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.

Cardiovascular reflex tests in patients with systemic lupus erythematosus: clinical performance and utility.

Background This review summarizes current knowledge about cardiovascular reflex tests (CVRTs) and other selected autonomic nervous system (ANS) assessment tests in systemic lupus erythematosus (SLE) patients and assesses their clinical utility in this group of patients. Methods The PubMed database was searched for terms associated with CVRTs and SLE. Only papers available in full text and published in English were considered. Ultimately, 13 were selected and analyzed. Results In most of the studies CVRTs results were reported more likely to be abnormal in patients with SLE when compared with controls. The reported prevalence of ANS dysfunction in SLE, diagnosed using CVRTs, ranged from 23.5% to 82.7% of patients, likely because of different definitions of ANS dysfunction, variability in methods of performing CVRTs, and potential confounding factors. In general CVRTs results did not correlate with SLE activity or disease duration, but some CVRTs results correlated with some peptides associated with ANS function, including neuropeptide Y and vasoactive intestinal peptide. Conclusion Patients with SLE generally have abnormal or borderline results of CVRTs, which indicate prevalent abnormalities of the ANS in SLE. Performance of CVRTs requires good standardization of test conditions and familiarity with the proper administration and interpretation of these tests.

Depression, heart rate variability, and acute myocardial infarction.

BACKGROUND: Clinical depression is associated with an increased risk for mortality in patients with a recent myocardial infarction (MI). Reduced heart rate variability (HRV) has been suggested as a possible explanation for this association. The purpose of this study was to determine if depression is associated with reduced HRV in patients with a recent MI. METHODS AND RESULTS: Three hundred eighty acute MI patients with depression and 424 acute MI patients without depression were recruited. All underwent 24-hour ambulatory electrocardiographic monitoring after hospital discharge. In univariate analyses, 4 indices of HRV were significantly lower in patients with depression than in patients without depression. Variables associated with HRV were then compared between patients with and without depression, and potential confounds were identified. These variables (age, sex, diabetes, and present cigarette smoking) were entered into an analysis of covariance model, followed by depression status. In the final model, all but one HRV index (high-frequency power) remained significantly lower in patients with depression than in patients without depression. CONCLUSIONS: We conclude that greater autonomic dysfunction, as reflected by decreased HRV, is a plausible mechanism linking depression to increased cardiac mortality in post-MI patients.

Effect of 21 mg transdermal nicotine patches and smoking cessation on heart rate variability.

The effect of smoking cessation on cardiac autonomic tone, as reflected by indexes of heart rate variability (HRV), has not been reported. Current smokers (n = 54, mean +/- SD age 43 +/- 12 years) who desired to quit, and were smoking > or = 1 pack/day and had made > or = 1 prior attempt at quitting, had 24-hour electrocardiographic recordings. They then attended smoking cessation classes and used transdermal nicotine patches while abstaining from smoking. After 4 to 6 weeks of using 21 mg patches, the 24-hour electrocardiogram was repeated (n = 35). Four weeks after cessation of patch use, the 24-hour electrocardiogram was again recorded in subjects who continued to be abstinent (n = 25). Time and frequency domain measures of HRV based on normal R to R (NN) intervals were computed for all recordings. Smoking cessation significantly decreased heart rate, and increased all 24-hour time and frequency domain indexes of HRV. Part of this change occurred in the transition from smoking to the patch, and further changes occurred with cessation of patch use. For example, the standard deviation of average NN intervals was 114 +/- 28 ms at baseline, 121 +/- 41 ms with the patch, and 135 +/- 26 ms after quitting. At 4 weeks after cessation of all nicotine use, the average heart rate remained higher, and HRV remained lower than values reported for healthy, middle-aged adults.

Differing effects of age on heart rate variability in men and women.

