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BACKGROUND: Deleterious mutations in KCNQ1 may lead to an autosomal dominant form of long QT syndrome (LQTS) (Romano-Ward) or autosomal recessive form (Jervell and Lange-Nielsen). Both are associated with severe ventricular tachyarrhythmias due to the reduction of the slowly activating delayed rectifier K+ current (IKs). Our objective was to investigate the functional consequences of KCNQ1-R562S mutation in an atypical form of KCNQ1-linked LQTS. METHODS: Mutant KCNQ1-R562S was analyzed via confocal imaging, surface biotinylation assays, co-immunoprecipitation, phosphatidylinositol-4,5-bisphosphate pulldown test, whole-cell patch clamp, and computational intrinsic disorder analyses. RESULTS: Protein expression, assembly with KCNE1, and trafficking to the surface membrane of KCNQ1-R562S were comparable with wild-type channels. The most significant functional effect of the R562S mutation was a depolarizing shift in the voltage dependence of activation that was dependent on association with KCNE1. The biophysical abnormality was only partially dominant over coexpressed wild-type channels. R562S mutation impaired C-terminal association with membrane phosphatidylinositol-4,5-bisphosphate. These changes led to compromised rate-related accumulation of repolarizing current that is an important property of normal IKs. CONCLUSIONS: KCNQ1-R562S mutation reduces effective IKs due to channel gating alteration with a mild clinical expression in the heterozygous state due to minimal dominant phenotype. In the homozygous state, it is exhibited with a moderately severe LQTS phenotype due to the incomplete absence of IKs.

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Implantable cardioverter defibrillators (ICDs) have been demonstrated to improve survival for both primary and secondary prevention of sudden cardiac arrest. However, studies suggest that ICD therapy is underused in appropriate candidates. Sex and racial disparities in ICD use have been suggested. We sought to characterize the referral patterns of high-risk patients for the primary prophylaxis of sudden cardiac arrest at a tertiary academic medical center serving a diverse population in an urban US setting. Electronic hospital databases were retrospective reviewed for patients meeting criteria for prophylactic ICD implantation. We evaluated the association of gender, age, race, and primary language with the referral and subsequent implantation of an ICD. We identified 1,055 patients satisfying prophylactic ICD criteria: 600 men, mean age 62.6 years, 27.6% black, 19.3% white, 23.3% Hispanic, and 49.8% primary language of English. Of the 673 patients (63.7%) referred for ICD evaluation, 345 underwent implantation, 125 declined, and 203 had significant co-morbidities that precluded implantation. Gender, race, and primary language were not associated with referral for ICD or with decision to proceed with implantation. Patients of increased age were less likely to be referred for ICD and were more likely to refuse implantation. ICD therapy was not considered in 146 patients eligible for prophylactic implantation. In conclusion, referral rates for ICD consideration were higher at our institution than in previous reports. Nonetheless, 14% of appropriate patients were not considered. This argues for the importance of increased education for patients and referring physicians.

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BACKGROUND: Newer three-dimensional imaging technologies provide insight into cardiac shape and geometry from views previously unobtainable. Standard formulae like the continuity equation (CE) that rely on inherent assumptions about left ventricular outflow tract (LVOT) shape may need to be revisited. In the CE, small changes in LVOT diameter may significantly change calculated aortic valve area (AVA). Using 64-slice Multi-detector CT (MDCT), we performed LVOT planimetry to obviate the need for any geometric assumptions. METHODS: 64-slice MDCT was performed in 30 consecutive patients. The diameter-derived LVOT area (ALVOTdiam) was calculated from a view analogous to the 2D echo parasternal long axis. Direct planimetry of the LVOT (ALVOTplan) was performed just beneath the aortic valve in a plane perpendicular to the LVOT long axis. Further, assuming an ellipsoid outflow tract shape, LVOT area (ALVOTellip) was calculated using piab from the long and short diameters of the planimetered LVOT view. Eccentricity index (EI) was estimated by subtracting the ratio of shortest and longest LVOT diameters from one. RESULTS: ALVOTdiam always measured smaller than ALVOTplan (mean 3.7 +/- 1.2 cm2 vs. 4.1 +/- 1.3 cm2, respectively). The median EI was 0.18 (95% CI = 0.16-0.2; P = 0.0001). ALVOTellip more closely agreed with ALVOTplan (correlation = 0.96; P < 0.0001) than did ALVOTdiam (correlation = 0.87; P < 0.0001). CONCLUSION: Using MDCT, the LVOT was shown to be elliptical in most patients. Applying the CE which assumes roundness of the LVOT consistently underestimated the LVOT area which may affect estimated AVA. Planimetry of the LVOT utilizing three-dimensional imaging modalities such as 3-D echocardiography, MRI, or MDCT may render a more precise AVA.

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