Epidemiological studies have found that transportation noise increases the risk for cardiovascular morbidity and mortality, with solid evidence for ischemic heart disease, heart failure, and stroke. According to the World Health Organization, at least 1.6 million healthy life years are lost annually from traffic-related noise in Western Europe. Traffic noise at night causes fragmentation and shortening of sleep, elevation of stress hormone levels, and increased oxidative stress in the vasculature and the brain. These factors can promote vascular (endothelial) dysfunction, inflammation, and arterial hypertension, thus elevating cardiovascular risk. The present review focusses on the indirect, nonauditory cardiovascular health effects of noise. We provide an updated overview of epidemiological research on the effects of transportation noise on cardiovascular risk factors and disease, and mechanistic insights based on the latest clinical and experimental studies and propose new risk markers to address noise-induced cardiovascular effects in the general population. We will discuss the potential effects of noise on vascular dysfunction, oxidative stress, and inflammation in humans and animals. We will elaborately explain the underlying pathomechanisms by alterations of gene networks, epigenetic pathways, circadian rhythm, signal transduction along the neuronal-cardiovascular axis, and metabolism. We will describe current and future noise mitigation strategies. Finally, we will conduct an overall evaluation of the status of the current evidence of noise as a significant cardiovascular risk factor.

Aims : Mental stress substantially contributes to the initiation and progression of human disease, including cardiovascular conditions. We aim to investigate the underlying mechanisms of these contributions since they remain largely unclear. Methods and results : Here, we show in humans and mice that leucocytes deplete rapidly from the blood after a single episode of acute mental stress. Using cell-tracking experiments in animal models of acute mental stress, we found that stress exposure leads to prompt uptake of inflammatory leucocytes from the blood to distinct tissues including heart, lung, skin, and, if present, atherosclerotic plaques. Mechanistically, we found that acute stress enhances leucocyte influx into mouse atherosclerotic plaques by modulating endothelial cells. Specifically, acute stress increases adhesion molecule expression and chemokine release through locally derived norepinephrine. Either chemical or surgical disruption of norepinephrine signalling diminished stress-induced leucocyte migration into mouse atherosclerotic plaques. Conclusion : Our data show that acute mental stress rapidly amplifies inflammatory leucocyte expansion inside mouse atherosclerotic lesions and promotes plaque vulnerability.

Aim: Recent evidence suggests that arterial hypertension could be alternatively explained as a physiological adaptation response to water shortage, termed aestivation, which relies on complex multi‐organ metabolic adjustments to prevent dehydration. Here, we tested the hypothesis that chronic water loss across diseased skin leads to similar adaptive water conservation responses as observed in experimental renal failure or high salt diet.Methods: We studied mice with keratinocyte‐specific overexpression of IL‐17A which develop severe psoriasis‐like skin disease. We measured transepidermal water loss and solute and water excretion in the urine. We quantified glomerular filtration rate (GFR) by intravital microscopy, and energy and nitrogen pathways by metabolomics. We measured skin blood flow and transepidermal water loss (TEWL) in conjunction with renal resistive indices and arterial blood pressure.Results: Psoriatic animals lost large amounts of water across their defective cutaneous epithelial barrier. Metabolic adaptive water conservation included mobilization of nitrogen and energy from muscle to increase organic osmolyte production, solute‐driven maximal anti‐diuresis at normal GFR, increased metanephrine and angiotensin 2 levels, and cutaneous vasoconstriction to limit TEWL. Heat exposure led to cutaneous vasodilation and blood pressure normalization without parallel changes in renal resistive index, albeit at the expense of further increased TEWL.Conclusion: Severe cutaneous water loss predisposes psoriatic mice to lethal dehydration. In response to this dehydration stress, the mice activate aestivation‐like water conservation motifs to maintain their body hydration status. The circulatory water conservation response explains their arterial hypertension. The nitrogen‐dependency of the metabolic water conservation response explains their catabolic muscle wasting.

