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

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

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Association Between Silent Myocardial Infarction and Long‐Term Risk of Sudden Cardiac Death

Journal of the American Heart Association ◽

10.1161/jaha.120.017044 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Yun‐Jiu Cheng ◽

Yu‐He Jia ◽

Feng‐Juan Yao ◽

Wei‐Yi Mei ◽

Yuan‐Sheng Zhai ◽

...

Keyword(s):

Myocardial Infarction ◽

Sudden Cardiac Death ◽

Cardiac Death ◽

Population Attributable Fraction ◽

Cardiovascular Health Study ◽

Primary Study ◽

Hazard Ratios ◽

Increased Risk ◽

Silent Myocardial Infarction

Background Although silent myocardial infarction (SMI) is prognostically important, the risk of sudden cardiac death (SCD) among patients with incident SMI is not well established. Methods and Results We examined 2 community‐based cohorts: the ARIC (Atherosclerosis Risk in Communities) study (n=13 725) and the CHS (Cardiovascular Health Study) (n=5207). Incident SMI was defined as electrocardiographic evidence of new myocardial infarction during follow‐up visits that was not present at the baseline. The primary study end point was physician‐adjudicated SCD. In the ARIC study, 513 SMIs, 441 clinically recognized myocardial infarctions (CMIs), and 527 SCD events occurred during a median follow‐up of 25.4 years. The multivariable hazard ratios of SMI and CMI for SCD were 5.20 (95% CI, 3.81–7.10) and 3.80 (95% CI, 2.76–5.23), respectively. In the CHS, 1070 SMIs, 632 CMIs, and 526 SCD events occurred during a median follow‐up of 12.1 years. The multivariable hazard ratios of SMI and CMI for SCD were 1.70 (95% CI, 1.32–2.19) and 4.08 (95% CI, 3.29–5.06), respectively. The pooled hazard ratios of SMI and CMI for SCD were 2.65 (2.18–3.23) and 3.99 (3.34–4.77), respectively. The risk of SCD associated with SMI is stronger with White individuals, men, and younger age. The population‐attributable fraction of SCD was 11.1% for SMI, and SMI was associated with an absolute risk increase of 8.9 SCDs per 1000 person‐years. Addition of SMI significantly improved the predictive power for both SCD and non‐SCD. Conclusions Incident SMI is independently associated with an increased risk of SCD in the general population. Additional research should address screening for SMI and the role of standard post–myocardial infarction therapy.

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Anthropometric indices and the risk of incident sudden cardiac death among adults with and without diabetes: over 15 years of follow-up in The Tehran Lipid and Glucose Study

Diabetology & Metabolic Syndrome ◽

10.1186/s13098-021-00701-z ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Seyyed Saeed Moazzeni ◽

Seyed Saeed Tamehri Zadeh ◽

Samaneh Asgari ◽

Fereidoun Azizi ◽

Farzad Hadaegh

Keyword(s):

Sudden Cardiac Death ◽

Cardiac Death ◽

Categorical Variables ◽

P Value ◽

Inverse Association ◽

Multivariable Model ◽

Anthropometric Indices ◽

Group A ◽

Fourth Quartile

Abstract Background We investigated the association of anthropometric indices including body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), and hip circumference (HC) with the risk of incident sudden cardiac death (SCD) among Iranian population with and without type 2 diabetes mellitus (T2DM). Methods The study population included 9,089 subjects without and 1,185 subjects with T2DM, aged ≥ 20 years. Participants were recruited in 1999–2001 or 2001–2005, and followed for incident SCD annually, up to 20 March 2018. Multivariate Cox proportional hazard models, adjusted for traditional risk factors of cardiovascular disease, were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of anthropometric indices (as continuous and categorical variables). Results During a follow-up of over 15 years, 144 (1.58%) and 86 (7.26%) incident SCD occurred in non-T2DM and T2DM groups, respectively. Among non-T2DM group, a 1 standard deviation (SD) increase in WHtR was associated with higher risk of incident SCD by a HR of 1.23 (95% CI: 1.00–1.50) in the multivariable model. From the first quartile to the fourth quartile of WHtR, the trend of SCD risk was significant in age- and sex-adjusted analysis (P-value for trend: 0.041). Other indices did not show significant associations with SCD. Among T2DM group, a 1 SD increase in WHR had a HR of 1.36 (1.05–1.76) in the multivariable model. Considering WHR as categorical variables, the trend of SCD risk across quartiles of WHR was significant. Furthermore, a 1 SD increase in HC led to reduced risk of incident SCD with a HR of 0.75 (0.58–0.97) in multivariable analysis; this lower risk remained significant even after adjustment for WC. Compared to the first quartile, the fourth quartile of HC also showed a HR of 0.50 (0.25–0.99) (P-value for trend = 0.018). BMI, WC, and WHtR did not have significant associations with incident SCD. Conclusion In our long-term population-based study, we demonstrated central but not general obesity (as assessed by WHR in participants with T2DM, and WHtR in participants without T2DM) as a herald of incident SCD. Moreover, HC can have an inverse association with SCD among participants with T2DM.

