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ZusammenfassungLuftverschmutzung, Verkehrslärm und Hitzewellen sind umweltbedingte Gesundheitsrisikofaktoren, die häufig in urbanen Räumen kolokalisiert sind. Diese Risikofaktoren können singulär oder in Interaktion auftreten und wirken und sind vor allem für kardiovaskuläre und zerebrale gesundheitliche Nebenwirkungen verantwortlich. Bekannt ist, dass diese Umweltstressoren eine endotheliale Dysfunktion, oxidativen Stress, Gefäßentzündungen und die Aktivierung des autonomen Nervensystems verursachen können und darüber vermittelt die Entwicklung von kardiometabolischen und zerebralen Erkrankungen fördern. Die vorliegende Übersichtsarbeit diskutiert die pathophysiologischen Mechanismen umweltbedingter Erkrankungen sowie den Effekt präventiver Maßnahmen für das Herz-Kreislauf-Risiko. Ein erhöhtes Bewusstsein für die Belastung der öffentlichen Gesundheit durch diese Umweltrisikofaktoren und die Integration dieser Erkenntnisse in medizinischen Leitlinien können dazu beitragen, die Anstrengungen zu intensivieren, das Ausmaß von Luftverschmutzung, Lärm und Hitzewellen gesetzlich zu limitieren.

Smoking is a well-established risk factor for chronic non-communicable diseases. However, the relationship between cigarette smoking and the risk of developing mental health conditions remains largely elusive. This study examined the relationship between cigarette smoking as well as smoking cessation and prevalent and incident symptoms of depression, anxiety, and sleep disturbance in the general population.In a cohort of 15,010 individuals from the Gutenberg Health Study (aged 35-74 years at enrollment), prevalent (at baseline from 2007 to 2012) and incident symptoms (at follow-up from 2012 to 2017) of depression, anxiety, and sleep disturbance were determined by validated questionnaires and/or medical records. Smoking status, pack-years of smoking in current and former smokers, and years since quitting smoking in former smokers were assessed by a standardized computer-assisted interview.In multivariable logistic regression models with comprehensive adjustment for covariates, smoking status was independently associated with prevalent and incident symptoms of depression (Patient Health Questionnaire-9 ≥ 10), whereas this association was weaker for anxiety (Generalized Anxiety Disorder Scale-2 ≥ 3) and sleep disturbance (Patient Health Questionnaire-9 1). Among current and former smokers, smoking ≥30 or ≥10 pack-years, respectively, yielded in general the highest effect estimates. Smoking cessation was weakly associated with the prevalence and incidence of all outcomes, here consistent associations were observed for prevalent symptoms of depression.The observational nature of the study does not allow for causal inferences.The results of the present study suggest that cigarette smoking is positively and that smoking cessation is negatively associated with symptoms of common mental health conditions, in particular of depression.

Environmental risk factors, including noise, air pollution, chemical agents, ultraviolet radiation (UVR) and mental stress have a considerable impact on human health. Oxidative stress and inflammation are key players in molecular pathomechanisms of environmental pollution and risk factors. In this review, we delineate the impact of environmental risk factors and the protective actions of the nuclear factor erythroid 2-related factor 2 (NRF2) in connection to oxidative stress and inflammation. We focus on well-established studies that demonstrate the protective actions of NRF2 and its downstream pathways against different environmental stressors. State-of-the-art mechanistic considerations on NRF2 signaling are discussed in detail, e.g. classical concepts like KEAP1 oxidation/electrophilic modification, NRF2 ubiquitination and degradation. Specific focus is also laid on NRF2-dependent heme oxygenase-1 induction with detailed presentation of the protective down-stream pathways of heme oxygenase-1, including interaction with BACH1 system. The significant impact of all environmental stressors on the circadian rhythm and the interactions of NRF2 with the circadian clock will also be considered here. A broad range of NRF2 activators is discussed in relation to environmental stressor-induced health side effects, thereby suggesting promising new mitigation strategies (e.g. by nutraceuticals) to fight the negative effects of the environment on our health., S.Ste. holds an excellence grant and a research grant related to noise/hypertension from the Else Kroner ¨ Fresenius Foundation. T.M. is PI of the DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany. S.Ste., T.M. and A.D. were supported by vascular biology research grants from the Boehringer Ingelheim Foundation for the collaborative research group ‘Novel and neglected cardiovascular risk factors: Molecular mechanisms and therapeutics’. A.C. holds grant PID2019-110061RB-I00 from MICINN. M.T.B.J. and K.F. hold stipends from the TransMed PhD Program of the University Medical Center Mainz funded by the Boehringer Ingelheim Foundation.

