Validation of left ventricular volume and ejection fraction measurements by high-definition blood flow imaging: Comparisons with cardiac magnetic resonance imaging and contrast echocardiography.

BACKGROUND: We recently reported the efficacy of High-definition blood flow imaging (HDI) in the assessment of left ventricular (LV) function and demonstrated that the results are comparable to those obtained by contrast echocardiography (CE). The present study validates HDI in measurements of LV volumes and ejection fraction (EF) by simultaneous comparisons with CE and cardiac magnetic resonance imaging (CMR). METHODS: Eighteen patients (age range 25-79 years) with limited echocardiographic images had measurements of LV end-diastolic volume (EDV, mL), end-systolic volume (ESV, mL), and EF (%) by HDI, CE, and CMR. RESULTS: Using the three techniques, measurements of EDV, ESV, and EF correlated well with correlation coefficients (r) ranging from .91 to .98 in comparisons between HDI and CMR, and .89 to .97 in comparisons between CE and CMR. The limits of agreement for the inter-methods comparisons by Bland-Altman analysis (mean ± 1.96 SD) between HDI and CMR were 4.92 ± 16.87% for EF, 21.53 ± 32.18 mL for EDV, and 10.69 ± 36.12 mL for ESV, between CE and CMR, the agreement limits were 2.48 ± 18.52% (LVEF), 24.58 ± 47.41 mL (EDV), and 14.09 ± 43.55 mL (ESV). CONCLUSIONS: Measurements of LV volumes and EF by HDI and CE correlated well with CMR. Using CMR as the gold standard, the agreements in measurements of LV volumes were superior for HDI compared to CE. In measurements of EF, CE showed less mean difference when compared to HDI. HDI measurements compared well with those obtained by CMR.

Atherogenic L5 LDL induces cardiomyocyte apoptosis and inhibits KATP channels through CaMKII activation.

BACKGROUND: Cardiac Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation plays a critical role in cardiomyocyte (CM) apoptosis and arrhythmia. Functional ATP-sensitive potassium (KATP) channels are essential for cardiac protection during ischemia. In cultured CMs, L5 low-density lipoprotein (LDL) induces apoptosis and QTc prolongation. L5 is a highly electronegative and atherogenic aberrant form of LDL, and its levels are significantly higher in patients with cardiovascular-related diseases. Here, the role of L5 in cardiac injury was studied by evaluating the effects of L5 on CaMKII activity and KATP channel physiology in CMs. METHODS: Cultured neonatal rat CMs (NRCMs) were treated with a moderate concentration (ie, 7.5 µg/mL) of L5 or L1 (the least electronegative LDL subfraction). NRCMs were examined for apoptosis and viability, CaMKII activity, and the expression of phosphorylated CaMKIIδ and NOX2/gp91phox. The function of KATP and action potentials (APs) was analyzed by using the patch-clamp technique. RESULTS: In NRCMs, L5 but not L1 significantly induced cell apoptosis and reduced cell viability. Furthermore, L5 decreased Kir6.2 expression by more than 50%. Patch-clamp analysis showed that L5 reduced the KATP current (IKATP) density induced by pinacidil, a KATP opener. The partial recovery of the inward potassium current during pinacidil washout was susceptible to subsequent inhibition by the IKATP blocker glibenclamide. Suppression of IKATP by L5 significantly prolonged the AP duration. L5 also significantly increased the activity of CaMKII, the phosphorylation of CaMKIIδ, and the expression of NOX2/gp91phox. L5-induced apoptosis was prevented by the addition of the CaMKII inhibitor KN93 and the reactive oxygen species scavenger Mn (III)TBAP. CONCLUSIONS: L5 but not L1 induces CM damage through the activation of the CaMKII pathway and increases arrhythmogenicity in CMs by modulating the AP duration. These results help to explain the harmful effects of L5 in cardiovascular-related disease.

High-definition blood flow imaging in the assessment of left ventricular function: Initial experience and comparison with contrast echocardiography.

