Normalized Heart Rate Research Articles

Coronary microembolization sheep model by adjusting the number of microspheres based on coronary blood flow.

A heart failure (HF) model using coronary microembolization in large animals is indispensable for medical research. However, the heterogeneity of myocardial response to microembolization is a limitation. We hypothesized that adjusting the number of injected microspheres according to coronary blood flow could stabilize the severity of HF. This study aimed to evaluate the effect of microsphere injection based on the left coronary artery blood flow in an animal model. Microembolization was induced by injecting different numbers of microspheres (polystyrene, diameter: 90 μm) into the left descending coronary artery of the two groups of sheep (400 and 600 times coronary blood flow [ml/min]). Hemodynamic parameters, the pressure-volume loop of the left ventricle, and echocardiography findings were examined at 0.5, 1.5, 3.5, and 6.5 h after microembolization. End-diastolic pressure and normalized heart rate increased over time, and were significantly higher in 600 × coronary blood flow group than those in 400 × coronary blood flow group (p=0.04 and p < 0.01, respectively). The maximum rate of left-ventricular pressure rise and normalized stroke volume decreased over time, and were significantly lower in 600 × coronary blood flow group than those in 400 × coronary blood flow group (p < 0.01 and p < 0.01, respectively). The number of microspheres per coronary blood flow was significantly correlated with the decrease in stroke volume and the maximum rate of left ventricular pressure rise in 6.5 h (r=0.74, p=0.01 and r=0.71, p=0.02, respectively). Adjusting the number of injected microspheres based on the coronary blood flow enabled the creation of HF models with different degrees of severity.

Evaluating the impacts of situational awareness and mental stress on takeover performance under conditional automation

Several safety concerns emerge for the transition of control from the automated driving system to a human driver after the vehicle issues a takeover warning under conditional vehicle automation (SAE Level 3). In this context, recent advances in in-vehicle driver monitoring systems enable tracking drivers’ physiological indicators (e.g., eye-tracking and heart rate (HR) measures) to assess their real-time situational awareness (SA) and mental stress. This study seeks to analyze differences in driver’s SA and mental stress over time (i.e., successive experiment runs) using these physiological indicators to assess their impacts on takeover performance. We use eye-tracking measures (i.e., on-road glance rate and road attention ratio) as indicators of driver’s SA during automated driving. Further, we use the pre-warning normalized HR (NHR) and HR variability (HRV) as well as the change in NHR and HRV after the takeover warning as indicators of mental stress immediately before and the change in mental stress after the takeover warning, respectively. To analyze the effects of driver state (in terms of SA and mental stress) on the overall takeover performance, this study uses a comprehensive metric, Takeover Performance Index (TOPI), proposed in our previous work (Agrawal & Peeta, 2021). The TOPI combines multiple driving performance indicators while partly accounting for their interdependencies. Results from statistical analyses of data from 134 participants using driving simulator experiments illustrate significant differences in driver state over successive experiment runs, except for the change in mental stress after the takeover warning. Some significant correlations were found between the physiological indicators of SA and mental stress used in this study. Takeover performance model results illustrate a significant negative effect of change in NHR after the takeover warning on the TOPI. However, none of the other physiological indicators show significant impacts on takeover performance. The study findings provide valuable insights to auto manufacturers for designing integrated in-vehicle driver monitoring and warning systems that enhance road safety and user experience.

Diagnosis of paroxysmal atrial fibrillation from thirty-minute heart rate variability data using convolutional neural networks

