Electrophysiological mechanism of the characteristic electrocardiographic morphology of torsade de pointes tachyarrhythmias in the long-QT syndrome: detailed analysis of ventricular tridimensional activation patterns

BACKGROUND: The long-QT syndrome (LQTS) is an electrophysiological (EP) entity characterized by prolongation of cardiac repolarization and the occurrence of polymorphic ventricular tachyarrhythmias (VTs), sometimes with a twisting QRS morphology, better known as torsade de pointes (TdP). In the present study, detailed analysis of ventricular tridimensional activation patterns during nonsustained TdP VT was performed to provide an EP mechanism of the periodic transition in QRS axis. METHODS AND RESULTS: The studies were conducted with the anthopleurin-A canine model of LQTS. Tridimensional isochronal maps of ventricular activation were constructed from 256 bipolar electrograms obtained from the use of 64 plunge needle electrodes. In 26 episodes of nonsustained TdP VT, detailed activation maps could be accurately constructed during QRS-axis transitions in surface ECGs. The initial beat of all VTs consistently arose as a subendocardial focal activity, whereas subsequent beats were due to reentrant excitation in the form of rotating scrolls. The VT ended when reentrant excitation was terminated. In 22 of 26 episodes, the transition in QRS axis coincided with the transient bifurcation of a predominantly single rotating scroll into two simultaneous scrolls involving both the right ventricle and left ventricle separately. The common mechanism for initiation or termination of bifurcation was the development of functional conduction block between the anterior or posterior right ventricle free wall and the ventricular septum. In 4 of 26 episodes, a fast polymorphic VT, with an apparent shift in QRS axis, was due to a predominantly single localized circuit that varied its location and orientation from beat to beat, with the majority of ventricular myocardium being activated in a centrifugal pattern. CONCLUSIONS: The study provides for the first time an EP mechanism for the characteristic periodic transition of the QRS axis during TdP VT in the LQTS.     

Low penetrance in the long-QT syndrome: clinical impact

BACKGROUND: It is still currently held that most patients affected by the long-QT syndrome (LQTS) show QT interval prolongation or clinical symptoms. This is reflected by the assumption in linkage studies of a penetrance of 90%. We had previously suggested that a larger-than-anticipated number of LQTS patients might be affected without showing clinical signs. We have now exploited the availability of molecular diagnosis to test this hypothesis. METHODS AND RESULTS: We identified 9 families with "sporadic" cases of LQTS, ie, families in which, besides the proband, none of the family members had clinical signs of the disease. Mutation screening by conventional single-strand conformational polymorphism and sequencing was performed on DNA of probands and family members to identify mutation carriers. Of 46 family members considered on clinical grounds to be nonaffected, 15 (33%) were found instead to be gene carriers. Penetrance was found to be 25%. In these families, conventional clinical diagnostic criteria had a sensitivity of only 38% in correctly identifying carriers of the genetic defect. CONCLUSIONS: This study demonstrates that in some families, LQTS may appear with a very low penetrance, a finding with multiple clinical implications. The family members considered to be normal and found to be silent gene carriers are unexpectedly at risk of generating affected offspring and also of developing torsade de pointes if exposed to either cardiac or noncardiac drugs that block potassium channels. It is no longer acceptable to exclude LQTS among family members of definitely affected patients on purely clinical grounds. Conversely, it now appears appropriate to perform molecular screening in all family members of genotyped patients.     

