Abstract:
BACKGROUND:Familial polymorphic ventricular tachycardia (FPVT) is characterized by exercise-induced arrhythmias and sudden cardiac death due to missense mutations in the cardiac ryanodine receptor (RyR2), an intracellular Ca2+ release channel required for excitation-contraction coupling in the heart. METHODS AND RESULTS:Three RyR2 missense mutations, P2328S, Q4201R, and V4653F, which occur in Finnish families, result in similar mortality rates of approximately 33% by age 35 years and a threshold heart rate of 130 bpm, above which exercise induces ventricular arrhythmias. Exercise activates the sympathetic nervous system, increasing cardiac performance as part of the fight-or-flight stress response. We simulated the effects of exercise on mutant RyR2 channels using protein kinase A (PKA) phosphorylation. All 3 RyR2 mutations exhibited decreased binding of calstabin2 (FKBP12.6), a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, FPVT-mutant RyR2 channels showed a significant gain-of-function defect consistent with leaky Ca2+ release channels and a significant rightward shift in the half-maximal inhibitory Mg2+ concentration (IC50). Treatment with the experimental drug JTV519 enhanced binding of calstabin2 to RyR2 and normalized channel function. CONCLUSIONS:Sympathetic activation during exercise induces ventricular arrhythmias above a threshold heart rate in RyR2 mutation carriers. Simulating the downstream effects of the sympathetic activation by PKA phosphorylation of RyR2 channels containing these FPVT missense mutations produced a consistent gain-of-function defect. RyR2 function and calstabin2 depletion were rescued by JTV519, suggesting stabilization of the RyR2 channel complex may represent a molecular target for the treatment and prevention of exercise-induced arrhythmias and sudden death in these patients.
journal_name
Circulationjournal_title
Circulationauthors
Lehnart SE,Wehrens XH,Laitinen PJ,Reiken SR,Deng SX,Cheng Z,Landry DW,Kontula K,Swan H,Marks ARdoi
10.1161/01.CIR.0000132472.98675.ECsubject
Has Abstractpub_date
2004-06-29 00:00:00pages
3208-14issue
25eissn
0009-7322issn
1524-4539pii
01.CIR.0000132472.98675.ECjournal_volume
109pub_type
杂志文章相关文献
CIRCULATION文献大全abstract:BACKGROUND:The quantity and intensity of physical activity required for the primary prevention of coronary heart disease (CHD) remain unclear. Therefore, we examined the association of the quantity and intensity of physical activity with CHD risk and the impact of other coronary risk factors. METHODS AND RESULTS:We fo...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.102.9.975
更新日期:2000-08-29 00:00:00
abstract::Two-dimensional echocardiography can provide serial cross-sectional images of the left ventricular cavity. We examined whether such serial images from steady-state ejecting hearts would allow three-dimensional reconstruction and accurate volume estimation without major geometric assumptions. Cross-circulated, paced do...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.60.2.320
更新日期:1979-08-01 00:00:00
abstract:BACKGROUND:Aortic valve replacement remains the treatment of choice for aortic valve disease, even in the extreme elderly who may present with advanced symptoms. Defining risk factors for short-term survival was the object of this study. METHODS AND RESULTS:This was a retrospective analysis of 717 patients at least 70...
