Abstract: STUDY OBJECTIVE: To evaluate the sensitivity and specificity of various predictors of hypotension during onset of spinal anesthesia in elderly patients. DESIGN: Prospective study. SETTING: 32 ASA physical status I, II, and III patients, aged >/=60 years, scheduled for elective lower limb surgery with spinal anesthesia. INTERVENTIONS: Patients received spinal anesthesia with 10-17.5 mg of bupivacaine. No prophylactic ephedrine or fluid preloading was used. MEASUREMENTS: A 5-minute baseline was recorded and during onset of spinal anesthesia, hemodynamic changes were measured every 10 seconds from the radial artery pressure curve. Data collection ended when patients were ready for surgery, or if ephedrine was given to increase mean arterial pressure. MAIN RESULTS: 21 patients had hypotension. Baseline blood pressure variability low-frequency band power (BPV LF) >8 mmHg(2) and near-infrared spectroscopy (NIRS) reduction >/=5% had high sensitivity (0.73 and 0.90, respectively) and specificity (0.78 and 0.64, respectively), and were significantly associated with the development of hypotension. CONCLUSIONS: Only NIRS and BPV LF could significantly predict hypotension among the elderly.

Abstract: AIMS: Hypoglycaemia-induced cardiac arrhythmias may be involved in the pathogenesis of the 'dead-in-bed syndrome' in patients with type 1 diabetes. Evidence suggests that the renin-angiotensin system (RAS) influences the occurrence of arrhythmias. The aim of this study was to explore if basal RAS activity affects cardiac repolarization during hypoglycaemia, thereby potentially carrying prognostic information on risk of the 'dead-in-bed syndrome'. METHODS AND RESULTS: Nine subjects with high RAS activity and nine subjects with low RAS activity were subjected to single-blinded placebo-controlled hypoglycaemia (nadir plasma glucose 2.4 mmol/L). QTc/QTcF and QT dynamics were registered by Holter monitoring. QTc prolonged during [8 (+/-2.3) ms, P < 0.01] and after [11 (+/-3) ms, P < 0.001] hypoglycaemia. Dynamic QT parameters reacted ambiguously. Low RAS activity was associated with a slightly more pronounced QT prolongation [6 (+/-3) ms, P = 0.04]. Adrenaline tended to increase more in the low-RAS group (P = 0.08) and was correlated to QTc (r = 0.67, P < 0.01) and QTcF (r = 0.58, P < 0.05) during hypoglycaemia. CONCLUSION: Low basal RAS activity may be associated with a slightly more pronounced QT prolongation during hypoglycaemia, when compared with high RAS activity. The impact, however, is modest and the clinical consequence is unclear.

Abstract: AIMS: Activity in the renin-angiotensin system (RAS) may influence the susceptibility to cardiac arrhythmia. To study the effect of basal RAS activity on cardiac repolarization during myocardial stress induced by hypoglycaemia or hypoxaemia in healthy humans. METHODS AND RESULTS: Ten subjects with high RAS activity and 10 subjects with low RAS activity were studied on three different occasions: (i) hypoglycaemia (nadir P-glucose 2.7 +/- 0.5 mmol/L), (ii) hypoxaemia (nadir pO(2) 5.8 +/- 0.5 kPa), and (iii) normoglycaemic normoxia (control day). QT parameters were registered by Holter monitoring. Hypoglycaemia and hypoxaemia induced QTc prolongation (P < 0.001, both stimuli). The QT/RR slope and the VR increased as a function of hypoglycaemia, but were unaffected by hypoxaemia. Low RAS activity was associated with a steeper QT/RR slope in the recovery phase after both stimuli: hypoglycaemia: P = 0.04; hypoxia: P = 0.03. RAS activity had no impact on QTc [P = 0.48 (hypoglycaemia) and P = 0.40 (hypoxaemia)] or any of the other outcome variables. CONCLUSION: Basal RAS activity has significant impact on QT dynamics, but not the corrected QT interval, during recovery from hypoglycaemia and hypoxaemia. The impact, however, is modest and more subtle than initially expected. The clinical relevance is unclear.

Abstract: Calculation of approximate entropy (ApEn) requires a priori determination of two unknown parameters, m and r. While the recommended values of r, in the range of 0.1-0.2 times the standard deviation of the signal, have been shown to be applicable for a wide variety of signals, in certain cases, r values within this prescribed range can lead to an incorrect assessment of the complexity of a given signal. To circumvent this limitation, we recently advocated finding the maximum ApEn value by assessing all values of r from 0 to 1, and found that maximum ApEn does not always occur within the prescribed range of r values. Our results indicate that finding the maximum ApEn leads to the correct interpretation of a signal's complexity. One major limitation, however, is that the calculation of all choices of r values is often impractical due to the computational burden. Our new method, based on a heuristic stochastic model, overcomes this computational burden, and leads to the automatic selection of the maximum ApEn value for any given signal. Based on Monte Carlo simulations, we derive general equations that can be used to estimate the maximum ApEn with high accuracy for a given value of m. Application to both synthetic and experimental data confirmed the advantages claimed with the proposed approach.

