Functional improvement after successful catheter ablation for long-standing persistent atrial fibrillation.

AIMS: Identifying patients who benefit from restored sinus rhythm (SR) would optimize the selection of candidates for ablation of long-standing persistent atrial fibrillation (LSPAF). This prospective study sought to identify the hitherto unknown factors associated with global functional improvement after successful radiofrequency catheter ablation of LSPAF. METHODS AND RESULTS: In 171 LSPAF patients (84% of the total consecutive 203 patients) who were examined in SR 12 months after ablation, the individual per cent change from baseline value in maximum oxygen consumption at exercise test (VO2 max), left ventricular ejection fraction (LVEF), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and five-dimensional descriptive system (EQ-5D) of quality-of-life questionnaire were classified in quartiles by 0 (worse) to 3 (best) grades. The individual grades were summed into a composite score (SCORE, 0 … 12) reflecting global functional improvement. Significant improvement in VO2 max (3.4 ± 4.7 mL/kg/min), LVEF (7.5 ± 9.1%), NT-proBNP (-861 ± 809 pg/mL), and EQ-5D (0.7 ± 0.12) was observed (all P < 0.0001). On multivariable analysis, younger age (P = 0.001), male gender (P = 0.02), timely post-ablation left atrial appendage (LAA) outflow (P = 0.005) with improvement in outflow velocity (P = 0.0002), and withdrawal of Class I/III antiarrhythmic drugs (P < 0.05) were positively and independently correlated with the SCORE. CONCLUSIONS: Younger male patients benefited most from catheter ablation of LSPAF. Delayed or non-improved LAA outflow and inability to discontinue Class I/III antiarrhythmic medication reduced the post-ablation functional improvement.

Sex and race differences in QRS duration.

AIMS: The study investigated healthy subjects to study sex and race differences in QRS durations and the dependency of QRS durations on heart rates and other physiologic correlates. METHODS AND RESULTS: QRS duration and its heart rate dependency were evaluated in 420 615 electrocardiograms obtained in 523 healthy subjects including 111 females of African origin, 130 Caucasian females, 125 males of African origin, and 129 Caucasian males. The distributions of QRS/RR slopes and QRS durations at RR intervals of 1 and 0.5 s were compared between sex- and race-defined subgroups. At high heart rates, QRS duration was increased in ∼35% of all subjects, while in the others, QRS was shortened (no differences between the subgroups). At RR interval of 1 s, the QRS duration was 97.4 ± 4.6, 99.8 ± 6.0, 101.6 ± 5.3, and 104.8 ± 6.3 ms in African females, Caucasian females, African males, and Caucasian males, respectively (all differences P < 0.001). Similar statistical differences were found at an RR of 0.5 s. When accounting for the differences in lean body mass, the difference between African and Caucasian subjects was as large as the difference between females and males. Within each subgroup, the normal QRS durations differed by 15-20 and 18-25 ms at RR intervals of 1 and 0.5 s, respectively. CONCLUSION: The QRS widths are heart rate dependent and different not only between women and men but also between African and Caucasian individuals. Difference in cardiac resynchronization therapy efficacy might be expected between patients of African and Caucasian origin stratified by QRS duration.

A prospective evaluation of haemodynamics, functional status, and quality of life after radiofrequency catheter ablation of long-standing persistent atrial fibrillation.

AIMS: Clinical benefit from ablation for long-standing persistent atrial fibrillation has remained unknown. We hypothesized that successful ablation of long-standing persistent atrial fibrillation would improve haemodynamics, functional status, and quality of life. METHODS AND RESULTS: A total of 160 patients (aged 59 ± 9 years, 23% females) undergoing ablation of long-standing (median of 28 months) persistent atrial were enrolled in this prospective study. Morphological and functional echocardiographic parameters, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), maximum oxygen consumption during exercise test (VO2 max), and quality of life were assessed at baseline and 1 year after the ablation.  At the 1-year follow-up visit, 81% patients were examined in sinus rhythm (after repeat ablation in 38% patients). Left atrial appendage outflow velocity increased from 44 ± 20 to 58 ± 23 cm/s, left ventricular ejection fraction from 54 ± 9 to 59 ± 5%, and VO2 max from 20.4 ± 6.4 to 23.7 ± 8.1 mL/kg/min; NT-proBNP decreased from median 897 (interquartile range 603-1424) to 230 (interquartile range 120-420) pg/mL (all P < 0.0001). These beneficial effects of ablation were predominantly associated with the presence of sinus rhythm. Quality of life (range 0-100) increased significantly (EQ-5D index: from 68.8 ± 12.5 to 75.4 ± 14.4; EQ-VAS score: from 62.8 ± 13.2 to 70.6 ± 13.8; both P < 0.0001). CONCLUSION: Ablation of long-standing persistent atrial fibrillation was associated with significant recovery of haemodynamics and exercise capacity that projected onto the long-term improvement in quality of life.

