Margaret Herbst

Production of Arrhythmias by Elevated Carboxyhemoglobin in Patients with Coronary Artery Disease

OBJECTIVE To assess the effects of exposure to 4% and 6% carboxyhemoglobin on ventricular arrhythmias in patients with coronary artery disease. DESIGN Randomized, double-blind, crossover design. SETTING Exercise laboratory with an environmentally controlled exposure. PATIENTS Forty-one nonsmokers with documented coronary artery disease. INTERVENTION On day 1, a training session with no exposure, the baseline carboxyhemoglobin level was measured, and a supine bicycle exercise test was done. On days 2 to 4, patients were exposed to room air, 100 ppm carbon monoxide (target, 4% carboxyhemoglobin) or 200 ppm carbon monoxide (target, 6% carboxyhemoglobin), and they then did supine bicycle exercise with radionuclide ventriculography. Ambulatory electrocardiogram recordings were made during the 4 consecutive days to determine the frequency of ventricular premature depolarization (VPD) at various intervals. MEASUREMENTS AND MAIN RESULTS The frequency of single VPD/h was significantly greater on the 6% carboxyhemoglobin day than on the room air day during the exercise period (167.72 +/- 37.99 for 6% carboxyhemoglobin compared with 127.32 +/- 28.22 for room air, P = 0.03). During exercise, the frequency of multiple VPD/h was greater on the 6% carboxyhemoglobin day compared with room air (9.59 +/- 3.70 on the 6% carboxyhemoglobin compared with 3.18 +/- 1.67 on room air, P = 0.02). Patients who developed increased single VPD during exercise on the 6% carboxyhemoglobin day were significantly older than those who had no increased arrhythmia, whereas patients who developed complex arrhythmias were also older and, in addition, exercised longer and had a higher peak workload during exercise. CONCLUSION The number and complexity of ventricular arrhythmias increases significantly during exercise after carbon monoxide exposure producing 6% carboxyhemoglobin compared with room air but not after exposure producing 4% carboxyhemoglobin.

Concentrated Ambient Ultrafine Particle Exposure Induces Cardiac Changes in Young Healthy Volunteers

RATIONALE Exposure to ambient ultrafine particles has been associated with cardiopulmonary toxicity and mortality. Adverse effects specifically linked to ultrafine particles include loss of sympathovagal balance and altered hemostasis. OBJECTIVES To characterize the effects of acute exposure to ambient ultrafine particles in young healthy humans. METHODS Nineteen healthy nonsmoking male and female subjects between the ages of 18 and 35 were exposed to filtered air or to an atmosphere in which captured ultrafine (<0.16 microm) particles were concentrated by a factor of up to 20-fold over ambient levels with the use of particle concentrators fitted with size-selective outlets (ultrafine concentrated ambient particles [UFCAPs]). Subjects underwent bronchoalveolar lavage 18 hours after each exposure. Cardiovascular endpoints measured included pulmonary function, clinical chemistry, and hematological parameters, as well as heart rate variability and repolarization indices. MEASUREMENTS AND MAIN RESULTS Exposure to UFCAPs was statistically associated with an increase in frequency domain markers of heart rate variability, specifically indicative of elevated vagal input to the heart. Consistent with this finding were increases in the variance associated with the duration of the QT interval. In addition, UFCAP exposure resulted in a significant increase in blood levels of the fibrin degradation product D-dimer as well as a modest elevation in the inflammatory chemokine IL-8 recovered in the lavage fluid. CONCLUSIONS These findings show mild inflammatory and prothrombic responses and are suggestive of alterations in cardiac repolarization induced by UFCAP inhalation.

