Abstract 12008: Nos1 Adapter Protein Nos1ap Overexpression Alters Qtc Intervals in Transgenic Mice

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Tatjana Williams ◽  
Anahi P Arias-Loza ◽  
Marco Abeßer ◽  
Joachim Schmitt ◽  
Kai Schuh ◽  
...  
Keyword(s):  
Ion Channels ◽  
Sudden Cardiac Death ◽  
Transgenic Mice ◽  
Cardiac Death ◽  
Genetic Alterations ◽  
Luciferase Assay ◽  
Qtc Interval ◽  
Cross Sectional ◽  
Programmed Stimulation ◽  
Increased Susceptibility

Background: Congenital long- or short-QT syndrome may lead to life-threatening ventricular tachycardia and sudden cardiac death. Apart from rare disease-causing mutations in ion channels, common genetic variations in the neuronal nitric oxide synthase (NOS1) regulator NOS1AP, have recently been associated with QT interval variations in a human whole-genome association study. In fact, NOS1AP SNPs have been linked to increases in QTc intervals and sudden cardiac death. We therefore speculate that myocardial NOS1AP overexpression may lead to a decrease of the QTc interval and an increased susceptibility to rhythm disorders. Methods and Results: We generated transgenic mice (TG) with a conditional myocardial NOS1AP overexpression and focused on electrical alterations. Conditional overexpression of NOS1AP resulted in a 147% ventricular increase in TG mice compared to WT littermates. NOS1AP was mainly located at the sarcolemma where it interacted with NOS1 and the L-type Ca2+- channel. HW/BW ratio, ventricular ANP expression, ventricular cross-sectional area and collagen deposition were not altered in NOS1AP mice under baseline conditions. However, NOS1AP overexpressing mice showed a clear decrease of QTc intervals (33 vs. 48 ms). They were more prone to bradycardia (resting heart rate 467 bpm vs. 666 bpm). Atrial programmed stimulation repeatedly caused atrial tachycardia. Ventricular programmed stimulation caused VT in some mice with NOS1AP overexpression. We also investigated the functional effect of the human rs16847548 (T/C). We found that this SNP decreased NOS1AP promoter activity in a viral NOS1AP luciferase assay, suggesting that this SNP downregulates NOS1AP expression in humans. Conclusion: Myocardial overexpression of NOS1AP leads to a significant shortening of the QTc interval with an increased susceptibility to atrial and ventricular rhythm disorders. SNP rs16847548 in NOS1AP resulted in downregulation of NOS1AP expression which provides an explanation for elongation of QTc intervals. In summary, not only a mutation in ion channels itself but also genetic alterations in expression of ion channel modifiers, such as NOS1AP, have an impact on QTc intervals.

Abstract 271: Nos1ap Alters Qtc Intervals Upon Overexpression in Mice

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Tatjana Williams ◽  
Daniel Oppelt ◽  
Anahi Paula Arias-Loza ◽  
Marco Abesser ◽  
Joachim Schmitt ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Sudden Cardiac Death ◽  
Nitric Oxide Synthase ◽  
Cardiac Death ◽  
Association Studies ◽  
Neuronal Nitric Oxide Synthase ◽  
Genetic Alterations ◽  
Programmed Stimulation ◽  
Oxide Synthase

Rationale: The QT interval duration (QTc) reflects cardiac depolarization. It may predispose individuals to ventricular tachycardia and sudden cardiac death if prolonged (long QTc), shortened (short QTc) or otherwise unregularly. Whole-genome association studies have linked genetic variations in the neuronal nitric oxide synthase adapter protein NOS1AP to variations in QTc intervals and sudden cardiac death. Hypothesis: We hypothesize NOS1AP functions as an L-type-Ca2+ channel modulator via its interaction with the neuronal nitric oxide synthase NOS1. Therefore, alterations in myocardial NOS1AP expression should temper with QTc intervals and increase susceptibility to rhythm disorders. Methods and results: We generated conditional double transgenic mice by crossbreeding pTRE-6xHN-Nos1AP animals with α-MHC-tTA mice; NOS1AP expression is therefore restricted to cardiomyocytes and under control of doxycycline (Tet-Off system). Double transgenic animals were investigated with the main focus upon electrical alterations. Heart rates were similar in NOS1AP overexpressing and non-induced animals. Atrial programmed stimulation repeatedly caused atrial tachycardia, while ventricular programmed stimulation caused VT in NOS1AP overexpressing mice. There was a clear decrease of QTc intervals in NOS1AP overexpressing mice paralleld by a significantly reduced survival (only 56% after 12 weeks vs 100% in non-induced mice. Induced QTc alterations and accompanied deaths subsided upon readministration of doxycycline. We also investigated the functional effect of the human SNP rs16847548 (T/C). We found that this SNP decreased NOS1AP transcriptional activity in vitro and therefore suggest this leads to a decrease in NOS1AP expression in humans. Conclusion: Myocardial overexpression of NOS1AP leads to short QTc syndrome with increased susceptibility to atrial and ventricular rhythm disorders and cardiac death. SNP rs16847548 in NOS1AP resulted in less NOS1AP promoter activity in vitro which could explain the alteration in QTc intervals. In summary, not only mutations in ion channels themselves but also genetic alterations in the expression of ion channel modulators such as NOS1AP, have an impact on QTc intervals.

