A novel mutation in transmembrane protein 168 causes fatal ventricular arrhythmogenesis in Brugada syndrome

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Ogita ◽  
D.P Zankov ◽  
A Shimizu
Keyword(s):  
Ventricular Tachycardia ◽  
Current Density ◽  
Brugada Syndrome ◽  
Transmembrane Protein ◽  
Left Ventricular ◽  
Public Institution ◽  
Na Channel ◽  
Funding Source ◽  
Wild Type ◽  
Na Current

Abstract   Brugada syndrome (BrS) is diagnosed by a typical electrocardiography (ECG) with ST-segment elevation in precordial leads and tends to induce sudden cardiac death (SCD) due to ventricular tachycardia/fibrillation. About 20% of SCDs in non-structural cardiac diseases are considered to be caused by BrS. In patients with BrS, loss of function mutations in the Na+ channel is often observed, but the causative gene mutation is not detected for about 70% of BrS patients. Here, we investigated a family with clinically diagnosed BrS, in which no known gene mutations related to BrS had not been found, by whole exome sequencing. Novel heterozygous variant (c. 1616G>A, p. R539Q) in transmembrane protein 168 (TMEM168) was identified only in symptomatic family members. Similar to endogenous TMEM168, both wild-type and mutant TMEM168 localized at the nuclear membrane. Na+ current density in whole-cell patch-clamp recordings was significantly reduced in HL-1 cardiomyocytes transfected with TMEM168 R539Q mutant, compared with those with wild-type TMEM168. Next, heterozygous Tmem168 1616G>A knock-in mice were generated by the CRISPR/Cas9 genome editing technology. Although the knock-in mice had no abnormalities in ECG at the physiological state, the treatment with ajmaline caused various arrhythmias including ventricular tachycardia/fibrillation in the knock-in mice, but not in wild-type mice. Na+ current density and the parameters of action potentials were remarkably impaired in the cardiomyocytes of the knock-in mice. Optical mapping analysis in the whole heart showed the reduced left ventricular conduction velocity in the knock-in mice. The expression of Nav1.5, an α-subunit of the cardiac Na+ channel, was significantly decreased in the mutant TMEM168-transfected HL-1 cells and the knock-in hearts. We found that the decrease was caused by the enhanced ubiquitination of Nav1.5, which was mediated by increased binding of Nedd4–2 E3 ubiquitin ligase to Nav1.5 in the knock-in hearts. Co-immunoprecipitation experiments demonstrated that overactivity of Nedd4–2 is a result of Tmem168 mutant-mediated sequestration of a chaperon protein αB-crystallin, a Nav1.5-binding molecule that interferes with the interaction of Nedd4–2 with Nav1.5. These findings reveal the molecular mechanism of TMEM168 R539Q mutation-induced fatal ventricular arrhythmias in BrS. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): JSPS Grants-in-aid for Scientific Research

scholarly journals Abnormal Na channel gating in murine cardiac myocytes deficient in myotonic dystrophy protein kinase

2003 ◽  
Vol 12 (2) ◽  
pp. 147-157 ◽  
Author(s):  
Hwa C. Lee ◽  
Manoj K. Patel ◽  
Dilawaar J. Mistry ◽  
Qingcai Wang ◽  
Sita Reddy ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Current Density ◽  
Channel Gating ◽  
Resting Membrane Potential ◽  
Na Channel ◽  
Na Channels ◽  
Wild Type ◽  
Membrane Excitability ◽  
Na Current ◽  
Deficient Mice

