Determinants of Prolonged QT Interval and Their Contribution to Sudden Death Risk in Coronary Artery Disease

Chugh, Sumeet S.; Reinier, Kyndaron; Singh, Tanvi; Uy‐Evanado, Audrey; Socoteanu, Carmen; Peters, Dawn; Mariani, Ronald; Gunson, Karen; Jui, Jonathan

doi:10.1161/circulationaha.108.797035

Cited by 228 publications

(219 citation statements)

References 36 publications

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“…More importantly, ECG data obtained from radiotelemetry recording demonstrated that in vivo transfection of Ca v 2.2‐α shRNA into AVG neurons not only increased the QT interval, QTc interval, QTd, QTcd, and Tpe but also induced a spontaneous ventricular tachyarrhythmia in conscious rats (Figures 6 and 7). It has been found that prolongation of the QT and QTc intervals, increase of the QTd and QTcd (a marker of spatial heterogeneity of ventricular repolarization), and prolonged Tpe (a marker of transmural dispersion of ventricular repolarization) are associated with increased risk of malignant ventricular arrhythmias and sudden cardiac death 49, 50, 51, 52. The results in the present study provide direct evidence that blunted ventricular vagal activity increases the susceptibility to ventricular arrhythmias and induces ventricular arrhythmias.…”

Section: Discussionsupporting

confidence: 63%

Reduced N‐Type Ca ²⁺ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis

Zhang

Cao

et al. 2018

JAHA

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BackgroundAttenuated cardiac vagal activity is associated with ventricular arrhythmogenesis and related mortality in patients with chronic heart failure. Our recent study has shown that expression of N‐type Ca2+ channel α‐subunits (Cav2.2‐α) and N‐type Ca2+ currents are reduced in intracardiac ganglion neurons from rats with chronic heart failure. Rat intracardiac ganglia are divided into the atrioventricular ganglion (AVG) and sinoatrial ganglion. Ventricular myocardium receives projection of neuronal terminals only from the AVG. In this study we tested whether a decrease in N‐type Ca2+ channels in AVG neurons contributes to ventricular arrhythmogenesis.Methods and ResultsLentiviral Cav2.2‐α shRNA (2 μL, 2×107 pfu/mL) or scrambled shRNA was in vivo transfected into rat AVG neurons. Nontransfected sham rats served as controls. Using real‐time single‐cell polymerase chain reaction and reverse‐phase protein array, we found that in vivo transfection of Cav2.2‐α shRNA decreased expression of Cav2.2‐α mRNA and protein in rat AVG neurons. Whole‐cell patch‐clamp data showed that Cav2.2‐α shRNA reduced N‐type Ca2+ currents and cell excitability in AVG neurons. The data from telemetry electrocardiographic recording demonstrated that 83% (5 out of 6) of conscious rats with Cav2.2‐α shRNA transfection had premature ventricular contractions (P<0.05 versus 0% of nontransfected sham rats or scrambled shRNA‐transfected rats). Additionally, an index of susceptibility to ventricular arrhythmias, inducibility of ventricular arrhythmias evoked by programmed electrical stimulation, was higher in rats with Cav2.2‐α shRNA transfection compared with nontransfected sham rats and scrambled shRNA‐transfected rats.ConclusionsA decrease in N‐type Ca2+ channels in AVG neurons attenuates vagal control of ventricular myocardium, thereby initiating ventricular arrhythmias.

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Section: Discussionsupporting

confidence: 63%

Reduced N‐Type Ca ²⁺ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis

Zhang

Cao

et al. 2018

JAHA

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“…Whether QTc contributes to increased hospital mortality in those with delirium is unknown 34. Prolonged QT interval is known to predict mortality in a variety of other conditions that are frequently encountered in the AMU such as: coronary artery disease,35 heart failure36 and diabetes mellitus 37, 38. Survival curves of those with/without prolonged QTc separated well within 50 days of admission, in a hospital‐wide study 7.…”