Effect of atorvastatin on dynamic parameters of myocardial repolarization in healthy subjects.

BACKGROUND: Antiarrhythmic properties of statins were suggested as a part of their pleiotropic effects. The aim of the present study was to evaluate the effects of atorvastatin on myocardial repolarization as manifested on surface electrocardiograms (ECGs) in healthy subjects. METHODS AND RESULTS: Forty young healthy volunteers (20 men, 20 women) underwent a single-dose double-blind 3-way crossover study of 20 and 80 mg of atorvastatin and placebo. Long-term 13-hour 12-lead ECGs were obtained in each subject and each study period starting 15 minutes before drug administration. Each study period contained 18 time-points of 5-minute durations when the subjects were in resting supine positions. Digital ECG recordings were analyzed automatically, and the results were completed blindly before statistical analyses. Dynamic parameters of myocardial repolarization and T-wave morphology descriptors were evaluated. Although some trends were observed, no significant drug-related changes in any of investigated ECG repolarization descriptors were found. CONCLUSION: In comparison with placebo, single doses of atorvastatin had no effect on repolarization heterogeneity in healthy subjects. The observation confirms safe profile of the drug with limited proarrhythmic potential.

Short-Term Beat-to-Beat QT Variability Appears Influenced More Strongly by Recording Quality Than by Beat-to-Beat RR Variability.

Increases in beat-to-beat variability of electrocardiographic QT interval duration have repeatedly been associated with increased risk of cardiovascular events and complications. The measurements of QT variability are frequently normalized for the underlying RR interval variability. Such normalization supports the concept of the so-called immediate RR effect which relates each QT interval to the preceding RR interval. The validity of this concept was investigated in the present study together with the analysis of the influence of electrocardiographic morphological stability on QT variability measurements. The analyses involved QT and RR measurements in 6,114,562 individual beats of 642,708 separate 10-s ECG samples recorded in 523 healthy volunteers (259 females). Only beats with high morphology correlation (r > 0.99) with representative waveforms of the 10-s ECG samples were analyzed, assuring that only good quality recordings were included. In addition to these high correlations, SDs of the ECG signal difference between representative waveforms and individual beats expressed morphological instability and ECG noise. In the intra-subject analyses of both individual beats and of 10-s averages, QT interval variability was substantially more strongly related to the ECG noise than to the underlying RR variability. In approximately one-third of the analyzed ECG beats, the prolongation or shortening of the preceding RR interval was followed by the opposite change of the QT interval. In linear regression analyses, underlying RR variability within each 10-s ECG sample explained only 5.7 and 11.1% of QT interval variability in females and males, respectively. On the contrary, the underlying ECG noise contents of the 10-s samples explained 56.5 and 60.1% of the QT interval variability in females and males, respectively. The study concludes that the concept of stable and uniform immediate RR interval effect on the duration of subsequent QT interval duration is highly questionable. Even if only stable beat-to-beat measurements of QT interval are used, the QT interval variability is still substantially influenced by morphological variability and noise pollution of the source ECG recordings. Even when good quality recordings are used, noise contents of the electrocardiograms should be objectively examined in future studies of QT interval variability.

Intra-subject stability of different expressions of spatial QRS-T angle and their relationship to heart rate.