Electrophysiological basis for the enhanced cardiac arrhythmogenic effect of isoprenaline in aged spontaneously hypertensive rats

We used normotensive (WKY) and spontaneously hypertensive rats (SHR) of 2, 6 and 18 months of age to get insight into the mechanisms responsible for the increased incidence of ventricular arrhythmias in hypertensive heart disease. We studied: (1) isoprenaline-induced spontaneous activity in isolated papillary muscle; (2) action potential characteristics; (3) beta-adrenoceptor and A1-adenosine receptor number and affinity; and (4) intracellular cyclic AMP (cAMP) levels. The saturation binding assay was performed in enzymatically isolated ventricular myocytes using the hydrophilic antagonist 3H-CGP 12177 for beta-adrenoceptors and 3H-DPCPX for A1-adenosine receptors. cAMP was measured by a competitive binding assay in myocytes before and after exposure to isoprenaline. Intracellular action potential was recorded from papillary muscles by means of 3 M KCl-filled glass microelectrodes. The presence of isoprenaline-induced automaticity was assessed by interrupting the electrical stimulation periodically. In isolated papillary muscles, isoprenaline (10 nM) induced spontaneous activity more frequently in 18-month-old SHR (90.0%) than in 6-(25.0%, P < 0.05) and 2-month-old SHR (0%, P < 0.001). No age-related statistically significant differences in isoprenaline-induced automaticity were observed in WKY. The incidence of isoprenaline-induced automaticity was higher in 18-month-old SHR than in age-matched WKY (22.2%, P < 0.05). KD and Bmax for beta-adrenoceptors and A1-receptors were not significantly modified in different groups. cAMP levels before and after isoprenaline stimulation were significantly lower in 18-month-old SHR than in age-matched WKY. Action potential duration (APD) was markedly prolonged in both normotensive and hypertensive rats during aging. APD was significantly prolonged in 18-month-old SHR compared to the WKY. A "diastolic depolarization", caused by the presence of delayed after-depolarizations, became apparent in the oldest animals. The slope of the delayed after-depolarization was increased by isoprenaline (1-10 nM) in 18-month-old SHR and this effect was significantly greater than that observed in 18-month-old WKY (P < 0.05). In conclusion, beta-adrenergic responsiveness is enhanced in hypertensive rats during aging, resulting in a greater incidence of abnormal automaticity. This effect does not appear to be related to changes in beta-adrenoceptor or A1-receptor density or affinity; it is likely that the electrophysiological alterations may play a role in this phenomenon.     

Quantification of ischaemia induced vulnerability by precordial T wave alternans analysis in dog and human

OBJECTIVE: The aim was to examine the regional specificity of T wave alternans and the value of precordial ECG monitoring for non-invasive tracking of cardiac vulnerability during acute coronary artery occlusion and reperfusion in animals and humans. METHODS: The left ventricular ECG was monitored during two acute occlusions of the left anterior descending coronary artery and subsequent reperfusion in each of 61 chloralose anaesthetised dogs, and over 150,000 beats were analysed. In subgroups of these animals, lead II and precordial lead V5 were monitored or epicardial electrograms were recorded. In seven patients, lead II and precordial leads V1-6 were monitored during angioplasty. T wave alternans magnitude was quantified by complex demodulation. The same recording equipment and analytical methods were used in the clinical and experimental studies. RESULTS: A close temporal correspondence and linear correlation was found between T wave alternans magnitude--but not ST segment depression or ventricular premature beat incidence--and the incidence of spontaneous ventricular tachycardia and fibrillation during acute coronary artery occlusion and reperfusion. Epicardial electrograms showed alternans to be regionally specific, occurring in the ischaemic but not in the normal zones, and to predict spontaneous ventricular fibrillation and ventricular tachycardia (sensitivity = 79%, specificity = 86%). A significant linear relationship (r2 = 0.86, p < 0.01) between alternans magnitude detected in V5 and the left ventricular intracavitary lead indicates that the precordial leads could be used to assess cardiac vulnerability from the body surface. Lead V5 showed greater resolution than lead II. In humans, the precordial leads overlying the ischaemic zone were superior to lead II or Frank leads for alternans detection during both the occlusion and the reperfusion phases. In both animals and humans, alternation invariably occurred during the first half of the T wave, coinciding with the vulnerable period of the cardiac cycle and suggesting an important electrophysiological link to cardiac vulnerability. CONCLUSIONS: Alternans is regionally specific and is linearly projected to the precordium. Quantification of its magnitude in the precordial ECG may provide a non-invasive means for tracking cardiac vulnerability during acute myocardial ischaemia and reperfusion in both animals and humans.     