DMPK is a serine/threonine kinase implicated in the human disease myotonic muscular dystrophy (DM). Skeletal muscle Na channels exhibit late reopenings in Dmpk-deficient mice and peak current density is reduced, implicating DMPK in regulation of membrane excitability. Since complete heart block and sudden cardiac death occur in the disease, we tested the hypothesis that cardiac Na channels also exhibit abnormal gating in Dmpk-deficient mice. We made whole cell and cell-attached patch clamp recordings of ventricular cardiomyocytes enzymatically isolated from wild-type, Dmpk+/−, and Dmpk−/− mice. Recordings from membrane patches containing one or a few Na channels revealed multiple Na channel reopenings occurring after the macroscopic Na current had subsided in both Dmpk+/− and Dmpk−/− muscle, but only rare reopenings in wild-type muscle (>3-fold difference, P < 0.05). This resulted in a plateau of non-inactivating Na current in Dmpk-deficient muscle. The magnitude of this plateau current was independent on the magnitude of the test potential from −40 to 0 mV and was also independent of gene dose. Macroscopic Na current density was similar in wild-type and Dmpk-deficient muscle, as was steady-state Na channel gating. Decay of macroscopic currents was slowed in Dmpk−/− muscle, but not in Dmpk+/− or wild-type muscle. Entry into, and recovery from, inactivation were similar at multiple test potentials in wild-type and Dmpk-deficient muscle. Resting membrane potential was depolarized, and action potential duration was significantly prolonged in Dmpk-deficient muscle. Thus in cardiac muscle, Dmpk deficiency results in multiple late reopenings of Na channels similar to those seen in Dmpk-deficient skeletal muscle. This is reflected in a plateau of non-inactivating macroscopic Na current and prolongation of cardiac action potentials.

Electromechanical delay by speckle-tracking echocardiography: a novel tool for distinguishing between Brugada syndrome and isolated right bundle branch block

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
F D'Ascenzi ◽  
M Sanz De La Garza ◽  
F Anselmi ◽  
L Nunno ◽  
E Arbelo ◽  
...  
Keyword(s):  
Right Bundle Branch Block ◽  
Brugada Syndrome ◽  
Speckle Tracking ◽  
Speckle Tracking Echocardiography ◽  
Left Ventricular ◽  
Public Institution ◽  
Funding Source ◽  
Electromechanical Delay ◽  
Bundle Branch Block

Abstract Background The electrocardiographic (ECG) definition of Brugada syndrome (BS) can be challenging because benign ECG abnormalities, such as right bundle branch block (RBBB), may mimic pathological ECG characteristics of BrS. However, although myocardial delay and deformation can be quantified by advanced imaging, it has not yet been used to differentiate between BrS and RBBB. Purpose The aim of this study was to characterize the electro-mechanical behavior of the heart of patients with type-1 BrS and subjects with isolated complete RBBB in order to differentiate these conditions. Methods In this two-center study, 66 subjects were analyzed by standard and speckle-tracking echocardiography (STE): 22 type-1 BrS, 24 isolated complete RBBB, and 20 healthy subjects. The participants were not treated by any drug potentially influencing myocardial conduction. Results Standard echocardiographic parameters did not differ among the groups. STE demonstrated that right ventricular (RV) mechanical dispersion (MD) was greater in RBBB as compared to BrS and controls (p&lt;0.05). In patients with isolated RBBB, the greatest delay of RV time-to-peak longitudinal strain (TTP) was found in RV free-wall basal segments. Mean absolute deviations of TTP calculated for each left ventricular (LV) region were greater in patients with RBBB as compared to those with BrS and to controls with a localisation of the delay in LV antero-septal, anterior, lateral, and infero-septal basal segments (figure 1). Conclusions Advanced echocardiographic techniques may help to differentiate between BrS and RBBB. Indeed, STE allows to identify an electro-mechanical conduction delay in RBBB patients that is not found in patients affected by type-1 BrS. Electromechanical delay by STE Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Italian Society of Cardiology

scholarly journals Sustained ventricular tachycardia of left, right or both bundle branch block morphology in patients with Arrhythmogenic Cardiomyopathy

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Milman ◽  
M Laredo ◽  
R Roudijk ◽  
G Peretto ◽  
A Andorin ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Right Bundle Branch Block ◽  
Left Bundle Branch Block ◽  
Clinical Course ◽  
Left Ventricular ◽  
Funding Source ◽  
Arrhythmogenic Cardiomyopathy ◽  
Icd Implantation ◽  
Bundle Branch Block ◽  
Group 3