Association between digoxin use and sudden cardiac death in individuals with the rs10494366 variant of the NOS1AP gene

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
N Soroush ◽  
A Aarnoudse ◽  
F Shokri ◽  
M Van Den Berg ◽  
F Ahmadizar ◽  
...  
Keyword(s):  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Smoking Status ◽  
Adaptor Protein ◽  
Therapeutic Window ◽  
P Value ◽  
Qtc Interval ◽  
Total Study Population ◽  
Increased Risk

Abstract Background Digoxin is one of the oldest cardiovascular medications still used to treat heart failure and atrial fibrillation. Due to its narrow therapeutic window, it is associated with life threatening intoxication and arrhythmias, and with QTc-shortening. Common genetic variation in the nitric oxide synthase-1 adaptor protein (NOS1AP) has been associated with QTc interval prolongation. Purpose We investigated whether the rs10494366 variant of the NOS1AP gene modified the risk of SCD in patients using digoxin. Methods In a prospective population-based cohort study, we included data of the three cohorts, started as of January 1st, 1991 until January 1st 2014. Digoxin current use on the date of cardiac death in cases and the same day of follow-up in the remainder of the cohort was a time-dependent exposure. The main outcome was SCD defined as sudden and unexpected death as a result of cardiac causes, according to international criteria. Identification and adjudication of SCD was performed independently, before the start of this study. We used Cox proportional hazard regression analysis to investigate the associations between NOS1AP rs10494366 variant and incident SCD among digoxin users compared to non-users. Associations were adjusted for age, sex (model 1) in addition to BMI, prevalent diabetes, myocardial infarction, baseline hypertension and smoking status (past, current, never) (model 2). Results We included 14,594 individuals, with a mean age of 65.3 (SD 10.3) years. Almost 59% were female. The cumulative incidence of SCD was 9.5% (609 cases) by the end of follow up. Among them, 98 (16%) individuals were exposed to digoxin at the time of death. In model 1, NOS1AP rs10494366 variant was not associated with SCD in the total study population. However, an interaction term of the gene with the daily dose of digoxin was significantly associated with increased risk of SCD (p-value 0.0001). In model 2, the risk of SCD in current users of digoxin was 4.2 [95% CI 1.3–13.8] for the GG genotype; 2.1 [95% CI 1.1–4.2] for the GT genotype, and 1.5 [95% CI 0.7–3.2] for the TT genotype. Conclusion NOS1AP rs10494366 variant modified the risk of sudden cardiac death in users of digoxin. Our study suggests that individuals with the homozygous minor GG allele have a fourfold increased risk of sudden cardiac death. Funding Acknowledgement Type of funding source: None

Abstract 63: Potential Genetic and Pharmacological Protection from Virus-induced Ventricular Arrhythmias and Sudden Cardiac Death

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Nathalie Strutz-eebohm ◽  
Katja Steinke ◽  
Ulrike Henrion ◽  
Matthias Rohbeck ◽  
Karin Klingel ◽  
...  
Keyword(s):  
Ion Channels ◽  
Sudden Cardiac Death ◽  
Action Potentials ◽  
Cardiac Death ◽  
Ventricular Arrhythmias ◽  
Proper Function ◽  
Channel Trafficking ◽  
Cardiac Ion Channels ◽  
Evolutionary Advantage ◽  
Group B

In patients as well as in mouse models, enteroviral infections, especially Coxsackie group B viruses (CVB1-6), frequently induce ventricular arrhythmias and sudden cardiac death. The cardiac action potential requires proper function of cardiac ion channels. CVB3 alters Kv7.1 channel trafficking potentially leading to changes in action potentials and increasing likelihood of arrhythmias. Genetic variants of cardiac ion channels can cause changes in channel trafficking that may preserve from CVB3 modulations and present an evolutionary advantage. Here, we show that a common polymorphic Kv7.1 channel variant uses alternative trafficking pathways and may thus exert a benefit during CVB3 infections. Genetic and pharmacological disruption of a CVB3-stimulated Serum- and Glucocorticoid inducible Kinase 1 (SGK1) pathways blunts Kv7.1 channel dysfunctions. Our results suggest that escape from CVB3-induced SGK1-stimulation by genetic variation in Kv7.1 may be protective and inhibition of SGK1 may present a pharmacological approach to reduce the pro-arrhythmic risk associated with acute coxsackievirus infections.