Three-dimensional angle between the QRS complex and T wave vectors is a known powerful cardiovascular risk predictor. Nevertheless, several physiological properties of the angle are unknown or poorly understood. These include, among others, intra-subject profiles and stability of the angle relationship to heart rate, characteristics of angle/heart-rate hysteresis, and the changes of these characteristics with different modes of QRS-T angle calculation. These characteristics were investigated in long-term 12-lead Holter recordings of 523 healthy volunteers (259 females). Three different algorithmic methods for the angle computation were based on maximal vector magnitude of QRS and T wave loops, areas under the QRS complex and T wave curvatures in orthogonal leads, and weighted integration of all QRS and T wave vectors moving around the respective 3-dimensional loops. These methods were applied to orthogonal leads derived either by a uniform conversion matrix or by singular value decomposition (SVD) of the original 12-lead ECG, giving 6 possible ways of expressing the angle. Heart rate hysteresis was assessed using the exponential decay models. All these methods were used to measure the angle in 659,313 representative waveforms of individual 10-s ECG samples and in 7,350,733 individual beats contained in the same 10-s samples. With all measurement methods, the measured angles fitted second-degree polynomial regressions to the underlying heart rate. Independent of the measurement method, the angles were found significantly narrower in females (p < 0.00001) with the differences to males between 10o and 20o, suggesting that in future risk-assessment studies, different angle dichotomies are needed for both sexes. The integrative method combined with SVD leads showed the highest intra-subject reproducibility (p < 0.00001). No reproducible delay between heart rate changes and QRS-T angle changes was found. This was interpreted as a suggestion that the measurement of QRS-T angle might offer direct assessment of cardiac autonomic responsiveness at the ventricular level.

Influence of heart rate correction formulas on QTc interval stability.

Monitoring of QTc interval is mandated in different clinical conditions. Nevertheless, intra-subject variability of QTc intervals reduces the clinical utility of QTc monitoring strategies. Since this variability is partly related to QT heart rate correction, 10 different heart rate corrections (Bazett, Fridericia, Dmitrienko, Framingham, Schlamowitz, Hodges, Ashman, Rautaharju, Sarma, and Rabkin) were applied to 452,440 ECG measurements made in 539 healthy volunteers (259 females, mean age 33.3 ± 8.4 years). For each correction formula, the short term (5-min time-points) and long-term (day-time hours) variability of rate corrected QT values (QTc) was investigated together with the comparisons of the QTc values with individually corrected QTcI values obtained by subject-specific modelling of the QT/RR relationship and hysteresis. The results showed that (a) both in terms of short-term and long-term QTc variability, Bazett correction led to QTc values that were more variable than the results of other corrections (p < 0.00001 for all), (b) the QTc variability by Fridericia and Framingham corrections were not systematically different from each other but were lower than the results of other corrections (p-value between 0.033 and < 0.00001), and (c) on average, Bazett QTc values departed from QTcI intervals more than the QTc values of other corrections. The study concludes that (a) previous suggestions that Bazett correction should no longer be used in clinical practice are fully justified, (b) replacing Bazett correction with Fridericia and/or Framingham corrections would improve clinical QTc monitoring, (c) heart rate stability is needed for valid QTc assessment, and (d) development of further QTc corrections for day-to-day use is not warranted.

Sex and Rate Change Differences in QT/RR Hysteresis in Healthy Subjects.

While it is now well-understood that the extent of QT interval changes due to underlying heart rate differences (i.e., the QT/RR adaptation) needs to be distinguished from the speed with which the QT interval reacts to heart rate changes (i.e., the so-called QT/RR hysteresis), gaps still exist in the physiologic understanding of QT/RR hysteresis processes. This study was designed to address the questions of whether the speed of QT adaptation to heart rate changes is driven by time or by number of cardiac cycles; whether QT interval adaptation speed is the same when heart rate accelerates and decelerates; and whether the characteristics of QT/RR hysteresis are related to age and sex. The study evaluated 897,570 measurements of QT intervals together with their 5-min histories of preceding RR intervals, all recorded in 751 healthy volunteers (336 females) aged 34.3 ± 9.5 years. Three different QT/RR adaptation models were combined with exponential decay models that distinguished time-based and interval-based QT/RR hysteresis. In each subject and for each modelling combination, a best-fit combination of modelling parameters was obtained by seeking minimal regression residuals. The results showed that the response of QT/RR hysteresis appears to be driven by absolute time rather than by the number of cardiac cycles. The speed of QT/RR hysteresis was found decreasing with increasing age whilst the duration of individually rate corrected QTc interval was found increasing with increasing age. Contrary to the longer QTc intervals, QT/RR hysteresis speed was faster in females. QT/RR hysteresis differences between heart rate acceleration and deceleration were not found to be physiologically systematic (i.e., they differed among different healthy subjects), but on average, QT/RR hysteresis speed was found slower after heart rate acceleration than after rate deceleration.