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Serum glucose and insulin are associated with QTc and RR intervals in nondiabetic elderly

Acta Endocrinologica ◽

10.1530/eje-09-0878 ◽

2010 ◽

Vol 162 (2) ◽

pp. 241-248 ◽

Cited By ~ 18

Author(s):

Charlotte van Noord ◽

Miriam C J M Sturkenboom ◽

Sabine M J M Straus ◽

Albert Hofman ◽

Jan A Kors ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Cardiac Death ◽

Serum Glucose ◽

Qtc Interval ◽

Rotterdam Study ◽

Fasting Serum ◽

Rr Intervals ◽

Fasting Serum Glucose ◽

Rr Interval ◽

Increased Risk

AimsTo study whether nondiabetic persons with impaired fasting serum glucose and hyperinsulinemia have QTc/QT interval prolongation and RR interval shortening in the electrocardiogram (ECG), and whether these were associated with an increased risk of sudden cardiac death.MethodsThis study consisted of two analyses. First, a cross-sectional analysis was used as part of the population-based Rotterdam Study including 1050 men and 1520 women (≥55 years) without diabetes mellitus. Participants in round 3 of the Rotterdam Study for whom an ECG and fasting serum glucose and fasting insulin measurements were available were eligible for the study. Participants using digoxin or QTc-prolonging drugs and participants with left ventricular hypertrophy and left and right bundle branch block were excluded. The endpoints of the study were the lengths of the QTc, QT, and RR intervals. The associations were examined by means of linear regression analysis. Secondly, in all 6020 participants of the Rotterdam Study with an ECG, the associations between the QTc, QT, and RR intervals and sudden cardiac death were examined by means of Cox regression analysis.ResultsOverall, there was a significant association between impaired fasting serum glucose and the QTc interval with an increase of 2.6 ms (95% confidence interval (CI): 0.3; 5.0) in those with fasting glucose >6 mmol/l. Hyperinsulinemia was also associated with QTc prolongation (3.0 ms (0.8; 5.3)) in those with fasting insulin ≥100 pmol/l. Impaired fasting glucose (IFG) and hyperinsulinemia were significantly associated with a decrease of the RR interval (−33.7 ms (−48.8; −18.6) and −44.4 ms (−58.7; −30.0) respectively). Participants in the fourth quartile of the QTc and QT intervals had a significantly increased risk of sudden cardiac death compared to participants in the first quartile (hazard ratio (HR) 2.87 (95% CI: 2.02–4.06); HR 3.05 (1.99–4.67) respectively). Furthermore, there was a significant inverse association between the fourth quartile of the RR interval compared to the first quartile and the risk of sudden cardiac death (HR 0.49 (0.34–0.80)).ConclusionIn this population-based study, we demonstrated that IFG and hyperinsulinemia are associated with a significantly increased QTc interval and with significant shortening of the RR interval, the latter probably due to an increased sympathetic activity. In addition, we demonstrated that both a prolonged QTc interval and a shortened RR interval are associated with an increased risk of sudden cardiac death.

