Abstract:
BACKGROUND:Genetic testing for long-QT syndrome (LQTS) has diagnostic, prognostic, and therapeutic implications. Hundreds of causative mutations in 12 known LQTS-susceptibility genes have been identified. Genetic testing that includes the 3 most commonly mutated genes is available clinically. Distinguishing pathogenic mutations from innocuous rare variants is critical to the interpretation of test results. We sought to quantify the value of mutation type and gene/protein region in determining the probability of pathogenicity for mutations. METHODS AND RESULTS:Type, frequency, and location of mutations across KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3) were compared between 388 unrelated "definite" (clinical diagnostic score >or=4 and/or QTc >or=480 ms) cases of LQTS and >1300 healthy controls for each gene. From these data, estimated predictive values (percent of mutations found in definite cases that would cause LQTS) were determined according to mutation type and location. Mutations were 10 times more common in cases than controls (0.58 per case versus 0.06 per control). Missense mutations were the most common, accounting for 78%, 67%, and 89% of mutations in KCNQ1, KCNH2, and SCN5A in cases and >95% in controls. Nonmissense mutations have an estimated predictive value >99% regardless of location. In contrast, location appears to be critical for characterizing missense mutations. Relative frequency of missense mutations between cases and controls ranged from approximately 1:1 in the SCN5A interdomain linker to infinity in the pore, transmembrane, and linker in KCNH2. These correspond to estimated predictive values ranging from 0% in the interdomain linker of SCN5A to 100% in the transmembrane/linker/pore regions of KCNH2. The estimated predictive value is also high in the linker, pore, transmembrane, and C terminus of KCNQ1 and the transmembrane/linker of SCN5A. CONCLUSIONS:Distinguishing pathogenic mutations from rare variants is of critical importance in the interpretation of genetic testing in LQTS. Mutation type, mutation location, and ethnic-specific BACKGROUND:should be viewed as variants of uncertain significance and prompt further investigation to clarify the likelihood of disease causation. However, mutations in regions such as the transmembrane, linker, and pore of KCNQ1 and KCNH2 may be defined confidently as high-probability LQTS-causing mutations. These findings will have implications for other genetic disorders involving mutational analysis.
journal_name
Circulationjournal_title
Circulationauthors
Kapa S,Tester DJ,Salisbury BA,Harris-Kerr C,Pungliya MS,Alders M,Wilde AA,Ackerman MJdoi
10.1161/CIRCULATIONAHA.109.863076subject
Has Abstractpub_date
2009-11-03 00:00:00pages
1752-60issue
18eissn
0009-7322issn
1524-4539pii
CIRCULATIONAHA.109.863076journal_volume
120pub_type
杂志文章相关文献
CIRCULATION文献大全abstract:BACKGROUND:C-reactive protein (CRP) may have proatherogenic but also vasoprotective properties. We tested the hypothesis that the configuration of CRP (pentameric, or native [nCRP], versus monomeric, or modified [mCRP]) determines these different characteristics in an in vivo model. METHODS AND RESULTS:We investigated...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.105.556530
更新日期:2005-08-16 00:00:00
abstract::The concept of plaque stabilization was developed to explain how lipid lowering could decrease adverse coronary events without a substantial reduction in the regression of atherosclerosis. Plaques were stabilized by reducing serum cholesterol leading to several favorable pathobiological changes in the vessel wall of l...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.0000012528.89469.8e
更新日期:2002-04-23 00:00:00
abstract::Global ventricular function was evaluated by both multiple gated cardiac blood pool scans (MUGA) and contrast ventriculograms in a group of 17 patients with suspected coronary artery disease. The contrast ventriculograms were analyzed frame by frame to generate a volume versus time curve for each patient, while the tr...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.56.6.1024
更新日期:1977-12-01 00:00:00
abstract:BACKGROUND:Endothelial integrity is essential for maintaining vascular homeostasis, and endothelial denudation results in neointimal thickening. Balloon-expandable endovascular stents provide a luminal scaffolding within atherosclerotic arteries with minimal direct contact between balloon and endothelium. We wondered w...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.94.11.2909
更新日期:1996-12-01 00:00:00
abstract:BACKGROUND:Although early intravenous beta-blocker therapy during acute myocardial infarction (AMI) reduces the incidence of fatal arrhythmias in patients not treated with thrombolytic agents, its antiarrhythmic effect in thrombolysed patients remains controversial. We investigated prospectively the arrhythmia incidenc...
journal_title:Circulation
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1161/01.cir.89.3.1051
更新日期:1994-03-01 00:00:00
abstract::Prospective data was recorded on 217 percutaneous transluminal angioplasty (PTA) procedures performed in the superficial femoral and popliteal arteries over an 8-year period. After the initial procedure, patients were followed with serial noninvasive studies and, in 71 patients, repeat angiography. The mean follow-up ...