Spatial distribution of physiologic 12-lead QRS complex.

The normal physiologic range of QRS complex duration spans between 80 and 125 ms with known differences between females and males which cannot be explained by the anatomical variations of heart sizes. To investigate the reasons for the sex differences as well as for the wide range of normal values, a technology is proposed based on the singular value decomposition and on the separation of different orthogonal components of the QRS complex. This allows classification of the proportions of different components representing the 3-dimensional representation of the electrocardiographic signal as well as classification of components that go beyond the 3-dimensional representation and that correspond to the degree of intricate convolutions of the depolarisation sequence. The technology was applied to 382,019 individual 10-s ECG samples recorded in 639 healthy subjects (311 females and 328 males) aged 33.8 ± 9.4 years. The analyses showed that QRS duration was mainly influenced by the proportions of the first two orthogonal components of the QRS complex. The first component demonstrated statistically significantly larger proportion of the total QRS power (expressed by the absolute area of the complex in all independent ECG leads) in females than in males (64.2 ± 11.6% vs 59.7 ± 11.9%, p < 0.00001-measured at resting heart rate of 60 beats per minute) while the second component demonstrated larger proportion of the QRS power in males compared to females (33.1 ± 11.9% vs 29.6 ± 11.4%, p < 0.001). The analysis also showed that the components attributable to localised depolarisation sequence abnormalities were significantly larger in males compared to females (2.85 ± 1.08% vs 2.42 ± 0.87%, p < 0.00001). In addition to the demonstration of the technology, the study concludes that the detailed convolution of the depolarisation waveform is individual, and that smoother and less intricate depolarisation propagation is the mechanism likely responsible for shorter QRS duration in females.

Exosomes released by imatinib­resistant K562 cells contain specific membrane markers, IFITM3, CD146 and CD36 and increase the survival of imatinib­sensitive cells in the presence of imatinib.

Chronic myeloid leukemia (CML) is a malignant hematopoietic disorder distinguished by the presence of a BCR­ABL1 fused oncogene with constitutive kinase activity. Targeted CML therapy by specific tyrosine kinase inhibitors (TKIs) leads to a marked improvement in the survival of the patients and their quality of life. However, the development of resistance to TKIs remains a critical issue for a subset of patients. The most common cause of resistance are numerous point mutations in the BCR­ABL1 gene, followed by less common mutations and multiple mutation-independent mechanisms. Recently, exosomes, which are extracellular vesicles excreted from normal and tumor cells, have been associated with drug resistance and cancer progression. The aim of the present study was to characterize the exosomes released by imatinib­resistant K562 (K562IR) cells. The K562IR­derived exosomes were internalized by imatinib­sensitive K562 cells, which thereby increased their survival in the presence of 2 µM imatinib. The exosomal cargo was subsequently analyzed to identify resistance­associated markers using a deep label­free quantification proteomic analysis. There were >3,000 exosomal proteins identified of which, 35 were found to be differentially expressed. From this, a total of 3, namely the membrane proteins, interferon­induced transmembrane protein 3, CD146 and CD36, were markedly upregulated in the exosomes derived from the K562IR cells, and exhibited surface localization. The upregulation of these proteins was verified in the K562IR exosomes, and also in the K562IR cells. Using flow cytometric analysis, it was possible to further demonstrate the potential of CD146 as a cell surface marker associated with imatinib resistance in K562 cells. Taken together, these results suggested that exosomes and their respective candidate surface proteins could be potential diagnostic markers of TKI drug resistance in CML therapy.

Novel Low-Voltage MultiPulse Therapy to Terminate Atrial Fibrillation.

OBJECTIVES: This first-in-human feasibility study was undertaken to translate the novel low-voltage MultiPulse Therapy (MPT) (Cardialen, Inc., Minneapolis, Minnesota), which was previously been shown to be effective in preclinical studies in terminating atrial fibrillation (AF), into clinical use. BACKGROUND: Current treatment options for AF, the most common arrhythmia in clinical practice, have limited success. Previous attempts at treating AF by using implantable devices have been limited by the painful nature of high-voltage shocks. METHODS: Forty-two patients undergoing AF ablation were recruited at 6 investigational centers worldwide. Before ablation, electrode catheters were placed in the coronary sinus, right and/or left atrium, for recording and stimulation. After the induction of AF, MPT, which consists of up to a 3-stage sequence of far- and near-field stimulation pulses of varied amplitude, duration, and interpulse timing, was delivered via temporary intracardiac leads. MPT parameters and delivery methods were iteratively optimized. RESULTS: In the 14 patients from the efficacy phase, MPT terminated 37 of 52 (71%) of AF episodes, with the lowest median energy of 0.36 J (interquartile range [IQR]: 0.14 to 1.21 J) and voltage of 42.5 V (IQR: 25 to 75 V). Overall, 38% of AF terminations occurred within 2 seconds of MPT delivery (p < 0.0001). Shorter time between AF induction and MPT predicted success of MPT in terminating AF (p < 0.001). CONCLUSIONS: MPT effectively terminated AF at voltages and energies known to be well tolerated or painless in some patients. Our results support further studies of the concept of implanted devices for early AF conversion to reduce AF burden, symptoms, and progression.

ACE gene insertion/deletion polymorphism has a mild influence on the acute development of left ventricular dysfunction in patients with ST elevation myocardial infarction treated with primary PCI.

BACKGROUND: We evaluated the associations among angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism, ACE activity and post-myocardial infarction (MI) left ventricular dysfunction and acute heart failure (AHF) early after presentation with MI with ST-segment elevation (STEMI). METHODS: A total of 556 patients with STEMI treated by primary PCI (421 patients without AHF and 135 patients with AHF) were the study population. The activity of BNP, NT-ProBNP and ACE were measured at hospital admission and 24 h after MI onset. Left ventricular angiography was done before PCI; echocardiography was undertaken between the third and fifth day after MI. RESULTS: In comparison with the II genotypes group, the DD/ID group had a higher level of ACE activity upon hospital admission (p < 0.001). We found a significantly higher level of ACE activity in patients with moderate LV dysfunction (EF 40-54%) in comparison both with patients with preserved LV function (EF ≥ 55%) and with patients with severe LV dysfunction (p = 0.028). A non-significant trend towards a higher incidence of mild AHF (22.1% vs. 16.02%, p = 0,093), a significantly higher value of end-systolic volume (ESV/BSA) (30.0 ± 12.3 vs. 28.5 ± 13.0; p < 0.05) and lower EF (50.2 ± 11.1 vs. 52.7 ± 11.7; p < 0.05) in the DD/ID genotypes group was noted. Even after multiple adjustments according to multivariate models, the EF for the DD/ID group remained significantly lower (p = 0,033). The DD/ID genotypes were associated with a significantly higher risk of EF <45% (OR 2.04 [95% CI 1.28; 3.25]). CONCLUSIONS: These results suggest that the I/D polymorphism of ACE is associated with the development of LV dysfunction in the acute phase after STEMI. We demonstrated for the first time an association of the low ACE activity with the severe LV dysfunction, although patients with moderate LV dysfunction had higher level ACE activity than patients with preserved LV function.

Dynamic properties of selected repolarization descriptors.

