A Heterozygous Deletion Mutation in the Cardiac Sodium Channel Gene SCN5A with Loss- and Gain-of-Function Characteristics Manifests as Isolated Conduction Disease, without Signs of Brugada or Long QT Syndrome.

BACKGROUND: The SCN5A gene encodes for the α-subunit of the cardiac sodium channel NaV1.5, which is responsible for the rapid upstroke of the cardiac action potential. Mutations in this gene may lead to multiple life-threatening disorders of cardiac rhythm or are linked to structural cardiac defects. Here, we characterized a large family with a mutation in SCN5A presenting with an atrioventricular conduction disease and absence of Brugada syndrome. METHOD AND RESULTS: In a large family with a high incidence of sudden cardiac deaths, a heterozygous SCN5A mutation (p.1493delK) with an autosomal dominant inheritance has been identified. Mutation carriers were devoid of any cardiac structural changes. Typical ECG findings were an increased P-wave duration, an AV-block I° and a prolonged QRS duration with an intraventricular conduction delay and no signs for Brugada syndrome. HEK293 cells transfected with 1493delK showed strongly (5-fold) reduced Na(+) currents with altered inactivation kinetics compared to wild-type channels. Immunocytochemical staining demonstrated strongly decreased expression of SCN5A 1493delK in the sarcolemma consistent with an intracellular trafficking defect and thereby a loss-of-function. In addition, SCN5A 1493delK channels that reached cell membrane showed gain-of-function aspects (slowing of the fast inactivation, reduction in the relative fraction of channels that fast inactivate, hastening of the recovery from inactivation). CONCLUSION: In a large family, congregation of a heterozygous SCN5A gene mutation (p.1493delK) predisposes for conduction slowing without evidence for Brugada syndrome due to a predominantly trafficking defect that reduces Na(+) current and depolarization force

Gender disparities in cardiac cellular electrophysiology and arrhythmia susceptibility in human failing ventricular myocytes

Gender disparities in ECG variables and susceptibility to arrhythmia exist. The basis of these sex-related distinctions in cardiac electrophysiology has been extensively studied in various species, but is virtually unexplored in humans. The aim of this study was to clarify the cellular basis of electrophysiological gender disparities in human cardiac myocytes. Human midmyocardial left ventricular myocytes were isolated from explanted hearts of male and female patients in end-stage heart failure at the time of cardiac transplantation. The action potentials, sarcolemmal ion currents, and susceptibility to the generation of early afterdepolarizations were studied using whole-cell patch-clamp methodology. The functional effects of gender disparities in sarcolemmal ion currents were assessed by computer simulations using the Priebe-Beuckelmann or the ten Tusscher-Noble-Noble-Panfilov human ventricular cell models. Female myocytes had significantly longer action potentials and greater susceptibility to early afterdepolarizations than male myocytes. All other action potential parameters (resting membrane potential, amplitude, plateau level, upstroke velocity, maximal velocity of phase-1 and phase-3 repolarization) had similar values for both genders. In female myocytes, the transient outward potassium current (I(to1)) tended to be smaller, while the L-type calcium current (I(Ca,L)) and quasi-steady state current (I(QSS)) tended to be larger. Computer simulations showed that these subtle differences in sarcolemmal ion currents may conspire to cause the observed gender disparities in action potential properties. Female failing myocytes have longer action potentials and a greater susceptibility to early afterdepolarizations than male failing myocytes. These gender disparities may be due to slightly larger depolarizing I(Ca,L) in conjunction with slightly smaller repolarizing I(QSS) and I(to1) in female myocyte

Paleoerosion rates from cosmogenic 10be in a 1.3 Ma terrace sequence: response of the Meuse to changes in climate and rock uplift

River-borne quartz carries a cosmogenic nuclide memory that is a function of the catchment-wide erosion rate. This record may be preserved in fluvial deposits such as river terraces. If the age of a terrace is independently known and transport time in the river system is relatively short, then the upstream erosion rate at the time of terrace deposition can be determined. We have used cosmogenic nuclides to date river terraces in the lower Meuse catchment, the Netherlands, and to obtain a 1.3 Ma record of paleoerosion rates in a 10(4)-km(2) drainage basin comprising the Ardennes Mountains. Paleoerosion rates were uniform within the range of 25-35 mm/ka from 1.3 to 0.7 Ma. After 0.7 Ma, erosion rates have increased progressively to Late Pleistocene values of around 80 mm/ka. Around 0.7 Ma, both climatic and tectonic boundary conditions changed. The amplitude and duration of climate cycles increased significantly, resulting in long periods of sustained low temperatures in the Meuse catchment. In addition, an episode of magmatic underplating and mafic volcanism in the nearby Eifel caused up to 250 m of surface uplift in the Meuse catchment. The main streams in the region have responded to the perturbation at 0.7 Ma within a few 10(5) yr. Our data indicate that the catchment-wide response time is much longer. Further investigations are required to attribute the observed increase in paleoerosion rates to one or the other mechanism discussed