Heart rate variability (HRV) analysis has proved to be an important tool for assessing autonomic nervous system. For instance, it has been used during dipyridamole echocardiographic test to differentiate ischemic from nonischemic responses [6]. RR Interval analysis can provide additional information that can lead to early detection of a possible change in the activity of the autonomic nervous system. HRV analysis can be done using Wavelet Transform. This thesis presents a modification of an existing algorithm for extracting the R-R interval from EKG data sets and the use of wavelet transform (WT) technique to compute the timerequency domain energy quantities. The project used data obtained previously from a study of the effects of two pharmacological agents, atropine and propranolol, on laboratory rats. Results showed that the ratio of high frequency energy over the total energy (HF/total) of atropine treated rats was higher than baseline (control).

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T-type Ca²+ channels (TTCCs) are expressed in cardiac pacemaker cells and conduction system of mammals. However, the roles of TTCCs in heart rate (HR) generation and regulation, and arrhythmias are not well understood. In the mouse, the major TTCC expressed in the heart is Cav3.1/a1G, and therefore we used Cav3.1/ 1G transgenic (TG) and knockout (KO) mice respectively to define the role of TTCC in the heart rate generation, regulation and arrhythmias. Telemetric (conscious) and surface (anesthetized) electrocardiogram (ECG) were used to determine the baseline HR and the effect of isoproterenol (ISO) on the HR in vivo. To reduce the complication of in vivo HR regulation, Langendorff ECG (a technique to record ECG from the surface of Langendorff-perfused, spontaneously-beating, mouse hearts) was used to measure HR at baseline and after ISO stimulation. The basal firing rates and ISO-induced dose-response on the firing rate of sinoatrial nodal cells (SANCs) were studied. Whole cell voltage clamp was used to study the effects of ISO on ICa-L and ICa-T and the underlying mechanism with ventricular myocytes of 1G DTG (Cav3.1/a1G double transgenic) mice. The ICa-T before and after ISO application on a1G DTG, KO and control SAN cells were also measured. At baseline, telemetric ECG ( a technique to record ECG by a wireless ambulatory central monitoring system from the implanted transmitters) recording showed no significant difference in HR between the Cav3.1/a1G TG mice, Cav3.1/a1G KO mice and control mice. ISO increased the HR in conscious mice to the same extent in both DTG and KO mice. However, when the central nervous system regulation is depressed (anesthetized) or removed (ex-vivo Langendorff perfusion), the percentage of HR increase after ISO application was significantly enhanced in the TG mice but reduced in the KO mice. At the cellular level, both at baseline and under all different ISO concentrations, Cav3.1/a1G KO SANCs had significantly slower firing rates than those of control SANCs. ISO induced smaller beating rate increase in Cav3.1/a1G KO than in C57BL/6 control mice. Cav3.1/a1G DTG SANCs have similar firing rates as those of control SANCs at baseline. At a low ISO concentration (10-9M), the beating rate increase induced by ISO in Cav3.1/a1G DTG SANCs is a little higher but not significant than that in FVB control SANCs. However, at higher ISO concentrations (10-8 and 10-7 M), ISO induced more increases in beating rate in Cav3.1/a1G DTG SANCs than in FVB control SANCs. In DTG mice, the enhanced increase of heart rate by ISO, a ß-adrenergic agonist, is due to the upregulation of the activity of Cav3.1/a1G. The upregulation of Cav3.1/a1G activity is through protein kinase A (PKA). Db-cAMP, a PKA activator, can greatly increase the T-type calcium current (ICa-T), and H89, a PKA inhibitor, blocks ISO effect on ICa-L and ICa-T in Cav3.1/a1G DTG ventricular myocytes, ISO also significantly increases Cav3.1/1G T-type Ca²+ currents in sinoatrial nodal cells. In telemetric ECG recordings, the data showed that inactivation of Cav3.1/a1G increases the incidence of AVB (atrioventricular block, impaired conduction or blocking of the impulse at the level of the atrioventricular junction, resulting in a lack of electrical and/or mechanical coordination between the atria and the ventricles) after ISO application compared to control mice. In addition, there are more PVB (premature ventricular beat, the heartbeat that is initiated by the heart ventricles rather than by the sinoatrial node) observed in Langendorff ECG in Cav3.1/a1G KO mice after ISO application. In conclusion, Cav3.1/a1G TTCC might play important roles in basal HR generation and in sympathetic/adrenergic regulation of HR, in which PKA could be an important mediator. Ablation of Cav3.1/a1G increases the susceptibility of arrhythmia after ISO application. / Physiology