Abstract: T-wave morphology descriptors are sensitive to drug-induced changes and may be a useful addition to the QT interval in cardiac safety trials. Intrasubject heart rate dependence of T-wave morphology was investigated in a sample of 39 healthy individuals. Ten-second electrocardiograms were obtained from daytime Holter recordings. Duration parameters (QT, ToTe, TpTe, and others), a number of basic T-wave morphology parameters (amplitude, area, and others) as well as advanced morphology descriptors (asymmetry, flatness, and others) were measured automatically. Heart rate dependence was examined by means of analysis of covariance. The results showed clear heart rate dependence for the QT interval (R(2) = 0.53-0.57) and a moderate degree of heart rate dependence for the basic morphology parameters (amplitude, area, and others) (R(2) = 0.17-0.42). Both the advanced T-wave descriptors (asymmetry, flatness, and others), ToTe intervals and TpTe intervals, were practically independent of heart rate (R(2) = 0-0.08), making heart rate correction unnecessary for these parameters.

Abstract: INTRODUCTION: The Brugada Syndrome (BrS), an inherited syndrome associated with a high incidence of sudden cardiac arrest, has been linked to mutations in four different genes leading to a loss of function in sodium and calcium channel activity. Although the transient outward current (I(to)) is thought to play a prominent role in the expression of the syndrome, mutations in I(to)-related genes have not been identified as yet. METHODS AND RESULTS: One hundred and five probands with BrS were screened for ion channel gene mutations using single strand conformation polymorphism (SSCP) electrophoresis and direct sequencing. A missense mutation (R99H) in KCNE3 (MiRP2) was detected in one proband. The R99H mutation was found 4/4 phenotype positive and 0/3 phenotype-negative family members. Chinese hamster ovary (CHO)-K1 cells were co-transfected using wild-type (WT) or mutant KCNE3 and either WT KCND3 or KCNQ1. Whole-cell patch clamp studies were performed after 48 hours. Interactions between Kv4.3 and KCNE3 were analyzed in co-immunoprecipitation experiments in human atrial samples. Co-transfection of R99H-KCNE3 with KCNQ1 produced no alteration in current magnitude or kinetics. However, co-transfection of R99H KCNE3 with KCND3 resulted in a significant increase in the I(to) intensity compared to WT KCNE3+KCND3. Using tissues isolated from left atrial appendages of human hearts, we also demonstrate that K(v)4.3 and KCNE3 can be co-immunoprecipitated. CONCLUSIONS: These results provide definitive evidence for a functional role of KCNE3 in the modulation of I(to) in the human heart and suggest that mutations in KCNE3 can underlie the development of BrS.

Abstract: BACKGROUND: The T(peak)T(end) (T(p)T(e)) interval is believed to reflect the transmural dispersion of repolarization. Accordingly, it should be a risk factor in long QT syndrome (LQTS). The aim of the study was to determine the effect of genotype on T(p)T(e) interval and test whether it was related to the occurrence of syncope. METHODS: Electrocardiograms were taken in 95 patients with LQTS drawn from the Danish long QT registry (44 patients with KvLQT1, 43 with HERG, and 8 with SCN5A mutations) and manually evaluated for the QT, QT(peak), and RR interval. RESULTS AND CONCLUSION: (1) T(p)T(e) cannot be used to distinguish symptomatic from asymptomatic patients with LQTS; (2) HERG patients have longer T(p)T(e) than KvLQT1 patients; and (3) there is no need to heart rate-correct T(p)T(e) intervals in patients with LQTS.

Abstract: Mutations in one of the ion channels shaping the cardiac action potential can lead to action potential prolongation. However, only in a minority of cardiac arrest cases mutations in the known arrhythmia-related genes can be identified. In two patients with arrhythmia and cardiac arrest, we identified the point mutations P91L and E33V in the KCNA5 gene encoding the Kv1.5 potassium channel that has not previously been associated with arrhythmia. We functionally characterized the mutations in HEK293 cells. The mutated channels behaved similarly to the wild-type with respect to biophysical characteristics and drug sensitivity. Both patients also carried a D85N polymorphism in KCNE1, which was neither found to influence the Kv1.5 nor the Kv7.1 channel activity. We conclude that although the two N-terminal Kv1.5 mutations did not show any apparent electrophysiological phenotype, it is possible that they may influence other cellular mechanisms responsible for proper electrical behaviour of native cardiomyocytes.

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Abstract: Patients with untreated heart failure (HF) exhibit a blunted hemodynamic and neuroendocrine response to a high sodium intake, leading to excessive sodium and water retention. However, it is not known whether this is the case for patients with compensated HF receiving angiotensin-converting enzyme inhibitors and beta-adrenoreceptor blockers. Therefore, we determined the hemodynamic and neuroendocrine responses to 1 wk of a low-sodium diet (70 mmol/day) and 1 wk of a high-sodium diet (250 mmol/day) in 12 HF patients and 12 age-matched controls in a randomized, balanced fashion. During steady-state conditions, hemodynamic and neuroendocrine examinations were performed at rest and during bicycle exercise. In seated HF patients, high sodium intake increased body weight (1.6 +/- 0.4%), plasma volume (9 +/- 2%), cardiac index (14 +/- 6%), and stroke volume index (21 +/- 5%), whereas mean arterial pressure was unchanged. Therefore, the total peripheral resistance decreased by 10 +/- 4%. Similar hemodynamic changes were observed during an incremental bicycle exercise test. Plasma concentrations of angiotensin II and norepinephrine were suppressed, whereas plasma pro-B-type natriuretic peptide remained unchanged. In conclusion, high sodium intake was tolerated without any excessive sodium and water retention in medically treated patients with compensated HF. The observation that high sodium intake improves cardiac performance, induces peripheral vasodilatation, and suppresses the release of vasoconstrictor hormones does not support the advice for HF patients to restrict dietary sodium.