Gender and age are both known to affect heart rate variability (HRV). Their interaction is not known. HRV, determined from 24-hour Holter recordings, was compared between gender-matched older (15 men and 15 women, aged 67 +/- 3 years, range 64 to 76) and younger (15 men and 15 women, aged 33 +/- 4 years, range 26 to 42) subjects selected for an age difference of approximately 35 years. HRV for older and younger subjects was compared separately by gender. HRV was also compared by gender within groups. Heart rates were significantly higher, and all time and frequency domain indexes of HRV were significantly lower among the older than among the younger men. Among the women only the shorter term indexes of HRV were significantly lower in the older group. When HRV was compared by gender within age groups, there were no significant differences between men and women in the older group. In the younger group, men had lower heart rates, and all 24-hour time domain indexes of HRV, except those that reflect vagal modulation of heart rate, were significantly higher than those in women. We conclude that HRV is comparable in older men and women. However, HRV is differently affected by age. In men, for whom initial levels of HRV are significantly higher, older age is associated with a global reduction in HRV, reflecting reductions in both sympathetic and parasympathetic modulation and a loss of circadian variability. In women, older age is associated mainly with a decline in shorter term indexes of HRV without significant changes in circadian variability.

Heart rate variability is independent of age, gender, and race in congestive heart failure with a recent acute exacerbation.

Among normal adults, indexes of heart rate variability are affected by age, gender, and race. These effects are not seen among patients with congestive heart failure with a recent acute exacerbation, in whom indexes of heart rate variability are remarkably uniform and appear to be determined primarily by their recent cardiac failure.

Effects of digoxin and enalapril on heart period variability and response to head-up tilt in normal subjects.

To test the effects of digitalis and angiotensin-converting enzyme inhibition on the RR interval variability in an electrocardiogram, 20 normal subjects were given digoxin 0.25 mg, enalapril 10 mg, and placebo twice daily in a randomized, double-blind, crossover study. Continuous 24-hour electrocardiographic recordings obtained on day 5 of each treatment were analyzed and several time domain and power spectral measures of heart period variability were calculated. Digoxin markedly increased (up to 51%) indexes of vagal modulation of heart period without changing mean RR interval. Enalapril did not change any measure of heart period variability despite a modest hypotensive effect. To determine the effect of each treatment on the response to orthostatic stress, 10 subjects also underwent 15 minutes of 60 degrees head-up tilt; power spectra were calculated for 15 minutes at 0 degree and at 60 degrees of tilt. Neither active treatment affected the response to head-up tilt.

Heart rate variability reflects severity of COPD in PiZ alpha1-antitrypsin deficiency.

BACKGROUND: Analysis of heart rate variability (HRV) is a powerful method of assessing severity of conditions affecting the autonomic nervous system. STUDY OBJECTIVE: To determine if HRV is decreased and if HRV reflects severity in COPD. DESIGN: Prospective determination of HRV from 24-h outpatient Holter recordings. PATIENTS: Eighteen individuals with PiZ alpha1-antitrypsin deficiency: 13 with COPD and 5 with normal FEV1. HRV was also determined in 18 matched normal control subjects. Approximately 3 years after the initial recording, all COPD subjects were contacted to determine current status. MEASUREMENTS: Indexes of heart rate (HR) and HRV were compared for groups of patients with and without COPD and their control subjects. RESULTS: Mean and minimum HRs were higher in COPD patients. Virtually all indexes of HRV were significantly decreased in COPD patients. No differences were found in HR or HRV between PiZ individuals with normal FEV1 and their age-and gender-matched control subjects. Patients who had a change in status (ie, death, lung transplant, listed for transplant) had significantly higher daytime HRs, lower values for HRV indexes reflecting mixed sympathetic and parasympathetic modulation of HR, and reduced daytime high-frequency spectral power, an index of cardiac vagal modulation. Significant correlations (r=0.48 to 0.88) were found between FEV1 and these and other indexes of HRV. Most other indexes of HRV also tended to be lower for the group whose status had changed. CONCLUSION: PiZ alpha1-antitrypsin deficiency COPD is associated with abnormal cardiac autonomic modulation. Indexes of HRV appear to reflect severity and may have prognostic value in COPD patients.

Time domain measurements of heart rate variability.

