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Inhalation Toxicology, 18:1077–1082, 2006
Copyright
c
Informa Healthcare
ISSN: 0895-8378 print / 1091-7691 online
DOI: 10.1080/08958370600945473
Effects of Ambient Particles and Carbon Monoxide
on Supraventricular Arrhythmias in a Rat Model
of Myocardial Infarction
Gregory A. Wellenius
Department of Environmental Health, Harvard School of Public Health, Boston, and Cardiovascular
Epidemiology Research Unit, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
Brent A. Coull
Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA
Joao R. F. Batalha, Edgar A. Diaz, Joy Lawrence, and John J. Godleski
Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA
The association between short-term increases in particulate air pollution and increased car-
diovascular morbidity and mortality is well documented. Recent studies suggest an association
between particulate matter with aerodynamic diameter <2.5 µm (PM
2.5
) and supraventricu-
lar arrhythmias (SVA), but the results have been inconsistent. We evaluated this hypothesis
in a rat model of acute myocardial infarction (AMI). Diazepam-sedated Sprague-Dawley rats
with AMI were exposed (1 h) to either filtered air (n = 16), concentrated ambient fine parti-
cles (CAPS; mean = 645.7 µg/m
3
; n = 23), carbon monoxide (CO; 35 ppm; n = 19), or CAPs
and CO (n = 24). Each exposure was immediately preceded and followed by a 1-h exposure to
filtered air (baseline and postexposure periods, respectively). Surface electrocardiograms were
recorded and the frequency of supraventricular premature beats was quantified. Among rats in
the CAPS group, the probability of observing any SVA decreased from baseline to the exposure
and postexposure periods. This patterm was significantly different than that observed for the
filtered air group during the exposure period (p = .048) only. In the subset of rats with one or
more SVA during the baseline period, the change in SVA rate from baseline to exposure period
was significantly lower in the CAPS (p = .04) and CO (p = .007) groups only, as compared to
the filtered air group. No significant effects were observed in the group simultaneously exposed
to CAPS and CO. Thus, the results of this study do not support the hypothesis that exposure to
ambient air pollution increases the risk or frequency of supraventricular arrhythmias.
The association between short-term increases in particulate
air pollution and increased cardiovascular morbidity and mortal-
ity is well documented. Putative biologic mechanisms include
Received 13 June 2006; accepted 19 July 2006.
The authors are grateful to Dr. Murray Mittleman for critically re-
viewing the article. This study was supported by grants R827353 from
the U.S. Environmental Protection Agency and T32-HL007118 from
the National Institutes of Health (NIH). The project described was sup-
ported by grant F32-ES013804 from the National Institute of Envi-
ronmental Health Sciences (NIEHS), NIH. Its contents are solely the
responsibility of the authors and do not necessarily represent the official
views of the NIEHS, NIH.
Address correspondence to Gregory A. Wellenius, ScD, Cardio-
vascular Epidemiology Research Unit, Beth Israel Deaconess Medical
Center, 330 Brookline Avenue, Deaconess 301, Boston, MA 02215,
USA. E-mail: gwelleni@bidmc.harvard.edu
changes in autonomic nervous system function, hemodynam-
ics, hemostatic factors, and a systemic inflammatory response
(Brook et al., 2004).
Several recent epidemiologic studies have reported an as-
sociation between particulate matter with aerodynamic diame-
ter <2.5 µm (PM
2.5
) and ventricular arrhythmias (Peters et al.,
2000; Rich et al., 2005; Riediker et al., 2004). A similar associa-
tion has been observed in a controlled exposure study in humans
(Gong et al., 2004) and in animals exposed to residual oil fly ash,
a component of PM
2.5
(Campen et al., 2000; Watkinson et al.,
1998; Wellenius et al., 2002).
Although not generally considered life-threatening,
supraventricular arrhythmias reduce cardiac output and can
initiate ventricular arrhythmias (Podrid, 2006). Relatively few
epidemiologic studies have evaluated the link between PM
2.5
and supraventricular arrhythmias. While there is some evidence
1077
1078 G. A. WELLENIUS ET AL.
from these studies in favor of such a link (Brauer et al., 2001;
Gong et al., 2004; Riediker et al., 2004), the results have
been inconsistent (Devlin et al., 2003; Gong et al., 2003; Rich
et al., 2006). To our knowledge, only one previous animal
toxicological study has specifically addressed this question and
that study found no effect (Nadziejko et al., 2004).