Background: Heart failure (HF) coincides with cardiomyocyte telomere shortening. Arterial hypertension is the most prominent risk factor for HF. Both HF and arterial hypertension are associated with dysregulation of the neurohormonal axis. How neurohormonal activation is linked to telomere shortening in the pathogenesis of HF is incompletely understood. methods: Cardiomyocyte telomere length was assessed in a mouse model of hypertensive HF induced by excess neurohormonal activation (AngII [angiotensin II] infusion, high salt diet, and uninephrectomy), in AngII-stimulated cardiomyocytes and in endomyocardial biopsies from patients with HF. Superoxide production, expression of NOX2 (NADPH oxidase 2) and PRDX1 (peroxiredoxin 1) and HDAC6 (histone deacetylase 6) activity were assessed. Results: Telomere shortening occurred in vitro and in vivo, correlating with both left ventricular (LV) dilatation and LV systolic function impairment. Telomere shortening coincided with increased superoxide production, increased NOX2 expression, increased HDAC6 activity, loss of the telomere-specific antioxidant PRDX1, and increased oxidative DNA-damage. NOX2 knockout prevented PRDX1 depletion, DNA-damage and telomere shortening confirming this enzyme as a critical source of reactive oxygen species. Cotreatment with the NOX inhibitor apocynin ameliorated hypertensive HF and telomere shortening. Similarly, treatment with the HDAC6 inhibitor tubastatin A, which increases PRDX1 bioavailability, prevented telomere shortening in adult cardiomyocytes. To explore the clinical relevance of our findings, we examined endomyocardial biopsies from an all-comer population of patients with HF with reduced ejection fraction. Here, cardiomyocyte telomere length predicted the recovery of cardiac function. Conclusions: Cardiomyocyte telomere shortening and oxidative damage in heart failure with reduced ejection fraction induced by excess neurohormonal activation depends on NOX2-derived superoxide and may help to stratify HF therapy.

Heart failure (HF) ensuing myocardial infarction (MI) is characterized by the initiation of a systemic inflammatory response. We aimed to elucidate the impact of myelomonocytic cells and their activation by angiotensin II on vascular endothelial function in a mouse model of HF after MI. HF was induced in male C57BL/6J mice by permanent ligation of the left anterior descending coronary artery. Compared to sham, HF mice had significantly impaired endothelial function accompanied by enhanced mobilization of Sca-1⁺c-Kit⁺ haematopoietic stem cells and Sca-1⁻c-Kit⁺ common myeloid and granulocyte-macrophage progenitors in the bone marrow as well as increased vascular infiltration of CD11b⁺Ly6G⁻Ly6C^high monocytes and accumulation of CD11b⁺ F4/80⁺ macrophages, assessed by flow cytometry. Using mice with Cre-inducible expression of diphtheria toxin receptor in myeloid cells, we selectively depleted lysozyme M⁺ myelomonocytic cells for 10 days starting 28 days after MI. While the cardiac phenotype remained unaltered until 38 days post-MI, myeloid cell depletion attenuated vascular accumulation of Nox2⁺CD45⁺ cells, endothelial dysfunction, oxidative stress, and vascular expression of adhesion molecules and angiotensin II receptor type 1 (AT1R). Pharmacological blockade of this receptor for 4 weeks did not significantly alter cardiac function, but mimicked the effects of myeloid cell depletion: telmisartan (20 mg/kg/day, fed to C57BL/6J mice) diminished bone marrow myelopoesis and myeloid reactive oxygen species production, attenuated endothelial leucocyte rolling and vascular accumulation of CD11b⁺Ly6G⁻Ly6C^high monocytes and macrophages, resulting in improved vascular function with less abundance of Nox2⁺CD45⁺ cells. Endothelial dysfunction in HF ensuing MI is mediated by inflammatory Nox2⁺ myeloid cells infiltrating the vessel wall that can be targeted by AT1R blockade.

Despite major advances in acute interventions for myocardial infarction (MI), adverse cardiac remodeling and excess fibrosis after MI causing ischemic heart failure (IHF) remain a leading cause of death worldwide. Here we identify a profibrotic coagulation signaling pathway that can be targeted for improved cardiac function following MI with persistent ischemia. Quantitative phosphoproteomics of cardiac tissue revealed an upregulated mitogen-activated protein kinase (MAPK) pathway in human IHF. Intervention in this pathway with trametinib improves myocardial function and prevents fibrotic remodeling in a murine model of non-reperfused MI. MAPK activation in MI requires myeloid cell signaling of protease-activated receptor 2 linked to the cytoplasmic domain of the coagulation initiator tissue factor (TF). They act upstream of pro-oxidant NOX2 NADPH oxidase, ERK1/2 phosphorylation, and activation of profibrotic TGF-β1. Specific targeting with the TF inhibitor nematode anticoagulant protein c2 (NAPc2) starting 1 day after established experimental MI averts IHF. Increased TF cytoplasmic domain phosphorylation in circulating monocytes from patients with subacute MI identifies a potential thromboinflammatory biomarker reflective of increased risk for IHF and suitable for patient selection to receive targeted TF inhibition therapy.