Diminishment of respiratory sinus arrhythmia foreshadows doxorubicin-induced cardiomyopathy.

BACKGROUND: The development of a microcomputer-based device permits quick, simple, and noninvasive quantification of the respiratory sinus arrhythmia (RSA) during quiet breathing. METHODS AND RESULTS: We prospectively and serially measured the radionuclide left ventricular ejection fraction and the RSA amplitude in 34 cancer patients receiving up to nine monthly bolus treatments with doxorubicin hydrochloride (60 mg/m2). Of the eight patients who ultimately developed symptomatic doxorubicin-induced congestive heart failure, seven (87.5%) demonstrated a significant decline in RSA amplitude; five of 26 subjects without clinical symptoms of cardiotoxicity (19.2%) showed a similar RSA amplitude decline. On average, significant RSA amplitude decline occurred 3 months before the last planned doxorubicin dose in patients destined to develop clinical congestive heart failure. CONCLUSION: Overall, RSA amplitude abnormality proved to be a more specific predictor of clinically significant congestive heart failure than did serial resting radionuclide ejection fractions.

Respiratory and non-respiratory sinus arrhythmia: implications for heart rate variability

The quantity of blood arriving at the left side of the heart oscillates throughout the breathing cycle due to the mechanics of breathing. Neurally regulated fluctuations in the length of the heart period act to dampen oscillations of the left ventricular stroke volume entering the aorta. We have reported that stroke volume oscillations but not spectral frequency variability stroke volume measures can be used to estimate the breathing frequency. This study investigated with the same recordings whether heart period oscillations or spectral heart rate variability measures could function as estimators of breathing frequency. Continuous 270 s cardiovascular recordings were obtained from 22 healthy adult volunteers in the supine and upright postures. Breathing was recorded simultaneously. Breathing frequency and heart period oscillation frequency were calculated manually, while heart rate variability spectral maximums were obtained using heart rate variability software. These estimates were compared to the breathing frequency using the Bland–Altman agreement procedure. Estimates were required to be \±10% (95% levels of agreement). The 95% levels of agreement measures for the heart period oscillation frequency (supine: -27.7 to 52.0%, upright: -37.8 to 45.9%) and the heart rate variability spectral maximum estimates (supine: -48.7 to 26.5% and -56.4 to 62.7%, upright: -37.8 to 39.3%) exceeded 10%. Multiple heart period oscillations were observed to occur during breathing cycles. Both respiratory and non-respiratory sinus arrhythmia was observed amongst healthy adults. This observation at least partly explains why heart period parameters and heart rate variability parameters are not reliable estimators of breathing frequency. In determining the validity of spectral heart rate variability measurements we suggest that it is the position of the spectral peaks and not the breathing

Respiratory Sinus Arrhythmia and Emotional Responding to Dyadic Discussions of a Disagreement as Predictors of Helping Related Subjective Well-Being in Older Mothers and Their Adult Daughters

The current study considered affect-related variables as predictors of the quality of helping relationships between older mothers and their adult daughters. Specifically, self-reported and observed emotional responses to the dyadic discussion of a disagreement between mothers and daughters, as well as baseline measures of respiratory sinus arrhythmia were considered as predictors of mothers' and daughters' satisfaction with their helping relationships. Relationship satisfaction was measured by considering mothers' and daughters' subjective well-being specifically in regards to the help they gave and received. Overall, these variables predicted more variance in mothers' satisfaction with their helping relationships than daughters', and RSA (respiratory sinus arrhythmia) was a stronger predictor than the self-reported or observed emotional reactions to the dyadic discussion of a disagreement. Implications of these findings and limitations to the current study are discussed.

