Background— The prevalence of genetic arrhythmogenic diseases is unknown. For the long-QT syndrome (LQTS), figures ranging from 1:20 000 to 1:5000 were published, but none was based on actual data. Our objective was to define the prevalence of LQTS. Methods and Results— In 18 maternity hospitals, an ECG was performed in 44 596 infants 15 to 25 days old (43 080 whites). In infants with a corrected QT interval (QTc) >450 ms, the ECG was repeated within 1 to 2 weeks. Genetic analysis, by screening 7 LQTS genes, was performed in 28 of 31 (90%) and in 14 of 28 infants (50%) with, respectively, a QTc >470 ms or between 461 and 470 ms. A QTc of 451 to 460, 461 to 470, and >470 ms was observed in 177 (0.41%), 28 (0.06%), and 31 infants (0.07%). Among genotyped infants, disease-causing mutations were found in 12 of 28 (43%) with a QTc >470 ms and in 4 of 14 (29%) with a QTc of 461 to 470 ms. One genotype-negative infant (QTc 482 ms) was diagnosed as affected by LQTS on clinical grounds. Among family members of gen...

Prevalence of the Congenital Long-QT Syndrome

K(+) channels play a crucial role in regulating the excitability of neurons. Many K(+) channels are, in turn, regulated by neurotransmitters. One of the first neurotransmitter-regulated channels to be identified, some 25 years ago, was the M channel. This was categorized as such because its activity was inhibited through stimulation of muscarinic acetylcholine receptors. M channels are now known to be composed of subunits of the Kv7 (KCNQ) K(+) channel family. However, until recently, the link between the receptors and the channels has remained elusive. Here, we summarize recent developments that have begun to clarify this link and discuss their implications for physiology and medicine.

Pathways modulating neural KCNQ/M (Kv7) potassium channels

Individuals with congenital or acquired prolongation of the QT interval, or long QT syndrome (LQTS), are at risk of life-threatening ventricular arrhythmia. LQTS is commonly genetic in origin but can also be caused or exacerbated by environmental factors. A missense mutation in the L-type calcium channel Ca(V)1.2 leads to LQTS in patients with Timothy syndrome. To explore the effect of the Timothy syndrome mutation on the electrical activity and contraction of human cardiomyocytes, we reprogrammed human skin cells from Timothy syndrome patients to generate induced pluripotent stem cells, and differentiated these cells into cardiomyocytes. Electrophysiological recording and calcium (Ca(2+)) imaging studies of these cells revealed irregular contraction, excess Ca(2+) influx, prolonged action potentials, irregular electrical activity and abnormal calcium transients in ventricular-like cells. We found that roscovitine, a compound that increases the voltage-dependent inactivation of Ca(V)1.2 (refs 6-8), restored the electrical and Ca(2+) signalling properties of cardiomyocytes from Timothy syndrome patients. This study provides new opportunities for studying the molecular and cellular mechanisms of cardiac arrhythmias in humans, and provides a robust assay for developing new drugs to treat these diseases.

Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome

The congenital long-QT syndrome (LQTS) is a life-threatening cardiac arrhythmia syndrome that represents a leading cause of sudden death in the young. LQTS is typically characterized by a prolongation of the QT interval on the ECG and by the occurrence of syncope or cardiac arrest, mainly precipitated by emotional or physical stress.

Since 1975,1 2 hereditary variants, the Romano-Ward (RW) syndrome2,3 and the extremely severe Jervell and Lange-Nielsen (JLN) syndrome,4,5 which is associated with congenital deafness, have been included under the comprehensive name of LQTS, one of the best understood monogenic diseases. The usual mode of inheritance for RW is autosomal dominant, whereas JLN shows autosomal recessive inheritance or sporadic cases of compound heterozygosity.

Several reasons make LQTS an important disease. It can often be a lethal disorder, and symptomatic patients left without therapy have a high mortality rate, 21% within 1 year from the first syncope.6 However, with proper treatment, mortality is now ≈1% during a 15-year follow-up.7 This makes inexcusable the existence of symptomatic but undiagnosed patients. LQTS is without doubt the cardiac disease in which molecular biology and genetics have made the greatest progress and unquestionably is the best example of genotype-phenotype correlation. In this regard, it represents a paradigm for sudden cardiac death, and its progressive unraveling helps to better understand the mechanisms underlying sudden death in more complex disorders, such as ischemic heart disease and heart failure.

This review will outline the current knowledge about the genetics of LQTS and provide essential clinical data, whereas its primary focus will be on our approach to the clinical management of these patients.

The electrocardiographic QT interval represents the depolarization and the repolarization phases of the cardiac action potential. The interplay of several ion channels determines the action potential …

Long-QT syndrome: from genetics to management.

