BACKGROUND: Variations of inferior vena cava (IVC) area and collapsibility serve as early markers of congestion and predict risk for heart failure (HF) events. OBJECTIVES: The aim of this first-in-human study (FUTURE-HF [First in Human Clinical Investigation of the FIRE1 System in Heart Failure Patients]) was to evaluate the safety and feasibility of a novel implantable IVC sensor for remote management in patients with HF. This paper is the final report on primary (3-month) and exploratory (6-month) endpoints. METHODS: Patients with HF hospitalizations within the previous year, with elevated natriuretic peptide levels, and on optimal HF treatment were included. The primary safety endpoints were procedural success without device- or procedure-related complications at 3 months. The primary technical endpoint was signal acquisition following implantation and at a clinic visit within 3 months. Sensor-derived IVC area was compared with computed tomography (CT)-based IVC dimensions. Patient adherence to daily readings and exploratory clinical findings at 6 months were assessed. RESULTS: Fifty patients underwent successful implantation (mean age 65 ± 9 years, 14% women, 72% in NYHA functional class III), with 49 contributing to the primary safety and technical endpoints at 3 months. Sensor-derived IVC area demonstrated excellent agreement with CT measurement (mean absolute error 13.53 mm2 [3.55%] R2 = 0.98). Median adherence was 96% at 6-month follow-up. Exploratory analyses of clinical outcomes suggested improvements in N-terminal pro-B-type natriuretic peptide, NYHA functional class, and quality of life and reduced HF events. CONCLUSIONS: This first-in-human experience demonstrated that the implantation of an IVC sensor was safe and feasible. Sensor-derived IVC area demonstrated excellent correlation with CT-derived IVC area, and exploratory clinical outcomes suggest that this may serve as a novel tool for ambulatory management of congestion to facilitate remote care in HF. (First in Human Clinical Investigation of the FIRE1 System in Heart Failure Patients [FUTURE-HF]; NCT04203576).

• Klíčová slova
• FUTURE-HF, congestion monitoring, heart failure, inferior vena cava sensor, remote care, volume status,
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: The reduction of fluoroscopic exposure during catheter ablation of supraventricular arrhythmias is widely adopted by experienced electrophysiology physicians with a relatively short learning curve and is becoming the standard of care in many parts of the world. While observational studies in the United States and some parts of Western Europe have evaluated the minimal fluoroscopic approach, there are scarce real-world data for this technique and the generalizability of outcomes in other economic regions. METHOD: The AALARA study is a prospective, observational, multicenter, and multinational open-label study. Patients were recruited from 13 countries across Central Eastern Europe, North and South Africa, the Middle East, and the CIS (Commonwealth of Independent States), with different levels of operator expertise using minimal fluoroscopic exposure techniques. Data on radiation exposure, procedural success, complications, recurrence, and quality of life changes were collected and analyzed. RESULT: A total of 680 patients were enrolled and followed for 6 months. The majority were ablation naïve with the commonest arrhythmia ablated being typical AVNRT (58%) followed by Atrial Flutter (23%). Zero fluoroscopy exposure was observed in almost 90% of the cases. Fluoroscopy was most commonly used during the ablation phase of the procedure. We observed a high acute success rate (99%), a low complication rate (0.4%), and a 6-month recurrence rate of 3.8%. There was a significant improvement in the patient's symptoms and quality of life as measured by patient global assessment. CONCLUSION: The routine use of a 3D mapping system during right-sided ablation was associated with low radiation exposure and associated with high acute success rate, low complications, and recurrence rate along with significant improvement in quality of life. The data confirm the reproducibility of this approach in real-world settings across different healthcare systems, and operator experience supporting this approach to minimize radiation exposure without compromising efficacy and safety. TRIAL REGISTRATION: NCT04716270.