Evidence for a respiratory component, similar to mammalian respiratory sinus arrhythmia, in the heart rate variability signal from the rattlesnake, Crotalus durissus terrificus

Autonomic control of heart rate variability and the central location of vagal preganglionic neurones (VPN) were examined in the rattlesnake ( Crotalus durissus terrificus), in order to determine whether respiratory sinus arrhythmia (RSA) occurred in a similar manner to that described for mammals. Resting ECG signals were recorded in undisturbed snakes using miniature datalogging devices, and the presence of oscillations in heart rate (f(H)) was assessed by power spectral analysis (PSA). This mathematical technique provides a graphical output that enables the estimation of cardiac autonomic control by measuring periodic changes in the heart beat interval. At fH above 19 min(-1) spectra were mainly characterised by low frequency components, reflecting mainly adrenergic tonus on the heart. By contrast, at f(H) below 19 min(-1) spectra typically contained high frequency components, demonstrated to be cholinergic in origin. Snakes with a f(H) > 19 min(-1) may therefore have insufficient cholinergic tonus and/or too high an adrenergic tonus acting upon the heart for respiratory sinus arrhythmia ( RSA) to develop. A parallel study monitored f(Hd) simultaneously with the intraperitoneal pressures associated with lung inflation. Snakes with a fH < 19 min(-1) exhibited a high frequency (HF) peak in the power spectrum, which correlated with ventilation rate (f(V)). Adrenergic blockade by propranolol infusion increased the variability of the ventilation cycle, and the oscillatory component of the f(H) spectrum broadened accordingly. Infusion of atropine to effect cholinergic blockade abolished this HF component, confirming a role for vagal control of the heart in matching f(H) and f(V) in the rattlesnake. A neuroanatomical study of the brainstem revealed two locations for vagal preganglionic neurones (VPN). This is consistent with the suggestion that generation of ventilatory components in the heart rate variability (HRV) signal are dependent on spatially distinct loci for cardiac VPN. Therefore, this study has demonstrated the presence of RSA in the HRV signal and a dual location for VPN in the rattlesnake. We suggest there to be a causal relationship between these two observations.

Adaption of cardio-respiratory balance during day-rest compared to deep sleep—An indicator for quality of life?

Heart rate and breathing rate fluctuations represent interacting physiological oscillations. These interactions are commonly studied using respiratory sinus arrhythmia (RSA) of heart rate variability (HRV) or analyzing cardiorespiratory synchronization. Earlier work has focused on a third type of relationship, the temporal ratio of respiration rate and heart rate (HRR). Each method seems to reveal a specific aspect of cardiorespiratory interaction and may be suitable for assessing states of arousal and relaxation of the organism. We used HRR in a study with 87 healthy subjects to determine the ability to relax during 5 day-resting periods in comparison to deep sleep relaxation. The degree to which a person during waking state could relax was compared to somatic complaints, health-related quality of life, anxiety and depression. Our results show, that HRR is barely connected to balance (LF/HF) in HRV, but significantly correlates to the perception of general health and mental well-being as well as to depression. If relaxation, as expressed in HRR, during day-resting is near to deep sleep relaxation, the subjects felt healthier, indicated better mental well-being and less depressive moods.

Chronic and acute stress in atherosclerosis : the role of endothelial function and arterial elasticity