Paroxysmal atrial fibrillation (PAF) is the initial stage of atrial fibrillation, one of the most common arrhythmia types. PAF worsens with time and affects the patient?s life quality negatively. In this study, we aimed to diagnose PAF early, so patients can start taking precautions before this disease gets worse. We used the atrial fibrillation prediction database, an open data from Physionet and constructed our approach using convolutional neural networks. Heart rate variability (HRV) features are calculated from time-domain measures, frequency-domain measures using power spectral density estimations (fast Fourier transform, Lomb-Scargle, and Welch periodogram), time-frequencydomain measures using wavelet transform, and nonlinear Poincare plot measures. We also normalized these features using min-max normalization and z-score normalization methods. In addition, we also applied alternatively the heart rate normalization (HRN), which gave promising results in a few HRV-based research, before calculating these features. Thus, HRV data, HRN data, and HRV features extracted from six different combinations of these normalizations, in addition to no normalization cases, were applied to the convolutional neural networks classifier. We tuned the classifiers using 90% of samples and tested the classifiers' performances using 10% of data. The proposed approach resulted in 95.92% accuracy, 100% precision, 91.84% recall, and 95.74% f1-score in HRV with z-score feature normalization. When the heart rate normalization was also applied, the proposed approach reached 100% accuracy, 100% precision, 100% recall, and 100% f1-score in HRV with z-score feature normalization. The proposed method with heart rate normalization and z-score normalization methods resulted in better classification performance than similar studies in the literature. In addition, although deep learning models offer no use of separate feature extraction processes, this study reveals that using HRV-specific feature extraction techniques may improve the performance of deep learning algorithms in HRV-based studies. Comparing the existing studies, we concluded that our approach provides a much better tool to diagnose PAF patients.

Maximum acceptable speed based on physiological performance for different alignments of rural roads under the influence of visibility in fog—a driving simulator study

Objectives: The goals of this research are to: (i) investigate whether the driver’s physiological performance has a significant impact on driving speed choice, considering the visibility level under fog conditions and the horizontal and vertical alignment of a rural road; (ii) quantify the relationships among these variables; (iii) calculate the maximum acceptable speed that meets the driver’s physiological tolerance threshold.Methods: A driving simulator study was conducted. A total of 30 participants were recruited, and each completed 5 driving simulator trials under varying visibility levels, radii of curvature and vertical grades. A multiple linear regression model was established to measure the association between normalized heart rate, driving speed, visibility, radius of curvature and gradient.Results: The results indicated that driving speed, visibility, radius of curvature and gradient all significantly affected the normalized heart rate. For instance, an increase in driving speed and vertical grade and a reduction in the radius of curvature are related to an increase in normalized heart rate. Moreover, an acceptable speed model that considered the driver’s normalized heart rate was constructed, given the visibility level and horizontal and vertical alignment.Conclusions: The study shows a significant correlation between the drivers’ physiological performance and his or her driving speed choice under the influence of visibility in fog. Given visibility conditions and road alignment parameters, we can calculate the maximum acceptable speed that meets the driver’s physiological requirements. Such findings should be indicative of real-time traffic management that could reduce the crash risk under inadequate visibility conditions in fog.

Systemic Outcomes of (Pyr1)-Apelin-13 Infusion at Mid-Late Pregnancy in a Rat Model with Preeclamptic Features

Preeclampsia is a syndrome with diverse clinical presentation that currently has no cure. The apelin receptor system is a pleiotropic pathway with a potential for therapeutic targeting in preeclampsia. We established the systemic outcomes of (Pyr1)-apelin-13 administration in rats with preeclamptic features (TGA-PE, female transgenic for human angiotensinogen mated to male transgenic for human renin). (Pyr1)-apelin-13 (2 mg/kg/day) or saline was infused in TGA-PE rats via osmotic minipumps starting at day 13 of gestation (GD). At GD20, TGA-PE rats had higher blood pressure, proteinuria, lower maternal and pup weights, lower pup number, renal injury, and a larger heart compared to a control group (pregnant Sprague-Dawley rats administered vehicle). (Pyr1)-apelin-13 did not affect maternal or fetal weights in TGA-PE. The administration of (Pyr1)-apelin-13 reduced blood pressure, and normalized heart rate variability and baroreflex sensitivity in TGA-PE rats compared to controls. (Pyr1)-apelin-13 increased ejection fraction in TGA-PE rats. (Pyr1)-apelin-13 normalized proteinuria in association with lower renal cortical collagen deposition, improved renal pathology and lower immunostaining of oxidative stress markers (4-HNE and NOX-4) in TGA-PE. This study demonstrates improved hemodynamic responses and renal injury without fetal toxicity following apelin administration suggesting a role for apelin in the regulation of maternal outcomes in preeclampsia.

