三氧化二砷诱导豚鼠心脏QT间期延长及其分子机制研究

目的 观察三氧化二砷（As2O3）对豚鼠心脏QT间期的影响，并探讨其对延迟整流钾通道蛋白mRNA表达的影响。方法 按静脉给予的As2O3剂量，将豚鼠随机分为4组：0（对照组）、0．4、0．8、1．6mg／kg组。测量不同时间点的心电图，观察校正QT间期（QTc）的变化。用反转录聚合酶链式反应（RT—PCR）方法观察As2O3对心肌延迟整流钾通道蛋白mRNA表达的影响。结果 在120min时，As2O3 0．8、1．6mg／kg组QTc分别为（368±29）、（388±31）ms，与对照组[（324±20）ms]比较，明显延长（t值分别为9．26、16．37，P〈0．01）。RT-PCR结果显示，与对照组比较，As2O3,1．6mg／kg可以使豚鼠心肌缓慢型延迟整流钾通道蛋白（KvLQT1）mRNA表达降低（t=12．83，P〈0．01），而对快速型延迟整流钾通道蛋白（ERG）mRNA表达则无明显影响。结论 As2O3可引起豚鼠心脏QT间期延长，其机制可能与抑制KvLQT1 mRNA表达有关。     

右室心尖部和间隔部S1S2刺激电重构后对跨室壁复极离散的影响

目的通过观察右室不同部位S1S2刺激电重构后对室壁QRS间期、QRS波起始至T波顶点间期（QTp）、QT间期和T波峰末间期（Tp2e）影响,分析不同部位起搏对跨室壁复极离散的影响。方法选取因阵发性室上性心动过速拟行射频消融患者18例,随机分心尖部刺激组（RVA组,n=9）和间隔部刺激组（RVS组,n=9）,分别行S1S2刺激,测量每组体表起搏心电图V1导联S2刺激的QRS间期、QRS波起始至T波顶点间期（QTp）、QT间期和T波峰末间期（Tp2e）并进行统计分析。结果 RVS组较RVA组的QRS间期、QTp无差异、至S1S2500/260ms后QT间期及Tp2e明显减低;两组均随S1S2刺激间期缩短QT间期及Tp2e明显增大,而QRS间期及QTp无差异。结论电重构后RVS组比RVA组心室跨壁复极离散低、心脏同步性较好,是选择起搏的较好部位。     

三氧化二砷诱导QT间期延长及其离子靶点的实验研究

目的观察不同给药方法情况下,三氧化二砷(arsenictrioxide,As2O3)对豚鼠心肌QT间期的影响,同时探讨As2O3诱导QT间期延长的离子靶点。方法分别采用静脉一次性注射和缓慢滴注的方法,观察As2O3对豚鼠心肌QTc(校正的QT间期)的影响;应用双微电极电压钳技术探讨As2O3对快速型延迟整流钾电流(IKr/HERG)的作用。结果静脉一次性注射As2O3后,0.8、1.6mg/kgAs2O3可以使QTc明显延长(与对照组相比,t=4.907、P<0.01),并且这种作用具有明显的剂量依赖性。但缓慢静脉滴注As2O3(2mg/kg),与对照组相比,QTc无明显变化。双微电极电压钳结果显示,50、100μmol/LAs2O3可明显抑制IKr/HERG电流,当控制电压为0mV时,分别使IKr/HERG电流值从对照组的(2.4±0.6)μA减少到(1.4±0.2)μA(抑制率为41.7%,t=7.071、P<0.01)和(1.0±0.4)μA(抑制率为58.3%,t=8.682、P<0.01)。结论缓慢静脉滴注As2O3可以减少长QT的产生;抑制IKr/HERG是As2O3诱导QT间期延长的重要离子靶点之一。     