Atherosclerosis is the main underlying pathology of coronary heart disease. Coronary heart disease is a serious health problem in Finland, and it is the leading cause of morbidity and mortality in industrialized countries. Psychological stress correlates with coronary heart disease events – myocardial infarction and sudden death, which are the most common clinical syndromes of atherosclerotic narrowing of arteries. The present series of studies examines the interaction between stress and endothelial function in relation to atherosclerosis. The study also aims to give new information on the mechanisms through which stress has its effect on atherosclerosis progression, focusing on possible relations between psychological stress and the functioning of the endothelium. Our project is based on data from one of the largest national epidemiological studies, the Cardiovascular Risk in Young Finns study, which has monitored the development of risk factors for coronary heart disease in 3596 young adults since 1980. The present study combines experimental stress research with epidemiology and uses an advanced method for examining atherosclerosis development in healthy subjects (intima-media thickness ultrasound measurement). The physiological parameters used were heart rate, respiratory sinus arrhythmia and pre-ejection period. Chronic stress was assessed by vital exhaustion. The ultrasound measurements that served as the indexes of preclinical atherosclerosis were carotid intima-media thickness, brachial flow-mediated dilatation and carotid artery compliance. The effects of cardiovascular risk factors found to be important were taken into account: serum cholesterols level, triglyceride level, serum insulin level and systolic and diastolic blood pressure. There were 69, 1596, 81 and 1721 participants in studies I-IV, respectively. The results showed that both chronic and acute stress may exert an effect on atherosclerosis in subjects with impaired endothelial responses. The findings are consistent with the idea that risk factors are more harmful if the endothelium is not working properly. Chronic stress was found to be a risk if it has resulted in ineffective cardiac stress reactivity or delayed recovery. Men were shown to be at increased risk for atherosclerotic progression in early life, which suggests men’s decreased stress coping ability in relation to stressful psychosocial coronary risk factors. Autonomic imbalance may be the common mechanism of the stress influence on atherosclerosis development. The results of the present study contain background information for the identification the first stages of atherosclerosis, and they may be useful for preventive medicine programs for young adults and could help to improve cardiovascular health in Finland as well as in other countries.

Contingency Learning and Reactivity in Preterm and Full-Term Infants at 3 Months

Learning difficulties in preterm infants are thought to reflect impairment in arousal regulation. We examined relationships among gestational age, learning speed, and behavioral and physiological reactivity in 55 preterm and 49 full-term infants during baseline, contingency, and nonreinforcement phases of a conjugate mobile paradigm at 3 months corrected age. For all infants, negative affect, looking duration, and heart rate levels increased during contingency and nonreinforcement phases, whereas respiratory sinus arrhythmia (RSA, an index of parasympathetic activity) decreased and cortisol did not change. Learners showed greater RSA suppression and less negative affect than nonlearners. This pattern was particularly evident in the preterm group. Overall, preterm infants showed less learning, spent less time looking at the mobile, and had lower cortisol levels than full-term infants. Preterm infants also showed greater heart rate responses to contingency and dampened heart rate responses to nonreinforcement compared to full-term infants. Findings underscore differences in basal and reactivity measures in preterm compared to full-term infants and suggest that the capacity to regulate parasympathetic activity during a challenge enhances learning in preterm infants.

The developmental character of cardiac autonomic responses to an acute noxious event in 4- and 8-month-old healthy infants

Heart rate (HR) has been widely studied as a measure of an individual's response to painful stimuli. It remains unclear whether changes in mean HR or the variability of HR are specifically related to the noxious stimulus (i.e. pain). Neither is it well understood how such changes reflect underlying neurologic control mechanisms that produce these responses, or how these mechanisms change during the first year of life. To study the changes in cardiac autonomic modulation that occur with acute pain and with age during early infancy, the relationship between respiratory activity and short-term variations of HR (i.e. respiratory sinus arrhythmia) was quantified in a longitudinal study of term born healthy infants who underwent a finger lance blood collection at 4 months of age (n = 24) and again at 8 months of age (n = 20). Quantitative respiratory activity and HR were obtained during baseline, lance, and recovery periods. Time and frequency domain analyses from 2.2-min epochs of data yielded mean values, spectral measures of low (0.04-0.15 Hz) and high (0.15-0.80 Hz) frequency power (LF and HF), and the LF/HF ratio. To determine sympathetic and parasympathetic cardiac activity, the transfer relation between respiration and HR was used. At both 4 and 8 months, mean HR increased significantly with the noxious event (p > 0.01). There were age-related differences in the pattern of LF, HF, and LF/HF ratio changes. Although these parameters all decreased (p > 0.01) at 4 months, LF and LF/HF increased at 8 months and at 8 months HF remained stable in response to the noxious stimulus. Transfer gain changes with the lance demonstrated a change from predominant vagal baseline to a sympathetic condition at both ages. The primary finding of this study is that a response to an acute noxious stimulus appears to produce an increase in respiratory-related sympathetic HR control and a significant decrease in respiratory-related parasympathetic control at both 4 and 8 months. Furthermore, with increasing age, the sympathetic and parasympathetic changes appear to be less intense, but more sustained.

