Noise causes cardiovascular disease: it's time to act

Abstract

Background: Chronic transportation noise is an environmental stressor affecting a substantial portion of the population. The World Health Organization (WHO) and various studies have established associations between transportation noise and cardiovascular disease (CVD), such as myocardial infarction, stroke, heart failure, and arrhythmia. The WHO Environmental Noise Guidelines and recent reviews confirm a heightened risk of cardiovascular incidents with increasing transportation noise levels.

Objective: We present a narrative review of the evidence from epidemiologic studies and translation studies on the adverse cardiovascular effects of transportation noise.

Methods: We describe the results of a recent Umbrella+ review that combines the evidence used in the 2018 WHO Environmental Noise Guidelines with more recent (post-2015) high-quality systematic reviews of original studies. High-quality systematic reviews were included based on the quality of literature search, risk of bias assessment, and meta-analysis methodology using AMSTAR 2.

Results: Epidemiologic studies show that exposure to high levels of road traffic noise for several years lead to numerous adverse health outcomes, including premature deaths, ischemic heart disease (IHD), chronic sleep disturbances, and increased annoyance. Mechanistically, noise exposure triggers oxidative stress, inflammation, endothelial dysfunction, and circadian rhythm disruptions. These processes involve the activation of NADPH oxidase, mitochondrial dysfunction, and nitric oxide synthase uncoupling, leading to vascular and cardiac damage. Studies indicate that chronic noise exposure does not result in habituation, and susceptible individuals, such as those with pre-existing CVD, are particularly vulnerable.

Keywords: Epidemiology; Exposure assessment; Health studies; Human well-being; Meta-analysis; Noise pollution.

Fig. 1. Meta-analysis of cohort studies on cardiovascular mortality in relation to transportation noise, stratified by source.

Relative risks refer to a 10 dB increase in L_den. Adapted with permission from [9].

Fig. 2. Key data on health effects of noise through the brain-heart/vessel-axis.

Left panel: Main results of animal studies regarding brain-heart/vessel interaction. Middle and right panel: Proof-of-concept translational study in humans demonstrating the association between transport (road and aircraft) noise-induced cerebral (amygdala relative to cortical) metabolic activity and arterial inflammation increasing major adverse cardiovascular events (MACE) [29, 30]. Reused with permission from ref. [30].

Fig. 3. Key effects of noise observed in human field studies.

A Effects of 30 and 60 aircraft noise events on the brachial artery (Noise30 and Noise60) of 70 healthy subjects. Vitamin C effects were assessed in a subgroup of the cohort. A priming effect of aircraft noise on endothelial function was observed, i.e., previous exposure to Noise30 caused Noise60 to have a significantly stronger reduction of flow-mediated dilation [52]. Serum adrenaline levels also increased significantly. B Effects of 30 and 60 railway noise events on flow-mediated brachial artery dilation in 70 healthy subjects. Vitamin C effects were assessed in a subgroup. C Methodology of FMD. D Effects of aircraft noise on oxidative stress markers (3-nitrotyrosine [3-NT] and 8-isoprostane) in serum that were measured in the samples of the aircraft noise study and published in ref. [32]. Adapted from [32] with permission. Copyright ©2018, Oxford University Press.

Fig. 4. Oxidative stress pathways activated by noise.

Noise causes stress hormone release (catecholamines and cortisol) and downstream endocrinal activation of vasoconstrictors activating common disease pathways, such as oxidative stress. Angiotensin II (AT-II) and endothelin-1 (ET-1) lead to the formation of diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (PIP₂), a potent activator of protein kinase C (PKC), via their receptors and the activation of phospholipase C (PLC). (1) PKC via phosphorylation of p47^phox at serine 328 causes activation of the phagocytic NADPH oxidase (NOX-2) and potentially NOX-1. The expression of NOX-2 is upregulated by noise-triggered immune cell infiltration (lysozyme M-positive (LysM⁺) cells) and systemic inflammatory conditions. NOX-2 (and NOX-1, especially in the brain) produces superoxide (O₂^•−) and via dismutation also hydrogen peroxide (H₂O₂). NOX-4 was not changed by noise and NOX-5 (relevant for humans) was not studied so far. (2) Dysfunction of endothelial nitric oxide synthase (eNOS) is mediated by noise-dependent activation of PKC and phosphorylation of threonine 495. Alternatively, NOX-2-dependent ROS formation may activate PKC [53] and protein tyrosine kinase 2 (PYK-2) [54, 55], causing adverse phosphorylation at tyrosine 657 and threonine 495. Uncoupling of eNOS may be induced by noise-driven oxidative depletion of tetrahydrobiopterin (BH₄) and S-glutathionylation (-SSG) of eNOS by ROS originating from NOX-2 [56]. Semi-uncoupled eNOS may represent a potent source of peroxynitrite. (3) Noise also leads to mitochondrial ROS formation, generating both O₂^•− and H₂O₂. Noradrenaline (NA) and adrenaline (A) originating from sympathetic activation are substrates of monoamine oxidases (MAO) that produce H₂O₂. NA and A can also activate PKC through adrenergic receptor (α₁-AR). PKC seems to activate the mitochondrial K_ATP channel by phosphorylation of a threonine residue with subsequent depolarization of the mitochondrial membrane (ΔΨ_m↓) and O₂^•− formation from respiratory complexes I, II and III. Mitochondrial H₂O₂ / O₂^•− and calcium are released to the cytosol upon the mitochondrial permeability transition pore (mPTP) opening (e.g., by thiol oxidation of the regulatory subunit cyclophilin D (CypD) [57]). K_ATP channel activation and mPTP opening can also be stimulated by redox-crosstalk with H₂O₂ (probably also O₂^•− via peroxynitrite) derived from NOX-2 [58]. So far, there is no evidence for the role of xanthine oxidase in noise’s non-auditory (indirect) effects. This scheme was adapted from [35] with permission and created using biorender.com.