Risk of Death in Heart Disease is Associated With Elevated Urinary Globotriaosylceramide

BACKGROUND: Elevated urinary globotriaosylceramide (Gb(3)) has been considered a hallmark of Fabry disease, an X‐linked lysosomal disorder that is a risk factor for most types of heart disease. METHODS AND RESULTS: We screened 1421 consecutive patients with common forms of heart disease for Fabry disease by measuring urinary Gb(3) in whole urine using tandem mass spectrometry, α‐galactosidase A activity in dried blood spots, and we looked for GLA mutations by parallel sequencing of the whole gene (exons and introns) in pooled genomic DNA samples followed by Sanger sequencing verification. GLA variants were found in 13 patients. In the 1408 patients without GLA mutations, urinary Gb(3) levels were significantly higher in heart disease patients compared to 116 apparently healthy controls (median difference=10.0 ng/mL and P<0.001). Urinary lipid profiling showed that levels of 5 other lipids significantly distinguished between urine of patients with Fabry disease (n=7) and heart disease patients with elevated urinary Gb(3) (n=6). Sphingomyelin and Gb(3) levels were abnormal in the left ventricular wall of patients with ischemic heart failure. Elevated levels of urinary Gb(3) were independently associated with increased risk of death in the average follow‐up of 17 months (hazard ratio=1.59 for increase in Gb(3) of 200, 95% CI=1.36 and 1.87, and P<0.0001). CONCLUSIONS: In heart disease patients who do not have Fabry disease or GLA gene mutations, a higher level of urinary Gb(3) is positively associated with near‐term mortality. The elevation of urinary Gb(3) and that of other lipids suggests that heart disease is associated with multiorgan lipid abnormalities. CLINICAL TRIAL REGISTRATION: URL: clinicaltrials.gov. Unique Identifier: NCT01019629.