FD represents an under-recognized cause of LVH and is often misdiagnosed, especially the “cardiac variant” which lacks the typical extra-cardiac findings [10].

Several studies showed that in patients initially diagnosed with HCM the prevalence of FD can vary from 0.5% up to 12% [11, 12]. Therefore, the algorithm of differential diagnosis for patients with unexplained LVH should always include FC, especially when they present as late-onset disease. The best strategy to augment detection of FD is based on an integrated clinic and multi-modality imaging approach. The clinical assessment should not be restricted to cardiological examinations since some cardiomyopathies are manifestations of systemic disorders and those that could be considered “comorbidities” are signs that must rise the suspicion of a specific disease. The recognition of clinical and instrumental ‘red flags’ [8] in the setting of unexplained LVH must guide rational selection of further diagnostic tests including genetic analysis for FD [13].

According to current guidelines, in genetically proven FD patients, LV wall thickness $>$12 mm, not explainable by other causes, is a marker of cardiac involvement and a criterion to start enzymatic replacement therapy (ERT) (Class I of recommendation) [14].

In FD, LVH is usually concentric [15] (Fig. 2A–C) but FC can also present with eccentric, apical [16], and asymmetric septal hypertrophy [17, 18, 19].

Fig. 2.

Example of advanced Fabry cardiomyopathy. (A) Parasternal long-axis view: the red line shows the maximal wall thickness (30 mm). (B) Parasternal short-axis view: the green arrows point to the prominent hypertrophic papillary muscles. The anterolateral papillary muscle is also bifid (double arrow). (C) Apical four chambers view showing severe concentric LVH with reduced LV cavity dimensions and moderate right ventricular hypertrophy. (D) Subcostal view: the violet line shows the measurement of right ventricular wall thickness (7 mm, n.v. 5 mm).

Whatever the distribution of LVH, this results in an increase of the left ventricular mass index (LVMi, defined as $>$95 g/m${}^2$ for women and $>$115 g/m${}^2$ for men) [20]. LVH is more common in males than females at any given age and this difference was accounted as roughly a decade in a large international FD cohort (714 patients, mean age of patients with LVH 42 $\pm$ 14.5 years in men vs 50.1 $\pm$ 12.0 years in women) [5].

Sex differences in disease expression are expected, due to the X-linked mode of inheritance of the disease, and clinical FD manifestations in heterozygotes female were considered rare or mild in the past. However, starting from the early 2000s, this paradigm has been challenged by accumulating evidence indicating that females are affected more commonly than previously described [21, 22, 23], with the severity of LVH strongly correlated with increasing age [21].

Wu et al. [24] analyzed the cardiovascular manifestations of untreated FD patients with the aim to define the relationship between disease severity, $\alpha$-GAL activity and cardiac findings. Males with low $\alpha$-GAL activity and concomitant renal disease were those with most severe LVH, but the latter was present also in females older than 20 years and their log-corrected plasma $\alpha$-GAL activity levels were inversely correlated with LVMi.

It is worth noting that in patients with other concomitant conditions causing increased LV afterload, it can be difficult to discriminate LVH etiology. In these cases, a comprehensive echocardiographic assessment looking also to functional parameters (i.e., Tissue Doppler and speckle tracking echocardiography) along with other imaging tools such as cardiac magnetic resonance (CMR) are keys for an optimal management. The development of LVH is associated over time with symptoms of heart failure and episodes of arrhythmia (bradyarrhythmia, conduction block, and ventricular tachycardia) [5]. In the largest longitudinal study conducted so far, in which almost 3.000 FD patients were observed before the start of ERT, systemic hypertension and LVH were the strongest predictors of major cardiovascular events, including cardiac-related death [25].

Some morphologic LV abnormalities have been described in patients with FD, among which the “binary sign” and prominent papillary muscles [9].