journal_title:Circulation
pub_type: 杂志文章
doi:
更新日期:1991-02-01 00:00:00
abstract:BACKGROUND:Ischemia reperfusion injury (IRI) predisposes to the formation of donor-specific antibodies, a factor contributing to chronic rejection and late allograft loss. METHODS:We describe a mechanism underlying the correlative association between IRI and donor-specific antibodies by using humanized models and pati...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.119.042501
更新日期:2020-02-11 00:00:00
abstract::Subaortic stenosis is well known to complicate the clinical course of patients with single ventricle or univentricular hearts, and we have previously suggested that the development of subaortic stenosis in such patients may be causal to and/or accelerated by previous banding of the main pulmonary trunk. To further def...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.73.4.758
更新日期:1986-04-01 00:00:00
abstract:BACKGROUND:Precise knowledge of the expected "normal" lumen diameter at a given coronary anatomic location is a first step toward developing a quantitative estimate of coronary disease severity that could be more useful than the traditional "percent stenosis." METHODS AND RESULTS:Eighty-three arteriograms were careful...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.86.1.232
更新日期:1992-07-01 00:00:00
abstract:BACKGROUND:Depressed ventricular performance and neurohormonal activation are key pathophysiological features of congestive heart failure (CHF). Although angiotensin-converting enzyme inhibitors and beta-adrenoceptor blockers exert beneficial effects in CHF, mortality remains unacceptably high, and the development of f...
journal_title:Circulation
pub_type: 临床试验,杂志文章
doi:10.1161/01.cir.103.19.2336
更新日期:2001-05-15 00:00:00
abstract:BACKGROUND:Early intervention with thrombolytic agents has been shown unequivocally to reduce mortality after acute myocardial infarction. Presently used agents have disadvantages such as short half-life, immunogenicity, hypotension, and bleeding complications. Therefore, there is a need to develop improved thrombolyti...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.86.2.548
更新日期:1992-08-01 00:00:00
abstract:BACKGROUND:The incidence of perinatal morbidity arising from birth hypoxia or asphyxia has not changed significantly in recent years despite marked improvements in labor management. Perinatal mortality in these circumstances may therefore reflect antenatal compromise and subsequent alteration of the fetal capacity to r...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.0000033827.48974.c8
更新日期:2002-10-22 00:00:00
abstract:BACKGROUND:Z-Val-Ala-Asp(OMe)-CH2F (ZVAD-fmk), a tripeptide inhibitor of the caspase interleukin-1beta-converting enzyme family of cysteine proteases, may reduce myocardial reperfusion injury in vivo by attenuating cardiomyocyte apoptosis within the ischemic area at risk. METHODS AND RESULTS:Sprague-Dawley rats were s...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.97.3.276
更新日期:1998-01-27 00:00:00
abstract:BACKGROUND:It has been suggested that intracellular Ca2+ overload in cardiac myocytes leads to the development of diabetic cardiomyopathy. Troglitazone, an insulin-sensitizing agent, is a promising therapeutic agent for diabetes and has been shown to prevent diabetes-induced myocardial changes. To elucidate the underly...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.99.22.2942
更新日期:1999-06-08 00:00:00
abstract:BACKGROUND:Early detection of adverse effects of novel therapies and understanding of their mechanisms could improve the safety and efficiency of drug development. We have retrospectively applied large-scale proteomics to blood samples from ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in...
journal_title:Circulation
pub_type: 杂志文章,随机对照试验
doi:10.1161/CIRCULATIONAHA.117.028213
更新日期:2018-03-06 00:00:00
abstract:BACKGROUND:There is compelling experimental evidence that autologous skeletal muscle (SM) cell transplantation improves postinfarction cardiac function. This study assessed whether this benefit is still manifested in the clinically relevant setting of a treatment by ACE inhibitors. METHODS AND RESULTS:A myocardial inf...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/hc37t1.094593
更新日期:2001-09-18 00:00:00
abstract::The endogenous opioid system includes three major families of peptides: dynorphins (derived from pre-proenkephalin B), endorphins (derived from pre-proopiomelanocortin), and enkephalins (derived from pre-proenkephalin A). Multiple species of opioid peptides are derived from these major precursors and many of them poss...
journal_title:Circulation
pub_type: 杂志文章,评审
doi:
更新日期:1987-01-01 00:00:00
abstract:BACKGROUND:Although the American Heart Association/American College of Sports Medicine's Preparticipation Questionnaire (AAPQ) is a recommended preexercise cardiovascular screening tool, it has never been systematically evaluated. The purpose of this research is to provide preliminary evidence of its effectiveness amon...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.113.004160
更新日期:2014-03-11 00:00:00
abstract::Although thrombolytic therapy has been a major advance in the treatment of acute myocardial infarction, in at least 25% of patients the artery remains occluded after administration. In these patients, the strategy of "rescue" or "salvage" angioplasty is frequently used although follow-up data are limited. Sixty-three ...
