Chronic vagus nerve stimulation is associated with multi-year improvement in intrinsic heart rate recovery and left ventricular ejection fraction in ANTHEM-HF.

PURPOSE: Disturbed autonomic function is implicated in high mortality rates in heart failure patients. High-intensity vagus nerve stimulation therapy was shown to improve intrinsic heart rate recovery and left ventricular ejection fraction over a period of 1 year. Whether these beneficial effects are sustained across multiple years and are related to improved baroreceptor response was unknown. METHODS: All patients (n = 21) enrolled in the ANTHEM-HF clinical trial (NCT01823887, registered 4/3/2013) with 24 h ambulatory electrocardiograms at all time points and 54 normal subjects (PhysioNet database) were included. Intrinsic heart rate recovery, based on ~ 2000 spontaneous daily activity-induced heart rate acceleration/deceleration events per patient, was analyzed at screening and after 12, 24, and 36 months of chronic vagus nerve stimulation therapy (10 or 5 Hz, 250 µs pulse width, 18% duty cycle, maximum tolerable current amplitude). RESULTS: In response to chronic high-intensity vagus nerve stimulation (≥ 2.0 mA), intrinsic heart rate recovery (all time points, p < 0.0001), heart rate turbulence slope, an indicator of baroreceptor reflex gain (all, p ≤ 0.02), and left ventricular ejection fraction (all, p ≤ 0.04) were improved over screening at 12, 24, and 36 months. Intrinsic heart rate recovery and heart rate turbulence slope were inversely correlated at both screening (r = 0.67, p < 0.002) and 36 months (r = 0.78, p < 0.005). CONCLUSION: This non-randomized study provides evidence of an association between improvement in intrinsic heart rate recovery and left ventricular ejection fraction during high-intensity vagus nerve stimulation for a period of ≥ 3 years. Correlated favorable effects on heart rate turbulence slope implicate enhanced baroreceptor function in response to chronic, continuously cyclic vagus nerve stimulation as a physiologic mechanism.

Sudden death and its predictors in myocardial infarction survivors in an Indian population.

OBJECTIVE: This study was conducted to assess the incidence of sudden cardiac death (SCD) in post myocardial infarction patients and to determine the predictive value of various risk markers in identifying cardiac mortality and SCD. METHODS: Left ventricular function, arrhythmias on Holter and microvolt T wave alternans (MTWA) were assessed in patients with prior myocardial infarction and ejection fraction ≤ 40%. The primary outcome was a composite of cardiac death and resuscitated cardiac arrest during follow up. Secondary outcomes included total mortality and SCD. RESULTS: Fifty-eight patients were included in the study. Eight patients (15.5%) died during a mean follow-up of 22.3 ± 6.6 months. Seven of them (12.1%) had SCD. Among the various risk markers studied, left ventricular ejection fraction (LVEF) ≤ 30% (Hazard ratio 5.6, 95% CI 1.39 to 23) and non-sustained ventricular tachycardia (NSVT) in holter (5.7, 95% CI 1.14 to 29) were significantly associated with the primary outcome in multivariate analysis. Other measures, including QRS width, heart rate variability, heart rate turbulence and MTWA showed no association. CONCLUSIONS: Among patients with prior myocardial infarction and reduced left ventricular function, the rate of cardiac death was substantial, with most of these being sudden cardiac death. Both LVEF ≤30% and NSVT were associated with cardiac death whereas only LVEF predicted SCD. Other parameters did not appear useful for prediction of events in these patients. These findings have implications for decision making for the use of implantable cardioverter defibrillators for primary prevention in these patients.

Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial.

