Non-linear heart rate variability and risk stratification in cardiovascular disease

Traditional time and frequency domain heart rate variability (HRV) have cardiac patients at risk of mortality post-myocardial infarction. More recently, non linear HRV has been applied to risk stratification of cardiac patients. In this review we describe studies of non linear HRV and outcome in cardiac patients. We have included studies that used the three most common non-linear indices: power law slope, the short term fractal scaling exponent and measures based on Poincare plots. We suggest that a combination of traditional and non-linear HRV may be optimal for risk stratification. Considerations in using non linear HRV in a clinical setting are described.     

Heart rate variability analysis

The expansion of heart rate variability analysis has been facilitated by the remarkable development of computer sciences and digital signal processing during the last thirty years. The beat-to-beat fluctuation of the heart rate originates from the momentary summing of sympathetic and parasympathetic influences on the sinus node. According to the extensive associations of the autonomic nervous system, several factors affect heart rate and its variability such as posture, respiration frequency, age, gender, physical or mental load, pain, numerous disease conditions, and different drugs. Heart rate variability can be quantitatively measured by time domain and frequency domain methods that are detailed in the paper. Non-linear methods have not spread in the clinical practice yet. Various cardiovascular and other pathologies as well as different forms of mental and physical load are associated with altered heart rate variability offering the possibility of predicting disease outcome and assessing stress.     

Heart rate variability and sports

This article presents a review of the literature and some author’s data on the problem of using heart rate variability in sports and sports medicine practice.     

Heart rate variability in weightlifters

On the basis of the literature and original data, heart rate variability (HRV) in weightlifters has been studied. The results showed that the distribution mode (a parameter of mathematical analysis that is equal to the most frequent length of RR intervals) indicates the intensity of physical exercise. Specific changes in the autonomic balance in athletes as dependent on their degree of training and sports qualification are important characteristics of adaptations to physical loads. For example, the degree of training of weightlifters is reflected by the level of the respiratory component as an index of the activity of the parasympathetic nervous system. Adaptation to physical exercise leads to an increase in the power of the spectrum of neurohumoral modulation and to changes in the ratio between the levels of the total spectral power of HRV.     

Heart rate variability analysis in general medicine

Autonomic nervous system plays an integral role in homeostasis. Autonomic modulation can frequently be altered in patients with cardiac disorders as well as in patients with other critical illnesses or injuries. Assessment of heart rate variability is based on analysis of consecutive normal R-R intervals and may provide quantitative information on the modulation of cardiac vagal and sympathetic nerve input. The hypothesis that depressed heart rate variability may occur over a broad range of illness and injury, and may inversely correlated with disease severity and outcome has been tested in various clinical settings over the last decade. This article reviews recent literature concerning the potential clinical implications and limitations of heart rate variability assessment in general medicine.     

Genetic variability of proto-oncogenes for breast cancer risk and prognosis

This paper summarizes the results of a study on human breast cancers performed mainly at the Centre René Huguenin in collaboration with other American and French groups, and supported in part by a Grant from the Association pour la Recherche sur le Cancer (ARC) Villejuif. During this work, the following conclusions emerged: c-myc proto-oncogene amplification is a common alteration in ductal invasive tumors, more frequently found in recurrent and metastatic tumors, suggesting a role for c-myc in tumor progression. However, in the current state of our study, it does not appear to be linked to prognosis; parts of the short arm of chromosome 11 are deleted in 20% of tumors resulting in hemizygosity for several genes (c-ha-ras, beta globin, pTH, calcitonin, catalase). These deletions seem to be linked with aggressiveness of tumors; a restriction fragment length polymorphism (RFLP) study of c-ha-ras has shown a significant association of the frequency of rare ha-ras alleles in cancer patients compared to that of normal individuals. Although this result is currently a matter of controversy, further studies must be independently repeated to be conclusive; -- another RFLP was found in c-mos proto-oncogene, which is detected only in patients with breast cancers or other types of tumors. The molecular basis for this RFLP has been elucidated. The significance of this association is unknown.     

Heart rate variability biofeedback as a method for assessing baroreflex function: a preliminary study of resonance in the cardiovascular system

This study describes the use of a biofeedback method for the noninvasive study of baroreflex mechanisms. Five previously untrained healthy male participants learned to control oscillations in heart rate using biofeedback training to modify their heart rate variability at specific frequencies. They were instructed to match computer-generated sinusoidal oscillations with oscillations in heart rate at seven frequencies within the range of 0.01–0.14 Hz. All participants successfully produced high-amplitude target-frequency oscillations in both heart rate and blood pressure. Stable and predictable transfer functions between heart rate and blood pressure were obtained in all participants. The highest oscillation amplitudes were produced in the range of 0.055–0.11 Hz for heart rate and 0.02–0.055 Hz for blood pressure. Transfer functions were calculated among sinusoidal oscillations in the target stimuli, heart rate, blood pressure, and respiration for frequencies at which subjects received training. High and low target-frequency oscillation amplitudes at specific frequencies could be explained by resonance among various oscillatory processes in the cardiovascular system. The exact resonant frequencies differed among individuals. Changes in heart rate oscillations could not be completely explained by changes in breathing. The biofeedback method also allowed us to quantity characteristics of inertia, delay, and speed sensitivity in baroreflex system. We discuss the implications of these findings for using heart rate variability biofeedback as an aid in diagnosing various autonomic and cardiovascular system disorders and as a method for treating these disorders.     