scholarly journals Prolonged QTc Interval and Risk of Sudden Cardiac Death in a Population of Older Adults

2006 ◽  
Vol 47 (2) ◽  
pp. 362-367 ◽  
Author(s):  
Sabine M.J.M. Straus ◽  
Jan A. Kors ◽  
Marie L. De Bruin ◽  
Cornelis S. van der Hooft ◽  
Albert Hofman ◽  
...  
Keyword(s):  
Older Adults ◽  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Qtc Interval

scholarly journals Role of genetic and electrolyte abnormalities in prolonged QTc interval and sudden cardiac death in end-stage renal disease patients

PLoS ONE ◽  
2018 ◽  
Vol 13 (7) ◽  
pp. e0200756 ◽  
Author(s):  
Monica Coll ◽  
Carles Ferrer-Costa ◽  
Sara Pich ◽  
Catarina Allegue ◽  
Emilio Rodrigo ◽  
...  
Keyword(s):  
Sudden Cardiac Death ◽  
Renal Disease ◽  
End Stage Renal Disease ◽  
Cardiac Death ◽  
Qtc Interval ◽  
Stage Renal Disease ◽  
End Stage ◽  
Electrolyte Abnormalities

Electrocardiographic and echocardiographic abnormalities associated with mitral valve prolapse in patients with Marfan syndrome

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Lasne ◽  
O Milleron ◽  
G Delorme ◽  
F Arnoult ◽  
N Hanna ◽  
...  
Keyword(s):  
Sudden Cardiac Death ◽  
Mitral Valve ◽  
Marfan Syndrome ◽  
Mitral Valve Prolapse ◽  
Cardiac Death ◽  
Ventricular Arrhythmias ◽  
Qtc Interval ◽  
Interval Prolongation ◽  
High Prevalence ◽  
Qtc Interval Prolongation

Abstract Introduction Marfan syndrome (MFS) is responsible for cardiovascular disorders such as aortic aneurism and mitral valve prolapse (MVP). A malignant MVP phenotype combining clinical, electrical and morphological features has been described in symptomatic patients who have experienced sudden cardiac death or complex ventricular arrhythmias. We have taken advantage of the high prevalence of MVP in MFS patient to study the clinical, electrical and echocardiographic abnormalities associated with MVP. Purpose The aim of this study is to describe the clinical, electrical and morphological cardiac abnormalities associated with MVP in a cohort of MFS patients with FBN1 mutations with a high prevalence of MVP and who did not suffer from severe ventricular arrhythmias. Methods All consecutive patients coming to the National Reference Center for Marfan syndrome were evaluated prospectively i.e. clinical examination, 12-lead electrocardiogram, standard transthoracic echocardiography study and molecular genetic screening. Results 352 consecutive patients were included from April 2015 to October 2016 [250 FBN1 mutation carriers (MFS) and 102 healthy relatives (HR)]. None of the patients had a history of sudden cardiac death or complex ventricular arrhythmia. MFS vs HR: MFS patients were younger (33 vs 41yo p<0.001) and 2/3 were women in both groups. In the MFS group, abnormal T waves repolarization in lateral leads were more common [172 MFS (70.2%) vs. 87 HR (86.14%) p<0,0012], as was MVP [38.37% vs 1.96%; p<0,0001], and diastolic hypertrophy of the basal segment of the inferolateral wall (thickness >11mm) [22.31% vs. 9.18%; p<0.0001]. In MFS, MVP affected either one valve (21.22%), or both (17.14%), and was not associated with electric abnormalities. However, diastolic basal inferolateral wall hypertrophy was associated with mitral valve prolapse (p<0,0001), QTc interval prolongation (p<0.0229), abnormal T waves repolarization in the inferior leads (p=0.004), and higher aortic Z-Score (p=0.274). Conclusion In MFS patients, the prevalence of MVP is high and no significant association between MVP and electrical abnormalities was found. In contrast, basal inferolateral wall hypertrophy is associated with MVP and repolarization disorders in inferior leads and QTc interval prolongation, i.e, electrocardiographic abnormalities described in malignant MVP. QTc and basal inferolateral hypertrophy Funding Acknowledgement Type of funding source: None

scholarly journals 424 - Cardiac Healthcare Disparities in Schizophrenia at the End-of-Life

2021 ◽  
Vol 33 (S1) ◽  
pp. 45-46
Author(s):  
Baruth J. ◽  
Bateman D. ◽  
Bateman P. ◽  
Kovacs R. ◽  
Lapid M.
Keyword(s):  
Cardiovascular Disease ◽  
Sudden Cardiac Death ◽  
End Of Life ◽  
Healthcare Utilization ◽  
Cardiac Death ◽  
Healthcare Disparities ◽  
Density Lipoprotein ◽  
Control Group ◽  
Qtc Interval ◽  
To Receive

