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.

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.

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.

Effect of exercise training on heart rate variability in healthy older adults.

OBJECTIVE: To determine the effect of exercise training on cardiac autonomic modulation in normal older adults by using analysis of heart rate variability. SUBJECTS: The exercise group consisted of 7 men and 9 women aged 66 +/- 4 years. The comparison group consisted of 7 men and 9 women also aged 66 +/- 4 years. METHOD: Heart rate variability was determined from 24-hour Holter recordings before and after 12 months of supervised exercise, which consisted of 3 months of stretching and 9 months of 5 hours/week aerobic exercise at approximately 70% of maximal oxygen uptake. Heart rate variability was measured at baseline and 12 months later in the comparison group, who had not changed their usual activity level. RESULTS: In the exercise group maximal oxygen consumption increased from 1.8 +/- 0.5 L/min to 2.2 +/- 0.7 L/min (P <.05). The standard deviation of normal interbeat intervals increased from 126 +/- 21 ms to 142 +/- 25 ms. Mean nighttime heart rate decreased from 67 +/- 6 beats/min to 63 +/- 5 beats/min. Increased fitness level had little effect on indexes of heart rate variability, which reflect parasympathetic or mixed sympathetic/parasympathetic modulation of heart rate. There was no change in heart rate or heart rate variability in the comparison group. CONCLUSIONS: Exercise training increases total heart rate variability in normal older adults. The most marked alterations are in nocturnal heart rate. Heart rate variability is stable over a 1-year period in older adults who do not alter their activity level.

Using missing data techniques to explore the lack of survival effect: illustration with the CABG patch trial.

The Multicenter Automatic Defibrillator Implantation Trial (MADIT) showed a conclusive 54 per cent reduction in mortality in patients with inducible sustained monomorphic ventricular tachycardia (VT) and impaired left ventricular function who received an implantable defibrillator compared with those who did not. The Coronary Artery Bypass Graft (CABG) Patch Trial, which studied a patient population with a similar extent of left ventricular dysfunction and overall cardiovascular risk, demonstrated no mortality benefit from placement of an implantable defibrillator. All patients in the MADIT trial were 'VT inducible', while this criterion was neither required nor evaluated for entry into the CABG Patch Trial. A statistical approach to estimating with good accuracy the fraction of CABG Patch patients who were inducible at the time of their randomization from the prevalence of VT inducibility in the surviving CABG Patch Trial control population during follow-up is presented. This more generally applicable approach estimates the mixing percentage using missing data techniques. We present the mathematical and physiological basis of the assumptions underpinning the mixture model and its estimation procedure. The mixture model forms the basis for the electrophysiological substudy to the CABG Patch Trial, which directly tests the hypothesis that the difference in the frequency of inducible VT between the MADIT and CABG Patch patients populations is sufficient to account for the difference in effect on mortality.

Changes in 24-hour heart rate variability during normal pregnancy.

OBJECTIVE: We studied the effects of normal pregnancy on heart rate variability as a noninvasive index of maternal cardiovascular autonomic modulation. STUDY DESIGN: Twenty-four-hour Holter recordings were obtained for 8 healthy pregnant volunteers during early pregnancy (

Mechanisms of death in the CABG Patch trial: a randomized trial of implantable cardiac defibrillator prophylaxis in patients at high risk of death after coronary artery bypass graft surgery.