Assessment of HRV through time domain variables is a simple and practical method of assessing autonomic function. In this capacity its utility has been demonstrated in normal subjects and in diverse cardiac and noncardiac pathologic states. It can be used to assess the effects of drugs and other interventions, including exercise and psychological and physical stress on cardiac autonomic tone. Importantly, decreased HRV is almost uniformly associated with adverse outcome. The prognostic information appears to incorporate both alterations in autonomic tone and longer term components and is best assessed using ambulatory ECG recordings. Defining the clinical applicability and physiologic mechanisms of changes in HRV remain active areas of research.

Effect of moricizine on heart rate variability in normal subjects.

We investigated the effects of moricizine HCl, a type Ic anti-arrhythmic agent, on heart rate variability. Decreased heart rate variability is a risk factor for mortality in post-MI and other patient populations, and some antiarrhythmic drugs decrease heart rate variability. Normal volunteers (10 M, 11 F, age 19-39 years) received blinded placebo and moricizine HCl at 200 mg twice daily for 5 days. On day 4, a 24-h ECG was obtained, and time and frequency domain measures of heart rate variability based on normal-to-normal intervals were computed. Moricizine decreased both time and frequency domain measures of heart rate variability. Significant reductions were seen for SDNNIDX (the average S.D. for N-Ns for each 5-min interval in ms) and pNN50 (the proportion of successive N-N differences > 50 ms in percent) in the time domain, and very low (0.0033-0.04 Hz), low (0.04-0.15 Hz) and high (0.15-0.4 Hz) frequency power. Similar patterns of change in heart rate variability were seen when data for daytime and nighttime periods were analyzed separately. rMSSD (the root mean square successive difference of N-N intervals in ms), pNN50 and high frequency power are primarily indices of parasympathetic tone. SDNNIDX, and very low and low frequency power reflect both sympathetic and parasympathetic tone and longer term variability. Thus, moricizine decreases both vagal tone and longer term components of heart rate variability. This decrease produced by moricizine is similar to that reported with other type 1 antiarrhythmics.

Assessment of ultra low frequency band power of heart rate variability: validation of alternative methods.

UNLABELLED: Alternative methods for assessing ULF spectral power using data from commercial Holter analysers were studied. Different heuristics for ULF calculation were compared with standard research software-based determination of ULF. SETTING: University Hospital. PATIENTS: 43 patients in NYHA classes I-IV heart failure and seven normals of similar ages. METHODS: SDNN, SDANN, ULF, VLF, LF, HF calculated from 24 h Holter monitoring using Oxford scanner software (method 1). ULF power also calculated by subtracting the sum of VLF. LF and HF powers obtained from the Holter scanner from the total variance (method 2) from 2 x ln(SDANN) (method 3), and by performing a standard, research-quality 24-h EFT analysis on the beat files (standard). Results of methods 1-3 were compared with standard using two-way ANOVA with repeated measures, regression analysis and a graphical technique. RESULTS: ULF calculated by method 1 correlated r=0.66 with standard but means differed substantially. In contrast, ULF calculated by method 2 correlated r=0.99 with standard with no significant differences between means. ULF calculated from SDANN (method 3) correlated r=0.983 with standard but means, while similar, were significantly lower (P=0.005). CONCLUSION: ULF reported by commercial HOLTER software is not equivalent to ULF power derived from 24 h FFT analysis. ULF calculated by method 2 can be considered equivalent to the ULF derived by standard 24-h FFT. ULF estimated by method 3 offers direct ULF power estimation from a temporal measure of HRV and can be useful when spectral values are not available.

Severe depression is associated with markedly reduced heart rate variability in patients with stable coronary heart disease.

