Linking noise to cardiovascular disease pathogenesis

This editorial refers to ‘Effects of noise on vascular function, oxidative stress, and inflammation: mechanistic insight from studies in mice’^†, by T. Münzel et al., on page 2838.

The influence of sound on cardiovascular physiology is well established. Since the time of Orpheus in ancient Greece, whose songs and music could effect behavioural and physical changes, through to modern times, certain types of sounds or music are known to have beneficial effects on cardiovascular physiology. More detailed studies have highlighted the importance of tempo, melodic structure, and periods of silence as crucial factors impacting on heart rate, blood pressure, cerebral blood flow, and barrow reflex function.¹ Equally, disruptive noise and/or disturbance from sleep are well recognized stressors that acutely increase heart rate and blood pressure and cause long-term changes in settings of repetitive exposure. Transient arousal from sleep in healthy individuals leads to significant surges in heart rate and blood pressure,² and loud or disruptive noises or music are strong stimulators of the sympathetic nervous system.

A large body of observational and epidemiological evidence relates chronic exposure to environmental noise stress, such as traffic or aircraft noise, with increased cardiovascular risk, including high blood pressure,³ metabolic disease, and the incidence of cardiovascular events. A recent meta-analysis suggested a relative risk for coronary artery disease of 1.06 (1.03–1.09) per 10 dB increase in noise exposure above 50 dB. Males and the elderly appeared particularly sensitive, and adjustment for air pollution did not attenuate the association between noise exposure and coronary artery disease.⁴ The sources and characteristics of noise pollution may be important,⁵ with aircraft noise being potentially more detrimental than other sources.⁶ The conclusions of epidemiological studies are of major potential importance for global health in large urban populations. However, the causality of noise pollution in cardiovascular pathogenesis cannot be ascertained or quantified with confidence, due to potential confounding factors, and due to limited experimental approaches to identify causal mechanisms.

In this issue of the journal, Münzel and colleagues describe a new mouse model to evaluate the effects of environmental noise on the cardiovascular system, and on the cellular and molecular mechanisms relating noise to cardiovascular disease pathogenesis.⁷ They exposed mice to a regimen of intermittent noise, mimicking aircraft noise, delivered in short episodes at an intensity of 72 dB. This noise level is less than the high intensity noise (100 dB) used in previous studies, that is physically harmful. Furthermore, the investigators used ‘random’ white noise at the same average intensity level as a control. Exposure to noise for 4 days resulted in elevated blood pressure and heart rate, was associated with detrimental changes in vascular endothelial function, vascular production of reactive oxygen species, and increased blood stress hormones and biomarkers of inflammation. Furthermore, noise exposure induced striking changes in gene expression profile in mouse aortas, notably in genes related to VSMC (vascular smooth muscle cell) contractile proteins, TGF-β (transforming growth factor-β) and SMAD signalling, the NF-κB (nuclear factor-κB) pathway, and adrenergic signal transduction.

This new mouse model of controlled noise exposure, identifying some of the mechanisms linking noise exposure to cardiovascular risk, now opens up a number of important opportunities for further research. First, a mouse model allows reproducible studies of the effects of noise, independent of the potential limitations of observational studies, where the effects of traffic and aircraft noise exposure are confounded by associations with exposure to air pollution, social and housing factors, and where the intensity and effects of noise are difficult to quantify. Secondly, the study already demonstrates that this new model is able to identify and dissect cellular and molecular mechanisms linking noise exposure with cardiovascular pathophysiology, which in future will allow more sophisticated interventions and genetic models to identify the specific aspects of noise exposure that are most important in cardiovascular pathophysiology. In the present study, the authors did not comment on whether the effects of noise were independent of, or dependent upon, the impact on the sleep/wake cycle, indicators of circadian biology, feeding behaviour, or metabolism, or whether the circadian effects of noise on sleep and behaviour is also reflected in the intrinsic circadian rhythms within the vascular system. These will all be interesting questions for future research. Equally, the ability to use established mouse models of cardio-metabolic disease, and targeted knockouts to test the requirements of key signalling pathways will be directly applicable to this model.

