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 ␣-index and sequence analysis. Methods and Results-The ␣-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 highest r values (rϭ.70). However, the limits of agreement calculated by means of the Bland and Altman method were wide for both noninvasive methods. Conclusions-The

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. (Circulation. 2006;114:368-376.)

Objective: The aims of this study were to determine the relationships between oscillations in systolic blood pressure and heart period at different breathing frequencies and to investigate the role of sympathetic contribution to this relationship. Methods: Fourteen healthy Ž . volunteers underwent three randomized periods of controlled breathing at 6, 10 and 16 breathsrmin. ECG RR , respiratory signal Ž . Ž . RESP and systolic blood pressure SBP were continuously recorded. and RESP, and RR and SBP RR-SBP were also assessed. When the K of RR-SBP in the respiratory band was ) 0.5, we considered the phase and calculated the closed-loop gain between the two signals. Seven subjects were also studied after chronic metoprolol treatment. Results: Although the mean values of RR and SBP did not differ between the three periods of breathing, the higher the Ž . respiratory rate, the smaller the RR and SBP . The phase was always negative SBP changes preceded RR changes , thus Resp Resp Resp Resp suggesting a baroreflex link. The higher the respiratory rate, the lower the gain and phase. Pharmacological b-adrenoceptor blockade increased the gain and shifted the phase, but the relationships found at baseline between the respiratory rate and both the gain and phase remained unchanged. Conclusions: The effect of breath rate on the relationship between heart rate and systolic pressure variabilities is a frequency-dependent phenomenon that is also independent of the sympathetic drive. q

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