老年慢性心力衰竭患者心室结构-心电重构与心律失常的关系

目的探讨老年心肌梗死后慢性心力衰竭（CHF）患者心室结构-心电重构与心律失常的关系。方法收集老年心肌梗死后CHF患者55例[心功能（NYHA分级）:II级23例,III级15例,Ⅳ级17例]及心肌梗死后心功能（NYHA）I级患者30例,采用超声心动图,标准12导联心电图及24小时动态心电图检测其心室腔大小,QT间期,校正QT间期（QTc）及心律失常。结果与心功能I级组比较,CHF组心室腔显著扩大[CHF组:左室舒张末直径（LVEDD）（57±8）mm,左室收缩末直径（LVESD）（45±8）mm;心功能I级组:LVEDD（45±5）mm,LVESD（31±5）mm,P<0.05]。两组间心室复极指标无显著差异[CHF组:QT（0.41±0.07）s,QTc（0.44±0.06）s;心功能I级组:QT（0.41±0.04）s,QTc（0.44±0.04）s]。两组间室性心律失常亦无显著差异[CHF组:室性早搏（VPB）（219±598）次/24h;心功能I级组:VPB（345±504）次/24h]。结论老年心肌梗死后CHF时,心室结构重构显著,心室腔显著扩大,但在本研究中心室结构重构未见引起显著心电重构,心室复极延长及室性心律失常未见显著增加。     

QT Prolongation: A Case of Arsenical Pericardial and Pleural Effusion

Arsenic trioxide is an effective treatment for patients with acute promyelocytic leukaemia (APL) who have relapsed from or are refractory to all trans-retinoic acid and anthracycline chemotherapy. Cardiac effects observed include electrocardiographic changes such as QTc prolongation, T-wave abnormalities, torsades de pointes and sudden death. We describe a case of a man, 76 years old, who was admitted to our department for dyspnoea in APL in treatment with arsenic trioxide. Chest radiograph illustrated an enlarged cardiac silhouette and bilateral pleuric effusion and the ECG evidenced QT prolongation. The patient was also submitted to transthoracic echocardiography that revealed moderate pericardial effusion without signs of cardiac tamponade and a normal biventricular function. This condition was considered to be associated with arsenic trioxide polyserosit and the drug therapy was immediately discontinued and steroid drugs started. After 2 weeks of arsenic trioxide therapy suspension there was evidence of complete resolution of pericardial and pleuric effusion and the ECG showed normal QT interval.     

The perplexing complexity of cardiac arrhythmias: Beyond electrical remodeling

Cardiac arrhythmias continue to pose a major medical challenge and significant public health burden. Atrial fibrillation, the most prevalent arrhythmia, affects more than two million Americans annually and is associated with a twofold increase in mortality. In addition, more than 250,000 Americans each year suffer ventricular arrhythmias, often resulting in sudden cardiac death. Despite the high incidence and societal impact of cardiac arrhythmias, presently there are insufficient insights into the molecular mechanisms involved in arrhythmia generation, propagation, and/or maintenance or into the molecular determinants of disease risk, prognosis, and progression. In addition, present therapeutic strategies for arrhythmia abatement often are ineffective or require palliative device therapy after persistent changes in the electrical and conduction characteristics of the heart have occurred, changes that appear to increase the risk for arrhythmia progression. This article reviews our present understanding of the complexity of mechanisms that regulate cardiac membrane excitability and cardiac function and explores the role of derangements in these mechanisms that interact to induce arrhythmogenic substrates. Approaches are recommended for future investigations focused on providing new mechanistic insights and therapeutic interventions.     

高盐摄入及补钾对健康成人QT间期离散度的影响

目的 探讨慢性盐负荷及补钾对健康成人QT间期离散度(QTd)、T波峰-末间期(Tp-Te)的影响.方法 选取64例28～60岁血压正常者参与为期3周的慢性盐负荷及补钾试验,包括基线调查3 d(基线期),低盐饮食(低盐期)、高盐饮食(盐负荷期)和高盐补钾饮食(高盐补钾期)各7d.各期均测量体质量、血压,记录心电图,测量QT间期、QTd、校正QTd (QTdc)及Tp-Te.结果 低盐期QTd、QTdc、Tp-Te均＜基线期(QTd,45.6± 15.6对52.1 ±23.4,P＜0.05;QTdc,55.6±19.4对61.6±23.6,P＜0.05;Tp-Te,79.8±8.5对85.0±10.6,P＜0.01);盐负荷后QTdc、Tp-Te＞低盐期(QTdc,60.3±19.4对55.6±19.4,P＜0.05;Tp-Te,83.0±10.1对79.8±8.5,P＜0.01);在高盐摄入的基础上大剂量口服补钾QTd、QT-dc、Tp-Te均较高盐期缩小(QTd,42.6±15.1对47.4±19.0,P＜0.05;QTdc,52.2±18.0对60.3±19.4,P＜0.05;Tp-Te,79.1 ±8.5对83.0±10.1,P＜0.01).结论 盐负荷可升高血压并使QTd、QTde及Tp-Te增加,补钾可以减低高盐对QTd、QTdc、Tp-Te的影响,提示补钾可通过缩短心肌复极时间,降低心脏复极不均一性,对心律失常可能有一定预防作用.     