Coarse particulate matter (PM2.5- 10) affects heart rate variability, blood lipids, and circulating eosinophils in adults with asthma

Introduction We investigated whether markers of airway and systemic inflammation, as well as heart rate variability (HRV) in asthmatics, change in response to fluctuations in ambient particulate matter (PM) in the coarse [PM with aerodynamic diameter 2.5–10 μm (PM2.5–10)] and fine (PM2.5) size range. Methods Twelve adult asthmatics, living within a 30-mile radius of an atmospheric monitoring site in Chapel Hill, North Carolina, were followed over a 12-week period. Daily PM2.5–10 and PM2.5 concentrations were measured separately for each 24-hr period. Each subject had nine clinic visits, at which spirometric measures and peripheral blood samples for analysis of lipids, inflammatory cells, and coagulation-associated proteins were obtained. We also assessed HRV [SDNN24HR (standard deviation of all normal-to-normal intervals in a 24-hr recording), ASDNN5 (mean of the standard deviation in all 5-min segments of a 24-hr recording)] with four consecutive 24-hr ambulatory electrocardiogram measurements. Linear mixed models with a spatial covariance matrix structure and a 1-day lag were used to assess potential associations between PM levels and cardiopulmonary end points. Results For a 1-μg/m3 increase in coarse PM, SDNN24HR, and ASDNN5 decreased 3.36% (p = 0.02), and 0.77%, (p = 0.05) respectively. With a 1-μg/m3 increase in coarse PM, circulating eosinophils increased 0.16% (p = 0.01), triglycerides increased 4.8% (p = 0.02), and very low-density lipoprotein increased 1.15% (p = 0.01). No significant associations were found with fine PM, and none with lung function. Conclusion These data suggest that small temporal increases in ambient coarse PM are sufficient to affect important cardiopulmonary and lipid parameters in adults with asthma. Coarse PM may have underappreciated health effects in susceptible populations.

Endothelial Dysfunction: Associations with Exposure to Ambient Fine Particles in Diabetic Individuals

Background Exposure to fine airborne particulate matter [≤2.5 μm in aerodynamic diameter (PM2.5)] has been associated with cardiovascular and hematologic effects, especially in older people with cardiovascular disease. Some epidemiologic studies suggest that adults with diabetes also may be a particularly susceptible population. Objectives The purpose of this study was to analyze the short-term effects of ambient PM2.5 on markers of endothelial function in diabetic volunteers. Methods We conducted a prospective panel study in 22 people with type 2 diabetes mellitus in Chapel Hill, North Carolina (USA), from November 2004 to December 2005. We acquired daily measurements of PM2.5 and meteorologic data at central monitoring sites. On 4 consecutive days, we measured endothelial function by brachial artery ultrasound in all participants and by pulsewave measurements in a subgroup. Data were analyzed using additive mixed models with a random participant effect and adjusted for season, day of the week, and meteorology. Results Flow-mediated dilatation decreased in association with PM2.5 during the first 24 hr, whereas small-artery elasticity index decreased with a delay of 1 and 3 days. These PM2.5-associated decrements in endothelial function were greater among participants with a high body mass index, high glycosylated hemoglobin A1c, low adiponectin, or the null polymorphism of glutathione S-transferase M1. However, high levels of myeloperoxidase on the examination day led to strongest effects on endothelial dysfunction. Conclusions These data demonstrate that PM2.5 exposure may cause immediate endothelial dysfunction. Clinical characteristics associated with insulin resistance were associated with enhanced effects of PM on endothelial function. In addition, participants with greater oxidative potential seem to be more susceptible.

Association of cardiac and vascular changes with ambient PM2.5 in diabetic individuals

Background and ObjectiveExposure to fine airborne particles (PM2.5) has been shown to be responsible for cardiovascular and hematological effects, especially in older people with cardiovascular disease. Some epidemiological studies suggest that individuals with diabetes may be a particularly susceptible population. This study examined effects of short-term exposures to ambient PM2.5 on markers of systemic inflammation, coagulation, autonomic control of heart rate, and repolarization in 22 adults (mean age: 61 years) with type 2 diabetes.MethodsEach individual was studied for four consecutive days with daily assessments of plasma levels of blood markers. Cardiac rhythm and electrocardiographic parameters were examined at rest and with 24-hour ambulatory ECG monitors. PM2.5 and meteorological data were measured daily on the rooftop of the patient exam site. Data were analyzed with models adjusting for season, weekday, meteorology, and a random intercept. To identify susceptible subgroups, effect modification was analyzed by clinical characteristics associated with insulin resistance as well as with oxidative stress and by medication intake.ResultsInterleukin (IL)-6 and tumor necrosis factor alpha showed a significant increase with a lag of two days (percent change of mean level: 20.2% with 95%-confidence interval [6.4; 34.1] and 13.1% [1.9; 24.4], respectively) in association with an increase of 10 μg/m3 in PM2.5. Obese participants as well as individuals with elevated glycosylated hemoglobin, lower adiponectin, higher ferritin or with glutathione S-transferase M1 null genotype showed higher IL-6 effects. Changes in repolarization were found immediately as well as up to four days after exposure in individuals without treatment with a beta-adrenergic receptor blocker.ConclusionsExposure to elevated levels of PM2.5 alters ventricular repolarization and thus may increase myocardial vulnerability to arrhythmias. Exposure to PM2.5 also increases systemic inflammation. Characteristics associated with insulin resistance or with oxidative stress were shown to enhance the association.