A number of morphological indices have been proposed to characterize electrocardiographic patterns of ventricular repolarization mostly studying spatial and temporal patterns of T waves. Comparisons between different clinical populations exist but data on the suitability of the T-wave descriptors to characterize and quantify physiologic regulations of ventricular repolarization are lacking. To initiate such investigations, a study was conducted comparing the influence of provoked heart rate changes on the duration of QT interval, the roundness of T wave loop expressed by the relative T wave area, and on the 3-dimensional QRS-T angle. A population of 40 healthy subjects (18 women, mean age 30.4 ± 8.1 years) was studied. In each subject, provocative tests involving changes from strict supine to unsupported sitting and to unsupported standing positions were repeated twice during each of 3 separate monitoring days. Continuous 12-lead electrocardiograms were obtained during the provocative tests. The speed of the adaptation of the repolarization descriptors to heart rate changes was characterized by λ parameters of previously published exponential decay model of R-R interval related hysteresis. The comparisons showed that the adaptation of QT interval to heart rate changes was much slower than that of the investigated T-wave morphological descriptors: the mean (SD) values of λ parameters were 5.01 ± 1.13, 12.72 ± 8.66, and 12.90 ± 11.37 for QT interval, QRS-T angle, and relative T-wave area, respectively (P < .001 for the difference between QT interval and both morphological descriptors). The study suggests that the different numerical quantifiers of vertricular repolarization that may be derived from standard electrocardiographic tracings likely represent separate and distinct physiologic entities.

Heart Rate Dependency and Inter-Lead Variability of the T Peak - T End Intervals.

The electrocardiographic (ECG) assessment of the T peak-T end (Tpe) intervals has been used in many clinical studies, but several related physiological aspects have not been reported. Specifically, the sources of the Tpe differences between different ECG leads have not been systematically researched, the relationship of Tpe duration to underlying heart rate has not been firmly established, and little is known about the mutual correspondence of Tpe intervals measured in different ECG leads. This study evaluated 796,620 10-s 12-lead ECGs obtained from long-term Holters recorded in 639 healthy subjects (311 female) aged 33.8 ± 9.4 years. For each ECG, transformation to orthogonal XYZ lead was used to measure Tpe in the orthogonal vector magnitude (used as a reference for lead-to-lead comparisons) and to construct a three-dimensional T wave loop. The loop roundness was expressed by a ratio between its circumference and length. These ratios were significantly related to the standard deviation of Tpe durations in different ECG leads. At the underlying heart rate of 60 beats per minute, Tpe intervals were shorter in female than in male individuals (82.5 ± 5.6 vs 90.0 ± 6.5 ms, p < 0.0001). When studying linear slopes between Tpe intervals measured in different leads and the underlying heart rate, we found only minimal heart rate dependency, which was not systematic across the ECG leads and/or across the population. For any ECG lead, positive Tpe/RR slope was found in some subjects (e.g., 79 and 25% of subjects for V2 and V4 measurements, respectively) and a negative Tpe/RR slope in other subjects (e.g., 40 and 65% for V6 and V5, respectively). The steepest positive and negative Tpe/RR slopes were found for measurements in lead V2 and V4, respectively. In all leads, the Tpe/RR slope values were close to zero, indicating, on average, Tpe changes well below 2 ms for RR interval changes of 100 ms. On average, longest Tpe intervals were measured in lead V2, the shortest in lead III. The study concludes that the Tpe intervals measured in different leads cannot be combined. Irrespective of the measured ECG lead, the Tpe interval is not systematically heart rate dependent, and no heart rate correction should be used in clinical Tpe investigations.

Heart Rate Influence on the QT Variability Risk Factors.

QT interval variability, mostly expressed by QT variability index (QTVi), has repeatedly been used in risk diagnostics. Physiologic correlates of QT variability expressions have been little researched especially when measured in short 10-second electrocardiograms (ECGs). This study investigated different QT variability indices, including QTVi and the standard deviation of QT interval durations (SDQT) in 657,287 10-second ECGs recorded in 523 healthy subjects (259 females). The indices were related to the underlying heart rate and to the 10-second standard deviation of RR intervals (SDRR). The analyses showed that both QTVi and SDQT (as well as other QT variability indices) were highly statistically significantly (p < 0.00001) influenced by heart rate and that QTVi showed poor intra-subject reproducibility (coefficient of variance approaching 200%). Furthermore, sequential analysis of regression variance showed that SDQT was more strongly related to the underlying heart rate than to SDRR, and that QTVi was influenced by the underlying heart rate and SDRR more strongly than by SDQT (p < 0.00001 for these comparisons of regression dependency). The study concludes that instead of QTVi, simpler expressions of QT interval variability, such as SDQT, appear preferable for future applications especially if multivariable combination with the underlying heart rate is used.