BACKGROUND: The CABG Patch trial compared prophylactic implantable cardiac-defibrillator (ICD) implantation with no antiarrhythmic therapy in coronary bypass surgery patients who had a left ventricular ejection fraction <0.36 and an abnormal signal-averaged ECG. There were 102 deaths among the 446 ICD group patients and 96 deaths among the 454 control group patients, a hazard ratio of 1.07 (P=0.63). The mechanisms of death were classified, and hypotheses were tested about the effects of ICD therapy on arrhythmic and nonarrhythmic cardiac deaths in the CABG Patch Trial and the Multicenter Automatic Defibrillator Implantation Trial (MADIT). METHODS AND RESULTS: The 198 deaths in the trial were reviewed by an independent Events Committee and classified by the method of Hinkle and Thaler. Only 54 deaths (27%) occurred out of hospital; 145 deaths (73%) were witnessed. Seventy-nine (82%) of the 96 deaths in the control group and 76 (75%) of the 102 deaths in the ICD group were due to cardiac causes. Cumulative arrhythmic mortality at 42 months was 6.9% in the control group and 4.0% in the ICD group (P=0. 057). Cumulative nonarrhythmic cardiac mortality at 42 months was 12. 4% in the control group and 13.0% in the ICD group (P=0.275). Death due to pump failure was significantly associated with death >1 hour from the onset of symptoms, dyspnea within 7 days of death, and overt heart failure within 7 days of death. CONCLUSIONS: In the CABG Patch Trial, ICD therapy reduced arrhythmic death 45% without significant effect on nonarrhythmic deaths. Because 71% of the deaths were nonarrhythmic, total mortality was not significantly reduced.

A concise promoter region of the heart fatty acid-binding protein gene dictates tissue-appropriate expression.

The heart fatty acid-binding protein (HFABP) is a member of a family of binding proteins with distinct tissue distributions and diverse roles in fatty acid metabolism, trafficking, and signaling. Other members of this family have been shown to possess concise promoter regions that direct appropriate tissue-specific expression. The basis for the specific expression of the HFABP has not been previously evaluated, and the mechanisms governing expression of metabolic genes in the heart are not completely understood. We used transient and permanent transfections in ventricular myocytes, skeletal myocytes, and nonmyocytic cells to map regulatory elements in the HFABP promoter, and audited results in transgenic mice. Appropriate tissue-specific expression in cell culture and in transgenic mice was dictated by 1.2 kb of the 5'-flanking sequence of FABP3, the HFABP gene. Comparison of orthologous murine and human genomic sequences demonstrated multiple regions of near-identity within this promoter region, including a CArG-like element close to the TATA box. Binding and transactivation studies demonstrated that this element can function as an atypical myocyte enhancer-binding factor 2 site. Interactions with adjacent sites are likely to be necessary for fully appropriate, tissue-specific, developmental and metabolic regulation.

RR interval dynamics before atrial fibrillation in patients after coronary artery bypass graft surgery.

BACKGROUND: Atrial fibrillation/flutter (AF) is a frequent complication of coronary artery bypass graft surgery (CABG) that leads to increased costs and morbidity. We hypothesized that heart rate variability (HRV), an indicator of cardiac sympathovagal balance, is altered before the onset of postoperative AF. Because nonlinear methods of HRV analysis provide information about heart rate dynamics not evident from usual HRV measures, we also hypothesized that approximate entropy (ApEn), a nonlinear measure of HRV, might have predictive value. METHODS AND RESULTS: Analysis of HRV was performed in 3 sequential 20-minute intervals preceding the onset of postoperative AF (24 episodes in 18 patients). These data were compared with corresponding intervals in 18 sex- and age-matched postoperative control subjects who did not develop AF. Patients had left ventricular ejection fractions >45% before surgery and were not receiving beta-blockers during ambulatory ECG monitoring after surgery. Logistic regression demonstrated that on the basis of averaged values for the three 20-minute intervals, increased heart rate and decreased ApEn were independently associated with AF. Heart rate dynamics before AF was associated with either lower (n= 19) or higher (n=5) RR interval variation by traditional measures of HRV or quantitative Poincaré analysis, suggesting the possibility of divergent autonomic conditions before AF onset. CONCLUSIONS: In the hour before AF after CABG surgery, higher heart rate and lower heart rate complexity compared with values in control patients were independent predictors of AF. Decreased ApEn occurs in patients with either increased or decreased HRV by traditional measures and may provide a useful tool for risk stratification or investigation of mechanisms.