A complicating factor in many epidemiological studies is
that PM
2.5
exists in outdoor air as a complex mixture that in-
cludes gaseous pollutants such as carbon monoxide (CO). CO
is a ubiquitous gaseous pollutant produced by incomplete com-
bustion of carbonaceous fuels and substances. Typical sources
of CO include vehicle exhaust, industrial processes, home heat-
ing systems, and cigarette smoke. Numerous studies have found
an association between short-term increases in ambient CO lev-
els and increased risk of cardiovascular morbidity and mortality
(Burnett et al., 1997; Hoek et al., 2001; Morris et al., 1995).
In the United States, daily mean ambient levels of CO range
from 0.5 to 2 ppm (Samet et al., 2000). Acute CO poisoning,
which occurs at much higher CO levels, has historically been
associated with the development of cardiac arrhythmias, includ-
ing conduction disorders, atrial and ventricular fibrillation, and
atrial and ventricular premature beats (Marius-Nunez, 1990).
Using a rat model of myocardial infarction, we previously
showed that exposure to CO was associated with a 60.4% re-
duction (95% confidence interval [CI]: 80.7, 18.8; p = .012)
in the frequency of ventricular arrhythmias, while exposure to
concentrated ambient fine particles (CAPS) was associated with
a 64.2% increase (95% CI: 17.7, 227.6%; p = .16) in the fre-
quency of ventricular arrhythmias (Wellenius et al., 2004). The
purpose of the current analysis was to assess whether exposure to
CAPS and/or CO alters the risk of supraventricular arrhythmias
in this animal model.
METHODS
Animals
Adult, male Sprague-Dawley rats weighing ∼ 250 g (Charles
River Laboratories, Inc., Wilmington, MA) were maintained
and studied in accordance with the National Institutes of Health
guidelines for the care and use of animals in research. Animals
were housed (12-h light/dark cycle) in plastic cages with pine
chip bedding (Northeastern Products Corp., Warrensburg, NY)
and received food (LabDiet, PMI Nutrition International, Inc.,
Brentwood, MO) and water ad libitum. All protocols were ap-
proved by the Harvard Medical Area Standing Committee on
Animals.
Surgical Protocol
Left-ventricular MI was induced by thermocoagulation as
previously described (Wellenius et al., 2002). Briefly, under in-
halation anesthesia, a left thoracotomy was performed via the
third or fourth intercostal space to gain access to the left ven-
tricular wall of the heart. Myocardial infarction was induced by
briefly and repeatedly applying the tip (0.5 inch fine electrode)
of a portable thermocautery unit (2200
◦
C, Aaron Medical Indus-
tries, Inc., St. Petersburg, FL) to one or more visible branches of
the left coronary artery. Visible discoloration of the affected re-
gion indicated that blood flow had been successfully interrupted.
Each animal was allowed to recover for a minimum of 12 h.
Experimental Design
To investigate the cardiac effects of air pollution, 85 rats were
randomized to one of four groups: (1) filtered air (n = 17), (2)
CAPS only (n = 23), (3) CO only (n = 21), or (4) both CAPS
and CO (CAPS + CO; n = 24). Data from one rat in the filtered
air group and two rats in the CO-only group were lost due to
technical problems. The CO target dose was 35 ppm, equal to
the current 1-h U.S. National Ambient Air Quality Standard.
All exposures were1hinduration (exposure period), and were
immediately preceded and followed by1hofexposure to filtered
air (preexposure and postexposure periods, respectively).
Exposure Technology and Characterization
For all experiments, animals were placed in one of four
sealed Plexiglas chambers for exposure, as previously described
(Wellenius et al., 2004). Briefly, within each exposure chamber,
rats were sedated (diazepam, ip, 12 mg/kg) and placed in indi-
vidual holders facing the air inlet. The flow rate for each chamber
was maintained at 15 L/min (LPM). CO exposures were gen-
erated by the addition of a small constant flow (approximately
230 cm
3
/min) of high concentration CO from a certified cylin-
der (2510 ppm, Matheson Tri-Gas, Inc., Montgomeryville, PA)
upstream of the two CO exposure chambers (CO only and CO +
CAPS chambers). CO in both chambers was measured contin-
uously using two Langan monitors adapted for active sampling
(Chang et al., 2001).