Abstract Aims In arrhythmogenic cardiomyopathy (ACM) sustained monomorphic ventricular tachycardia (VT) typically displays left bundle branch block (LBBB) morphology. Sustained VT with right bundle branch block (RBBB) morphology is very rare despite the frequent left ventricular involvement. The present study sought to assess the prevalence of spontaneous sustained LBBB-VT, RBBB-VT or both as well as clinical and genetic differences associated with these VT types. Methods and results Twenty-six centers from 11 European countries provided information on 952 patients with ACM and &gt;1 episode of sustained VT observed during the patients' clinical course. VT was classified as: LBBB-VT; RBBB-VT or LBBB+RBBB-VT. Among 952 patients, 881 (92.5%) had LBBB-VT alone, 71 (7.5%) had RBBB-VT [alone in 42 (4.4%) patients or with LBBB-VT in 29 (3.0%) patients]. Male prevalence was 90.5%, 79.2% and 55.9% in the RBBB-VT, LBBB-VT and LBBB+RBBB-VT groups, respectively (P=0.001). Patients' age at first VT did not differ amongst the 3 VT groups. ICD implantation was more frequent for the RBBB-VT and the LBBB+RBBB groups (≈90% each) vs. 67.9% for the LBBB-VT group (P=0.001). Death incidence (9.5%–17.2%) was not significantly different between the 3 groups (P=0.425). Plakophylin-2 mutations predominated in the LBBB-VT and LBBB-VT+RBBB-VT groups (47.2% and 27.3%, respectively) and Desmoplakin mutations in the RBBB-VT group (36.7%). Conclusion This large European survey demonstrates: 1) Sustained RBBB-VT is documented in 7.5% patients with ACM; 2) Males markedly predominate in the RBBB-VT and LBBB-VT groups but not in the LBBB+RBBB VT group; 3) Distribution of desmosomal mutations appears to be different in the 3 VT groups. Funding Acknowledgement Type of funding source: None

scholarly journals Using biomarkers to identify diabetic patients with multiple silent cardiac abnormalities

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
V.H Chong ◽  
J.S.S Singh ◽  
E Dow ◽  
R.J McCrimmon ◽  
C.C Lang ◽  
...  
Keyword(s):  
Primary Prevention ◽  
Cardiac Troponin ◽  
Cardiovascular Events ◽  
High Sensitivity ◽  
Left Ventricular ◽  
Public Institution ◽  
Diabetic Patients ◽  
Funding Source ◽  
Cardiac Abnormality ◽  
Cardiac Abnormalities

Abstract Background Primary prevention of cardiovascular events in people with Type 2 diabetes mellitus (T2DM) needs to improve due to risk of cardiovascular events. A major problem in T2DM is the high incidence of silent yet potentially lethal cardiac abnormalities, namely myocardial ischaemia (MI), left ventricular hypertrophy (LVH), left ventricular systolic dysfunction (LVSD), left ventricular diastolic dysfunction (LVDD), and left atrial enlargement (LAE). All these independently predict cardiovascular events and mortality. There is not a single study with comprehensive enough cardiac phenotyping to document the prevalence of all the aforementioned 5 cardiac abnormalities. To improve primary prevention of cardiovascular disease in diabetes, we need to first identify the type of silent cardiac abnormality and treat accordingly. However cardiac phenotyping in all people with T2DM would be prohibitively expensive. Purpose Our study examines the prevalence of all 5 cardiac abnormalities, and the accuracy of biomarkers in identifying them in a cohort of patients with well-controlled T2DM and blood pressure (BP) with no known cardiovascular symptom or disease. Methods This is a cross-sectional study of randomly selected patients with T2DM with no known cardiovascular symptom or disease, clinic BP or average 24-hour BP ≤140/80mmHg, and HbA1c ≤64mmol/mol. Patients with renal impairment, atrial fibrillation, moderate to severe valvular heart disease were excluded. All participants underwent transthoracic echocardiogram, electrocardiogram and dobutamine stress echocardiogram (DSE). Those who did not tolerate DSE or whose DSE was inconclusive, a myocardial perfusion scan or computed tomography coronary angiogram was done. Biomarkers such as BNP, NT-proBNP, high-sensitivity cardiac Troponin I (hs-cTnI), and high sensitivity cardiac Troponin T (hs-cTnT) were measured. Results Of 246 participants (mean age 66 years, 63% male), 141 (57.3%) had silent cardiac abnormalities. 90 (36.6%) had 1 cardiac abnormality, 44 (17.9%) had 2 cardiac abnormalities and 7 (2.8%) had 3 cardiac abnormalities. The most prevalent abnormality was LAE, n=106 (43.1%); followed by LVH, n=71 (28.9%); LVDD, n=13 (5.3%); MI, n=8 (3.3%); LVSD, n=1 (0.4%). Both NT-proBNP and hs-cTnI performed best in detecting silent cardiac abnormalities with p-values of 0.02 and 0.0004, and AUC 0.66 and 0.68 respectively. Increasing NT-proBNP (p=0.002) and hs-cTnI (p=0.002) levels correlated to increasing number of concomitant cardiac abnormalities. Our key new finding is that biomarkers identify those with multiple silent cardiac abnormalities. Conclusion BNP and high-sensitivity cardiac Troponin appear to identify those with multiple silent cardiac abnormalities which may make them useful screening tests so that cardiac investigations are focused on this high-risk subset, with a view to intensifying potential therapies on this subset to reduce the cardiotoxic effect of diabetes. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Chief Scientist Office