Abstract: We present a new, simple, and fast computational technique, termed the incremental slope (IS), that can accurately distinguish between deterministic from stochastic systems even when the variance of noise is as large or greater than the signal, and remains robust for time-varying signals. The IS method is more accurate than the widely utilized Poincare plot analysis especially when the data are severely contaminated by noise. The efficacy of the IS is demonstrated with several simulated deterministic and stochastic signals.

Abstract: Mutations in the SCN5A gene coding for the alpha-subunit of the cardiac Na(+) ion channel cause long QT syndrome, Brugada syndrome, idiopathic ventricular fibrillation, sick sinus node syndrome, progressive conduction disease, dilated cardiomyopathy and atrial standstill. These diseases exhibit variable expressivity, and identification of gene carriers is clinically important, particularly in sudden infant and adult death syndromes. The SCN5A gene comprises 28 exons distributed over 100 kbp of genomic sequence at chromosome 3p21. Disease-causing mutations are private and scattered over the DNA sequence, making it difficult to screen for specific mutations. We developed a multiplex capillary-electrophoresis single-strand conformation polymorphism (Multi-CE-SSCP) mutation screening protocol on the ABI 3100 platform and applied it to 10 previously slab-gel SSCP identified mutations and SNPs and used it to identify one novel deletion. The method is highly efficient, with a turnover of 23 patients per 24 h and a false positive rate of 0.5% of the analyzed amplicons. Each variant has a particular elution pattern, and all 20 carriers of the H558R polymorphism out of 57 persons were correctly identified. We suggest that the method could become part of routine work-up of patients with suspicious syncope and of members of families with sudden unexplained death.

Abstract: BACKGROUND: QT dynamics parameters are used only in sinus rhythm. However, because many patients with paroxysmal atrial fibrillation undergo antiarrhythmic treatment that changes QT, developing methods for measuring QT dynamics during atrial fibrillation is important. OBJECTIVES: The purpose of this study was to evaluate whether QT dynamics in atrial fibrillation can be measured more reliably if additional RR intervals are included in the QT calculation. METHODS: QT and RR intervals were measured in 15 patients with atrial fibrillation and sinus rhythm on the same 24-hour Holter recording. Full QT adaptation is not instantaneous but lags behind over several beats. To correct for this lag, we adapted a weighted average method using five successive RR intervals. Linear regression was performed on (QT, RR) and (QT, RR(modified)) pairs. Variability ratio (standard deviation of all QT intervals/standard deviation of all RR intervals) and modified variability ratio (standard deviation of all QT intervals/modified standard deviation of all RR intervals) were calculated. RESULTS: QT-RR slope was reduced in atrial fibrillation compared with sinus rhythm (0.076 +/- 0.009 vs 0.113 +/- 0.0013, P = .0005). When correcting for lag, using the QT-RR(modified) slope, the slope in atrial fibrillation became similar to the slope in sinus rhythm (0.126 +/- 0.013 vs 0.126 +/- 0.013, P = .9547). The variability ratio was reduced in atrial fibrillation compared with sinus rhythm (0.175 +/- 0.017 vs 0.240 +/- 0.031, P = .009), but when correcting for the lag, the modified variability ratio was similar in atrial fibrillation and sinus rhythm (0.262 +/- 0.029 vs 0.267 +/- 0.038, P = .80). CONCLUSION: The results of this study demonstrate that QT dynamics can be measured reliably in atrial fibrillation using 24-hour Holter recordings.

Abstract: The long QT syndrome (LQTS) is a genetic disorder, typically characterized by a prolonged QT interval in the ECG due to abnormal cardiac repolarization. LQTS may lead to syncopal episodes and sudden cardiac death. Various parameters based on T-wave morphology, as well as the QT interval itself have been shown to be useful discriminators, but no single ECG parameter has been sufficient to solve the diagnostic problem. In this study we present a method for discrimination among persons with a normal genotype and those with mutations in the KCNQ1 (KvLQT1 or LQT1) and KCNH2 (HERG or LQT2) genes on the basis of parameters describing T-wave morphology in terms of duration, asymmetry, flatness and amplitude. Discriminant analyses based on 4 or 5 parameters both resulted in perfect discrimination in a learning set of 36 subjects. In both cases cross-validation of the resulting classifiers showed no misclassifications either.

Abstract: Diagnosis of long QT syndrome (LQTS) is difficult. A prolonged QT interval is easily overlooked, and in 10% of all patients with LQTS, the QT interval is normal. Genotyping is unfortunately not able to detect all patients and healthy subjects correctly. Although QT prolongation is the most used risk parameter, there is no clear correlation between the prolonged QT interval and the risk of arrhythmias in drug-induced LQTS. Quantification of T-wave morphology is a promising method that is able to provide more information about repolarization than QT prolongation alone. It is a fact that ECG evaluation can serve as a guide for genotyping and can reduce the costs by suggesting which gene to start sequencing, but it is fiction that the ECG can replace genotyping.

Abstract:

Abstract: OBJECTIVE: Previous studies have indicated moderate-to-poor reproducibility of heart rate variability (HRV) but the reproducibility of blood pressure variability (BPV) and spectral measures of baroreceptor sensitivity (BRS) are not well established. METHODS: We measured normal-to-normal heart beat (RR) interval and finger blood pressure (Finapres) in 14 healthy individuals on three different days. The protocol was 1 h of supine rest and 1 h of 60-degree head-up tilt. Time-series of consecutive 300-s segments as well as 1024-s segments of RR intervals and systolic, diastolic and mean blood pressures were extracted for the assessment of day-to-day and short-term reproducibility. Power spectrum analysis (Fourier) and transfer function analysis was performed. Reproducibility was assessed using the coefficient of variation (CV). The reproducibility of the mean RR interval, mean systolic, diastolic and mean blood pressure was good (CV<10 %). However, there was only moderate-to-poor reproducibility of the spectral parameters of HRV (CV range 18-36%) and BPV (16-44%) and moderate reproducibility of BRS (14-20%). CONCLUSION: Spectral estimates of BRS had only moderate reproducibility although it was better than the spectral estimates of HRV and BPV.