The prognostic value of the QT interval and QT interval dispersion in all-cause and cardiac mortality and morbidity in a population of Danish citizens

Aims. To evaluate the prognostic value of the QT interval and QT intervaldispersion in total and in cardiovascular mortality, as wellas in cardiac morbidity, in a general population. Methods and results. The QT interval was measured in all leads from a standard 12-leadECG in a random sample of 1658 women and 1797 men aged 30–60years. QT interval dispersion was calculated from the maximaldifference between QT intervals in any two leads. All causemortality over 13 years, and cardiovascular mortality as wellas cardiac morbidity over 11 years, were the main outcome parameters.Subjects with a prolonged QT interval (430ms or more) or prolongedQT interval dispersion (80ms or more) were at higher risk ofcardiovascular death and cardiac morbidity than subjects whoseQT interval was less than 360ms, or whose QT interval dispersionwas less than 30ms. Cardiovascular death relative risk ratios,adjusted for age, gender, myocardial infarct, angina pectoris,diabetes mellitus, arterial hypertension, smoking habits, serumcholesterol level, and heart rate were 2·9 for the QTinterval (95% confidence interval 1·1–7·8)and 4·4 for QT interval dispersion (95% confidence interval1·0–19·1). Fatal and non-fatal cardiac morbidityrelative risk ratios were similar, at 2·7 (95% confidenceinterval 1·4–5·5) for the QT interval and2·2 (95% confidence interval 1·1–4·0)for QT interval dispersion. Conclusion. Prolongation of the QT interval and QT interval dispersion independentlyaffected the prognosis of cardiovascular mortality and cardiacfatal and non-fatal morbidity in a general population over 11years.     

Genetic testing to predict sudden cardiac death: current perspectives and future goals

It is known that monogenic traits may predispose young and otherwise healthy individuals to die suddenly. Diseases such as Long QT Syndrome, Brugada Syndrome and Arrhythmogenic Right Ventricular Cardiomyopathy are well known causes of arrhythmic death in young individuals. For several years the concept of “genetic predisposition” to sudden cardiac death has been limited to these uncommon diseases. In the last few years clinical data have supported the view that risk of dying suddenly may cluster in families, supporting the hypothesis of a genetic component for sudden cardiac death. In this review I will try to provide an overview of current knowledge about genetics of sudden death. I will approach this topic by discussing first where we stand in the use of genetics for risk stratification and therapy selection in monogenic diseases and I will then move to discuss the contribution of genetics to patient profiling in acquired cardiovascular diseases.     

Prolonged cardiac repolarisation during spontaneous nocturnal hypoglycaemia in children and adolescents with type 1 diabetes