Objective: To compile and critique research on the diagnostic accuracy of individual orthopaedic physical examination tests in a manner that would allow clinicians to judge whether these tests are valuable to their practice. Methods: A computer-assisted literature search of MEDLINE, CINAHL, and SPORTDiscus databases (1966 to October 2006) using keywords related to diagnostic accuracy of physical examination tests of the shoulder. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool was used to critique the quality of each paper. Meta-analysis through meta-regression of the diagnostic odds ratio (DOR) was performed on the Neer test for impingement, the Hawkins2Kennedy test for impingement, and the Speed test for superior labral pathology. Results: Forty-five studies were critiqued with only half demonstrating acceptable high quality and only two having adequate sample size. For impingement, the metaanalysis revealed that the pooled sensitivity and specificity for the Neer test was 79% and 53%, respectively, and for the Hawkins2Kennedy test was 79% and 59%, respectively. For superior labral (SLAP) tears, the summary sensitivity and specificity of the Speed test was 32% and 61%, respectively. Regarding orthopaedic special tests (OSTs) where meta-analysis was not possible either due to lack of sufficient studies or heterogeneity between studies, the list that demonstrates both high sensitivity and high specificity is short: hornblowers’s sign and the external rotation lag sign for tears of the rotator cuff, biceps load II for superior labral anterior to posterior (SLAP) lesions, and apprehension, relocation and anterior release for anterior instability. Even these tests have been under-studied or are from lower quality studies or both. No tests for impingement or acromioclavicular (AC) joint pathology demonstrated significant diagnostic accuracy. Conclusion: Based on pooled data, the diagnostic accuracy of the Neer test for impingement, the Hawkins2Kennedy test for impingement and the Speed test for labral pathology is limited. There is a great need for large, prospective, well-designed studies that examine the diagnostic accuracy of the numerous physical examination tests of the shoulder. Currently, almost without exception, there is a lack of clarity with regard to whether common OSTs used in clinical examination are useful in differentially diagnosing pathologies of the shoulder.

/pdf/physical-examination-tests-of-the-shoulder-a-systematic-4tmtf7divs.pdf

Physical examination tests of the shoulder: a systematic review with meta-analysis of individual tests

A-kinase anchoring proteins (AKAPs) recruit signaling molecules and present them to downstream targets to achieve efficient spatial and temporal control of their phosphorylation state In the heart, sympathetic nervous system (SNS) regulation of cardiac action potential duration (APD), mediated by β-adrenergic receptor (βAR) activation, requires assembly of AKAP9 (Yotiao) with the IKs potassium channel α subunit (KCNQ1) KCNQ1 mutations that disrupt this complex cause type 1 long-QT syndrome (LQT1), one of the potentially lethal heritable arrhythmia syndromes Here, we report identification of (i) regions on Yotiao critical to its binding to KCNQ1 and (ii) a single putative LQTS-causing mutation (S1570L) in AKAP9 (Yotiao) localized to the KCNQ1 binding domain in 1/50 (2%) subjects with a clinically robust phenotype for LQTS but absent in 1,320 reference alleles The inherited S1570L mutation reduces the interaction between KCNQ1 and Yotiao, reduces the cAMP-induced phosphorylation of the channel, eliminates the functional response of the IKs channel to cAMP, and prolongs the action potential in a computational model of the ventricular cardiocyte These reconstituted cellular consequences of the inherited S1570L-Yotiao mutation are consistent with delayed repolarization of the ventricular action potential observed in the affected siblings Thus, we have demonstrated a link between genetic perturbations in AKAP and human disease in general and AKAP9 and LQTS in particular

https://www.pnas.org/content/pnas/104/52/20990.full.pdf

Mutation of an A-kinase-anchoring protein causes long-QT syndrome

The A-kinase anchoring protein Yotiao facilitates complex formation between adenylyl cyclase type 9 and the IKs potassium channel in heart.

Dual roles of the A kinase-anchoring protein Yotiao in the modulation of a cardiac potassium channel: a passive adaptor versus an active regulator.

A-kinase anchoring proteins (AKAPs) create compartmentalized environment inside the cell to bring various signaling molecules to their targets. In the heart, a slowly activating potassium channel (IKs) important for cardiac repolarization is tightly regulated by the sympathetic nervous system in an AKAP-dependent manner. IKs channel forms a macromolecular complex with AKAP9 and other enzymes, such as protein kinase A, phosphatase, adenylyl cyclase, and phosphodiesterase, all of which are responsible to control the phosphorylation state of the channel. Such a complex thus ensures the IKs channel to be regulated properly to maintain the normal cardiac rhythm. Disruptions of various elements of the complex have been found to cause severe pathological consequences, including the long QT syndrome.

/pdf/a-kinase-anchoring-protein-9-and-iks-channel-regulation-10f6b7b29x.pdf

A-kinase anchoring protein 9 and IKs channel regulation.

The subunits KCNQ1 and KCNE1 generate the slowly activating, delayed rectifier potassium current, IKs, that responds to sympathetic stimulation and is critical for human cardiac repolarization. The A-kinase anchoring protein Yotiao facilitates macromolecular complex formation between IKs and protein kinase A (PKA) to regulate phosphorylation of KCNQ1 and IKs currents following beta-adrenergic stimulation. We have previously shown that adenylyl cyclase Type 9 (AC9) is associated with a KCNQ1-Yotiao-PKA complex and facilitates isoproterenol-stimulated phosphorylation of KCNQ1 in an immortalized cell line. However, requirement for AC9 in sympathetic control of IKs in the heart was unknown. Using a transgenic mouse strain expressing the KCNQ1-KCNE1 subunits of IKs, we show that AC9 is the only adenylyl cyclase (AC) isoform associated with the KCNQ1-KCNE1-Yotiao complex in the heart. Deletion of AC9 resulted in the loss of isoproterenol-stimulated KCNQ1 phosphorylation in vivo, even though AC9 represents less than 3% of total cardiac AC activity. Importantly, a significant reduction of isoproterenol-stimulated IKs currents was also observed in adult cardiomyocytes from IKs-expressing AC9KO mice. AC9 and Yotiao co-localize with N-cadherin, a marker of intercalated disks and cell–cell junctions, in neonatal and adult cardiomyocytes, respectively. In conclusion, AC9 is necessary for sympathetic regulation of PKA phosphorylation of KCNQ1 in vivo and for functional regulation of IKs in adult cardiomyocytes.

https://www.mdpi.com/2073-4409/8/9/981/pdf

Regulation of IKs Potassium Current by Isoproterenol in Adult Cardiomyocytes Requires Type 9 Adenylyl Cyclase

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Lei Chen

Author Tools

Chat about Author