OBJECTIVES: The study aimed to assess the accuracy and reproducibility of the high-definition blood flow imaging (HD-Flow) in evaluation of left ventricular (LV) function by comparison with contrast echocardiography (Contrast). BACKGROUND: Contrast improves endocardial border visualization and assists in precise assessment of LV function. HD-Flow, a novel ultrasound technique that enhances blood flow discrimination in LV, could possibly be used for improving endocardial border definition without contrast. METHODS: Eighty patients with technically limited transthoracic echocardiograms had HD-Flow, and contrast performed sequentially. LV endocardial visualization, image acquisition time, wall motion, volumes, ejection fraction (EF), stroke volume (SV), and stroke volume index (SVI) were compared. Inter- and intra-observer agreements were examined in a randomly selected subgroup. RESULTS: Both HD-Flow and contrast significantly improved the percentage of the well-defined endocardial border segments (71% at baseline vs 94.1% by HD-Flow vs 94.9% by contrast, X2  = 401, P < 0.001). The acquisition time for HD-Flow was significantly less when compared to contrast (2.13 ± 1.18 minutes vs 10.96 ± 3.51 minutes, P < 0.001). LV end-diastolic volume (EDV), end-systolic volume (ESV), EF, SV, and SVI measured by the two methods correlated well (EDVr = 0.97, ESVr = 0.96, EFr = 0.90, SVr = 0.77, SVIr = 0.74, all P < 0.001). In comparison, HD-Flow was neither significantly different in detecting LV wall motion abnormality nor in EF, SV, and SVI measurements, but slightly underestimated LV volumes. CONCLUSIONS: HD-Flow imaging is feasible and user-friendly in enhancing LV endocardial definition. This technique is useful in both qualitative and quantitative assessment of LV function.

Echocardiographic assessment of the right ventricle in the current era: Application in clinical practice.

The right ventricle has unique structural and functional characteristics. It is now well recognized that the so-called forgotten ventricle is a key player in cardiovascular physiology. Furthermore, there is accumulating evidence that demonstrates right ventricular dysfunction as an important marker of morbidity and mortality in several commonly encountered clinical situations such as heart failure, pulmonary hypertension, pulmonary embolism, right ventricular myocardial infarction, and adult congenital heart disease. In contrast to the left ventricle, echocardiographic assessment of right ventricular function is more challenging as volume estimations are not possible without the use of three-dimensional (3D) echocardiography. Guidelines on chamber quantification provide a standardized approach to assessment of the right ventricle. The technique and limitations of each of the parameters for RV size and function need to be fully understood. In this era of multimodality imaging, echocardiography continues to remain a useful tool for the initial assessment and follow-up of patients with right heart pathology. Several novel approaches such as 3D and strain imaging of the right ventricle have expanded the usefulness of this indispensable modality.

Outcomes of pre-emptive and rescue use of percutaneous left ventricular assist device in patients with structural heart disease undergoing catheter ablation of ventricular tachycardia.

PURPOSE: Patient selection and timing of percutaneous left ventricular assist device (pLVAD) insertion for maximal benefit during ventricular tachycardia (VT) ablation is not well defined. We aimed to assess the outcomes of pre-emptive and rescue use of pLVAD during VT ablation in patients with ischemic and non-ischemic cardiomyopathy. METHODS: Between January 2009 and October 2011, 93 patients underwent VT ablation. Three groups were compared: (1) Rescue group (n = 12)-patients who required emergent pLVAD insertion due to hemodynamic collapse during VT ablation, (2) Pre-emptive group (n = 24)-patients who had pre-ablation pLVAD insertion, and (3) Non-pLVAD group (n = 57)-patients who did not undergo pLVAD insertion. Procedural outcomes including 30-day mortality were compared. RESULTS: Thirty-day mortality was higher in the Rescue group compared to the Pre-emptive group (58 vs. 4 %, p = 0.003) and non-pLVAD (58 vs. 3 %, p = 0.001) group. There was no significant difference in 30-day mortality or long-term freedom of VT between the pre-emptive and non-pLVAD groups. CONCLUSIONS: Despite rescue pLVAD insertion, hemodynamic collapse during VT ablation is associated with a persistently high 30-day mortality. Further studies are warranted to predict hemodynamic collapse and to refine the role of pLVAD in this setting.

