Beat-to-beat QT interval variability in coronary patients

Changes in ventricular repolarization have been described in patients after myocardial infarction, whereas data for coronary patients without prior myocardial infarction are lacking. This study was designed to evaluate ventricular repolarization in coronary patients with effort angina pectoris. Beat-to-beat QT interval variability (QTV) using 5-minute resting high-resolution ECG recordings was measured in 26 men (mean age 62.1 years) with effort angina pectoris and without prior myocardial infarction, and in 30 age-matched men without clinically evident coronary heart disease (controls). To evaluate the degree of coronary artery disease in coronary patients, coronary angiography was performed. Coronary patients displayed significantly higher values of QTV compared with the control patients (P < .001). Rate adaptation of QT interval correlated significantly with the degree of coronary artery disease in the study group patients (P < .05). The significant association between QTV and coronary heart disease suggests altered ventricular repolarization in coronary patients without prior myocardial infarction.     

Beat-to-beat interplay of heart rate, ventricular depolarization, and repolarization

To improve malignant arrhythmia risk stratification, the causal and random components of spatiotemporal dynamics of heart rate (RR distances), ventricular depolarization sequence, and repolarization disparity were studied based on body surface potential map records taken for 5 minutes, in resting, supine position on 14 healthy subjects (age range, 20-65 years) and on 6 arrhythmia patients (age range, 59-70 years). Beat-to-beat QRS and QRST integral maps, Karhunen-Loève (KL) coefficients, RR, and nondipolarity index time series were computed. Tight relationship was found between RR and QRS integrals in healthy subjects with less association in arrhythmia patients. Tight KL-domain multiple linear association (r² > 0.72) was found between the QRS and QRST integral dynamics (ie, depolarization sequence and repolarization disparity). Beat-to-beat probability of the generation of significant nondipolarity index spikes was proportional to the QRST KL-component standard deviations (SD_i) and inversely proportional with the mean dipolar KL components (M_i) of the average QRST integral map.     

Hepcidin as a new biomarker for detecting autologous blood transfusion

Autologous blood transfusion (ABT) is an efficient way to increase sport performance. It is also the most challenging doping method to detect. At present, individual follow‐up of haematological variables via the athlete biological passport (ABP) is used to detect it. Quantification of a novel hepatic peptide called hepcidin may be a new alternative to detect ABT. In this prospective clinical trial, healthy subjects received a saline injection for the control phase, after which they donated blood that was stored and then transfused 36 days later. The impact of ABT on hepcidin as well as haematological parameters, iron metabolism, and inflammation markers was investigated. Blood transfusion had a particularly marked effect on hepcidin concentrations compared to the other biomarkers, which included haematological variables. Hepcidin concentrations increased significantly: 12 hr and 1 day after blood reinfusion, these concentrations rose by seven‐ and fourfold, respectively. No significant change was observed in the control phase. Hepcidin quantification is a cost‐effective strategy that could be used in an “ironomics” strategy to improve the detection of ABT. Am. J. Hematol. 91:467–472, 2016. © 2016 Wiley Periodicals, Inc.     

DeltaT50--a new method to assess temporal ventricular repolarization variability

Background

Increased beat-to-beat variability in cardiac repolarization time is a tentative risk marker of drug-induced torsades de pointes. We developed a new, automatic method based on the temporal variability of the T-wave down slope to assess this variability.

Method and Results

Leads V₁ to V₆ of resting electrocardiograms were recorded in 42 healthy subjects (18-68 years, 22 men). The temporal variability at 50% of the T-wave down slope, deltaT50 (1.5 ± 0.41 milliseconds; range, 0.86-2.66 milliseconds), was measured with an accuracy of 1 millisecond on at least 9 pairs of electrocardiogram complexes with a signal-to-noise ratio more than 10 and changes in the R-R interval less than 150 milliseconds. The correlation between repeated measurements of deltaT50 was high. DeltaT50 was measured without corrections for age, sex, heart rate, T-wave amplitude, signal-to-noise ratio, R-R variability, and QTcF because none of these factors explained more than 4% of the within-subject deltaT50 variability.

Conclusion

The beat-to-beat repolarization variability was measured with high fidelity with the deltaT50 method and was a robust measure in healthy volunteers.     

