervation. Recent studies have evaluated the extent of such accumulation and consequences using [¹²³I]-metaiodobenzylguanidine-SPECT or dedicated PET tracers, showing that denervated areas are associated with LV dysfunction in patients with or without LGE.^74–77 Furthermore, evidence has previously been found that sympathetic neurons appear more vulnerable than myocardial cells to the effect of AFD. Imbriaco et al.⁷⁶ demonstrated that cardiac sympathetic neuronal damage often appears before myocardial fibrosis in AFD patients. Their work highlights the potential of ¹²³I-metaiodobenzylguanidine imaging as a tool for early disease detection. This aspect is particularly valuable as it may precede myocardial fibrosis, enabling early detection of cardiac involvement. These results were confirmed by Spinelli et al.⁷⁵ revealing a valuable connection between reduced cardiac MIBG uptake and cardiac involvement in AFD. Their research suggests that LV longitudinal function impairment may manifest as an early sign of the disease. Finally, Massalha and Slart⁷⁷ emphasized the importance of identifying phenotypic markers before the development of irreversible fibrosis. They highlighted the need for a comprehensive, multimodal imaging approach, including techniques like ¹²³I-metaiodobenzylguanidine imaging as well as the potential of ¹¹C-meta-hydroxy-ephedrine PET for more accurate quantification of cardiac autonomic function.

In summary, nuclear cardiac imaging has provided essential insights into the pathophysiology underling Fabry disease. Future studies are required to establish the clinical role of nuclear imaging in Fabry disease, particularly novel molecular imaging techniques.

Early cardiac alterations in AFD

AFD depicts a large spectrum of clinical features with a high variability of symptoms onset depending on the residual enzymatic alpha-GAL-A activity.⁷⁸ In the classical early-onset form occurring in male patients with enzymatic activity < 1%, cardiovascular signs develop during the second to third decade of life along with multisystem clinical involvement.^79,80 ECG abnormalities such as short PR interval and repolarization abnormalities precede structural heart disease and symptoms onset (Figure 7).^7,9,81 LVH appears in approximately one-half of men and one-third of women beyond 30 years of age.^7,82 Thus, in children and young adults with LVH, the diagnosis of AFD is very unlikely.⁷⁸ After cardiomyopathy features become apparent, ∼60% of patients complain of a variety of cardiac symptoms including the following:

• Exertional dyspnoea, mainly attributed to HFpEF in up to a quarter of patients (with severe heart failure and NYHA Class III/IV reported in 10%).

• Chest pain due to microvascular dysfunction (23%), occasionally to chronotropic incompetence and rarely to epicardial coronary artery disease (the reported rate of myocardial infarction is 2%).

• Palpitations (15–43%) caused most frequently by atrial (17% atrial fibrillation) but also ventricular arrhythmias (8% non-sustained ventricular tachycardia).

• Syncope of any aetiology, more frequent in men (1.7–5.6%) due to sinus node dysfunction/severe conduction disturbances (up to 30%) and arrhythmias.⁷⁸ Hypertension is uncommon in the absence of concomitant renal involvement.⁷⁸ During the cardiomyopathy stage, the typical ECG findings become apparent such as high voltage and a ‘strain’ pattern (ST depression and T wave inversion on a resting ECG, marker of LVH).⁷ Progression to heart failure with reduced ejection fraction is observed in 6–8% of patients, mostly in those cases deprived of enzyme replacement therapy (ERT), and is associated with increased mortality rates.⁷⁵

Figure 7

ECG features in AFD. Representative case of ECG in AFD with short PR interval, QRS, and repolarization abnormalities.

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Staging and prognostic stratification of cardiac AFD

LVH has been traditionally considered the strongest prognostic determinant in AFD.^60,83 Myocardial fibrosis detected by LGE is also a well-established predictor of cardiovascular outcomes in these patients, with an independent value from the presence of LVH, and its progression over time has been associated with an excess risk of ventricular arrhythmias.^59,84

In the last decade, important advances in cardiac imaging have led to a better understanding of the pathophysiology of cardiac AFD and novel tools for a more accurate prognostication.⁸⁵

Concerning conventional echocardiography, Meucci et al.^85,86 recently proposed a staging system of cardiac AFD:

• Stage 0, no signs of cardiac involvement

• Stage 1, LVH

• Stage 2, left atrial enlargement

• Stage 3, ventricular impairment (LV ejection fraction < 50% or mean E/E′ ≥ 15 or TAPSE < 17 mm)

In a multicentric cohort of 314 patients with AFD, more advanced stages of cardiac damage were independently associated with an increasing risk of cardiovascular events on long-term follow-up and demonstrated an incremental prognostic value in comparison with the isolated assessment of LVH.⁵¹

