Spatiotemporal repolarization dispersion before and after exercise in patients with long QT syndrome type 1 versus controls: probing into the arrhythmia substrate.

Congenital long QT syndrome (LQTS) carries an increased risk for syncope and sudden death. QT prolongation promotes ventricular extrasystoles, which, in the presence of an arrhythmia substrate, might trigger ventricular tachycardia degenerating into fibrillation. Increased electrical heterogeneity (dispersion) is the suggested arrhythmia substrate in LQTS. In the most common subtype LQT1, physical exercise predisposes for arrhythmia and spatiotemporal dispersion was therefore studied in this context. Thirty-seven patients (57% on ß-blockers) and 37 healthy controls (mean age, 31 vs. 35; range, 6-68 vs. 6-72 yr) performed an exercise test. Frank vectorcardiography was used to assess spatiotemporal dispersion as Tampl, Tarea, the ventricular gradient (VG), and the Tpeak-end interval from 10-s signal averages before and 7 ± 2 min after exercise; during exercise too much signal disturbance excluded analysis. Baseline and maximum heart rates as well as estimated exercise intensity were similar, but heart rate recovery was slower in patients. At baseline, QT and heart rate-corrected QT (QTcB) were significantly longer in patients (as expected), whereas dispersion parameters were numerically larger in controls. After exercise, QTpeakcB and Tpeak-endcB increased significantly more in patients (18 ± 23 vs. 7 ± 10 ms and 12 ± 17 vs. 2 ± 6 ms; P < 0.001 and P < 0.01). There was, however, no difference in the change in Tampl, Tarea, and VG between groups. In conclusion, although temporal dispersion of repolarization increased significantly more after exercise in patients with LQT1, there were no signs of exercise-induced increase in global dispersion of action potential duration and morphology. The arrhythmia substrate/mechanism in LQT1 warrants further study.NEW & NOTEWORTHY Physical activity increases the risk for life-threatening arrhythmias in LQTS type 1 (LQT1). The arrhythmia substrate is presumably altered electrical heterogeneity (a.k.a. dispersion). Spatiotemporal dispersion parameters were therefore compared before and after exercise in patients versus healthy controls using Frank vectorcardiography, a novelty. Physical exercise prolonged the time between the earliest and latest complete repolarization in patients versus controls, but did not increase parameters reflecting global dispersion of action potential duration and morphology, another novelty.

Accelerated QT adaptation following atropine-induced heart rate increase in LQT1 patients versus healthy controls: A sign of disturbed hysteresis.

Hysteresis, a ubiquitous regulatory phenomenon, is a salient feature of the adaptation of ventricular repolarization duration to heart rate (HR) change. We therefore compared the QT interval adaptation to rapid HR increase in patients with the long QT syndrome type 1 (LQT1) versus healthy controls because LQT1 is caused by loss-of-function mutations affecting the repolarizing potassium channel current IKs , presumably an important player in QT hysteresis. The study was performed in an outpatient hospital setting. HR was increased in LQT1 patients and controls by administering an intravenous bolus of atropine (0.04 mg/kg body weight) for 30 s. RR and QT intervals were recorded by continuous Frank vectorcardiography. Atropine induced transient expected side effects but no adverse arrhythmias. There was no difference in HR response (RR intervals) to atropine between the groups. Although atropine-induced ΔQT was 48% greater in 18 LQT1 patients than in 28 controls (p < 0.001), QT adaptation was on average 25% faster in LQT1 patients (measured as the time constant τ for the mono-exponential function and the time for 90% of ΔQT; p < 0.01); however, there was some overlap between the groups, possibly a beta-blocker effect. The shorter QT adaptation time to atropine-induced HR increase in LQT1 patients on the group level corroborates the importance of IKs in QT adaptation hysteresis in humans and shows that LQT1 patients have a disturbed ultra-rapid cardiac memory. On the individual level, the QT adaptation time possibly reflects the effect-size of the loss-of-function mutation, but its clinical implications need to be shown.

Noninvasive electrophysiological differences between women and men: differences in body size not an explanation.