Utility of short-term variability of repolarization as a marker for monitoring a safe exercise training program in patients with cardiac diseases

In order to begin searching for new markers for safe exercise training in patients with cardiac diseases, we tested the sensitivity and reliability of the short-term variability of repolarization (STV(QT)) in comparison with QT interval, QTc, and T(peak)-T(end) interval (T(p-e)) in patients with cardiac diseases. Nine patients (8 men, 1 woman; 58 ± 10 years) were enrolled. The cardiac rehabilitation (CR) program consisted of walking, bicycling on an ergometer, and calisthenics for 30-50 minutes/session and 3-5 sessions/week for 3 months. ECGs of 31 consecutive sinus beats were obtained before and after the CR program. RR and QT intervals were measured in the aVL lead. The mean orthogonal distance from the diagonal to the points of the Poincaré plots was determined using the following equation; STV(QT) [= Σ |QT(n+1)-QT(n)/(30 × 2(1/2))], as a marker of temporal dispersion of repolarization. Also, T(p-e) of 5 consecutive beats was measured as a marker of spatial dispersion. No fatal arrhythmias were observed in the CR. No significant difference was observed in the RR or QT interval between at baseline and at the end of the CR program. Meanwhile, QTc, STV(QT) and T(p-e) decreased significantly from 429 ± 27 to 400 ± 17 (P < 0.01), from 6.8 ± 1.3 to 4.7 ± 1.4 msec (P < 0.001), and from 74.8 (61.2/79.1) to 64.8 (51.4/70.7) msec (median (25th/75th percentile), P < 0.01), respectively. STV(QT) together with T(p-e) and QTc may reflect the time-courses of safe exercise training.     

Beat-to-beat QT interval variability in children: normal and physiologic data

Background

QT interval variability provides information on ventricular vulnerability. However, QT interval variability in children has not been adequately evaluated.

Methods

One hundred seventy-three consecutive nursing infants and children (male-female, 106:67) up to school age with no intrinsic cardiac disease were included in this study, and they were categorized into 6 age-related groups. The QT variability index (QTVI) was calculated based on an electrocardiogram; and age-specific standard values, sex-specific classification, and a standard growth curve covering 0 to 7 years were constructed.

Results

The QTVI decreased in an age-dependent manner, reached constant values after school age, and exhibited no sex-specific differences in 6 age-related groups.

Conclusions

Based on the age-dependent standardized QTVI values, it is possible to estimate the instability of ventricular repolarization in pediatric patients with better accuracy.     

Prolonged action potential durations,increased dispersion of repolarization,and polymorphic ventricular tachycardia in a mouse model of proarrhythmia

Introduction: In the congenital long QT syndrome, inhomogeneously prolonged action potentials, bradycardia, and hypokalemia can cause afterdepolarizations and torsade de pointes. Other genetic factors may contribute to similar forms of ventricular tachycardias in hypertrophied or failing hearts, especially if the outward current I_Kr is blocked pharmacologically. We sought to develop a mouse heart model for such arrhythmias in order to identify the proarrhythmic potential in transgenic animals. Methods and results: Hearts of adult wild-type (CD1) mice were isolated and the aorta was retrogradely perfused. Three monophasic action potentials and a volume-conducted ECG were simultaneously recorded. Sotalol (10^-5M and 2 × 10^-5M) prolonged action potential duration (APD) in a concentration-dependent and reverse frequency-dependent fashion (from 34 ± 1 to 48 ± 2 ms at 100 ms basic cycle length (BCL), from 38 ± 2 to 54 ± 3 ms at 180 ms BCL for APD90, p < 0.05). Sotalol did not alter the relation between refractoriness and APD (ERP/APD ratio = 0.76 - 0.93). AV nodal block caused ventricular bradycardia and doubled dispersion of APD (APD70max-min: 11 ± 1 vs. 4 ± 1 ms, APD90max-min: 12 ± 1 vs. 5 ± 1 ms, p < 0.05). If combined with hypokalemia, afterdepolarizations induced polymorphic ventricular tachycardias in 1 of 8 hearts at K⁺ =3.0 mM and in 10 of 12 hearts at K⁺ = 2.0 mM. Prior to polymorphic ventricular tachycardia, dispersion of APD further increased (APD70max-min: 17 ± 3 ms; APD90max-min: 25 ± 3 ms; p < 0.05). Conclusions: This isolated beating mouse heart model can be used to study drug-induced action potential prolongation and repolarization-related ventricular arrhythmias provoked by bradycardia and hypokalemia. It may be suitable to identify a genetic predisposition to ventricular arrhythmias that may only become apparent under such proarrhythmic conditions.     