Global risk factors of contrast-induced acute kidney injury: systematic review and meta-analysis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
L Liu ◽  
Y Liu ◽  
S Chen ◽  
E.Y.M Chung ◽  
L Lei ◽  
...  
Keyword(s):  
Risk Factors ◽  
Systematic Review ◽  
Acute Kidney Injury ◽  
Meta Analysis ◽  
Kidney Injury ◽  
Left Ventricular ◽  
Public Institution ◽  
Left Ventricular Ejection ◽  
Modifiable Risk Factors ◽  
Funding Source

Abstract Background Administration of iodinated contrast is common but may be associated with contrast-induced acute kidney injury (CI-AKI), particularly in at-risk patients. There is no recent systematic review of potentially modifiable risk factors. Methods We searched MEDLINE, Embase and the Cochrane Database of Systematic Reviews (to 30 th June 2019) for observational studies assessing risk factors associated with CI-AKI. Twelve potentially modifiable risk factors were finally included in this thematic review and meta-analysis. Random or fixed meta-analysis was performed to derive the adjusted odds ratio (aOR), and the population attributable risk (PAR) was calculated for each risk factor globally and by region. Findings We included 157 studies (2,297,863 participants). The global incidence of CI-AKI was 5.4%. The potentially modifiable risk factors included high contrast volume (PAR 33%), eight cardiovascular risk factors (diuretic use, multivessel coronary artery disease, acute coronary syndrome, hypertension, hypotension, heart failure, reduced left ventricular ejection fraction and intra-aortic balloon pump use) (combined PAR 76.2%) and three noncardiovascular risk factors (renal dysfunction, diabetes mellitus and anaemia) (combined PAR 47.4%) with geographical differences. Bubble chart of the 12 risk factors Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): National Science Foundation of China

Optimal doses of heart failure medication in women and men: perspective from daily clinical care

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Bots ◽  
N.C Onland-Moret ◽  
I.I Tulevski ◽  
G.A Somsen ◽  
H.M Den Ruijter
Keyword(s):  
Heart Failure ◽  
Clinical Care ◽  
Daily Practice ◽  
Left Ventricular ◽  
Cubic Splines ◽  
Public Institution ◽  
Angiotensin Ii Receptor Blocker ◽  
Funding Source ◽  
Target Dose ◽  
Natural Cubic Splines