RGS3 and RGS4 are GTPase activating proteins in the heart.

RGS family members are regulatory molecules that act as GTPase activating proteins (GAPs) for G alpha subunits of heterotrimeric G proteins. RGS proteins are able to deactivate G protein subunits of the Gi alpha, Go alpha and Gq alpha subtypes when tested in vitro and in vivo. Although the function of RGS proteins in cardiac physiology is unknown, their ability to deactivate Galpha subunits suggests that they may inhibit the action of muscarinic, alpha-adrenergic, endothelin, and other agonists. To evaluate the role of RGS family members in the regulation of cardiac physiology, we investigated the expression pattern of two RGS genes in normal and diseased rat heart tissue. RGS3 and RGS4 mRNAs and proteins were detected in adult myocardium. RGS3 and RGS4 gene expression was markedly enhanced in two model systems of cardiac hypertrophy: growth factor-stimulated cultured neonatal rat cardiomyocytes and pulmonary artery-banded (PAB) mice. RGS3 and RGS4 mRNA levels were reduced in failing myocardium obtained from SHHF/Mcc-fa(cp) (SHHF) rats. These findings support the hypothesis that RGS gene expression is highly regulated in myocardium and imply that RGS family members play an important role in the regulation of cardiac function.

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.

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.

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.

Heart rate variability in a case of pheochromocytoma.

Indices of heart rate variability (HRV) reflect cardiac autonomic tone and may be markedly affected by pheochromocytoma. The effect of pheochromocytoma on HRV was determined by Holter monitoring before diagnosis, under pre-operative alpha-blockade and 5 and 19 months after surgery in a 40 year-old female. Mean heart rates, although higher under alpha-blockade, were unchanged by surgery but indices of HRV reflecting both short term (vagally mediated) and longer term (mediated by vagal, sympathetic and other influences) rhythms were diminished under alpha-blockade and post-surgery. High frequency power (0.15-0.40 Hz), an index of vagal tone, declined from 512 ms2 pre-diagnosis to 220 ms2 under alpha-blockade to just over 100 ms2 post-surgery. Low frequency power (0.04-0.15 Hz), a measure reflecting both vagal and sympathetic tone, declined from 409 ms2 pre-diagnosis to 186 ms2 under alpha-blockade and was just over 200 ms2 post-surgery. SDNN, the standard deviation of normal-to-normal interbeat intervals over 24 hours, declined from 118 ms pre-diagnosis to just over 70 ms both under alpha-blockade and post-surgery. The ratio of low frequency to high frequency power (LF/HF ratio) increased to 0.84 under alpha-blockade, and doubled after surgery (0.79; before, 2.05; after). These changes in HRV may provide insights into the effects of endogenous catecholamines and intrinsic counter-regulatory autonomic mechanisms on HRV.

Osteopontin expression is increased in the heritable cardiomyopathy of Syrian hamsters.

BACKGROUND: Osteopontin, a noncollagenous matrix protein, is transiently expressed in the heart after experimental cardiac injury, but its expression in states of continuing cardiac remodeling is unknown. We evaluated osteopontin expression in the heritable cardiomyopathy of the Syrian hamster. METHODS AND RESULTS: Hamster hearts were obtained for RNA isolation and analysis and in situ hybridization from two groups: normal control animals (n = 4) and untreated cardiomyopathic hamsters (n = 5). Osteopontin mRNA was 12-fold greater in cardiomyopathic hearts compared with normal controls (1.76 +/- 0.31 versus 0.14 +/- 0.04 arbitrary units normalized to GAPDH, mean +/- SEM, P < .05). In situ hybridization was used to define the origin of osteopontin in the heart. Osteopontin mRNA above background levels was not detected in sections from noncardiomyopathic hamster hearts but was readily detected in sections from cardiomyopathic hamsters, in which it originated in cells morphologically consistent with tissue macrophages. CONCLUSIONS: In the hamster, osteopontin is expressed in heritably cardiomyopathic hearts under conditions of chronic injury and repair, and the source of ostopontin message appears to be issue macrophage-like cells in foci of inflammation. This model could be used to evaluate the biological role of osteopontin in myocardial inflammation and remodeling.