Healthy soil is foundational to human health. Healthy soil is needed to grow crops, provides food, and sustains populations. It supports diverse ecosystems and critical ecological services such as pollination. It stores water and prevents floods. It captures carbon and slows global climate change. Soil pollution is a great and growing threat to human health. Soil may be polluted by heavy metals, organic chemicals such as pesticides, biological pathogens, and micro/nanoplastic particles. Pollution reduces soil’s ability to yield food. It results in food crop contamination and disease. Soil pollutants wash into rivers causing water pollution. Deforestation causes soil erosion, liberates sequestered pollutants, and generates airborne dust. Pollution of air, water, and soil is responsible for at least 9 million deaths each year. More than 60% of pollution-related disease and death is due to cardiovascular disease. Recognizing the importance of pollution to human health, the European Commission and the EU Action Plan for 2050: A Healthy Planet for All, have determined that air, water, and soil pollution must be reduced to levels that cause no harm to human or ecosystem health. We are thus required to create a toxic-free environment, respect the concept of a safe operating space for humanity, and sustain the health of our planet for future generations. This review article summarizes current knowledge of the links between soil health and human health and discusses the more important soil pollutants and their health effects.

Aims Environmental stressors such as traffic noise represent a global threat, accounting for 1.6 million healthy life years lost annually in Western Europe. Therefore, the noise-associated health side effects must be effectively prevented or mitigated. Non-pharmacological interventions such as physical activity or a balanced healthy diet are effective due to the activation of the adenosine monophosphate-activated protein kinase (α1AMPK). Here, we investigated for the first time in a murine model of aircraft noise-induced vascular dysfunction the potential protective role of α1AMPK activated via exercise, intermittent fasting, and pharmacological treatment. Methods and results Wild-type (B6.Cg-Tg(Cdh5-cre)7Mlia/J) mice were exposed to aircraft noise [maximum sound pressure level of 85 dB(A), average sound pressure level of 72 dB(A)] for the last 4 days. The α1AMPK was stimulated by different protocols, including 5-aminoimidazole-4-carboxamide riboside application, voluntary exercise, and intermittent fasting. Four days of aircraft noise exposure produced significant endothelial dysfunction in wild-type mice aorta, mesenteric arteries, and retinal arterioles. This was associated with increased vascular oxidative stress and asymmetric dimethylarginine formation. The α1AMPK activation with all three approaches prevented endothelial dysfunction and vascular oxidative stress development, which was supported by RNA sequencing data. Endothelium-specific α1AMPK knockout markedly aggravated noise-induced vascular damage and caused a loss of mitigation effects by exercise or intermittent fasting. Conclusion Our results demonstrate that endothelial-specific α1AMPK activation by pharmacological stimulation, exercise, and intermittent fasting effectively mitigates noise-induced cardiovascular damage. Future population-based studies need to clinically prove the concept of exercise/fasting-mediated mitigation of transportation noise-associated disease.