The binary sign is the appearance of a clear black and white interface of the LV myocardium due to the adjacency of a bright, hyperechogenic region to a relatively low echo intensity region. This was firstly described by Pieroni et al. [26] in a study aimed to identify non-invasive imaging hallmarks of FD comparing echocardiographic features of patients with FC, HCM, and LVH secondary to arterial hypertension. They found that binary sign was present in as much as 83% of FC patients. The match of echocardiography with histologic and ultrastructural findings demonstrated that the binary appearance reflects an endomyocardial glycosphingolipids compartmentalization. Indeed, the hyperechogenic component consists of a thickened glycolipid-rich endocardium, followed by a subendocardial empty space containing free glycosphingolipids and an inner severely affected myocardial layer, with a subendocardial-midwall layer gradient of disease severity in which the hypoechogenic component represents myocardial layers that are relatively spared from glycolipid storage. This finding triggered further research, which contrariwise demonstrated a much lower prevalence of the binary sign (roughly 20%), questioning its value as a screening marker of FD [27]. However, the higher occurrence of this sign in patients with overt cardiac involvement and advanced disease, may partially explain the discrepancies observed among studies enrolling patients with different degree of LVH [27, 28] and nowadays the presence of this sign in Fabry patients in the pre-hypertrophic stage is still unknown. In conclusion, even if the binary sign is not an “infallible diagnostic hallmark”, it may have a value in rising the suspicion of FD in the differential diagnosis of unexplained LVH.

Papillary muscles hypertrophy and hyperechogenicity have been described in FD (Fig. 2A–C) and they might contribute not only to the increased LV mass but also to the development of mitral regurgitation. Niemann et al. [29] investigated the diagnostic value of this findings in a study on 101 consecutive patients with concentric LVH of various etiologies (FD, Friedreich ataxia, isolated arterial hypertension, amyloidosis) vs healthy control subjects. Enlarged absolute papillary muscle area was evidenced in 75%, and increased PM_LV_ratio (ratio of papillary muscle size to LV circumference) was found in 78% of 28 FD patients. Nevertheless, also this sign does not allow to certainly discriminate FD from other etiologies of LVH.

Non-compaction and apical aneurisms have also been described in FD, but their meaning is not clear yet [30, 31, 32].

Unlike HCM, resting left ventricular outflow tract obstruction (LVOTO) has been rarely described in FD, and it has been long considered an exclusion criterion for FC. However, in the last years a growing number of cases of FC with LVOTO or midventricular obstruction have been described [33, 34, 35, 36, 37, 38, 39, 40]. Calcagnino et al. [38] reported a case series of FD patients with drug-refractory exertional symptoms in which exercise echocardiography revealed provocable LVOTO, caused by effort-related reduction in cavity size and papillary muscle hypertrophy. Cecchi et al. [39] firstly reported FC diagnosis whose suspicion was raised by the cardiac surgeon during surgical myectomy for obstructive hypertrophic cardiomyopathy, based on the peculiar yellowish appearance of the myocardium with spongy consistency, in patients with no other cardiac and noncardiac FD red flags. These evidences highlight the key role of exercise echocardiography to unveil latent LVOTO when a patient complaints dyspnea as well as the importance of suspecting FD even if the clinical picture suggests HCM.

We recently described the evolution over time of severe FC towards a midventricular obstructive form in 3 patients [40]. In our experience, this evolution occurred in men with the classic form, significant diagnostic delay and severe LVH before ERT initiation. We proposed that this newly described cardiac phenotype could represent an adverse outcome of the disease [40].

LV systolic function, as measured by ejection fraction (EF), is generally preserved in patients with FD until advanced stages of the disease (Fig. 3A).

Fig. 3.

Example of Fabry cardiomyopathy with normal LV ejection fraction (LVEF) but impaired indexes of longitudinal systolic function. (A) Apical four chambers view: LVEF 65% measured by biplane Simpson method; (B, C) Tissue Doppler mitral annular velocities at lateral and septal corners respectively, showing low systolic velocities (6.5 cm/s at both sides); (D) 2D speckle tracking analysis bull’s-eye plot, showing reduced LV-GLS value (–15%).