Cortical and autonomic modulation of attentional control /

Whereas the role of the anterior cingulate cortex (ACC) in cognitive control has received considerable attention, much less work has been done on the role of the ACC in autonomic regulation. Its connections through the vagus nerve to the sinoatrial node of the heart are thought to exert modulatory control over cardiovascular arousal. Therefore, ACC is not only responsible for the implementation of cognitive control, but also for the dynamic regulation of cardiovascular activity that characterizes healthy heart rate and adaptive behaviour. However, cognitive control and autonomic regulation are rarely examined together. Moreover, those studies that have examined the role of phasic vagal cardiac control in conjunction with cognitive performance have produced mixed results, finding relations for specific age groups and types of tasks but not consistently. So, while autonomic regulatory control appears to support effective cognitive performance under some conditions, it is not presently clear just what factors contribute to these relations. The goal of the present study was, therefore, to examine the relations between autonomic arousal, neural responsivity, and cognitive performance in the context of a task that required ACC support. Participants completed a primary inhibitory control task with a working memory load embedded. Pre-test cardiovascular measures were obtained, and ontask ERPs associated with response control (N2/P3) and error-related processes (ERN/Pe) were analyzed. Results indicated that response inhibition was unrelated to phasic vagal cardiac control, as indexed by respiratory sinus arrhythmia (RSA). However, higher resting RSA was associated with larger ERN ampUtude for the highest working memory load condition. This finding suggests that those individuals with greater autonomic regulatory control exhibited more robust ACC error-related responses on the most challenging task condition. On the other hand, exploratory analyses with rate pressure product (RPP), a measure of sympathetic arousal, indicated that higher pre-test RPP (i.e., more sympathetic influence) was associated with more errors on "catch" NoGo trials, i.e., NoGo trials that simultaneously followed other NoGo trials, and consequently, reqviired enhanced response control. Higher pre-test RPP was also associated with smaller amplitude ERNs for all three working memory loads and smaller ampUtude P3s for the low and medium working memory load conditions. Thus, higher pretest sympathetic arousal was associated with poorer performance on more demanding "catch" NoGo trials and less robust ACC-related electrocortical responses. The findings firom the present study highlight tiie interdependence of electrocortical and cardiovascular processes. While higher pre-test parasympathetic control seemed to relate to more robust ACC error-related responses, higher pre-test sympathetic arousal resulted in poorer inhibitory control performance and smaller ACC-generated electrocortical responses. Furthermore, these results provide a base from which to explore the relation between ACC and neuro/cardiac responses in older adults who may display greater variance due to the vulnerabihty of these systems to the normal aging process.

Autonomic and Electrophysiological Correlates of Cognitive Control in Aging

This thesis tested a model of neurovisceral integration (Thayer & Lane, 2001) wherein parasympathetic autonomic regulation is considered to play a central role in cognitive control. We asked whether respiratory sinus arrhythmia (RSA), a parasympathetic index, and cardiac workload (rate pressure product, RPP) would influence cognition and whether this would change with age. Cognitive control was measured behaviourally and electrophysiologically through the error-related negativity (ERN) and error positivity (Pe). The ERN and Pe are thought to be generated by the anterior cingulate cortex (ACC), a region involved in regulating cognitive and autonomic control and susceptible to age-related change. In Study 1, older and younger adults completed a working memory Go/NoGo task. Although RSA did not relate to performance, higher pre-task RPP was associated with poorer NoGo performance among older adults. Relations between ERN/Pe and accuracy were indirect and more evident in younger adults. Thus, Study 1 supported the link between cognition and autonomic activity, specifically, cardiac workload in older adults. In Study 2, we included younger adults and manipulated a Stroop task to clarify conditions under which associations between RSA and performance will likely emerge. We varied task parameters to allow for proactive versus reactive strategies, and motivation was increased via financial incentive. Pre-task RSA predicted accuracy when response contingencies required maintenance of a specific item in memory. Thus, RSA was most relevant when performance required proactive control, a metabolically costly strategy that would presumably be more reliant on autonomic flexibility. In Study 3, we included older adults and examined RSA and proactive control in an additive factors framework. We maintained the incentive and measured fitness. Higher pre-task RSA among older adults was associated with greater accuracy when proactive control was needed most. Conversely, performance of young women was consistently associated with fitness. Relations between ERN/Pe and accuracy were modest; however, isolating ACC activity via independent component analysis allowed for more associations with accuracy to emerge in younger adults. Thus, performance in both groups appeared to be differentially dependent on RSA and ACC activation. Altogether, these data are consistent with a neurovisceral integration model in the context of cognitive control.