Background:Schizophrenia is a serious mental illness associated an early mortality of 15 to 20 years. Eighty percent of deaths are due to cardiovascular disease, and the risk of sudden cardiac death is three- times greater than the general population. Both modifiable and non-modifiable risk factors like lifestyle, medication side-effects, genetics, and healthcare disparities have been identified, but this relationship is not fully understood.Research Objective:To examine cardiac-related healthcare utilization of individuals with schizophrenia at the end-of-life.Method:As a retrospective cohort study the Mayo Clinic Unified Data Platform (UDP) was used to identify a schizophrenia group (SG) (n = 610) 50 years or older with a death date between 1/1/1999 – 1/1/2019 and control group (n = 610) matched by gender (53% women) and age of death (72.8 ± 12.4 years). Measures of cardiovascular healthcare utilization were evaluated within a 12-month period prior to death. Pearson’s chi-square (χ2), analysis of variance was used (ANOVA), and logistic regression were used for statistical analysis.Results:SG was more likely than controls to be unmarried, unemployed, or from racial minority groups (all p<0.001) and was more likely to have diabetes mellitus (p<0.001) or cardiovascular disease (p=0.004). SG was less likely to receive an electrocardiogram (ECG) (p<0.001), echocardiogram (p=0.003), or cardiac catheterization procedure (p<0.001), and more likely to receive hemoglobin A1C testing (p<0.001). Of those receiving an ECG, SG had a greater mean QTc interval (453.8 ms vs. 438.0 ms; p<0.001) and were twice as likely to have an ECG result interpreted as “prolonged QTc” (p<0.001).Between group differences for utilization of troponin or low-density lipoprotein testing, or pacemaker- related procedures were not statistically significant.Conclusion:Individuals with schizophrenia in this cohort were less likely to receive cardiovascular evaluations and interventions during their last year of life. Despite the higher likelihood for prolonged QTc, a recognized biomarker of cardiac risk, SG was less likely to receive an ECG. Given the greater cardiac comorbidity and higher risk of sudden cardiac death in schizophrenia, interventions are needed to address these disparities in care.

scholarly journals Cardiac autonomic dysfunction in patients with systemic lupus, rheumatoid arthritis and sudden death risk

2010 ◽  
Vol 138 (1-2) ◽  
pp. 26-32 ◽  
Author(s):  
Branislav Milovanovic ◽  
Ljudmila Stojanovic ◽  
Nebojsa Milicevic ◽  
Karin Vasic ◽  
Bojko Bjelakovic ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Blood Pressure ◽  
Heart Rate ◽  
Sudden Cardiac Death ◽  
Autonomic Dysfunction ◽  
Cardiac Death ◽  
Healthy Subjects ◽  
Qtc Interval ◽  
Systemic Lupus ◽  
Risk Predictors

Introduction. The manifestations of autonomic nervous system (ANS) dysfunction in autoimmune diseases have been the subject of many studies. However, the published results pertaining to such research are controversial. Sudden cardiac death due to fatal arrhythmias is frequent in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Objective. To analyze risk predictors of sudden cardiac death related to the degree of autonomic dysfunction. Methods. We performed cardiovascular ANS assessment in 90 patients in this case-controlled study, including 52 (6 male, 46 female) patients with SLE, 38 (6 male, 32 female) with RA and 41 (23 male, 17 female) healthy subjects. The methodology included a comprehensive ECG analysis (with Schiller software AT-10) of QTc interval, late potentials, short-term heart rate variability (HRV) and nonlinear HRV (Poincare plot) analysis; 24-hour Holter ECG monitoring with ECG QTc interval analysis, HRV analysis; 24-hour blood pressure monitoring with systolic and diastolic blood pressure variability; cardiovascular autonomic reflex tests (according to Ewing). Vagal dysfunction was established by performing 3 tests: Valsalva maneuver, deep breathing test and heart rate response to standing test. Dysfunction of the sympathetic nervous system was examined by applying 2 tests: blood pressure response to standing and handgrip test. Results. In all cardiovascular reflex tests, the frequencies of abnormal results were significantly higher among the patients than among the healthy subjects. Severe autonomic dysfunction was more common in RA. QTc interval was more prolonged in patients with SLE. Both diseases were associated with depressed heart rate variability compared to controls, the reduction being greater in RA patients. In the patients with SLE, autonomic dysfunction is predominantly with higher sympathetic activity while in RA vagal predominance is evident. Conclusion. SLE and RA are associated with severe autonomic dysfunction and the presence of significant risk predictors related to the onset of sudden cardiac death.

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