Section: Discussionmentioning

confidence: 99%

Incidence and outcomes of long QTc in acute medical admissions

et al. 2018

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SummaryAimsProlonged QT interval on electrocardiogram (ECG) increases the risk of ventricular arrhythmia. Patients admitted to acute medical units (AMU) may be at risk of QT prolongation from multiple, recognised risk factors. Few data exist regarding incidence or outcomes of QT prolongation in acute general medical admissions.The aims were to determine the incidence of Bazett's‐corrected QT (QTc) prolongation upon admission to AMU; the relationship between QTc and inpatient mortality, length of stay and readmission; proportion with prolonged QTc subsequently administered QT interval‐prolonging drugs.MethodsRetrospective, observational study of 1000 consecutive patients admitted to an AMU in a large urban hospital. Exclusion criteria: age <18 years, ventricular pacing, poor quality/absent ECG . QTc determined manually from ECG obtained within 4‐hours of admission. QTc prolongation considered ≥470 milliseconds (males) and ≥480 milliseconds (females). In both genders, >500 milliseconds was considered severe. Study end‐points, (a) incidence of QTc prolongation at admission; (b) inpatient mortality, length of stay and readmission rates; (c) proportion with QTc prolongation subsequently administered QT interval‐prolonging drugs.ResultsOf 1000 patients, 288 patients were excluded, therefore final sample was n = 712. Patient age (mean ± SD) was 63.1 ± 19.4 years; females 49%. QTc prolongation was present in n = 50 (7%) at admission; 1.7% had QTc interval >500 ms. Of the 50 patients admitted with prolonged QTc, 6 (12%) were subsequently administered QT interval‐prolonging drugs. QTc prolongation was not associated with worse inpatient mortality or readmission rate. Length of stay was greater in those with prolonged QTc, 7.2 (IQR 2.4‐13.2) days vs 3.3 (IQR 1.3‐10.0; P = 0.004), however, in a regression model, presence of QTc did not independently affect length of stay.Conclusions QTc interval prolongation is frequent among patients admitted to AMU. QT interval‐prolonging drugs are commonly prescribed to patients presenting with prolonged QTc but whether this affects clinical outcomes is uncertain.

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“…Longer QTc is well known to be independently associated with SCD in men and women 6, 22. In the case‐control Oregon Sudden Unexpected Death Study of patients with CAD (40% women), QTc was longer in those with SCD compared with controls (450±45 versus 433±37 ms, P <0.0001), and abnormally prolonged QTc was associated with a 5‐fold increased risk of SCD 23. In our study, women with SCD had a mean QTc of 446±27 ms.…”

Section: Discussionmentioning

confidence: 99%

Sudden Cardiac Death in Women With Suspected Ischemic Heart Disease, Preserved Ejection Fraction, and No Obstructive Coronary Artery Disease: A Report From the Women's Ischemia Syndrome Evaluation Study

Mehta

Johnson

Kenkre

et al. 2017

JAHA

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BackgroundSudden cardiac death (SCD) is often the first presentation of ischemic heart disease; however, there is limited information on SCD among women with and without obstructive coronary artery disease (CAD). We evaluated SCD incidence in the WISE (Women's Ischemia Syndrome Evaluation) study.Methods and ResultsOverall, 904 women with suspected ischemic heart disease with preserved ejection fraction and core laboratory coronary angiography were followed for outcomes. In case of death, a death certificate and/or a physician or family narrative of the circumstances of death was obtained. A clinical events committee rated all deaths as cardiovascular or noncardiovascular and as SCD or non‐SCD. In total, 96 women (11%) died over a median of 6 years (maximum: 8 years). Among 65 cardiovascular deaths, 42% were SCD. Mortality per 1000 person‐hours increased linearly with CAD severity (no CAD: 5.8; minimal: 15.9; obstructive: 38.6; P<0.0001). However, the proportion of SCD was similar across CAD severity: 40%, 58%, and 38% for no, minimal, and obstructive CAD subgroups, respectively (P value not significant). In addition to traditional risk factors (age, diabetes mellitus, smoking), a history of depression (P=0.018) and longer corrected QT interval (P=0.023) were independent SCD predictors in the entire cohort. Corrected QT interval was an independent predictor of SCD in women without obstructive CAD (P=0.033).Conclusions SCD contributes substantially to mortality in women with and without obstructive CAD. Corrected QT interval is the single independent SCD risk factor in women without obstructive CAD. In addition to management of traditional risk factors, these data indicate that further investigation should address mechanistic understanding and interventions targeting depression and corrected QT interval in women.

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Determinants of Prolonged QT Interval and Their Contribution to Sudden Death Risk in Coronary Artery Disease

Cited by 228 publications

References 36 publications

Reduced N‐Type Ca ²⁺ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis

Reduced N‐Type Ca ²⁺ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis

Incidence and outcomes of long QTc in acute medical admissions

Sudden Cardiac Death in Women With Suspected Ischemic Heart Disease, Preserved Ejection Fraction, and No Obstructive Coronary Artery Disease: A Report From the Women's Ischemia Syndrome Evaluation Study

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Determinants of Prolonged QT Interval and Their Contribution to Sudden Death Risk in Coronary Artery Disease

Cited by 228 publications

References 36 publications

Reduced N‐Type Ca 2+ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis

Reduced N‐Type Ca 2+ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis

Incidence and outcomes of long QTc in acute medical admissions

Sudden Cardiac Death in Women With Suspected Ischemic Heart Disease, Preserved Ejection Fraction, and No Obstructive Coronary Artery Disease: A Report From the Women's Ischemia Syndrome Evaluation Study

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Reduced N‐Type Ca ²⁺ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis

Reduced N‐Type Ca ²⁺ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis