Robert L. Bard

Insights Into the Mechanisms and Mediators of the Effects of Air Pollution Exposure on Blood Pressure and Vascular Function in Healthy Humans

Fine particulate matter air pollution plus ozone impairs vascular function and raises diastolic blood pressure. We aimed to determine the mechanism and air pollutant responsible. The effects of pollution on heart rate variability, blood pressure, biomarkers, and brachial flow-mediated dilatation were determined in 2 randomized, double-blind, crossover studies. In Ann Arbor, 50 subjects were exposed to fine particles (150 &mgr;g/m3) plus ozone (120 parts per billion) for 2 hours on 3 occasions with pretreatments of an endothelin antagonist (Bosentan, 250 mg), antioxidant (Vitamin C, 2 g), or placebo. In Toronto, 31 subjects were exposed to 4 different conditions (particles plus ozone, particles, ozone, and filtered air). In Toronto, diastolic blood pressure significantly increased (2.9 and 3.6 mm Hg) only during particle-containing exposures in association with particulate matter concentration and reductions in heart rate variability. Flow-mediated dilatation significantly decreased (2.0% and 2.9%) only 24 hours after particle-containing exposures in association with particulate matter concentration and increases in blood tumor necrosis factor &agr;. In Ann Arbor, diastolic blood pressure significantly similarly increased during all of the exposures (2.5 to 4.0 mm Hg), a response not mitigated by pretreatments. Flow-mediated dilatation remained unaltered. Particulate matter, not ozone, was responsible for increasing diastolic blood pressure during air pollution inhalation, most plausibly by instigating acute autonomic imbalance. Only particles from urban Toronto additionally impaired endothelial function, likely via slower proinflammatory pathways. Our findings demonstrate credible mechanisms whereby fine particulate matter could trigger acute cardiovascular events and that aspects of exposure location may be an important determinant of the health consequences.

Usefulness of Visceral Obesity (Waist/ Hip Ratio) in Predicting Vascular Endothelial Function in Healthy Overweight Adults

Vascular endothelial dysfunction (VED) is associated with obesity; however, its etiology remains controversial. By determining the predictors of fasting and postprandial endothelial function in overweight adults without other cardiovascular risk factors, we were able to investigate novel mechanisms directly linking obesity to VED. Thirty-two healthy adults (body mass index [BMI] > or =27 kg/m(2)) underwent determination of fasting low-density lipoprotein (LDL) particle size, high sensitivity C-reactive protein levels, anthropometric measurements, and endothelial function by flow-mediated dilation (FMD) of the brachial artery. Postprandial lipemia and FMD were measured 4 hours after ingestion of a high-fat meal. Blood pressures and fasting levels of lipoproteins, glucose, insulin, and fatty acids were within normal limits in all subjects. An abdominal fat pattern, as determined by an increased waist/hip ratio (WHR), was the sole significant predictor of FMD (r = -0.58, p = 0.001), despite no significant correlation between whole body obesity (BMI) and FMD. At comparable levels of BMI, obese subjects with a WHR > or =0.85 had a significantly blunted FMD compared with those with a WHR <0.85 (3.93 +/- 2.85% vs 8.34 +/- 5.47%, p = 0.016). Traditional coronary risk factors, C-reactive protein, postprandial lipemia, and LDL particle size did not predict FMD. We found no appreciable alteration in the postprandial state from fasting FMD (6.31 +/- 4.62% vs 6.25 +/- 5.47%, p = 0.95). The same results were found when women were analyzed alone. Increased abdominal adiposity determined by a simple WHR is a strong independent predictor of VED even in healthy overweight adults; this is a finding unexplained by alterations in conventional risk factors, systemic inflammation, or the atherogenic lipoprotein pattern.

The relationship between diabetes mellitus and traffic-related air pollution.

Objective: Air pollution is associated with an increased risk for cardiovascular events. Many of the biological pathways involved could also promote diabetes mellitus (DM). We therefore investigated the association between DM prevalence and exposure to traffic-related air pollution (nitrogen dioxide [NO 2]). Methods: Study participants were patients who attended two respiratory clinics in Hamilton (n = 5228) and Toronto (n = 2406). The diagnosis of DM was ascertained by linkage to administrative databases of the Ontario universal Health Insurance Plan for patients aged 40 years and above. Geographic Information systems methodology was used to assign individual estimates of NO2 based on a network of samplers in each city. Logistic regression was used to estimate the relations between NO2 exposures and the odds of DM diagnosis. Results: After adjusting for age, body mass index, and neighborhood income there were positive effects in women on the odds ratio for DM for each 1 ppb NO2 exposure in Toronto (OR 1.055, 95% CI: 0.99 to 1.11) and Hamilton (OR 1.029, 95% CI: 0.98 to 1.08). In a meta-analytic model including both cities, there was a significant effect in women (OR = 1.04; 95% CI: 1.00 to 1.08). Across the inter-quartile range (∼4 ppb NO2) there was nearly a 17% increase in the odds of DM for women. There were no positive associations among men. Conclusions: Exposure to NO2, a marker of traffic-related air pollutants, was associated with DM prevalence among women. Exposure estimate errors in men may explain the apparent gender difference. These results suggest that common air pollutants are associated with DM and warrant more investigation to determine if this is a cause-and-effect relationship.