The heart rate variability (HRV) signal has been employed as a measure of sympathovagal balance in the human autonomic nervous system (ANS). It is known that aging affects the functional characteristics of the ANS. It has been suggested that complexity as measured by nonlinear dynamical indices, decays with age. We developed several algorithms and test protocols to characterize nonlinear dynamics in the HRV signal and to test the hypothesis that aging reduces the complexity within the HRV signal. Continuous HRV signal was obtained from 93 healthy subjects (41 males and 52 females) ranging in age between 5 and 78 years under controlled laboratory conditions in supine state. Subjects were from pediatric (PED, 5-12 years, n=15, 9 male, 6 female), adolescent (ADO, 13-17 years, n=16, 6 male, 10 female), adult (ADL, 18-30 years, n=22, 12 male, 10 female), middle aged (MDA, 31-60 years, n=21, 8 male, 13 female) and elderly (ELD, 61+ years, n=19, 6 male, 13 female) age groups. The length of data was 1000 or more R-R intervals for adequate computation. Stationary Holter HRV data from these controls were also used for the present study. Our results are as follows: There is a continuous systematic decay in the power-law scaling (beta), which decreases from -1.162 ± 0.388 for the PED group to -1.95 ± 0.6 for the ELD group (F = 6.649, p < 0.001; R = 0.475, p < 0.001. Approximate entropy (ApEn) decreases with age from 1.456 ± 0.093 for the PED group to 1.272 ± 0.135 for the ELD group (F = 7.82, p < 0.001; R = 0.519, p < 0.001. The detrended fluctuation analysis (DFA) of short-term data yielded an increase in short-range DFA scaling exponent (alpha)1 from 0.774 ± 0.204 for the PED group to 1.138 ± 0.289 for the ELD group (F = 7.535, p < 0.001), and in long-range DFA scaling exponent (alpha)2 increased from 0.667 ± 0.082 for the PED group to 0.86 ± 0.172 for the ELD group (F= 4.841,p < 0.001). The detrended fluctuation analysis (DFA) of long-term data yielded an increase in short-range DFA scaling exponent (alpha)1 from 1.052 ± 0.218 for the PED group to 1.204 ± 0.205 for the ELD group (F = 1.922), and in long-range DFA scaling exponent (alpha)2 increased from 0.961 ± 0.081 for the PED group to 1.076 ± 0.102 for the ELD group (F = 4.06, p < 0.01). Surrogate data analysis demonstrated that the hypothesis that the HRV signal is generated by a linear stochastic process is not always rejected. In summary, the HRV signal lends itself to an analysis using nonlinear dynamical methods and studies in patients may yield useful clinical information in the future. / Thesis / Master of Engineering (ME)

The present study investigated the efficacy of heart rate feedback training in the treatment of panic disorder. Eight patients with anxiety disorders participated in 7 feedback sessions, in which they were instrumentally trained to produce increases and decreases in heart rate in the presence of visual feedback. When they could successfully differentiate between the increase and decrease responses, subjects were instructed to use the decrease response to control anxiety and panic, and to avoid the increase response. Subjects were not made aware of the target responses until training was completed. Clinical improvement was measured through the administration of a psychometric test battery and a daily anxiety/panic diary. A non-anxious Control group, consisting of 10 subjects, was utilized to provide comparisons with the Anxiety group in the areas of feedback skill, baseline psychophysiology, and change in anxiety levels with the development of feedback skill. As a result of feedback training, Anxiety patients learned to produce increases and decreases in heart rate in the presence and absence of feedback. They also reported a decline in anxiety and panic over the course of feedback training. To evaluate whether clinical improvement was related specifically to feedback skill as opposed to non-specific treatment factors, dose-response relations were examined, where a dose was defined as a subject's degree of differentiation between increases and decreases in heart rate, as measured by a t-test. Clinical improvement was measured as the change in number of panic attacks per day, compared to baseline. A positive, significant correlation was found between subjects' degree of feedback skill and decline in panic at a one-month follow-up. A number of alternative explanations for the dose-response relationship are discussed, as well as the limitations of this study. It is concluded that further well-controlled studies will be required to confirm these findings, and to determine the source of the dose-response relationship, although this study provides encouraging evidence for the use of feedback training as a behavioral treatment for panic disorder. / Thesis / Master of Science (MS)

