Frank P. Schmidt

Effect of nighttime aircraft noise exposure on endothelial function and stress hormone release in healthy adults

Aims Aircraft noise disturbs sleep, and long-term exposure has been shown to be associated with increases in the prevalence of hypertension and an overall increased risk for myocardial infarction. The exact mechanisms responsible for these cardiovascular effects remain unclear. Methods and results We performed a blinded field study in 75 healthy volunteers (mean age 26 years), who were exposed at home, in random order, to one control pattern (no noise) and two different noise scenarios [30 or 60 aircraft noise events per night with an average maximum sound pressure level (SPL) of 60 dB(A)] for one night each. We performed polygraphy during each study night. Noise caused a worsening in sleep quality (P < 0.0001). Noise60, corresponding to equivalent continuous SPLs of 46.3 dB (Leq) and representing environmental noise levels associated with increased cardiovascular events, caused a blunting in FMD (P = 0.016). As well, although a direct comparison among the FMD values in the noise groups (control: 10.4 ± 3.8%; Noise30: 9.7 ± 4.1%; Noise60: 9.5 ± 4.3%, P = 0.052) did not reach significance, a monotone dose-dependent effect of noise level on FMD was shown (P = 0.020). Finally, there was a priming effect of noise, i.e. the blunting in FMD was particularly evident when subjects were exposed first to 30 and then to 60 noise events (P = 0.006). Noise-induced endothelial dysfunction (ED) was reversed by the administration of Vitamin C (P = 0.0171). Morning adrenaline concentration increased from 28.3 ± 10.9 to 33.2 ± 16.6 and 34.1 ± 19.3 ng/L (P = 0.0099). Pulse transit time, reflecting arterial stiffness, was also shorter after exposure to noise (P = 0.003). Conclusion In healthy adults, acute nighttime aircraft noise exposure dose-dependently impairs endothelial function and stimulates adrenaline release. Noise-induced ED may be in part due to increased production in reactive oxygen species and may thus be one mechanism contributing to the observed association of chronic noise exposure with cardiovascular disease.

Environmental stressors and cardio-metabolic disease: part II–mechanistic insights

Environmental factors can act as facilitators of chronic non-communicable diseases. Ambient noise and air pollution collectively outrank all other environmental risk factors in importance, contributing to over 75% of the disease and disability burden associated with known environmental risk factors. In the first part of this review, we discussed the global burden and epidemiologic evidence supporting the importance of these novel risk factors as facilitators of cardiometabolic disease. In this part, we will discuss pathophysiological mechanisms responsible for noise and air pollution-mediated effects. Akin to traditional cardiovascular risk factors, a considerable body of evidence suggests that these environmental agents induce low-grade inflammation, oxidative stress, vascular dysfunction, and autonomic nervous system imbalance, thereby facilitating the development of diseases such as hypertension and diabetes. Through their impact on traditional risk factors and via additional novel mechanisms, environmental risk factors may have much larger impact on cardiovascular events than currently appreciated. In the second part of this review, we discuss deficiencies and gaps in knowledge and opportunities for new research.

Environmental stressors and cardio-metabolic disease: part I-epidemiologic evidence supporting a role for noise and air pollution and effects of mitigation strategies.

Traffic noise and air pollution together represent the two most important environmental risk factors in urbanized societies. The first of this two-part review discusses the epidemiologic evidence in support of the existence of an association between these risk factors with cardiovascular and metabolic disease. While independent effects of these risk factors have now clearly been shown, recent studies also suggest that the two exposures may interact with each other and with traditional risk factors such as hypertension and type 2 diabetes. From a societal and policy perspective, the health effects of both air pollution and traffic noise are observed for exposures well below the thresholds currently accepted as being safe. Current gaps in knowledge, effects of intervention and their impact on cardiovascular disease, will be discussed in the last section of this review. Increased awareness of the societal burden posed by these novel risk factors and acknowledgement in traditional risk factor guidelines may intensify the efforts required for effective legislation to reduce air pollution and noise.

