Abstract:
BACKGROUND:Brugada syndrome (BrS) primarily associates with the loss of sodium channel function. Previous studies showed features consistent with sodium current (INa) deficit in patients carrying desmosomal mutations, diagnosed with arrhythmogenic cardiomyopathy (or arrhythmogenic right ventricular cardiomyopathy). Experimental models showed correlation between the loss of expression of desmosomal protein plakophilin-2 (PKP2) and reduced INa. We hypothesized that PKP2 variants that reduce INa could yield a BrS phenotype, even without overt structural features characteristic of arrhythmogenic right ventricular cardiomyopathy. METHODS AND RESULTS:We searched for PKP2 variants in the genomic DNA of 200 patients with a BrS diagnosis, no signs of arrhythmogenic cardiomyopathy, and no mutations in BrS-related genes SCN5A, CACNa1c, GPD1L, and MOG1. We identified 5 cases of single amino acid substitutions. Mutations were tested in HL-1-derived cells endogenously expressing NaV1.5 but made deficient in PKP2 (PKP2-KD). Loss of PKP2 caused decreased INa and NaV1.5 at the site of cell contact. These deficits were restored by the transfection of wild-type PKP2, but not of BrS-related PKP2 mutants. Human induced pluripotent stem cell cardiomyocytes from a patient with a PKP2 deficit showed drastically reduced INa. The deficit was restored by transfection of wild type, but not BrS-related PKP2. Super-resolution microscopy in murine PKP2-deficient cardiomyocytes related INa deficiency to the reduced number of channels at the intercalated disc and increased separation of microtubules from the cell end. CONCLUSIONS:This is the first systematic retrospective analysis of a patient group to define the coexistence of sodium channelopathy and genetic PKP2 variations. PKP2 mutations may be a molecular substrate leading to the diagnosis of BrS.
journal_name
Circulationjournal_title
Circulationauthors
Cerrone M,Lin X,Zhang M,Agullo-Pascual E,Pfenniger A,Chkourko Gusky H,Novelli V,Kim C,Tirasawadichai T,Judge DP,Rothenberg E,Chen HS,Napolitano C,Priori SG,Delmar Mdoi
10.1161/CIRCULATIONAHA.113.003077subject
Has Abstractpub_date
2014-03-11 00:00:00pages
1092-103issue
10eissn
0009-7322issn
1524-4539pii
CIRCULATIONAHA.113.003077journal_volume
129pub_type
杂志文章相关文献
CIRCULATION文献大全abstract::To determine the long-term efficacy of apical left ventricular to aortic conduits in palliating complex left ventricular outflow obstruction, we reviewed our entire experience of 20 pediatric patients who underwent placement of a composite porcine valve-bearing conduit from the left ventricular apex to the aorta from ...
journal_title:Circulation
pub_type: 杂志文章
doi:
更新日期:1991-11-01 00:00:00
abstract:BACKGROUND:Morbidity and mortality after conventional repair of thoracoabdominal aneurysms remain high. Alternative techniques have been proposed and are the subject of this report. METHODS AND RESULTS:Endovascular grafts that have a means of incorporating the visceral vessels into the aortic repair were divided into ...
journal_title:Circulation
pub_type: 杂志文章,评审
doi:10.1161/CIRCULATIONAHA.107.716134
更新日期:2008-04-29 00:00:00
abstract:BACKGROUND:We measured cardiovagal baroreflex gain and its vascular mechanical and neural components during dynamic baroreflex engagement in 10 young untrained men, 6 older untrained men, and 12 older, physically active men. METHODS AND RESULTS:Our newly developed assessment of beat-to-beat carotid diameters during ba...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.103.20.2424
更新日期:2001-05-22 00:00:00
abstract::We studied 14 patients to determine whether sustained-release diltiazem is a satisfactory long-term substitute for the combination of propranolol plus hydrochlorothiazide (HCTZ), control phase, in the treatment of systemic hypertension with coexisting chronic stable angina pectoris. All patients had either one- or two...
journal_title:Circulation
pub_type: 杂志文章
doi:
更新日期:1989-12-01 00:00:00
abstract:BACKGROUND:Long-term beta-adrenergic blockade does not appear to be associated with drug-induced training in patients with congestive heart failure (CHF); whether exercise training can increase peak aerobic capacity in patients with CHF who are treated with beta-adrenergic blockers is currently unknown. METHODS AND RE...
journal_title:Circulation
pub_type: 临床试验,杂志文章
doi:10.1161/01.cir.95.7.1764
更新日期:1997-04-01 00:00:00
abstract:BACKGROUND:Long-term comparative data of first-generation drug-eluting stents are scarce. We investigated clinical and angiographic outcomes of sirolimus-eluting (SES) and paclitaxel-eluting stents (PES) at 5 years as part of the Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization (SIRTAX)...
