196 Chapter 6 Fabry cardiomyopathy and lysoGb3 Besides the extensively studied ECG and echocardiography markers, overall disease markers can be of help to predict the disease course and aid in decision making for treatment initiation. The best plasma marker available in FD is lysoGb3 (a water-soluble deacylated form of Gb3). Of note, we have recently shown that in a single patient, plasma lysoGb3 reaches an equilibrium early in life and does not change subsequently which makes it a suitable marker of disease severity, independent of age (chapter 5). In this thesis, we connected these data and investigated the relationship between plasma lysoGb3 and cardiac morphological and functional markers, that are related to cardiac complications such as cardiovascular death, sudden cardiac death, life-threatening arrhythmias, ischemic heart disease and heart failure hospitalization in previous studies [3235]. We found that plasma lysoGb3 can accurately distinguish between men and women with classical versus non-classical FD with very high accuracy. In men with cFD, the plasma lysoGb3 is almost always above 40 nmol/L. A lysoGb3 between 2.3-40 nmol/L is found in female patients with cFD or male patients with non-classical FD. A lysoGb3 < 2.3 nmol/L is characteristic for women with non-classical FD. We found that the higher the plasma lysoGb3 level, the more severe the cardiac morphological and functional changes were. This suggests that, for example, in a female patient with cFD with a relatively low lysoGb3 level (e.g. 3.5 nmol/L), the risk for development of cardiac complications early in life is low and this can weigh in when determining the follow-up frequency and the consideration of start of Fabry specific therapy. Thus, measuring the plasma lysoGb3 and the described ECG and echo parameters can help to identify women at risk for cardiac complications within the heterogeneous group of female patients with a cFD phenotype. In the group of patients with a lysoGb3 level < 2.3 nmol/L echocardiographic markers only deviate from the static reference ranges from the seventh decade onwards. This may not differ significantly from the course in the general healthy population, once risk factors such as obesity and hypertension are taken into account. Fabry cardiomyopathy: revising guidelines to start treatment for cardiac manifestations We propose a two-track approach to detect early cardiac involvement and later deterioration in FD patients. This method would involve assessing both the rate of change and absolute values of ECG and echocardiographic markers and comparing them to reference values from the same sex and age category in healthy controls. The revision of the guidelines [13] by incorporating a composite score for the assessment of early cardiac disease in Fabry patients is proposed.
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