AbstractSmoking tobacco cigarettes is a significant (cardiovascular) health risk factor. Although the number of tobacco cigarette users declined over the last decades, shisha smoking and e-cigarette vaping partially compensated for this health benefit. E-cigarettes may create highly addicted dual users (vaping and smoking). E-cigarettes seem not to represent a healthier alternative to tobacco smoking, although they may be less harmful. E-cigarette vaping causes oxidative stress, inflammation, endothelial dysfunction, and associated cardiovascular sequelae. This is primarily due to a significant overlap of toxic compounds in the vapor compared to tobacco smoke and, accordingly, a substantial overlap of pathomechanistic features between vaping and smoking. Whereas the main toxins in vapor are reactive aldehydes such as formaldehyde and acrolein, the toxic mixture in smoke is more complex, comprising particulate matter, reactive gases, transition metals, volatile organic compounds, and N-nitrosamines. However, it seems that both lifestyle drugs impair endothelial function to a quite similar extent, which may be due to the role of oxidative stress as the central pathomechanism to mediate endothelial dysfunction and vascular damage. Finally, the main selling argument for e-cigarette use that they help to quit smoking and get rid of nicotine addiction may be false because it seems that e-cigarettes instead trigger the opposite—younger entrance age and more frequent use. With our review, we summarize the adverse health impact of tobacco cigarettes and e-cigarettes, emphasizing the detrimental effects on endothelial function and cardiovascular health.

Traffic noise and air pollution are environmental stressors found to increase risk for cardiovascular events. The burden of disease attributable to environmental stressors and cardiovascular disease globally is substantial, with a need to better understand the contribution of specific risk factors that may underlie these effects. Epidemiological observations and experimental evidence from animal models and human controlled exposure studies suggest an essential role for common mediating pathways. These include sympathovagal imbalance, endothelial dysfunction, vascular inflammation, increased circulating cytokines, activation of central stress responses, including hypothalamic and limbic pathways, and circadian disruption. Evidence also suggests that cessation of air pollution or noise through directed interventions alleviates increases in blood pressure and intermediate surrogate pathways, supporting a causal link. In the second part of this review, we discuss the current understanding of mechanisms underlying and current gaps in knowledge and opportunities for new research.

Traffic noise and air pollution are 2 major environmental health risk factors in urbanized societies that often occur together. Despite cooccurrence in urban settings, noise and air pollution have generally been studied independently, with many studies reporting a consistent effect on blood pressure for individual exposures. In the present reviews, we will discuss the epidemiology of air pollution and noise effects on arterial hypertension and cardiovascular disease (part I) and the underlying pathophysiology (part II). Both environmental stressors have been found to cause endothelial dysfunction, oxidative stress, vascular inflammation, circadian dysfunction, and activation of the autonomic nervous system, thereby facilitating the development of hypertension. We also discuss the effects of interventions, current gaps in knowledge, and future research tasks. From a societal and policy perspective, the health effects of both air pollution and traffic noise are observed well below the current guideline recommendations. To this end, an important goal for the future is to increase the acceptance of environmental risk factors as important modifiable cardiovascular risk factors, given their substantial impact on the burden of cardiovascular disease.

Background The sodium-glucose co-transporter 2 inhibitor empagliflozin improves cardiovascular outcome in patients with type 2 diabetes mellitus (T2DM) and heart failure. Experimental studies suggest a direct cardiac effect of empagliflozin associated with an improvement in left ventricular diastolic function. Methods In the randomized, double-blind, two-armed, placebo-controlled, parallel group trial EmDia, patients with T2DM and elevated left ventricular E/E´ ratio were enrolled and randomized 1:1 to receive empagliflozin 10 mg/day versus placebo. The primary endpoint was the change of left ventricular E/E´ ratio after 12 weeks of intervention. Results A total of 144 patients with T2DM and an elevated left ventricular E/e´ ratio (age 68.9 ± 7.7 years; 14.1% women; E/e´ ratio 9.61[8.24/11.14], left ventricular ejection fraction 58.9% ± 5.6%). After 12 weeks of intervention, empagliflozin resulted in a significant higher decrease in the primary endpoint E/e´ ratio by − 1.18 ([95% confidence interval (CI) − 1.72/− 0.65]; P n = 30). Additional effects of empagliflozin on body weight, HbA1c, uric acid, red blood cell count, hemoglobin, mean corpuscular hemoglobin, and hematocrit were detected (all P E/e´ by empagliflozin could be explained by the variables examined. Conclusions Empagliflozin improves diastolic function in patients with T2DM and elevated end-diastolic pressure. Since the positive effects were consistent in patients with and without heart failure with preserved ejection fraction, the data add a mechanistic insight for the beneficial cardiovascular effect of empagliflozin. Trial registration Clinicaltrials.gov, unique identifier: NCT02932436. Graphical abstract