Ambient fine particles were concentrated using the Harvard
ambient particle concentrator (HAPC), the characteristics of
which have been described in detail previously (Godleski et al.,
2000; Lawrence et al., 2004; Savage et al., 2003). Briefly, the
HAPC concentrates ambient fine particulate matter with an aero-
dynamic diameter ≤2.5 µm (PM
2.5
)to∼30× ambient levels
without altering its size distribution or chemical composition.
Particles with diameters >2.5 µm are removed upstream of the
HAPC, while ultrafine particles (<0.1 µm) and ambient gases
are neither enriched nor excluded. CAPS mass concentration
was determined gravimetrically from 1-h integrated samples and
particle number concentration was measured continuously (5-
min averages) using a condensation particle counter (CPC model
3022A; TSI, Inc., Shoreview, MN).
Electrocardiographic Data Acquisition and Analysis
The day of an experiment, electrodes for obtaining electrocar-
diograms (ECG) were implanted subcutaneously in a standard
Lead II configuration (right arm, left leg, and right leg) under
light inhalation anesthesia, as previously described (Wellenius
et al., 2002). ECG signals were bandpass filtered, amplified,
AIR POLLUTION AND SUPRAVENTRICULAR ARRHYTHMIAS 1079
digitized (500 Hz/animal), and stored using a customized PC-
based data acquisition system (Mathworks, Inc., Natick, MA)
with a 12-bit analog-to-digital converter (National Instruments
Corp., Austin, TX). In order to obtain stable ECG recordings
in unrestrained animals, rats were lightly sedated with a single
dose of diazepam (ip, 12 mg/kg) 15–20 min before the begin-
ning of the experiment. ECG recordings from diazepam-sedated
animals were of high quality and measures of heart rate were
consistent from minute to minute.
Offline, ECG signals were viewed and analyzed using cus-
tomized software scripts in Matlab (Mathworks, Inc.). Arrhyth-
mia grade and frequency were manually determined by an in-
vestigator blinded to the exposure status of each rat. The number
of each type of arrhythmia observed in the hour before exposure
(baseline value), during the exposure hour (exposure value),
and in the hour following exposure (postexposure value) was
recorded for each animal. ECG data were unusable for 10 of
246 (4.1%) possible observation periods. Results from the anal-
ysis of supraventricular ectopic beats (SVEB; including prema-
ture atrial complexes and premature junctional complexes) are
presented here; results from the analysis of heart rate and ven-
tricular arrhythmias have been previously published (Wellenius
et al., 2004).
Statistical Analysis
First, we tested the hypothesis that exposure to CAPS and
CO increases the risk of observing one or more SVEB (Hypoth-
esis 1). We used repeated-measures logistic regression (Diggle
et al., 2002) to model the odds of a given rat having one or more
SVEB during a given time period. This model, fitted using gener-
alized estimating equations (GEE), included indicator variables
for time (exposure and postexposure periods), group (CAPS,
CO, and CAPS + CO), and two-way interactions between these
variables. An exchangeable covariance structure was assumed
and inferences were based on empirical (robust) standard er-
rors. To explore the dose-response relationship we also consid-
ered models where CAPS mass concentration or CAPS number
concentrations were treated as linear continuous variables.
Second, we tested the hypothesis that among rats with one or
more SVEB during the pre-exposure period, exposure to CAPS
or CO increases SVEB frequency either during or following
exposure (Hypothesis 2). We used repeated-measures Poisson
regression fit by GEE to model the SVEB frequency in each
period. This model included indicator variables for time and
group, as well as 2-way interactions between these variables.
We allowed for Poisson overdispersion in the data, assumed
an exchangeable covariance structure, and based inferences on
empirical (robust) standard errors.
The above approach is analogous to methods developed for
zero-inflated count data (Agresti & Min, 2005) which are ap-
propriate when there are many more subjects with no arrhyth-
mias than would be expected under a Poisson model (Lambert,
1992). Statistical analyses were performed using PROC GEN-
MOD in SAS version 9.1 (SAS Institute, Cary, NC). Statisti-
cal significance for all models was based on a two-sided α =
0.05.