OBJECTIVE: The purpose of this study was to investigate the relationship between depression and heart rate variability in cardiac patients. METHODS: Heart rate variability was measured during 24-hour ambulatory electrocardiographic (ECG) monitoring in 40 medically stable out-patients with documented coronary heart disease meeting current diagnostic criteria for major depression, and 32 nondepressed, but otherwise comparable, patients. Patients discontinued beta-blockers and antidepressant medications at the time of study. Depressed patients were classified as mildly (n = 21) or moderately-to-severely depressed (n = 19) on the basis of Beck Depression Inventory scores. RESULTS: There were no significant differences among the groups in age, gender, blood pressure, history of myocardial infarction, diabetes, or smoking. Heart rates were higher and nearly all indices of heart rate variability were significantly reduced in the moderately-to-severely versus the nondepressed group. Heart rates were also higher and mean values for heart rate variability lower in the mildly depressed group compared with the nondepressed group, but these differences did not attain statistical significance. CONCLUSION: The association of moderate to severe depression with reduced heart rate variability in patients with stable coronary heart disease may reflect altered cardiac autonomic modulation and may explain their increased risk for mortality.

The effect of participation in an exercise training program on cardiovascular reactivity in sedentary middle-aged males.

Exaggerated cardiovascular reactivity to mental stressors may be a risk factor for cardiovascular disease. To determine if participation in a moderate intensity aerobic exercise training program reduces cardiovascular reactivity to laboratory stressors, 40 sedentary middle-aged males were randomly assigned: training group (n = 25) and control group (n = 15). Cardiovascular reactivity during and after three mental stressors (passive responding, push-button Stroop and verbal Stroop) and mild exercise (bicycle ergometer) was assessed before and after an 8-week intervention. VO2(peak) was determined using the Balke protocol. Among 19 subjects who completed the training, VO2(peak) increased 13.7%. Also, trained compared to untrained subjects showed significant reductions in baseline and absolute heart rate responses to all stressors. Baseline adjusted heart rates were significantly lower during push-button Stroop recovery and during verbal Stroop. Blood pressure, T-wave amplitude, finger pulse amplitude and pulse transit time responses were unaffected by exercise training. It was concluded that participation in a short-term, moderate intensity aerobic exercise training program may have a cardioprotective effect by significantly reducing absolute and baseline-adjusted heart rate responses to stressors.

Clinical and demographic determinants of heart rate variability in patients post myocardial infarction: insights from the cardiac arrhythmia suppression trial (CAST).

BACKGROUND: Clinical and demographic determinants of heart rate variability (HRV), an almost universal predictor of increased mortality, have not been systematically investigated in patients post myocardial infarction (MI). HYPOTHESIS: The study was undertaken to evaluate the relationship between pretreatment clinical and demographic variables and HRV in the Cardiac Arrhythmia Suppression Trial (CAST). METHODS: CAST patients were post MI and had > or =6 ventricular premature complexes/h on pretreatment recording. Patients in this substudy (n = 769) had usable pretreatment and suppression tapes and were successfully randomized on the first antiarrhythmic treatment. Tapes were rescanned; only time domain HRV was reported because many tapes lacked the calibrated timing signal needed for accurate frequency domain analysis. Independent predictors of HRV were determined by stepwise selection. RESULTS: Coronary artery bypass graft surgery (CABG) after the qualifying MI was the strongest determinant of HRV. The markedly decreased HRV associated with CABG was not associated with increased mortality. Ejection fraction and diabetes were also independent predictors of HRV. Other predictors for some indices of HRV included beta-blocker use, gender, time from MI to Holter, history of CABG before the qualifying MI, and systolic blood pressure. Decreased HRV did not predict mortality for the entire group. For patients without CABG or diabetes, decreased standard deviation of all NN intervals (SDANN) predicted mortality. Clinical and demographic factors accounted for 31% of the variance in the average of normal-to-normal intervals (AVGNN) and 13-26% of the variance in other HRV indices. CONCLUSIONS: Heart rate variability post MI is largely independent of clinical and demographic factors. Antecedent CABG dramatically reduces HRV. Recognition of this is necessary to prevent misclassification of risk in patients post infarct.

Heart-rate and blood-pressure responses to speech alone compared with cognitive challenges in the Stroop task.