Aging and pain perception in ischemic heart disease

Age is a recognized risk factor for coronary artery disease, but the relationship between age and silent ischemia is not well understood. We analyzed the data from 35 rest/stress radionuclide ventriculography examinations in patients with documented ischemic coronary artery disease who had experienced 1 mm ST segment depression accompanied by angina during exercise testing. An index of ischemic cardiac pain perception (PPI) was calculated by subtracting the time of onset of 1 mm ST segment depression from the time of onset of angina. The mean value of PPI was -97 +/- 311 seconds. PPI was significantly correlated with age (r = 0.37, p = 0.03). This suggests that as age increases, perception of pain during myocardial ischemic episodes becomes muted. This relationship remained significant when we controlled for the presence of medication and severity of disease (change in ejection fraction from rest to peak exercise). These findings suggest that age is an independent risk factor for a decreased perception of ischemic cardiac pain, and thus for silent myocardial ischemia.

Beta-endorphin response to exercise and mental stress in patients with ischemic heart disease

UNLABELLED We compared symptomatic, hemodynamic and opioid responses of heart disease patients to exercise testing and a stressful public speaking task. Plasma beta-endorphins were measured at rest and immediately post stress. Nineteen of 50 patients had angina during exercise; 31 had asymptomatic ischemia. No patient had angina during the speech, but two had ECG changes and 39% had radionuclide changes indicating ischemia. Patients with asymptomatic ischemia on exercise had a significantly greater beta-endorphin response than those with angina. Public speaking elicited a significantly larger beta-endorphin increase relative to change in double product (an index of stress) than did exercise. CONCLUSIONS (1) Patients with silent vs painful ischemia experience a greater beta-endorphin response to exercise. (2) beta-endorphin response to a speech stressor is greater than to exercise when controlled for an index of stress. (3) Increased beta-endorphin response to a speech stressor may partially explain the predominance of silent ischemia during psychological stress.

Tobacco smoke exposure and altered nasal responses to live attenuated influenza virus.

Background Epidemiologic evidence links tobacco smoke and increased risk for influenza in humans, but the specific host defense pathways involved are unclear. Objective We developed a model to examine influenza-induced innate immune responses in humans and test the hypothesis that exposure to cigarette smoke alters nasal inflammatory and antiviral responses to live attenuated influenza virus (LAIV). Methods This was an observational cohort study comparing nasal mucosal responses to LAIV among young adult active smokers (n = 17), nonsmokers exposed to secondhand smoke (SHS; n = 20), and unexposed controls (n = 23). Virus RNA and inflammatory factors were measured in nasal lavage fluids (NLF) serially after LAIV inoculation. For key end points, peak and total (area under curve) responses were compared among groups. Results Compared with controls, NLF interleukin-6 (IL-6) responses to LAIV (peak and total) were suppressed in smokers. Virus RNA in NLF cells was significantly increased in smokers, as were interferon-inducible protein 10:virus ratios. Responses in SHS-exposed subjects were generally intermediate between controls and smokers. We observed significant associations between urine cotinine and NLF IL-6 responses (negative correlation) or virus RNA in NLF cells (positive correlation) for all subjects combined. Conclusions Nasal inoculation with LAIV results in measurable inflammatory and antiviral responses in human volunteers, thus providing a model for investigating environmental effects on influenza infections in humans. Exposure to cigarette smoke was associated with suppression of specific nasal inflammatory and antiviral responses, as well as increased virus quantity, after nasal inoculation with LAIV. These data suggest mechanisms for increased susceptibility to influenza infection among persons exposed to tobacco smoke.

