Pierre Maison-Blanche

Conditional Mineralocorticoid Receptor Expression in the Heart Leads to Life-Threatening Arrhythmias

Background—Life-threatening cardiac arrhythmia is a major source of mortality worldwide. Besides rare inherited monogenic diseases such as long-QT or Brugada syndromes, which reflect abnormalities in ion fluxes across cardiac ion channels as a final common pathway, arrhythmias are most frequently acquired and associated with heart disease. The mineralocorticoid hormone aldosterone is an important contributor to morbidity and mortality in heart failure, but its mechanisms of action are incompletely understood. Methods and Results—To specifically assess the role of the mineralocorticoid receptor (MR) in the heart, in the absence of changes in aldosteronemia, we generated a transgenic mouse model with conditional cardiac-specific overexpression of the human MR. Mice exhibit a high rate of death prevented by spironolactone, an MR antagonist used in human therapy. Cardiac MR overexpression led to ion channel remodeling, resulting in prolonged ventricular repolarization at both the cellular and integrated levels and in severe ventricular arrhythmias. Conclusions—Our results indicate that cardiac MR triggers cardiac arrhythmias, suggesting novel opportunities for prevention of arrhythmia-related sudden death.

Instant Power Spectrum Analysis of Heart Rate Variability During Orthostatic Tilt Using a Time-/Frequency-Domain Method

BACKGROUND Spectral analysis of heart rate (HR) variability (HRV) requires, as a rule, some level of stationarity and, as a result, is inadequate to quantify biological transients. A time-/frequency-domain method (TF) was developed to obtain an instant spectral power (SP) of HRV during tilt. METHODS AND RESULTS HR was recorded by Holter monitoring in volunteers and analyzed with a TF, the smoothed pseudo-Wigner-Ville transformation (SPWVT), with the table inclination randomly set or continuously increased while the table rotated in head-up position. (1) The SPWVT assesses, beat by beat, the instant center frequency (ICF) of the SP. ICF correlates better with instant HR than the ratio of low- (LF) to high-frequency (HF) oscillations. The transient effect of tilt is better characterized as a shift of SP toward lower frequencies than by changes in amplitudes. (2) The method evidences variations of HR from one second to another. During the passage to head-up position, the vagal withdrawal and the sympathetic activation occur nearly simultaneously, as indicated by the instant changes in both LF and HF amplitudes and ICF. (3) The averaged results of the SPWVT give results similar to those previously obtained with autoregressive algorithms. CONCLUSIONS The SPWVT is a new tool to explore HR transitions such as periods before episodes of arrhythmias on a time scale of one beat and allows quantification of an instant frequency index (ICF) that closely reflects the instantaneous relationship between sympathetic and vagal modulations.

Dispersion of Ventricular Repolarization Reality? Illusion? Significance?

The QT interval is considered to be a surrogate of cellular action potential duration. However, it yields a limited view of the complex electrogenesis of the ventricular repolarization (VR). Evidence of T-wave end inequality among surface ECG traces back to Wilson et al,1 and it was recently revived by the concept of dispersion.2 Because of its apparent simplicity, QT dispersion became fashionable, and a growing literature is now devoted to its potential prognostic interest. The study by Zabel et al3 seems timely to temper the enthusiasm. In a prospectively collected cohort of patients, it offers evidence that avoiding technical biases of measurement, QT dispersion is not a prognostic marker. This contrasts with the confirmation that ejection fraction, heart rate variability, and simply heart rate are indeed good predictors of events. It suggests some reflections about the correct and comprehensive use of a concept that still needs to be validated. ### Measurement of QT Duration QT interval can be measured manually or with dedicated algorithms. The performances of the 2 approaches were compared in a remarkable study conducted by the late Jos Willems.4 The aim was to assess the diagnostic performances of computerized systems.5 In view of the interobserver and intraobserver variability in determining wave recognition points, an elaborate reviewing scheme was devised to obtain a group estimate that should define the “truth,” ultimately serving as a standard for computer measurement. Five experts defined individually the P- and QRS-wave onset and offset and the T-wave offset. The database was formed of 250 digitized (500 Hz) 12 standard leads and Frank XYZ leads, including a 25% proportion of normal hearts and a variety of ventricular hypertrophies and infarctions but no bundle-branch block or long-QT syndrome. The interexpert variation was expressed as 2 SD of the difference between the median and the individual …

Circadian modulation of QT rate dependence in healthy volunteers: Gender and age differences

QT rate dependence is known to be linked with both circadian variations of the autonomic tone and gender. However, age and heart rate variability (HRV) influences are not well established. The QT/RR relationship was evaluated, separately during the day and at night, on 24-hour electrocardiogram in 60 healthy subjects (30 men) divided into three homogeneous groups (group 1, 20-29; group 2 30-39; group 3, 40-50 years). QT rate dependence was larger during the day in both genders. Women showed stronger QT rate dependence (0.195 during the day vs. 0.154 in men P< .0001). The circadian modulation decreased with increasing age (day/night slope differences: group 1, 0.038; group 2, 0.031; group 3, 0.001; analysis of variance P<.05). In addition, QT rate dependence increased as mean RR decreased (r = -0.58, P<.0001) and decreased as HRV parameters increased. Multiple influences on QT rate dependence can be found: not only circadian and gender modulation, but also age, heart rate, and HRV interventions.

