Background— Brugada syndrome is associated with a high risk of sudden cardiac death and is caused by mutations in the cardiac voltage-gated sodium channel gene. Previously, the R282H-SCN5A mutation in the sodium channel gene was identified in patients with Brugada syndrome. In a family carrying the R282H-SCN5A mutation, an asymptomatic individual had a common H558R-SCN5A polymorphism and the mutation on separate chromosomes. Therefore, we hypothesized that the polymorphism could rescue the mutation. Methods and Results— In heterologous cells, expression of the mutation alone did not produce sodium current. However, coexpressing the mutation with the polymorphism produced significantly greater current than coexpressing the mutant with the wild-type gene, demonstrating that the polymorphism rescues the mutation. Using immunocytochemistry, we demonstrated that the R282H-SCN5A construct can traffic to the cell membrane only in the presence of the H558R-SCN5A polymorphism. Using fluorescence resonance energy transfer and protein fragments centered on H558R-SCN5A, we demonstrated that cardiac sodium channels preferentially interact when the polymorphism is expressed on one protein but not the other. Conclusions— This study suggests a mechanism whereby the Brugada syndrome has incomplete penetrance. More importantly, this study suggests that genetic polymorphisms may be a potential target for future therapies aimed at rescuing specific dysfunctional protein channels.

Background—Depressed baroreflex sensitivity obtained by means of a phenylephrine test plays a prognostic role in patients with a previous myocardial infarction. Our purpose was to evaluate the correlation and agreement between the baroreflex sensitivity obtained with phenylephrine and that obtained by two noninvasive methods: the α-index and sequence analysis.Methods and Results—The α-index was measured by means of the spectral analysis of RR and systolic blood pressure variabilities in both the high- and low-frequency bands; sequences were identified from simultaneously recorded time series in which the RR and systolic blood pressure concurrently increased or decreased. Noninvasive baroreflex sensitivity tests were performed during both spontaneous and controlled respiration. Fifty-two consecutive patients with recent myocardial infarction underwent the analyses. Although the correlations between phenylephrine and either of the noninvasive methods were always significant, those found during controlled respiration had the highestrvalues (r=.70). However, the limits of agreement calculated by means of the Bland and Altman method were wide for both noninvasive methods.Conclusions—The results obtained by means of noninvasive baroreflex sensitivity assessments should not be used in clinical practice as an alternative to those obtained by the phenylephrine method.

To obtain data relating to the reproducibility of the time and frequency domain measurements obtained from 10-min ECG recordings. Eighteen normal volunteers underwent evaluations of time and frequency domain heart rate variability 2 weeks and 7 months after baseline analysis. The time domain parameters were mean NN, the standard deviation of NN intervals, the percentage of successive NN intervals > 50 ms and the root mean square successive difference of NN intervals. The frequency domain evaluations (total power, low frequency, and high frequency) were made by means of both the Fast Fourier Transform algorithm (FFT) and the autoregressive method (AR) from 10-min ECG recordings made under three different conditions: rest, controlled respiration, and after a passive head-up tilt test. Reproducibility was evaluated by means of the interclass correlation coefficient (ICC), comparing baseline values with the results obtained at the second week and the seventh month. Time domain evaluation were also made from 10-min ECG. All of the time domain measurements had an ICC > or = 0.75, except for the standard deviation of NN intervals, which had an ICC of 0.57. The frequency domain parameters obtained by means of either FFT or AR showed similar reproducibility. Low frequency was reproducible under all three conditions, total power only at rest, and high frequency only during controlled respiration. The reproducibility of frequency domain parameters depends on the analysed condition. These results are of primary importance when the effects of drugs or other interventions on heart rate variability are under investigation.