BACKGROUND: Protection from lethal ventricular arrhythmias leading to sudden cardiac death (SCD) is a crucial challenge after acute myocardial infarction (AMI). Cardiac sympathetic and parasympathetic activity can be noninvasively assessed using heart rate variability (HRV) and heart rate turbulence (HRT). The EMBODY trial was designed to determine whether the Sodium-glucose cotransporter 2 (SGLT2) inhibitor improves cardiac nerve activity. METHODS: This prospective, multicenter, randomized, double-blind, placebo-controlled trial included patients with AMI and type 2 diabetes mellitus (T2DM) in Japan; 105 patients were randomized (1:1) to receive once-daily 10-mg empagliflozin or placebo. The primary endpoints were changes in HRV, e.g., the standard deviation of all 5-min mean normal RR intervals (SDANN) and the low-frequency-to-high-frequency (LF/HF) ratio from baseline to 24 weeks. Secondary endpoints were changes in other sudden cardiac death (SCD) surrogate markers such as HRT. RESULTS: Overall, 96 patients were included (46, empagliflozin group; 50, placebo group). The changes in SDANN were + 11.6 and + 9.1 ms in the empagliflozin (P = 0.02) and placebo groups (P = 0.06), respectively. Change in LF/HF ratio was - 0.57 and - 0.17 in the empagliflozin (P = 0.01) and placebo groups (P = 0.43), respectively. Significant improvement was noted in HRT only in the empagliflozin group (P = 0.01). Whereas intergroup comparison on HRV and HRT showed no significant difference between the empagliflozin and placebo groups. Compared with the placebo group, the empagliflozin group showed significant decreases in body weight, systolic blood pressure, and uric acid. In the empagliflozin group, no adverse events were observed. CONCLUSIONS: This is the first randomized clinical data to evaluate the effect of empagliflozin on cardiac sympathetic and parasympathetic activity in patients with T2DM and AMI. Early SGLT2 inhibitor administration in AMI patients with T2DM might be effective in improving cardiac nerve activity without any adverse events. TRIAL REGISTRATION: The EMBODY trial was registered by the UMIN in November 2017 (ID: 000030158). UMIN000030158; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034442 .

Influence of disease severity and cardiac autonomic tone on ventricular repolarization and dispersion in electrocardiographic assessment of patients with systemic lupus erythematosus.

BACKGROUND: There are no data on the influence of disease severity and cardiac autonomic tone on ventricular repolarization and dispersion in 24-hour Holter monitoring in systemic lupus erythematosus (SLE). METHODS: Consecutive 92 SLE and 51 healthy subjects were studied. The standard 12-lead electrocardiography (ECG), Holter monitoring with heart rate turbulence (HRT) and QT, Tp-e and Tp-e/QT ratio assessment (including corrected values) were performed. Subjects with conditions causing repolarization abnormalities or insufficient number of beats suitable for QT evaluation were excluded (17 SLE and 8 controls). RESULTS: Finally, 75 SLE and 43 sex- and age-matched controls were included to the study. In SLE patients, the median disease severity score (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI)) was 3.0. The mean values of QTc, cTp-e and cTp-e/QTc were significantly higher in SLE patients than in controls. QTc ≥ 460 ms was observed in 18.7% of patients using standard ECG and in 58.7% using Holter monitoring. With Holter monitoring, patients with SLICC/ACR-DI >3.0 presented longer QTc than those with SLICC/ACR-DI ≤3.0 (418±15 vs. 409 ± 16, p = 0.04), while cTp-e and cTp-e/QTc values were similar. Patients with abnormal HRT presented longer cTp-e and higher cTp-e/QTc than those with normal HRT (92 ± 52 vs. 71 ± 16 ms, p = 0.04; 0.244 ± 0.126 vs. 0.187 ± 0.035, p = 0.03), while QTc values were similar. No differences in QT and Tp-e parameters were observed according to disease duration. CONCLUSION: In SLE patients, Holter monitoring revealed QTc prolongation more frequently than standard ECG. Longer QTc values were observed in patients with more advanced disease, while increased cTp-e and cTp-e/QTc were related to cardiac autonomic dysfunction expressed by abnormal HRT.

Autonomic dysfunction in cardiac amyloidosis assessed by heart rate variability and heart rate turbulence.

BACKGROUND: Cardiac amyloidosis (CA) is characterized by left ventricular hypertrophy (LVH) and autonomic nervous imbalance due to amyloid infiltration. However, autonomic dysfunction is often seen in heart failure (HF) with LVH from other etiologies. We aimed to characterize autonomic dysfunction in CA from other etiologies of LVH. METHODS: Fifty-five HF patients with LVH (35 males, mean age 65 ± 16 years) were enrolled. LVH was defined as left ventricular mass index measured by echocardiography >95 g/m2 in women and 115 g/m2 in men. The etiology was as follows: amyloid light chain (AL)-CA, n = 14; hypertrophic cardiomyopathy, n = 21; and aortic stenosis (AS), n = 20. With the patient in a clinically stable condition, heart rate variability (HRV) and heart rate turbulence (HRT), which reflect autonomic dysfunction, were measured using Holter monitoring and compared among the three groups. RESULTS: Brain natriuretic peptide levels, LVH severity, left ventricular ejection fraction, and tissue Doppler index E/e' did not differ among the three groups. However, severe abnormalities of HRV and HRT were obtained in AL-CA. In the ROC analysis to identify AL-CA in HF with LVH, the best cutoff value for standard deviation of all R-R intervals, standard deviation of the 5-min mean R-R intervals, turbulence onset, and turbulence slope were 68.5 ms (AUC: 0.865), 58.5 ms (AUC: 0.834), 0.25% (AUC: 0.813), and 1.00 ms/RR (AUC 0.736), respectively. CONCLUSION: Autonomic dysfunction is a hallmark of AL-CA, and its noninvasive assessment by Holter monitoring may be a useful tool for differential diagnosis of HF with LVH.