基于生物信息学的结直肠腺癌miRNA预后模型的建立

目的通过生物信息学分析构建结直肠腺癌的miRNA预后模型。方法通过癌症基因组图谱(The Cancer Genome Atlas,TCGA)获取结直肠腺癌患者的miRNA表达谱与相应的临床数据,通过差异分析明确肿瘤组与正常对照组之间差异表达的miRNA。随后,将具有生存状态和生存时间的患者(n=484)随机分为训练集(n=244)和测试集(n=240),对训练集的差异miRNAs和患者的总生存期进行单因素和多因素Cox分析来构建预后模型,并用Kaplan-Meier法与受试者工作特征曲线(receiver operating characteristic,ROC)在训练集与合并数据集中验证模型的效能。此外,用单因素和多因素Cox分析验证miRNA模型是否为结直肠腺癌患者的独立预后因素。为了明确miRNAs的生物学功能,对miRNAs的靶基因进行了KEGG、GO富集分析。结果我们从TCGA数据库中获得了肿瘤组织与正常组织之间520个差异表达的miRNAs,在训练集中通过单基因与多因素Cox分析筛选出7个miRNA(hsa-miR-891a-5p、hsa-miR-664b-3p、hsa-miR-485-5p、hsa-miR-486-5p、hsa-miR-3615、hsa-miR-21-3p和hsa-miR-3677-3p)用以构建模型,并将患者分为高风险组与低风险组,Kaplan-Meier分析结果提示高风险组患者的总生存期明显低于低风险组患者。训练集、测试集与合并数据集的ROC表明该模型预测5年生存期的曲线下面积(area under the curve,AUC)分别是0.722、0.747和0.735,提示该模型有较好的预测能力。此外,多因素Cox分析提示该模型是患者的独立风险因素。基因富集分析结果提示miRNAs相关的靶基因与Hippo信号通路、cGMP-PKG信号通路、细胞生长等通路密切相关。结论本研究建立了一个miRNA预后模型能够有效地预测结直肠腺癌患者的总生存时间,并为研究miRNA在结直肠腺癌发生发展的作用提供了新的方向。     

Developmental changes in IKr and IKs contribute to age-related expression of dofetilide effects on repolarization and proarrhythmia

OBJECTIVE: Clinical and experimental studies suggest that immature hearts are as or more sensitive than adult hearts to adverse effects of I(Kr) blocking drugs. We hypothesized that age-dependent changes in I(Kr) and I(Ks) contribute to the different repolarization reserves and proarrhythmic effects of I(Kr) blockers in the young and adult heart. METHODS: Dogs aged 1-150 days and adults were used to study (1) proarrhythmic effects in situ of the I(Kr) blocker dofetilide; (2) dofetilide effects on action potential duration (APD) recorded with microelectrodes from left ventricular (LV) slabs; (3) I(Kr) and I(Ks) in single LV myocytes using whole-cell voltage clamp. RESULTS: In situ, dofetilide-induced proarrhythmia occurred in 40% of adults, 86% of young (20-150 day) dogs and 0% of neonatal (1-19 day) dogs (P<0.05). Isolated tissue experiments showed no transmural gradient for repolarization from neonate through 3 months of age, after which the gradient increased through adulthood. In the presence of dofetilide, the greatest APD prolongation occurred in neonates. Yet, transmural dispersion did not increase in neonates but significantly increased in young and adults. Dofetilide-induced early after depolarization (EAD) incidence was 23% in adults, 59% in young and 8% in neonates (P<0.05). I(Kr) but not I(Ks) was expressed at <30 days, whereas both currents were present in adult myocardium. CONCLUSIONS: Our data suggest that a lack of I(Ks) results in a greater dependence on I(Kr) for repolarization in neonates and is associated with exaggerated effects of I(Kr)-blockade on APD. However, APD prolongation alone is insufficient for expression of proarrhythmia, which also requires transmural dispersion of repolarization and EADs. The extent to which APD prolongation, transmural dispersion and EADs are manifested at various ages in the absence and presence of I(Kr) blocking drugs appears to be the ultimate determinant of proarrhythmia.     