Functional knockout of the transient outward current, long-QT syndrome, and cardiac remodeling in mice expressing a dominant-negative Kv4 alpha subunit

Amino acid changes S180A (S-->A at site 180), H197Y, Y277F, T285A, and A308S are known to shift the maximum wavelength of absorption (lambda max) of red and green visual pigments toward blue, essentially in an additive fashion. To test the generality of this "five-sites" rule, we have determined the partial amino acid sequences of red and green pigments from five mammalian orders (Artiodactyla, Carnivora, Lagomorpha, Perissodactyla, and Rodentia). The result suggests that cat (Felis catus), dog (Canis familiaris), and goat (Capra hircus) pigments all with AHYTA at the five critical sites have lambda max values of approximately 530 nm, whereas rat (Rattus norvegicus) pigment with AYYTS has a lambda max value of approximately 510 nm, which is accurately predicted by the five-sites rule. However, the observed lambda max values of the orthologous pigments of European rabbit (Oryctolagus cuniculus), white-tailed deer (Odocoileus virginianus), gray squirrel (Sciurus carolinensis), and guinea pig (Cavia procellus) are consistently more than 10 nm higher than the predicted values, suggesting the existence of additional molecular mechanisms for red and green color vision. The inferred amino acid sequences of ancestral organisms suggest that the extant mammalian red and green pigments appear to have evolved from a single ancestral green-red hybrid pigment by directed amino acid substitutions.     

A mathematical model for analysis of pharmacologically induced changes in the kinetics of cardiac muscle

A mathematical model of the isometric contraction of cardiac muscle is developed and utilized to characterize the inotropic and lusitropic effects of cardioactive compounds in isolated guinea pig left atria. In contrast to metrics that are based on minima and maxima of an isometric twitch and its derivative function, the entire time course of the twitch is used to quantify the kinetics of the contraction-relaxation cycle. The model relates observed tension to a time-dependent activation function that describes generation of internal force and a coupling function that determines mechanical response to the activation function. The model is structured so that it is suitable for nonlinear curve fitting to observed data. Results obtained using the model for fitting experimental data from tissues treated with different classes of cardioactive compounds agree with more qualitative results presented by other authors. Experiments using the model to fit data over an extended (90 min) time course revealed differences in the kinetic profiles of milrinone and forskolin. Computer simulations that demonstrate the effect of each model parameter on twitch kinetics are presented, and the relationships between the model and other theoretical and empirical models of cardiac muscle are discussed. The mathematical model is useful to enable a more quantitative understanding of the kinetics of cardiac muscle contraction and relaxation and identify compounds that may be selective for inotropic or lusitropic effects.     

The expression of normal ventricular repolarization in the body surface distribution of T potentials

Isopotential maps from 120 normal subjects were obtained from 192 simultaneously recorded electrocardiographic leads. Maps were plotted at 1 msec intervals during the QRS and 5 msec intervals during the ST-T deflection. Repetition of QRS features was evident during all but the first few msec of the initial half of serial T maps. This suggests similarities of the normal sequence of ventricular excitation and recovery. Such similarities have been demonstrated by direct studies but are not evident from other electrocardiographic examinations. Serial maps during later portions of the T wave showed decreasing intensity of potentials with little change of body surface locations. This also correlates with an established feature of ventricular repolarization, namely that potential difference boundaries with stable locations are widely distributed during part of that process. Findings suggest isopotential maps show features of ventricular recovery not apparent from less extensive examinations.     