Stability of index of heart rate variability in patients with congestive heart failure.

Stability of indexes of heart rate variability (HRV) has not been established for patients with congestive heart failure (CHF). We therefore measured Holter-derived HRV indexes in 17 stable patients with class II or III CHF (mean age 52 +/- 9 yr; 5 men and 12 women) on two occasions 2 weeks apart. Stability was determined via paired t tests and intraclass correlation coefficients (ICCs). ICCs for time domain indexes of HRV were > or = 0.86 for 24 hours, > or = 0.73 for daytime, and > or = 0.72 for nighttime indexes reflecting longer-term variability. After log transformation, ICCs for the short-term 24-hour measures PNN50 (percentage of N-N intervals > 50 msec different from preceding interval) and RMSSD (the root mean square of successive differences) were 0.85 and 0.67. ICCs for frequency domain indexes of HRV were 0.86 to 0.91. We compared HRV indexes, serum norepinephrine (NE) levels, and respiratory sinus arrhythmia induced by paced breathing, also considered measures of autonomic tone. NE correlated weakly with average R-R interval, and all indexes of HRV reflecting longer-term variation (r = -0.32 to r = -0.50). ICC was 0.78 for NE. Respiratory sinus arrhythmia was highly repeatable (ICC = 0.70) but did not correlate significantly with NE or any measure of HRV. We conclude that time and frequency domain indexes of HRV are stable over time in CHF patients without intervening events.

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.

Comparison of the patterns of expression of rat intestinal fatty acid binding protein/human growth hormone fusion genes in cultured intestinal epithelial cell lines and in the gut epithelium of transgenic mice.

The intestinal fatty acid binding protein gene (Fabpi) provides a good model system for studying how gene transcription is regulated in enterocytes as a function of their differentiation program and location along the duodenal-to-colonic axis. We have compared and contrasted the transcriptional activity of four fusion genes composed of elements from the 5'-nontranscribed domain of rat Fabpi linked to the human growth hormone gene (I-FABP/hGH) in transgenic mice and in five primate epithelial cell lines derived from intestine, liver, kidney, and cervix. Nucleotides -103 to +28 of rat Fabpi are able to direct appropriate lineage-specific and geographic patterns of hGH expression in transgenic mice. I-FABP-103 to +28/hGH is preferentially expressed in Caco-2 cells, which emulate some of the features of differentiated small intestinal enterocytes after they reach confluence. However, other I-FABP/hGH fusion genes that exhibit differentiation-dependent changes in their expression along the crypt-to-villus axis do not manifest the same pattern of differentiation-dependent change in activity in this cell line. Correlation of their patterns of expression in vivo and ex vivo suggest that nonproliferating Caco-2 cells mimic some of the features of the transcriptional regulatory environment of enterocytes located in the upper crypt. Nucleotides -103 to +28 of rat Fabpi contain one copy of a repeated 14-base pair element that is conserved in the orthologous mouse and human genes and represented in several other homologous and nonhomologous genes, which are expressed in villus-associated enterocytes. This element binds to two members of the steroid hormone receptor superfamily of transcription factors produced in enterocytes and Caco-2 cells: hepatic nuclear factor-4 (HNF-4) and apolipoprotein regulatory protein-1 (ARP-1). Co-transfection studies performed in Caco-2 cells and in a monkey kidney cell line (CV-1) that lacks endogenous pools of ARP-1 and HNF-4 suggest that ARP-1 and HNF-4 can function to activate I-FABP-103 to +28/hGH+3 through their interactions with the 14-base pair element. This activation appears to be affected by elements located between nucleotides -277 and -104 and other transcription factors.

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.