Efficacy and safety of Shenfu injection for septic shock: A systematic review and meta-analysis of randomized controlled trials

ObjectiveTo evaluate the efficacy and safety of Shenfu injection (SFI) combined with standard therapy versus standard therapy for septic shock, three groups of patients with septic shock were analyzed based on the level of mean arterial lactate. They were mean arterial lactate level < 4.5 mmol/L, 4.5 mmol/L ≤ mean arterial lactate level < 7 mmol/L and mean arterial lactate level ≥ 7 mmol/L. MethodsRandomized controlled trials (RCT) from PubMed, Cochrane library, Embase, CENTRAL, SinoMed, Wanfang, CNKI, and Weipu (VIP) databases from the inception to September 2018 were searched. Relative risks (RR), weighted mean difference (WMD), along with 95% confidence interval (95%CI) were used to analyze the main outcomes. Statistical analysis was performed using Rev.Man 5.3. The qualities of the involved studies were accessed by the ROB according to the Cochrane handbook. Results19 randomized controlled trials with 1505 participants were included. Compared with standard therapy, SFI plus standard therapy cannot decrease the 28-day mortality for all of the three groups. Compared with the other two subgroups (mean arterial lactate level < 4.5 mmol/L and mean arterial lactate level ≥ 7 mmol/L), the 4.5 mmol/L ≤ mean arterial lactate level < 7 mmol/L group has a trend to decrease 28-day mortality (RR: 0.67; 95% CI: 0.38–1.19; P = 0.17). In addition, adding SFI could have further increased mean arterial pressure (MAP) at 6-hours (RR: 7.05; 95% CI: 4.14–9.97) and further normalized heart rate (HR) when compared with standard therapy (RR: –17.48; 95% CI: [−19.39–(−15.57)]. ConclusionFor septic shock patients with 4.5 mmol/L ≤ mean arterial lactate level < 7 mmol/L, when the Traditional Chinese Medicine syndrome meet Yang-Qi deficiency, clinicians could choose SFI as a supplementary drug. But further high-quality and large-scale RCT should be performed to verify it. PROSPERO registration numberCRD42018090320.

ASSESSMENT OF LEFT VENTRICULAR DYSFUNCTION IN PATIENTS WITH CORONARY HEART DISEASE DURING MINIMALLY INVASIVE SURGERY ACCORDING TO LUNG COMPUTED TOMOGRAPHY DATA

Objective: to assess whether multislice computed tomography (MSCT) of the lung can be used to diagnose the early manifestations of heart failure in patients with coronary heart disease (CHD) during minimally invasive surgical interventions.Material and methods. Lung MSCT was performed in 54 patientsaged 43 to 89 years with CHD before and after interventions. The identified group included 24 patients who had undergone coronary stenting, 26 who had cardiac pacemaker implantation, and 4 patients who had conduction pathways ablation. Left ventricular failure was assessed by hemodynamic disorders in the pulmonary circulation, by taking into account the use of known pathophysiological data. Successive lung MSCT examinations were performed before and after minimally invasive surgical interventions, by recording local densitometric changes in the lung parenchyma.Results. A procedure was proposed to objectively assess comparable ling MSCT images in the same patient in the special imaging window. The density of the lung parenchyma reduced by more than 10 Hounsfield units in 24 patients in the next periods after surgery, which was regarded as a sign of better left ventricular pumping function. Conclusion. The study showed that lung MSCT was highly sensitive in diagnosing left ventricular dysfunction in patients with CHD with improved coronary blood flow and normalized heart rate.