Immediate effect of the MitraClip® procedure on mitral ring geometry in primary and secondary mitral regurgitation

AIMS Percutaneous treatment of mitral regurgitation (MR) has been shown to reduce MR severity and improve functional outcomes. Surgical treatment of MR usually includes mitral annulus reduction. The influence of the MitraClip on annulus geometry is not clear. We wanted to investigate whether the procedure itself reduces annulus diameter and if there may be differences between secondary or functional (SMR) and primary (PMR) MR. METHODS AND RESULTS We retrospectively assessed 3D echocardiography (3D-TEE) data of 55 patients acquired during the procedure shortly before and after clip placement for changes in annulus diameter and area. Measurements were done with QLAB software. Patients were categorized as having either SMR (n = 41) or PMR (n = 14). In SMR, we were able to demonstrate a significant reduction in annulus area (meanΔ 1.30 ± 1.44 cm2; P < 0.001), anterior-posterior (AP)-diameter (meanΔ 0.28 ± 0.32 cm; P < 0.001), tenting area (meanΔ 0.39 ± 0.49 cm2; P < 0.001). No significant change could be found for latero-medial (LM)-diameter. In contrast, we could not demonstrate significant changes in any of the parameters described above in patients with PMR. CONCLUSION Percutaneous treatment with the MitraClip device can produce immediate reductions in mitral annulus size in SMR, probably supporting procedural success. It also reduces tenting, which may have prognostic implications. In contrast, these effects on mitral geometry cannot be demonstrated in PMR. Knowledge of this difference between SMR and PMR may be important to improve procedural strategies.

Effects of noise on vascular function, oxidative stress, and inflammation: mechanistic insight from studies in mice

Abstract Aims Epidemiological studies indicate that traffic noise increases the incidence of coronary artery disease, hypertension and stroke. The underlying mechanisms remain largely unknown. Field studies with nighttime noise exposure demonstrate that aircraft noise leads to vascular dysfunction, which is markedly improved by vitamin C, suggesting a key role of oxidative stress in causing this phenomenon. Methods and results We developed a novel animal model to study the vascular consequences of aircraft noise exposure. Peak sound levels of 85 and mean sound level of 72 dBA applied by loudspeakers for 4 days caused an increase in systolic blood pressure, plasma noradrenaline and angiotensin II levels and induced endothelial dysfunction. Noise increased eNOS expression but reduced vascular NO levels because of eNOS uncoupling. Noise increased circulating levels of nitrotyrosine, interleukine-6 and vascular expression of the NADPH oxidase subunit Nox2, nitrotyrosine-positive proteins and of endothelin-1. FACS analysis demonstrated an increase in infiltrated natural killer-cells and neutrophils into the vasculature. Equal mean sound pressure levels of white noise for 4 days did not induce these changes. Comparative Illumina sequencing of transcriptomes of aortic tissues from aircraft noise-treated animals displayed significant changes of genes in part responsible for the regulation of vascular function, vascular remodelling, and cell death. Conclusion We established a novel and unique aircraft noise stress model with increased blood pressure and vascular dysfunction associated with oxidative stress. This animal model enables future studies of molecular mechanisms, mitigation strategies, and pharmacological interventions to protect from noise-induced vascular damage.

Supervised exercise training in peripheral arterial disease increases vascular shear stress and profunda femoral artery diameter

Background Arteriogenesis is promoted by flow- and pressure-related forces such as tangential wall stress and laminar shear stress. Exercise training (ET) is known to promote arteriogenesis in peripheral arterial disease (PAD) patients. It remains unclear whether supervised ET (SET) promotes arteriogenesis more efficiently than non-SET (nSET). Methods and results Forty PAD patients participated in a SET or nSET training programme (n = 20 each) and were compared to 20 healthy individuals without any history of cardiovascular events. Femoral artery diameter, flow and velocity were measured by ultrasound. Tangential wall stress and laminar shear stress were calculated for femoral arteries. Follow-up was performed after a mean of 7.65 ± 1.62 months. At follow-up, only the SET group showed a significant increase in lumen diameter of the profunda femoral artery (p = 0.03), accompanied by an increase of tangential wall stress (p = 0.002). Laminar shear stress decreased, but remained higher for the SET group compared to controls (p < 0.01). Individual changes in walking distance were higher for SET patients (p = 0.01) than nSET patients (p = 0.07). Profunda femoral lumen diameter and tangential wall stress correlated directly with walking distance (r = 0.446; p < 0.001), as well as with each other (r = 0.743; p < 0.0001). Conclusions Our results indicate that SET promotes arteriogenesis more efficiently than nSET. Femoral lumen diameter and flow might help with the monitoring of ET efficiency and potential arteriogenesis.