• Klíčová slova
• 3D mapping, catheter ablation, fluoroscopy, interventional electrophysiology, zero radiation,
• MeSH
• fluoroskopie MeSH
• katetrizační ablace * metody   MeSH
• kvalita života MeSH
• lidé středního věku MeSH
• lidé MeSH
• prospektivní studie MeSH
• radiační expozice * MeSH
• registrace MeSH
• supraventrikulární tachykardie chirurgie   MeSH
• zobrazování trojrozměrné MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH

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.

• Klíčová slova
• ECG measurements, healthy volunteers, heart rate, heart rate hysteresis, long-term ECG, polynomial regression, sex differences, spatial QRS-T angle,
• Publikační typ
• časopisecké články MeSH

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.

• Klíčová slova
• ECG noise contents, QT variability, RR variability, healthy volunteers, immediate RR interval effect, long-term ECG, regression-based correction, short-term ECG measurements,
• Publikační typ
• časopisecké články MeSH

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.

• Klíčová slova
• MultiPulse Therapy, atrial fibrillation, cardioversion, defibrillation,
• MeSH
• elektrická defibrilace MeSH
• elektrody MeSH
• fibrilace síní * chirurgie   MeSH
• lidé MeSH
• srdeční síně MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Geografické názvy
• Minnesota MeSH

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.

• MeSH
• algoritmy MeSH
• dospělí MeSH
• elektrokardiografie metody   MeSH
• kardiologie metody   normy   MeSH
• lidé středního věku MeSH
• lidé MeSH
• počítačové zpracování signálu MeSH
• reprodukovatelnost výsledků MeSH
• srdeční frekvence fyziologie   MeSH
• syndrom dlouhého QT diagnóza   patofyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

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.

• MeSH
• algoritmy MeSH
• analýza dat MeSH
• biologická variabilita populace MeSH
• dospělí MeSH
• elektrofyziologické jevy * účinky léků   MeSH
• elektrokardiografie * metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• sexuální faktory MeSH
• srdce účinky léků   fyziologie   MeSH
• výpočetní biologie metody   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

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.

• Klíčová slova
• QT/RR adaptation, QT/RR hysteresis, age influence, best-fit models, healthy subjects, non-linear regression modelling, sex differences,
• Publikační typ
• časopisecké články MeSH

Chronic myeloid leukemia (CML) is a malignant hematopoietic disorder distinguished by the presence of a BCR‑ABL1 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 BCR‑ABL1 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 imatinib‑resistant K562 (K562IR) cells. The K562IR‑derived exosomes were internalized by imatinib‑sensitive K562 cells, which thereby increased their survival in the presence of 2 µM imatinib. The exosomal cargo was subsequently analyzed to identify resistance‑associated markers using a deep label‑free 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, interferon‑induced 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.

• Klíčová slova
• chronic myeloid leukemia, imatinib mesylate, drug resistance, proteomics, exosome, tyrosine kinase inhibitor, surface marker,
• MeSH
• antigen CD146 metabolismus   MeSH
• antigeny CD36 metabolismus   MeSH
• apoptóza účinky léků   MeSH
• bcr-abl fúzní proteiny antagonisté a inhibitory   genetika   MeSH
• buňky K562 MeSH
• chemorezistence MeSH
• chronická myeloidní leukemie farmakoterapie   genetika   patologie   MeSH
• exozómy účinky léků   metabolismus   MeSH
• imatinib mesylát farmakologie   terapeutické užití   MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• lidé MeSH
• membránové proteiny metabolismus   MeSH
• nádorové buněčné linie MeSH
• proteiny vázající RNA metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigen CD146 MeSH
• antigeny CD36 MeSH
• bcr-abl fúzní proteiny MeSH
• BCR-ABL1 fusion protein, human MeSH Prohlížeč
• IFITM3 protein, human MeSH Prohlížeč
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH
• membránové proteiny MeSH
• proteiny vázající RNA MeSH

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.

• Klíčová slova
• QT variability, QT variability index, RR variability, sequential analysis of regression variance, underlying heart rate,
• Publikační typ
• časopisecké články MeSH