Research Article Volume 116 | Issue 8 | August 2008
Environ Health Perspect; DOI:10.1289/ehp.10689
Adverse Cardiovascular Effects with Acute Particulate Matter and Ozone Exposures: Interstrain Variation in Mice
Ali K. Hamade, Richard Rabold, and Clarke G. Tankersley
Increased ambient particulate matter (PM) levels are associated with cardiovascular morbidity and mortality, as shown by numerous epidemiology studies. Few studies have investigated the role of copollutants, such as ozone, in this association. Furthermore, the mechanisms by which PM affects cardiac function remain uncertain. We hypothesized that PM and O3 induce adverse cardiovascular effects in mice and that these effects are strain dependent.
After implanting radiotelemeters to measure heart rate (HR) and HR variability (HRV) parameters, we exposed C57Bl/6J (B6), C3H/HeJ (HeJ), and C3H/HeOuJ (OuJ) inbred mouse strains to three different daily exposures of filtered air (FA), carbon black particles (CB), or O3 and CB sequentially [O3CB; for CB, 536 ± 24 μg/m3; for O3, 584 ± 35 ppb (mean ± SE)].
We observed significant changes in HR and HRV in all strains due to O3CB exposure, but not due to sequential FA and CB exposure (FACB). The data suggest that primarily acute HR and HRV effects occur during O3CB exposure, especially in HeJ and OuJ mice. For example, HeJ and OuJ mice demonstrated dramatic increases in HRV parameters associated with marked brady-cardia during O3CB exposure. In contrast, depressed HR responses occurred in B6 mice without detectable changes in HRV parameters.
These findings demonstrate that important interstrain differences exist with respect to PM- and O3-induced cardiac effects. This interstrain variation suggests that genetic factors may modulate HR regulation in response to and recuperation from acute copollutant exposures.
Citation: Hamade AK, Rabold R, Tankersley CG. 2008. Adverse Cardiovascular Effects with Acute Particulate Matter and Ozone Exposures: Interstrain Variation in Mice. Environ Health Perspect 116:1033–1039; http://dx.doi.org/10.1289/ehp.10689
Address correspondence to C.G. Tankersley, Department of Environmental Health Sciences, Bloomberg School of Public Health, Room E7612, Johns Hopkins University, 615 North Wolfe St., Baltimore, MD 21205 USA. Telephone: (410) 614-8283. Fax: (410) 955-0299. E-mail: firstname.lastname@example.org.
This work was supported by grant AG-21057 from the National Institute on Aging, National Institutes of Health.
The authors declare they have no competing financial interests.
Received: 19 July 2007
Accepted: 18 April 2008
Advance Publication: 22 April 2008
Numerous epidemiology studies have documented associations between particulate matter (PM) and cardiovascular morbidity and mortality (Bell et al. 2005; Dominici et al. 2005). Although the exact mechanisms by which air pollutants may mediate adverse health effects remain unclear, varying the physicochemical properties of PM and the exposure conditions result in different adverse effects on cardiac function, including the neural regulation of the heart (Schulz et al. 2005). In addition, the existence of copollutants and their adverse cardiovascular health effects have not been suitably investigated. For example, a recent human study suggested that PM and ozone influenced cardiac autonomic control (Chuang et al. 2007). In that study, the negative impact of O3 on heart rate variability (HRV) was equivalent to or more profound than the effects of PM. The mechanisms for these HRV effects of PM in combination with O3 merit further investigation, particularly in animal models.
Although numerous animal studies have examined the cardiac effects of PM, few did so in conjunction with copollutants such as O3. In one such study, Watkinson et al. (2001) showed a decreased heart rate [HR; beats per minute (bpm)] due to O3 as a single pollutant. Likewise, our laboratory has recently described the strain differences in PM-mediated autonomic neural control of HR between C3H/HeJ (HeJ) and C57Bl/6J (B6) mice (Tankersley et al. 2007). That study suggested that genetic susceptibility factors may be important in the neural regulation of PM-induced HR effects. In the present study, we tested the hypothesis that genetic susceptibility factors play a major role in PM-induced cardiac effects, particularly in the face of O3 preexposure. We based this hypothesis on previous findings showing greater pulmonary infiltration of neutrophils in B6 than in HeJ mice after O3 exposure by inhalation (Tankersley and Kleeberger 1994). Other studies using these same strains showed increased macrophage activity in B6 mice after inhalation of sulfate-coated CB particles (Ohtsuka et al. 2000). These effects are believed to be mediated in part via the Toll-like receptor 4 (Tlr4) signaling pathway. In HeJ mice, the Tlr4 gene is mutated and not functional (Kleeberger et al. 2000; Poltorak et al. 1998). Alternatively, C3H/HeOuJ (OuJ) mice are coisogenic relative to HeJ mice and demonstrate a fully functional Tlr4 gene construct and downstream signaling pathway (Qureshi et al. 1999).