Abstract Background Heart failure (HF) guidelines recommend equal target doses for women and men. Recently, these recommendations have been challenged as research suggested that women with HF with reduced Ejection Fraction (HFrEF) may reach optimal treatment effect at half of the guideline-recommended dose while men may require the full dose. However, it is unclear how often women and men reach guideline-recommended target doses in daily practice. Purpose To evaluate whether women and men with HF reach guideline-recommended target doses for Angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blocker (ARB), β-blockers (BB) and mineralocorticoid receptor antagonists (MRA) in daily practice. Methods We extracted data from 13 outpatient cardiology clinics for all individuals diagnosed with HF within 14 days leading up to their visit who were prescribed at least one guideline-recommended HF medication. HF was defined based on a combination of the cardiologist's diagnosis and left ventricular systolic or diastolic dysfunction determined during echocardiography. Guideline-recommended medication groups and target doses were taken from the 2016 ESC HF guidelines or from literature for medications not mentioned in the guidelines. To enable comparison between medications and medication groups, daily dose was converted to percentage of target dose. Mean change in percentage of target dose over consecutive medication prescriptions was modelled for men and women using natural cubic splines. Results We included 1254 patients with HF (48% women). Women were on average older at diagnosis (71 vs 67 years) and more often had hypertension (54.9 vs 44.3%), but less often had diabetes mellitus (13.5 vs 19.4%), a history of coronary heart disease (7.8 vs 19.6%,) or past cardiovascular interventions (8.7 vs 23.0%) than men. In total, 1069 patients were prescribed an ACEI/ARB (46% women), 920 a BB (48% women) and 243 an MRA (43% women). Women were more often prescribed only one medication than men (39.6 vs 33.2%, p=0.014). Approximately 14% of first prescriptions for all medications were at 100% of target dose or higher for both women and men, with the majority of prescriptions being either at 1–49% of target dose (47.2 vs 45.5%, respectively) or 50–99% of target dose (39.1 vs 40.8%, respectively). The natural cubic splines showed that this distribution did not change over consecutive drug prescriptions in either women or men. Only MRA prescriptions for men showed an upward trend and reached 100% of target dose. Conclusion In daily practice, both women and men were unlikely to reach guideline-recommended target doses for both ACEI/ARBs and BBs. For MRAs, women were less likely to reach target dose than men. Optimal dosing in HF is difficult for both sexes, but in light of recent evidence, the challenge in daily practice seems to lie more in undertreatment of men than overtreatment of women. Figure 1 (women in red, men in blue) Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): ZonMw

SCN10A-knock-out improves survival and proarrhythmia in a transgenic heart failure mouse model

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
P.R.F Bengel ◽  
C Krekeler ◽  
S Ahmad ◽  
N Hartmann ◽  
P Tirilomis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Model ◽  
Sodium Channel ◽  
Structural Parameters ◽  
Left Ventricular ◽  
Heart Weight ◽  
Na Channel ◽  
Funding Source ◽  
Patch Clamp Technique ◽  
Knock Out

Abstract Background In heart failure (HF) both Ca2+/Calmodulin-dependent protein-kinase II (CaMKII) and late sodium current (INaL) are known to contribute to arrhythmogenesis as they contribute to action-potential (AP) prolongation and the occurrence of early- (EADs) and delayed afterdepolarizations (DADs). Further, augmented CaMKII and INaL maintain a vicious cycle as they both can activate each other. We recently found that the sodium channel isoform NaV1.8 is upregulated in HF and hypertrophy and that it is involved in INaL-generation. In the current study we investigated the effects of NaV1.8-knock-out (KO) on HF-progression and arrhythmogenesis in a CaMKII-overexpressing HF mouse model. Methods/Results CaMKII overexpressing mice (CaMKII+/T) were crossbred with NaV1.8-KO mice (SCN10A−/−). To our surprise knock-out of NaV1.8 in CaMKII+/T mice (SCN10A−/−/CaMKII+/T) significantly improved survival (median survival 103 days vs 74.5 CaMKII+/T, p&lt;0.01). CaMKII+/T mice exhibited a strong HF phenotype compared to WT with increased heart-weight to tibia length ratio as well as reduced ejection fraction and left-ventricular end-diastolic diameter obtained by echocardiography. However, these structural parameters did not differ between SCN10A−/−/CaMKII+/T and CaMKII+/T. Therefore, cellular electrophysiology experiments were performed in isolated cardiomyocytes for a better understanding of the observed improvement in survival. INaL, measured by patch-clamp technique, was significantly augmented in CaMKII+/T vs WT and SCN10A−/−, while SCN10A−/−/CaMKII+/T showed significantly less INaL than CaMKII+/T alone. Further, AP-duration (APD) was significantly reduced in SCN10A−/−/CaMKII+/T vs CaMKII+/T while AP-amplitude, resting membrane-potential and upstroke velocity (dv/dtmax) remained unchanged. In addition, the occurrence of afterdepolarizations was significantly lower in SCN10A−/−/ CaMKII+/T vs CaMKII+/T. Confocal microscopy using the dye Fluo-4AM was performed and significantly less diastolic Ca2+-waves occurred in SCN10A−/−/CaMKII+/T compared to CaMKII+/T. In order to analyze an organ-specific SCN10A-KO, we generated homozygous SCN10A-KO lines of induced pluripotent stem cells by using CRISPR/Cas9 technology. 2-month old iPSC-cardiomyocytes lacking NaV1.8 were treated with low dose isoprenaline and showed significantly less INaL, thereby serving as a final proof of the relevant role of this Na+-channel on INaL-generation in the cardiomyocyte. Conclusion We found a survival benefit by selective knock-out of the neuronal sodium channel isoform NaV1.8 in a proarrhythmic HF mouse model with augmented CaMKII expression. However, in our model NaV1.8-knock-out showed no effects on HF progression, while cellular proarrhythmic triggers were attenuated. Taken together with our findings in IPS-cardiomyocytes treated with the CRSIPR/Cas9 technology NaV1.8 plays a significant role for the generation of INaL and cellular arrhythmogenic triggers in the cardiomyocyte. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Deutsche Stiftung für Herzforschung