Cardiovascular and respiratory effects of two doses of fentanyl in the presence or absence of bradycardia in isoflurane-anesthetized dogs

ObjectiveTo compare the cardiopulmonary effects of low and high doses of fentanyl before and after the correction of bradycardia in isoflurane-anesthetized dogs. Study designProspective, randomized crossover trial. AnimalsEight healthy male Beagle dogs weighing 11.1 ± 1.3 kg [mean ± standard deviation (SD)] and aged approximately 1 year. MethodsThe dogs were anesthetized with isoflurane [1.3 × minimum alveolar concentration (MAC)] on two occasions and fentanyl was administered intravenously; either low-dose fentanyl, loading dose (33 μg kg–1) and infusion (0.2 μg kg–1 minute–1) or a high-dose, loading dose (102 μg kg–1) and infusion (0.8 μg kg–1 minute–1). Cardiopulmonary variables were measured at three time points in equipotent isoflurane concentrations (1.3 MAC): before fentanyl administration (ISO), during fentanyl-induced bradycardia (ISO–F) and after administration of glycopyrrolate normalized heart rate (ISO–FNHR). Data are mean ± SD. ResultsHeart rate and cardiac index (CI) decreased and systemic vascular resistance index (SVRI) increased at ISO–F in both treatments. Bradycardia and vasoconstriction at ISO–F were greater in high than in low-dose fentanyl (42 ± 7 versus 57 ± 15 beats minute–1 and 3457 ± 1108 versus 2528 ± 968 dyne second cm–5 m–2), respectively. Oxygen delivery index (DO2I) decreased only during high-dose fentanyl. CI and DO2I were higher in both treatments at ISO–FNHR than at ISO–F; however, they were higher only during the high-dose fentanyl than at ISO. SVRI was higher at ISO–F than at ISO and ISO–FNHR in both treatments, and was higher at ISO–F in the high than in the low-dose treatment. Conclusions and clinical relevanceAn overall improvement in cardiovascular function of dogs anesthetized with equipotent isoflurane doses (1.3 MAC) was observed after the treatment of bradycardia only with the high-dose fentanyl.

Relationship between QT and JT peak interval variability in prepubertal children.

The QT variability index (QTVI) is a noninvasive index of repolarization lability that has been applied to subjects with cardiovascular disease. QTVI provides a ratio of normalized QT variability to normalized heart rate variability, and therefore includes an assessment of autonomic nervous activity. However, measurement of QT time is particularly difficult in children, who exhibit physiologically high heart rates compared with adults. In this study, we developed a set of standard values of J-point to Tpeak interval (JTp) for infants by age, and assessed the correlation of QTVI with the JTp variability index (JTpVI). Subjects included 623 infants and children (0-7years of age) without heart disease and 57 healthy university students. All subjects were divided into three groups by age. QTVI and JTpVI were calculated based on an electrocardiogram, and age-specific standard values, a gender-specific classification, and a standard growth curve were constructed. JTpVI markedly decreased in infancy and slowly decreased thereafter, reaching adult values by school age. There was also a strong correlation of JTpVI with QTVI (r=.856). JTp can be used to evaluate the variability of the repolarization time in healthy infants, and may be useful for detection of early repolarization abnormalities.

Pharmacological treatment with mirtazapine rescues cortical atrophy and respiratory deficits in MeCP2 null mice.

Loss of MeCP2 (Methyl CpG binding protein 2) in Rett syndrome (RTT) causes brain weight decrease, shrinkage of the cortex with reduced dendritic arborization, behavioral abnormalities, seizures and cardio-respiratory complications. The observed monoamine neurotransmitters reduction in RTT suggested antidepressants as a possible therapy. We treated MeCP2-null mice from postnatal-day 28 for two weeks with desipramine, already tested in RTT, or mirtazapine, an antidepressant with limited side-effects, known to promote GABA release. Mirtazapine was more effective than desipramine in restoring somatosensory cortex thickness by fully rescuing pyramidal neurons dendritic arborization and spine density. Functionally, mirtazapine treatment normalized heart rate, breath rate, anxiety levels, and eliminated the hopping behavior observed in MeCP2-null mice, leading to improved phenotypic score. These morphological and functional effects of mirtazapine were accompanied by reestablishment of the GABAergic and glutamatergic receptor activity recorded in cortex and brainstem tissues. Thus, mirtazapine can represent a new potential pharmacological treatment for the Rett syndrome.