Heart-rate and blood-pressure responses are assumed to reflect the "stressfulness" of cognitive tasks. Cardiovascular responses to speech are often assumed to be negligible. To test these assumptions, 34 middle-aged men (mean age 45.0 +/- 6.1) performed three versions of the Stroop color-conflict task, passive responding, push-button, and verbal. Although difficulty of passive responding was rated 11.8 (fairly light), push-button 16.1 (between hard and very hard), and verbal Stroop 14.5 (hard), all were significantly different. Analysis of variance showed during tasks heart-rate responses and systolic blood pressure did not differ. Recovery average heart-rate and over-all heart-rate patterns were not different for the difficult tasks but were significantly different from the easy task. Diastolic blood-pressure changes during tasks were more similar for verbal tasks despite the difference in difficulty. Stressor heart-rate and systolic blood-pressure responses did not reflect the difficulty of this stressful task. Verbalization of responses contributed significantly to cardiovascular reactivity.

The relationship of heart rate and heart rate variability to non-diabetic fasting glucose levels and the metabolic syndrome: the Cardiovascular Health Study.

BACKGROUND: Increased heart rate (HR) and diminished heart rate variability (HRV) are signs of early cardiovascular autonomic neuropathy. We tested the hypotheses that increased HR and diminished HRV are present in people: (i) with increased fasting glucose (FG) levels not in the range of diabetes mellitus (DM), and (ii) in people with the metabolic syndrome (MetS) independent of elevated FG levels. METHODS: HR and HRV were determined in 1267 adults (mean age 72 years) who had Holter monitoring and FG measures: 536 had normal FG levels (NORM, FG 4.5-5.5 mmol/l), 363 had mildly impaired FG (IFG-1, FG 5.6-6.0 mmol/l), 182 had significantly impaired FG (IFG-2, FG 6.1-6.9 mmol/l) and 178 had DM (FG > 6.9 mmol/l or use of glucose-lowering agents/insulin). HR and HRV in NORM/IFG-1 was further compared by the number of components of the MetS and compared by the presence or absence of MetS in IFG-2/DM. RESULTS: HRV indices were more impaired in IFG-2 and DM than in NORM or IFG-1. There were few differences in HRV indices between NORM and IFG-1 or between IFG-2 and DM. In NORM/IFG-1 participants, having > or = 2 components of the MetS was associated with a greater decrease in HRV compared with having no or one components. In IFG-2/DM participants, MetS was associated with decreased HRV compared with no MetS. CONCLUSIONS: Increased HR and diminished HRV occur in the non-diabetic FG range. Diminished HRV is associated with the MetS, independent of FG levels. Both these results suggest that factors associated with increasing non-diabetic FG levels and the MetS play a role in the onset of cardiac autonomic impairment.

Association between short term and long term communication in pathological autonomic control.

Autonomic Information Flow (AIF) reflects the time scale dependence of autonomic communications such as vagal, sympathetic, and slower rhythms and their complex interplay. We investigated the hypothesis that pathologically disturbed short term control is associated with simplified complex long term control. This particular characteristic of altered autonomic communication was evaluated in different medical patient groups. Holter recordings were assessed in patients with multiple organ dysfunction (MODS) (26 survivors, 10 non-survivors); with heart failure (14 low risk-without history of aborted cardiac arrest (CA), 13 high risk--with history of CA); with idiopathic dilated cardiomyopathy (IDC) (26 low risk, 11 high risk of CA), after myocardial infarction (MI) (1221 low risk--survivors, 55 high risk--non-survivors); after abdominal aorta surgery (AAS, 32 length of stay in hospital LOS>7 days, 62 LOS < or =7 days). AIF of short and long time scales was investigated. We found a fundamental association of increased short term randomness and decreased long term randomness due to pathology. Concerning risk, high risk patients were characterized by increased short term complexity and decreased long term complexity in all patients groups with the exception of the IDC patients. We conclude that different time scales of AIF represent specific pathophysiological aspects of altered autonomic communication and control. The association of altered short term control with simplified long term behavior might be a pathophysiologically relevant compensation mechanism in the case of a disturbed fastest actuator. This knowledge might be useful for the development of comprehensive therapeutic strategies besides the predictive implications.