2D or 3D speckle tracking echocardiography may offer additive information, not only for early diagnosis before LVH occurs but also for refining patients’ risk stratification.^66,87

Of interest, a recent CMR study conducted in 200 AFD patients validated a risk model for predicting 5-year risk of adverse cardiovascular events based on three variables: age, LV mass index, and a novel T1 mapping parameter, T1 dispersion (standard deviation of per voxel myocardial T1 relaxation times).⁶⁷ However, despite being attractive from the pathophysiological point of view, the application of T1 dispersion may be time-consuming and is still largely limited to the research setting.

Regarding T2 mapping, increased T2 values in the LGE segments have been associated with troponin elevation and with disease progression, supporting a crucial role played by myocardial inflammation in the pathophysiology of cardiac AFD.^68,88

In light of this evidence, Nordin et al.^61,62 proposed and validated a model of AFD progression stages based on CMR findings in a cohort of 182 patients:

• Stage 1, glycolipid accumulation, starting in childhood and characterized by a progressive attenuation of T1 without LVH or LGE

• Stage 2, inflammation and/or myocyte hypertrophy, with development of LVH (more extreme in men) and T2 elevation with LGE in the basal inferolateral segment (sometimes preceding LVH, especially in females)

• Stage 3, fibrosis and/or impairment, with a pseudo-normalization of T1 values and wall thinning in the basal inferolateral segment and progression of LGE to other LV segments

Cardiac imaging for monitoring response to treatment in AFD

Echocardiography

Echocardiography is the first-line imaging modality for monitoring of AFD cardiomyopathy and is suggested annually in adults and bi-annually in adolescents with cardiac involvement.⁵

Consensus documents by expert groups provide indications for disease-specific treatment initiation that are primarily based on disease variant (classic/late-onset) and sex.⁴ Importantly, in the presence of LVH, defined by a LV wall thickness > 12 mm or myocardial fibrosis by LGE, treatment initiation is advised, regardless from the disease form and sex.⁴ Conversely, pre-hypertrophic signs of cardiac involvement (i.e. T1 attenuation or LV GLS impairment) are not taken into consideration by current recommendations and decision-making in these cases needs to be individualized.

LV wall thickness changes after ERT are variable.⁸⁹ LV mass has been mostly shown to remain unchanged after several years of therapy, but it may also increase in male and older patients and decrease in female patients. Nonetheless, a reduction in LV mass has been demonstrated after treatment in patients with a specific genotype⁹⁰ and in patients with an increased LV mass index at baseline.^91,92 Moreover, reduction of LV mass has been shown after treatment with migalastat.⁹¹

Diastolic function assessed with standard Doppler techniques has been shown to remain unchanged or slightly improve after 12 months of ERT. An improved E/E′ ratio, which is more sensitive than mitral flow E/A ratio, may show improvement in diastolic filling pressures with ERT.⁸

Strain measurements by speckle tracking may indicate the progression of cardiomyopathy in AFD and indicate ERT. The reduced strain and strain rate speckle tracking measurements of AFD patients may improve with ERT in those patients who do not have LGE on CMR. Left atrial strain by speckle tracking echocardiography may improve with ERT and correlates with decreased indexed left atrial volume.⁸

Cardiac magnetic resonance

Multiparametric CMR has gained a crucial role in the monitoring of treatment response in AFD. Indeed, CMR enables a more accurate and reproducible quantification of LVH and, mostly, provides a crucial insight into the myocardial pathology, allowing a non-invasive assessment of glycolipid storage and other disease processes including inflammation and fibrosis. A considerable amount of myocardial fibrosis, inflammation, and mostly severe down-regulation of mannose-phosphate receptors could lead to ERT resistance. There may be major concerns on the opportunity for ERT administration in the very advanced phases of the disease.⁹²

Several CMR studies reported a reduction of LV mass after ERT initiation in AFD patients with either LVH and absence or a small amount of LGE.⁹² Conversely, patients with extensive LGE showed stable or increased LGE despite no changes in LVH after treatment initiation.^63,93 Moreover, in a recent multicentric study,⁶³ 1 year of ERT was associated with an attenuation of T1 lowering and reduction of LV wall thickness in 20 newly treated patients (58% male, 60% with LVH). Conversely, in AFD patients with more advanced and stable on-treatment disease (median ERT duration of 4.2 years), T2 increased in the LGE segments over 1 year, together with a rise of troponin levels and worsening LV GLS, despite no changes in LVH, T1, or LGE quantification.⁹⁴ Taken together, these results support the efficacy of ERT in reducing myocardial lipid burden and progression of cardiac remodelling when started in a timely manner. On the other hand, limited CMR data on cardiac response to chaperone therapy are available. Particularly, treatment with migalastat has been associated with a stabilization of LV mass and, in a recent small-size study, with a trend towards an improvement of T1 lowering that was more evident in patients with an early stage of disease.⁹⁵