Characterization and referral patterns of ST-elevation myocardial infarction patients admitted to chest pain units rather than directly to catherization laboratories. Data from the German Chest Pain Unit Registry

BACKGROUND Direct transfer to the catheterization laboratory for primary percutaneous coronary intervention (PCI) is standard of care for patients with ST-segment elevation myocardial infarction (STEMI). Nevertheless, a significant number of STEMI-patients are initially treated in chest pain units (CPUs) of admitting hospitals. Thus, it is important to characterize these patients and to define why an important deviation from recommended clinical pathways occurs and in particular to quantify the impact of deviation on critical time intervals. METHODS AND RESULTS 1679 STEMI patients admitted to a CPU in the period from 2010 to 2015 were enrolled in the German CPU registry (8.5% of 19,666). 55.9% of the patients were delivered by an emergency medical system (EMS), 16.1% transferred from other hospitals and 15.2% referred by a general practitioner (GP). 12.7% were self-referrals. 55% did not get a pre-hospital ECG. Compared to the EMS, referral by GPs markedly delayed critical time intervals while a pre-hospital ECG demonstrating ST-segment elevation reduced door-to-balloon time. When compared to STEMI patients (n=21,674) enrolled in the ALKK-registry, CPU-STEMI patients had a lower risk profile, their treatment in the CPU was guideline-conform and in-hospital mortality was low (1.5%). CONCLUSIONS CPU-STEMI patients represent a numerically significant group because a pre-hospital ECG was not documented. Treatment in the CPU is guideline-conform and the intra-hospital mortality is low. The lack of a pre-hospital ECG and admission via the GP substantially delay critical time intervals suggesting that in patients with symptoms suggestive an ACS, the EMS should be contacted and not the GP.

Phenotypic and functional characterization of neutrophils and monocytes from patients with myelodysplastic syndrome by flow cytometry.

Myelodysplastic syndrome (MDS) is a clonal stem cell disorder frequently associated with inefficient granulopoiesis showing dysplastic polymorphonuclear neutrophils (PMNs). To assess PMN functionality in MDS in a clinical routine setting, 30 MDS patients and ten healthy volunteers were analyzed for PMN and monocyte phenotype and function (degranulation, CD62L shedding, oxidative burst and phagocytosis) upon stimulation with lipopolysaccharide by multi-color flow cytometry (MCFC). Our data show a heterogeneous pattern for CD66, CD16 and CD64 expression on PMNs of MDS patients. CD62L shedding rate and CD66 degranulation were reduced. Interestingly, we detected correlations between the WHO adapted prognostic scoring system (WPSS) and CD16 expression on PMNs as well as the international prognostic scoring system (IPSS) and CD11b degranulation by MCFC, suggesting clinical relevance of MCFC based function testing. In conclusion, MCFC of myelodysplastic immunophenotypes and PMN functionality are applicable in clinical settings, but further prospective studies are needed to assess the practical clinical value of such analyses.

Invasive treatment of NSTEMI patients in German Chest Pain Units – Evidence for a treatment paradox

BACKGROUND Patients with non ST-segment elevation myocardial infarction (NSTEMI) represent the largest fraction of patients with acute coronary syndrome in German Chest Pain units. Recent evidence on early vs. selective percutaneous coronary intervention (PCI) is ambiguous with respect to effects on mortality, myocardial infarction (MI) and recurrent angina. With the present study we sought to investigate the prognostic impact of PCI and its timing in German Chest Pain Unit (CPU) NSTEMI patients. METHODS AND RESULTS Data from 1549 patients whose leading diagnosis was NSTEMI were retrieved from the German CPU registry for the interval between 3/2010 and 3/2014. Follow-up was available at median of 167days after discharge. The patients were grouped into a higher (Group A) and lower risk group (Group B) according to GRACE score and additional criteria on admission. Group A had higher Killip classes, higher BNP levels, reduced EF and significant more triple vessel disease (p<0.001). Surprisingly, patients in group A less frequently received early diagnostic catheterization and PCI. While conservative management did not affect prognosis in Group B, higher-risk CPU-NSTEMI patients without PCI had a significantly worse survival. CONCLUSIONS The present results reveal a substantial treatment gap in higher-risk NSTEMI patients in German Chest Pain Units. This treatment paradox may worsen prognosis in patients who could derive the largest benefit from early revascularization.