The purpose of this study was 3-fold. First, we determined whether there are interstrain differences in HR and HRV characteristics among the B6, HeJ, and OuJ mice. Second, we examined the HR and HRV responses to PM [i.e., carbon black (CB)] after preexposure to filtered air (FA) and O3 in HeJ and OuJ mice compared with B6 mice. Third, we more specifically tested the hypothesis that the Tlr4 gene mutation and signaling pathway modulates the cardiac response to the O3CB exposure. This hypothesis is supported by observations showing the activation of TLR4 signaling associated with O3-induced lung injury and inflammation (Kleeberger et al. 2000). We found robust interstrain variation in response to PM with preexposure to O3, which significantly decreased HR and increased HRV compared with FA. Furthermore, we detected no differences in HR regulation between HeJ and OuJ mice.
Materials and Methods
We purchased male mice of three inbred strains, B6 (n = 8), HeJ (n = 5), and OuJ (n = 6), from Jackson Labs (Bar Harbor, ME). Mice were housed under a 12/12-hr light/dark cycle in an animal facility at the Johns Hopkins Bloomberg School of Public Health. Room temperature was maintained at 21 ± 1ºC (mean ± SE), and regular lab chow and drinking water were provided ad libitum. We treated animals humanely and with regard for alleviation of suffering. All experiments were conducted with approval from the Animal Care and Use Committee of the Johns Hopkins University Medical Institutions.
The surgical procedure for transmitter implant (model TA10ETAF20) and the radiotelemetry system (both from Data Sciences International, St. Paul, MN) used to measure core temperature (TCO) and HR and to sample electrocardiograph (ECG) recordings have been described elsewhere (Tankersley et al. 2003). Briefly, we anesthetized each animal intraperitoneally with a mixture of 10 mg/mL acepromazine and 100 mg/mL ketamine (1:10) at a dose of 2 μL/g body weight. We removed abdominal and chest fur, applied Betadine to the exposed region of skin, and established a sterile field surrounding the animal. The transmitter was inserted through a midline abdominal incision and sutured to the abdominal muscle; the negative ECG lead was guided through the muscle and directed subcutaneously to the right shoulder. The positive ECG lead, also guided through the muscle, was directed laterally and positioned approximately 1 cm below the rib cage, and both leads were sutured to the muscle tissue in a lead II position in traditional human ECGs. Surgery required 30 min, and recovery from anesthesia occurred within 60–90 min. We allowed mice to recover from surgery for at least 2 weeks before we started data collection, which began at 18–20 weeks of age.
CB and O3 exposure protocol
We exposed all mice to three different daily exposure protocols, and acclimated them to exposure chambers 1 day before any given exposure. Each exposure protocol lasted 1 day, and the sequence of exposure for each mouse occurred in the following order (Figure 1): a) 2 hr FA followed by another 3 hr FA (FAFA); b) 2 hr FA followed by 3 hr CB (FACB); and c) 2 hr O3 followed by 3 hr CB (O3CB). The first 2-hr exposure consistently occurred between 0915 and 1115 hours, and this was followed with a second 3-hr exposure occurring between 1300 and 1600 hours. A 75-min recovery period occurred between the two sequential exposures from 1115 to 1230 hours to allow for animal transfer between different exposure chambers (~ 15 min), and animal reacclimation to the second chamber (~ 60 min). The reacclimation period was sufficient to eliminate confounding effects of animal handling on preexposure HR and HRV data collection, which consistently occurred between 1230 and 1300 hours.