Repeating noninvasive risk stratification improves prediction of outcome in ICD patients.

BACKGROUND: Noninvasive risk stratification aims to detect abnormalities in the pathophysiological mechanisms underlying ventricular arrhythmias. We studied the predictive value of repeating risk stratification in patients with an implantable cardioverter-defibrillator (ICD). METHODS: The EUTrigTreat clinical study was a prospective multicenter trial including ischemic and nonischemic cardiomyopathies and arrhythmogenic heart disease. Left ventricular ejection fraction ≤40% (LVEF), premature ventricular complexes >400/24 hr (PVC), non-negative microvolt T-wave alternans (MTWA), and abnormal heart rate turbulence (HRT) were considered high risk. Tests were repeated within 12 months after inclusion. Adjusted Cox regression analysis was performed for mortality and appropriate ICD shocks. RESULTS: In total, 635 patients had analyzable baseline data with a median follow-up of 4.4 years. Worsening of LVEF was associated with increased mortality (HR 3.59, 95% CI 1.17-11.04), as was consistent abnormal HRT (HR 8.34, 95%CI 1.06-65.54). HRT improvement was associated with improved survival when compared to consistent abnormal HRT (HR 0.10, 95%CI 0.01-0.82). For appropriate ICD shocks, a non-negative MTWA test or high PVC count at any moment was associated with increased arrhythmic risk independent of the evolution of test results (worsening: HR 3.76 (95%CI 1.43-9.88) and HR 2.50 (95%CI 1.15-5.46); improvement: HR 2.80 (95%CI 1.03-7.61) and HR 2.45 (95%CI 1.07-5.62); consistent: HR 2.47 (95%CI 0.95-6.45) and HR 2.40 (95%CI 1.33-4.33), respectively). LVEF improvement was associated with a lower arrhythmic risk (HR 0.34, 95%CI 0.12-0.94). CONCLUSIONS: Repeating LVEF and HRT improved the prediction of mortality, whereas stratification of ventricular arrhythmias may be improved by repeating LVEF measurements, MTWA and ECG Holter monitoring.

Evolution of Heart Rate Variability and Heart Rate Turbulence in Patients with Depressive Illness Treated with Selective Serotonin Reuptake Inhibitors.

Background and objectives: Major depressive disorder (MDD) and cardiovascular diseases (CVDs) represent serious and prevalent medical conditions. Autonomic nervous system (ANS) dysfunctions, expressed by parameters of heart rate variability (HRV) and heart rate turbulence (HRT), have been repeatedly associated with depression. The aim of our study was to identify potential HRV and HRT alterations in patients with MDD, before and after selective serotonin reuptake inhibitor (SSRI) therapy, and to observe any correlations between these parameters and the severity of depressive symptoms. Another aim was to evidence if there was a normalization or improvement of HRV and HRT parameters that paralleled the reduction of the intensity of depressive symptoms. Materials and Methods: We studied heart rate variability (HRV) and heart rate turbulence (HRT) in a sample of 78 patients, aged under 51 years, who were referred to our outpatient clinic between June 2017 and December 2019, for complaints in the context of a new onset major depressive disorder (MDD), before and after therapy with SSRIs. Results: By using 24 h Holter ECG monitoring, we evidenced alterations of HRV and HRT parameters, significantly correlated with the severity of depressive symptoms (p < 0.001), as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Our results indicated that these parameters improved following one and six months of SSRI therapy, when a partial or total remission of depressive symptoms was achieved (p < 0.001). Changes in HRV parameters were correlated with the reduction of the severity of depression. Conclusions: In our study group, we highlighted, through 24 h ECG Holter monitoring, frequent and clear HRV and HRT abnormalities that were statistically correlated with the severity of depressive symptoms. Furthermore, we were able to document a progressive improvement of these parameters, which corresponded with the improvement of depressive symptoms under SSRI therapy, when compared to the values measured before the commencement of antidepressant pharmacotherapy.

Prognostic Significance of Heart Rate Turbulence Parameters in Patients with Noncompaction Cardiomyopathy.