Environmental stressors and cardiovascular disease: the evidence is growing

The Global Burden of Disease Study estimated that the worldwide impact of air pollution [particulate matter (PM)2.5] was as many as 4.2 million deaths and 103 million disability-adjusted life years (DALYs) in 2015. Exposure to ozone caused an additional 254 000 deaths and a loss of 4.1 million DALYs from chronic obstructive pulmonary disease in 2015. In addition, high acute NO2 exposure levels are associated with a significant increase in cardiovascular mortality. Similar to the pervasive influence of air pollution, noise and its ‘socalled’ non-auditory effects are pervasive in the urban environment. The non-auditory effects include annoyance, sleep disturbance, and psychological stress, and are widely suspected to cause worldwide disability. According to the World Health Organization (WHO), at least 1 million DALYs are lost every year in western European countries because of environmental noise, and cardiovascular disease (CVD) contributes to the vast majority of these deaths. Traffic noise and air pollution have also been associated with increased risk of metabolic syndrome, obesity, and type 2 diabetes. Taken together, there is a growing body of evidence that the environmental exposure to traffic noise and air pollution can cause CVD, including coronary heart disease, myocardial infarction, arterial hypertension, heart failure, arrhythmia, and stroke. In general, studies addressing the effects of the environmental stressors noise and air pollution on traditional biological cardiovascular risk factors are rather limited. With the present study, Cai et al. investigated the associations of daytime road traffic noise and air pollution, estimated as PM10 and NO2, in two large European population-based cohorts, from respectively, Norway (HUNT) and the Netherlands (Lifelines), on high sensitivity C-reactive protein (hs-CRP), blood lipids, and glucose levels. After pooling of the cohorts, an interquartile range (IQR) higher noise [5.1 dB(A)] was associated with 1.1% higher hsCRP, 0.7% higher triglycerides, and 0.5% higher HDL; only the association with HDL was robust to adjustment for air pollution. An IQR higher PM10 (2.0lg/m ) or NO2 (7.4 lg/m ) was associated with higher triglycerides independent of adjustment for noise. Additionally, for NO2, a significant association with hsCRP was established. In Lifelines, an IQR higher noise [4.2 dB(A)] and PM10 (2.4lg/m ) was associated with 0.2% and 0.6% higher fasting glucose, respectively, both remaining robust to mutual adjustment. The authors concluded that long-term exposures to road traffic noise and ambient air pollution were associated with significant changes in blood biochemistry, providing a possible link between these exposures and the increased cardio-metabolic disease risk observed in epidemiological studies. As commented by the authors, the observed effects of road traffic noise and air pollution on CVD risk factors were small. However, given the high proportion of the population exposed to high levels of these pollutants, the effect of this observation could be that the entire distribution of these risk factors may be shifted towards a less favourable profile at population level, i.e. ‘at-risk’ populations may be increased. Only a limited number of studies have estimated exposure to both air pollution and traffic noise within the same study, and assessed effects of mutual adjustment. These studies mostly suggested that traffic noise and air pollution may independently contribute to the risk of cardiovascular incidence and mortality: a meta-analysis indicated that correction for either air or traffic noise pollution did not change the association of the other with respect to CVD outcome. However, some studies have found the association between road traffic noise and CVD to disappear after adjustment for air pollution, and vice versa, and this field clearly needs more research. For diabetes, the very studies including both air pollution and traffic noise indicated that traffic noise may increase risk independently of air pollution, whereas for air pollution the picture was not clear. The present study by Cai et al., which included both exposures, did not clarify this question, as for some biomarkers association with one exposure disappeared after adjustment for the other exposure,