Acute effects of ambient particulate matter on blood pressure: differential effects across urban communities.

Recent studies have suggested a link between exposure to ambient particulate matter <2.5 &mgr;m in diameter (PM2.5) and adverse cardiovascular outcomes. The objective of this study was to examine the effects of differing community-level exposure to PM2.5 on daily measures of blood pressure (BP) among an adult population. During the period May 2002 through April 2003, BP was examined at 2 time points for 347 adults residing in 3 distinct communities of Detroit, Michigan. Exposure to PM2.5 was assessed in each community during this period, along with multivariate associations between PM2.5 and BP. In models combining all 3 of the communities, PM2.5 was significantly associated with systolic blood pressure; a 10-&mgr;g/m3 increase in daily PM2.5 was associated with a 3.2-mm Hg increase in systolic blood pressure (P=0.05). However, in models that added a location interaction, larger effects were observed for systolic blood pressure within the community with highest PM2.5 levels; a 10-&mgr;g/m3 increase in daily PM2.5 was associated with a 8.6-mm Hg increase in systolic blood pressure (P=0.01). We also found young age (<55 years) and not taking BP medications to be significant predictors of increased BP effects. Among those taking BP medications, the PM2.5 effect on BP appeared to be mitigated, partially explaining the age effect, because those participants <55 years of age were less likely to take BP medications. Short-term increases in exposure to ambient PM2.5 are associated with acute increases in BP in adults, especially within communities with elevated levels of exposure.

A Negative Carotid Plaque Area Test Is Superior to Other Noninvasive Atherosclerosis Studies for Reducing the Likelihood of Having Underlying Significant Coronary Artery Disease

Objective—Coronary calcium score (CCS), carotid plaque area (CPA), intima-media thickness (IMT), and C-reactive protein (CRP) are independent predictors of cardiovascular prognosis. Although each test may enhance risk stratification, their comparative abilities to screen for underlying coronary stenoses in individual patients is less established. Methods and Results—Forty-two patients who had a 16-slice coronary computed tomography angiogram (CTA) performed were invited to have CPA, IMT, and CRP measured. CPA was defined as the sum of all the cross-sectional areas of each plaque >1 mm in diameter found in all carotid vessels bilaterally. CCS and the number plus degree of stenotic coronary arteries were determined by CTA. The presence of clinically significant coronary artery disease (CAD) was defined as the existence of any stenosis ≥50%. CTA identified clinically significant CAD in 43% of the patients. CPA >0 was more sensitive (72%) and specific (58%) than a CCS >0 (58% and 55%) for identifying CAD. A “clean” carotid artery (CPA=0) provides a superior negative predictive value (74%) and likelihood ratio of a negative test (0.48) than all other studies, in particular versus a CCS=0 (65% and 0.72). The areas under the receiver-operator curves for CPA and CCS in relation to any CAD were similar (0.640 versus 0.675). Carotid IMT and CRP performed poorly compared with CPA and CCS. For detecting CAD in only the left main or left anterior descending artery, the negative predictive value and likelihood ratio of a negative test remained superior for CPA (87% and 0.33) compared with CCS (80% and 0.56). In our population with a prevalence of these coronary lesions of 30%, the post-test probability in any patient with a negative CPA result is reduced to 10%. Conclusion—CPA determination is superior to CCS, IMT, and CRP in its ability to reduce the likelihood of clinically significant underlying CAD in patients of varying cardiac risk.

Differences in blood pressure and vascular responses associated with ambient fine particulate matter exposures measured at the personal versus community level.