There are numerous sex-related differences in cardiac electrophysiology and arrhythmia propensity but very little knowledge about the reasons. Difference in body size has been proposed as one reason and was tested in this study of >20 cardiac electrophysiology parameters in 319 (158 women) apparently healthy 50- to 64-yr-old subjects from a randomly enrolled population sample, the pilot SCAPIS (Swedish Cardiopulmonary Bioimaging Study), using Frank vectorcardiography. We studied conventional conduction intervals, parameters reflecting electrical heterogeneity (dispersion) in the ventricles, QRS- and T-vector directions, spatial QRS-T angles, and T-vector loop morphology. Body surface area (BSA; 2 methods) and lean body mass (LBM), both estimated from body weight and height, were used as body size parameters. According to multivariable linear regression analysis adjusted for sex, there was no association between electrophysiological parameters and body size apart from QRS duration and QRSarea. In conclusion, most electrophysiological parameters assessed completely noninvasively and showing statistically significant differences between women and men on the group level show no association with BSA or LBM. Scaling (indexing) the electrophysiological parameters for body size parameters is therefore not an option. Consequently, the explanation for the sex-related electrophysiological differences should be sought along other lines.NEW & NOTEWORTHY We sought explanations for sex-related differences in >20 cardiac electrophysiology parameters including conventional conduction intervals in 319 (158 women) apparently healthy 50- to 64-yr-old subjects using Frank vectorcardiography, a novelty. Our hypothesis that body size was partly explanatory for such differences had to be refuted apart from QRS duration and QRSarea. Scaling (indexing) electrophysiological parameters for body size is therefore not an option and explanations for electrophysiological sex-related differences are to be sought elsewhere.

A prospective clinical study on the mechanisms underlying critical illness myopathy-A time-course approach.

BACKGROUND: Critical illness myopathy (CIM) is a consequence of modern critical care resulting in general muscle wasting and paralyses of all limb and trunk muscles, resulting in prolonged weaning from the ventilator, intensive care unit (ICU) treatment and rehabilitation. CIM is associated with severe morbidity/mortality and significant negative socioeconomic consequences, which has become increasingly evident during the current COVID-19 pandemic, but underlying mechanisms remain elusive. METHODS: Ten neuro-ICU patients exposed to long-term controlled mechanical ventilation were followed with repeated muscle biopsies, electrophysiology and plasma collection three times per week for up to 12 days. Single muscle fibre contractile recordings were conducted on the first and final biopsy, and a multiomics approach was taken to analyse gene and protein expression in muscle and plasma at all collection time points. RESULTS: (i) A progressive preferential myosin loss, the hallmark of CIM, was observed in all neuro-ICU patients during the observation period (myosin:actin ratio decreased from 2.0 in the first to 0.9 in the final biopsy, P < 0.001). The myosin loss was coupled to a general transcriptional downregulation of myofibrillar proteins (P < 0.05; absolute fold change >2) and activation of protein degradation pathways (false discovery rate [FDR] <0.1), resulting in significant muscle fibre atrophy and loss in force generation capacity, which declined >65% during the 12 day observation period (muscle fibre cross-sectional area [CSA] and maximum single muscle fibre force normalized to CSA [specific force] declined 30% [P < 0.007] and 50% [P < 0.0001], respectively). (ii) Membrane excitability was not affected as indicated by the maintained compound muscle action potential amplitude upon supramaximal stimulation of upper and lower extremity motor nerves. (iii) Analyses of plasma revealed early activation of inflammatory and proinflammatory pathways (FDR < 0.1), as well as a redistribution of zinc ions from plasma. CONCLUSIONS: The mechanical ventilation-induced lung injury with release of cytokines/chemokines and the complete mechanical silencing uniquely observed in immobilized ICU patients affecting skeletal muscle gene/protein expression are forwarded as the dominant factors triggering CIM.

Adaptation of ventricular repolarization dispersion during heart rate increase in humans: A roller coaster process.