Using a subgroup of eight randomly selected mice from the three test strains, we conducted a fourth exposure protocol consisting of 2 hr of O3 followed by 3 hr of FA (O3FA), using the same rigorous time schedule as described above. This allowed us to determine whether time-dependent HR and HRV changes during the 3-hr exposure were attributable to the added effects of CB exposure or simply due to the recovery from O3 preexposure.
CB and O3 exposure assessment
Preexposure to either O3 or FA occurred in individual stainless steel chambers for 2 hr. O3 was produced by an O3 generator using ultraviolet light (Orec, Phoenix, AZ), which we monitored with a 1003-AH Dasibi monitor (Dasibi Environmental, Glendale, CA). The target O3 concentration for the 2-hr exposure was 0.5 ppm.
We conducted the second exposure to CB or FA in individual Plexiglas chambers for 3 hr. The CB (Regal 660; density, 1.95 g/cm3; specific surface area, 112 m2/g; empirical formula, C910H34O10; composition, 96.90% carbon, 1.42% oxygen, 0.30% hydrogen) was aerosolized by a Wright Dust Feeder (BGI, Inc., Waltham, MA). To assess exposure concentration, we collected particles on 25-mm-diameter glass fiber filters for gravimetric analysis using a Mettler Toledo microbalance (Mettler Toledo, Columbus, OH). We also monitored particles with an Aerodynamic Particle Sizer (model 3320; TSI, Shoreview, MN) for mass median aerodynamic diameter (MMAD) and count median diameter (CMD) assessments.
TCO, HR, and HRV measurements
We derived the HR and HRV measurements obtained during and immediately before and after the second 3-hr exposure from 3-min ECG samples collected every 15 min. Each 3-min ECG sample was analyzed using a peak detect algorithm (Data Sciences International, St. Paul, MN), which was achievable in samples lacking motion or body-position artifacts. We examined the resulting tachograms (peak interval vs. time) individually to detect and correct errors in intervals associated with arrhythmias or missed peak detections. Parameters in the time domain consisted of average HR, standard deviation of normal-to-normal intervals (SDNN) as a measure of total HRV, and the root mean square of successive differences between adjacent R-R intervals (rMSSD) as a measure of beat-to-beat HRV. From the frequency domain, we extracted the HRV ratio of low frequency (LF) to high frequency (HF). The LF range was calculated as the area under each density curve from 0.2 to 1.5 Hz, and the HF range was calculated between 1.5 Hz and the Nyquist frequency (HR frequency divided by 2, which was typically between 4 and 5 Hz). We averaged the four individual hourly measurements to represent the HR and HRV responses for each time point during exposure.
In addition to HR and HRV measurements obtained before, during, and after the second 3-hr exposure, we also collected measurements on the morning before (MB) and on the morning after (MA) each exposure protocol. On consecutive mornings, we consistently obtained the measurements during the period between 0730 and 0900 hours. Individual measurements obtained on consecutive mornings represent the average of five data samples collected during each 90-min period. We compared MA and MB measurements to assess whether prolonged cardiac effects were evident after each exposure. Likewise, we assessed the 24-hr circadian pattern of HR and TCO for each animal on a weekly basis to determine whether there were longer-term residual effects of surgery or cumulative effects of repeated exposure protocols. The procedures to assess circadian pattern in mice have been described elsewhere (Tankersley et al. 2003). We summarized individual circadian pattern characteristics by determining the mean, minimum, and maximum values for HR and TCO from each average 24-hr cycle before and after each exposure protocol.
Oxygen consumption assessment
We repeatedly measured oxygen consumption (VO2) on consecutive mornings (MA and MB) using an indirect open-circuit calorimetric system (Oxymax Deluxe; Columbus Instruments, Columbus, OH) in-line with 200 mL cylindrical Plexiglas chambers. We delivered unhumidified compressed air through the chamber under the control of a calibrated flow meter, and adjusted the flow to maintain a small difference between chamber inflow (21% O2 in nitrogen gas) and outflow O2 concentrations. We dried the air flow out of the chamber with a column of anhydrous calcium sulfate and sampled it for 30 sec for fractional concentrations of O2 using a limited-diffusion oxygen sensor (Columbus Instruments). We captured sensor output with data-acquisition software (Oxymax version 5.3; Columbus Instruments) and recorded it with a computer. We conducted gas-analyzer calibrations before each experiment using standardized gas mixtures (Puritan Bennett, Linthicum Heights, MD). We obtained intermittent reference air measurements to correct for sensor drift; we also normalized the VO2 data to standard temperature, pressure, and dry conditions and as a function of body weight.