AimsTraffic noise may play an important role in the development and deterioration of ischaemic heart disease. Thus, we sought to determine the mechanisms of cardiovascular dysfunction and inflammation induced by aircraft noise in a mouse model of myocardial infarction (MI) and in humans with incident MI.Methods and resultsC57BL/6J mice were exposed to noise alone (average sound pressure level 72 dB; peak level 85 dB) for up to 4 days, resulting in pro-inflammatory aortic gene expression in the myeloid cell adhesion/diapedesis pathways. The noise alone promoted adhesion and infiltration of inflammatory myeloid cells in vascular/cardiac tissue, paralleled by an increased percentage of leucocytes with a pro-inflammatory, reactive oxygen species (ROS)-producing phenotype and augmented expression of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase type 2 (Nox2)/phosphorylation of nuclear factor ‘kappa light chain enhancer’ of activated B-cells (phospho-NFκB) in peripheral blood. Ligation of the left anterior descending artery resulted in worsening of cardiac function, pronounced cardiac infiltration of CD11b+ myeloid cells and Ly6Chigh monocytes, and induction of interleukin (IL) 6, IL-1β, CCL-2, and Nox2, being aggravated by noise exposure prior to MI. MI induced stronger endothelial dysfunction and more pronounced increases in vascular ROS in animals preconditioned with noise. Participants of the population-based Gutenberg Health Cohort Study (median follow-up:11.4 years) with incident MI revealed elevated C-reactive protein at baseline and worse left ventricular ejection fraction (LVEF) after MI in case of a history of noise exposure and subsequent annoyance development.ConclusionAircraft noise exposure before MI substantially amplifies subsequent cardiovascular inflammation and aggravates ischaemic heart failure, facilitated by a pro-inflammatory vascular conditioning. Our translational results suggest that measures to reduce environmental noise exposure will be helpful in improving the clinical outcome of subjects with MI.

ZusammenfassungDie Weltgesundheitsorganisation gibt an, dass die Stadtplanung mittlerweile als kritischer Bestandteil einer umfassenden Lösung zur Bekämpfung umweltbedingter Gesundheitsschäden gesehen wird. Die vorliegende Übersicht befasst sich mit nicht übertragbaren Krankheiten mit dem Schwerpunkt auf Herz-Kreislauf-Erkrankungen und dem Urbanisierungsprozess in Bezug auf Umweltrisiken wie Lärm, Luftverschmutzung, Temperatur und Licht im Freien. Es wird dargelegt, warum sich Wärmeinseln in städtischen Gebieten entwickeln können und wie die Begrünung von Städten die öffentliche Gesundheit verbessern und Klimaprobleme, Nachhaltigkeit und Lebensfähigkeit adressieren kann. Darüber hinaus thematisieren wir Stadtplanung, Verkehrsinterventionen und neuartige Technologien zur Bewertung externer Umweltexpositionen, z. B. Einsatz digitaler Technologien, um zukünftig herzgesunde Städte zu fördern. Zuletzt heben wir neue Paradigmen des integrativen Denkens hervor, wie das Exposom und die planetare Gesundheit, indem wir den Zusammenhang zwischen Exposition und Gesundheitsauswirkungen kritisch evaluieren und unser Verständnis der Gesamtheit der Expositionen gegenüber der Umwelt des Menschen erweitern.