Background Higher ambient fine particulate matter (PM2.5) levels can be associated with increased blood pressure and vascular dysfunction. Objectives To determine the differential effects on blood pressure and vascular function of daily changes in community ambient- versus personal-level PM2.5 measurements. Methods Cardiovascular outcomes included vascular tone and function and blood pressure measured in 65 non-smoking subjects. PM2.5 exposure metrics included 24 h integrated personal- (by vest monitors) and community-based ambient levels measured for up to 5 consecutive days (357 observations). Associations between community- and personal-level PM2.5 exposures with alterations in cardiovascular outcomes were assessed by linear mixed models. Results Mean daily personal and community measures of PM2.5 were 21.9±24.8 and 15.4±7.5 μg/m3, respectively. Community PM2.5 levels were not associated with cardiovascular outcomes. However, a 10 μg/m3 increase in total personal-level PM2.5 exposure (TPE) was associated with systolic blood pressure elevation (+1.41 mm Hg; lag day 1, p<0.001) and trends towards vasoconstriction in subsets of individuals (0.08 mm; lag day 2 among subjects with low secondhand smoke exposure, p=0.07). TPE and secondhand smoke were associated with elevated systolic blood pressure on lag day 1. Flow-mediated dilatation was not associated with any exposure. Conclusions Exposure to higher personal-level PM2.5 during routine daily activity measured with low-bias and minimally-confounded personal monitors was associated with modest increases in systolic blood pressure and trends towards arterial vasoconstriction. Comparable elevations in community PM2.5 levels were not related to these outcomes, suggesting that specific components within personal and background ambient PM2.5 may elicit differing cardiovascular responses.

Attenuation of haemodynamic, metabolic and energy expenditure responses to isoproterenol in patients with hypertension

Objective Overweight and heightened sympathetic activity are more common in hypertensive than normotensive subjects. β-adrenoceptor down-regulation has been described in hypertension. We tested the hypothesis that chronic sympathetic overactivity impairs β-adrenergic-mediated thermogenesis and thereby favours gain of weight in hypertension. Participants The study included 13 hypertensive subjects aged 35.3 ± 7.9 years and 25 normotensive subjects of control of similar age. Methods To measure β-adrenergically mediated haemodynamic, metabolic and thermogenic responsiveness, increasing doses of isoproterenol diluted in 2.5 ml saline were injected as intravenous boluses (0.1, 0.25, 0.5, 1.0 and 2.0 μg/m2). On a separate day, isoproterenol was infused continuously intravenously in increasing doses (10, 20 and 40 ng/kg per min), each dose for 30 min. Results The sitting heart rate and body mass were greater in hypertensives (P = 0.000, and P = 0.005, respectively). The heart rate responses to 1 and 2 μg/m2 isoproterenol bolus (P = 0.01 and P = 0.03, respectively) were reduced in hypertensives. The energy expenditure (P = 0.002) and oxygen consumption (P = 0.0004) increase with 40 ng/kg per min isoproterenol infusion, and glucose and phosphate responses at both 20 (P = 0.01 and P = 0.05) and 40 (P = 0.001 and P = 0.02) ng/kg per min isoproterenol infusion were attenuated in hypertensives. The baseline heart rate negatively correlated with heart rate (P = 0.015) response to isoproterenol bolus and blood pressure (P = 0.02) response to isoproterenol infusion. The urinary noradrenaline negatively correlated with heart rate response to isoproterenol bolus (P = 0.001), and with systolic blood pressure (P = 0.02) and energy expenditure responsiveness to isoproterenol infusion (P = 0.04). Furthermore, plasma noradrenaline negatively correlated with heart rate responsiveness to isoproterenol bolus (P = 0.004). Conclusions These results show a generalized decrease of β-adrenergic responsiveness in stage 1 hypertension and support the concept that sympathetic overactivity, via down-regulation of β-adrenoceptor-mediated thermogenic responses, may facilitate the development of obesity in hypertension.

Hemodynamic, autonomic, and vascular effects of exposure to coarse particulate matter air pollution from a rural location

Background: Fine particulate matter (PM) air pollution is associated with numerous adverse health effects, including increased blood pressure (BP) and vascular dysfunction. Coarse PM substantially contributes to global air pollution, yet differs in characteristics from fine particles and is currently not regulated. However, the cardiovascular (CV) impacts of coarse PM exposure remain largely unknown. Objectives: Our goal was to elucidate whether coarse PM, like fine PM, is itself capable of eliciting adverse CV responses. Methods: We performed a randomized double-blind crossover study in which 32 healthy adults (25.9 ± 6.6 years of age) were exposed to concentrated ambient coarse particles (CAP; 76.2 ± 51.5 μg/m3) in a rural location and filtered air (FA) for 2 hr. We measured CV outcomes during, immediately after, and 2 hr postexposures. Results: Both systolic (mean difference = 0.32 mmHg; 95% CI: 0.05, 0.58; p = 0.021) and diastolic BP (0.27 mmHg; 95% CI: 0.003, 0.53; p = 0.05) linearly increased per 10 min of exposure during the inhalation of coarse CAP when compared with changes during FA exposure. Heart rate was on average higher (4.1 bpm; 95% CI: 3.06, 5.12; p < 0.0001) and the ratio of low-to-high frequency heart rate variability increased (0.24; 95% CI: 0.07, 0.41; p = 0.007) during coarse particle versus FA exposure. Other outcomes (brachial flow-mediated dilatation, microvascular reactive hyperemia index, aortic hemodynamics, pulse wave velocity) were not differentially altered by the exposures. Conclusions: Inhalation of coarse PM from a rural location is associated with a rapid elevation in BP and heart rate during exposure, likely due to the triggering of autonomic imbalance. These findings add mechanistic evidence supporting the biological plausibility that coarse particles could contribute to the triggering of acute CV events. Citation: Brook RD, Bard RL, Morishita M, Dvonch JT, Wang L, Yang HY, Spino C, Mukherjee B, Kaplan MJ, Yalavarthi S, Oral EA, Ajluni N, Sun Q, Brook JR, Harkema J, Rajagopalan S. 2014. Hemodynamic, autonomic, and vascular effects of exposure to coarse particulate matter air pollution from a rural location. Environ Health Perspect 122:624–630; http://dx.doi.org/10.1289/ehp.1306595