Abstract: In a 7-week-old infant who experienced sudden infant death syndrome (SIDS), a novel missense mutation was identified in KCNH2, causing a lysine-to-glutamic acid amino acid substitution at position 101 (K101E). KCNH2 codes for the HERG ion channel and mutations in the gene are associated with congenital long-QT syndrome (LQTS), and in the family of this case of SIDS, the mutation was associated with Torsades de pointes tachycardia, making SIDS the most likely outcome of congenital LQTS.

Abstract: OBJECTIVES: The purpose of this study was to compare measures of repolarization dynamics (QT dynamics) with other Holter risk predictors, left ventricular systolic function, and demographic characteristics to establish whether QT dynamics add independent information on risk stratification after myocardial infarction (MI). A novel QT dynamics parameter, the QT/RR variability ratio (VR), was introduced in this study. BACKGROUND: Abnormal repolarization contributes to arrhythmogenesis, and quantification of QT dynamics may have prognostic value after MI. METHODS: A 24-hour Holter recording was performed in 481 consecutive MI patients. Recordings from 311 patients were included in the analysis. QT/RR slope and intercept, mean and standard deviation of all QT, QTc, and RR intervals, and VR (defined as the ratio between the standard deviation of all QT intervals and the standard deviation of all RR interval) were calculated. Ventricular premature beats and ventricular tachycardia were counted. RESULTS: During 3-year follow-up, 70 deaths from all causes occurred. All parameters except mean of all QT intervals and standard deviation of all QTc intervals univariately predicted all-cause mortality. In multivariate Cox analysis, only VR per 0.1 (hazard ratio [HR]: 1.9 [1.5-2.4]), left ventricular ejection fraction per 5% (HR: 1.2 [1.1-1.3]), ventricular premature beats per 10 beats/hour (HR: 1.03 [1.002-1.06]), and age per 10 years (HR: 1.6 [1.3-2.0]) independently predicted all-cause mortality. CONCLUSIONS: Measures of QT dynamics univariately predicted total mortality. VR, left ventricular ejection fraction, ventricular premature beats, and age made up the optimal Cox model for risk stratification after MI. VR seems to be a promising risk factor for identifying sudden arrhythmic death.

Abstract: BACKGROUND: Ventricular extrasystoles are characterized by a fixed coupling interval to the last QRST complex preceding it. OBJECTIVES: We hypothesized that this QRST complex differed from QRST complexes of other sinus beats not followed by ventricular extrasystoles. Further, we investigated whether phase 2 reentry, demonstrated in animal experiments to initiate ventricular extrasystoles, ventricular tachycardia, and ventricular fibrillation, also plays a role in humans. METHODS: We examined 18 patients with ventricular extrasystoles and/or ventricular tachycardia by signal averaging of the ECG (group A) or by single-beat analysis of intracardiac electrograms (group B). Group A consisted of six patients without structural heart disease and one patient with the Brugada syndrome. Six of the seven patients had right ventricular outflow tract ventricular extrasystoles. Group B consisted of 11 patients undergoing radiofrequency ablation. Eight of the 11 patients had right ventricular outflow tract extrasystoles. RESULTS: In six of the seven patients in group A, we demonstrated significant ST-elevation and/or T-wave changes in the sinus beat preceding ventricular extrasystoles compared with the second last sinus beat in one or more of the three orthogonal leads X, Y, and Z. In 9 of the 11 patients in group B, single-beat analysis of unipolar and bipolar electrograms recorded close to successful ablation sites demonstrated similar changes, that is, ST-elevation (median peak voltage gradient 150 muV, range 0-1,700) and T-wave changes in the sinus beat prior to ventricular ectopy. In addition, J-point elevation was demonstrated in several cases. In total, significant changes were demonstrated in 15 of the 18 patients studied (83%). CONCLUSION: J-point elevation, ST-elevation, and T-wave changes documented in the last sinus beat prior to ventricular extrasystoles are in agreement with phase 2 reentry, suggesting that this may be the responsible mechanism for ventricular extrasystoles and ventricular tachycardia/fibrillation. The phenomenon has been demonstrated in only animal experiments to date.

Abstract: OBJECTIVES: The aim of this study was to develop an objective method to distinguish between HERG and KvLQT1 genotypes on the surface ECG. BACKGROUND: The two most prevalent genes affected in long QT syndrome (LQTS) are KvLQT1 (KCNQ1) and HERG (KCNH2), which are mutated in >90% of patients with a reported LQTS genotype. It is known that T waves have lower amplitude and more notches in HERG patients than T waves in KvLQT1 patients, but this semiquantitative method lacks the discriminative power to be used in a clinical setting. We developed a simple mathematical method that allowed us to quantify T wave shape in LQTS mutations for clinical use. METHODS: ECGs from 24 HERG patients, 13 KvLQT1 LQTS patients, and 13 healthy relatives were examined. The repolarizing integral (RI) was constructed from the T wave. The resulting RI is sigmoid and was modeled using the Hill equation as (RI(t) = V(max)*[t(n)/[K(m)(n) + t(n)]]). V(max) is equivalent to the total T wave area, K(m) is the time when 50% of the T wave area is reached, and n is a measure of the slope of the sigmoid RI. RESULTS: The RI correlated nearly perfectly to the fitted sigmoid, r = 0.99. In lead V(2), V(max) was larger in KvLQT1 (0.148 +/- 0.021) (mean +/- SE) compared to HERG (0.080 +/- 0.012) and controls (0.067 +/- 0.021). The Hill coefficient n of the RI discriminated perfectly between HERG (2.00 +/- 0.11) and KvLQT1 (4.11 +/- 0.15). CONCLUSIONS: RI allows distinguishing between HERG and KvLQT1 mutations based solely on the T wave morphology in the present LQTS population.