Oxygen pulse (VO2/HR)
We derived the measurement of O2 pulse as the ratio of VO2 to HR, as an indicator of cardiac stroke volume (SV) (Bhambhani et al. 1994). The following equations show a logical proportionality between O2 pulse and SV: If cardiac output (CO) = SV × HR, and Fick’s principle defines CO = VO2/(venous O2 – arterial O2), then SV ≈VO2/HR, provided that the O2-carrying capacity of blood (venous O2 – arterial O2) remains relatively constant.
We present the results as mean ± SE. For results obtained before, during, and after the second 3-hr exposure to either CB or FA, we used a three-way analysis of variance (ANOVA) to evaluate the effects of strain, time, and exposure. We applied adjustments to the effects of time and exposure to account for repeated measures. We also used a similar three-way ANOVA, including adjustments for repeated measures, to evaluate MA and MB results. For results obtained from 24-hr circadian pattern characteristics, we performed a two-way ANOVA adjusted for repeated measures to assess the effects of strain and exposure. We determined significant mean comparisons using the Duncan’s multiple range test with an α of p < 0.01 to adjust for the higher probability of type I error in multiple comparisons. Given the absence of statistically detectable differences between HeJ and OuJ mice, we combined these substrains to represent the C3 strain (n = 11 mice) and repeated the analyses. We used a similar analytic approach to determine statistically significant differences between O3CB and O3FA exposures.
Figure 2 shows the average profiles for the number and mass concentrations of the CB exposure aerosol. Generally, animals were exposed to particles that were in the fine mode (PM ≤2.5 μm in aerodynamic diameter). A time-weighted gravimetric analysis of the generated CB aerosol immediately downstream of the exposure chamber showed an exposure concentration of 536 ± 24 μg/m3. The particle size distribution of the CB aerosol was characterized by a CMD of 0.7 μm and an MMAD of 1.01 μm, with a geometric standard deviation (GSD) of 1.56 μm. The average O3 concentration was 584 ± 35 ppb.
Circadian pattern characteristics
In addition to measuring body weight, we assessed homeostatic stability after surgery and repeated exposures using weekly measurements of the 24-hr mean, minimum, and maximum for TCO and HR (Table 1). Although a significant strain effect (F df=2 = 13.1; p < 0.01) influenced variation in body weight, no detectable differences among the strains were due to the different exposure conditions. In addition, we found significant variation among the strains in several circadian pattern characteristics, such as the mean daily HR (F df=2 = 13.0; p < 0.01); however, we detected no differences in any circadian pattern characteristics across the three exposure protocols. These findings suggest no longer-term effects of surgery or repeated exposure on the homeostatic stability in these animals. With respect to strain variation, generally TCO was significantly (p < 0.01) lower in HeJ mice compared with the other strains. The minimum TCO was significantly (p < 0.01) higher in OuJ mice than in the other strains. B6 mice demonstrated a significantly (p < 0.01) lower HR compared with the other strains, which was consistent before each exposure protocol.
MA and MB responses
HR at MA was significantly lower (F df=1 = 10.2; p < 0.01) than HR at MB, independent of strain and exposure effects (Table 2). This effect was particularly apparent in the HR response of B6 mice after O3CB exposure. In general, SDNN and rMSSD were significantly (p < 0.01) higher in B6 mice than in the other strains, and we detected no effects of exposure associated with these HRV parameters. In contrast, the interaction between exposure and strain in the LF/HF ratio was significant (F df=4 = 9.8; p < 0.01); this was attributable to a significant(p < 0.01) decrease in OuJ mice after O3CB exposure. Although we observed no significant variation between MA and MB VO2 responses, the interactive effect of strain on O2 pulse after exposure was significant (F df=2 = 5.8; p < 0.03). Specifically, in B6 mice the MA O2 pulse after FACB and O3CB exposures was significantly (p < 0.01) greater relative to FAFA exposure.