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High Oxalate Concentrations Correlate with Increased Risk for Sudden Cardiac Death in Dialysis Patients

Journal of the American Society of Nephrology ◽

10.1681/asn.2020121793 ◽

2021 ◽

pp. ASN.2020121793

Author(s):

Anja Pfau ◽

Theresa Ermer ◽

Steven Coca ◽

Maria Tio ◽

Bernd Genser ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Kidney Failure ◽

Cardiac Death ◽

Cardiovascular Events ◽

Elevated Serum ◽

Continuous Variable ◽

Cox Proportional Hazards ◽

Dialysis Patients ◽

Increased Risk

Background The clinical significance of accumulating toxic terminal metabolites such as oxalate in kidney failure patients is not well understood. Methods To evaluate serum oxalate concentrations and risk of all-cause mortality and cardiovascular events in a cohort of kidney failure patients requiring chronic dialysis, we performed a post-hoc analysis of the randomized German Diabetes Dialysis Study (4D Study); this study included 1255 European hemodialysis patients with diabetes followed up for a median of 4 years. The results obtained via Cox proportional hazards models were confirmed by competing risk regression and restricted cubic spline modeling in the 4D cohort and validated in a separate cohort of 104 US dialysis patients after a median follow-up of 2.5 years. Results A total of 1108 patients had baseline oxalate measurements, with a median oxalate concentration of 42.4 µM. During follow-up, 548 died, including 139 (25.4%) from sudden cardiac death. A total of 413 patients reached the primary composite cardiovascular endpoint (cardiac death, nonfatal myocardial infarction, and fatal or nonfatal stroke). Patients in the highest oxalate quartile (≥59.7 µM) had a 40% increased risk for cardiovascular events (adjusted hazard ratio [aHR], 1.40; 95% confidence interval [95% CI], 1.08 to 1.81) and a 62% increased risk of sudden cardiac death (aHR, 1.62; 95% CI, 1.03 to 2.56), compared with those in the lowest quartile (≤29.6 µM). The associations remained when accounting for competing risks and with oxalate as a continuous variable. Conclusions Elevated serum oxalate is a novel risk factor for cardiovascular events and sudden cardiac death in dialysis patients. Further studies are warranted to test whether oxalate-lowering strategies improve cardiovascular mortality in dialysis patients.

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Long-term Non-Invasive ECG-based Risk Stratification of Sudden Cardiac Death: Extended 5-year Results

International Cardiovascular Forum Journal ◽

10.17987/icfj.v11i0.393 ◽

2017 ◽

Vol 11 ◽

Author(s):

Elena Okisheva ◽

Dmitry Tsaregorodtsev ◽

Vitaly Sulimov

Keyword(s):

Sudden Cardiac Death ◽

Risk Stratification ◽

Predictive Value ◽

Cardiac Death ◽

Ecg Monitoring ◽

Non Invasive ◽

Increased Risk ◽

All Cause Mortality ◽

High Negative Predictive Value

Objectives: To evaluate predictive value of heart rate turbulence (HRT), deceleration capacity (DC) and microvolt T-wave alternans (mTWA) for risk stratification for sudden cardiac death (SCD) in patients after myocardial infarction (MI) during 60 months of follow-up.Methods: We studied 111 patients after MI occurred > 60 days (27 [9; 84] months) before enrollment (84 men; mean age 64.1±10.5 years). All subjects had 24-hour ambulatory ECG monitoring with HRT, DC and mTWA evaluation. Follow-up period was 60 months; primary endpoint was SCD, secondary endpoint included all non-sudden cardiovascular deaths.Results: During follow-up, we registered 19 cases of SCD and 11 cases of non-sudden cardiovascular deaths (including 7 fatal MI and 3 fatal strokes). DC had high negative predictive value (97.4% for all-cause mortality and 93.7% for SCD). DC values below 4.15 for all-cause mortality and 2.0 for SCD significantly increased risk of all-cause mortality (OR 8.5, 95% CI 2.9 to 24.6, р<0.001) и SCD (OR 9.6, 95% CI 3.2 to 28.5, р<0.001). Combined risk assessment at 12 months revealed that the most significant combination was HRT2 and mTWA100 > 53 mcV, which increased risk both of all-cause mortality (30.7-fold) and SCD (63.3-fold); however, at 60 months this predictive value for SCD decreased (OR = 20.8 (95% CI 2.8 to 114.0), p <0.001).Conclusion: Evaluation of HRT, DC and mTWA during 24-hour ECG monitoring may define the high risk of cardiovascular mortality and SCD in post-MI patients especially during the first 12 months after the baseline examination.

