Caren Swift

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. Methods and 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. Clinical Trial Registration URL: clinicaltrials.gov. Unique Identifier: NCT01019629.

Quantitative neuroimaging in mucolipidosis type IV

Mucolipidosis type IV (MLIV) is an autosomal recessive disorder resulting from mutations in the MCOLN1 gene. This gene encodes the endosomal/lysosomal transient receptor potential channel protein mucolipin-1 (TRPML1). Affected patients suffer from neurodevelopmental abnormalities and progressive retinal dystrophy. In a prospective natural history study we hypothesized the presence of an additional slow cerebral neurodegenerative process. We have recruited 5 patients, tested their neurodevelopmental status, and measured cerebral regional volumes and white matter integrity using MRI yearly. Over a period of up to 3 years, MLIV patients remained neurologically stable. There was a trend for increased cortical and subcortical gray matter volumes and increased ventricular size, while white matter and cerebellar volumes decreased. Mean diffusivity (MD) was increased and fractional anisotropy (FA) values were below normal in all analyzed brain regions. There was a positive correlation between motor scores of the Vineland Scale and the FA values in the corticospinal tract (corr coef 0.39), and a negative correlation with the MD values (corr coef -0.50) in the same brain region. We conclude from these initial findings that deficiency in mucolipin-1 affects the entire brain but that there might be a selective regional cerebral neurodegenerative process in MLIV. In addition, these data suggest that diffusion-weighted imaging might be a good biomarker for following patients with MLIV. Therefore, our findings may be helpful for designing future clinical trials.

Oxidative stress reflected by increased F2-isoprostanes is associated with increasing urinary 11-dehydro thromboxane B2 levels in patients with coronary artery disease

Acetylsalicylic acid (ASA, aspirin) iswidely prescribed as an aid in primary and secondary prevention of coronary artery disease (CAD) as it inhibits N95% of platelet cyclooxygenase-1 (COX-1) activity, reducing the production of thromboxane A2 (TxA2) [1]. However, the non-platelet inflammatory COX-2 pathway remains active minimally affected by ASA. Based on the clinical development of complications or on laboratory tests, an inadequate response to ASA has been referred to as “aspirin resistance” [2] which is associatedwith increased risk of adverse outcomes [3]. Oxidative stress has been recently recognized as a relevant underlying mechanism to explain incomplete ASA response. Along with the enzymatic pathways (COX-1; COX-2), there is a non-enzymatic arachidonic acid pathway that produces F2-isoprostanes by oxidative stress damage which candirectly activate platelets by stimulating platelet thromboxane prostanoid receptors (TPR) [4] and is not affected by ASA [5]. 8isoprostaglandin-F2α (8-isoPGF2α) is considered a reliable laboratory biomarker of in vivo oxidative stress and a reliable noninvasive

Prognostic value of urinary 11‐dehydro‐thromboxane B2 for mortality: A cohort study of stable coronary artery disease patients treated with aspirin

There is a variable cardiovascular risk reduction attributable to aspirin because of individual differences in the suppression of thromboxane A2 and its downstream metabolite 11‐dehydro‐thromboxane B2 (11dhTxB2). The aim of this study is to evaluate the optimal cut point of urinary 11dhTxB2 for the risk of mortality in aspirin‐treated coronary artery disease (CAD) patients.