Beta1-Adrenergic blocker bisoprolol reverses down-regulated ion channels in sinoatrial node of heart failure rats

Bisoprolol, an antagonist of β1-adrenergic receptors, is effective in reducing the morbidity and mortality in patients with heart failure (HF). It has been found that HF is accompanied with dysfunction of the sinoatrial node (SAN). However, whether bisoprolol reverses the decreased SAN function in HF and how the relevant ion channels in SAN change were relatively less studied. SAN function and messenger RNA (mRNA) expression of sodium channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) channel subunits were assessed in sham-operated rats, abdominal arterio-venous shunt (volume overload)-induced HF rats, and bisoprolol- treated HF rats. SAN cells of rats were isolated by laser capture microdissection. Quantitative real-time PCR analysis was used to quantify mRNA expression of sodium channels and HCN channel subunits in SAN. Intrinsic heart rate declined and sinus node recovery time prolonged in HF rats, indicating the suppressed SAN function, which could be improved by bisoprolol treatment. Nav1.1, Nav1.6, and HCN4 mRNA expressions were reduced in SAN in HF rats compared with that in control rats. Treatment with bisoprolol could reverse both the SAN function and the Nav1.1, Nav1.6, and HCN4 mRNA expression partially. These data indicated that bisoprolol is effective in HF treatment partially due to improved SAN function by reversing the down-regulation of sodium channels (Nav1.1 and Nav1.6) and HCN channel (HCN4) subunits in SAN in failing hearts (AU)

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ß1-Adrenergic blocker bisoprolol reverses down-regulated ion channels in sinoatrial node of heart failure rats.

Bisoprolol, an antagonist of ß1-adrenergic receptors, is effective in reducing the morbidity and mortality in patients with heart failure (HF). It has been found that HF is accompanied with dysfunction of the sinoatrial node (SAN). However, whether bisoprolol reverses the decreased SAN function in HF and how the relevant ion channels in SAN change were relatively less studied. SAN function and messenger RNA (mRNA) expression of sodium channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) channel subunits were assessed in sham-operated rats, abdominal arterio-venous shunt (volume overload)-induced HF rats, and bisoprolol- treated HF rats. SAN cells of rats were isolated by laser capture microdissection. Quantitative real-time PCR analysis was used to quantify mRNA expression of sodium channels and HCN channel subunits in SAN. Intrinsic heart rate declined and sinus node recovery time prolonged in HF rats, indicating the suppressed SAN function, which could be improved by bisoprolol treatment. Nav1.1, Nav1.6, and HCN4 mRNA expressions were reduced in SAN in HF rats compared with that in control rats. Treatment with bisoprolol could reverse both the SAN function and the Nav1.1, Nav1.6, and HCN4 mRNA expression partially. These data indicated that bisoprolol is effective in HF treatment partially due to improved SAN function by reversing the down-regulation of sodium channels (Nav1.1 and Nav1.6) and HCN channel (HCN4) subunits in SAN in failing hearts.

Neuronally released vasoactive intestinal polypeptide alters atrial electrophysiological properties and may promote atrial fibrillation.

BACKGROUND: Vagal hyperactivity promotes atrial fibrillation (AF), which has been almost exclusively attributed to acetylcholine. Vasoactive intestinal polypeptide (VIP) and acetylcholine are neurotransmitters co-released during vagal stimulation. Exogenous VIP has been shown to promote AF by shortening action potential duration (APD), increasing APD spatial heterogeneity, and causing intra-atrial conduction block. OBJECTIVE: The purpose of this study was to investigate the effects of neuronally released VIP on atrial electrophysiologic properties during vagal stimulation. METHODS: We used a specific VIP antagonist (H9935) to uncover the effects of endogenous VIP released during vagal stimulation in canine hearts. RESULTS: H9935 significantly attenuated (1) the vagally induced shortening of atrial effective refractory period and widening of atrial vulnerability window during stimulation of cervical vagosympathetic trunks (VCNS) and (2) vagal effects on APD during stimulation through fat-pad ganglion plexus (VGPS). Atropine completely abolished these vagal effects during VCNS and VGPS. In contrast, VGPS-induced slowing of local conduction velocity was completely abolished by either VIP antagonist or atropine. In pacing-induced AF during VGPS, maximal dominant frequencies and their spatial gradients were reduced significantly by H9935 and, more pronouncedly, by atropine. Furthermore, VIP release in the atria during vagal stimulation was inhibited by atropine, which may account for the concealment of VIP effects with muscarinic blockade. CONCLUSION: Neuronally released VIP contributes to vagal effects on atrial electrophysiologic properties and affects the pathophysiology of vagally induced AF. Neuronal release of VIP in the atria is inhibited by muscarinic blockade, a novel mechanism by which VIP effects are concealed by atropine during vagal stimulation.