In exploring the mechanisms, the authors highlight the potential role of noise causing neuroendocrine activation through angiotensin II (Ang II), endothelin 1, and the NADPH oxidases. Strikingly, the effect of high noise exposure on endothelial function was already pronounced at day 1, while the effects on vasoconstriction or blood pressure developed later. Endothelial dysfunction, characterized by decreased nitriuc oxide (NO) generation, developed in spite of increased endothelial nitric oxide synthaase (eNOS) Ser1177 phosphorylation, and was attributed to eNOS uncoupling due to increased eNOS glutathionylation and vascular superoxide production. The importance of this observation is that exposure to aircraft noise apparently causes similar molecular changes in the vasculature to those that have previously described in relation to classical risk factors for atherosclerosis⁸ such as diabetes⁹ or hypercholesterolaemia.¹⁰ This includes a central role for increased NADPH oxidase activity both in the vasculature¹¹ and in the heart.¹² Nox2 NADPH oxidase rather than Nox1 is implicated in noise-dependent vascular dysfunction, which is especially important in the context of Ang II stimulation in endothelial cells.

The authors also observed a striking increase in cardiac NADPH oxidase activity. This was not associated with cardiac remodelling as this model is short term, but may be of critical relevance for more chronic effects of noise exposure on cardiac function. While not addressed by this study, systemic endothelial dysfunction and macrophage perivascular infiltration are also associated with cognitive impairment,¹³ which may contribute to the accelerated cognitive decline reported in people chronically exposed to aircraft environments.¹⁴ Such cognitive impairment has been described in relation to chronic noise exposure and stress responses, even in children.¹⁵

The study also identifies vascular infiltration with myelomonocytic cells as an important consequence of noise exposure. While there is a large variability of responses in individual animals, significant increases in macrophage content are observed early following noise exposure, which may have implications not only for vascular dysfunction but also for hypertension, atherosclerosis, and myocardial infarction.¹⁶ AT1 receptors on macrophages have been reported to be essential for microvascular endothelial dysfunction, again supporting a possible role for aircraft noise pollution in cognitive dysfunction.13

Nox2 activation, induced by Ang II signalling through AT1 and possibly AT2 receptors, may be critical in the cardiovascular response to noise. Indeed, gene expression profiling revealed major changes in the VSMC contraction pathway and TGF-β and SMAD signalling, cell cycle control, apoptosis, and kinase-mediated growth and proliferation signalling, all of which may be both Ang II and Nox2 mediated.¹⁷ It would be particularly important to understand whether Nox2 is indeed causally involved in vascular phenotype analysis, for example using Nox2 knockout mice or Nox2 inhibitors, and the cell-specific requirement for Nox2, for example in the heart, vascular wall, brain, or inflammatory cells.

Figure 1.

Potential mechanisms linking noise to cardiovascular disease pathogenesis.

There will be more to learn about the upstream regulation of the cardiovascular response to noise. Most probably, stress-related responses are implicated, with early changes in dopamine levels and subsequently the stress hormones norepinephrine and cortisol, and Ang II. While increases of blood pressure and increased sensitivity to vasoconstrictors can be attributed to these responses, the role of dopamine deserves further attention. Dopamine, through dopamine receptor type-5 (DR5), appears to reduce systemic blood pressure, most probably by increasing renal vasodilation, improving endothelial function, and enhancing natriuresis in the kidney.¹⁸ Thus, the increase in dopamine may be in part compensatory and might be used for further therapeutic interventions. Alternatively, dopamine may act primarily as a precursor to the formation of norepinephrine and epinephrine.

Finally, this new model system, through identifying mechanisms, will enable testing of adjunctive interventions or therapies that could ameliorate or prevent the effects of noise pollution on the cardiovascular system. It will be interesting to see how limitation of noise exposure, or mitigation of noise intensity or periodicity, in relation to the circadian cycle, might bring disproportionate beneficial effects to reduce the cardiovascular consequences of noise. Alternatively, it will be important to test whether existing therapies such as ACE inhibitors or Ang II receptor antagonists can improve or prevent the effects of noise on the cardiovascular system. Whether the adverse effects of noise on the cardiovascular system are amplified or exacerbated by co-existent diabetes, atherosclerosis, or myocardial infarction could all be tested, and mechanisms probed, using the new mouse model described by Münzel and colleagues.

In conclusion, the global impact of environmental noise on cardiovascular disease pathogenesis and risk is a major public health problem. The new mouse model described by Münzel and colleagues is a crucial step towards understanding the characteristics and effects of noise on cardiovascular pathophysiology, in identifying cellular and molecular mechanisms, and identifying potential therapeutic targets.