Physiologic heart rate dependency of the PQ interval and its sex differences.

On standard electrocardiogram (ECG) PQ interval is known to be moderately heart rate dependent, but no physiologic details of this dependency have been established. At the same time, PQ dynamics is a clear candidate for non-invasive assessment of atrial abnormalities including the risk of atrial fibrillation. We studied PQ heart rate dependency in 599 healthy subjects (aged 33.5 ± 9.3 years, 288 females) in whom drug-free day-time 12-lead ECG Holters were available. Of these, 752,517 ECG samples were selected (1256 ± 244 per subject) to measure PQ and QT intervals and P wave durations. For each measured ECG sample, 5-minute history of preceding cardiac cycles was also obtained. Although less rate dependent than the QT intervals (36 ± 19% of linear slopes), PQ intervals were found to be dependent on underlying cycle length in a highly curvilinear fashion with the dependency significantly more curved in females compared to males. The PQ interval also responded to the heart rate changes with a delay which was highly sex dependent (95% adaptation in females and males after 114.9 ± 81.1 vs 65.4 ± 64.3 seconds, respectively, p < 0.00001). P wave duration was even less rate dependent than the PQ interval (9 ± 10% of linear QT/RR slopes). Rate corrected P wave duration was marginally but significantly shorter in females than in males (106.8 ± 8.4 vs 110.2 ± 7.9 ms, p < 0.00001). In addition to establishing physiologic standards, the study suggests that the curvatures and adaptation delay of the PQ/cycle-length dependency should be included in future non-invasive studies of atrial depolarizations.

Identification of molecular targets for selective elimination of TRAIL-resistant leukemia cells. From spots to in vitro assays using TOP15 charts.

The resistance of malignant cells to chemotherapy calls for the development of novel anti-cancer drugs. TNF-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic cytokine, which selectively induces apoptosis in malignant cells. We derived two TRAIL-resistant HL-60 subclones, HL-60/P1 and HL-60/P2, from a TRAIL-sensitive HL-60 acute promyelocytic leukemia cell line. To identify therapeutically exploitable "weaknesses" of the TRAIL-resistant leukemia cells that could be used as molecular targets for their elimination, we performed proteomic (2-DE) analysis and compared both TRAIL-resistant subclones with the original TRAIL-sensitive HL-60 cells. We identified over 40 differentially expressed proteins. To significantly narrow the lists of candidate proteins, we excluded proteins that are known to be often differentially expressed, regardless of experiment type and tissue (the so-called "TOP15" proteins). Decreased expression of DNA replication and maintenance proteins MCM7 and RPA32 in HL-60/P1 cells, and the marked down-regulation of enzyme adenosine deaminase in HL-60/P2 cells, suggests increased sensitivity of these cells to DNA-interfering drugs, and adenosine and its homologues, respectively. In a series of in vitro assays, we confirmed the increased toxicity of etoposide and cisplatin to TRAIL resistant HL-60/P1 cells, and adenosine and vidarabine to HL-60/P2, compared with TRAIL-sensitive HL-60 cells.

Systematic comparisons of electrocardiographic morphology increase the precision of QT interval measurement.