Tacrolimus-induced encephalopathy and polyneuropathy in a renal transplant recipient.

Tacrolimus is an immunosuppressant frequently used following solid organ transplantation, including renal transplantation. Peripheral neuropathy is an uncommon neurological side effect of tacrolimus and has rarely been reported in renal transplantation. We report a patient who received a living-related donor kidney transplant and presented with altered mental status and new-onset bilateral foot drop. Laboratory tests including cerebrospinal fluid tests excluded infection, and MRI of the brain showed chronic microvascular ischaemic changes. Electromyography and nerve conduction study confirmed bilateral common peroneal nerve demyelination. He was also found to have inadvertently overdosed on tacrolimus at home. After switching from tacrolimus to cyclosporine, the patient's symptoms improved within 5 months. His renal function was maintained with an immunosuppressant regimen of cyclosporine, prednisone and mycophenolic acid. The prompt recognition of tacrolimus as a potential neurotoxic drug in a patient with renal transplant and substituting tacrolimus with a different immunosuppressant may prevent permanent neurological damage.

Ionic mechanisms underlying the effects of vasoactive intestinal polypeptide on canine atrial myocardium.

BACKGROUND: Vasoactive intestinal polypeptide (VIP) is released from intracardiac neurons during vagal stimulation, ischemia, and heart failure, which are associated with increased vulnerability to atrial fibrillation. VIP shortens atrial effective refractory periods in dogs. Endogenous VIP contributes to vagally mediated acceleration of atrial electric remodeling. VIP is also shown to prolong the duration of acetylcholine-induced atrial fibrillation. However, the ionic mechanisms underlying VIP effects are largely unknown. METHODS AND RESULTS: The effects of VIP on transmembrane ion channels were studied in canine atrial cardiomyocytes using patch-clamp techniques. VIP increased delayed rectifier K+ current and L-type calcium current but decreased the transient outward K+ current and sodium current. Optical mapping technique was used to assess effects of VIP on action potential durations (APDs) in isolated canine left atria. VIP shortened APD and slowed conduction velocity in a dose-dependent manner. Furthermore, VIP increased spatial heterogeneity of APD and conduction velocity, as assessed by the SDs of APD and conduction velocity, and atrial fibrillation inducibility. CONCLUSIONS: Through its diverse effects on ion channels, VIP shortens APD with increased APD spatial heterogeneity and decreases intra-atrial conduction velocity, which may play an important role in the pathogenesis of atrial arrhythmias in scenarios where VIP release is increased.

Loss of function of hNav1.5 by a ZASP1 mutation associated with intraventricular conduction disturbances in left ventricular noncompaction.

BACKGROUND: Defects of cytoarchitectural proteins can cause left ventricular noncompaction, which is often associated with conduction system diseases. We have previously identified a p.D117N mutation in the LIM domain-binding protein 3-encoding Z-band alternatively spliced PDZ motif gene (ZASP) in a patient with left ventricular noncompaction and conduction disturbances. We sought to investigate the role of p.D117N mutation in the LBD3 NM_001080114.1 isoform (ZASP1-D117N) for the regulation of cardiac sodium channel (Na(v)1.5) that plays an important role in the cardiac conduction system. METHODS AND RESULTS: Effects of ZASP1-wild-type and ZASP1-D117N on Na(v)1.5 were studied in human embryonic kidney-293 cells and neonatal rat cardiomyocytes. Patch-clamp study demonstrated that ZASP1-D117N significantly attenuated I(Na) by 27% in human embryonic kidney-293 cells and by 32% in neonatal rat cardiomyocytes. In addition, ZASP1-D117N rightward shifted the voltage-dependent activation and inactivation in both systems. In silico simulation using Luo-Rudy phase 1 model demonstrated that altered Na(v)1.5 function can reduce cardiac conduction velocity by 28% compared with control. Pull-down assays showed that both wild-type and ZASP1-D117N can complex with Na(v)1.5 and telethonin/T-Cap, which required intact PDZ domains. Immunohistochemical staining in neonatal rat cardiomyocytes demonstrates that ZASP1-D117N did not significantly disturb the Z-line structure. Disruption of cytoskeletal networks with 5-iodonaphthalene-1-sulfonyl homopiperazine and cytochalasin D abolished the effects of ZASP1-D117N on Na(v)1.5. CONCLUSIONS: ZASP1 can form protein complex with telethonin/T-Cap and Na(v)1.5. The left ventricular noncompaction-specific ZASP1 mutation can cause loss of function of Na(v)1.5, without significant alteration of the cytoskeletal protein complex. Our study suggests that electric remodeling can occur in left ventricular noncompaction subject because of a direct effect of mutant ZASP on Na(v)1.5.