BACKGROUND: Noncompaction cardiomyopathy (NC) is a rare congenital heart disease characterized by progressive heart failure and life-threatening arrhythmias. Heart rate turbulence (HRT) has been defined as a noninvasive prognostic method to reveal the cardiac death risk in high-risk patients. OBJECTIVES: We aimed to assess the cardiac autonomic functions and their relations to the mortality in NC patients. METHODS: A total of 60 NC patients and 70 healthy controls were included in this study. All participants underwent 24-h Holter recording to assess the HRT parameters, included turbulence onset (TO), turbulence slope (TS), standard deviation of NN intervals of all normal beats (SDNN) and mean RR interval. RESULTS: NC patients had higher levels of TO than the control group (0.43 ± 4.66% vs. -1.82 ± 2.19%, p = 0.024), but the TS levels of NC patients were lower than those of the control group (3.43 ± 3.28 vs. 4.94 ± 2.86 ms/RR, p = 0.024). Thirteen patients died during follow-up (mean 83.3 ± 32.5 months). TS was the strongest univariate mortality predictor (hazard ratio 10.01 [95% CI 2.22-42.52]; p = 0.004) in univariate Cox regression analysis. In multivariate analysis, LVEF ≤0.40 and TS ≤2.5 ms/RR interval were the only independent predictors of mortality (hazard ratio 5.29; p = 0.004, hazard ratio 13.45; p = 0.001, respectively). CONCLUSIONS: Patients with NC showed abnormal HRV and HRT parameters when compared to healthy subjects. Furthermore, impaired HRT reaction in NC is an independent predictor of mortality.

Comparison of non-invasive assessment of arrhythmias, conduction disturbances and cardiac autonomic tone in systemic sclerosis and systemic lupus erythematosus.

Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are connective tissue diseases presenting cardiac complications including different arrhythmias, then direct electrocardiographic comparison may be useful in everyday clinical decision making. We examined 86 adult SSc patients, 76 with SLE and 45 healthy controls. Among other examinations all subjects underwent 24-h Holter monitoring with time-domain heart rate variability and heart rate turbulence evaluation. Patients with various co-existing conditions which might markedly influence arrhythmias and autonomic modulation were excluded from further analysis (SSc n = 12, SLE n = 6). Finally, 76 SSc and 70 SLE subjects were eligible for this study, mean age 51.9 ± 13.1 and 46.5 ± 12.7 years (p = 0.11), with median disease duration 6.0 and 8.5 years (p = 0.15), respectively. As compared to SLE, patients with SSc were characterised by more frequent incidence of various supraventricular and ventricular arrhythmias. As compared to SSc, patients with SLE presented prolonged corrected QT intervals and also significant correlations between corrected QT length and heart rate variability indices. Both SSc and SLE subjects presented impaired sympathetic cardiac autonomic modulation, while indices associated with parasympathetic activity in SLE were not diminished. Disease duration was not associated with arrhythmias' occurrence (except for ventricular tachycardia in SSc, p = 0.02) and also with autonomic function in both groups of patients. Patients with SSc and SLE differ in terms of arrhythmias, conduction disturbances and cardiac autonomic tone. Regular Holter monitoring should be considered as a part of routine evaluation in connective tissue diseases patients, especially in systemic sclerosis.

The role of heart rate variability, heart rate turbulence, and deceleration capacity in predicting cause-specific mortality in chronic heart failure.

BACKGROUND: The volume of regional denervated myocardium (D-M) on positron emission tomography has been recently suggested as a strong independent predictor of cause-specific mortality from sudden cardiac arrest (SCA) in chronic heart failure. We sought to evaluate whether ECG indices of global autonomic function predict risk of SCA to a similar degree as regional D-M. METHODS: Subjects enrolled in the Prediction of Arrhythmic Events using Positron Emission Tomography (PAREPET) study were included in this study. Patients completed a 24-hour Holter ECG at enrollment and were followed up at 3-month intervals. SCA events were adjudicated by two board-certified cardiologists. Other cardiovascular death events were classified as nonsudden cardiac death (NSCD). Eight measures of heart rate variability were analyzed: SDNN, RMSSD, low-frequency (LF) and high-frequency (HF) power, heart rate turbulence onset and slope, and acceleration and deceleration capacity. We used competing risk regression to delineate cause-specific mortality from SCA versus NSCD. RESULTS: Our sample included 127 patients (age 67 ±â€¯12, 92% male). After a median follow-up of 4.1 years, there were 22 (17%) adjudicated SCA and 18 (14%) adjudicated NSCD events. In multivariate Cox-regression, LF power was the only HRV parameter to predict time-to-SCA. However, in competing risk analysis, reduced LF power was preferentially associated with NSCD rather than SCA (HR = 0.92 [0.85-0.98], p = 0.019). CONCLUSION: Depressed LF power might indicate impaired vagal reflex, which suggests that increasing vagal tone in these patients would have a protective effect against NSCD beyond that achieved by the mere slowing of heart rate using ß-blockers.