Abstract 19072: Cardiac Autonomic Dysfunction in Mice Lacking Methyl CpG Binding Protein 2

Background: Rett Syndrome (RTT) is an X-linked dominant neurodevelopmental disorder primarily caused by mutations in Methyl-CpG-binding protein ( MECP2 ), a transcriptional regulator. Twenty-five percent of all deaths in RTT are sudden and unexpected, and autonomic nervous system (ANS) dysfunction is hypothesized to be the cause of sudden deaths in RTT. However, the role of MeCP2 in cardiac autonomic function has not been investigated in depth. Design/Methods: Male (2 months) and female (9 months) Mecp2 deficient and wildtype mice were implanted with ETA-F10 telemeters and 24h recordings were taken to calculate heart rate, heart rate variability, and incidence of arrhythmic events. Effects of pharmacological stimulants or inhibitors on heart rate were normalized to saline injection response. Results: Male Mecp2 deficient mice (NULL) have a decreased heart rate (WT = 634 ±3, NULL = 518 ±8, p&lt;0.001), while female deficient mice (NULL/+) do not present with a decreased heart rate. Interestingly, NULL and NULL/+ mice both have a high incidence of sinus pauses and AV block (WT 1/5, NULL 6/6, NULL /+ 4/4, p&lt;0.05). Additionally, both NULL and NULL/+ mice have increased bradycardia events defined as a heart rate below 200 bpm, (WT = 17 ±6, NULL = 307 ±94, NULL/+ = 198 ±67, p&lt;0.05) and an increased heart rate variability. The normalized heart rate response to atropine, a parasympathetic blocker, of NULL mice was above wildtype levels (p&lt;0.05) Chemical denervation by combined antagonism of parasympathetic (atropine) and sympathetic (propranolol) resulted in NULL mice having an increased normalized heart rate response compared to wildtype (p&lt;0.05). Finally, the incidence of AVB/sinus pauses counts per 30 minutes post-acute treatment with atropine and chemical denervation (NULL saline 49 ±10, NULL atropine 8 ±5, NULL atropine/propranolol 0.5 ±0.5 p&lt;0.05) decreased the severity of the cardiac phenotype in NULL mice. Conclusions: In summary, Mecp2 is required for a normal heart rhythm. Loss of Mecp2 causes bradycardia, sinus pauses, AV block, and increased heart rate variability that may be attributed by aberrant innervation. Acute atropine and chemical denervation was therapeutic and ameliorated the cardiac phenotype observed in Mecp2 deficient mice.

QT Variability Index as a tool for risk stratification of sudden cardiac death

Sudden cardiac death is the leading cause of mortality in patients with chronic heart failure (CHF) and history of myocardial infarction. Selection of patients at risk of sudden cardiac death is dramatically important to choose the correct therapeutic approach. The QT Variability Index (QTVI) is a non-invasive measure of repolarization lability that has been applied to a wide variety of subjects with cardiovascular disease. It is a ratio of normalized QT variability to normalized heart rate variability, and therefore includes an assessment of the autonomic nervous system tone. As opposed to T wave alternans, QTVI assesses variance in repolarization at all frequencies. Recent studies suggest that QTVI may help clinicians choosing the appropriate implantable cardiovester defibrillator timing implantation, in patients with dilated or hypertrophic cardiomyopathy or CHF because of its efficacy in patient evaluation and follow-up.

QT Variability Index

The QT Variability Index (QTVI) is a non-invasive measure of repolarization lability that has been applied to a wide variety of subjects with cardiovascular disease. It is a ratio of normalized QT variability to normalized heart rate variability, and therefore includes an assessment of autonomic nervous system tone. The approach assesses beat-to-beat variability in the duration of the QT and U wave in conventional surface electrocardiographic recordings, as well as determines the heart rate variability (HRV) from the same recording. As opposed to T wave alternans, QTVI assesses variance in repolarization at all frequencies. Nineteen studies have published data on QTVI in healthy individuals, while 20 have evaluated its performance in cohorts with cardiovascular disease. Six studies have assessed the utility of QTVI in predicting VT/VF, cardiac arrest, or cardiovascular death. A prospective study utilizing QTVI to determine therapy allocation has not been performed, and therefore the final determination of the value of the metric awaits definitive exploration.