Smooth muscle cell-specific SOCS3 deficiency promote pericardial fibrosis and diastolic dysfunction in aging mice

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Yanai ◽  
H Yasukawa ◽  
K Mawatari ◽  
T Sasaki ◽  
J Takahashi ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Diastolic Dysfunction ◽  
Interstitial Fibrosis ◽  
Muscle Cells ◽  
Left Ventricular ◽  
Funding Source ◽  
Wild Type

Abstract Background Suppressor of cytokine signaling-3 (SOCS3) is a cytokine-inducible negative regulator of signal transducer and activator of transcription-3 (STAT3) signaling pathway. We have previously shown that cardiac-specific SOCS3 deficiency spontaneously develop cardiac dysfunction with advanced age. However, the role of SOCS3 in smooth muscle cells in cardiovascular pathophysiology remains elusive. In this study, we determined whether STAT3 and SOCS3 in smooth muscle cells would play a role in cardiovascular pathophysiology. Methods and results To target inactivation of the SOCS3 gene to smooth muscle cells, SOCS3-flox mice were bred with transgenic mice expressing Cre recombinase under control of the mouse SM22-α promoter (sm-SOCS3-KO mice). Left ventricular weight to body weight ratio was significantly increased in sm-SOCS3-KO mice compared with wild-type mice at 12 months of age (p&lt;0.05). Echocardiographic analyses of smSOCS3-KO mice showed significantly increased left ventricular diastolic dysfunction compared with wild-type from 12 months of age (p&lt;0.05). Sirius-red staining revealed that thickness of pericardium and cardiac interstitial fibrosis in sm-SOCS3-KO mice were markedly greater compared with wild-type mice at 12 months of age (p&lt;0.05). Western blot analyses showed that phosphorylated STAT3 was significantly increased in sm-SOCS3-KO hearts compared with wild-type mice at 12 months of age (p&lt;0.05), whereas no significant differences were observed at 2 months of age. To investigate the mechanism that gave rise to promoted cardiac fibrosis and diastolic dysfunction during aging in sm-SOCS3-KO, we conducted a real-time PCR array analysis for fibrosis. The expression of pro-fibrotic CTGF (connective tissue growth factor), PDGFb (platelet growth factor-b), and TGF (transforming growth factor) family genes including TGFb1, TGFb2, and TGFb3, were significantly higher in sm-SOCS3-KO hearts than those in wild-type at 6 months of age. Conclusion Thus, smooth muscle cell-specific SOCS3 deletion induces increased pericardial fibrosis, cardiac interstitial fibrosis, and increased diastolic dysfunction in aging mice, possibly through the augmentation of pro-fibrotic growth factors. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grant JSPS KAKENHI

scholarly journals Na channel distribution in vertebrate skeletal muscle.