The purpose of this study was to assess heart rate variability (HRV) in patients with coronary artery disease (CAD): reproducibility, circadian variability and the effects of stress (coronary angiogram). Sixty-one patients who had a coronary angiogram underwent 48-hour Holter monitoring during a period of high stress beginning 4-hours post-angiography (Day 1 and 2), and again two weeks later during a period of low stress (Day 3 and 4); both 24-hour time domain and power spectral measures were computed. To determine reproducibility, intraclass correlation coefficients were calculated for both time and frequency domain indices on Days 3 and 4. The intraclass correlation coefficient for the standard deviation of normal RR-intervals over 24-hours (SDNN) was 0.91, while the standard deviation of the mean of all 5-minute segments of normal RR-intervals for 24-hours (SDANN) was 0.85. The most reproducible time domain measure was pNN50 (defined as the percentage of differences between adjacent normal RR-intervals that are greater than 50 ms computed over 24-hours) with an intraclass correlation coefficient of 0.95. As for the frequency domain measures including low frequency (LF) area, high frequency (HF) area, low frequency to high frequency area ratio (LF:HF area), LF central frequency (cf), and total area (TA), intraclass correlations were found to be the best at 0300-hours and the worst at 1500-hours. Circadian pattern was determined on Day 4 of Holter monitoring. A main effect for time was found for heart rate (HR), LF area, HF area, and TA of the power spectra. Over a 24-hour period, HR, LF area, HF area and TA were the lowest at 0300-hours compared to all other times. There was also a main effect for myocardial infarction (MI) for the frequency domain indices LF area, HF area, LF:HF area ratio, and LFcf. Low frequency area and LF:HF area ratio were significantly elevated (both p<0.05), while both HF area (p<0.05) and LFcf (p<0.01) were reduced in patients with a prior Ml compared to those with no MI. As well, a significant interaction between time of day and Ml, and time of day and beta-blocker therapy was observed. Patients with coronary artery disease and a prior Ml demonstrated a reduced circadian pattern over 24-hours for HR. Likewise, the circadian pattern of HR for those on beta-blockers was also attenuated. The effects of stress was determined by comparing Day 1 to Day 4 of ambulatory Holter monitoring. The time domain measure SDNN was found to be significantly reduced during Day 1 (mean ± SEM; 111.67 ± 6.13 ms) compared to Day 4 (121.54 ± 6.94 ms; p<0.05). Patients with normal left ventricular function (LVF) showed a significant increase from Day 1 to 4 for both SDNN (p<0.01) and SDANN (p<0.05). In contrast, those with LV dysfunction had an attenuated response. Similarly, those CAD patients on beta-blockers demonstrated a significant increase for the time domain measure SDNN (p<0.05), unlike those not on beta-blockers. In the frequency domain, LF:HF area was significantly greater on Day 1 (1.74 ± 0.09) compared to Day 4 (1.64 ± 0.09; p<0.05). These findings suggest that HRV measures are reproducible, that a circadian pattern for HRV exists in patients with CAD, and that stress induced by an invasive procedure such as a coronary angiogram enhances sympathetic input to the SA node in the heart and thereby alters the sympathovagal balance, which is restored two weeks later. / Thesis / Master of Science (MSc)

Anxiety and its cognitive component of worry have been related to exaggerated cardiovascular reactivity and delayed recovery to laboratory stressors, and to increased risk of cardiovascular disease. Previous research on the anxiety-cardiovascular system relationship, including data from Knepp and Friedman (2008), are included to support this project. Two experiments were completed during the course of this study. The first consisted of two peripheral-based body positioning tasks. The second experiment used an active versus passive sympathetic stress task paradigm (mental arithmetic, hand cold pressor). Subjects were nonsmokers free of cardiovascular and neurological disease. Trait worry was examined through the Penn State Worry Questionnaire (PSWQ). Blood pressure recordings and cardiac recordings through ECG and ICG were done in each experiment during seven epochs: an anticipatory baseline with three baselines preceding and three recovery periods following each task. Repeated measures analysis was run on all cardiovascular measures. In the first experiment, high worriers had worsened blood pressure reactivity to task. The second experiment found that high worriers had increased stroke volume across all epochs. There were mixed findings in the studies relating to subjects acclimated to the laboratory experience. Future directions of research relating anxiety, worry, and cardiovascular risk factors are discussed. / Ph. D.

