Voltage-Gated Ion Channel Dysfunction Precedes Cardiomyopathy Development in the Dystrophic Heart

Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is associated with severe cardiac complications including cardiomyopathy and cardiac arrhythmias. Recent research suggests that impaired voltage-gated ion channels in dystrophic cardiomyocytes accompany cardiac pathology. It is, however, unknown if the ion channel defects are primary effects of dystrophic gene mutations, or secondary effects of the developing cardiac pathology.To address this question, we first investigated sodium channel impairments in cardiomyocytes derived from dystrophic neonatal mice prior to cardiomyopahty development, by using the whole cell patch clamp technique. Besides the most common model for DMD, the dystrophin-deficient mdx mouse, we also used mice additionally carrying an utrophin mutation. In neonatal cardiomyocytes, dystrophin-deficiency generated a 25% reduction in sodium current density. In addition, extra utrophin-deficiency significantly altered sodium channel gating parameters. Moreover, also calcium channel inactivation was considerably reduced in dystrophic neonatal cardiomyocytes, suggesting that ion channel abnormalities are universal primary effects of dystrophic gene mutations. To assess developmental changes, we also studied sodium channel impairments in cardiomyocytes derived from dystrophic adult mice, and compared them with the respective abnormalities in dystrophic neonatal cells. Here, we found a much stronger sodium current reduction in adult cardiomyocytes. The described sodium channel impairments slowed the upstroke of the action potential in adult cardiomyocytes, and only in dystrophic adult mice, the QRS interval of the electrocardiogram was prolonged.Ion channel impairments precede pathology development in the dystrophic heart, and may thus be considered potential cardiomyopathy triggers

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large‐scale studies. In response, we used cross‐sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) Consortium to infer age‐related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta‐analysis and one‐way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3–90 years

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) Consortium to examine age‐related trajectories inferred from cross‐sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3–90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter‐individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age‐related morphometric patterns

Calcium channel properties in wt and dystrophic neonatal cardiomyocytes.

<p><b>A.</b> Original barium current traces (five episodes displayed) of a wt and mdx-utr cardiomyocyte, elicited by the pulse protocol on top. The prepulse was used to eliminate currents through T-type calcium channels. <b>B.</b> Current-voltage relationships derived from a series of experiments on wt and dystrophic cardiomyocytes as shown in A. <b>C.</b> Comparison of the current decay kinetics between wt and dystrophic cardiomyocytes at various membrane voltages. τ –values were derived from single exponential fits of the current decay after channel activation. * indicates a significant difference (ANOVA, p<0.05) between the three tested groups. Tukey's Post Hoc test revealed a significant difference (p<0.05) between mdx-utr and wt, but not between mdx-utr and mdx. <b>D.</b> Voltage-dependency of steady-state inactivation in wt and dystrophic cardiomyocytes. For n-values see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020300#pone-0020300-t001" target="_blank">Table 1</a>.</p

Sodium channel properties in wt and dystrophic adult cardiomyocytes.

<p><b>A.</b> Original current traces of a typical wt, mdx, and mdx-utr cardiomyocyte, elicited by the pulse protocol in B. <b>B.</b> Current-voltage relationships derived from a series of experiments as shown in A. <b>C.</b> Maximum current densities in wt and dystrophic cardiomyocytes. *** indicates that ANOVA revealed a significant difference (p<0.001) between the three tested groups. <b>D.</b> Comparison of the voltage-dependencies of activation and steady-state inactivation between wt and dystrophic cardiomyocytes. For detailed statistics and n-values see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020300#pone-0020300-t001" target="_blank">Table 1</a>.</p