Decreased intrasubject variability of QTc values is needed to increase the power and reduce the size of the so-called thorough QT studies. One source of QTc variability is the lack of systematic measurements when electrocardiograms (ECG) with closely matching morphologies are not measured in an exactly corresponding way. The inaccuracy can be eliminated by postprocessing of QT measurements by ECG pattern matching. This study tested the effects of pattern matching in ECG measurements in two populations of healthy subjects (n = 48 + 56) and in a population of patients with advanced Parkinson's disease (n = 130) in whom both day-time and night-time data were available. Intrasubject QTc variability was measured by intrasubject standard deviations (SD) of QTc values obtained with manual measurements before and after pattern-matching measurement alignments. In each subject, QT values (n = 230-320) in one drug-free long-term ECG recording were evaluated. The pattern-matching adjustment of the QT measurement decreased the intrasubject QTc variability from 5.2 +/- 1.0 to 4.5 +/- 1.0 ms (P < 10(-14)) from 6.4 +/- 1.7 to 5.5 +/- 1.6 ms (P < 10(-10)) from 5.6 +/- 1.5 to 4.6 +/- 1.4 ms (P < 10(-34)) and from 6.1 +/- 1.9 to 5.0 +/- 1.7 ms (P < 10(-33)), in the two populations of healthy subjects and in the day-time and night-time recordings of Parkinson's disease patients, respectively. Hence, morphological pattern adjustment of QT interval measurements improves the quality of the QT data with substantial practical implications. Reductions in intrasubject QTc variability were reproducibly found in different populations and thus the technology might be recommended for every thorough QT/QTc study. Noticeable reductions of necessary study size are likely achievable in this way.

Sex differences in heart rate responses to postural provocations.

Sex differences are known in several facets of cardiac electrophysiology, mostly concerning myocardial repolarisation. In this study, heart rate and heart rate variability (HRV) responses to postural provocations were compared in 175 and 176 healthy females and males, respectively (aged 33.1 ±â€¯9.1 years). Two different postural provocative tests with position changes supine→sitting→standing→supine and supine→standing→sitting→supine (15-min standing, 10-min other positions) were performed up to 4 times in each subject. Heart rate and heart rate variability spectral indices were measured in 5-min windows before positional changes. At supine position, females had averaged heart rate approximately 5 beats per minute (bpm) faster than males and this sex difference was practically constant during the postural changes. In both sexes, change supine→sitting and supine→standing increased heart rate by approximately 10 and 30 bpm, respectively, with no statistical differences between the sex groups. At supine baseline, females had normalised high frequency components (nHF) of HRV approximately 7% larger compared to males (p < 0.001). While the same difference in nHF was found at sitting, the change to standing position lead to significantly larger nHF reduction in females compared to males (mean changes 22.5 vs 17.2%, p < 0.001). This shows that despite similar heart rate increase, females respond to standing by more substantial shifts in cardiac sympatho-vagal modulations. This makes it plausible to speculate that the differences in autonomic reactions to stress contribute to the known sex-differences in psychosocial responses to stressful situations and to the known difference in susceptibility to ventricular fibrillation between females and males.

Comparison of two modes of long-term ECG monitoring to assess the efficacy of catheter ablation for paroxysmal atrial fibrillation.

AIMS: Optimal ECG monitoring in detecting recurrences of atrial fibrillation (AF) or atrial tachycardia (AT) after catheter ablation has not been well established. The purpose of this prospective study was to compare the utility of daily ECG monitoring with episodic card recorder (ECR) vs. periodic monitoring with episodic loop recorder (ELR) for the detection of post-blanking AF/AT recurrences during early (Months 4-6) and late (Months 7-12) periods after catheter ablation for paroxysmal AF. METHODS: The study included 105 consecutive patients, who received ECR for 12 months and were instructed to send at least 2 random ECG recordings daily with extra-recordings during symptoms. The patients were simultaneously monitored for one week with ELR at the end of each period (Months 6 and 12). RESULTS: Thirty-one and 12 patients with AF/AT recurrence were identified by means of ECR and ELR, respectively. In patients with complete and valid data, ELR technology was inferior to ECR by detecting AF/AT in 5 (31%) of 16 and 5 (26%) of 19 patients with arrhythmia identified by ECR in the early and late period, respectively. Overall, ELR had a sensitivity of 8/23 (35%) for detecting AF/AT recurrence. There was no single patient with AF/AT recurrence on ELR that would not be known from ECR monitoring. Only 2 patients with arrhythmia recurrence were completely asymptomatic throughout the study period. CONCLUSION: Daily ECG monitoring with ECR was better than periodic monitoring with ELR in detecting AF/AT recurrences during the follow-up periods. Entirely asymptomatic patients with AF/AT recurrences were rare.