Comparison of Sum Absolute QRST Integral, and Temporal Variability in Depolarization and Repolarization, Measured by Dynamic Vectorcardiography Approach, in Healthy Men and Women

BackgroundRecently we showed the predictive value of sum absolute QRST integral (SAI QRST) and repolarization lability for risk stratification of sudden cardiac death (SCD) in heart failure patients. The goal of this study was to compare SAI QRST and metrics of depolarization and repolarization variability in healthy men and women.MethodsOrthogonal ECGs were recorded at rest for 10 minutes in 160 healthy men and women (mean age 39.6±14.6, 80 men). Mean spatial TT′ angle, and normalized variances of T loop area, of spatial T vector amplitude, of QT interval and Tpeak-Tend area were measured for assessment of repolarization lability. Normalized variances of spatial QRS vector and QRS loop area characterized variability of depolarization. In addition, variability indices (VI) were calculated to adjust for normalized heart rate variance. SAI QRST was measured as the averaged arithmetic sum of areas under the QRST curve.ResultsMen were characterized by shorter QTc (430.3±21.7 vs. 444.7±22.2 ms; P<0.0001) and larger SAI QRST (282.1±66.7 vs.204.9±58.5 mV*ms; P<0.0001). Repolarization lability negatively correlated with spatial T vector amplitude. Adjusted by normalized heart rate variance, QT variability index was significantly higher in women than in men (−1.54±0.38 vs. −1.70±0.33; P = 0.017). However, in multivariate logistic regression after adjustment for body surface area, QTc, and spatial T vector amplitude, healthy men had 1.5–3 fold higher probability of having larger repolarization lability, as compared to healthy women (T vector amplitude variability index odds ratio 3.88(95%CI 1.4–11.1; P = 0.012).ConclusionsHealthy men more likely than women have larger repolarization lability.

Abstract 9792: Chrontropic Incompetence in Heart Failure and the Relationship of Minute Ventilation and Chronotropic Response During Exercise

BACKGROUND: Cardiac pulmonary mismatch is prevalent in heart failure patients that exhibit chronotropic incompetence (CI). Wilkoff’s model provides evaluation of metabolic chronotropic response (MCR) during exercise. In addition to CI we evaluated a new measure of the normalized heart rate to normalized minute ventilation relationship during exercise (HRn/VEn) which,in combination with the MCR slope, may provide discriminating information in regards to identifying those normal subjects and heart failure patients who would most likely benefit from adaptive rate pacing. Normalization allows comparison of subjects and identification of patients with CI regardless of Age, functional capacity, and during submaximal workloads. METHOD: We studied the resulting MCR slopes and the HRn/VEn slopes in 40 normal subjects (N) (age 37±9) and 40 heart failure patients (HF) implanted with BiV CRT-D devices (age 62±9) during graded exercise testing by using standard cardiopulmonary exercise testing techniques. Exercise tests were performed to peak exercise (as quantified by the respiratory exchange ratio (RER) RER = 1.13±0.09 N and 1.11±0.07 HF) and the end stage heart rate and minute ventilation data was used in the calculations of the MCR slope and HRn/VEn slopes. RESULTS: Mean MCR slopes were 1.0±0.14 (N) and 0.52±0.23 (HF). The mean HRn/VEn slope were 1.34±0.26 (N) and 0.66±0.28 (HF). Details are presented in the table. DISSCUSION/CONCLUSSION: When CI is present there is also a significant derangement in the heart rate to pulmonary relationship as shown by the HRn/VEn slopes. A MCR slope of 0.7 which is considered to be severely CI corresponds to a decreased HRn/VEn slope of 0.881 (95% confidence interval of the normal relationship). HF CI patients (MCR slopes &lt;0.7) also exhibit low HRn/VEn measures (&gt; 2 standard deviations from the mean of normal group).