Abstract: BACKGROUND: Long QT syndrome [LQTS] is a congenital cardiac disease characterised by prolonged QTC-time, syncopes and sudden cardiac death. LQTS is caused by mutations in genes coding for ion channels involved in the action potential. KCNE5 codes for a novel beta-subunit of the ion channel conducting the delayed rectifier repolarizing current IKs. As KCNE5 is expressed in the human heart and suppresses the IKs current in heterologous systems, it is a candidate gene that may be mutated in LQTS families where no causative mutations in known LQTS associated genes have been found. We examined whether this was the case. METHODS: Genomic DNA from LQTS patients [n=88] and normal controls [n=90] was screened for mutations in KCNE5 by endonuclease-enhanced single strand conformation polymorphism analysis [EE-SSCP], and DNA sequencing of aberrant conformers. Mutations in other LQTS associated ion channels were excluded by SSCP. RESULTS: No mutations were found in the coding region of the KCNE5 gene in LQTS patients. One polymorphism, a T-to-C transition at nucleotide 97, causing an amino acid polymorphism P33S, was present in 16 persons, nine heterozygotes and seven homozygotes. The T-allele frequency was 0.13 in LQTS patients and 0.10 in controls.

Abstract: BACKGROUND: Measures of QT dynamics express repolarization abnormalities that carry prognostic information, but the reproducibility of beat-to-beat QT dynamics has never been established. The QT interval is prolonged at night, but how the circadian rhythm and heart rate influence the dynamic QT measurements is still unsettled. The aims of the present study were: (1) to describe the reproducibility of beat-to-beat QT dynamics with respect to intrasubject, between-subject, and between-observer variability and (2) to describe the normal range, circadian variation, and heart rate dependence of QT dynamics. METHODS: Ambulatory Holter recordings were performed three times on 20 healthy volunteers and were analyzed by two experienced cardiologists. Slope and intercept of the QT/RR regression, the variability of QT and R-R intervals expressed as the standard deviation, and the relation between QT and RR variability expressed as a variability ratio were measured among other QT dynamics. RESULTS: The reproducibility of all QT dynamics was good. All QT dynamics showed circadian variation when calculated on an hourly basis. The day/night variation in slope could be explained by the differences in heart rate, whereas the day/night variation in intercept was heart rate independent. CONCLUSION: The present study shows that reliable automatic QT measurements could be performed, encouraging further evaluation of the clinical value of QT dynamics in risk stratification of cardiac patients.

Abstract: INTRODUCTION: The aim of this study was to evaluate and compare heart rate and heart rate variability (HRV) in risk prediction after acute myocardial infarction (MI) and to evaluate the effect of beta-blocker treatment on the prognostic performance of heart rate and HRV. METHODS AND RESULTS: Three hundred sixty-six patients underwent 24-hour Holter recording 1 to 6 days after an MI. HRV was expressed as the standard deviation of all normal-to-normal intervals. Left ventricular systolic function was evaluated using the wall motion index. Half of the patients were taking a beta-blocker at the time of Holter recording. Mean follow-up was 44 months (median 34) after MI. By the end of follow-up, 82 patients had died. Mortality at 1 and 3 years was 12.5% and 22.6%, respectively. HRV, heart rate, wall motion index, number of ventricular premature beats per hour, and ventricular tachycardia were all significantly (P < 0.05) associated with mortality in univariate analysis, independent of beta-blocker therapy. In multivariate Cox analysis, only heart rate, wall motion index, number of ventricular premature beats per hour, and age had independent prognostic value (P < 0.001). In any model, including heart rate, HRV had no predictive value. CONCLUSION: The prognostic information of HRV is contained completely in heart rate, which carries prognostic information further than that of HRV. This result was independent of beta-blocker treatment.

Abstract: AIMS: Syncope in long QT syndrome (LQTS) is expected to be due to Torsades de Pointes ventricular tachycardia (TdP). Often these patients faint in situations with emotional stress. The aim of the present study was to evaluate whether neurocardiogenic syncope occurs in LQTS. METHODS AND RESULTS: Ten untreated consecutive LQTS patients (age 11-72 years, median 37.5 years, five males and five females from five different families (one KvLQT1 mutation, two HERG mutations in three families and one without established genetic background)) were examined by a head-up tilt-table test (HUT). If syncope did not occur within 25 min, the patient received 0.25 mg nitroglycerine sublingually and the HUT was continued for 20 min. Nine out of 10 patients had a positive HUT. The syncope resulted from a combined vasodepressor and bradycardiac response. There were no cases of TdP. No syncope occurred in a 42-year-old asymptomatic male LQTS patient with a borderline prolonged QTc of 0.45 s and a HERG mutation. In 11 of 21 patients referred for syncope without LQTS a positive HUT was found (P < 0.10). CONCLUSION: Syncope in LQTS can be of neurocardiogenic origin and is not necessarily due to TdP. The reason for neurocardiogenic syncope in LQTS is unknown, but involvement of the autonomic nervous system outside the heart is possible.