Depression and Type A behavior pattern in patients with coronary artery disease: Relationships to painful versus silent myocardial ischemia and β- endorphin responses during exercise

&NA; A sample of 45 patients with a history of coronary heart disease and documented myocardial ischemia during exercise testing were evaluated in an investigation of the possible relationships between psychological factors (depression and Type A behavior pattern), plasma beta‐endorphin response and pain experience during maximal exercise‐induced ischemia. Depression was assessed using the MMPI‐D subscale, while Type A was evaluated using the Structured Interview. All patients developed ischemia during exercise as defined by ST‐segment depression; however, only 18 patients reported anginal pain. Patients with high depression scores (MMPI‐D greater than or equal to 70; n = 13) showed lesser increases in plasma beta‐endorphin levels, tended more often to report anginal pain and rated pain as more severe during exercise than patients with low depression scores (MMPI‐D less than 60; n = 18). Hemodynamic responses and severity of ischemia (assessed by ejection fraction changes and wall‐motion abnormalities) did not differ between depression groups. Even after adjustment for group differences in exercise duration, depression was significantly associated with a lesser beta‐endorphin response in the sample as a whole and, among patients reporting angina, with earlier pain onset and greater pain duration and severity. In contrast, when Type A versus B/X subgroups were compared, no differences in pain experience, beta‐endorphin response or measures of ischemia were obtained. These findings suggest that in patients with ischemic heart disease, there may be a relationship between depression and anginal pain which may in part involve a blunted or absent beta‐endorphin response.

Nasal lavage natural killer cell function is suppressed in smokers after live attenuated influenza virus

BackgroundModified function of immune cells in nasal secretions may play a role in the enhanced susceptibility to respiratory viruses that is seen in smokers. Innate immune cells in nasal secretions have largely been characterized by cellular differentials using morphologic criteria alone, which have successfully identified neutrophils as a significant cell population within nasal lavage fluid (NLF) cells. However, flow cytometry may be a superior method to fully characterize NLF immune cells. We therefore characterized immune cells in NLF by flow cytometry, determined the effects of live attenuated influenza virus (LAIV) on NLF and peripheral blood immune cells, and compared responses in samples obtained from smokers and nonsmokers.MethodsIn a prospective observational study, we characterized immune cells in NLF of nonsmokers at baseline using flow cytometry and immunohistochemistry. Nonsmokers and smokers were inoculated with LAIV on day 0 and serial nasal lavages were collected on days 1-4 and day 9 post-LAIV. LAIV-induced changes of NLF cells were characterized using flow cytometry. Cell-free NLF was analyzed for immune mediators by bioassay. Peripheral blood natural killer (NK) cells from nonsmokers and smokers at baseline were stimulated in vitro with LAIV followed by flow cytometric and mediator analyses.ResultsCD45(+)CD56(-)CD16(+) neutrophils and CD45(+)CD56(+) NK cells comprised median 4.62% (range 0.33-14.52) and 23.27% (18.29-33.97), respectively, of non-squamous NLF cells in nonsmokers at baseline. LAIV did not induce changes in total NK cell or neutrophil percentages in either nonsmokers or smokers. Following LAIV inoculation, CD16(+) NK cell percentages and granzyme B levels increased in nonsmokers, and these effects were suppressed in smokers. LAIV inoculation enhanced expression of activating receptor NKG2D and chemokine receptor CXCR3 on peripheral blood NK cells from both nonsmokers and smokers in vitro but did not induce changes in CD16(+) NK cells or granzyme B activity in either group.ConclusionsThese data are the first to identify NK cells as a major immune cell type in the NLF cell population and demonstrate that mucosal NK cell cytotoxic function is suppressed in smokers following LAIV. Altered NK cell function in smokers suggests a potential mechanism that may enhance susceptibility to respiratory viruses.