ZusammenfassungDie Exposition der Bevölkerung durch hochfrequente elektromagnetische Felder (HF-EMF) wird durch die körpernahe Nutzung von drahtlosen Kommunikationsgeräten dominiert. Die Exposition durch körperferne Sendeanlagen liegt im Durchschnitt mehrere Größenordnungen unterhalb der internationalen Richtwerte. Mit der zunehmenden mobilen Datennutzung und der damit verbundenen Nutzung von höheren Frequenzen für 5G ist mit einer Verdichtung des Mobilfunknetzes zu rechnen. Damit steigt aber nicht notgedrungen die HF-EMF-Gesamtexposition der Bevölkerung, da Mobiltelefone bei besserer Signalqualität weniger stark emittieren. 5G ist eine technologische Weiterentwicklung der bisherigen Mobilfunktechnologie mit gleichen biophysikalischen Eigenschaften. Bisher konnten keine gesundheitlichen Auswirkungen unterhalb der Richtwerte konsistent nachgewiesen werden. Beobachtete biologische Effekte wie beispielsweise auf die elektrische Aktivität des Gehirns oder auf das oxidative Gleichgewicht bei hoher lokaler Exposition im Bereich der Expositionsrichtwerte stellen nach heutigem Kenntnisstand kein Gesundheitsrisiko dar.

ZusammenfassungTabakrauchen ist ein Hauptauslöser chronischer nicht übertragbarer Krankheiten und ein Risikofaktor für kardiovaskuläre und pulmonale Erkrankungen. Obwohl der weltweite Tabakkonsum während der letzten 2 Jahrzehnte reduziert wurde, zeigt der Gebrauch von E-Zigaretten und Wasserpfeifen (Shisha) eine pandemische Zunahme mit hohem Anteil jüngerer Anwender. E-Zigaretten sind keine komplett schadensfreie Alternative zu herkömmlichen Tabakzigaretten, auch weil die zahlreichen Geschmacksaromen und die einfache/schnelle Verwendung eine steigende Zahl von abhängigen Anwendern hervorbringt. E-Zigaretten sind nicht unbedingt geeignet, die Nikotinabhängigkeit hinter sich zu lassen. Diese Arbeit bietet eine Übersicht über die kardiovaskulären Gesundheitsauswirkungen des Shisharauchens und E-Zigaretten-Dampfens mit Fokus auf die negativen Effekte auf die Endothelfunktion. Die schädlichen biologischen Auswirkungen der toxischen Inhaltsstoffe dieser Produkte werden vor allem im Hinblick auf oxidativen Stress und Entzündungsreaktionen diskutiert. Abschließend wird der aktuelle Stand hinsichtlich der Empfehlungen, gesetzlichen Regelungen und kommerziellen Werbung kurz zusammengefasst.

ZusammenfassungAktuelle Befunde der großen globalen epidemiologischen Studien wie dem „Global Burden of Disease“-Projekt legen nahe, dass bereits jetzt nahezu ⅔ der jährlichen globalen Todesfälle ursächlich auf chronische nicht übertragbare Erkrankungen wie Atherosklerose oder Diabetes zurückzuführen sind. Dies liegt vor allem an der Überalterung der Menschen in westlichen Gesellschaften, aber auch einer zunehmenden Belastung durch Boden-, Wasser- und Luftverschmutzung, Lärmbelastung, mentale Stressfaktoren und weitere Umweltrisikofaktoren. Vor etwa 15 Jahren wurde das Exposom-Konzept etabliert, um die Auswirkungen unserer Umwelt auf die Gesundheit zu erforschen. Das Exposom beschreibt dabei die Summe aller Expositionen, die lebenslang auf uns einwirken und dabei biochemische und metabolische Prozesse in unserem Körper überwiegend ungünstig verändern und so zu Gesundheitsschäden und frühzeitigen Todesfällen beitragen. Mit dieser Übersicht wird das Exposom-Konzept anhand von ausgewählten Studien erklärt und seine Bedeutung für die zukünftige Gesundheitsforschung sowie die präventive Medizin, vor allem im Hinblick auf kardiovaskuläre Erkrankungen und Therapie, erläutert.

