Plasma Globotriaosylsphingosine Level as a Primary Screening Target for Fabry Disease in Patients With Left Ventricular Hypertrophy.

BACKGROUND: Although previous studies have suggested a certain prevalence of Fabry disease (FD) in left ventricular hypertrophy (LVH) patients, the screening of FD is difficult because of its wide-ranging clinical phenotypes. We aimed to clarify the utility of combined measurement of plasma globotriaosylsphingosine (lyso-Gb3) concentration and α-galactosidase A activity (α-GAL) as a primary screening of FD in unexplained LVH patients.Methods and Results:Between 2014 and 2016, both lyso-Gb3 and α-GAL were measured in 277 consecutive patients (male 215, female 62, age 25-79 years) with left ventricular wall thickness >12 mm on echocardiogram: 5 patients (1.8%) screened positive (2 (0.7%) showed high lyso-Gb3 and 4 (1.4%) had low α-GAL levels). Finally, 2 patients (0.7%) were diagnosed with clinically significant FD. In 1 case, a female heterozygote with normal α-GAL levels had genetic variants of unknown significance and was diagnosed as FD by endomyocardial biopsy. The other case was a male chronic renal failure patient requiring hemodialysis, and he had a p.R112H mutation. In both cases there were high lyso-Gb3 levels. CONCLUSIONS: The serum lyso-Gb3 level can be relevant for clinically significant FD, and combined measurement of lyso-Gb3 and α-GAL can provide better screening of FD in unexplained LVH patients.

Different effects of palmitoyl-L-carnitine and palmitoyl-CoA on mitochondrial function in rat ventricular myocytes.

Although mitochondrial oxidative catabolism of fatty acid (FA) is a major energy source for the adult mammalian heart, cardiac lipotoxity resulting from elevated serum FA and enhanced FA use has been implicated in the pathogenesis of heart failure. To investigate the effects of intermediates of FA metabolism [palmitoyl-l-carnitine (Pal-car) and palmitoyl-CoA (Pal-CoA)] on mitochondrial function, we measured membrane potential (DeltaPsi(m)), opening of the mitochondrial permeability transition pore (mPTP), and the production of ROS in saponin-treated rat ventricular myocytes with a laser scanning confocal microscope. Our results revealed that 1) lower concentrations of Pal-car (1 and 5 muM) caused a slight hyperpolarization of DeltaPsi(m) [tetramethylrhodamine ethyl ester (TMRE) intensity increased to 115.5 +/- 5.4% and 110.7 +/- 1.6% of baseline, respectively, P < 0.05] but did not open the mPTP, 2) a higher concentration of Pal-car (10 microM) depolarized DeltaPsi(m) (TMRE intensity decreased to 61.9 +/- 12.2% of baseline, P < 0.01) and opened the mPTP (calcein intensity decreased to 70.7 +/- 2.8% of baseline, P < 0.01), 3) Pal-CoA depolarized DeltaPsi(m) without opening the mPTP, and 4) only the higher concentration of Pal-car (10 muM) increased ROS generation (2',7'-dichlorofluorescein diacetate intensity increased to 3.4 +/- 0.3-fold of baseline). We concluded that excessive exogenous intermediates of long-chain saturated FA may disturb mitochondrial function in different ways between Pal-car and Pal-CoA. The distinct mechanisms of the deteriorating effects of long-chain FA on mitochondrial function are important for our understanding of the development of cardiac diseases in systemic metabolic disorders.