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Telemedicine-based early rule out and followup ECG algorithm for COVID-19 patients

EP Europace ◽

10.1093/europace/euab116.518 ◽

2021 ◽

Vol 23 (Supplement_3) ◽

Author(s):

OE Turan ◽

RY Yilancioglu ◽

C Alak ◽

AA Baskurt ◽

B Hunuk ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Cardiac Death ◽

Retrospective Cohort ◽

Care Group ◽

Ecg Monitoring ◽

Funding Sources ◽

Increased Risk ◽

Rule Out ◽

Funding Acknowledgements

Abstract Funding Acknowledgements Type of funding sources: None. Background Drugs with the potential to prolong QT are used in the treatment of coronavirus 19 (COVID-19) pneumonia. We have developed a telemedicine-based corrected QT (QTc) follow-up algorithm that allows early rule out for follow up. Aims In this study, we investigated the availability and safety of the algorithm. Study design Retrospective cohort Methods Consecutive patients; administered hydroxychloroquine (HCQ) for COVID-19 pneumonia were enrolled into digital ECG recording program which includes QTc follow-up algorithm. Results Patients were classified into three groups as those, excluded promptly from the QTc follow-up based on two consecutive ECG findings (early rule out, n = 92) and those, for whom the follow-up was continued (n = 12) and usual care group (n = 68). Of note, 237 ECG tracings were performed in our algorithm population contrary to standard practice of daily recommended ECG monitoring which could have yielded 975 ECG tracings along with accompanied risks of exposure. This way; we ended in 738 (75.7%) fewer ECG tracings. Sustained ventricular arrhythmia or sudden cardiac death was not observed in the entire patient population. Conclusions It is safe to rely on telemedicine-based early rule out algorithm in COVID-19 patients, receiving hydroxychloroquine treatment. This algorithm abolished the need for further ECG in majority of patients without increased risk during follow up. These algorithms can significantly reduce the healthcare worker exposures by eliminating the need for ECG follow-up promptly. Abstract Figure. Covid-19 Follow up Algorithm

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RESEARCH THE VALUE OF THE COMBINATION OF T WAVE ALTERNANS AND NT-PROBNT IN PREDICTING SUDDEN CARDIAC DEATH

Journal of Medicine and Pharmacy ◽

10.34071/jmp.2012.1.10 ◽

2012 ◽

pp. 74-83

Author(s):

Anh Tien Hoang ◽

Nhat Quang Nguyen

Keyword(s):

Myocardial Infarction ◽

Sudden Cardiac Death ◽

Cardiac Death ◽

Ventricular Arrhythmias ◽

Healthy Person ◽

Treadmill Test ◽

T Wave ◽

T Wave Alternans

Background: Decades of research now link TWA with inducible and spontaneous clinical ventricular arrhythmias. This bench-to-bedside foundation makes TWA, NT-ProBNP a very plausible index of susceptibility to ventricular arrythmia, and motivates the need to define optimal combination of TWA and NT-ProBNP in predicting ventricular arrythmia in myocardial infarction patients. We research this study with 2 targets: 1. To evaluate the role of TWA in predicting sudden cardiac death in myocardial infarction patients. 2. To evaluate the role of NT-ProBNP in predicting sudden cardiac death in myocardial infarction patients 3. Evaluate the role of the combined NT-ProBNP and TWA in predicting sudden cardiac death in myocardial infarction patients. Methods: Prospective study with follow up the mortality in 2 years: 71 chronic myocardial infarction patients admitted to hospital from 5/2009 to 5/20011 and 50 healthy person was done treadmill test to caculate TWA; ECG, echocardiography, NT-ProBNP. Results: Cut-off point of NT-ProBNP in predicting sudden cardiac death is 3168 pg/ml; AUC = 0,86 (95% CI: 0,72 - 0,91); Cut-off point of TWA in predicting sudden cardiac death is 107 µV; AUC = 0,81 (95% CI: 0,69 - 0,87); NT-ProBNP can predict sudden cardiac death with OR= 7,26 (p<0,01); TWA can predict sudden cardiac death with OR= 8,45 (p<0,01). The combined NT-ProBNP and TWA in predicting ventricular arrythmia in heart failure patients: OR= 17,91 (p<0,001). Conclusions: The combined NT-ProBNP and TWA have the best predict value of sudden cardiac death in myocardial infarction patients, compare to NT-ProBNP or TWA alone

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An Emulation of Randomized Trials of Administrating Antipsychotics in PTSD Patients for Outcomes of Suicide-Related Events

Journal of Personalized Medicine ◽

10.3390/jpm11030178 ◽

2021 ◽

Vol 11 (3) ◽

pp. 178

Author(s):

Noah R. Delapaz ◽

William K. Hor ◽

Michael Gilbert ◽

Andrew D. La ◽

Feiran Liang ◽

...