HR and HRV responses to CB with and without O3 preexposure
The relative changes in HR and HRV responses (i.e., compared with FAFA) during the latter 3-hr period of the FACB and O3CB exposures were indistinguishable between HeJ and OuJ mice; hence, we combined these substrains and identify them here as the C3 strain. Figure 3 shows a significant (F df=4 = 11.4; p < 0.01) interaction between the effects of exposure and time on the HR response in B6 and C3 mice. This effect was largely attributable to a significant (p < 0.01) decrease in HR responses after the O3 preexposure in both B6 and C3 strains. In addition, the recovery in HR during the 3-hr CB exposure was significant (p < 0.01) in both strains. However, we detected no strain differences between B6 and C3 mice in either the decline or the recovery of HR associated with O3CB exposure. Also, we detected no change in HR during CB exposure after FA preexposure in either strain.
Figures 4 and 5 show the changes in SDNN and rMSSD during CB exposure after either FA or O3 preexposure. We observed significant interactive effects of exposure, time, and strain on the SDNN (F df=4 = 11.5; p < 0.01) and rMSSD (F df=4 = 7.0; p < 0.01) parameters. These interactive effects were attributable to significantly (p < 0.01) greater changes in SDNN and rMSSD associated with O3CB exposure in C3 compared with B6 mice. Although we detected no differences between FACB and O3CB exposure protocols in either SDNN or rMSSD for B6 mice, the changes in these HRV parameters were notably (p < 0.01) elevated in C3 mice during O3CB exposure. In addition, the time course of recovery in these HRV parameters during the 3-hr CB exposure was significant (p < 0.01) in only the C3 strain.
The interaction of exposure and strain on the changes in LF/HF during CB with either FA or O3 preexposure was significant (F df=4 =7.3; p < 0.02; Figure 6). The effect was attributable to a modest difference between FACB and O3CB exposure in C3 mice.
HR and HRV responses after O3 with and without CB
Figure 7 shows HR and HRV responses to either FA or CB after O3 preexposure. The significant effect of time on HR (F df=4 = 5.0; p < 0.01) was due, in part, to a significantly more rapid HR recovery associated with O3FA exposure. With respect to SDNN and rMSSD, we observed significant effects of both time (F df=4 = 5.8 and 5.0, respectively; p < 0.01) and exposure (F df=1 = 11.0 and 9.8, respectively; p < 0.02). In particular, rMSSD remained significantly (p < 0.01) elevated during the 3-hr exposure to CB relative to FA after preexposure to O3.
The results from the present study demonstrate profound strain differences in cardiac function during CB exposure with acute O3 preexposure. The most obvious difference between B6 and C3 strains is in the HRV parameters after sequential exposure to O3 and CB (Figures 4 and 5). In contrast to a modest effect of O3CB in B6 mice, C3 mice showed dramatic changes in SDNN and rMSSD responses, indicating that HR regulation was uniquely different between strains. Despite these strain-specific differences in HRV, relative changes in HR responses were similar between B6 and C3 strains (Figure 3). The strain difference in HRV responses appeared to be dependent on O3 preexposure, because FACB exposure did not produce significant changes in these cardiac functional parameters. Further exploratory findings in the same mice exposed to O3CB also showed differences in HRV responses compared with O3FA exposure (Figure 7). These HRV effects include a notable elevation in rMSSD with O3CB accompanied by a delay in HR recovery. These results suggest that a sequential exposure to CB altered HR regulation after O3 preexposure. Therefore, the most salient finding in the present study points to B6 and C3 strain differences in HR regulation in mice exposed sequentially to O3 and CB. This finding suggests that robust genetic determinants can variably alter HR regulatory mechanisms when adapting to these copollutants.