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 interval dispersion in total and in cardiovascular mortality, as well as in cardiac morbidity, in a general population. METHODS AND RESULTS: The QT interval was measured in all leads from a standard 12-lead ECG in a random sample of 1658 women and 1797 men aged 30-60 years. QT interval dispersion was calculated from the maximal difference between QT intervals in any two leads. All cause mortality over 13 years, and cardiovascular mortality as well as cardiac morbidity over 11 years, were the main outcome parameters. Subjects with a prolonged QT interval (430 ms or more) or prolonged QT interval dispersion (80 ms or more) were at higher risk of cardiovascular death and cardiac morbidity than subjects whose QT interval was less than 360 ms, or whose QT interval dispersion was less than 30 ms. Cardiovascular death relative risk ratios, adjusted for age, gender, myocardial infarct, angina pectoris, diabetes mellitus, arterial hypertension, smoking habits, serum cholesterol level, and heart rate were 2.9 for the QT interval (95% confidence interval 1.1-7.8) and 4.4 for QT interval dispersion (95% confidence interval 1.0-19-1). Fatal and non-fatal cardiac morbidity relative risk ratios were similar, at 2.7 (95% confidence interval 1.4-5.5) for the QT interval and 2.2 (95% confidence interval 1.1-4.0) for QT interval dispersion. CONCLUSION: Prolongation of the QT interval and QT interval dispersion independently affected the prognosis of cardiovascular mortality and cardiac fatal and non-fatal morbidity in a general population over 11 years.     

Construction and validation of risk assessments in a six-year follow-up of forensic patients: A tridimensional analysis.

Evaluations of risk were conducted for 162 Canadian mentally disordered criminal defendants through the assembly of actuarial data, scores from special-to-purpose psychometric instruments, and scaled global predictions of dangerousness to others by clinicians and nonclinical raters. Violent conduct by participants was tracked across legal and medical institutions and the community for a subsequent 6 years, with aggregate violence base rates reaching 62%. Decisions about risk were strongly associated with participant attributes and presentations during forensic interviews, but neither linear regression equations involving background and scale items nor direct discretionary judgments could account for more than 25% of variance in the frequency of outcome violence. Predictive accuracy maximized after 3 years, and was strongest for hospital-based violence. Professional clinicians were no more accurate than nonclinical raters. Implications of these findings for the sociolegal control of violence, and for the resurgent "second generation" of risk research, are explored. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Missense mutation in the pore region of HERG causes familial long QT syndrome

BACKGROUND: Long QT syndrome (LQT) is an inherited cardiac disorder that results in syncope, seizures, and sudden death. In a family with LQT, we identified a novel mutation in human ether-a-go-go-related gene (HERG), a voltage-gated potassium channel. METHODS AND RESULTS: We used DNA sequence analysis, restriction enzyme digestion analysis, and allele-specific oligonucleotide hybridization to identify the HERG mutation. A single nucleotide substitution of thymidine to guanine (T1961G) changed the coding sense of HERG from isoleucine to arginine (Ile593Arg) in the channel pore region. The mutation was present in all affected family members; the mutation was not present in unaffected family members or in 100 normal, unrelated individuals. CONCLUSIONS: We conclude that the Ile593Arg missense mutation in HERG is the cause of LQT in this family because it segregates with disease, its presence was confirmed in three ways, and it is not found in normal individuals. The Ile593Arg mutation may result in a change in potassium selectivity and permeability leading to a loss of HERG function, thereby resulting in LQT.     

T wave alternans as a predictor of recurrent ventricular tachyarrhythmias in ICD recipients: prospective comparison with conventional risk markers