Nitric oxide-dependent bradycardia in mutant analbuminemic rats

Nagase analbuminemic rats (NAR) are natural mutant Sprague-Dawley rats which do not express albumin due to a single splice mutation in the albumin gene. We accidentally discovered that NAR have a significant bradycardia compared with wild type Sprague-Dawley rats, and the present study was carried out to investigate the mechanism of bradycardia in analbuminemic rats. In vitro studies showed that the basal spontaneous beating rate of isolated atria is similar in NAR compared with wild type animals. However, the chronotropic responsiveness of isolated atria to cholinergic stimulation was markedly increased in NAR, an effect which was prevented by incubation with a nitric oxide synthase (NOS) or guanylyl cyclase inhibitor. NAR had a significant increase in plasma nitrite/nitrate concentrations. Administration of a NOS inhibitor for 5 days normalized heart rate in NAR. The level of NOS isoforms, caveolin-1 and caveolin-3 expression in the atria was assessed by real time PCR. There was no significant difference in the expression of NOS isoforms or caveolin-3 in NAR compared with wild type controls. However, NAR exhibited a significant decrease in caveolin-1 expression in the atria. Since caveolin-1 is known to inhibit endothelial NOS activity in cardiomyocytes, we suggest that decreased caveolin-1 levels may have a role in increased nitric oxide production in NAR. Our data suggest that a NOS/cGMP-dependent mechanism might be involved in increased responsiveness to vagal stimulation and bradycardia in analbuminemic condition.

QT variability index on 24-hour Holter independently predicts mortality in patients with heart failure: analysis of Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca (GISSI-HF) trial

Increased temporal variability of repolarization, as reflected by QT interval variability measured over 10-15 minutes, predicted spontaneous ventricular arrhythmias and death in implantable cardioverter-defibrillator patients in mild to moderate heart failure (HF). The purpose of this study was to test our hypothesis that increased mean QT variability over 24 hours would be associated with increased cardiovascular (CV) mortality in a heterogeneous HF population. The Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure trial prospectively enrolled subjects with HF of any cause. Twenty-four-hour Holter recordings from 268 subjects were analyzed using a template-matching, semiautomatic algorithm to measure QT and heart rate time series in sequential 5-minute epochs over 24 hours. The QT variability index (QTVI) was expressed as the log ratio of the normalized QT variance over normalized heart rate variance. Total and CV mortality were assessed as a function of continuous and dichotomous QTVI (>-0.84) in univariate and multivariable Cox proportional hazards models, adjusting for significant clinical predictors. After a median of 47 months, there were 53 deaths, of which 44 were from CV causes. A significant association with the outcome was found for QTVI both as continuous and dichotomous variables after adjustment for clinical covariates (age >70, New York Heart Association class III-IV, left ventricular ejection fraction, nonsustained ventricular tachycardia, creatinine): QTVI hazard ratio (HR) 4.0 (confidence interval [CI] 1.8-88; P = .008) for total and 4.4 (CI 1.9-10.1; P = .0006) for CV mortality; QTVI >-0.84 HR 2.0 (CI 1.1-3.6; P = .02) for total and 2.1 (CI 1.1-3.8; P = .02) for CV mortality. Increased repolarization lability, as reflected in QTVI measured over 24 hours, is associated with increased risk for total and CV mortality in a heterogeneous population with chronic HF.

154 SENSORY BIAS PREDICTS POSTURAL STABILITY, ANXIETY, AND COGNITIVE PERFORMANCE IN HEALTHY ADULTS WALKING IN NOVEL DISCORDANT CONDITIONS