Engineered endothelial progenitor cells that overexpress prostacyclin protect vascular cells.

Prostacyclin (PGI2) is a potent vasodilator and important mediator of vascular homeostasis; however, its clinical use is limited because of its short (<2-min) half-life. Thus, we hypothesize that the use of engineered endothelial progenitor cells (EPCs) that constitutively secrete high levels of PGI2 may overcome this limitation of PGI2 therapy. A cDNA encoding COX-1-10aa-PGIS, which links human cyclooxygenase-1 (COX-1) to prostacyclin synthase (PGIS), was delivered via nucleofection into outgrowth EPCs derived from rat bone marrow mononuclear cells. PGI2-secreting strains (PGI2-EPCs) were established by continuous subculturing of transfected cells under G418 selection. Genomic PCR, RT-PCR, and Western blot analyses confirmed the overexpression of COX-1-10aa-PGIS in PGI2-EPCs. PGI2-EPCs secreted significantly higher levels of PGI2 in vitro than native EPCs (P < 0.05) and showed higher intrinsic angiogenic capability; conditioned medium (CM) from PGI2-EPCs promoted better tube formation than CM from native EPCs (P < 0.05). Cell- and paracrine-mediated in vitro angiogenesis was attenuated when COX-1-10aa-PGIS protein expression was knocked down. Whole-cell patch-clamp studies showed that 4-aminopyridine-sensitive K(+) current density was increased significantly in rat smooth muscle cells (rSMCs) cocultured under hypoxia with PGI2-EPCs (7.50 ± 1.59 pA/pF; P < 0.05) compared with rSMCs cocultured with native EPCs (3.99 ± 1.26 pA/pF). In conclusion, we successfully created EPC strains that overexpress an active novel enzyme resulting in consistent secretion of PGI2. PGI2-EPCs showed enhanced intrinsic proangiogenic properties and provided favorable paracrine-mediated cellular protections, including promoting in vitro angiogenesis of native EPCs and hyperpolarization of SMCs under hypoxia.

Vagal stimulation promotes atrial electrical remodeling induced by rapid atrial pacing in dogs: evidence of a noncholinergic effect.

BACKGROUND: Atrial electrical remodeling (AER) is one of the mechanisms by which atrial fibrillation (AF) begets AF. It is known that vagal activity increases the propensity for AF. However, vagal effects on AER have not been fully investigated. METHODS: Adult mongrel dogs were divided in four groups: group I, rapid atria pacing (RAP); group II, RAP plus vagal nerve stimulation (VNS); group III, RAP and VNS with atropine (0.2 mg/kg/h, intravenous), and group IV, group III plus vasoactive intestinal polypeptide (VIP) antagonist ([D-p-Cl-Phe(6), Leu(17)]-VIP, 0.125 µg/kg/h). VNS was performed bilaterally through vagosympathetic trunks to achieve second-degree AV block or sinus rate slowing of >30 beats per minute. Atrial effective refractory periods (AERPs) were determined in the coronary sinus and right atrial appendage every hour at drive cycle lengths (DCLs) 350 ms, 300 ms, and 250 ms. RESULTS: During 5 hours RAP with or without VNS, AERP shortened progressively from baseline at both pacing sites and at all DCLs (P < 0.01). Furthermore, RAP-induced AERP shortening was more pronounced with VNS (P < 0.01). With atropine, the AERP shortening during VNS was blunted (P < 0.01), but was still significantly more pronounced than that in group I (P < 0.05). However, VNS effect on AERP shortening was eliminated completely with the combination of atropine and VIP antagonist (P = 0.15 vs group I). CONCLUSION: Increased vagal activity promotes RAP-induced AER, which could not be totally accounted for by cholinergic effect but could be blocked by the combination of atropine and VIP antagonist. Vagally released VIP may have important role in the vagal promotion of AER.

