Genomics and Cardiac Arrhythmias

Roberts, Robert

doi:10.1016/j.jacc.2005.08.059

Cited by 75 publications

(38 citation statements)

References 82 publications

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“…There is clinical and experimental evidence for atrial enlargement and fibrosis as key histopathological substrates for AF. 50 Both features were observed in our model and would increase the likelihood of re-entry and possibly contribute to the observed AF and AVB. We previously reported that activation of the insulin-like growth factor 1-PI3K(p110␣) pathway protected the heart against fibrosis in response to pressure overload, whereas a reduction in PI3K(p110␣) signaling lead to increased fibrosis.…”

Section: Discussionmentioning

confidence: 57%

Reduced Phosphoinositide 3-Kinase (p110α) Activation Increases the Susceptibility to Atrial Fibrillation

Pretorius

Woodcock

et al. 2009

The American Journal of Pathology

153

133

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Atrial fibrillation (AF) is the most common sustained arrhythmia presenting at cardiology departments. A limited understanding of the molecular mechanisms responsible for the development of AF has hindered treatment strategies. The purpose of this study was to assess whether reduced activation of phosphoinositide 3-kinase (PI3K, p110␣) makes the compromised heart susceptible to AF. Risk factors for AF, including aging, obesity, and diabetes, have been associated with insulin resistance that leads to depressed/defective PI3K signaling. However, to date, there has been no link between PI3K(p110␣) and AF. To address this question, we crossed a cardiac-specific transgenic mouse model of dilated cardiomyopathy (DCM) with a cardiac-specific transgenic mouse expressing a dominant negative mutant of PI3K (dnPI3K; reduces PI3K activity). Adult (ϳ4.5 months) double-transgenic (dnPI3K-DCM), single-transgenic (DCM-Tg, dnPI3K-Tg), and nontransgenic mice were subjected to morphological, functional/ECG, microarray, and biochemical analyses. dnPI3K-DCM mice developed AF and had depressed cardiac function as well as greater atrial enlargement and fibrosis than DCM-Tg mice. AF was not detected in other groups. Aged DCM-Tg mice (ϳ15 months) with a similar phenotype to dnPI3K-DCM mice (4.5 months) did not develop AF , suggesting loss of PI3K activity directly contributed to the AF phenotype. Furthermore, increasing PI3K activity reduced atrial fibrosis and improved cardiac conduction in DCM-Tg mice. Finally, in atrial appendages from patients with AF, PI3K activation was lower compared with tissue from patients in sinus rhythm. These results suggest a link between PI3K(p110␣) and AF. (Am J Pathol

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Section: Discussionmentioning

confidence: 57%

Reduced Phosphoinositide 3-Kinase (p110α) Activation Increases the Susceptibility to Atrial Fibrillation

Pretorius

Woodcock

et al. 2009

The American Journal of Pathology

153

133

View full text Add to dashboard Cite

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“…28 In the majority of cases of WPW syndrome, there is no familial involvement; however, a significant minority of cases are inherited as a single-gene disorder or occur as part of a syndrome with a strong genetic basis. 25,29,30 Recently PRKAG2 gene missense mutations have been identified to be involved in familial WPW syndrome, often in association with cardiac hypertrophy. 30 Animal studies have shown that mutations in the Alk3 gene result in disrupted formation of the annulus fibrosus, which causes ventricular preexcitation via posterior paraseptal bypass tracts.…”

Section: Discussionmentioning

confidence: 99%

Accessory Atrioventricular Myocardial Connections in the Developing Human Heart

et al. 2008

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Background-Fetal and neonatal atrioventricular (AV) reentrant tachycardias can be life-threatening but resolve in most cases during the first year of life. The transient presence of accessory AV myocardial connections during annulus fibrosus development may explain this phenomenon. Methods and Results-A total of 45 human embryonic, fetal, and neonatal sectioned hearts (4 to 36 weeks of development)were studied immunohistochemically. Accessory myocardial AV connections were quantified and categorized according to their specific location, and 3D reconstructions were made. Between 4 and 6 weeks of development, the atrial and ventricular myocardium was continuous at the primitive AV canal. At 6 to 10 weeks, numerous accessory myocardial AV connections were identified in the left (45%), right (35%), and septal (20%) regions of the AV junction. Most right-sided accessory connections comprised distinct myocardial strands, whereas left-sided connections consisted of larger myocardial continuities. At 10 to 20 weeks, all accessory AV connections comprised discrete myocardial strands and gradually decreased in number. The majority of accessory connections were located in the right AV junction (67%), predominantly in the lateral aspect (45%). Seventeen percent of the accessory connections were observed in the left AV junction, and 16% were observed in the septal region. 3D reconstructions of the developing AV nodal area at these stages demonstrated multiple AV node-related accessory connections. From 20 weeks until birth, and in neonatal hearts, no further accessory myocardial AV connections were observed. Conclusions-Isolation of the AV junction is a gradual and ongoing process, and right lateral accessory myocardial AV connections in particular are commonly found at later stages of normal human cardiac development. These transitory accessory connections may act as substrate for AV reentrant tachycardias in fetuses or neonates. (Circulation. 2008;117: 2850-2858.)

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“…9 Even in these monogenic disorders, the relationship between genotype and phenotype is far from straightforward. Significant genetic and allelic heterogeneity exists, with multiple mutations in many distinct genes responsible for each arrhythmic syndrome.…”

Section: Clinical Perspective P 23mentioning

confidence: 99%

Cardiac Sodium Channel Gene Variants and Sudden Cardiac Death in Women

et al. 2008

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Background-Several cardiac ion channel genes have been implicated in monogenic traits with a high risk of sudden cardiac death (SCD). Mutations or rare variants in these genes have been proposed as potential contributors to more common forms of SCD, but this hypothesis has not been assessed systematically. Methods and Results-We directly sequenced the entire coding region and splice junctions of 5 cardiac ion channel genes, SCN5A, KCNQ1, KCNH2, KCNE1, and KCNE2, in 113 SCD cases from 2 large prospective cohorts of women (Nurses' Health Study) and men (Health Professional Follow-Up Study). Controls from the same population were then screened for the presence of mutations or rare variants identified in cases, and sequence variants without prior functional data were expressed in Xenopus oocytes to assess their biophysical consequences. No mutations or rare variants were identified in any of the 53 subjects who were men. In contrast, in 6 of 60 women (10%), we identified 5 rare missense variants in SCN5A that either had been associated previously with long-QT syndrome (A572D and G615E), had been reported to alter sodium channel function (F2004L), or had not been reported previously in control populations (A572F and W1205C). Of the 4 variants without prior functional data, 3 variants were located in the I-II linker (A572D, A572F, and G615E), and all resulted in significantly shorter recovery times from inactivation. When compared with 733 control samples from the same population, the overall frequency of these rare variants in SCN5A was significantly higher in the SCD cases (6/60, 10.0%) than in controls (12/733, 1.6%; Pϭ0.001). Conclusion-Functionally significant mutations and rare variants in SCN5A may contribute to SCD risk among women.(Circulation. 2008;117:16-23.)

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Genomics and Cardiac Arrhythmias

Cited by 75 publications

References 82 publications

Reduced Phosphoinositide 3-Kinase (p110α) Activation Increases the Susceptibility to Atrial Fibrillation

Reduced Phosphoinositide 3-Kinase (p110α) Activation Increases the Susceptibility to Atrial Fibrillation

Accessory Atrioventricular Myocardial Connections in the Developing Human Heart

Cardiac Sodium Channel Gene Variants and Sudden Cardiac Death in Women

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