Zusammenfassung Hintergrund Lärmbelästigung, insbesondere durch Verkehrslärm, stellt ein massives Problem in der Bevölkerung dar und ist mit gesundheitlichen Einschränkungen assoziiert. Ziel der Arbeit Anhand von Daten der bevölkerungsrepräsentativen Gutenberg-Gesundheitsstudie (GHS) werden die Prävalenz der Lärmbelästigung durch verschiedene Quellen sowie relevante Determinanten bestimmt. Material und Methoden Die GHS ist eine populationsbasierte, prospektive Kohortenstudie in Deutschland, die Personen im Alter von 35 bis 74 Jahren einbezieht. 15.010 Probanden aus der Stadt Mainz und dem Landkreis Mainz-Bingen wurden von 2007 bis 2012 befragt, inwiefern sie sich in letzter Zeit durch Flug‑, Straßen‑, Schienen‑, Industrie- und Nachbarschaftslärm belästigt gefühlt haben (Angaben von „überhaupt nicht“ bis „äußerst“). Es wurde jeweils zwischen der Lärmbelästigung am Tag sowie während des Schlafens differenziert. Um die Beziehungen zwischen soziodemographischen Variablen, kardiovaskulären Risikofaktoren sowie Erkrankungen und Lärmbelästigung zu untersuchen, wurden multivariable logistische Regressionsmodelle verwendet. Ergebnisse Etwa 80 % der Probanden fühlten sich durch Lärm belästigt. Fluglärmbelästigung am Tag stellte die vorherrschende Lärmbelästigungsquelle mit der höchsten Prävalenz stark (9,6 %) und äußerst lärmbelästigter Probanden dar (5,4 %), gefolgt von Straßenverkehrs- (stark: 4,0 %; äußerst: 1,6 %) und Nachbarschaftslärmbelästigung (stark: 3,5 %; äußerst: 1,3 %). Die Lärmbelästigung nahm eher mit zunehmender Altersdekade ab. Relevante Determinanten der Lärmbelästigung umfassten mitunter Geschlecht, Alter, sozioökonomischen Status, Depression, Angststörung, Schlafstörung und Vorhofflimmern. Diskussion Lärmbelästigung betrifft einen Großteil der Bevölkerung und ist assoziiert mit soziodemographischen Variablen und kardiovaskulären Risikofaktoren sowie Erkrankungen.

Background. Long-term hematopoietic stem cells (LT-HSCs) reside in bone marrow niches with tightly controlled reactive oxygen species (ROS) levels. ROS increase results into LT-HSC differentiation and stem cell exhaustion. Paraoxonase 2 (PON2) has been shown to be important for ROS control. Objectives. We investigate the effects of inactivation of the PON2 gene on hematopoietic cell differentiation and activity. Methods and Results. In young mice with inactivated Pon2 gene (Pon2-/-, -/- BM outcompeted WT BM at early time points. ROS levels were significantly increased in Pon2-/- whole BM, but not in Pon2-/- LT-HSCs. In more differentiated stages of hematopoiesis, Pon2 deficiency led to a misbalanced erythropoiesis both in physiologic and stress conditions. In older mice (>9 months), Pon2 depletion caused an increase in LT-HSCs as well as increased levels of granulocyte/macrophage progenitors (GMPs) and myeloid skewing, indicating a premature aging phenotype. No significant changes in ROS levels in old Pon2-/- LT- and short-term (ST-) HSCs were observed, but a significant reduction of spontaneous apoptotic cell death was measured. RNA-seq analysis in Pon2-/- LT-HSCs identified overrepresentation of genes involved in the C-X-C chemokine receptor type 4 (Cxcr4) signaling, suggesting compensatory mechanisms to overcome ROS-mediated accelerated aging in hematopoietic progenitor cells. Conclusions. In summary, our current data indicate that PON2 is involved in the regulation of HSC functions.

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.