Prostacyclin administration as a beneficial supplement to the conventional cancer chemotherapy.

Prostacyclin (PGI(2)) and its analogues protect from cardiovascular disease through pleiotropic effects such as vasodilation, inhibition of platelet aggregation, leukocyte adhesion, and vascular smooth muscle cell (VSMC) proliferation. Additionally, prostacyclin synthase (PGIS) and PGI(2) also possess anti-cancer properties. As of late (2009-2010), numerous studies have identified the deleterious side-effects of chemotherapy on the cardiovascular system, which have been deemed as a serious clinical issue. Cardiomyocyte damage, induced by oxidative stress, is one of the clinical consequences caused by routine cancer chemotherapy. Previous studies indicate iloprost, a PGI(2) analogue, can protect against doxorubicin-induced (DOX) cardiomyocyte injury in vitro and in vivo without compromising tumor suppression. Therefore, we hypothesize PGI(2) can be used as a cardioprotective supplement to attenuate the damaging cardiac effects caused by the traditional cancer chemotherapy regimen.

A nonsense SCN5A mutation associated with Brugada-type electrocardiogram and intraventricular conduction defects.

Mutations of SCN5A, gene-encoding alpha-subunit of cardiac sodium channel, can cause mixed phenotypes of Brugada syndrome (BrS) and cardiac conduction diseases (CCD). We have identified a nucleotide change of SCN5A (4178T > G), which results in a nonsense mutation, L1393X, in a 36-year-old Caucasian man who presented with intraventricular conduction delays and BrS-type electrocardiogram change. To study biophysical characteristics of L1393X-SCN5A, electrophysiological and immuno-staining studies were performed using mammalian expression systems. While WT-SCN5A showed significant currents (93.3 +/- 10.6 pA/pF; 1 microg plasmid), L1393X (5 microg) did not generate any significant currents in NIH-3T3 cells. The cells cotransfected with WT (0.5 microg) and L1393X (0.5 microg) showed approximately 50% current amplitudes compared to the WT (1 microg). Voltage dependency of a steady-state activation and inactivation was not affected by the cotransfection of L1393X. Immuno-histochemical stainings demonstrated that L1393X proteins were expressed in the plasma membranes. Our study demonstrated that L1393X-SCN5A does not form functional channel proteins, which might account for the patient's mixed phenotypes of BrS and CCD.

A novel SCN5A mutation V1340I in Brugada syndrome augmenting arrhythmias during febrile illness.

BACKGROUND: Mutations in the SCN5A gene, which encodes the cardiac sodium channel, have been implicated in the pathogenesis of Brugada syndrome (BrS). Febrile illnesses have been recognized to unmask and/or trigger the BrS phenotype. However, the pathophysiological mechanism has not been fully elucidated. OBJECTIVE: A novel SCN5A missense mutation, V1340I, was identified in a patient with BrS suffering from frequent episodes of polymorphic ventricular tachycardia (VT) and syncope associated with fever. The biophysical modifications of hNa(v)1.5 by V1340I were studied. METHODS: The effects of the V1340I mutation were studied in the 2 splice variants, SCN5A and SCN5A-Q1077del (delQ), using patch-clamp techniques at various temperatures between 22 degrees C and 40 degrees C. RESULTS: At 22 degrees C, V1340I-SCN5A generated markedly diminished sodium currents compared to the wild-type (WT) SCN5A. On the contrary, V1340I-delQ generated almost identical current density compared to the WT-delQ. However, V1340I-delQ significantly attenuated the peak current density compared to the WT-delQ at 32 degrees C, 37 degrees C and 40 degrees C. The voltage dependency of steady-state activation was leftward shifted both in WT-delQ and V1340I-delQ at 40 degrees C. In addition, the V1340I-delQ accelerated the recovery time course from fast inactivation compared to the WT-delQ at 40 degrees C. Immunohistochemical staining showed that both V1340I-SCN5A and V1340I-dQ were expressed in the plasma membrane. CONCLUSION: Our study supports the concept that febrile illness predisposes individuals who carry a loss of function SCN5A mutation, such as V1340I, to fever-induced ventricular arrhythmias in BrS by significantly reducing the sodium currents in the hyperthermic state.