Although the negative consequences of traumatic exposure across various domains of functioning have been well-documented, gaps and discrepancies continue to exist in the understanding of the impact of complex trauma, such as interpersonal violence (IPV), and how outcomes may vary across diverse populations and identities. In this cross-sectional study investigating the impact of traumatic exposure on physiological domains of functioning, a sample of female-identifying college students completed a number of self-reported measures (assessing past and present trauma exposure, complex posttraumatic stress disorder [CPTSD] symptoms, racial-ethnic minority status, and age of onset of first traumatic exposure) and provided resting high-frequency heart rate variability (hfHRV) data, which served as a biomarker for the potential impact of trauma exposure on physiological domains. Correlational and multiple regression analyses were conducted to determine the strength of relationships between variables and the predictive value of the models. Results indicated endorsement of IPV trauma was significantly associated with earlier age of onset, more severe levels of CPTSD symptoms, and higher hfHRV, but not racial-ethnic minority status. Racial-ethnic minority status was significantly related to more severe CPTSD symptoms. Type of trauma exposure was the only variable that emerged as having predictive value for changes in hfHRV. These findings suggest that experiencing IPV may have unique implications for trauma symptomatology and functioning above and beyond other forms of traumatic exposure, but that continued research must be conducted in order to draw more robust conclusions about the effects of exposure on physiological regulation across various racial-ethnic identities. / M.S. / Research has highlighted the consequences that extremely negative, stressful experiences, also called traumatic events, can have on the way humans think, emote, behave, and physically react. It can be more difficult to draw conclusions about the effects of interpersonal violence (IPV), or violence that occurs at the hands of another (i.e., family, partner, or community violence), due to the complex, severe, and long-term nature of symptoms that survivors experience. There is also limited research about what complex trauma looks like across diverse populations. This study aimed to investigate the impact of traumatic exposure on physiology, which falls under biology and broadly includes the functions of living things. A sample of female-identifying college students completed a number of self-reported measures (assessing trauma exposure, complex posttraumatic stress disorder [CPTSD] symptoms, racial-ethnic minority status, and age of onset of first traumatic exposure) and provided resting high-frequency heart rate variability (hfHRV) data, which measures variation in time between beats and served as a measure for the potential impact of trauma exposure on physiology. Results suggested that IPV exposure was associated with earlier age of first traumatic experience, more severe levels of CPTSD symptoms, and higher hfHRV. Racial-minority status was significantly related to more severe CPTSD symptoms. Type of trauma exposure significantly predicted changes in hfHRV. Findings suggest that experiencing IPV may uniquely influence trauma symptoms and functioning above and beyond other forms of traumatic exposure. Continued research will allow for stronger conclusions about the effects of traumatic exposure on physiology across various racial-ethnic identities.