Alterations of heart rate variability and turbulence in female patients with hyperthyroidism of various severities.

OBJECTIVE: The objective of the this study is to document the existence of statistically significant differences between parameters of heart rate variability (HRV) and heart rate turbulence (HRT), determined in women with overt hyperthyroidism (hT), compared to controls and to highlight their correlations with the level of thyroid hormones and the incidence of arrhythmias. METHODS: We studied the HRV in time and frequency domain, and the HRT in a group of 113 women with overt hT, without other cardiovascular risk factors or comorbidities, admitted to the endocrinology clinic of our hospital, between 2012 and 2016. Depending on the severity and duration of hT and levels of thyroid hormones, the patients were assigned to three groups: mild and moderate forms, severe hT with thyrotoxicosis and persistent cases with a relapse of hT. We performed 24 h Holter monitoring in all patients. RESULTS: HRV parameters in time domain (TD) were significantly depressed in patients comparing to controls. All patients had abnormal, positive values of turbulence onset (TO) with significant statistically differences (P < 0.0001) comparing to controls. Although positive, the values of turbulence slope (TS) decreased according to the severity of hT. CONCLUSION: Patients with hT had depressed values of HRV parameters in TD, correlated with the severity of the thyroid disease and with the incidence of arrhythmias. All patients presented pathological values of TO. TS values were positive, but lower compared to controls.

Abnormalities of heart rate turbulence and heart rate variability as indicators of increased cardiovascular risk in patients with systemic sclerosis.

INTRODUCTION: Systemic sclerosis (SSc) is a connective tissue disease manifested by progressive fibrosis of many internal organs including the cardiovascular system and development of autonomic disorders with sympathetic predominance. These abnormalities can increase cardiovascular mortality. AIM: To evaluate heart rate turbulence (HRT) and variability (HRV) parameters (indicator of autonomic imbalance) obtained from 24-hour ECG Holter monitoring, as predictors of the increased cardiovascular risk in patients with scleroderma. MATERIAL AND METHODS: Thirty-twoscleroderma patients and 30 healthy people were included. After clinical examination, ECG, routine laboratory tests and echocardiography, participants performed 24-hour Holter-ECG at home. For HRT assessment, turbulence onset (To) and turbulence slope (Ts) parameters were used. Both time and frequency domain analysis of HRV was used. The HRV circadian rhythm was also evaluated. RESULTS: Time domain: SDNN, SDNN-ix, SDANN and frequency domain: LF, VLF, ULF, NHF, NLF, parameters were lower, while p50NN was higher in SSc as compared to the control group. There was also a loss of the circadian rhythm for r-MSSD and p50NN present in the control group. Abnormal HRT parameters To and/or Ts occurred in the SSc group only. The median value of To = -1.24% and Ts = 11.13 ms/RR did not differ significantly as compared to the control group. CONCLUSIONS: The study confirmed the presence of HRV disturbances, including HRV circadian rhythm, as it may seem at an early stage of SSc. The HRT disorders may be characterized by the increasing changes with advancing disease. This indicates the presence of autonomic imbalance and an increased cardiovascular risk.

Utility of heart rate turbulence and T-wave alternans to assess risk for readmission and cardiac death in hospitalized heart failure patients.

BACKGROUND: Heart failure (HF) patients have a higher risk of recurrent HF and cardiac death, and electrical remodeling is considered to be an important factor for HF progression. The present study aimed to validate the utility of electrocardiogram and Holter monitoring for the risk stratification of HF patients. METHODS: Our study comprised 215 patients (144 males, mean age 62 years) who had been hospitalized due to acute decompensated HF. Electrocardiogram (QRS duration and QTc interval) and 24-hour Holter monitoring (heart rate variability, heart rate turbulence, and T-wave alternans [TWA]) were performed in stable condition before discharge. The clinical characteristics and outcomes were then investigated. RESULTS: During a median follow-up period of 2.7 years, there were 83 (38.6%) cardiac events (rehospitalization due to worsening HF [n = 51] or cardiac death [n = 32]). The patients with cardiac events had a lower turbulence slope (TS) and higher TWA compared to those without cardiac events (TS, 3.0 ± 5.5 ms/RR vs. 5.3 ± 5.6 ms/RR, P = 0.001; TWA, 66.1 ± 19.6 µV vs. 54.7 ± 15.1 µV, P < 0.001). Univariable analysis showed that TS, TWA, QRS duration, and QTc interval were associated with cardiac events (P = 0.004, P < 0.001, P = 0.037, and P = 0.024, respectively), while the multivariable analysis after the adjustment of multiple confounders showed that TS and TWA were independent predictive factors of cardiac events with a hazard ratio of 0.936 and 1.015 (95% confidence interval [CI]: 0.860-0.974, P = 0.006; and 95% CI: 1.003-1.027, P = 0.016), respectively. CONCLUSION: The measurement of TS and TWA is useful for assessing risk for rehospitalization and cardiac death in HF patients.