BACKGROUND: Regional differences in ventricular activation sequence and action potential duration and morphology result in dispersion in ventricular repolarization (VR). VR dispersion is a key factor in arrhythmogenesis. We studied the adaptation of global VR dispersion in humans during normal and abnormal ventricular activation, and the relation to the QT adaptation (hysteresis). METHODS: We measured global VR dispersion as T amplitude, T area, and ventricular gradient (VG), using continuous Frank vectorcardiography, in response to abrupt and sustained atrial (AP) or ventricular pacing (VP) aiming at 120 bpm, in 21 subjects with permanent pacemakers. RESULTS: Following pacing start, VR adaptation showed an initially rapid and complex tri-phasic pattern, most pronounced for T amplitude. There were major differences in the patterns of VR dispersion adaptation following abrupt AP vs VP, confirming that the adaptation pattern is activation dependent. In response to AP, an instantaneous decrease in VR dispersion occurred, followed by an increase and then a slow decrease, all at a lower level than baseline. In contrast, following VP there was an immediate increase to ~4× baseline in T amplitude and T area (but not in VG), with a subsequent biphasic adaptation lasting longer during VP than AP. The initial rapid changes occurred within the time for QT adaptation to reach steady-state. CONCLUSIONS: Our results corroborate and expand data from animal and invasive human studies, showing similarities of the adaptation pattern on different scales. The initial rapidly changing VR adaptation phase presumably reflects a window of increased vulnerability to arrhythmias.

Adaptation of ventricular repolarization time following abrupt changes in heart rate: comparisons and reproducibility of repeated atrial and ventricular pacing.

Adequate adaptation of ventricular repolarization (VR) duration to changes in heart rate (HR) is important for cardiac electromechanical function and electrical stability. We studied the QT and QTpeak adaptation in response to abrupt start and stop of atrial and ventricular pacing on two occasions with an interval of at least 1 mo in 25 study subjects with permanent pacemakers. Frank vectorcardiography was used for data collection. Atrial or ventricular pacing was performed for 8 min aiming at a cycle length (CL) of 500 ms. We measured the immediate response (IR), the time constant (τ) of the exponential phase, and T90 End, the time to reach 90% change of QT and QTpeak from baseline to steady state during and after pacing. During atrial pacing, the CL decreased on average 45% from mean (SD) 944 (120) to 518 (46) ms and QT decreased on average 18% from 388 (20) to 318 (17) ms. For QT, T90 End was 103 (24) s and 126 (15) s after start versus stop of atrial pacing; a difference of 24 (27) s (P = 0.006). The response pattern was similar for τ but IR did not differ significantly between pacing start and stop. The response pattern was similar for QTpeak and also for QT and QTpeak following ventricular pacing start and stop. The coefficients of variation for repeated measures were 7%-21% for T90 End and τ. In conclusion, the adaptation of VR duration was significantly more rapid following increasing than decreasing HR and intraindividually a relatively reproducible process.NEW & NOTEWORTHY We studied the duration of ventricular repolarization (VR) adaptation and its hysteresis, following increasing and decreasing heart rate by abrupt start and stop of 8-min atrial or ventricular pacing in study subjects with permanent pacemakers and repeated the protocol with ≥1 mo interval, a novel approach. VR adaptation was significantly longer following decreasing than increasing heart rate corroborating previous observations. Furthermore, VR adaptation was intraindividually a reproducible and, hence, robust phenomenon, a novel finding.

Automatic identification of a stable QRST complex for non-invasive evaluation of human cardiac electrophysiology.

BACKGROUND: A vectorcardiography approach to electrocardiology contributes to the non-invasive assessment of electrical heterogeneity in the ventricles of the heart and to risk stratification for cardiac events including sudden cardiac death. The aim of this study was to develop an automatic method that identifies a representative QRST complex (QRSonset to Tend) from a Frank vectorcardiogram (VCG). This method should provide reliable measurements of morphological VCG parameters and signal when such measurements required manual scrutiny. METHODS: Frank VCG was recorded in a population-based sample of 1094 participants (550 women) 50-65 years old as part of the Swedish CArdioPulmonary bioImage Study (SCAPIS) pilot. Standardized supine rest allowing heart rate stabilization and adaptation of ventricular repolarization preceded a recording period lasting ≥5 minutes. In the Frank VCG a recording segment during steady-state conditions and with good signal quality was selected based on QRST variability. In this segment a representative signal-averaged QRST complex from cardiac cycles during 10s was selected. Twenty-eight morphological parameters were calculated including both conventional conduction intervals and VCG-derived parameters. The reliability and reproducibility of these parameters were evaluated when using completely automatic and automatic but manually edited annotation points. RESULTS: In 1080 participants (98.7%) our automatic method reliably selected a representative QRST complex where its instability measure effectively identified signal variability due to both external disturbances ("noise") and physiologic and pathophysiologic variability, such as e.g. sinus arrhythmia and atrial fibrillation. There were significant sex-related differences in 24 of 28 VCG parameters. Some VCG parameters were insensitive to the instability value, while others were moderately sensitive. CONCLUSION: We developed an automatic process for identification of a signal-averaged QRST complex suitable for morphologic measurements which worked reliably in 99% of participants. This process is applicable for all non-invasive analyses of cardiac electrophysiology including risk stratification for cardiac death based on such measurements.

