👤 Brittany D Brumback

Arterial stiffness is a contributor to cognitive decline. Pressure time constants (PTCs: PTC1, PTC2) are new measures of arterial compliance (inverse of stiffness) which are based on a Windkessel model of arterial pulse pressure waveforms. The methodology for PTCs is open-source and scalable. We evaluated the cross-sectional association between PTCs from radial artery pressure waveforms and cognitive performance: Global cognitive function (Cognitive Abilities Screening Instrument, CASI; score range 0-100); processing speed (Digit Symbol Coding, DSC; 0-133); and working memory (Digit Span, DS; 0-30). Among 3134 adults from 6 U.S. communities in 2010-2012 (aged 54-94 years; 47% male; 41% White, 25% Black, 23% Hispanic/Latino, 12% Chinese), the mean ± SD was 283 ± 127 ms for PTC1, 85 ± 31 ms for PTC2, 89 ± 8 for CASI, 51 ± 18 for DSC, and 15 ± 4 for DS. In the entire sample (after adjustment for community, race/ethnicity, and variables in the dementia score called "Cardiovascular Risk Factors, Aging, and Incidence of Dementia"), neither PTC1 nor PTC2 was associated with CASI, DSC, or DS. In exploratory analyses, after adjustment, one SD higher PTC2 was associated with a 1.4 (95% confidence interval: 0.4, 2.5; p = 0.004) higher mean DSC score among the subset with at least one APOE-ε4 allele (N = 828) and a 0.8 (0.1, 1.5; p = 0.03) higher mean DSC score among those 65 years and older (N = 2020). Higher radial artery PTC2 (lower arterial stiffness) was associated with faster processing speed among carriers of APOE-ε4 and older adults. Future work should investigate the association of PTCs with other indicators of brain health. Show less

Several inherited arrhythmias, including Brugada syndrome and arrhythmogenic cardiomyopathy, primarily affect the right ventricle and can lead to sudden cardiac death. Among many differences, right and left ventricular cardiomyocytes derive from distinct progenitors, prompting us to investigate how embryonic programming may contribute to chamber-specific conduction and arrhythmia susceptibility. Here, we show that developmental perturbation of Wnt signaling leads to chamber-specific transcriptional regulation of genes important in cardiac conduction that persists into adulthood. Transcriptional profiling of right versus left ventricles in mice deficient in Wnt transcriptional activity reveals global chamber differences, including genes regulating cardiac electrophysiology such as Gja1 and Scn5a. In addition, the transcriptional repressor Hey2, a gene associated with Brugada syndrome, is a direct target of Wnt signaling in the right ventricle only. These transcriptional changes lead to perturbed right ventricular cardiac conduction and cellular excitability. Ex vivo and in vivo stimulation of the right ventricle is sufficient to induce ventricular tachycardia in Wnt transcriptionally inactive hearts, while left ventricular stimulation has no effect. These data show that embryonic perturbation of Wnt signaling in cardiomyocytes leads to right ventricular arrhythmia susceptibility in the adult heart through chamber-specific regulation of genes regulating cellular electrophysiology. Show less