Abstract: Current methods for detecting nonlinear determinism in a time series require long and stationary data records, as most of them assume that the observed dynamics arise only from the internal, deterministic workings of the system, and the stochastic portion of the signal (the noise component) is assumed to be negligible. To explicitly account for the stochastic portion of the data we recently developed a method based on a stochastic nonlinear autoregressive (SNAR) algorithm. The method iteratively estimates nonlinear autoregressive models for both the deterministic and stochastic portions of the signal. Subsequently, the Lyapunov exponents (LE) are calculated for the estimated models in order to examine if nonlinear determinism is present in the deterministic portion of the fitted model. To determine if nonlinear dynamic analysis of heart-rate fluctuations can be used to assess arrhythmia susceptibility by predicting the outcome of invasive cardiac electrophysiologic study (EPS), we applied the SNAR algorithm to noninvasively measured resting sinus-rhythm heart-rate signals obtained from 16 patients. Our analysis revealed that a positive LE was highly correlated to a patient with a positive outcome of EPS. We found that the statistical accuracy of the SNAR algorithm in predicting the outcome of EPS was 88% (sensitivity=100%, specificity=75%, positive predictive value=80%, negative predictive value=100%, p=0.0019). Our results suggest that the SNAR algorithm may serve as a noninvasive probe for screening high-risk populations for malignant cardiac arrhythmias.

Abstract: BACKGROUND: The voltage-gated, rapid-delayed rectifier current (I(Kr)) is important for repolarization of the heart, and mutations in the genes coding for the K+-ion channel conducting this current, i.e., KCNH2 for the alpha-subunit HERG and KCNE2 for the beta-subunit MiRP1, cause acquired and congenital long Q-T syndrome (LQTS) and other cardiac arrhythmias. METHODS: We developed a robust single-strand conformation polymorphism-heteroduplex screening analysis, with identical thermocycling conditions for all PCR reactions, covering all of the coding exons in KCNH2 and KCNE2. The method was used to screen 40 unrelated LQTS patients. RESULTS: Eleven mutations, of which six were novel, were found in KCNH2. Interestingly, six mutations were found in the region of the gene coding for the Per-Arnt-Sim (PAS) and PAS-S1 regions of the HERG protein, stressing the need to examine the entire gene when screening for mutations. No mutations were found in KCNE2, suggesting that direct involvement of MiRP1 in LQTS is rare. Furthermore, four novel single-nucleotide polymorphisms (SNPs) and one amino acid polymorphism (R1047L) were identified in KCNH2, and one novel SNP and one previously known amino acid polymorphism (T8A) were found in KCNE2. CONCLUSIONS: The potential role of rare polymorphisms in the HERG/MiRP1 K+-channel should be clarified with respect to drug interactions and susceptibility to arrhythmia and sudden death.

Abstract: Molecular genetic studies in congenital long QT syndrome have characterized genes and mechanisms of arrhythmias. At least six genes encoding cardiac potassium and sodium ionic channels have been described with several mutations in each gene. The altered function produces abnormal cardiac repolarization seen on ECG as prolongation of the QT-interval and T-wave abnormalities. This may increase the propensity for ventricular arrhythmias such as Torsade de Pointe, the cause of unexpected syncope and sudden death in young patients. Clinical manifestations vary depending on the genotype present. Gene-specific therapies have recently been tried. Initial therapy of choice for symptomatic and also asymptomatic children is administration of beta-blockers.

Abstract: In a four-generation family with long QT syndrome, syncopes and torsades de pointes ventricular tachycardia (TdP) were elicited by abrupt awakening in the early morning hours. The syndrome was associated with a novel KCNH2 missense mutation, G572R, causing the substitution of a glycine residue at position 572, at the end of the S5 transmembrane segment of the HERG K(+)-channel, with an arginine residue. This segment is involved in the channel pore and the mutation may cause a reduction in the rapidly activating delayed rectifier K+ current (Ikr), or changed gating properties of the ion channel, leading to prolonged cardiac repolarization. The electrocardiograms of affected persons showed prolonged QT interval and notched T waves. Despite treatment with atenolol, 200 mg twice daily, the proband still experienced TdP episodes. Three untreated relatives of the proband died suddenly, and unexpectedly, at 18, 32, and 57 years of age. The G572R mutation is thus associated with a high mortality rate, and the clinical presentation illustrates that some mutations may not be controllable by just beta-blockade.

Abstract: We describe a Swedish family with the proband and his brother suffering from severe Romano-Ward syndome (RWS) associated with compound heterozygosity for two mutations in the KVLQT1 (also known as KCNQ1 and KCNA9) gene (R518X and A525T). The mutations were found to segregate as heterozygotes in the maternal and the paternal lineage, respectively. None of the heterozygotes exhibited clinical long QT syndrome (LQTS). No hearing defects were found in the proband. The data strongly indicates that the compound heterozygosity for R518X and A525T is the cause of an autosomal recessive form of RWS in this family. Our findings support the implication of a higher frequency of gene carriers than previously expected. We suggest that relatives of 'sporadic RWS' patients should be considered potential carriers, at risk of dying suddenly from drug-induced LQTS.