Spatial peak and mean QRS-T angles: A comparison of similar but different emerging risk factors for cardiac death.

BACKGROUND: The spatial peak and mean QRS-T angles are scientifically but not clinically established risk factors for cardiovascular events including cardiac death. The study aims were to compare these angles, assess their association with hypertension (HT) and diabetes mellitus (DM), and explore the relation between the mean QRS-T angle and the ventricular gradient (VG; reflecting electrical heterogeneity), which both are derived from the QRSarea and Tarea vectors. METHODS: Altogether 1094 participants (aged 50-65 years, 550 women) from the pilot of the population-based Swedish CArdioPulmonary bioImage Study with Frank vectorcardiographic recordings were included and divided into 5 subgroups: apparently healthy n = 320; HT n = 311; DM n = 33; DM + HT n = 53; miscellaneous conditions n = 377. Abnormal peak and mean QRS-T angles were defined as >95th percentile. RESULTS: Peak QRS-T angles were generally narrower than the mean QRS-T angles; both were narrower in women than in men. Abnormal peak (>124°) and/or mean (>119°) QRS-T angles were found in 73 participants (6.7%). The concordance regarding abnormal versus normal-borderline QRS-T angles was good (Cohen's kappa 0.61). The prevalence of abnormal angles varied from 2.5% in healthy to 21.2% in DM. There was an inverse logarithmical relation between the mean QRS-T angle and the VG. CONCLUSIONS: The peak and mean QRS-T angles are not interchangeable but complementary. DM, HT, sex and absence of disease are important determinants of both QRS-T angles. The mean QRS-T angle and the VG relationship is complex. All three VCG derived measures reflect related but differing electrophysiological properties and have potential prognostic value vis-à-vis cardiovascular events.

Adaptation of ventricular repolarization duration and dispersion during changes in heart rate induced by atrial stimulation.

BACKGROUND: The duration of ventricular repolarization (VR) and its spatial and temporal heterogeneity are central elements in arrhythmogenesis. We studied the adaptation of VR duration and dispersion and their relationship in healthy human subjects during atrial pacing. METHODS: Patients 20-50 years of age who were scheduled for ablation of supraventricular tachycardia without preexcitation but otherwise healthy were eligible. Vectorcardiography recordings with Frank leads were used for data collection. Incremental atrial pacing from a coronary sinus electrode was performed by decrements of 10ms/cycle from just above sinus rate, and then kept at a fixed heart rate (HR) just below the Wenckebach rate for ≥5min and then stopped. VR duration was measured as QT and VR dispersion as T area, T amplitude and ventricular gradient. The primary measure (T90 End) was the time to reach 90% change from baseline to the steady state value during and after pacing. RESULTS: A complete study protocol was accomplished in 9 individuals (6 women). VR duration displayed a monophasic adaptation during HR acceleration lasting on average 20s. The median (Q1-Q3) T90 End for QT was 85s (51-104), a delay by a factor >4. All dispersion measures displayed a tri-phasic response pattern during HR acceleration and T90 End was 3-5 times shorter than for VR duration. CONCLUSIONS: Even during close to "physiological" conditions, complex and differing response patterns in VR duration and dispersion measures followed changes in HR. Extended knowledge about these responses in disease conditions might assist in risk evaluation and finding therapeutic alternatives.

Ventricular repolarization duration and dispersion adaptation after atropine induced rapid heart rate increase in healthy adults.