Aims/hypothesis It has been postulated that hypoglycaemia-related cardiac dysrhythmia and, in particular, prolonged cardiac repolarisation, may contribute to increased mortality rates in children and adolescents with type 1 diabetes.Methods We examined the prevalence of prolonged QT interval on ECG during spontaneous hypoglycaemia in 44 type 1 diabetic subjects (aged 7–18 years), and explored the relationships between serial overnight measurements of QT interval corrected for heart rate (QTc) and serum glucose, potassium and epinephrine levels. Each subject underwent two overnight profiles; blood was sampled every 15 min for glucose measurements and hourly for potassium and epinephrine. Serial ECGs recorded half-hourly between 23.00 and 07.00 hours were available on 74 nights: 29 with spontaneous hypoglycaemia (defined as blood glucose <3.5 mmol/l) and 45 without hypoglycaemia.Results Mean overnight QTc was longer in females than in males (412 vs 400 ms, p=0.02), but was not related to age, diabetes duration or HbA₁c. Prolonged QTc (>440 ms) occurred on 20 out of 74 (27%) nights, with no significant differences between male and female subjects, and was more prevalent on nights with hypoglycaemia (13/29, 44%) than on nights without (7/45, 15%, p=0.0008). Potassium levels were lower on nights when hypoglycaemia occurred (minimum potassium 3.4 vs 3.7 mmol/l, p=0.0003) and were inversely correlated with maximum QTc (r=–0.40, p=0.03). In contrast, epinephrine levels were not higher on nights with hypoglycaemia and were not related to QTc.Conclusions/interpretation In young type 1 diabetic subjects, prolonged QTc occurred frequently with spontaneous overnight hypoglycaemia and may be related to insulin-induced hypokalaemia.     

Relationship of QT interval variability to heart rate and RR interval variability

The study investigated whether the beat-to-beat QT interval variability relationship to the mean heart rate and the RR interval variability depended on the cardiovascular autonomic status changed by postural positioning. Repeated long-term 12-lead Holter recordings were obtained from 352 healthy subjects (mean age 32.7 ± 9.1 years, 176 females) while they underwent postural provocative tests involving supine, unsupported sitting and unsupported standing positions. Each recording was processed as a sequence of overlapping 10-second segments. In each segment, the mean RR interval, the coefficients of variance of the RR intervals (RRCV) and the QT intervals (QTCV) were obtained. In each subject, these characteristics, corresponding to different postural positions, were firstly averaged and secondly used to obtain within-subject correlation coefficients between the different characteristics at different postural positions. While the within-subject means of RRCV generally decreased when changing the position from supine to sitting and to standing (4.53 ± 1.95%, 4.12 ± 1.51% and 3.26 ± 1.56% in females and 3.99 ± 1.44%, 4.00 ± 1.24% and 3.53 ± 1.32% in males respectively), the means of QTCV systematically increased during these position changes (0.96 ± 0.40%, 1.30 ± 0.56% and 1.88 ± 1.46% in females and 0.85 ± 0.30%, 1.13 ± 0.41% and 1.41 ± 0.59% in males, respectively). The intra-subject relationship between QTCV, RRCV and mean RR intervals was highly dependent on postural positions. The study concludes that no universally applicable normalization of the QT interval variability for the heart rate and/or the RR interval variability should be assumed. In future studies of the QT variability, it seems preferable to report on the absolute values of QT variability, RR variability and mean heart rate separately.     

T wave morphology analysis distinguishes between KvLQT1 and HERG mutations in long QT syndrome

OBJECTIVES: The aim of this study was to develop an objective method to distinguish between HERG and KvLQT1 genotypes on the surface ECG. BACKGROUND: The two most prevalent genes affected in long QT syndrome (LQTS) are KvLQT1 (KCNQ1) and HERG (KCNH2), which are mutated in >90% of patients with a reported LQTS genotype. It is known that T waves have lower amplitude and more notches in HERG patients than T waves in KvLQT1 patients, but this semiquantitative method lacks the discriminative power to be used in a clinical setting. We developed a simple mathematical method that allowed us to quantify T wave shape in LQTS mutations for clinical use. METHODS: ECGs from 24 HERG patients, 13 KvLQT1 LQTS patients, and 13 healthy relatives were examined. The repolarizing integral (RI) was constructed from the T wave. The resulting RI is sigmoid and was modeled using the Hill equation as (RI(t) = V(max)*[t(n)/[K(m)(n) + t(n)]]). V(max) is equivalent to the total T wave area, K(m) is the time when 50% of the T wave area is reached, and n is a measure of the slope of the sigmoid RI. RESULTS: The RI correlated nearly perfectly to the fitted sigmoid, r = 0.99. In lead V(2), V(max) was larger in KvLQT1 (0.148 +/- 0.021) (mean +/- SE) compared to HERG (0.080 +/- 0.012) and controls (0.067 +/- 0.021). The Hill coefficient n of the RI discriminated perfectly between HERG (2.00 +/- 0.11) and KvLQT1 (4.11 +/- 0.15). CONCLUSIONS: RI allows distinguishing between HERG and KvLQT1 mutations based solely on the T wave morphology in the present LQTS population.     