Increased late sodium currents are related to transcription of neuronal isoforms in a pressure-overload model.

AIMS: The late and persistent sodium current (I(Na)) has been identified as a target for anti-arrhythmia drugs in patients with heart failure (HF). However, the underlying mechanism of late I(Na) (I(NaL)) production remains uncertain. We hypothesized that transcriptional alteration among sodium channel (NaCh) isoforms may contribute to I(NaL) in failing cardiomyocytes. METHODS AND RESULTS: Pressure-overload rat models were created by 16-week constriction of the ascending aorta (HF). Haemodynamic and electrocardiographic variables were studied in sham operation and HF rats. Action potential (AP) and I(Na) were recorded using whole-cell patch-clamp techniques. The expression of various NaCh isoforms was evaluated by immunocytochemistry, RT-PCR, and western blot. The HF group exhibited left ventricular enlargement, systolic dysfunction, and prolongation of QTc intervals (P < 0.05). Current-clamp recording indicated that AP durations (APDs) were more sensitive to tetrodotoxin. Voltage-clamp recordings showed that I(NaL) was increased (-1.54 +/- 0.43 vs. -1.08 +/- 0.38 pA/pF, P < 0.01) in HF, but transient I(Na) (I(NaT)) density was decreased (-14.61 +/- 2.30 vs. -26.15 +/- 5.17 pA/pF, P < 0.01). Correspondingly, the relative mRNA levels of the neuronal isoforms SCN1a and SCN8a increased 2.5- and 2.7-fold, respectively; SCN3a did not change, whereas SCN5a decreased by approximately 60% in HF. Protein levels paralleled their mRNA expression. CONCLUSION: The up-regulated expression of the neuronal NaCh isoforms SCN1a and SCN8a could be one mechanism of I(NaL) production, which may contribute to prolongation of APD in the failing heart.

alpha-1-syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption.

BACKGROUND: Long-QT syndrome (LQTS) is an inherited disorder associated with sudden cardiac death. The cytoskeletal protein syntrophin-alpha(1) (SNTA1) is known to interact with the cardiac sodium channel (hNa(v)1.5), and we hypothesized that SNTA1 mutations might cause phenotypic LQTS in patients with genotypically normal hNa(v)1.5 by secondarily disturbing sodium channel function. METHODS AND RESULTS: Mutational analysis of SNTA1 was performed on 39 LQTS patients (QTc> or =480 ms) with previously negative genetic screening for the known LQTS-causing genes. We identified a novel A257G-SNTA1 missense mutation, which affects a highly conserved residue, in 3 unrelated LQTS probands but not in 400 ethnic-matched control alleles. Only 1 of these probands had a preexisting family history of LQTS and sudden death with an additional intronic variant in KCNQ1. Electrophysiological analysis was performed using HEK-293 cells stably expressing hNa(v)1.5 and transiently transfected with either wild-type or mutant SNTA1 and, in neonatal rat cardiomyocytes, transiently transfected with either wild-type or mutant SNTA1. In both HEK-293 cells and neonatal rat cardiomyocytes, increased peak sodium currents were noted along with a 10-mV negative shift of the onset and peak of currents of the current-voltage relationships. In addition, A257G-SNTA1 shifted the steady-state activation (V(h)) leftward by 9.4 mV, whereas the voltage-dependent inactivation kinetics and the late sodium currents were similar to wild-type SNTA1. CONCLUSION: SNTA1 is a new susceptibility gene for LQTS. A257G-SNTA1 can cause gain-of-function of Na(v)1.5 similar to the LQT3.