The use of heart rate turbulence and heart rate variability in the assessment of autonomic regulation and circadian rhythm in patients with systemic lupus erythematosus without apparent heart disease.

Background Systemic lupus erythematosus is a progressive autoimmune disease. There are reports suggesting that patients even without overt signs of cardiovascular complications have impaired autonomic function. The aim of this study was to assess autonomic function using heart rate turbulence and heart rate variability parameters indicated in 24-hour ECG Holter monitoring. Methods Twenty-six women with systemic lupus erythematosus and 30 healthy women were included. Twenty-four hour ambulatory ECG-Holter was performed in home conditions. The basic parameters of heart rate turbulence and heart rate variability were calculated. The analyses were performed for the entire day and separately for daytime activity and night time rest. Results There were no statistically significant differences in the basic anthropometric parameters. The mean duration of disease was 11.52 ± 7.42. There was a statistically significant higher turbulence onset (To) value in patients with systemic lupus erythematosus, median To = -0.17% (minimum -1.47, maximum 3.0) versus To = -1.36% (minimum -4.53, maximum -0.41), P < 0.001. There were no such differences for turbulence slope (Ts). In the 24-hour analysis almost all heart rate variability parameters were significantly lower in the systemic lupus erythematosus group than in the healthy controls, including SDANN and r-MSSD and p50NN. Concerning the morning activity and night resting periods, the results were similar as for the whole day. In the control group, higher values in morning activity were noted for parameters that characterise sympathetic activity, especially SDANN, and were significantly lower for parasympathetic parameters, including r-MSSD and p50NN, which prevailed at night. There were no statistically significant changes for systemic lupus erythematosus patients for p50NN and low and very low frequency. There was a positive correlation between disease duration and SDNN, R = 0.417; P < 0.05 and SDANN, R = 0.464; P < 0.05, a negative correlation between low/high frequency ratio and r-MSSD, R = -0.454; P < 0.05; p50NN, R = -0.435; P < 0.05 and high frequency, R = -0.478; P < 0.05. In contrast, there was no statistically significant correlation between heart rate turbulence and other variables evaluated, including disease duration and the type of autoantibodies. CONCLUSION: Our study confirms the presence of autonomic disorders with respect to both heart rate variability and heart rate turbulence parameters and the presence of diurnal disturbances of sympathetic-parasympathetic balance. Further studies are required.

Heart rate variability in patients with systemic lupus erythematosus: a systematic review and methodological considerations.

Aim The aim of this review was to summarize current knowledge about the scientific findings and potential clinical utility of heart rate variability measures in patients with systemic lupus erythematosus. Methods PubMed, Embase and Scopus databases were searched for the terms associated with systemic lupus erythematosus and heart rate variability, including controlled vocabulary, when appropriate. Articles published in English and available in full text were considered. Finally, 11 publications were selected, according to the systematic review protocol and were analyzed. Results In general, heart rate variability, measured in the time and frequency domains, was reported to be decreased in patients with systemic lupus erythematosus compared with controls. In some systemic lupus erythematosus studies, heart rate variability was found to correlate with inflammatory markers and albumin levels. A novel heart rate variability measure, heart rate turbulence onset, was shown to be increased, while heart rate turbulence slope was decreased in systemic lupus erythematosus patients. Reports of associations of changes in heart rate variability parameters with increasing systemic lupus erythematosus activity were inconsistent, showing decreasing heart rate variability or no relationship. However, the low/high frequency ratio was, in some studies, reported to increase with increasing disease activity or to be inversely correlated with albumin levels. Conclusions Patients with systemic lupus erythematosus have abnormal heart rate variability, which reflects cardiac autonomic dysfunction and may be related to inflammatory cytokines but not necessarily to disease activity. Thus measurement of heart rate variability could be a useful clinical tool for monitoring autonomic dysfunction in systemic lupus erythematosus, and may potentially provide prognostic information.