Determinants of the spontaneous ectopic activity in repetitive monomorphic idiopathic ventricular tachycardia

Twenty-four hour ambulatory electrocardiographic tape recordings of 30 patients (16 men and 14 women, mean age 42 +/- 17 years) with repetitive monomorphic idiopathic ventricular tachycardia were analyzed using a new computerized system designed to study 15 RR cycles and mean heart rate of the 3 minutes preceding any defined event. The mean (+/- SD) number of events analyzed per patient in 24 hours was 610 +/- 483 for single premature ventricular complexes, 622 +/- 490 for couplets, 260 +/- 411 for runs of 3 complexes, 186 +/- 476 for runs of 4, 108 +/- 173 for runs of 5, 82 +/- 129 for runs of 6 to 10 and 83 +/- 116 for runs of more than 10 complexes. The heart rate was faster before runs of ventricular tachycardia than before isolated extrasystoles (p less than 0.01) and a positive linear correlation was observed between the mean preceding heart rate and the type of extrasystolic activity, the length of the runs increasing with increasing preceding heart rate (r = 0.98, p less than 0.001). A long RR interval just before the occurrence of runs was present in 77% of the cases (23 of 30) with or without an oscillatory pattern of RR intervals due to bigeminy or trigeminy, and the length of the runs correlated positively with the duration of this long preceding diastole (r = 0.90, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Assessment of Drug-induced QT Prolongation in Association with Heart Rate Changes

The formulas for heart rate (HR) correction of QT interval have been shown to overcorrect or undercorrect this interval with changes in HR. A Holter‐monitoring method avoiding the need for any correction formulas is proposed as a means to assess drug‐induced QT interval changes.

Time- and rate-dependent alterations of the QT interval precede the onset of torsade de pointes in patients with acquired QT prolongation.

OBJECTIVES The purpose of this study was to determine whether the QT interval dynamics that precede torsade de pointes are consistent with the initiation of this arrhythmia by early afterdepolarization-induced triggered activity. BACKGROUND Early afterdepolarization-induced triggered activity has been suggested as an electrophysiologic mechanism for torsade de pointes. Consequently, the initiation of torsade de pointes should involve time- and rate-dependent alterations of ventricular repolarization similar to those known to modulate the development of early afterdepolarizations. METHODS RR and QT intervals were measured in digitized 24-h ambulatory electrocardiographic recordings obtained from seven patients with acquired prolongation of ventricular repolarization. Each patient had one or more episodes of torsade de pointes. The relation between RR and QT intervals was determined before, during and after multiple episodes of torsade de pointes. RESULTS In patients with multiple episodes of ventricular arrhythmias, the onset of the arrhythmias was associated with a critical prolongation of the QT interval. In some episodes, prolongation of the QT interval was associated with sudden prolongation of the sinus cycle length, whereas in other episodes, the QT interval prolonged progressively at a constant cycle length. CONCLUSIONS The association between a critically prolonged QT interval and the onset of ventricular arrhythmias suggests that the initial complex of torsade de pointes is an early afterdepolarization-induced triggered response. However, prolongation of the QT interval itself was not sufficient to account for the initiation of torsade de pointes, suggesting that other, as yet unidentified factors are required.

Suppression of arrhythmias within hours after a single oral dose of amiodarone and relation to plasma and myocardial concentrations

In 65 patients a single oral dose of amiodarone (30 mg/kg) produced an antiarrhythmic effect on supraventricular or ventricular arrhythmias within 3 to 8 hours and lasted for 17 to 19 hours. On the second day a 15-mg/kg dose reproduced this effect within 3 to 9 hours. Plasma concentration of amiodarone increased to a maximum (2.2 +/- 1.7 mg/liter) mean +/- standard deviation) at 6 +/- 3.5 hours and plasma levels of N-desethylamiodarone (NDA) rose to 0.2 +/- 0.08 mg/liter at 12 +/- 6.4 hours. Sixty-one other patients were given a single 30-mg/kg dose 7 hours to 4 days before open heart surgery. Biopsies of the right atrial and left ventricular walls were taken during surgery. Myocardial concentration of amiodarone was maximal in the atrium after 7 hours (13 +/- 8 mg/kg) and in the ventricle after 24 hours (17 +/- 11 mg/kg). NDA myocardial concentration increased progressively until 24 hours and then remained stable over 4 days (1.5 mg/kg). The amiodarone myocardial to plasma concentration ratio was similar in the atrium and in the ventricle and averaged 22 and 10 for amiodarone and NDA, respectively. A significant relation existed between amiodarone concentration and the effect on ventricular premature complexes (r = 0.74, p less than 0.001) and between amiodarone plasma concentration and the effect on the atrioventricular conduction (r = 0.58, p less than 0.001). The plasma concentration of amiodarone corresponding to a 60% decrease in arrhythmias averaged 1.5 to 2 mg/liter.(ABSTRACT TRUNCATED AT 250 WORDS)

QT interval and arrhythmic risk assessment after myocardial infarction

To assess ventricular repolarization features as predictors of ventricular tachyarrhythmias (VT) in patients with previous myocardial infarction, we performed a dynamic study of QT interval from 24-hour electrocardiographic data. QT rate dependence was enhanced in patients with VT when compared with patients without VT.

Changes in Repolarization Dynamicity and the Assessment of the Arrhythmic Risk

At the present time, the assessment of the arrhythmic risk from surface ECG recordings is built on time‐domain and frequenct‐domain analysis of high resolution ECG acquisition together with in‐terlead variability of QT interval duration (QT dispersion). The corresponding raw ECG tracings are obtained in resting conditions. However, the dynamic aspects of the EGG signal is a rapidly evolving matter of interest. In addition to the beat‐to‐beat oscillations of the ventricular repolarization amplitude (QT ai‐ternans), there is growing evidence that the patterns of QT interval shortening with increasing heart rate are linked to suceptibility to ventricular arhythmias. In this report, we will mailnly address the association between QT dynamicity and the risk of developing torsades de pointes.