journal_title:Circulation
pub_type: 杂志文章
doi:
更新日期:1993-11-01 00:00:00
abstract::The modulated receptor hypothesis states that sodium channels have a specific receptor for antiarrhythmic drugs. Therefore, two agents that block sodium channels by binding to this receptor are expected to compete for occupancy. Glycylxylidide (GX) is a deethylated metabolite of lidocaine that accumulates in patients ...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.78.3.692
更新日期:1988-09-01 00:00:00
abstract:BACKGROUND:This experiment sought to determine the effects of fish oil on superoxide anion production in the myocardium and coronary arteries of atherosclerotic monkeys. Recent evidence indicates that dietary supplementation with fish oil preserves normal vasomotion of atherosclerotic coronary arteries and reduces dama...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.91.4.1123
更新日期:1995-02-15 00:00:00
abstract:BACKGROUND:Optimal management of acute pulmonary embolism (PE) requires medical expertise, diagnostic testing, and therapies that may not be available consistently throughout the entire week. We sought to assess whether associations exist between weekday or weekend admission and mortality and length of hospital stay fo...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.108.824292
更新日期:2009-02-24 00:00:00
abstract:BACKGROUND:Coronary sinus access by electrode catheters is easier in patients with atrioventricular junctional reentry tachycardia (AVJRT) than in patients with other supraventricular tachyarrhythmias. The reason for this has not been addressed. METHODS AND RESULTS:The size and shape of the proximal coronary sinus wer...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.92.3.436
更新日期:1995-08-01 00:00:00
abstract:BACKGROUND:The beneficial effect of low-dose aspirin in the prevention of coronary vasospasm is well documented. In this study, we investigated the contractile effect of human washed platelets on the human isolated coronary artery. We concentrated on the effect of low-dose aspirin (40 mg/d) taken by the platelet donor ...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.89.2.623
更新日期:1994-02-01 00:00:00
abstract::Cerebral and retinal ischemic events have been described in mitral valve prolapse. To determine whether platelets play a part in the pathogenesis of thromboembolism we studied 29 patients with mitral valve prolapse, including nine (group I) with thromboembolism (cerebral, retinal and deep venous), eight (group II) wit...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.63.3.552
更新日期:1981-03-01 00:00:00
abstract:BACKGROUND:Uncertainty exists regarding the frequency of early occlusion when the left internal mammary artery (LIMA) is anastomosed to the left anterior descending artery (LAD) through a sternotomy with conventional coronary artery bypass grafting (CABG). The issue has gained importance for comparison with less invasi...
journal_title:Circulation
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1161/01.cir.100.23.2353
更新日期:1999-12-07 00:00:00
abstract:BACKGROUND:Prior small to modest-sized studies suggest a benefit of intravascular ultrasound (IVUS) guidance in noncomplex lesions. Whether IVUS guidance is associated with improved clinical outcomes after drug-eluting stent (DES) implantation in an unrestricted patient population is unknown. METHODS AND RESULTS:Asses...
journal_title:Circulation
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1161/CIRCULATIONAHA.113.003942
更新日期:2014-01-28 00:00:00
abstract:BACKGROUND:The recent breakthrough in the generation of induced pluripotent stem (iPS) cells, which are almost indistinguishable from embryonic stem (ES) cells, facilitates the generation of murine disease- and human patient-specific stem cell lines. The aim of this study was to characterize the cardiac differentiation...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.108.778795
更新日期:2008-07-29 00:00:00
abstract:BACKGROUND:The potential biological significance of hydrogen sulfide (H(2)S) has attracted growing interest in recent years. The aim of this study was to characterize a novel, water-soluble, slow-releasing H(2)S compound [morpholin-4-ium 4 methoxyphenyl(morpholino) phosphinodithioate (GYY4137)] and evaluate its use as ...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.107.753467
更新日期:2008-05-06 00:00:00
abstract:BACKGROUND:Fibrosis and progressive failure are prominent pathophysiological features of hearts after myocardial infarction (MI). We examined the effects of inhibiting transforming growth factor-beta (TGF-beta) signaling on post-MI cardiac fibrosis and ventricular remodeling and function. METHODS AND RESULTS:MI was in...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.CIR.0000165066.71481.8E
更新日期:2005-05-17 00:00:00
abstract:BACKGROUND:One of the features of high-risk atherosclerotic plaques is a preponderance of macrophages. Experimental studies with hyperlipidemic rabbits have shown that ultrasmall superparamagnetic particles of iron oxide (USPIOs) accumulate in plaques with a high macrophage content and that this induces magnetic resona...
journal_title:Circulation
pub_type: 临床试验,杂志文章
doi:10.1161/01.CIR.0000068315.98705.CC
更新日期:2003-05-20 00:00:00
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). Exp...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.113.003077
更新日期:2014-03-11 00:00:00
abstract::A clinical study was conducted to evaluate the efficacy and safety of percutaneous coronary excimer laser angioplasty in 60 patients with coronary artery disease. Forty-nine patients had stable exertional angina, and 11 patients had unstable angina despite medical therapy. A novel 1.4-mm diameter catheter with 20 quar...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.81.6.1849
更新日期:1990-06-01 00:00:00
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:Vascular injury and atherothrombosis involve vessel infiltration by inflammatory leukocytes, migration of medial vascular smooth muscle cells to the intimal layer, and ultimately acute thrombosis. A strategy to simultaneously target these pathological processes has yet to be identified. The secreted protein,...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.112.105452
更新日期:2012-09-11 00:00:00
abstract:BACKGROUND:Recognition of the complex pathophysiology of heart failure and its high mortality has emphasized the need for prognostic markers that can be used in clinical assessment as well as in the design of mortality trials. Data from the Department of Veterans Affairs Cooperative Vasodilator-Heart Failure Trials (V-...