BACKGROUND: Proper adaptation of ventricular repolarization (VR) to rapid heart rate (HR) increase is crucial for cardiac electro-mechanical function. The pattern and temporal aspects of this adaptation and its components (duration and dispersion) during normal conduction are, however, incompletely known in humans and were the topic of this study. METHODS & RESULTS: The VR duration (QT & QTpeak) and dispersion (Tamplitude, Tarea & ventricular gradient; VG) responses were studied by continuous vectorcardiogram after a bolus injection of atropine 0.04mg/kg b.w. in 31 healthy young adults (16 men). The primary measure (T90 End) was the time to reach 90% change from baseline to end value 300s later. Mean (SD) of T90 End was 23 (9) s for a 41% RR decrease, 130 (35) s for a 16% QTend decrease and 110 (36) s for a 19% QTpeak decrease; the response was single-exponential for these measures. For 35-43% decreases of Tamplitude, Tarea & VG, mean (SD) of T90 End were 21 (10), 38 (20) and 40 (23) s and the response pattern was double-exponential with varying overshoot. CONCLUSIONS: VR duration and dispersion responses to a very rapid HR increase during normal conduction differed substantially. In contrast to the well-known single-exponential delay in VR duration adaptation the responses of VR dispersion measures were double-exponential and much more rapid. We describe a new and completely non-invasive phenotypic characterization of different components of VR adaptation.

Instability of repolarization in LQTS mutation carriers compared to healthy control subjects assessed by vectorcardiography.

BACKGROUND: Potassium channel dysfunction in congenital and acquired forms of long QT syndrome types 1 and 2 (LQT1 and LQT2) increases the beat-to-beat variability of the QT interval. OBJECTIVE: To study about the little known variability (instability) of other aspects of ventricular repolarization (VR) in humans by using vectorcardiography. METHODS: Beat-to-beat analysis was performed regarding vectorcardiography derived RR, QRS, and QT intervals, as well as T vector- and T vector loop-based parameters during 1-minute recordings of uninterrupted sinus rhythm at rest in 41 adult LQT1 (n = 31) and LQT2 (n = 10) mutation carriers and 41 age- and sex-matched control subjects. The short-term variability for each parameter, describing the mean orthogonal distance to the line of identity on the Poincaré plot, was calculated. RESULTS: Mutation carriers showed significantly larger (by a factor 2) instability in most VR parameters compared to controls despite higher instantaneous heart rate variability (STVRR) in the control group. The longer the QT interval, the greater was its instability, and the instability of VR dispersion measures. CONCLUSIONS: A greater instability of most aspects of VR already at rest seems to be a salient feature in both LQT1 and LQT2, which might pave the way for early afterdepolarizations and torsades de pointes ventricular tachycardia. In contrast, no signs of increased VR dispersion per se were observed in mutation carriers.

Fibre type-specific increase in passive muscle tension in spinal cord-injured subjects with spasticity.

Patients with spasticity typically present with an increased muscle tone that is at least partly caused by an exaggerated stretch reflex. However, intrinsic changes in the skeletal muscles, such as altered mechanical properties of the extracellular matrix or the cytoskeleton, have been reported in response to spasticity and could contribute to hypertonia, although the underlying mechanisms are poorly understood. Here we examined the vastus lateralis muscles from spinal cord-injured patients with spasticity (n = 7) for their passive mechanical properties at three different levels of structural organization, in comparison to healthy controls (n = 7). We also assessed spasticity-related alterations in muscle protein expression and muscle ultrastructure. At the whole-muscle level in vivo, we observed increased passive tension (PT) in some spasticity patients particularly at long muscle lengths, unrelated to stretch reflex activation. At the single-fibre level, elevated PT was found in cells expressing fast myosin heavy chain (MyHC) isoforms, especially MyHC-IIx, but not in those expressing slow MyHC. Type IIx fibres were present in higher than normal proportions in spastic muscles, whereas type I fibres were proportionately reduced. At the level of the isolated myofibril, however, there were no differences in PT between patients and controls. The molecular size of the giant protein titin, a main contributor to PT, was unchanged in spasticity, as was the titin : MyHC ratio and the relative desmin content. Electron microscopy revealed extensive ultrastructural changes in spastic muscles, especially expanded connective tissue, but also decreased mitochondrial volume fraction and appearance of intracellular amorphous material. Results strongly suggest that the global passive muscle stiffening in spasticity patients is caused to some degree by elevated PT of the skeletal muscles themselves. We conclude that this increased PT component arises not only from extracellular matrix remodelling, but also from structural and functional adaptations inside the muscle cells, which alter their passive mechanical properties in response to spasticity in a fibre type-dependent manner.