Abstract: Congenital long QT syndrome (LQTS) is characterised by prolongation of the QT interval on ECG and cardiac arrhythmias, syncopes and sudden death. A rapid and reliable genetic diagnosis of the disease may be of great importance for diagnosis and treatment of LQTS. Mutations in the KVLQT1 gene, encoding a potassium-channel subunit of importance for the depolarisation of cardiac myocytes, is believed to be associated with 50% of all LQTS cases. Our data confirms that KvLQT1 isoform 1 is encoded by 16 exons, and not 15, as reported previously. We have used genomic DNA sequences to design intronic PCR primers for amplification of 15 exons of KVLQT1 and optimised a non-radioactive single stranded conformation polymorphism/heteroduplex (SSCP/HD) method for detection of mutations in KVLQT1. The sensitivity of the method was 100% when it was tested on 15 in vitro constructed mutants. By multiplexing the PCR amplification of KVLQT1, it is possible to cover all 15 exons in four PCR reactions.

Abstract: INTRODUCTION: Inherited long QT syndrome (LQTS) recently has been associated with mutations in genes coding for potassium (KVLQT1, KCNE1, and HERG) or sodium (SCN5A) ion channels involved in regulating either sodium inward or potassium outward currents of heart cells, resulting in prolongation of the repolarization period. We describe a new mutation, a -1 donor splice site mutation in a kindred with two affected members (QTc = 0.61 and 0.54 sec). METHODS AND RESULTS: Single stranded conformation polymorphism (SSCP) analyses were performed on DNA fragments amplified by polymerase chain reaction from DNA extracted from whole blood. Aberrant conformers were analyzed by DNA sequencing. SSCP analysis of the KVLQT1 gene revealed an aberrant conformer in the affected family members. DNA sequencing confirmed the presence of a G-->A change in the last nucleotide of codon 344. This mutation does not cause an amino acid change, but a change of the splice site characteristics at the 3' end of exon 6. The mutation may affect, through deficient splicing, the putative sixth transmembrane segment of the K+ channel, and this type of mutation has not previously been described in KVLQT1. CONCLUSION: The clinical course of LQTS in the affected family members, in whom no deaths occurred despite 20 to 30 syncopes, can be explained by the ability of the cellular machinery to perform partial correct splicing in the mutant allele. This type of mutation may be misinterpreted as a normal variant, since it is a point mutation causing neither an amino acid change nor the introduction of a stop codon.

Abstract: The contribution of nonlinear dynamics to heart rate variability in healthy humans was examined using surrogate data analysis. Several measures of heart rate variability were used and compared. Heart rates were recorded for three hours and original data sets of 8192 R-R intervals created. For each original data set (n = 34), three surrogate data sets were made by shuffling the order of the R-R intervals while retaining their linear correlations. The difference in heart rate variability between the original and surrogate data sets reflects the amount of nonlinear structure in the original data set. Heart rate variability was analyzed by two different nonlinear methods, point correlation dimension and approximate entropy. Nonlinearity, though under 10 percent, could be detected with both types of heart rate variability measures. More importantly, not only were the correlations between these measures and the standard deviation of the R-R intervals weak, the correlation among the nonlinear measures themselves was also weak (generally less than 0.6). This suggests that in addition to standard linear measures of heart rate variability, the use of multiple nonlinear measures of heart rate variability might be useful in monitoring heart rate dynamics.

Abstract: Frequency domain analysis of heart rate variability (HRV) has been proposed as a semiquantitative method for assessing activities in the autonomic nervous system. We examined whether absolute powers, normalized powers, and the low frequency-to-high frequency ratio (LF/HF) derived from the HRV power spectrum could detect shifts in autonomic balance in a setting with low sympathetic nervous tone. Healthy subjects were examined for 3 h in the supine position during 1) control conditions (n = 12), 2) acute beta-blockade (n = 11), and 3) chronic beta-blockade (n = 10). Heart rate fell during the first 40 min of the control session (72 +/- 2 to 64 +/- 2 beats/min; P < 0. 005) and was even lower during acute and chronic beta-blockade (56 +/- 2 beats/min; P < 0.005). The powers of all spectral areas rose during the first 60 min in all three settings, more so with beta-blockade (P < 0.05). LF/HF was found to contain the same information as powers expressed in normalized units. LF/HF detected the shift in autonomic balance induced by beta-blockade but not the change induced by supine position. In conclusion, none of the investigated measures derived from power spectral analysis comprehensively and consistently described the changes in autonomic balance.

Abstract: Time series from biological system often displays fluctuations in the measured variables. Much effort has been directed at determining whether this variability reflects deterministic chaos, or whether it is merely "noise". The output from most biological systems is probably the result of both the internal dynamics of the systems, and the input to the system from the surroundings. This implies that the system should be viewed as a mixed system with both stochastic and deterministic components. We present a method that appears to be useful in deciding whether determinism is present in a time series, and if this determinism has chaotic attributes. The method relies on fitting a nonlinear autoregressive model to the time series followed by an estimation of the characteristic exponents of the model over the observed probability distribution of states for the system. The method is tested by computer simulations, and applied to heart rate variability data.

Abstract: Although it is doubtful whether the normal sinus rhythm can be described as low-dimensional chaos, there is evidence for inherent nonlinear dynamics and determinism in time series of consecutive R-R intervals. However, the physiological origin for these nonlinearities is unknown. The aim of this study was to test whether the known nonlinear input from spontaneous respiration is a source for the nonlinearities in heart rate variability. Twelve healthy subjects were examined in supine position with 3-h electrocardiogram recordings during both spontaneous and forced respiration in accordance with a metronome set to 12 min(-1). Nonlinear dynamics were measured as the correlation dimension and the nonlinear prediction error. Complexity expressed as correlation dimension was unchanged from normal respiration, 9.1 +/- 0.5, compared with forced respiration, 9.3 +/- 0.6. Also, nonlinear determinism expressed as the nonlinear prediction error did not differ between spontaneous respiration, 32.3 +/- 3.4 ms, and forced respiration, 31.9 +/- 5.7. It is concluded that the origin of the nonlinear dynamics in heart rate variability is not a nonlinear input from the respiration into the cardiovascular oscillator. Additional studies are needed to elucidate the mechanisms behind the nonlinear dynamics in heart rate variability.