RESULTS
CAPS mass concentration over the 13 exposure days ranged
from 78.0 to 2202.5 µg/m
3
(mean: 645.7; standard deviation
(SD): 760.3). Particle number concentration ranged from 13,900
to 93,500 particles/cm
3
(mean: 38,500; SD: 23,300). The mean
CO concentrations in the CO and CAPS+CO groups were 37.9
and 38.0 ppm, respectively.
Hypothesis 1: Exposure to CAPS and CO Increases
the Risk of Observing One or More SVEB
In a first analysis we used repeated-measures logistic regres-
sion to determine whether exposure to CAPS or CO increased
the probability of observing any SVEB. Figure 1A shows the
mean probability of observing any SVEB during each time pe-
riod for each group. Differences among the groups during the
preexposure period were not statistically significant.
Among rats in the filtered air group, the probability of ob-
serving any SVEB increased over time, but this effect was not
statistically significant. Among rats in the CAPS group, the prob-
ability of observing any SVEB decreased from baseline to the
exposure and postexposure periods (Figure 1A). Compared to
the filtered air group, this difference was statistically signifi-
cant during the exposure period ( p = .048), but not during the
postexposure period ( p = .10). The change in probability of
observing any SVEB was not significantly different in the CO
or CAPS + CO groups during either the exposure or postexpo-
sure periods, as compared to the filtered air group. We found no
association between the probability of observing any SVEB and
either CAPS mass concentration or CAPS number concentration
in any time period.
Hypothesis 2: Among Rats With SVEB at Baseline,
Exposure to CAPS or CO Increases the Number of SVEB
Observed Either During or Following Exposure
In the subset of rats with one or more SVEB at baseline
(n = 30), we used repeated-measures Poisson regression to
determine whether exposure to CAPS or CO altered SVEB fre-
quency. Figure 1B shows the mean number of SVEB/hour during
each time period for each group. During the preexposure period,
SVEB frequency was significantly greater in the CO group as
compared to the filtered air group ( p = .03). No other baseline
differences reached statistical significance.
Among rats in the filtered air group, the SVEB frequency
increased over time. This difference was statistically signifi-
cant during both the exposure ( p = .003) and postexposure
( p = .03) periods. Compared to the filtered air group, the
change from the preexposure to exposure period in SVEB fre-
quency was significantly lower in the CAPS ( p = .04) and
CO (p = .007) groups and marginally lower in the CAPS +
CO group ( p = .06). The change in SVEB frequency from
1080 G. A. WELLENIUS ET AL.
FIG. 1. (A) Predicted mean probability (95% confidence inter-
vals) of observing one or more SVEB by time period and treat-
ment group. (B) Predicted mean number of SVEB per hour by
time period and treatment group. Asterisk indicates statistically
significant ( p <.05) change from baseline; double asterisk, sta-
tistically significant ( p <.05) change from baseline compared
to change from baseline in filtered air group.
the preexposure to the postexposure period was not signifi-
cantly different in any group as compared to the filtered air
group. We found no association between SVEB frequency and
CAPS mass concentration in any time period. However, we
found that a 1000 particles/cm
3
increase in CAPS number con-
centration was associated with a 3.3% decrease in SVEB fre-
quency during the exposure period (95% confidence interval:
−5.3, −1.2%; p = .0024).
DISCUSSION
Watkinson et al. (1998) first noted the development of pre-
mature atrial beats in rats following intratracheal instillation
of residual oil fly ash. To our knowledge, only one previous
toxicological study has evaluated the effects of ambient par-
ticulate matter on the risk of SVEB (Nadziejko et al., 2004).
In that study, the authors exposed aged Fischer 344 rats to
filtered air, CAPS, ultrafine carbon particles, or sulfur diox-
ide for 4 h and found no effect of any exposure on the fre-
quency of premature supraventricular beats. Similarly, in the
current study, we found no evidence in support of the hypothe-
sis that exposure to either CAPS or CO increases the risk of
SVEB. On the contrary, we found that CAPS exposure was
associated with a lower risk of SVEB and that both CAPS
and CO exposure were associated with a lower rate of SVEB
in the subset of animals with supraventricular arrhythmias at
baseline.