However, longitudinal systolic function [41] can be affected in the early stage of cardiac involvement (Fig. 3B–D). Most FD patients without LVH undergoing echocardiography are gene-positive patients in whom the presence of cardiac involvement needs to be addressed. The distinction between “overt Fabry cardiomyopathy” (i.e., LVH) and latent cardiac involvement represents a crucial issue with strong impact on the therapeutic management, as guidelines and recommendations on FD suggest starting ERT as soon as any evidence of organ damage is detected.

Pieroni et al. [41] compared Tissue Doppler (TD) velocities of patients with Fabry mutations plus LVH (genotype positive/phenotype positive) vs patients with Fabry mutations without LVH (genotype positive/phenotype negative) and healthy controls. They showed that both systolic and diastolic TD velocities were statistically significant lower in patients with Fabry mutation without LVH compared to healthy controls, suggesting that decreased values of both lateral and septal S’ and e’ have a high sensitivity and specificity for identifying Fabry patients without LVH. The specificity and sensibility of these findings were partially confirmed lately [42] but it is now clear that impaired TD velocities are useful to differentiate gene-carriers of hypertrophic phenotypes vs normal or athlete’s heart [43].

Strain rate imaging, a TD-derived technique, is a more sensitive tool to assess myocardial function. Weideman et al. [44] found that radial, longitudinal systolic strain and peak systolic strain rate are impaired in FD. In another study, Weidman et al. [45] found that FD patients initially show systolic strain rate abnormalities that include decreased longitudinal function, involving the lateral wall first and the septal wall after. The increase in LV wall thickness accompanies the decline in radial function . When myocardial fibrosis is detected at CMR, this is associated with progressive deterioration in longitudinal and radial function. Moreover, myocardial fibrosis correlates with the “double peak” sign, a peculiar pattern that consists of a sharp first peak in early systole, followed by a rapid fall of strain rate near zero, and finally a second peak during isovolumetric relaxation (even if this is not pathognomonic for FD) [46].

FD is characterized by coronary microvascular dysfunction (CMD) that can occur before LVH development [47] and is correlated to the severity of myocardial storage, being worst in patients with LVH [48, 49]. Stress echocardiography is rarely used in the assessment of inducible myocardial ischemia in patients with hypertrophic phenotypes, due to the low sensitivity and the potential harm of dobutamine or other stressors. However, it is worth noting that the echo finding of akinesia and thinning of the inferolateral basal wall [50, 51], often encountered in the late stages of the disease, could be due to repetitive ischemic insult from severe CMD.

Two-dimensional speckle tracking-echocardiography (STE) is a novel echocardiographic technique that has gained increasing popularity in the last years, thanks to its ability in providing objective quantification of cardiac function [52]. STE is an imaging modality based on the assessment of myocardial deformation, through the analysis of “speckles” during the cardiac cycle. STE offers additional advantages over TD, thanks to its ability to assess regional function in all myocardial segments and the reduced angle dependence of measurements [52].

LV strain impairment has been documented in FD patients in all stages of cardiac involvement, with a marked reduction of global longitudinal (GLS) (above all in basal segments) [53] and circumferential strain (CS) [54]. Studies on patients in pre-hypertrophic phase showed that LV GLS is impaired as compared to controls, and specifically an early compromission of longitudinal basal-lateral strain has been documented [55]. Labombarda et al. [56] performed a study on LV mechanics investigating base-to-apex longitudinal and CS gradient (defined as the peak gradient difference between averaged basal and apical strain) in FD patients with and without LVH, HCM and healthy controls. They found that LS gradient did not differ between FD without LVH vs controls and between FD with LVH vs HCM patients. Conversely, the CS gradient was lower in pre-hypertrophic FD compared to controls, and lower in Fabry patients with overt cardiomyopathy compared to HCM. They proposed these results as helpful to identify early myocardial involvement in FD and in the differential diagnosis of FC vs HCM. However, the value of these parameters in large real-world cohorts has yet to be determined.