journal_title:Circulation
pub_type: 杂志文章,随机对照试验
doi:10.1161/CIRCULATIONAHA.110.004762
更新日期:2011-06-21 00:00:00
abstract:BACKGROUND:Peripheral adiposity confers protection against diabetes and atherosclerosis in elderly women. The underlying mechanisms, however, remain to be elucidated. METHODS AND RESULTS:On the basis on dual-energy X-ray absorptiometry measurements of central fat mass (CFM) and peripheral fat mass (PFM), we identified...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.CIR.0000144470.55149.E5
更新日期:2004-10-12 00:00:00
abstract:BACKGROUND:The suggestion that increased QT dispersion (QTD) is due to increased differences in local action potential durations within the myocardium is wanting. An alternative explanation was sought by relating QTD to vectorcardiographic T-loop morphology. METHODS AND RESULTS:The T loop is characterized by its ampli...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.99.11.1458
更新日期:1999-03-23 00:00:00
abstract:BACKGROUND:Diabetes is an independent risk factor for the development of neointimal hyperplasia and subsequent vein graft failure after coronary or peripheral artery bypass grafting. We evaluate a new mouse model of surgical vein grafting to investigate the mechanisms of neointimal formation in the setting of type 2 di...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.105.001339
更新日期:2006-07-04 00:00:00
abstract:BACKGROUND:Two types of ischemia, pacing-induced and coronary occlusion-induced, have different effects on left ventricular diastolic properties. During pacing-induced ischemia, the diastolic pressure-volume relation is said to shift upward, whereas during coronary occlusion, it is said to shift rightward or downward. ...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.91.9.2423
更新日期:1995-05-01 00:00:00
abstract:BACKGROUND:Tetralogy of Fallot is the most common form of congenital heart disease in implantable cardioverter-defibrillator (ICD) recipients, yet little is known about the value of ICDs in this patient population. METHODS AND RESULTS:We conducted a multicenter cohort study in high-risk patients with Tetralogy of Fall...
journal_title:Circulation
pub_type: 杂志文章,多中心研究
doi:10.1161/CIRCULATIONAHA.107.726372
更新日期:2008-01-22 00:00:00
abstract:BACKGROUND:Although hepatocyte growth factor (HGF), a novel angiogenic growth factor, plays an important role in angiogenesis, regulation of local HGF production under hypoxia has not yet been clarified in vascular smooth muscle cells (VSMC) and endothelial cells (EC). Thus, we have studied the role of HGF in hypoxia-i...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.100.suppl_2.ii-301
更新日期:1999-11-09 00:00:00
abstract:BACKGROUND:The mechanism of ECG changes and arrhythmogenesis in Brugada syndrome (BS) patients is unknown. METHODS AND RESULTS:A BS patient without clinically detected cardiac structural abnormalities underwent cardiac transplantation for intolerable numbers of implantable cardioverter/defibrillator discharges. The pa...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.105.532614
更新日期:2005-11-01 00:00:00
abstract:BACKGROUND:The role of angiotensin as a vasoconstrictor is well established. Lately, several other actions of this hormone on vascular smooth muscle (VSM) cells have been recognized including the induction of hypertrophy and/or DNA synthesis. Platelet-derived growth factor (PDGF), a mitogen recently shown to increase p...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.90.1.362
更新日期:1994-07-01 00:00:00
abstract::The rapid development of new drugs, therapies, and devices has created a dramatic increase in the number of trials needed to properly evaluate them. The majority of patients treated today, many of whom could be eligible for participation in these studies, are seen in community hospitals and medical practices that are ...
journal_title:Circulation
pub_type: 杂志文章,评审
doi:10.1161/01.CIR.0000128702.16441.75
更新日期:2004-06-01 00:00:00
abstract:BACKGROUND:The effects of ultrasound-guided high-pressure stenting on late stent and reference segment dimensions are unknown. In this study, we report about angiographic and ultrasound measurements to assess the amount and distribution of neointimal ingrowth within the stent and the changes of plaque burden and dimens...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.95.2.363
更新日期:1997-01-21 00:00:00
abstract::A consecutive series of 17 patients surgically treated for asymptomatic coronary artery disease was surveyed for survival, clinical status, and graft patency after a mean follow-up of 75 months. Documented myocardial infarction (MI), 14 transmural and 3 subendocardial, was the major indication for catheterization. All...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.60.2.14
更新日期:1979-08-01 00:00:00
abstract::Patients with heart failure frequently exhibit abnormal skeletal muscle metabolic responses to exercise, as assessed with 31P NMR. To investigate whether these metabolic abnormalities are due to intrinsic skeletal muscle changes, we performed gastrocnemius muscle biopsies on 22 patients with heart failure (peak VO2, 1...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.80.5.1338
更新日期:1989-11-01 00:00:00
abstract::An external cardiac pacemaker-monitor has been developed that provides safe, effective noninvasive ventricular stimulation that is well tolerated in conscious patients and allows clear recognition of electrocardiographic response. The noninvasive temporary pacemaker (NTP) has now been applied in 134 patients in five h...