Epidemiological studies suggest that short-term elevations in
ambient particle levels may increase the risk of supraventricu-
lar arrhythmias, but the results have been inconsistent. Riediker
et al. (2004) followed 10 healthy North Carolina Highway Pa-
trol troopers and found a positive association between PM
2.5
and
the number of SVEB. Brauer et al. (2001) followed 16 elderly
patients with chronic obstructive pulmonary disease (COPD)
and reported a similar association. On the other hand, Rich
et al. (2006) followed patients with implanted cardioverter–
defibrillators (ICDs) and found no significant association be-
tween PM
2.5
and the risk of paroxysmal atrial fibrillation. Con-
trolled exposure studies in humans have also yielded mixed re-
sults. Two studies in healthy volunteers did not find a statistically
significant association between CAPS and SVEB (Devlin et al.,
2003; Gong et al., 2003). However, a third study found a statisti-
cally significant positive association between CAPS and SVEB
in healthy volunteers, but a statistically significant negative as-
sociation in subjects with COPD (Gong et al., 2004).
Short-term inhalation exposure to low levels of CO corre-
sponding to 2–4% carboxyhemoglobin levels (COHb) have been
found to exacerbate myocardial ischemia in patients with docu-
mented coronary artery disease (Allred et al., 1989, 1991; Klein-
man et al., 1989). Although still controversial, several studies
suggest that there is little or no effect of CO on the incidence of
ventricular arrhythmias (Dahms et al., 1993; Kizakevich et al.,
2000). Furthermore, even exposure to CO resulting in COHb
values as high as 20% does not appear to affect ventricular elec-
trical properties in dogs (Foster, 1981; Verrier et al., 1990). We
are not aware of any reports on the effect of CO on atrial elec-
trical properties. One previous study in 16 healthy men noted
no apparent difference in the frequency of premature atrial beats
with COHb concentrations up to 19%, but very few premature
beats were observed (Kizakevich et al., 2000). The results from
the current study suggest that 1 h of exposure to 35 ppm CO
does not increase the risk or frequency of supraventricular ar-
rhythmias in rats. Although we did not measure COHb in the
AIR POLLUTION AND SUPRAVENTRICULAR ARRHYTHMIAS 1081
current study, based on existing literature we estimate that rats
in the CO and CAPS + CO groups may have achieved COHb
as high as 5% (Brunssen et al., 2003).
SVEB frequency may be strongly influenced by changes in
heart rate. In the FA group, SVEB frequency increased from the
preexposure to postexposure periods and heart rate increased
over time in a parallel fashion (data not shown). However, we
have previously shown in these same animals that the pattern
of change in heart rate over time is not significantly affected
by exposure to either CAPS or CO (Wellenius et al., 2004).
Therefore, it is unlikely that the results of the current study are
due to exposure-related changes in heart rate.
This study has several important limitations. First, less than
half of the rats in our study exhibited any SVEB. Aside from
posing a methodological challenge in the analysis, this also im-
pacted on statistical power and hence the precision of our es-
timates. Second, supraventricular arrhythmias are a heteroge-
neous group that includes atrial premature beats, junctional pre-
mature beats, supraventricular tachycardias, atrial fibrillation,
and atrial flutter, only some of which were observed and quan-
tified in the current study. Moreover, isolated supraventricular
premature beats are prevalent even in the absence of cardiovas-
cular disease and are not generally clinically important. Third,
the exposure and postexposure periods were each limited to 1
h. Therefore, it is unknown whether longer exposures would
elicit a different physiologic response. Moreover, it is possible
that physiologic responses to CAPS and CO lagged exposure by
more than 1 h. Fourth, since only mature, male, Sprague-Dawley
rats were studied, it is unknown if the effects of CAPS and CO
vary by gender, age, or species.
Rats were pharmacologically sedated during all experiments.
This approach allowed us to carry out these experiments under
conditions of minimal stress for the animals, thereby minimizing
stress-induced arrhythmias unrelated to the exposures of inter-
est. Diazepam, a benzodiazepine, was chosen as the sedative be-
cause it provides adequate sedation with only minor cardiovas-
cular effects (Rall, 1990). Although diazepam may be vagolytic
in humans and large animals, the expected effect is limited at
the doses employed in this study (reviewed by Wellenius et al.,
2002).
In summary, we found no evidence to support the hypothesis
that short-term exposure to ambient air particles or CO increases
the risk or frequency of supraventricular arrhythmias. Given the
paucity of published studies and inconsistent results, further ex-
periments in large-animal models or humans are needed to more
firmly establish the effects of ambient air pollution on supraven-
tricular arrhythmias.
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