Heart rate variability in normal and complicated pregnancies

The sympathetic division (SD) of the autonomic nervous system (ANS) was assessed by 23 tachometric parameters in 176 pregnant women using a Valenta medical diagnostic system. The activity of the ANS SD was shown to increase in the first trimester of pregnancy, progressively rise during the second and third trimesters, and decrease immediately before delivery. This is considered as a mechanism of adaptation to pregnancy. The activity of the ANS SD in pregnant women remained unchanged in mild gestosis; increased in moderate gestosis; and decreased in chronic hypertension, hypertensive circulatory disorders, and threatened preterm delivery. The role of the activity of the ANS SD in normal pregnancy and in obstetric complications is discussed.     

Heart rate variability during long truck driving work

We recorded ambulatory electrocardiograms of 6 long distance truck drivers during their work period in order to observe the affect of autonomic nervous function and symptoms while doing their work. We also recorded their work patterns every minute. The RR50 value and the LFP/HFP ratio were calculated every two minutes based on R-R interval data. RR50 was significantly higher during taking naps than during other periods of work shifts, while, the LFP/HFP ratio showed significantly lower during taking naps than during other periods of work shifts. RR50 in the morning was significantly higher than that in the afternoon. On the contrary, the LFP/HFP ratio showed opposite tendency. Only on the times of driving, RR50 was significantly higher in the morning than that in the afternoon. On the other hand, the LFP/HFP ratio showed an opposite tendency. These results show that the parasympathetic nervous activities were more dominant than sympathetic nervous activities in the morning during the subjects were doing long distance truck driving including midnight work. Driving while in high parasympathetic nervous activity levels may add to cardiovascular stress and lead to drowsiness. And this may result in disrupted attention. It is necessary to decrease work time and improve working conditions of truck drivers working long-hour shifts.     

Heart rate variability in elite American track-and-field athletes

Prolonged training leads to changes in autonomic cardiac balance. This sympathetic and parasympathetic balance can now be studied using heart rate variability (HRV). Studies have shown that endurance athletes have an elevated level of parasympathetic tone in comparison to sedentary people. The effect of resistance training on autonomic tone is less clear. We hypothesized a significant difference in HRV indices in endurance-trained vs. power-trained track-and-field athletes. One hundred forty-five athletes (58 women) were tested prior to the 2004 U.S.A. Olympic Trials. Heart rate variability data were collected using the Omegawave Sport Technology System. Subjects were grouped according to training emphasis and gender. The mean age of the athletes was 24.8 years in each group. There were significant (p < 0.01) differences by sex in selected frequency domain variables (HFnu, LFnu, LH, LHnu) and for PNN50 (p < 0.04) for the time domain variables. Two-factor analyses of variance showed differences for only the main effect of sex and not for any other grouping method or interaction. Elite athletes have been shown to have higher parasympathetic tone than recreational athletes and nonathletes. Our data show differences by sex, but not between aerobically and power-based athletes. Whether this is due to an aerobic component of resistance training, an overall prolonged training effect, or some genetic difference remains unclear. Further study is needed to assess the impact of resistance training programs on autonomic tone and cardiovascular fitness. This information will be valuable for the practitioner to use in assessing an athlete's response to a prescribed training regimen.     

Heart rate dynamics in iNOS knockout mice

Nitric oxide has both an inhibitory and excitatory role in the regulation of pre-ganglionic sympathetic neurons, involving the iNOS and nNOS systems respectively. The aim of the present study was to examine cardiovascular autonomic activity in iNOS knockout mice using spectral analysis of heart rate variability (HRV), and to determine the role of iNOS in altered HRV in endotoxaemia. Electrocardiograms were recorded in anaesthetised mice, and the R-R intervals digitized for spectral analysis of HRV and cardiac rhythm regularity using sample entropy analysis. The basal heart rate was higher in iNOS knockout mice compared with controls (465+/-8 vs 415+/-13 beat/min P<0.05), with a significant increase in the low frequency power of HRV spectra in iNOS knockout mice compared with controls (49.4+/-4.3 vs 33.8+/-5.6 normalized units, P<0.05), consistent with increased cardiac sympathetic activity. Endotoxaemia is known to decrease HRV, but the role of iNOS is unknown. LPS (20 mg/kg i.p) increased basal heart rate in both wild type and iNOS knockout mice, but caused a depression of HRV and sample entropy in both groups. Studies in isolated beating atria showed that the changes of HRV under basal or post-LPS conditions disappeared in vitro, suggesting that the autonomic system is responsible for altered HRV. We conclude that disruption of iNOS gene leads to an increase in the low frequency power of HRV consistent with increased cardiac sympathetic activity. These data also demonstrate that LPS-induced decrease of HRV is independent of iNOS.     