Blood Pressure and Vascular Effects of Leptin in Humans

BACKGROUND Leptin may play a role in mediating obesity-related hypertension. However, its effects on the vasculature and blood pressure (BP) remain poorly defined in humans. METHODS In the first study, we performed a short-term, placebo-controlled, randomized, double-blind, cross-over experiment investigating the actions of recombinant human leptin (r-metHuLeptin) in 15 nonobese adults. To compliment the acute study, we retrospectively analyzed available BP results from a previously performed 85-day, placebo-controlled, randomized, double-blind, parallel weight-loss study using r-metHuLeptin in 284 obese adults. RESULTS In the acute study, conduit artery endothelial function determined by brachial flow-mediated dilatation (FMD) increased 2 hours following 0.2 mg . Kg(1) subcutaneously (SC) of r-metHuLeptin versus placebo (+3.3% versus -2.8%, P = .02). BP remained unchanged 4 hours after injections. In the retrospective analysis of the weight loss study data, 10 mg every day before noon (QAM), 10 mg every day after noon (QPM), or 10 mg twice a day (BID) SC of r-metHuLeptin was found to not alter the degree of weight loss (-3.2 +/- 3.7 versus -2.9 +/- 3.2 Kg, P = .54), change in systolic (-1.6 + 12.9 versus -2.0 +/- 13.9 mmHg, P = .85) and diastolic BP (-0.2 +/- 8.7 versus -1.5 +/- 8.6, P = .30), as well as heart rate (-1.4 +/- 10.7 versus -1.4 +/- 10.4 beats/min, P = .98) compared to placebo. CONCLUSIONS In our acute study, marked hyperleptinemia rapidly enhanced endothelial function and did not alter BP. The available data from a longer-term study in healthy obese adults did not demonstrate a significant effect of hyperleptinemia upon BP. These combined findings do not support a direct role for leptin in linking obesity to hypertension, however more studies are required to corroborate these observations.

Exploration of the Rapid Effects of Personal Fine Particulate Matter Exposure on Arterial Hemodynamics and Vascular Function during the Same Day

Background Levels of fine particulate matter [≤ 2.5 μm in aerodynamic diameter (PM2.5)] are associated with alterations in arterial hemodynamics and vascular function. However, the characteristics of the same-day exposure–response relationships remain unclear. Objectives We aimed to explore the effects of personal PM2.5 exposures within the preceding 24 hr on blood pressure (BP), heart rate (HR), brachial artery diameter (BAD), endothelial function [flow-mediated dilatation (FMD)], and nitroglycerin-mediated dilatation (NMD). Methods Fifty-one nonsmoking subjects had up to 5 consecutive days of 24-hr personal PM2.5 monitoring and daily cardiovascular (CV) measurements during summer and/or winter periods. The associations between integrated hour-long total personal PM2.5 exposure (TPE) levels (continuous nephelometry among compliant subjects with low secondhand tobacco smoke exposures; n = 30) with the CV outcomes were assessed over a 24-hr period by linear mixed models. Results We observed the strongest associations (and smallest estimation errors) between HR and TPE recorded 1–10 hr before CV measurements. The associations were not pronounced for the other time lags (11–24 hr). The associations between TPE and FMD or BAD did not show as clear a temporal pattern. However, we found some suggestion of a negative association with FMD and a positive association with BAD related to TPE just before measurement (0–2 hr). Conclusions Brief elevations in ambient TPE levels encountered during routine daily activity were associated with small increases in HR and trends toward conduit arterial vasodilatation and endothelial dysfunction within a few hours of exposure. These responses could reflect acute PM2.5-induced autonomic imbalance and may factor in the associated rapid increase in CV risk among susceptible individuals.