Vagal dysregulation in early childhood and cardiovascular risk in adolescence

Objective: Poor behavioral self-regulation in the first 2 decades of life has been identified as an important precursor of disease risk in adulthood. However, physiological regulation has not been well studied as a disease risk factor before adulthood. We tested whether physiological regulation at the age of 2 years, in the form of vagal regulation of cardiac function (indexed by respiratory sinus arrhythmia [RSA] change), would predict three indicators of cardiovascular risk at the age of 16 years (diastolic and systolic blood pressure and body mass index). Methods: Data came from 229 children who participated in a community-based longitudinal study. At the age of 2 years, children were assessed for RSA baseline and RSA change (ln(ms)2) in response to a series of challenge tasks. These same children were assessed again at the age of 16 years for diastolic and systolic blood pressure (millimeters of mercury), height (meters), and weight (kilogram). Results: Regression analyses revealed that less RSA withdrawal at the age of 2 years predicted higher diastolic blood pressure at the age of 16 years, adjusting for demographic characteristics (B = -3.07, M [S E] = 1.12, p = .006). Follow-up analyses demonstrated that these predictions extended to clinically significant levels of diastolic prehypertension (odds ratio = 0.43, 95% confidence interval = 0.22–0.89). RSA withdrawal did not significantly predict adolescent body mass index or systolic blood pressure. Conclusions: Vagal regulation of cardiac function in early childhood predicts select indicators of cardiovascular risk 14 years later. Early signs of attenuated vagal regulation could indicate an increased risk for elevated blood pressure before adulthood. Future research should test biological, behavioral, and psychological mechanisms underlying these long-term predictions

Robust efficiency and actuator saturation explain healthy heart rate control and variability

The correlation of healthy states with heart rate variability (HRV) using time series analyses is well documented. Whereas these studies note the accepted proximal role of autonomic nervous system balance in HRV patterns, the responsible deeper physiological, clinically relevant mechanisms have not been fully explained. Using mathematical tools from control theory, we combine mechanistic models of basic physiology with experimental exercise data from healthy human subjects to explain causal relationships among states of stress vs. health, HR control, and HRV, and more importantly, the physiologic requirements and constraints underlying these relationships. Nonlinear dynamics play an important explanatory role––most fundamentally in the actuator saturations arising from unavoidable tradeoffs in robust homeostasis and metabolic efficiency. These results are grounded in domain-specific mechanisms, tradeoffs, and constraints, but they also illustrate important, universal properties of complex systems. We show that the study of complex biological phenomena like HRV requires a framework which facilitates inclusion of diverse domain specifics (e.g., due to physiology, evolution, and measurement technology) in addition to general theories of efficiency, robustness, feedback, dynamics, and supporting mathematical tools

Brainstem Sources of Cardiac Vagal Tone and Respiratory Sinus Arrhythmia

KEY POINTS: Cardiac vagal tone is a strong predictor of health, although its central origins are unknown. Respiratory‐linked fluctuations in cardiac vagal tone give rise to respiratory sinus arryhthmia (RSA), with maximum tone in the post‐inspiratory phase of respiration. In the present study, we investigated whether respiratory modulation of cardiac vagal tone is intrinsically linked to post‐inspiratory respiratory control using the unanaesthetized working heart‐brainstem preparation of the rat. Abolition of post‐inspiration, achieved by inhibition of the pontine Kolliker‐Fuse nucleus, removed post‐inspiratory peaks in efferent cardiac vagal activity and suppressed RSA, whereas substantial cardiac vagal tone persisted. After transection of the caudal pons, part of the remaining tone was removed by inhibition of nucleus of the solitary tract. We conclude that cardiac vagal tone depends upon at least 3 sites of the pontomedullary brainstem and that a significant proportion arises independently of RSA. ABSTRACT: Cardiac vagal tone is a strong predictor of health, although its central origins are unknown. The rat working heart‐brainstem preparation shows strong cardiac vagal tone and pronounced respiratory sinus arrhythmia. In this preparation, recordings from the cut left cardiac vagal branch showed efferent activity that peaked in post‐inspiration, ∼0.5 s before the cyclic minimum in heart rate (HR). We hypothesized that respiratory modulation of cardiac vagal tone and HR is intrinsically linked to the generation of post‐inspiration. Neurons in the pontine Kölliker‐Fuse nucleus (KF) were inhibited with bilateral microinjections of isoguvacine (50–70 nl, 10 mm) to remove the post‐inspiratory phase of respiration. This also abolished the post‐inspiratory peak of cardiac vagal discharge (and cyclical HR modulation), although a substantial level of activity remained. In separate preparations with intact cardiac vagal branches but sympathetically denervated by thoracic spinal pithing, cardiac chronotropic vagal tone was quantified by HR compared to its final level after systemic atropine (0.5 μm). Bilateral KF inhibition removed 88% of the cyclical fluctuation in HR but, on average, only 52% of the chronotropic vagal tone. Substantial chronotropic vagal tone also remained after transection of the brainstem through the caudal pons. Subsequent bilateral isoguvacine injections into the nucleus of the solitary tract further reduced vagal tone: remaining sources were untraced. We conclude that cardiac vagal tone depends on neurons in at least three sites of the pontomedullary brainstem, and much of it arises independently of respiratory sinus arrhythmia