journal_title:Circulation
pub_type: 杂志文章
doi:
更新日期:1990-03-01 00:00:00
abstract:BACKGROUND:Insulin sensitivity and cardiovascular risk profile were examined in 20 healthy, nonobese, middle-aged men who were long-term users of nicotine-containing chewing gum and in 20 matched control subjects who did not use nicotine. METHODS AND RESULTS:Long-term use of nicotine-containing chewing gum was associa...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.94.5.878
更新日期:1996-09-01 00:00:00
abstract:BACKGROUND:Adverse cardiovascular events associated with thrombotic occlusion occur in 4% to 12.8% of patients after coronary angioplasty. Recently, potent antiplatelet agents have been used to reduce those thrombotic complications. Tirofiban is a highly selective, short-acting inhibitor of fibrinogen binding to platel...
journal_title:Circulation
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1161/01.cir.96.5.1445
更新日期:1997-09-02 00:00:00
abstract:BACKGROUND:Some clinical data suggest that atrial-based pacing prevents paroxysmal atrial fibrillation (AF). This study tested the hypothesis that DDDR pacing compared with VDD pacing prevents AF after atrioventricular (AV) junction ablation. METHODS AND RESULTS:Patients were randomized to DDDR pacing (n=33) or to VDD...
journal_title:Circulation
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1161/01.cir.102.7.736
更新日期:2000-08-15 00:00:00
abstract:BACKGROUND:Previous studies have reported an association between chronic Helicobacter pylori infection and ischemic heart disease. However, it is not clear whether this association is really due to the virulence of the bacterium or is merely the result of confounding factors (in particular, age and social class). METH...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.97.17.1675
更新日期:1998-05-05 00:00:00
abstract:BACKGROUND:Increased carotid intimal-medial thickness (IMT) and coronary artery calcification (CAC) are used as 2 markers of early atherosclerosis. Our objectives were to assess whether increased IMT and CAC are related and to determine the relationship between cardiovascular risk factors and carotid IMT in young adult...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.100.8.838
更新日期:1999-08-24 00:00:00
abstract:BACKGROUND:Cardiac arrest without evident cardiac disease may be caused by subclinical genetic conditions. Provocative testing to unmask a phenotype is often necessary to detect primary electrical disease, direct genetic testing, and perform family screening. METHODS AND RESULTS:Patients with apparently unexplained ca...
journal_title:Circulation
pub_type: 杂志文章,多中心研究
doi:10.1161/CIRCULATIONAHA.109.853143
更新日期:2009-07-28 00:00:00
abstract:BACKGROUND:Pulmonary arterial hypertension (PAH) is a life-threatening disease, characterized by vascular smooth muscle cell hyperproliferation. The calcium/calmodulin-dependent phosphodiesterase 1 (PDE1) may play a major role in vascular smooth muscle cell proliferation. METHODS AND RESULTS:We investigated the expres...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.106.676809
更新日期:2007-05-01 00:00:00
abstract:BACKGROUND:Up to 50% of patients fail to meet ST-segment-elevation myocardial infarction (STEMI) guideline goals recommending a first medical contact-to-device time of <90 minutes for patients directly presenting to percutaneous coronary intervention-capable hospitals and <120 minutes for transferred patients. We sough...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.115.019474
更新日期:2016-08-02 00:00:00
abstract::Carotid artery stenting, compared with carotid endarterectomy, is emerging as an effective and less invasive method of revascularization for extracranial carotid artery stenosis. Carotid stenting is established as the treatment of choice for certain high-risk patient subsets, and ongoing clinical trials are evaluating...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.105.595512
更新日期:2006-04-25 00:00:00
abstract:BACKGROUND:Cardiac troponin I (cTnI), a sensitive and specific marker of myocardial cell injury, is useful in diagnosing and assessing prognosis in acute coronary syndromes. Small studies report that cTnI is elevated in severe heart failure (HF) and may predict adverse outcomes. METHODS AND RESULTS:The present study e...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.CIR.0000084543.79097.34
更新日期:2003-08-19 00:00:00
abstract:BACKGROUND:Inhibition of dopamine beta-hydroxylase (DBH) results in a decrease in norepinephrine synthesis. The present study was a randomized, blinded, placebo-controlled investigation of the long-term effects of therapy with the DBH inhibitor nepicastat (NCT) on the progression of left ventricular (LV) dysfunction an...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.102.16.1990
更新日期:2000-10-17 00:00:00