Keyword(s):

Randomized Clinical Trials ◽

Previous History ◽

Current Treatment ◽

Careful Consideration ◽

P Value ◽

Post Traumatic Stress ◽

Increased Risk ◽

History Of ◽

Almost All

Post-traumatic stress disorder (PTSD) is a prevalent mental disorder marked by psychological and behavioral changes. Currently, there is no consensus of preferred antipsychotics to be used for the treatment of PTSD. We aim to discover whether certain antipsychotics have decreased suicide risk in the PTSD population, as these patients may be at higher risk. A total of 38,807 patients were identified with a diagnosis of PTSD through the ICD9 or ICD10 codes from January 2004 to October 2019. An emulation of randomized clinical trials was conducted to compare the outcomes of suicide-related events (SREs) among PTSD patients who ever used one of eight individual antipsychotics after the diagnosis of PTSD. Exclusion criteria included patients with a history of SREs and a previous history of antipsychotic use within one year before enrollment. Eligible individuals were assigned to a treatment group according to the antipsychotic initiated and followed until stopping current treatment, switching to another same class of drugs, death, or loss to follow up. The primary outcome was to identify the frequency of SREs associated with each antipsychotic. SREs were defined as ideation, attempts, and death by suicide. Pooled logistic regression methods with the Firth option were conducted to compare two drugs for their outcomes using SAS version 9.4 (SAS Institute, Cary, NC, USA). The results were adjusted for baseline characteristics and post-baseline, time-varying confounders. A total of 5294 patients were eligible for enrollment with an average follow up of 7.86 months. A total of 157 SREs were recorded throughout this study. Lurasidone showed a statistically significant decrease in SREs when compared head to head to almost all the other antipsychotics: aripiprazole, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone (p < 0.0001 and false discovery rate-adjusted p value < 0.0004). In addition, olanzapine was associated with higher SREs than quetiapine and risperidone, and ziprasidone was associated with higher SREs than risperidone. The results of this study suggest that certain antipsychotics may put individuals within the PTSD population at an increased risk of SREs, and that careful consideration may need to be taken when prescribed.

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Nasal symptoms increase the risk of snoring and snoring increases the risk of nasal symptoms. A longitudinal population study

Sleep And Breathing ◽

10.1007/s11325-020-02287-8 ◽

2021 ◽

Author(s):

Maria Värendh ◽

Christer Janson ◽

Caroline Bengtsson ◽

Johan Hellgren ◽

Mathias Holm ◽

...

Keyword(s):

Risk Factors ◽

Respiratory Health ◽

Smoking Status ◽

Northern Europe ◽

Nasal Breathing ◽

Nasal Symptoms ◽

Increased Risk ◽

Study Population ◽

Independent Risk Factors

Abstract Purpose Humans have a preference for nasal breathing during sleep. This 10-year prospective study aimed to determine if nasal symptoms can predict snoring and also if snoring can predict development of nasal symptoms. The hypothesis proposed is that nasal symptoms affect the risk of snoring 10 years later, whereas snoring does not increase the risk of developing nasal symptoms. Methods In the cohort study, Respiratory Health in Northern Europe (RHINE), a random population from Denmark, Estonia, Iceland, Norway, and Sweden, born between 1945 and 1973, was investigated by postal questionnaires in 1999–2001 (RHINE II, baseline) and in 2010–2012 (RHINE III, follow-up). The study population consisted of the participants who had answered questions on nasal symptoms such as nasal obstruction, discharge, and sneezing, and also snoring both at baseline and at follow-up (n = 10,112). Results Nasal symptoms were frequent, reported by 48% of the entire population at baseline, with snoring reported by 24%. Nasal symptoms at baseline increased the risk of snoring at follow-up (adj. OR 1.38; 95% CI 1.22–1.58) after adjusting for age, sex, BMI change between baseline and follow-up, and smoking status. Snoring at baseline was associated with an increased risk of developing nasal symptoms at follow-up (adj. OR 1.22; 95% CI 1.02–1.47). Conclusion Nasal symptoms are independent risk factors for development of snoring 10 years later, and surprisingly, snoring is a risk factor for the development of nasal symptoms.

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