Risk of death in heart disease is associated with elevated urinary globotriaosylceramide.
BACKGROUND
Elevated urinary globotriaosylceramide (Gb3) has been considered a hallmark of Fabry disease, an X-linked lysosomal disorder that is a risk factor for most types of heart disease.


RESULTS
We screened 1421 consecutive patients with common forms of heart disease for Fabry disease by measuring urinary Gb3 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 Gb3 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 Gb3 (n=6). Sphingomyelin and Gb3 levels were abnormal in the left ventricular wall of patients with ischemic heart failure. Elevated levels of urinary Gb3 were independently associated with increased risk of death in the average follow-up of 17 months (hazard ratio=1.59 for increase in Gb3 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 Gb3 is positively associated with near-term mortality. The elevation of urinary Gb3 and that of other lipids suggests that heart disease is associated with multiorgan lipid abnormalities.


BACKGROUND
clinicaltrials.gov. Unique Identifier: NCT01019629.
Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX.
Raphael
R
Schiffmann
Sabrina
S
Forni
Caren
C
Swift
Nastry
N
Brignol
Xiaoyang
X
Wu
David J
DJ
Lockhart
Derek
D
Blankenship
Xuan
X
Wang
Paul A
PA
Grayburn
Matthew R G
MR
Taylor
Brian D
BD
Lowes
Maria
M
Fuller
Elfrida R
ER
Benjamin
Lawrence
L
Sweetman
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000652:urine; D016022:Case-Control Studies; D004796:Clinical Enzyme Tests; D004252:DNA Mutational Analysis; D000795:Fabry Disease / Q000150:complications / Q000175:diagnosis / Q000235:genetics / Q000401:mortality* / Q000652:urine*; D005260:Female; D006331:Heart Diseases / Q000175:diagnosis / Q000209:etiology / Q000401:mortality* / Q000652:urine*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D053719:Tandem Mass Spectrometry; D014281:Trihexosylceramides / Q000652:urine*; D015854:Up-Regulation; D000519:alpha-Galactosidase / Q000097:blood / Q000235:genetics
D015415:Biomarkers; D014281:Trihexosylceramides; C018549:globotriaosylceramide; C576330:GLA protein, human; D000519:alpha-Galactosidase
globotriaosylceramide; heart disease; risk factor; sphingolipids