Heart rate variability and methylphenidate in children with ADHD

Although an extensive number of studies support the efficacy and tolerability of stimulants in the treatment of attention deficit/hyperactivity disorder (ADHD), in recent years, increasing concerns have been raised about their cardiovascular safety. We investigated whether a time domain analysis of heart rate variability (HRV) recordings in 24-h ECG under medication with stimulants yielded new information about therapy control in ADHD. We analysed the HRV parameter standard deviation of all normal sinus RR intervals over 24 h (SDNN), percentage of successive normal sinus RR intervals > 50 ms (pNN50) and root-mean-square of the successive normal sinus RR interval difference (rMSSD) from 23 children diagnosed by ADHD (19 boys and 4 girls), aged 10.5 ± 2.2 years, who were consecutively referred to our outpatient clinic for paediatric cardiology. Eleven children received medication with methylphenidate (MPH), while twelve children were initially examined without medication. Of these, eight probands were re-examined after therapy with MPH was established. Controls comprised 19 children (10 boys, 9 girls) from our Holter ECG data base without any cardiac or circulatory disease. Compared to healthy controls, the ADHD children with and without MPH treatment showed significantly higher mean heart rates (ADHD without MPH: 94.3 ± 2.2; ADHD with MPH: 90.5 ± 1.8, controls: 84.7 ± 1.8). pNN50 (ADHD without MPH: 6.5 ± 2.7; ADHD with MPH: 14.2 ± 6.9, controls: 21.5 ± 9.0) and rMSSD (ADHD without MPH: 26.1 ± 4.1; ADHD with MPH: 36.7 ± 8.3, controls: 44.5 ± 10.1) were lowest in ADHD children without MPH, middle in ADHD children with MPH and highest in controls. SDNN values were not significantly different. The hourly analysis shows highly significant reduced pNN50 and rMSSD values in untreated ADHD children between 5:00 pm and 6:00 am while the pattern approaches to levels of controls during MPH treatment. Data of this pilot study indicate a decreased vagal tone with significantly diminished HRV and higher heart rates in unmedicated ADHD children. These parameters of autonomic activation are ameliorated by MPH treatment. No evidence for negative impact of MPH on HRV was detected. Further studies will clarify a potential cardio-protective effect of MPH in ADHD.     

Heart rate variability in subjects with different respiratory rates

The variability of the cardiac rhythm was studied in males with different initial respiratory rates. At rest and during voluntarily controlled breathing, subjects with medium respiratory rates were found to have a less variable heart rate than their counterparts with low or high respiratory rates.     

Heart rate variability and body temperature during the sleep onset period

Heart rate variability (HRV) and body temperature during the sleep onset period was examined. The core body temperature and electrocardiogram were recorded continuously beginning 1 h before lights out (LO) until the end of the first rapid eye movement sleep (REM) in 14 young healthy subjects. HRV was calculated by the MemCalc method. The time course changes in body temperature and HRV was analyzed before and after sleep onset, and during the following eight consecutive phases: the 60 min before LO, the 30 min before LO, LO, first stage 2 (sleep onset), first slow wave sleep (SWS), stage 2 just before REM, start of REM, and end of REM. A clear decline was observed in the ratio of the low frequency (LF) to high frequency (HF) component of HRV (LF/HF), normalized LF (LF/(LF + HF)), and body temperature prior to sleep onset both in the time course of the sleep onset period and in the consecutive phases. The HF increased prior to sleep onset in the consecutive phases, while no clear increase was observed in the time course of sleep onset period. Changes in LF/(LF + HF) and LF/HF preceded SWS and REM. These results suggest the existence of a strong coupling between the cardiac autonomic nervous system and body temperature at the sleep onset period that may not be circadian effects. Furthermore, LF/(LF + HF) and LF/HF may possibly anticipate sleep and the onset of each sleep stage.

     

Heart rate variability and cardiac reflexes in small for gestational age infants.