Nuclear cardiac imaging

One of the primary goals of ERT in AFD is to reduce the accumulation of Gb3 in cardiac tissues. Nuclear cardiology, either with SPECT or PET scans, can be used to detect and quantify the efficacy of disease-specific therapy. Given the ability of SPECT and PET to inform about coronary microvascular dysfunction, acute and chronic inflammation, and sympathetic cardiac innervation, further work is required to assess whether these approaches might prove of clinical use in the monitoring and treatment of AFD.

Interestingly, ERT seems not to affect coronary microvascular dysfunction.⁹⁶ In particular, preliminary results by Kalliokoski et al.⁹⁷ demonstrated that, despite the significant decrease in plasmatic Gb3 concentration and the improvement of patients’ symptoms, 12 months of ERT did not improve myocardial perfusion reserve.

There is growing evidence that inflammatory pathways are actively involved not only in myocardial AFD with mature fibrosis but also at a systemic level in early stages of the disease.⁹⁸ In this regard, cardiac simultaneous ¹⁸F-FDG-PET and CMR may allow differentiation of real scar, from fibrosis associated with active inflammation.

Nappi et al.⁹⁹ investigated the role of serial cardiac ¹⁸F-FDG-PET-MRI in AFD and the potential relationship of imaging results with the FASTEX score¹⁰⁰ evaluating disease stability. Despite the limited number of enrolled patients, the study supports the hypothesis that disease progression is slower in patients who started ERT in the absence of cardiac fibrosis at baseline, highlighting the potential for greater therapeutic benefit if ERT is initiated early in the disease course. Further studies are needed for confirmation.

Current gaps and future directions

Multimodality cardiac imaging plays a crucial role in the diagnosis and management of AFD, particularly in assessing the presence and severity of cardiac involvement.

In recent years, the rapid evolution of advanced imaging technology significantly contributed to a better understanding of cardiac involvement pathophysiology in AFD, highlighting the importance of myocardial ischaemia and inflammation as additional mechanisms contributing to cardiac damage.^7,94,101 In addition, the systematic application of CMR allowed to identify new markers of early cardiac involvement preceding overt cardiac hypertrophy.^102,103

On the other hand, a standardized staging of cardiac involvement is still lacking. Recent studies suggested a prognostic stratification based on echocardiographic stages,⁸ while a multiparametric staging based on clinical, ECG, and multimodality imaging findings has been recently proposed, but not yet validated in large cohorts.¹⁰⁴ With this regard, prognostic stratification of the risk of sudden cardiac death in AFD remains a major challenge, as risk model for sarcomeric hypertrophic cardiomyopathy is not validated for genocopies and phenocopies while no robust AFD-specific arrhythmic risk factors have been identified so far.¹⁰⁵

Similarly, monitoring of cardiac damage progression and efficacy of AFD-specific therapies remains challenging. The rarity of AFD together with its heterogeneity related to genetic and epigenetic factors,^106,107 as well as the different patterns of disease evolution in males and females, makes it difficult to identify imaging criteria defining progression, stability, or even regression of cardiac damage.

Cardiac imaging research networks adopting a standardized multimodality approach are essential to gather larger and more homogeneous populations and to identify imaging biomarkers of disease evolution and response to treatment. In addition, the application of artificial intelligence to ECG and imaging analysis can further contribute to improve early diagnosis and to identify biomarkers to monitor cardiac involvement and define prognosis. Initial experiences with artificial intelligence applied to ECG and CMR in other cardiomyopathies are promising.¹⁰⁸

Conclusions

Cardiac involvement in AFD is characterized by a storage cardiomyopathy which may evolve in hypertrophic/restrictive cardiomyopathy leading to LV diastolic dysfunction and heart failure. There are several typical imaging findings (Table 1) which may aid the diagnosis of FC, for which all imaging modalities may have an important role (Box 1). Also, echocardiography, CMR, and nuclear imaging may serve as tools to guide therapeutic choices and monitor the response to treatment in these patients (Box 2). This clinical consensus statement provided indications for clinicians for the joint use of multimodality imaging to improve the management of AFD.

Funding

None declared.

Data availability

No new data were generated or analysed in support of this research.

References

Author notes