Vijapurapu et al. [57] investigated the relationship of early mechanical dysfunction and sphingolipid storage by means of CMR in FD. Intriguingly, they found that in the early stage of the disease (genotype positive-LVH negative), LS impairs as native T1 reduces (i.e., areas of storage), while in FD with LVH, myocardial strain reduces with hypertrophy, storage (detected by a low T1), ECG abnormalities and scar (assessed by late gadolinium enhancement -LGE - ).

Kramer et al. [58] confirmed the link between strain and myocardial fibrosis, by finding a correlation between areas of LV strain impairment with those of LGE, suggesting that STE can be used as a tool for the indirect assessment of fibrosis in FC.

Diastolic function is commonly impaired in FC and it worsens with increasing LV wall thickness and fibrosis [9, 59]. However, restrictive pathophysiology is rarely observed, except in the most advanced stages of the disease. A possible explanation of why restrictive physiology is a feature of infiltrative disorders such as amyloidosis but not common in FD may underlie in the different pathophysiology, as amyloid deposition occurs in the interstitium, whereas glycolipid storage occurs intracellularly in FD [9].

In FD patients with or without LVH, the values and the ratio of early diastolic to late diastolic TD velocities are reduced, and the E/e’ ratio is higher compared with healthy controls [41]. Toro et al. [42] also demonstrated that isovolumetric contraction time 105 msec had an excellent capability for discriminating patients with pre-clinical stage FD, with a sensitivity of 100% and a specificity of 91%. Furthermore, strain rate during isovolemic relaxation (SRIVR), and the ratio of the peak transmitral E wave to SRIVR (E/SRIVR) demonstrated to effectively differentiate FD patients from healthy controls irrespectively of LVH, with SRIVR 0.235 sec${}^{-1}$ showing sensitivity of 94% and specificity of 92% [60].

Diastolic dysfunction seems closely linked to myocardial fibrosis in FD. Specifically, Liu et al. [61] demonstrated that septal E/e${}^{\prime }$ ratio is the best echocardiographic parameter associated with prevalence of LGE at CMR. However, as underlined by the authors, diastolic dysfunction is not a prerequisite for LGE in FD, since LGE can precede measurable functional impairments as very early marker of cardiac involvement, above all in females.

Glycolipid storage has been histologically described in atrial myocardium and this correlates with left atrial (LA) dilation, dysfunction and arrhythmias [5]. Atrial enlargement is often at most mild to moderate and the prevalence of LA enlargement is approximately 30%. In cohort studies FD patients have echocardiographic mean LA size greater than age-matched control subjects, but in some cases LA structure and function can remain relatively normal [62]. LA dilatation correlates with LV mass and myocardial fibrosis, and beyond LA myopathy also diastolic function has a role, as demonstrated by increased atrial reversal velocities and duration (i.e., increased LA pressures) [41].

Recent studies on LA speckle tracking analysis offered new insights in FD related LA functional impairment. Boyd et al. [63] demonstrated that LA volume is increased in FD patients, even in the absence of LVH. Importantly, in patients without LVH and with LA enlargement, diastolic function can be normal (E’ velocities similar to those of controls) and LA systolic strain and early diastolic strain rate are selectively lower in FD patients with LVH, reflecting reductions in LA and LV relaxation respectively, consequent to increased LV mass. However, regardless of LVH, both FD groups had significant reductions in systolic strain rate and increased LA stiffness index, suggesting that FC may not only cause LVH and fibrosis but can also alter atrial myocardial properties in the early phase of disease process. In line with these findings, Pichette et al. [64] showed reduced LA reservoir, conduit, and contractile functions manifested by decreases in peak positive and late diastolic strain by STE. In a comparative study between HCM vs FC patients, the former showed larger LA volume but both disorders had a severe decrease in LA function evaluated by means of STE. Moreover, also in the absence of significant LA dilatation, FD patients can show lower peak atrial LS compared to controls, and an inverse association between peak atrial LS and presence of central nervous system white matter lesions has been documented, suggesting a possible parallel early involvement of heart and brain [65].

All these findings support the hypothesis of an atrial myopathy, which can be independent of LVH and diastolic dysfunction.