INTRODUCTION: The current standard for arrhythmic risk stratification is electrophysiologic (EP) testing, which, due to its invasive nature, is limited to patients already known to be at high risk. A number of noninvasive tests, such as determination of left ventricular ejection fraction (LVEF) or heart rate variability, have been evaluated as additional risk stratifiers. Microvolt T wave alternans (TWA) is a promising new risk marker. Prospective evaluation of noninvasive risk markers in low- or moderate-risk populations requires studies involving very large numbers of patients, and in such studies, documentation of the occurrence of ventricular tachyarrhythmias is difficult. In the present study, we identified a high-risk population, recipients of an implantable cardioverter defibrillator (ICD), and prospectively compared microvolt TWA with invasive EP testing and other risk markers with respect to their ability to predict recurrence of ventricular tachyarrhythmias as documented by ICD electrograms. METHODS AND RESULTS: Ninety-five patients with a history of ventricular tachyarrhythmias undergoing implantation of an ICD underwent EP testing, assessment of TWA, as well as determination of LVEF, baroreflex sensitivity, signal-averaged ECG, analysis of 24-hour Holter monitoring, and QT dispersion from the 12-lead surface ECG. The endpoint of the study was first appropriate ICD therapy for electrogram-documented ventricular fibrillation or tachycardia during follow-up. Kaplan-Meier survival analysis revealed that TWA (P < 0.006) and LVEF (P < 0.04) were the only significant univariate risk stratifiers. EP testing was not statistically significant (P < 0.2). Multivariate Cox regression analysis revealed that TWA was the only statistically significant independent risk factor. CONCLUSIONS: Measurement of microvolt TWA compared favorably with both invasive EP testing and other currently used noninvasive risk assessment methods in predicting recurrence of ventricular tachyarrhythmias in ICD recipients. This study suggests that TWA might also be a powerful tool for risk stratification in low- or moderate-risk patients, and needs to be prospectively evaluated in such populations.     

QT interval dispersion in healthy subjects and survivors of sudden cardiac death: circadian variation in a twenty-four-hour assessment

Twenty-four-hour acquisition of QT dispersion (QTd) from the Holter and the circadian variation of QTd were evaluated in 20 survivors of sudden cardiac death (SCD), in 20 healthy subjects, and in 14 control patients without a history of cardiac arrest who were age, sex, diagnosis and therapy matched to 14 SCD patients. Computer-assisted QT measurements were performed on 24-hour Holter recordings; each recording was divided into 288 5-minute segments and templates representing the average QRST were generated. QTd was calculated as the difference between QT intervals in leads V1 and V5 for each template on Holter. The 24-hour mean QTd was significantly greater in SCD patients (40 +/- 28 ms) than in healthy subjects (20 +/- 10 ms) and control patients (15 +/- 5 ms) (p <0.05). There was a circadian variation in QTd with greater values at night (0 to 6 A.M.) than at daytime (10 A.M. to 4 P.M.) in healthy subjects (25 +/- 13 vs 15 +/- 8 ms, p <0.001) and control patients (18 +/- 10 vs 12 +/- 4 ms p <0.05), whereas in SCD patients there was no significant difference between night and day values (45 +/- 31 vs 37 +/- 28 ms, p = NS). It is concluded that QTd measured by Holter was greater in SCD patients than in healthy subjects and matched control patients during the entire day. QTd has a clear circadian variation in normal subjects, whereas this variation is blunted in SCD patients. QTd measured on Holter differentiates survivors of cardiac arrest and may be a useful tool for risk stratification.     

Enhanced activity of sodium-lithium countertransport in patients with cardiac syndrome X: a potential link between cardiac and metabolic syndrome X

OBJECTIVES: This study was aimed at assessing both stimulated insulinemia and the sodium-lithium countertransport in a selected group of patients with cardiac syndrome X. BACKGROUND: Hyperinsulinemia, which is frequently present in patients with cardiac syndrome X, is often associated with an enhanced activity of the sodium-lithium countertransport, an in vitro marker of sodium-hydrogen exchange. METHODS: Fifteen patients with syndrome X and 14 matched controls were studied. After pharmacological washout, sodium-lithium countertransport was assessed from lithium-loaded red blood cells. Postload insulin levels were evaluated by a double-antibody radioimmunoassay. RESULTS: Maximal velocity of sodium-lithium countertransport was higher in patients with syndrome X compared to controls (635+/-200 vs. 324+/-49 micromol/liter/h, p = 0.001). Fourteen of the 15 patients with syndrome X (93%) presented sodium-lithium countertransport values higher than the mean +2 SD of the control group. At 120 min, 12 patients with syndrome X (80%) had plasma levels of insulin >420 pmol/liter, which corresponds to the mean value +2 SD of controls (p = 0.006). CONCLUSIONS: Both enhanced activity of the sodium-lithium countertransport and stimulated hyperinsulinemia are present in the vast majority of patients with cardiac syndrome X. As enhanced activity of the sodium-lithium countertransport has the potential to cause both glucose intolerance and smooth muscle hyperreactivity, it might represent a common cause of the metabolic and vascular alterations frequently found in syndrome X.     