Cardiac autonomic function in type 1 and type 2 myotonic dystrophy.

OBJECTIVE: The aim of this study was to evaluate cardiac autonomic nervous system function using Holter-derived and standard electrocardiographic parameters in patients with myotonic dystrophy (dystrophia myotonica, DM) and no clinically overt heart involvement. METHODS: Eighty-four DM patients without conditions potentially influencing cardiac autonomic function were enrolled in the study: 44 with DM type 1 and 40 with DM type 2 (mean age 34.9 ± 11.5 and 47.8 ± 13.5 years, respectively). Two corresponding control groups of aged-matched healthy subjects were selected for DM1 (n = 35) and for DM2 (n = 30). Standard electrocardiography for QT interval dispersion and 24-h Holter monitoring with time-domain heart rate variability and heart rate turbulence were performed. RESULTS: No significant differences in time-domain heart rate variability parameters between DM1 or DM2 subjects and controls were observed. However, heart rate turbulence parameters were significantly impaired in DM1 patients as compared to their controls: turbulence onset (p = 0.025), and turbulence slope (p = 0.018). Moreover, turbulence slope was also impaired in DM2 patients (p = 0.042). As compared to controls, we observed an increased QT dispersion, both in DM1 (p = 0.003) and also in DM2 patients (p < 0.0001). No relationship between disease duration or neurological status and time-domain heart rate variability, heart rate turbulence, and QT dispersion was observed. INTERPRETATION: Despite normal time-domain heart rate parameters, impaired heart rate turbulence and increased QT dispersion may suggest cardiac autonomic nervous system dysfunction in DM patients. The present study is the first one in which heart rate turbulence and QT dispersion assessment were examined both in DM1 and DM2 patients.

T-Wave Alternans, Heart Rate Turbulence, and Ventricular Ectopy in Standard versus Daily Hemodialysis: Results from the FHN Daily Trial.

BACKGROUND: Hemodialysis (HD) patients are at high risk of sudden cardiac death (SCD). HD 6-times/week (6x/wk) may reduce SCD risk compared to usual 3-times/week HD (3x/wk) by mechanisms unknown. T-wave alternans (TWA), heart rate turbulence (HRT), and ventricular ectopy (VE) are elevated in HD patients, but their response to 6x/wk HD has not been assessed. METHODS: Baseline and 1-year Holter recordings were analyzed from enrollees in the Frequent Hemodialysis Network Daily Trial, a randomized trial comparing 3x/wk to 6x/wk in 245 chronic HD patients. TWA, HRT, and VE were assessed using MARS software. RESULTS: Sixty-eight patients (34 with 6x/wk) had complete baseline and 1-year Holter recordings. Mean age was 50 ± 13 years and 38% were female. Maximum TWA in the 3x/wk and 6x/wk groups were 52.4 µV at baseline and 51.2 µV at 1-year versus 54.0 and 49.9 µV, respectively (P = 0.28). The proportion of abnormal HRT (scores of 1 or 2) in the 3x/wk group decreased from 65% to 56% at 1-year versus 53% to 53% in the 6x/wk group (P = 0.58). Mean %VE changed from 1.6% to 2.9% in the 3x/wk group from baseline to 1-year and from 2.1% to 3.7% in the 6x/wk group (P = 0.85). CONCLUSIONS: There were no significant differences in HRT or VE at 1-year in chronic HD patients randomized to 6x/wk versus 3x/wk and a trend in TWA reduction. Additional studies are needed to evaluate the impact and mechanisms of SCD in HD.

Association of Heart Rate Turbulence With Arrhythmia Susceptibility and Heart Disease in Mice.