We made several other important observations in the present study. The comparison between OuJ and HeJ mice, for example, did not produce any detectable differences in HR regulation during either FACB or O3CB exposure. Therefore, these results suggest that the Tlr4 mutation in HeJ mice relative to OuJ mice did not affect the HR regulatory adaptive mechanisms associated with O3 or CB exposure. Another important observation suggests that HR responses to O3CB exposure among the strains were substantially below their strain-specific minimum HR associated with a normal circadian pattern (Figure 8). The strain-specific lower minimum and maximum HR characteristics seen in B6 relative to HeJ mice have been previously described (Tankersley et al. 2002, 2007). Here, the magnitude of the bradycardic response to O3CB exposure can be as much as 160 bpm below the normal minimum, as seen in HeJ mice. In contrast, the same bradycardic response to O3CB exposure is only 40 and 100 bpm below the normal minimum HR of OuJ and B6 mice, respectively. Although the precise mechanisms underlying this bradycardic response remain unclear, it is obvious from the strains examined in the present study that O3 preexposure does not lead to tachycardia; that is, HR responses requiring increased sympathetic tone and/or withdrawal of parasympathetic tone. It is also clear that the bradycardic response to O3 preexposure is associated with dramatic increases in SDNN and rMSSD in C3 mice and not in B6 mice, suggesting that the O3-induced bradycardia is likely dissociated from altered HRV characteristics. These new insights merit future studies to elucidate the specific cardiac effects of O3 exposure alone and in combination with PM. These studies should also consider the importance of genetic susceptibility factors.
In a previous study, our laboratory showed that B6 mice have significant withdrawal of cardiac parasympathetic tone during acute CB exposure (Tankersley et al. 2007). Specifically, CB-induced HR responses were significantly elevated compared with FA responses in B6 mice after sympathetic blockade using pro-pranolol. This elevated HR response was accompanied by a significantly reduced rMSSD, a measure of beat-to-beat HRV. Similar findings were not apparent in C3 mice. The results of the present study show that the O3-induced depression in HR was accompanied by a dramatic increase in rMSSD in C3 mice, but not in B6 mice. Although it is difficult to resolve the specific mechanisms leading to O3-induced bradycardia, it is reasonable to conclude that increases in parasympathetic tone and/or decreases in sympathetic tone lead to such bradycardia. The strain differences between B6 and C3 mice likely center on the differential balance between these two neural inputs. That is, one strain relies predominantly on withdrawal of sympathetic tone, whereas the HR response of the other strain is principally derived from a greater imposition of parasympathetic tone. Variation in HR regulation involving the balance of parasympathetic and sympathetic inputs may also lead to differences in HR and HRV responses between O3CB and O3FA exposures.
The changes in HR and HRV responses associated with the sequential effects of O3 and CB are generally confined to the time period immediately before and after exposure. Results comparing MA with MB suggest that modest but significant reductions in HR and HRV responses after O3CB are present in B6 and OuJ mice, respectively (Table 2). In addition, B6 mice showed a greater O2 pulse in the MAFACB exposure. Although it is unclear whether these findings are attributable to prolonged exposure effects, longer-term cardiac compensation may be occurring, especially in B6 mice. An increase in O2 pulse, for example, is coincident with a decreased HR, suggesting that CB exposure provokes a greater O2 delivery for each stroke of the heart. This elevated response may also imply that SV was elevated in CB-exposed B6 mice. If O2 pulse represents a surrogate for relative changes in SV, the results of the present study suggest that CB-induced changes in the heart include longer-term effects of a greater SV unique to B6 mice.
The present study suggests that O3-induced effects on HRV are greater than the same responses after CB. Although it mayappear that the O3-induced cardiac effects are more potent than those associated with CB exposure, comparable doses may be a limitation. This is especially difficult to ascertain in the absence of clear mechanisms of action underlying the cardiac effects of these copollutants. Evidence in the air pollution epidemiology supports the notion that O3 may be as effective as or more potent than PM with respect to risk of mortality and morbidity. For example, Chuang et al. (2007) showed larger reductions in HRV indices associated with PM using a 1-day average, but also demonstrated larger reductions using 2- and 3-day averages for O3. Other studies showed changes in HRV that were comparable for increases in O3 and PM (Gold et al. 2000; Schwartz et al. 2005a). Likewise, another study (Hong et al. 2002) showed the relative risk (RR) of cardiovascular mortality associated with increases in ambient O3 to be almost 2-fold higher (RR =2.9) than that associated with increases in PM ≤10 μm in aerodynamic diameter (RR = 1.5).