Abstract: Time series from biological system often display fluctuations in the measured variables. Much effort has been directed at determining whether this variability reflects deterministic chaos, or whether it is merely "noise". Despite this effort, it has been difficult to establish the presence of chaos in time series from biological sytems. The output from a biological system is probably the result of both its internal dynamics, and the input to the system from the surroundings. This implies that the system should be viewed as a mixed system with both stochastic and deterministic components. We present a method that appears to be useful in deciding whether determinism is present in a time series, and if this determinism has chaotic attributes, i.e., a positive characteristic exponent that leads to sensitivity to initial conditions. The method relies on fitting a nonlinear autoregressive model to the time series followed by an estimation of the characteristic exponents of the model over the observed probability distribution of states for the system. The method is tested by computer simulations, and applied to heart rate variability data.

Abstract: OBJECTIVES: The purpose of the study was to investigate the short- and long-term variations in the non-linear dynamics of heart rate variability, and to determine the relationships between conventional time and frequency domain methods and the newer non-linear methods of characterizing heart rate variability. METHODS: Twelve healthy subjects were investigated by 3-h ambulatory ECG recordings repeated on 3 separate days. Correlation dimension, non-linear predictability, mean heart rate, and heart rate variability in the time and frequency domains were measured and compared with the results from corresponding surrogate time series. RESULTS: A small significant amount of non-linear dynamics exists in heart rate variability. Correlation dimensions and non-linear predictability are relatively specific parameters for each individual examined. The correlation dimension is inversely correlated to the heart rate and describes mainly linear correlations. Non-linear predictability is correlated with heart rate variability measured as the standard deviation of the R-R intervals and the respiratory activity expressed as power of the high-frequency band. The dynamics of heart rate variability changes suddenly even during resting, supine conditions. The abrupt changes are highly reproducible within the individual subjects. CONCLUSIONS: The study confirms that the correlation dimension of the R-R intervals is mostly due to linear correlations in the R-R intervals. A small but significant part is due to non-linear correlations between the R-R intervals. The different measures of heart rate variability (correlation dimension, average prediction error, and the standard deviation of the R-R intervals) characterize different properties of the signal, and are therefore not redundant measures. Heart rate variability cannot be described as a single chaotic system. Instead heart rate variability consists of intertwined periods with different non-linear dynamics. It is hypothesized that the heart rate is governed by a system with multiple "strange" attractors.

Abstract: INTRODUCTION: The term chaos is used to describe erratic or apparently random time-dependent behavior in deterministic systems. It has been suggested that the variability observed in the normal heart rate may be due to chaos, but this question has not been settled. METHODS AND RESULTS: Heart rate variability was assessed by recordings of consecutive RR intervals in ten healthy subjects using ambulatory ECG. All recordings were performed with the subjects at rest in the supine position. To test for the presence of nonlinearities and/or chaotic dynamics, ten surrogate time series were constructed from each experimental dataset. The surrogate data were tailored to have the same linear dynamics and the same amplitude distribution as the original data. Experimental and surrogate data were then compared using various nonlinear measures. Power spectral analysis of the RR intervals showed a 1/f pattern. The correlation dimension differed only slightly between the experimental and the surrogate data, indicating that linear correlations, and not a "strange" attractor, are the major determinants of the calculated correlation dimension. A test for nonlinear predictability showed coherent nonlinear dynamic structure in the experimental data, but the prediction error as a function of the prediction length increased at a slower rate than characteristic of a low-dimensional chaotic system. CONCLUSION: There is no evidence for low-dimensional chaos in the time series of RR intervals from healthy human subjects. However, nonlinear determinism is present in the data, and various mechanisms that could generate such determinism are discussed.

Abstract: The effects of water deprivation on the urinary excretion rate of prostaglandin E2 (PGE2) were examined in conscious Brattleboro rats. In order to study the time course of the changes in the PGE2 excretory rate, urine was collected in 6 periods, Control: 0-1 hour (h.). 1: 3-4.5 h., 8-10 h., III: 12-15 h., IV: 24-28 h. and V: 32-36 h. after removal of water and food. It was found that the PGE2 excretion rate changed in a biphasic pattern. During the first 2 experimental periods it increased. Thereafter it decreased towards the control value. There was an increase in PGE2 excretion with urinary flows down to 3 microliter/(min*100 g b. wt). At further reductions in urinary flow rate, PG excretion decreased towards basal levels.

Abstract: Since hypertension is associated with changes in the handling of various cations (including sodium and lithium) across the cell membrane, the present study investigated the validity of the lithium clearance method in hypertension by comparing two measures of proximal reabsorption. Thus, fractional lithium excretion and transit time (TT)-occlusion time (OT; e-TT/T) were determined successively in the same spontaneously hypertensive rat (SHR, Okamoto strain). The rats were examined both before and after an acute saline load. The results show that the lithium clearance method can be used for the determination of proximal reabsorption in SHR. Utilizing the lithium clearance method, the changes in renal sodium handling underlying the exaggerated natriuresis were investigated in unanaesthetized catheterized rats. It was found that the exaggerated natriuresis was associated with an increased output from the proximal tubule, whereas no difference in distal sodium handling could be detected between SHR and normotensive Wistar-Kyoto rats (WKY).