INTRODUCTION: Recent studies have demonstrated the feasibility of measuring heart rate turbulence (HRT) as a marker of baroreflex function in healthy mice. The aim of this investigation was to measure HRT in a mouse model with induced structural heart defects and to determine if there were threshold values of HRT for inducible ventricular tachycardias (VTs). METHODS AND RESULTS: HRT was measured during electrophysiological investigations 2 weeks after transverse aortic constriction (TAC, n = 13) or myocardial cryoinfarction (MCI, n = 14). Sham-operated mice served as controls (n = 8 for TAC controls and n = 9 for MCI controls). Mice with heart disease lacked an early acceleration (turbulence onset [TO]) in heart rate after extrastimulus pacing (heart disease: 0.39% [0.19%-0.59%] vs. all controls: -0.04% [-0.25-0.19%]; P < 0.01). At a cutoff value of >0.25%, TO could be used to classify mice with induced heart disease with a sensitivity of 64.0% and specificity of 88.2% (P < 0.01) but did not identify mice at higher risk of induced VTs. Animals that were susceptible to VTs (n = 8) had lower values for turbulence slope (TS) compared with noninducible mice (6.2 milliseconds/beat [3.1-9.5 milliseconds/beat] vs. 10.1 milliseconds/beat [7.2-14.2 milliseconds/beat]; P = 0.03). TS <7.8 milliseconds/beat identified mice with inducible VTs with a sensitivity of 75.0% and specificity of 75.8% (P = 0.02). CONCLUSION: Measurement of HRT is feasible in mouse models with induced structural heart disease. More abnormal values for TO were found in the presence of structural heart disease but did not predict susceptibility to VTs. Decreased TS was associated with VTs induced by programmed stimulation.

Determinants of heart rate turbulence in individuals without apparent heart disease and in patients with stable coronary artery disease.

AIMS: To assess the characteristics and determinants of heart rate turbulence (HRT) in individuals without any apparent heart disease and in patients with coronary artery disease (CAD). METHODS AND RESULTS: Heart rate turbulence parameters, turbulence onset (TO), and turbulence slope (TS) were calculated on 24 h electrocardiogram recordings in 209 individuals without any heart disease (group 1) and in 157 CAD patients (group 2). In group 1, only age independently predicted abnormal TO (≥0%) [odds ratio (OR), 1.05; P<0.001], while predictors of abnormal TS (≤2.5 ms/RR) were age (OR, 0.85; P < 0.001) and hypertension (OR, 0.19; P = 0.028). In group 2 patients, only age independently predicted TO (OR, 1.03; P = 0.038), while age (OR, 0.90; P = 0.001) and left ventricular ejection fraction (LVEF; OR, 1.07; P = 0.008) predicted TS. Heart rate turbulence values were different in groups 1 and 2. Turbulence onset was (mean, standard deviation) -1.80 ± 2.24 vs. -0.73 ± 1.61%, respectively (P < 0.001), whereas TS was (median, interquartile interval) 5.83 (3.25-10.55) vs. 2.93 (1.73-5.81) ms/RR, respectively (P < 0.001). Coronary artery disease group, however, did not predict abnormal HRT parameters in multivariable analyses, both in the whole population and when comparing two subgroups matched for age and gender. Age and (for TS) LVEF, indeed, were the only independent predictors of abnormal HRT. CONCLUSIONS: Age is a major HRT determinant both in subjects without any apparent heart disease and in stable CAD patients. Hypertension and LVEF contribute independently to HRT in these two groups, respectively. Coronary artery disease group was not by itself associated with abnormal HRT parameters in multivariable analyses.

Severity of arterial and chronic thromboembolic pulmonary hypertension is associated with impairment of heart rate turbulence.

BACKGROUND: Heart rate turbulence (HRT) impairment is a validated and an independent indicator of cardiovascular death. There are limited data on HRT in pulmonary hypertension (PH), so we assessed potential HRT alterations in PH, especially in relation to its severity. METHODS: Thirty-three out of 41 patients were enrolled in the study aged 49.7 ± 15.9 years (22 with arterial, 11 with chronic thromboembolic PH). Routine evaluations, right heart catheterization, and 24-hour Holter monitoring with heart rate variability and HRT assessment were performed. RESULTS: HRT was significantly impaired in PH patients, as compared to 25 healthy controls: mean turbulence onset (TO) was -0.27% versus -2.60% (P < 0.0001), and median turbulence slope (TS) was 3.13 versus 13.5 msRR (P < 0.0001). Abnormal HRT (TO ≥ 0.0% and/or TS ≤ 2.5 ms/RR) was found in 63.3% of PH patients. Patients with PH and abnormal HRT presented more compromised functional, biochemical, and hemodynamic status than PH patients with normal TO and TS values. Multivariate stepwise regression analysis showed that TO value was related to oxygen desaturation <90% in 6-minute walking test (6-MWT; OR 0.41, P < 0.001) and was related to N-Terminal pro-B type Natriuretic Peptide concentration (OR 0.40, P < 0.001); TS was related to 6-MWT distance (OR 0.53, P < 0.0001). CONCLUSIONS: Patients with arterial or chronic thromboembolic PH are characterized by significant impairment of HRT which is related to the disease severity. We hypothesize that patients with abnormal HRT could be considered as subjects with an increased risk of cardiovascular death, however, it needs further investigation.