RR Interval Variability Is Inversely Related to Inflammatory Markers: The CARDIA Study

Abstract

Recent evidence reveals that the immune system is under the direct control of the vagus nerve via the "cholinergic anti-inflammatory pathway." Stimulation of vagus nerve activity significantly inhibits cytokine levels in animal models, and cholinergic agents inhibit cytokine release by human macrophages. Moreover, when vagus nerve activity is decreased or absent, cytokines are overproduced. Atherosclerosis is an inflammatory disease characterized by elevated levels of CRP and IL-6, but the relationship between cardiac vagal activity and cytokine levels in healthy humans is not well understood. Here we measured RR interval variability, an index of cardiac vagal modulation, and CRP and IL-6 in 757 subjects participating in a subset of the year 15 data collection in the CARDIA study of the evolution of risk factors in young adults. Univariate analysis revealed that all indices of RRV were strongly and inversely related to IL-6 (log pg/mL b = -0.08 and -0.17 for HF and LF power, P < 0.001 respectively) and CRP (log mg/L b = -0.14 and -0.26 for HF and LF power, P < 0.001 respectively) levels. In the multivariate model including gender, race, age, smoking, physical activity, SBP, BMI, and disease, the inverse relationship between RRV and inflammatory markers, although slightly attenuated, remained significant. These findings are consistent with the hypothesis that diminished descending vagal anti-inflammatory signals can allow cytokine overproduction in humans.

The autonomic phenotype of rumination

“…Recent evidence reveals that the immune system is under the direct control of the vagus nerve via the "cholinergic anti-inflammatory pathway" (Sloan et al, 2007). Specifically, the parasympathetic system has been found to inhibit the production of proinflammatory cytokines by activated monocytes/macrophages independently of gender, race, age, smoking, physical activity, BP, and BMI thus decreasing local and systemic inflammation (Marsland et al, 2007).…”

Does an acute inflammatory response temporarily attenuate parasympathetic reactivation?

“…Reductions in heart rate variability are known to occur concomitantly with inflammatory diseases [2,4,24]. Recent observational studies also note an association between increased inflammatory markers and reduced heart rate variability [8,21]. Therefore, we may suggest that acute inflammation affects not only the heart rate variability (an index of tonic parasympathetic modulation due to phasic fluctuations in vagal efferent activity) but also the heart rate recovery (an index of vagal reactivation/tone due to mean cholinergic signaling at the level of the sinoatrial node).…”

“…It is well known that increased inflammation and reduced autonomic nervous system function increase the risk of cardiovascular morbidity and mortality [13,28]. Observational studies have suggested that increased inflammatory markers are associated with reduced autonomic nervous system function in both healthy individuals [10,21] and patients with cardiovascular disease [8].…”

The autonomic nervous system and ischemic stroke: a reciprocal interdependence

“…Stimulation of vagus nerve activity induces a significant decrease in cytokine levels in animal models; conversely, vagotomy is able to enhance the cytokine response to invasive stimuli. The CARDIA study [72] detected, in a large sample of healthy young adult, an inverse relationship between RR internal variability and inflammatory markers. Elevated intracellular expression of proinflammatory cytokines has been detected in patients with carotid atherosclerosis (particularly with complicated plaques) and an increase in peripheral blood intracellular cytokines has been suggested to be a warning signal of plaque progression [61,62].…”