Everything should be made as simple as possible, but not simpler. —Albert Einstein

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by deficient activity of the enzyme α-galactosidase A. It is characterized by severe systemic involvement that ultimately leads to major organ failure and premature death in affected men and women. In fact, although FD was initially considered an X-linked recessive disorder, it is now widely accepted that heterozygous female patients can be severely affected. Although progression of the disease to organ failure generally occurs later in life, and symptom severity tends to be milder and more variable than in male patients, clinical manifestations in female carriers may range from a relative asymptomatic condition to severe symptoms manifesting in childhood and adolescence, resembling those observed in affected male patients.

The enzymatic deficit results in progressive intracellular accumulation of glycosphingolipids (mainly globotriaosylceramide [Gb3]) in different organs, including the heart, skin, kidneys, vessels, and peripheral and central nervous system. Storage of Gb3 occurs in all types of cardiac cells, including cardiomyocytes, conduction system cells, valvular fibroblasts, endothelial cells within all types of vessels, and vascular smooth muscle cells.

Cardiac involvement is characterized by progressive thickening of the cardiac walls, mimicking hypertrophic cardiomyopathy. Left ventricular hypertrophy (LVH) is usually concentric, but asymmetric hypertrophy has also been reported. Moreover, in the so-called cardiac variant of FD, the heart can be the organ solely or mainly involved. Recent studies based on the results of enzymatic screening in large series of male patients with diagnoses of hypertrophic cardiomyopathy have found a prevalence of FD ranging from 1% to 3%. Cardiac wall thickening represents the main consequence of Gb3 storage inside cardiomyocytes, although it has been recently demonstrated that Gb3 storage by itself appears unable to explain the degree of cardiac hypertrophy observed, suggesting that storage induces progressive cellular malfunctioning that may activate common signaling pathways, leading to hypertrophy, apoptosis, necrosis, and then fibrosis. From a pathophysiologic point of view, the main consequence of LVH is represented by diastolic dysfunction, while systolic dysfunction may occur in advanced stages of the disease.

In recent years, FD has been increasingly diagnosed by cardiologists, in particular since enzyme replacement therapy (ERT) became available in 2001, after the demonstration in randomized trials of its efficacy and safety in adults and children. However, after initial enthusiasm for a new specific therapy for a rare disorder, accumulating evidence suggested that the replacement of the defective enzyme would be much more effective if administered earlier in the course of the disease. In particular, a recent study based on cardiac magnetic resonance (CMR) findings demonstrated that in patients without fibrosis at baseline, ERT resulted in a significant reduction in left ventricular mass with an improvement in myocardial function (measured as systolic radial strain rate), while in contrast, patients with mild or severe fibrosis showed minor reductions in LVH and no improvement in myocardial function or exercise capacity. This study introduced the notion that ERT should be started before myocardial fibrosis develops to obtain long-term improvement in terms of cardiac morphology and function.

Accordingly, the early diagnosis of cardiac involvement has become a crucial issue in the management of patients with FD because in many cases, the detection of subclinical cardiac involvement may represent the first sign of organ damage, particularly in female carriers or male patients with prevalent or isolated cardiac involvement. In recent years, Doppler tissue imaging (DTI) has emerged as an important tool for the early detection of cardiac involvement. In 2003, it was demonstrated that Fabry cardiomyopathy is characterized by reduced myocardial contraction and relaxation velocities, measured using DTI, and that such abnormalities are detectable before the development of LVH and alterations of traditional echocardiographic parameters of diastolic function, thus providing a preclinical diagnosis of cardiac involvement. In that study, the gold standard for the diagnosis of cardiac involvement was represented by histologic and ultrastructural findings obtained through endomyocardial biopsy in all patients with LVH and in six of 10 patients with no LVH but presenting with cardiac symptoms. The role of DTI and DTI-derived techniques was further confirmed by Weidemann et al. in a subsequent study, showing that regional strain rate imaging detects functional changes at an early stage, preceding LVH, in patients with FD. Besides their clinical relevance, these studies also introduced the notion of cardiac involvement before overt LVH and fibrosis were evident. In fact, in FD it is important to distinguish between cardiomyopathy and cardiac involvement. The classical definition of cardiomyopathy requires the presence of some structural changes altering cardiac function, which in FD are represented by LVH and/or late enhancement (LE) seen using CMR imaging. On the other hand, these studies demonstrated that cardiac involvement, intended as the accumulation of glycosphingolipids inside cardiomyocytes, is already present, and detectable by DTI and strain rate imaging, before evident cardiomyopathy. The distinction between Fabry cardiomyopathy and cardiac involvement in FD is not just a semantic or technical one but a distinction that has an important impact on the therapeutic approach, because many national and international guidelines and recommendations on FD suggest starting ERT as soon as any evidence of organ damage is detected, either clinically or by diagnostic testing, including DTI and strain rate abnormalities among the markers of early organ damage.

With regard to the causes of early diastolic and systolic dysfunction before overt cardiac hypertrophy and fibrosis, these have been explained by in vitro studies that documented myofilament degradation and dysfunction of human cardiomyocytes isolated from endomyocardial biopsies of male patients with FD. Although this study was limited to a restricted population consisting only of male patients with advanced disease (massive LVH and evidence of LE on CMR), the evidence of a significant reduction of both active and passive force of isolated myocytes, and mostly the significant correlation between the in vitro measurements and the reduction of shortening and lengthening velocities recorded by pulsed-wave DTI, clearly demonstrated that glycosphingolipid storage inside myocytes determines profound structural and functional changes, leading to cardiac dysfunction independently from fibrosis. In fact, at variance with CMR LE findings, fibrosis did not appear extensive at morphometric studies performed on endomyocardial biopsies. In this regard, it should be remembered that LE reflects an extracellular expansion (whatever the cause) that does not necessarily denote myocardial fibrosis. In particular in FD, an assessment of the histologic substrate of LE has never been systematically performed, and therefore the causes and the significance of the typical localization of LE in the midwall layer of basal posterolateral segment are still largely unexplained. Therefore, the role of myocardial fibrosis in determining diastolic dysfunction, as well as the recent observation of LE in female carriers with no evidence of LVH, should be interpreted with caution.