Evaluation du systeme nerveux autonome dans l'hypertension arterielle essentielle

L’analyse spectrale de la fréquence cardiaque, de la pression artérielle systolique, de la pression artérielle diastolique ainsi que de la respiration par la transformée de Fourier rapide, est considérée comme une technique non invasive pour la détermination de l’activité du système nerveux autonome (SNA). Dans une population de sujets normaux volontaires, nous avons obtenu à l’état basal, des oscillations de basses fréquences (0,05-0,15Hz) reliées au système nerveux sympathique autonome et des oscillations de hautes fréquences (0,2Hz) représentant sur les intervalles entre chaque ondes R de l’électrocardiogramme (RR), l’arythmie sinusale respiratoire correspondant à une activité vagale. Nous avons comparé les tests de stimulation du système nerveux sympathique autonome déclenché par le passage de la position de repos (en décubitus dorsal), à la position orthostatique volontaire et le passage de la position de repos à la position orthostatique avec la table basculante à 60o. Nous avons également comparé un groupe normotendu à un groupe hypertendu qui a été soumis au passage du repos à l’orthostation volontaire et pour lesquels nous avons évalué la sensibilité du baroréflexe et la réponse sympathique par la mesure des catécholamines circulantes. Dans un groupe de sujets ayant une hypertension artérielle essentielle, nous avons évalué l’effet de la thérapie hypotensive, par le Trandolapril qui est un Inhibiteur de l’enzyme de conversion (IEC) de l`angiotensine. Dans ce groupe hypertendu, nous avons procédé, en plus de la stimulation sympathique par l’orthostation volontaire, à un exercice isométrique de trois minutes à 30 % de la force maximale. Nous avons également complété notre évaluation par la mesure de la densité de récepteurs ß2 adrénergiques sur lymphocytes et par la mesure des indices de contractilité à l’aide de l’échocardiographie en M mode. Les résultats ont montré, dans les groupes normaux volontaires, dans les deux types de stimulation du système nerveux sympathique par la position orthostatique, une augmentation significative des catécholamines plasmatiques avec une augmentation de la fréquence cardiaque et des basses fréquences de RR, confirmant ainsi que l’on est en état de stimulation sympathique. On observe en même temps une diminution significative des hautes fréquences de RR, suggérant un retrait vagal lors de cette stimulation. On a observé au test de la table basculante six cas d’hypotension orthostatique. On a comparé la position orthostatique volontaire entre le groupe de sujets normaux et le groupe de sujets hypertendus. L’analyse spectrale croisée de RR et de la pression artérielle systolique a permis d’évaluer dans l’hypertension artérielle (HTA), essentielle une sensibilité du baroréflexe atténuée, accompagnée d’une réactivité vagale réduite en présence d’une activité et d’une réactivité sympathique augmentées suggérant une altération sympathovagale dans l’HTA. Dans le groupe de sujets hypertendus traités (Trandolapril 2mg/jour), nous avons identifié un groupe de répondeurs au traitement par le Trandolapril et un groupe de non répondeurs à ce type de thérapie anti-hypertensive. Le groupe répondeur avait un profil hyper-adrénergique avec une hyper-réactivité sympathique, une fréquence cardiaque et des pressions artérielles diastolique et systolique plus élevées au repos. Dans le groupe total traité au Trandolapril, la densité des récepteurs ß2 adrénergiques a doublé, après thérapie, alors que la réactivité des basses fréquences obtenues à l’analyse spectrale a augmenté. Nous avons montré dans notre étude qu’un IECA a pu inhiber le mécanisme facilitateur de l’angII sur les terminaisons nerveuses sympathiques et a permis ainsi de réduire l’hyperactivité sympathique et le mécanisme de « down regulation » des récepteurs ß2 adrénergiques rendant ainsi l’expression de l’influence du SNA post synaptique plus efficace. Dans l’ensemble de nos protocoles cliniques, par l’utilisation de l’analyse spectrale des signaux RR, de la pression artérielle systolique,de la pression artérielle diastolique et de la respiration, nous avons montré que cette technique non invasive permet de décrire et de mieux comprendre les mécanismes physiologiques, physiopathologiques et pharmacologiques reliés au système nerveux autonome et à l’hypertension artérielle essentielle.