Although the mechanisms behind O3-induced cardiac changes remain unclear, onev hypothesis proposes that O3 leads to increased oxidative stress, resulting in lung inflammatory and permeability changes in addition to airway hyperreactivity (Tankersley and Kleeberger 1994; Zhang et al. 1995). These acute indicators of lung injury may provoke vagally mediated effects on the heart. The B6 strain is known to endure a greater O3-induced lung inflammatory and permeability response relative to C3 mice (Tankersley and Kleeberger 1994). However, in the present study, B6 mice showed a modest, statistically insignificant HRV response compared with the dramatic increase in C3 mice. These data suggest that the depression in HR and changes in HRV are not necessarily associated with O3-induced lung inflammation, changes in permeability, or airway hyperreactivity. Results in the present study also appear to diminish the possibility that the Tlr4 signaling pathway is important in cardiac changes induced by O3. Likewise, Jimba et al. (1995) showed no differences in O3-induced bradycardic effect in rats depleted of pulmonary C-fibers by neonatal capsaicin treatment. This study suggests that C-fiber stimulation of vagal afferents is not a likely mechanism linking O3-induced lung injury to altered HR regulation.
One way to test the interactive effects of air-pollutant–induced lung injury on adverse cardiac changes is to evaluate the impact of blocking the production of reactive oxygen species in the present animal model. Anti-oxidant effects have been demonstrated in an epidemiology study showing that omega-3 fatty acid supplementation can eliminate HRV changes associated with PM exposure (Romieu et al. 2005). Future studies might also employ longer-term exposures to CB and O3 to evaluate chronic cardiac changes. In addition, studies examining the effects of aging in these strains would be appropriate because elderly populations appear to be specifically susceptible to air-pollutant–induced cardiac effects. Finally, the results of the present study suggest that genetic variability affects cardiac responses after acute exposures to air pollutants, such as PM and O3. Certain genetic polymorphisms have been associated with susceptibility to air-pollutant–induced HRV changes (Park et al. 2006; Schwartz et al. 2005b). The genetic determinants underlying the dramatic HRV differences between B6 and C3 mice in response to O3 exposure warrant further investigation.
Figures and Tables
Bell ML, Dominici F, Samet JM. 2005. A meta-analysis of time-series studies of ozone and mortality with comparison to the national morbidity, mortality, and air pollution study. Epidemiology 16:436–445.
Chuang KJ, Chan CC, Su TC, Lee CT, Tang CS. 2007. The effect of urban air pollution on inflammation, oxidative stress, coagulation, and autonomic dysfunction in young adults. Am J Respir Crit Care Med 176(4):370–376.
Dominici F, McDermott A, Daniels M, Zeger SL, Samet JM. 2005. Revised analyses of the national morbidity, mortality, and air pollution study: mortality among residents of 90 cities. J Toxicol Environ Health A 68(13–14):1071–1092.
Park SK, O’Neill MS, Wright RO, Hu H, Vokonas PS, Sparrow D, et al. 2006. HFE genotype, particulate air pollution, and heart rate variability: a gene-environment interaction. Circulation 114(25):2798–2805.
Romieu I, Tellez-Rojo M, Lazo M, Manzano-Patino A, Cortez-Lugo M, Julien P, et al. 2005. Omega-3 fatty acid prevents heart rate variability reductions associated with particulate matter. Am J Respir Crit Care Med 172:1534–1540.
Schwartz J, Park SK, O’Neill MS, Vokonas PS, Sparrow D, Weiss S, et al. 2005b. Glutathione-S-transferase M1, obesity, statins, and autonomic effects of particles: gene-by-drug-by-environment interaction. Am J Respir Crit Care Med 172(12):1529–1533.
Tankersley CG, Irizarry R, Flanders S, Rabold R. 2002. Circadian rhythm variation in activity, body temperature, and heart rate between C3H/HeJ and C57BL/6J inbred strains. J Appl Physiol 92(2):870–877.
Watkinson WP, Campen MJ, Nolan JP, Costa DL. 2001. Cardiovascular and systemic responses to inhaled pollutants in rodents: effects of ozone and particulate matter. Environ Health Perspect 109(suppl 4):539–546.
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