To assess the influence of intrauterine growth retardation and postnatal development on heart rate variability (HRV) and cardiac reflexes, we studied 27 healthy small for gestational age (SGA) and 23 appropriate for gestational age (AGA) infants during a nap study. Resting HRV was assessed by point dispersion of Poincaré plots for overall (SDRR) and instantaneous beat-to-beat variability (SDDeltaRR) and the ratio (SDRR/SDDeltaRR). Heart rate reflex and arousal responses to a 60 degrees head-up tilt were determined. All tests/measures were repeated twice in quiet and active sleep and in prone and supine sleep positions at 1 and 3 mo of age. SGA infants exhibited higher resting sympathetic tone [SDRR/SDDeltaRR: 1.9 (95% confidence interval: 1.7, 2.0) and 1.7 (95% confidence interval: 1.5, 1.8) in SGA and AGA, respectively; P=0.046] and a tendency for a smaller tachycardic reflex response to the tilt [Deltaheart rate: 24 beats/min (95% confidence interval: 20, 28) and 30 (95% confidence interval: 25, 34)] in SGA and AGA, respectively; P=0.06]. HRV indexes were reduced in the prone compared with supine position (P<0.0001), but reflex tilt responses were unchanged with position. SGA/AGA differences were independent of sleep position. Gestational age weight status did not influence the likelihood of arousal, but prone sleeping per se reduced the odds 2.5-fold. The findings suggest reduced autonomic activity and cardiac reflexes in SGA infants. The finding that the sympathetic component of the control of HRV was higher in SGA infants could link with findings in adulthood of an association between being born SGA and a higher risk of cardiovascular disease.     

Depression, comorbid anxiety disorders, and heart rate variability in physically healthy, unmedicated patients: implications for cardiovascular risk

Context

There is evidence that heart rate variability (HRV) is reduced in major depressive disorder (MDD), although there is debate about whether this effect is caused by medication or the disorder per se. MDD is associated with a two to fourfold increase in the risk of cardiac mortality, and HRV is a robust predictor of cardiac mortality; determining a direct link between HRV and not only MDD, but common comorbid anxiety disorders, will point to psychiatric indicators for cardiovascular risk reduction.

Objective

To determine in physically healthy, unmedicated patients whether (1) HRV is reduced in MDD relative to controls, and (2) HRV reductions are driven by MDD alone, comorbid generalized anxiety disorder (GAD, characterized by anxious anticipation), or comorbid panic and posttraumatic stress disorders (PD/PTSD, characterized by anxious arousal).

Design, Setting, and Patients

A case-control study in 2006 and 2007 on 73 MDD patients, including 24 without anxiety comorbidity, 24 with GAD, and 14 with PD/PTSD. Seventy-three MDD and 94 healthy age- and sex-matched control participants were recruited from the general community. Participants had no history of drug addiction, alcoholism, brain injury, loss of consciousness, stroke, neurological disorder, or serious medical conditions. There were no significant differences between the four groups in age, gender, BMI, or alcohol use.

Main Outcome Measures

HRV was calculated from electrocardiography under a standardized short-term resting state condition.

Results

HRV was reduced in MDD relative to controls, an effect associated with a medium effect size. MDD participants with comorbid generalized anxiety disorder displayed the greatest reductions in HRV relative to controls, an effect associated with a large effect size.

Conclusions

Unmedicated, physically healthy MDD patients with and without comorbid anxiety had reduced HRV. Those with comorbid GAD showed the greatest reductions. Implications for cardiovascular risk reduction strategies in otherwise healthy patients with psychiatric illness are discussed.     

Heart rate variability in exercising humans: effect of water immersion

Power spectrum analysis of heart-rate variability was made in seven men [mean age 22 (SEM 1) years] in head-out water immersion (W) and in air (A, control) at rest and during steady-state cycling to maximal intensity (maximum oxygen uptake, V˙O_2max). At rest W resulted in a trebled increase in the total power (P < 0.05), coupled with minimal changes in the power (as a percentage of the total) of the high frequency peak (HF, centred at 0.26 Hz; 18% vs 28%) and of the low frequency peak (LF, 0.1 Hz; 24% vs 32%). A third peak at about 0.03 Hz (very low frequency, VLF) represented the remaining power both in W and A. These changes as a whole indicated that immersion caused a vagal dominance in cardiac autonomic interaction, due to the central pooling of blood and/or the pressure of water on the trunk. Exercise caused a decrease in the total power in W and A. The LF% did not change up to about 50% V˙O_2max, thereafter decreasing towards nil in both conditions. The HF% decreased in similar ways in W and A to about half at 55%–60% V˙O_2max and then increased to reach 1.5 times the resting values at V˙O_2max. The central frequency of HF increased linearly with oxygen uptake, showing a tendency to be higher in W than in A at medium to high intensities. The VLF% remained unchanged. The lack of differences in the LF peak between W and A during exercise would suggest that blood distribution had no effect on the readjustments in control mechanisms of arterial pressure. On the other hand, the findings of similar HF powers and the very similar values for ventilation in W and A confirmed the direct effect of the respiratory activity in heart rate modulation during exercise. Accepted: 25 August 1997