journal_title:Circulation
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:
更新日期:1993-06-01 00:00:00
abstract:BACKGROUND:Recently, it was reported that the degree of microvascular injury and left ventricular functional recovery during the chronic period can be predicted after treatment of the infarct-related artery based on the coronary flow velocity (CFV) pattern assessed using a Doppler guidewire. The aim of this prospective...
journal_title:Circulation
pub_type: 临床试验,杂志文章
doi:10.1161/01.cir.0000043022.44032.77
更新日期:2002-12-10 00:00:00
abstract:BACKGROUND:Swimming-induced pulmonary edema (SIPE) occurs during swimming or scuba diving, often in young individuals with no predisposing conditions, and its pathophysiology is poorly understood. This study tested the hypothesis that pulmonary artery and pulmonary artery wedge pressures are higher in SIPE-susceptible ...
journal_title:Circulation
pub_type: 临床试验,杂志文章
doi:10.1161/CIRCULATIONAHA.115.019464
更新日期:2016-03-08 00:00:00
abstract:BACKGROUND:To simplify extensive primary repair of the thoracic aorta in acute type A aortic dissection, we developed the open triple-branched stent graft placement technique. The early results of this new technique are reported. METHODS AND RESULTS:Between June 2008 and November 2009, 30 patients with acute Stanford ...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.110.946012
更新日期:2010-10-05 00:00:00
abstract:BACKGROUND:Adrenomedullin is a recently discovered endogenous peptide with hypotensive and natriuretic actions in normal animals. Circulating and ventricular adrenomedullin are elevated in congestive heart failure, suggesting a possible role in the pathophysiology of this disease. No studies have previously examined th...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.96.6.1983
更新日期:1997-09-16 00:00:00
abstract:BACKGROUND:Thrombin plays a role in mediating ischemic injury and cardiac arrhythmias, but the mechanisms involved are poorly understood. Because voltage-gated sodium channels (VGSCs) have not previously been considered, putative effects of thrombin on VGSC function were investigated in human isolated cardiomyocytes. ...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.0000034510.64828.96
更新日期:2002-10-15 00:00:00
abstract::Patients with systemic morphological right ventricles (RVs), including congenitally corrected transposition of the great arteries and dextro-transposition of the great arteries with a Mustard or Senning atrial baffle repair, have a high likelihood of developing systemic ventricular dysfunction. Unfortunately, there ar...
journal_title:Circulation
pub_type: 杂志文章,meta分析
doi:10.1161/CIR.0000000000000604
更新日期:2019-04-02 00:00:00
abstract:OBJECTIVE:To assess the outcome of 3 different surgical approaches for treatment of acute aortic dissection type A (AADA). METHODS AND RESULTS:Between October 1990 and October 2003, we operated on 295 patients (pts) for AADA. Follow-up was complete for 257 pts (87%). Supracommissural replacement (SCR) of the ascending...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.CIR.0000138948.14144.d6
更新日期:2004-09-14 00:00:00
abstract::Little is known of the functional capacity of coronary collaterals in humans without occlusive coronary artery disease. We, therefore, measured peripheral coronary pressure (PCP) and retrograde flow (RF) from coronary arteries at aortic valve replacement in seven patients without occlusive coronary artery disease. Usi...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.51.1.118
更新日期:1975-01-01 00:00:00
abstract:BACKGROUND:Cardiovascular disease (CVD) is the leading cause of death in the United States and is responsible for 17% of national health expenditures. As the population ages, these costs are expected to increase substantially. METHODS AND RESULTS:To prepare for future cardiovascular care needs, the American Heart Asso...
journal_title:Circulation
pub_type: 共识发展会议,杂志文章
doi:10.1161/CIR.0b013e31820a55f5
更新日期:2011-03-01 00:00:00
abstract:BACKGROUND:This study was performed to determine whether chronic cocaine abuse is associated with left ventricular hypertrophy in humans. METHODS AND RESULTS:A consecutive series of 40 chronic cocaine abusers 23-44 years old who were enrolled in an inpatient drug rehabilitation program were considered for the study. S...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.84.3.1130
更新日期:1991-09-01 00:00:00