Heart rate variability (HRV) has been used to evaluate cardiac autonomic function by measuring variations in electrocardiographic R-R intervals between cardiac cycles. HRV was first used to associate decreases in autonomic nervous system (ANS) control with an increased risk of mortality in coronary heart disease and in the diagnosis of diabetes (1). Current clinical research interest has extended to investigate uses of HRV to evaluate changes in the cardiovascular system due to disease, aging, physical activity, and cardiac rehabilitation treatment (2, 5). HRV scores are derivatives of R-R intervals and these may be represented as a function of either time or frequency domain parameters. Time domain analysis is the simplest and includes: the standard deviation of R-R intervals and the number of adjacent RR intervals that differ by >50ms (dRR50). Frequency domain measures involve more elaborate calculation and have been applied in studies to evaluate sympathetic and parasympathetic autonomic balance. The latter include: Low Frequency Power (LF), High Frequency Power (HF), and LF/HF ratio. HRV has been measured in a variety of ways, the most common being a continuous 24-hour collection of R-R data. In recent years, several investigators have sought to assess HRV by utilizing brief collection periods. Controversy exists about the potential of these short-term sampling intervals to yield reproducible and meaningful measurements of HRV. Many confounders such as respiration, stress, and body positioning can influence HRV, which is why a longer collection period has been accepted as the standard for providing a stable index of ANS function. However, short sampling periods would be useful to evaluate HRV when faced with time constraints. The purpose of the current study was to evaluate the reproducibility of HRV using 8-hour daytime measures with the Polar R-R RecorderTM (Polar Electro Oy, Kempele, Finland) and with short sampling duration of 512 cardiac cycles, using the Schiller AT-10TM device (Schiller AG, Baar, Switzerland). Methods: 10 apparently healthy adult volunteers participated in the study, which was conducted at the Sleep Disorders Clinic in Christiansburg, VA. Each subject performed two HRV trials with the Cardiovit AT-10TM device using recordings of 512 cardiac cycles. Within one or two days following the Schiller, the same subjects wore a Polar R-R RecorderTM device to obtain an 8-hour recording of HRV during waking hours; 24-hour urine samples were collected on the same day. Urine was analyzed for catecholamine levels, including norepinephrine and epinephrine in order to evaluate sympathetic nervous system globally. Each subject recorded their personal impressions of unavoidable physical activity and daytime stress demands on the day of the 8-hour recording and urine collection. This entire protocol was repeated one week later. On one of the days of the short sampling recording, VO2pk also was evaluated for each subject using a ramp protocol on the cycle ergometer and a metabolic cart. Results: The correlation analysis for the HRV response variables using the Schiller method indicated a high-to-very high correlation between trials within a day for the time domain measures (r = 0.75-0.99). The frequency domain measures, however, were low-to-moderately correlated (r = 0.24-0.66) between trials within a day for the Schiller method. Correlations between days for HRV response variables using the Schiller method were similarly low for both time (r < 0.5) and (r < 0.4) frequency domain measures. Correlation coefficients between days for the HRV response variables using the Polar method were moderate (r = 0.59-0.67) for the time domain and only low-moderate for the frequency domain measures (r = 0.37-0.69). However, an important finding was that Polar R-R data for two of the subjects contained excessive signal artifact, which affected the fidelity of the HRV scores. When these two cases were excluded from the group analyses, the resulting correlations were high-very high for all time and frequency domain measures (r = 0.70-0.93). The means for each response HRV time and frequency domain variable between the Polar method and Schiller method were significantly different (P < 0.05). Additional correlational analyses did not reveal any systematic associations between HRV measures and simple markers of sympathetic activity (urinary NE or E) and aerobic fitness (VO2pk) in this small sample of subjects. Conclusions: Due to this important change in reproducibility with the Polar method, the consequence of artifact-free recordings is unmistakable. Within the limitations of this small study sample it is concluded that, while HRV in apparently healthy adults may not be measured reliably with brief data collection periods, longer daytime sampling periods of 8 hours (e.g. Polar device) yields acceptable reliability for both time and frequency domain parameters of HRV. / Master of Science