Background Cigarette smoking is a threat to global human health and a leading cause of the cardiovascular disease (CVD) morbidity and mortality. Importantly, sex-specific differences in smoking-induced arterial stiffness, an early key event in the development of atherosclerotic CVD, remain still elusive. Thus, this study sought out to investigate sex-specific associations between smoking and measures of arterial stiffness. Methods and results Overall, 15,010 participants (7584 men and 7426 women aged 35–74 years) of the Gutenberg Health Study were examined at baseline during 2007–2012. Smoking status, pack-years of smoking, and years since quitting smoking were assessed by a standardized computer-assisted interview. Arterial stiffness and wave reflection were determined by stiffness index (SI) and augmentation index (AI). In the total sample, 45.8% had never smoked, 34.7% were former smokers, and 19.4% were current smokers. Median cumulative smoking exposure was 22.0 pack-years in current male smokers and 16.0 in current female smokers. In general, multivariable linear regression models adjusted for a comprehensive set of confounders revealed that smoking status, pack-years of smoking, and years since quitting smoking were dose-dependently associated with markers of arterial stiffness. In sex-specific analyses, these associations were overall more pronounced in men and SI was stronger related to the male sex, whereas differences between men and women in the case of AI appeared to be less substantial. Discussion The present results indicate that chronic smoking is strongly and dose-dependently associated with increased arterial stiffness in a large population-based cohort regardless of sex but with a stronger association in men.

Superoxide formation is a hallmark of cardiovascular disease with the involvement of different tissues and cell types. Identification of the cellular sources and subcellular localization of superoxide formation is important to understand the underlying disease pathomechanisms. In the present study, we used HPLC quantification of the superoxide-specific oxidation products of hydroethidine (HE or DHE) and its derivative hydropropidine (HPr+) for measurement of intra- and extracellular superoxide formation in isolated leukocytes and tissues of hypertensive rats. Superoxide generation by isolated leukocytes from human subjects as well as tissue samples of hypertensive rats (infusion of angiotensin-II for 7 days) was investigated using HPr+ and HE fluorescent probes with HPLC or plate reader detection. Both fluorescent dyes were used to test for intra- and extracellular superoxide formation using the supernatant or cell/tissue pellet for analysis. We demonstrate the correlation of impaired functional parameters (blood pressure, vascular function, and oxidative burst) and increased superoxide formation in different organ systems of hypertensive rats using the HPr+/HPLC method. In the cell model, the differences between HE and HPr+ and especially the advantage of the extracellular specificity of HPr+, due to its cell impermeability, became evident. Plate reader-based assays showed much higher background signal and were inferior to HPLC based methods. In conclusion, the HPr+/HPLC assay for superoxide determination is highly reliable in isolated immune cells and an animal model of arterial hypertension. In particular, the cell impermeability of HPr+ made it possible to differentiate between intra- and extracellular superoxide formation.

Epidemiological studies have found that transportation noise increases the risk of cardiovascular morbidity and mortality, with high-quality evidence for ischaemic heart disease. According to the WHO, ≥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 dysfunction, inflammation and hypertension, thereby elevating the risk of cardiovascular disease. In this Review, we focus on the indirect, non-auditory cardiovascular health effects of transportation noise. We provide an updated overview of epidemiological research on the effects of transportation noise on cardiovascular risk factors and disease, discuss the mechanistic insights from the latest clinical and experimental studies, and propose new risk markers to address noise-induced cardiovascular effects in the general population. We also explain, in detail, the potential effects of noise on alterations of gene networks, epigenetic pathways, gut microbiota, circadian rhythm, signal transduction along the neuronal-cardiovascular axis, oxidative stress, inflammation and metabolism. Lastly, we describe current and future noise-mitigation strategies and evaluate the status of the existing evidence on noise as a cardiovascular risk factor.

Background and Purpose Organic nitrates such as nitroglycerin (NTG) or pentaerythritol tetranitrate (PETN) have been used for over a century in the treatment of angina or ischaemic heart disease. These compounds are prodrugs which release their nitrovasodilators upon enzymic bioactivation by aldehyde dehydrogenase (ALDH2) or cytochromes P450 (CYP). Whereas ALDH2 is known to directly activate organic nitrates in vessels, the contribution of vascular CYPs is unknown and was studied here. Experimental Approach As all CYPs depend on cytochrome P450 reductase (POR) as electron donor, we generated a smooth muscle cell-specific, inducible knockout mouse of POR (smcPOR−/−) to investigate the contribution of POR/CYP to vascular biotransformation of organic nitrates. Key Results Microsomes containing recombinant CYPs expressed in human vascular tissues released nitrite from NTG and PETN with CYP2C9 and CYP2C8 being most efficient. SFK525, a CYP suicide inhibitor, blocked this effect. smcPOR−/− mice exhibited no obvious cardiovascular phenotype (normal cardiac weight and endothelium-dependent relaxation) and plasma and vascular nitrite production was similar to control (CTL) animals. NTG- and PETN-induced relaxation of isolated endothelium-intact or endothelium-denuded vessels were identical between CTL and smcPOR−/−. Likewise, nitrite release from organic nitrates in aortic rings was not affected by deletion of POR in smooth muscle cells (SMCs). In contrast, inhibition of ALDH2 by benomyl (10 μM) inhibited NTG-induced nitrite production and relaxation. Deletion of POR did not modulate this response. Conclusions and Implications Our data suggest that metabolism by vascular CYPs does not contribute to the pharmacological function of organic nitrates.

