MATERIALS AND METHODS: Atrial arrhythmogenesis was investigated in Langendorff-perfused young (3-4 month) and aged (>12 month), wild type (WT) and peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β-/-) murine hearts modeling age-dependent chronic mitochondrial dysfunction during regular pacing and programmed electrical stimulation (PES).
RESULTS AND DISCUSSION: The Pgc-1β-/- genotype was associated with a pro-arrhythmic phenotype progressing with age. Young and aged Pgc-1β-/- hearts showed compromised maximum action potential (AP) depolarization rates, (dV/dt)max, prolonged AP latencies reflecting slowed action potential (AP) conduction, similar effective refractory periods and baseline action potential durations (APD90) but shortened APD90 in APs in response to extrasystolic stimuli at short stimulation intervals. Electrical properties of APs triggering arrhythmia were similar in WT and Pgc-1β-/- hearts. Pgc-1β-/- hearts showed accelerated age-dependent fibrotic change relative to WT, with young Pgc-1β-/- hearts displaying similar fibrotic change as aged WT, and aged Pgc-1β-/- hearts the greatest fibrotic change. Mitochondrial deficits thus result in an arrhythmic substrate, through slowed AP conduction and altered repolarisation characteristics, arising from alterations in electrophysiological properties and accelerated structural change.
STUDY DESIGN: Diagnostic cross-sectional study.
METHODS: This study included consecutive CRS patients without prior sinus surgery. Computed tomography (CT) scans of the paranasal sinuses were blindly assessed and allergy status was confirmed by serum or skin testing. Individual sinus cavities were defined as either centrally limited or diffuse disease. The radiological pattern that may predict allergy was determined, and its diagnostic accuracy was calculated.
RESULTS: One hundred twelve patients diagnosed to have CRS, representing 224 sides, were assessed (age 46.31 ± 13.57 years, 38.39% female, 41.07% asthma, Lund-Mackay CT score 15.88 ± 4.35, 56.25% atopic). The radiological pattern defined by centrally limited changes in all of the paranasal sinuses was associated with allergy status (73.53% vs. 53.16%, P = .03). This predicted atopy with 90.82% specificity, 73.53% positive predictive value, likelihood positive ratios of 2.16, and diagnostic odds ratio of 4.59.
CONCLUSIONS: A central radiological pattern of mucosal disease is associated with inhalant allergen sensitization. This group may represent a CCAD subgroup of patients with mainly allergic etiology.
LEVEL OF EVIDENCE: 3b Laryngoscope, 128:2015-2021, 2018.
METHODS: We designed a 32-SNP panel for PGx testing in clinical laboratories. The variants were selected using the clinical annotations of the Pharmacogenomics Knowledgebase (PharmGKB) and include polymorphisms of CYP2C9, CYP2C19, CYP2D6, CYP3A5 and VKORC1 genes. The CYP2D6 gene allele quantification was determined simultaneously with TaqMan copy number assays targeting intron 2 and exon 9 regions. The genotyping results showed high call rate accuracy according to concordance with genotypes identified by independent analyses on Sequenome massarray and droplet digital PCR. Furthermore, 506 genomic samples across three major ethnic groups of Singapore (Malay, Indian and Chinese) were analysed on our workflow.
RESULTS: We found that 98% of our study subjects carry one or more CPIC actionable variants. The major alleles detected include CYP2C9*3, CYP2C19*2, CYP2D6*10, CYP2D6*36, CYP2D6*41, CYP3A5*3 and VKORC1*2. These translate into a high percentage of intermediate (IM) and poor metabolizer (PM) phenotypes for these genes in our population.
CONCLUSION: Genotyping may be useful to identify patients who are prone to drug toxicity with standard doses of drug therapy in our population. The simplicity and robustness of this PGx panel is highly suitable for use in a clinical laboratory.