journal_title:Circulation
pub_type: 临床试验,杂志文章
doi:10.1161/01.cir.71.5.937
更新日期:1985-05-01 00:00:00
abstract:BACKGROUND:Although surgery is indicated in patients with mitral regurgitation (MR) when left ventricular (LV) end-systolic (LVES) dimension is >40 mm, LV ejection fraction may decrease after mitral valve surgery. We hypothesize that significant LV remodeling before surgery is not reflected by standard echocardiographi...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.111.073239
更新日期:2012-05-15 00:00:00
abstract:BACKGROUND:Unstable atherosclerotic lesions typically have an abundant inflammatory cell infiltrate, including activated T cells, macrophages, and mast cells, which may decrease plaque stability. The pathophysiology of inflammatory cell recruitment and activation in the human atheroma is incompletely described. METHOD...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.102.18.2185
更新日期:2000-10-31 00:00:00
abstract::Patients with congestive heart failure have a high incidence of sudden cardiac death that is attributed to ventricular arrhythmias. The mortality rate in a group of patients with class III and IV heart failure is about 40% per year, and half of the deaths are sudden. Half of the patients with New York Heart Associatio...
journal_title:Circulation
pub_type: 杂志文章,评审
doi:
更新日期:1987-05-01 00:00:00
abstract:BACKGROUND:Increased diastolic chamber stiffness (increased DCS) during angina (demand ischemia) has been postulated to be generated by increased diastolic myocyte calcium concentration. METHODS AND RESULTS:We reproduced demand ischemia in isolated isovolumically contracting red-cell-perfused rabbit hearts by imposing...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.101.18.2185
更新日期:2000-05-09 00:00:00
abstract::We used Doppler echocardiography to quantitate the changes in intracardiac blood flow velocities and right and left ventricular stroke volumes in 80 normal human fetuses from 19 to 40 weeks gestation. Blood flow velocity spectra across the aortic, pulmonary, tricuspid, and mitral valves were digitized to obtain peak v...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.74.6.1208
更新日期:1986-12-01 00:00:00
abstract::We report noninvasive and invasive studies designed to clarify the mechanism of the third heart sound (S3) in humans. The noninvasive observations were made using a miniature accelerometer attached to the skin surface at the cardiac apex. In subjects with no S3, the tracings were either flat or showed very low undulat...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.67.2.399
更新日期:1983-02-01 00:00:00
abstract::Seven of 214 patients (3%) with acute myocardial infarction (120 inferior and 94 anterior) developed atrial fibrillation within 3 hr of the onset of chest pain. All seven patients had an inferior infarction and in all seven the left circumflex artery was occluded proximal to the origin of its left atrial circumflex br...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.75.1.146
更新日期:1987-01-01 00:00:00
abstract:BACKGROUND:Laminins are major components of basement membranes, well located to interact with platelets upon vascular injury. Laminin-111 (α1β1γ1) is known to support platelet adhesion but is absent from most blood vessels, which contain isoforms with the α2, α4, or α5 chain. Whether vascular laminins support platelet ...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.112.000799
更新日期:2013-07-30 00:00:00
abstract::The specific and sensitivity of serum creatine phosphokinase cardiac specific isoenzyme (MB) in the diagnosis of acute myocardial infarction (AMI) was evaluated. An ion-exchange chromatographic technique was used to isolate MB. Sera layered on mini-columns of DEAE-Sephadex were eluted with Tris-buffered sodium chlorid...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.51.5.855
更新日期:1975-05-01 00:00:00
abstract:BACKGROUND:Although intercellular adhesion molecule-1 (ICAM-1) is known to be expressed in balloon-injured arteries, it remains unknown whether ICAM-1 plays a role in the progression of intimal hyperplasia (IH) induced by balloon injury. METHODS AND RESULTS:We examined the ICAM-1 expression in rat carotid arteries at ...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.95.6.1515
更新日期:1997-03-18 00:00:00
abstract:BACKGROUND:Biological pacemakers (BPM) implanted in canine left bundle branch function competitively with electronic pacemakers (EPM). We hypothesized that BPM engineered with the use of mE324A mutant murine HCN2 (mHCN2) genes would improve function over mHCN2 and that BPM/EPM tandems confer advantage over either appro...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.106.617613
更新日期:2006-09-05 00:00:00