正常人的心室复极时间变异性研究

目的　使用频谱分析逐搏R波与T波间期 (RT)的变异性来研究正常人的心室复极时间变异性 (RDV)。方法　正常人 30例 ,采用 2 4小时动态心电图监测系统进行记录 ,通过计算机软件使用频谱技术同步分析RDV及心率变异性 (HRV)。结果　 (1)高频 (HF) (白天为 2 7 2± 16 83,夜间为2 0 9± 16 83,p <0 .0 5 )、低频 (LF) (白天 16 85± 9 36　夜间 12 84± 9 4 7,P <0 0 5 )显示出明显的昼夜节律性变化 ,夜间明显高于白天。 (2 )正常人RDV与HRV的频率成分性质上非常相似 ,RDV的频谱分析呈现与HRV相似的两个主要的频谱成分即高频 (HF)和低频 (LF)。结论　RDV提供了又一无创方法以评价心室复极的自主神经调节机制     

Circulating dendritic cells deficiencies as a new biomarker in classical Hodgkin lymphoma

No robust biomarkers have been yet validated to identify the recurrence of disease in classical Hodgkin Lymphoma (cHL) patients upon induction treatment. The relevance of the inflammatory microenvironment in cHL prompted us to investigate the key immunomodulator myeloid dendritic cells type-1 (mDC1), type-2 (mDC2) and plasmacytoid dendritic cells (pDC). Blood DC levels were assessed in 52 newly diagnosed patients through multiparametric flow-cytometry. All but two patients received ABVD regimen (doxorubicin, bleomycin, vinblastine, dacarbazine). The median counts of all DC subsets were lower in cHL patients than in healthy controls (P < 0·001). Median mDC counts were inferior for the advanced vs early stage patients for both mDC1s and mDC2s (P = 0·008; P = 0·0007 respectively). Also, median mDC2 counts were reduced in case of bulky (P = 0·0004) and extra-nodal (P = 0·046) disease. Patients with B symptoms had lower levels for mDC1s (P = 0·046), mDC2s (P = 0·009) and pDCs (P = 0·040). All the DC subtypes increased at the end of treatment in 26 patients (P < 0·001): 4·6-fold for mDC1, 2·4-fold for mDC2, 4·5-fold for pDC and aligned DCs subsets with the reference frequencies and the interquartile ranges of the controls. In conclusion, DCs may contribute to the disturbed immunological interplay typical of cHL, prompting a further evaluation of their value as a potential new biomarker.     

Pre-analytic variability in cardiovascular biomarker testing

The impact of laboratory medicine on clinical cardiology has dramatically increased over the years and a lot of cardiovascular biomarkers have been recently proposed. In order to avoid clinical mistakes, physicians should be well aware of all the aspects, which could affect the quality of laboratory results, remembering that pre-analytic variability is an often overlooked significant source of bias, determining the vast majority of laboratory errors. This review addresses the determinants of pre-analitycal variability in cardiovascular biomarker testing, focusing on the most widespread biomarkers, which are cardiac troponins and natriuretic peptides.     

Beat-to-beat morphologic variability of the electrocardiogram for the evaluation of chest pain in the emergency room.

The value of electrocardiographic, morphologic variability in the early diagnosis of acute myocardial infarction (AMI) and myocardial ischemia was evaluated in 49 nonselected patients presenting to the emergency room with chest pain. High-resolution electrocardiography was used to determine the morphologic variability of consecutive electrocardiographic complexes, and the ratio of the variance of the QRS onset to that of the entire electrocardiogram was calculated. A final diagnosis of AMI was confirmed in 8 patients, acute coronary insufficiency in 8, angina pectoris in 19, and a noncardiac origin for chest pain in 14. Patients with AMI had a significantly higher beat-to-beat electrocardiographic morphologic variability of the QRS onset (1.4 +/- 0.2) than did those with acute coronary insufficiency (1.1 +/- 0.2), angina pectoris (0.9 +/- 0.1) or noncardiac chest pain (0.8 +/- 0.1) (p < 0.05). The sensitivity of the clinical presentation, typical electrocardiographic changes and creatine phosphokinase levels for the diagnosis of an acute ischemic event on admission to the emergency room was 62, 25 and 37.5%, respectively. Relative variance of the QRS onset of > 0.86 had a sensitivity of 75% and a specificity of 61% for diagnosing an acute ischemic event. Logistic regression of these variables showed that the QRS onset relative variability is an independent predictor for an acute ischemic event. It is concluded that an increased beat-to-beat electrocardiographic variability in patients with AMI is present on admission to the emergency room and may assist in establishing the diagnosis in this setting.