Relation of ventricular repolarization to cardiac cycle length in normal subjects, hypertrophic cardiomyopathy, and patients with myocardial infarction.

BACKGROUND: Prolonged QT interval and QT dispersion have been reported to reflect an increased inhomogeneity of ventricular repolarization, which is believed to be responsible for the development of arrhythmic events in patients with long QT syndrome, coronary heart disease, and myocardial infarction, congestive heart failure, and hypertrophic cardiomyopathy (HC). HYPOTHESIS: This study was undertaken to determine whether an abnormal QT/RR dynamicity may reflect autonomic imbalance and may contribute to arrhythmogenesis in patients with heart disease. METHODS: The relation between QT, QTpeak (QTp), Tpeak-Tend (TpTe) intervals and cardiac cycle length was assessed in 70 normal subjects, 37 patients with HC, and 48 survivors of myocardial infarction (MI). A set of 10 consecutive electrocardiograms was evaluated automatically in each subject using QT Guard software (Marquette Medical Systems, Milwaukee, Wisc.). RESULTS: In patients with HC, all intervals were significantly prolonged compared with normals (p < 0.001 for QT and QTp; p < 0.04 for TpTc); in survivors of MI, this was true for the maximum QT and QTp intervals (p < 0.05). A strong linear correlation between QT, QTp, and RR intervals was observed in normals and in patients with MI and HC (r = 0.65-0.59, 0.82-0.77, 0.79-0.74, respectively, p < 0.0001). TpTe interval only showed a weak correlation with heart rate in normals (r = 0.24, p < 0.05) and was rate-independent in both patient groups (p = NS). Compared with normals, the slopes of QT/RR and QTp/RR regression lines were significantly steeper in patients with MI and HC (0.0990-0.0883, 0.1597-0.1551, 0.1653-0.1486, respectively). Regression lines were neither parallel nor identical between normals and patients (T > 1.96, Z > 3.07). There was no difference in steepness for TpTeR/RR lines between groups (0.0110, 0.0076, 0.0163, respectively). TpTe/QTp ratio was similar in normals and in patients with MI and HC (0.30 +/- 0.03, 0.31 +/- 0.07, 0.30 +/- 0.04, respectively), in the absence of any correlation between QTp and TpTe intervals, suggesting disproportional prolongation of both components of QT interval. CONCLUSION: Compared with normals, a progressive increase in QT and QTp intervals at slower heart rates in patients with MI and HC may indicate an enhanced variability of the early ventricular repolarization and may be one of the mechanisms of arrhythmogenesis.     

Specificities of atrial electrophysiology: Clues to a better understanding of cardiac function and the mechanisms of arrhythmias

The electrical properties of the atria and ventricles differ in several aspects reflecting the distinct role of the atria in cardiac physiology. The study of atrial electrophysiology had greatly contributed to the understanding of the mechanisms of atrial fibrillation (AF). Only the atrial L-type calcium current is regulated by serotonine or, under basal condition, by phosphodiesterases. These distinct regulations can contribute to I_Ca down-regulation observed during AF, which is an important determinant of action potential refractory period shortening. The voltage-gated potassium current, I_Kur, has a prominent role in the repolarization of the atrial but not ventricular AP. In many species, this current is based on the functional expression of K_V1.5 channels, which might represent a specific therapeutic target for AF. Mechanisms regulating the trafficking of K_V1.5 channels to the plasma membrane are being actively investigated. The resting potential of atrial myocytes is maintained by various inward rectifier currents which differ with ventricle currents by a reduced density of I_K1, the presence of a constitutively active I_KACh and distinct regulation of I_KATP. Stretch-sensitive or mechanosensitive ion channels are particularly active in atrial myocytes and are involved in the secretion of the natriuretic peptide. Integration of knowledge on electrical properties of atrial myocytes in comprehensive schemas is now necessary for a better understanding of the physiology of atria and the mechanisms of AF.