1986 ◽  
Vol 87 (6) ◽  
pp. 907-932 ◽  
Author(s):  
J H Caldwell ◽  
D T Campbell ◽  
K G Beam
Keyword(s):  
Skeletal Muscle ◽  
Current Density ◽  
Sharp Decrease ◽  
Na Channel ◽  
Na Current ◽  
Na Currents ◽  
Current Densities ◽  
Kinetics Of ◽  
A Current ◽  
Vertebrate Skeletal Muscle

The loose patch voltage clamp has been used to map Na current density along the length of snake and rat skeletal muscle fibers. Na currents have been recorded from (a) endplate membrane exposed by removal of the nerve terminal, (b) membrane near the endplate, (c) extrajunctional membrane far from both the endplate and the tendon, and (d) membrane near the tendon. Na current densities recorded directly on the endplate were extremely high, exceeding 400 mA/cm2 in some patches. The membrane adjacent to the endplate has a current density about fivefold lower than that of the endplate, but about fivefold higher than the membrane 100-200 micron from the endplate. Small local variations in Na current density are recorded in extrajunctional membrane. A sharp decrease in Na current density occurs over the last few hundred micrometers from the tendon. We tested the ability of tetrodotoxin to block Na current in regions close to and far from the endplate and found no evidence for toxin-resistant channels in either region. There was also no obvious difference in the kinetics of Na current in the two regions. On the basis of the Na current densities measured with the loose patch clamp, we conclude that Na channels are abundant in the endplate and near-endplate membrane and are sparse close to the tendon. The current density at the endplate is two to three orders of magnitude higher than at the tendon.

scholarly journals Brugada syndrome: A brand new case

2009 ◽  
Vol 66 (8) ◽  
pp. 667-670
Author(s):  
Ruzica Jurcevic ◽  
Lazar Angelkov ◽  
Dejan Vukajlovic ◽  
Velibor Ristic ◽  
Milosav Tomovic ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Ventricular Fibrillation ◽  
Brugada Syndrome ◽  
Electrophysiological Study ◽  
Structural Heart Disease ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Type I ◽  
Ventricular Ejection Fraction ◽  
St Segment Elevation

Background: Brugada syndrome (BS) is a disorder characterized by syncope or sudden death associated with one of several electrocardiographic (ECG) patterns characterized by incomplete right bundle branch block and ST elevation in the anterior precordial leads. Patients with BS are prone to develop ventricular tachyarrhythmias that may lead to syncope, cardiac arrest, or sudden cardiac death. Case report. A 58-year-old woman is the first described case of Brugada syndrome in Serbia with intermittent typical changes in basic electrocardiography (ECG): ST segment elevation in the precordial chest leads like dome or coved - major form or type I. For the last 27 years the patient had suffered of palpitations and dizziness, without syncopal events. Her sister had died suddenly during the night in sleep. During 24-hour Holter monitoring the patient had ventricular premature beats during the night with R/T phenomenon and during the recovery phase of exercise testing had rare premature ventricular beats as the consequence of parasympatethic stimulation. Late potentials were positive. Echocardiography revealed left ventricular ejection fraction of 60%. We performed coronary angiography and epicardial coronary arteries were without significant stenosis and structural heart disease was excluded. In the bigining of the electrophysiological study ECG was normal, and after administration of Propaphenon i.v. Brugada syndrome unmasked with appearance of type I ECG pattern. A programed ventricular stimulation induced non sustained ventricular tachycardia. One-chamber implantable cardioverter defibrillator was implanted and the patient was treated with a combination od amiodarone and metoprolol per os. After one-year follow-up, there were no episodes of ventricular tachycardia and ventricular fibrillation. Conclusion. Brugada syndrome is a myocardial disorder which prognosis and therapy are related to presence of ventricular fibrillation or ventricular tachycardia. Electrophysiologicaly induced malignant ventricular disorders class I are indication for implantation of cardioverter defibrilator, as also occurred in presented patient.

Sign in / Sign up

Export Citation Format

Share Document