Autonomic arousal in childhood anxiety disorders: associations with state anxiety and social anxiety disorder

Background Psychophysiological theories suggest that individuals with anxiety disorders may evidence inflexibility in their autonomic activity at rest and when responding to stressors. In addition, theories of social anxiety disorder, in particular, highlight the importance of physical symptoms. Research on autonomic activity in childhood (social) anxiety disorders, however, is scarce and has produced inconsistent findings, possibly because of methodological limitations. Method The present study aimed to account for limitations of previous studies and measured respiratory sinus arrhythmia (RSA) and heart rate (HR) using Actiheart heart rate monitors and software (Version 4) during rest and in response to a social and a non-social stressor in 60 anxious (30 socially anxious and 30 ‘other’ anxious), and 30 nonanxious sex-and age-matched 7–12 year olds. In addition, the effect of state anxiety during the tasks was explored. Results No group differences at rest or in response to stress were found. Importantly, however, with increases in state anxiety, all children, regardless of their anxiety diagnoses showed less autonomic responding (i.e., less change in HR and RSA from baseline in response to task) and took longer to recover once the stressor had passed. Limitations This study focused primarily on parasympathetic arousal and lacked measures of sympathetic arousal. Conclusion The findings suggest that childhood anxiety disorders may not be characterized by inflexible autonomic responding, and that previous findings to the contrary may have been the result of differences in subjective anxiety between anxious and nonanxious groups during the tasks, rather than a function of chronic autonomic dysregulation.

Evidence for sex differences in fetal programming of physiological stress reactivity in infancy

Associations between low birth weight and prenatal anxiety and later psychopathology may arise from programming effects likely to be adaptive under some, but not other, environmental exposures and modified by sex differences. If physiological reactivity, which also confers vulnerability or resilience in an environment-dependent manner, is associated with birth weight and prenatal anxiety, it will be a candidate to mediate the links with psychopathology. From a general population sample of 1,233 first-time mothers recruited at 20 weeks gestation, a sample of 316 stratified by adversity was assessed at 32 weeks and when their infants were aged 29 weeks (N = 271). Prenatal anxiety was assessed by self-report, birth weight from medical records, and vagal reactivity from respiratory sinus arrhythmia during four nonstressful and one stressful (still-face) procedure. Lower birth weight for gestational age predicted higher vagal reactivity only in girls (interaction term, p = .016), and prenatal maternal anxiety predicted lower vagal reactivity only in boys (interaction term, p = .014). These findings are consistent with sex differences in fetal programming, whereby prenatal risks are associated with increased stress reactivity in females but decreased reactivity in males, with distinctive advantages and penalties for each sex.

Clinical characterization of chronic chagasic cardiomyopathy in dogs

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Autonomic control of cardiorespiratory interactions in fish, amphibians and reptiles

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)