EDTA/THPED二元络合体系化学镀铜的沉积动力学分析

为增强对化学镀铜反应过程的调控,建立了乙二胺四乙酸(EDTA)/四羟丙基乙二胺(THPED)二元络合化学镀铜体系,基于Arrhenius和经验动力学公式对该二元络合体系的沉积动力学及控制步骤进行分析。研究表明,该二元络合体系的反应表观活化能(E_a)为15.2 kJ/mol,远低于活化能(E_a)为60.9 kJ/mol的EDTA单络合体系,对应各主要组分的反应级数比EDTA单络合剂体系高,其中C(OH^-)对二元络合体系沉积过程的作用与对单络合体系的作用完全不同,即促进了二元络合体系的沉积反应,又对单络合体系起抑制作用。二元络合体系各组分对动力学影响程度依次为：C(Cu²⁺)>C(OH-)>C(HCHO)>C(L)。混合电位测试结果显示阴极还原反应受铜络离子扩散过程的控制。获得了二元络合剂体系化学沉积过程的动力学方程模型。     

The polymer basis of kinetics and equilibria of enzymes: the accessible-volume origin of entropy changes in a class Abeta-lactamase

The occurrence of enzymatic catalysis, as for any chemical reaction, depends critically upon close contact of the reactants, since making/breaking of bonds occurs over distances of about 0.2 A. Unlike small molecules, each enzyme molecule acts as an ordered solvent and reactant. Each group important to the enzyme reaction interacts with the substrate, then moves away, and subsequently binds another substrate. In other words, the group undergoes round trips in structure. For a round trip, the thermochemical state functions deltaG, deltaH, deltaS, etc., are zero. As a consequence, control of the binding of substrate must reside in the nonbinding conformations of the polymer since they govern the different fractions of time the macromolecule is in the correct conformation for bonding. Applying standard macromolecular models to the enzymes suggests that the majority of free energy for an enzyme reaction resides in the enzyme structure as an entropic contribution. Enthalpic contributions come from bond formation with the substrates and substrate structural changes. Further, it is shown that the molecular mechanisms that can effect binding and allosteric control fall into only three classes. Three x-ray structures of class A beta-lactamases (native, mutant, and with substrate) show the individual binding groups at the active site change their accessible volumes depending on substrate binding and mutant form. From these volume differences, the deltaS of reaction is calculated. The x-ray-derived deltaG = - TdeltaS matches the deltaG = -RT ln k1 from changes in rate constants for the same set of beta-penicillinases.     

Pathogenesis of the low cardiac output syndrome in postreanimation states

Functional reserves of the cardiovascular system during sharp depression of the cardiac output in the postreanimation period after 15-minute cardiac arrest were studied in experiments on dogs (by loading with different fluid volumes). Acute hypervolemia did not produce any circulatory decompensation. Reinforcement of venous return and changes in the peripheral circulation due to polyglucine loading augmented the CVP temporarily, and produced a stable increase of the AP, of the cardiac output, systolic volume, the work of the left cardiac ventricle and of the total oxygen consumption by the organism. Meanwhile there was a decrease of the peripheral vascular resistance. In model experiments on dogs, which sustained 20-minute isolated compression ischemia the syndrome of low cardiac output developed too. This indicated the relation of this phenomenon to the disorders in the neuro-humoral regulation of blood circulation.