eliglustat-tartrate and Arrhythmias--Cardiac

Anderson Fabry disease is a life threatening, X-linked inborn metabolic defect of the lysosomal enzyme áalpha-galactosidase A. The deficiency of alpha-galactosidase A leads to a progressive accumulation of globotriaosylceramide (Gb(3)), the major glycosphingolipid substrate of the enzyme, within vulnerable cells, tissues, and organs, including the cardiovascular system. Cardiac involvement is frequent and patients with cardiac affection develop progressive hypertrophic infiltrative cardiomyopathy, valvular abnormalities, arrhythmias, and conduction abnormalities and may develop coronary heart disease. Hemizygous male patients have no detectable alpha-galactosidase A activity, while affected heterozygous females may have normal level of alpha-galactosidase A activity. Death occurs in male patients at 45 to 50 years, about 15 to 20 years earlier than in female patients due to a vicious circle from chronic renal insufficiency, arterial hypertension, atherosclerotic lesions and cerebrovascular hemorrhage or insults, and cardiomyopathy. Cardiac involvement in hetero- and hemizygotes will be discussed as well as the influence of enzyme replacement of alpha-galactosidase A.

Topics: Adult; alpha-Galactosidase; Animals; Arrhythmias, Cardiac; Biopsy; Cardiomyopathy, Hypertrophic; Cell Line; Child; Clinical Trials as Topic; Coronary Disease; Cricetinae; Diagnosis, Differential; Echocardiography; Electrocardiography; Endocardium; Enzyme Therapy; Fabry Disease; Female; Galactose; Heart Diseases; Heart Failure; Heart Valve Diseases; Humans; Hypertrophy, Left Ventricular; Incidence; Infant, Newborn; Infusions, Intravenous; Isoenzymes; Magnetic Resonance Imaging; Male; Middle Aged; Mitral Valve Prolapse; Myocardium; Sex Factors; Smoking

In patients with Fabry disease (FD), left ventricular hypertrophy and arrhythmias are frequently observed and cardiac involvement is the leading cause of death. Long-term efficacy of enzyme replacement therapy (ERT) on cardiac involvement is unclear. We assessed and compared long-term progression of cardiac involvement according to ERT and non-ERT.. We retrospectively assessed and compared long-term progression of cardiac involvement in adult patients with FD in the nationwide Danish cohort. We followed clinical signs, symptoms and findings by echocardiography, electrocardiography and Holter-monitoring.. We included 66 patients; 47 patients (27 women) received ERT (ERT group) and 19 patients (15 women) did not (non-ERT group). The groups were followed for a median of 8 [0-12] years and 6 [0-13] years, respectively. Comparison between ERT and non-ERT receiving patients by left ventricular mass (echocardiographic assessment) and Sokolow-Lyon voltage- and Cornell product criteria (electrocardiographic assessment) revealed no significant differences. In the ERT group, we observed no change in left ventricular mass but a decrease in Sokolow-Lyon voltage- and Cornell product criteria from baseline to follow-up; 30 mm [15-53] vs. 25 mm [3-44], p < 0.005 and 1710 mm·ms [480-3740] vs. 1520 mm·ms [550-5740], p < .05, respectively. There were no changes within the non-ERT group. During follow-up, cardiac symptoms and use of cardiovascular procedures and -medication increased significantly in the ERT group, whereas no differences were observed within the non-ERT group.. We raise concerns regarding the efficacy and benefit of ERT on cardiac involvement in Fabry disease and stress the need for further research.

Topics: Adolescent; Adult; Aged; alpha-Galactosidase; Arrhythmias, Cardiac; Denmark; Disease Progression; Echocardiography; Electrocardiography, Ambulatory; Enzyme Replacement Therapy; Fabry Disease; Female; Humans; Hypertrophy, Left Ventricular; Isoenzymes; Male; Middle Aged; Predictive Value of Tests; Retrospective Studies; Time Factors; Treatment Outcome; Young Adult

Fabry disease is an inherited lysosomal storage disorder caused by deficiency of the enzyme alpha-galactosidase A. The enzyme deficiency results in accumulation of glycosphingolipids in the lysosomes n nearly all cell types and tissues leading to a multisystem disease. MANIFESTATIONS include painful crisis, angiokeratomas, corneal dystrophy, and hypohydrosis. The severe renal, cerebrovascular, and cardiac involvement is predominantly responsible for premature mortality in Fabry patients. The disease is X-linked and manifests primarily in hemizygous males but also heterozygous females can be affected. CARDIAC INVOLVEMENT is frequent in Fabry disease. Patients develop hypertrophic cardiomyopathy, arrhythmias, conduction abnormalities, and valvular abnormalities. Although Fabry disease leads to a complex clinical syndrome, there are studies indicating that manifestations can be limited to the heart. The isolated cardiac variant of Fabry disease seems to be more common than previously thought: around 3-6% of male patients with left ventricular hypertrophy seem to suffer from this disease variant.. Recent advances in molecular biology and genetic engineering have enabled the development of enzyme replacement therapy in Fabry disease. Results from two independent therapy studies are indeed promising: Infusion of the enzyme preparation seems to be well tolerated and effective in catabolizing the lipid deposits. This enzyme replacement therapy could be one of the first examples for causal treatment of left ventricular hypertrophy. Therefore, early diagnosis of hypertrophy patients with the cardiac variant of Fabry disease is important.

Topics: Adolescent; Adult; alpha-Galactosidase; Angina Pectoris; Animals; Arrhythmias, Cardiac; Cardiomyopathy, Hypertrophic; Cell Line; Child; Cricetinae; Diagnosis, Differential; Electrocardiography; Fabry Disease; Female; Genetic Engineering; Heart Diseases; Heart Valve Diseases; Heterozygote; Homozygote; Humans; Hypertrophy, Left Ventricular; Isoenzymes; Male; Randomized Controlled Trials as Topic; Sex Factors; Time Factors