Objective: Celiac disease (CeD) is an autoimmune enteropathy triggered by dietary gluten, with a prevalence around 1%. Since many patients show heterogeneous symptoms, it is vastly underdiagnosed and yet without any treatment option besides lifelong gluten restriction. Vascular function in CeD patients compared to healthy controls has been assessed and hypothesized CeD as a cardiovascular risk factor. Herewith we aimed to explore the cardiovascular effects of CeD in a murine model, with special emphasis on endothelial dysfunction, vascular inflammation, and oxidative stress, known triggers for cardiovascular disease. Methods: NOD.DQ8 mice were raised on a zein-based, gluten-free diet. During the experiment, mice received gavage with peptic-tryptic digest of gliadin and were switched to a gluten-containing diet (Gliadin group). A control group (Zein group) was continued on gluten-free diet and received accordingly digested zein. Results: Blood pressure measurements revealed arterial hypertension in the Gliadin group. Endothelium-dependent relaxation was impaired in the Gliadin group compared to Zein, whereas no change in endothelium-independent was observed, tested by isometric tension recordings. Pro-inflammatory genes, like Tnfa and Nox2 were upregulated in the Gliadin group measured by quantitative rtPCR in aortic and intestinal tissue. Infiltration by intraepithelial T-lymphocytes into the epithelium of the small intestine was shown by IHC. In cardiac tissue, gliadin-treatment increased the oxidative stress parameters 3-nitrotyrosine and 4-hydroxy-2-nonenal shown in dot blots. To investigate the inflammatory link between gut and the cardiovascular system plasma proteomics were performed and revealed elevated levels of IL-17A. Conclusion: CeD is a cardiovascular risk factor. However, the mechanism remains unresolved. In a mouse model, we demonstrate that gluten treatment elevates blood pressure and impairs vascular function. Intestinal inflammation conveys to the cardiovascular system, leads to oxidative stress, and thereby impairs endothelial function. A potential mediator might be IL-17A, whose role in other autoimmunity-based cardiovascular risk factors (e.g., psoriasis) has already been demonstrated.

We estimated the association between outdoor light at night at the residence and risk of coronary heart disease (CHD) within a prospective cohort of older adults in Hong Kong.Over a median of 11 years of follow-up, we identified 3772 incident CHD hospitalizations and 1695 CHD deaths. Annual levels of outdoor light at night at participants' residential addresses were estimated using time-varying satellite data for a composite of persistent night-time illumination at ∼1 km2 scale. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of the association between outdoor light at night at the residence and risk of CHD. The association between light at night and incident CHD hospitalization and mortality exhibited a monotonic exposure-response function. An interquartile range (IQR) (60.0 nW/cm2/sr) increase in outdoor light at night was associated with an HR of 1.11 (95% CI: 1.03, 1.18) for CHD hospitalizations and 1.10 (95% CI: 1.00, 1.22) for CHD deaths after adjusting for both individual and area-level risk factors. The association did not vary across strata of hypothesized risk factors.Among older adults, outdoor light at night at the residence was associated with a higher risk of CHD hospitalizations and deaths. We caution against causal interpretation of these novel findings. Future studies with more detailed information on exposure, individual adaptive behaviours, and potential mediators are warranted to further examine the relationship between light at night and CHD risk.