We designed a gait training study that presented combinations of visual flow and support surface manipulations to investigate the response of healthy adults to novel discordant sensorimotor conditions. We aimed to determine whether a relationship existed between subjects visual dependence and their scores on a collective measure of anxiety, cognition, and postural stability in a new discordant environment presented at the conclusion of training (Transfer Test). A treadmill was mounted to a motion base platform positioned 2 m behind a large visual screen. Training consisted of three walking sessions, each within a week of the previous visit, that presented four 5-minute exposures to various combinations of support surface and visual scene manipulations, all lateral sinusoids. The conditions were scene translation only, support surface translation only, simultaneous scene and support surface translations in-phase, and simultaneous scene and support surface translations 180 out-of-phase. During the Transfer Test, the trained participants received a 2-minute novel exposure. A visual sinusoidal roll perturbation, with twice the original flow rate, was superimposed on a sinusoidal support surface roll perturbation that was 90 out of phase with the scene. A high correlation existed between normalized torso translation, measured in the scene-only condition at the first visit, and a combined measure of normalized heart rate, stride frequency, and reaction time at the transfer test. Results suggest that visually dependent participants experience decreased postural stability, increased anxiety, and increased reaction times compared to their less visually dependent counterparts when negotiating novel discordant conditions.

24-Hour QT variability in heart failure

Background Previous studies have shown that increased temporal variability of repolarization, as reflected by QT interval variability measured for 10 minutes, predicted spontaneous ventricular arrhythmias in implantable cardioverter defribrillator patients, but it is unclear how these measures perform in 24-hour recordings. Methods Twenty-four-hour digital Holter recordings from 372 subjects with chronic heart failure enrolled in Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca, (GISSI) Heart Failure study were analyzed using a template-matching, semiautomatic algorithm to measure QT and heart rate time series in sequential 5-minute epochs for 24 hours. QT variability was expressed as normalized QT variance (QTVN) or as the log ratio of the QTVN over normalized heart rate variance (QT variability index, or QTVI). Results A pronounced diurnal variation was seen in both QTVI and QTVN. Both were lowest in the midnight to 6 am time frame and increased throughout the day, peaking at noon to 6 pm, then decreasing 6 pm to midnight. For QTVI, all 4 time points were significantly different ( P < .0001). QT variability index correlated with heart rate ( r = 0.38, P < .0001) and was significantly higher for those in higher New York Heart Association (NYHA) classes ( r = 0.22, P = .0003). Normalized QT variance did not correlate with heart rate or NYHA but correlated negatively with serum potassium ( r = −0.22, P = .0002) and manifested the greatest increase during midmorning hours. Conclusions Repolarization lability as reflected in QT variability has a pronounced diurnal variation and increases significantly after 6 am, the time of greatest arrhythmic risk. QT variability for 24 hours might improve risk prediction in chronic heart failure patients and should be tested in appropriate trials.

Cardiac Characteristics of a Mouse Model of Timothy Syndrome

Timothy Syndrome (TS) is the only L-type Ca2+ channel (Cav1.2) defect linked to arrhythmias and sudden cardiac death (Splawski I et al. Cell 119: 19-31, 2004). Timothy SyTS results from a de novo gain-of-function mutation on the intracellular side of S6 from the first domain which affects the voltage dependent component of inactivation in Cav1.2 and results in prolongation of the QT interval.In addition to arrhythmogenesis, TS is associated with congenital heart disease, syndactyly and autism spectrum disorders. We created a knock-in mutation of TS in mice. Computer modeling suggested that the cardiac AP should be minimally affected under physiological conditions and in mice the arrhythmic potential should be observable only under pathophysiological conditions. The ECGs of conscious, unrestrained, unanesthetized mice and were performed double blinded. The QTc (38) in TS mice was prolonged, shifting from 44.3 ± 0.5 ms (n=8) for control mice to 47.2 ± 0.5 ms (n = 17) for mice expressing the TS mutation (P<0.01). Viewed qualitatively, many of the electrocardiograms from the TS mice showed a marked change in T-wave morphology. Other significant changes in conscious mice were also noted, the duration of the QRS complex shifted from 9.2 ± 0.4 ms (n=8) to 11.1 ± 0.2 ms (n = 17), heart rate showed a slight but not statistically significant increase and normalized heart rate variability showed a decrease from 5.1% ± 1.1 (n=8) to 2.6% ± 0.6 (n=17 P<0.05) indicating an increase in sympathetic tone in the TS mice. TS patients are particularly susceptible to arrhythmias in response to anesthesia and TS mice showed increased sensitivity to anesthetic (ketamine) with much loner QT prolongation and arrhythmias such as premature beats and apparent AV block.