The effects of B0, B20, and B100 soy biodiesel exhaust on aconitine-induced cardiac arrhythmia in spontaneously hypertensive rats.

CONTEXT: Diesel exhaust (DE) has been shown to increase the risk of cardiac arrhythmias. Although biodiesel has been proposed as a "safer" alternative to diesel, it is still uncertain whether it actually poses less threat. OBJECTIVE: We hypothesized that exposure to pure or 20% soy biodiesel exhaust (BDE) would cause less sensitivity to aconitine-induced arrhythmia than DE in rats. METHODS: Spontaneously hypertensive (SH) rats implanted with radiotelemeters were exposed once or for 5 d (4 h) to either 50 mg/m(3) (low), 150 mg/m(3) (medium), or 500 mg/m(3) (high) of DE (B0), 20% (B20) or 100% (B100) soy biodiesel exhaust. Arrhythmogenesis was assessed 24 h later by continuous infusion of aconitine, an arrhythmogenic drug, while heart rate (HR), and electrocardiogram (ECG) were monitored. RESULTS: Rats exposed once or for 5 d to low, medium, or high B0 developed arrhythmia at significantly lower doses of aconitine than controls, whereas rats exposed to B20 were only consistently sensitive after 5 d of the high concentration. B100 caused mild arrhythmia sensitivity at the low concentration, only after 5 d of exposure at the medium concentration and after either a single or 5 d at the high concentration. DISCUSSION AND CONCLUSIONS: These data demonstrate that exposure to B20 causes less sensitivity to arrhythmia than B0 and B100. This diminished effect may be due to lower irritant components such as acrolein and nitrogen oxides. Thus, in terms of cardiac health, B20 may be a safer option than both of the pure forms.

Acrolein inhalation alters arterial blood gases and triggers carotid body-mediated cardiovascular responses in hypertensive rats.

CONTEXT: Air pollution exposure affects autonomic function, heart rate, blood pressure and left ventricular function. While the mechanism for these effects is uncertain, several studies have reported that air pollution exposure modifies activity of the carotid body, the major organ that senses changes in arterial oxygen and carbon dioxide levels, and elicits downstream changes in autonomic control and cardiac function. OBJECTIVE: We hypothesized that exposure to acrolein, an unsaturated aldehyde and mucosal irritant found in cigarette smoke and diesel exhaust, would activate the carotid body chemoreceptor response and lead to secondary cardiovascular responses in rats. MATERIALS AND METHODS: Spontaneously hypertensive (SH) rats were exposed once for 3 h to 3 ppm acrolein gas or filtered air in whole body plethysmograph chambers. To determine if the carotid body mediated acrolein-induced cardiovascular responses, rats were pretreated with an inhibitor of cystathionine γ-lyase (CSE), an enzyme essential for carotid body signal transduction. RESULTS: Acrolein exposure induced several cardiovascular effects. Systolic, diastolic and mean arterial blood pressure increased during exposure, while cardiac contractility decreased 1 day after exposure. The cardiovascular effects were associated with decreases in pO2, breathing frequency and expiratory time, and increases in sympathetic tone during exposure followed by parasympathetic dominance after exposure. The CSE inhibitor prevented the cardiovascular effects of acrolein exposure. DISCUSSION AND CONCLUSION: Pretreatment with the CSE inhibitor prevented the cardiovascular effects of acrolein, suggesting that the cardiovascular responses with acrolein may be mediated by carotid body-triggered changes in autonomic tone. (This abstract does not reflect EPA policy.).

Cardiomyopathy confers susceptibility to particulate matter-induced oxidative stress, vagal dominance, arrhythmia and pulmonary inflammation in heart failure-prone rats.

Acute exposure to ambient fine particulate matter (PM2.5) is tied to cardiovascular morbidity and mortality, especially among those with prior cardiac injury. The mechanisms and pathophysiological events precipitating these outcomes remain poorly understood but may involve inflammation, oxidative stress, arrhythmia and autonomic nervous system imbalance. Cardiomyopathy results from cardiac injury, is the leading cause of heart failure, and can be induced in heart failure-prone rats through sub-chronic infusion of isoproterenol (ISO). To test whether cardiomyopathy confers susceptibility to inhaled PM2.5 and can elucidate potential mechanisms, we investigated the cardiophysiologic, ventilatory, inflammatory and oxidative effects of a single nose-only inhalation of a metal-rich PM2.5 (580 µg/m(3), 4 h) in ISO-pretreated (35 days × 1.0 mg/kg/day sc) rats. During the 5 days post-treatment, ISO-treated rats had decreased HR and BP and increased pre-ejection period (PEP, an inverse correlate of contractility) relative to saline-treated rats. Before inhalation exposure, ISO-pretreated rats had increased PR and ventricular repolarization time (QT) and heterogeneity (Tp-Te). Relative to clean air, PM2.5 further prolonged PR-interval and decreased systolic BP during inhalation exposure; increased tidal volume, expiratory time, heart rate variability (HRV) parameters of parasympathetic tone and atrioventricular block arrhythmias over the hours post-exposure; increased pulmonary neutrophils, macrophages and total antioxidant status one day post-exposure; and decreased pulmonary glutathione peroxidase 8 weeks after exposure, with all effects occurring exclusively in ISO-pretreated rats but not saline-pretreated rats. Ultimately, our findings indicate that cardiomyopathy confers susceptibility to the oxidative, inflammatory, ventilatory, autonomic and arrhythmogenic effects of acute PM2.5 inhalation.

A single exposure to acrolein desensitizes baroreflex responsiveness and increases cardiac arrhythmias in normotensive and hypertensive rats.

Short-term exposure to air pollutants has been linked to acute cardiovascular morbidity and mortality. Even in the absence of overt signs or symptoms, pollutants can cause subtle disruptions to internal compensatory mechanisms, which maintain homeostatic balance in response to various environmental and physiological stressors. We hypothesized that a single exposure to acrolein, a ubiquitous gaseous air pollutant, would decrease the sensitivity of baroreflex (BRS), which maintains blood pressure by altering heart rate (HR), modify cardiac electrophysiological properties and increase arrhythmia in rats. Wistar-Kyoto normotensive (WKY) and spontaneously hypertensive (SH) rats implanted with radiotelemeters and a chronic jugular vein catheter were tested for BRS using phenylephrine and sodium nitroprusside 2 days before and 1 h after whole-body exposure to 3 ppm acrolein (3 h). HR and electrocardiogram (ECG) were continuously monitored for the detection of arrhythmia in the pre-exposure, exposure and post-exposure periods. Whole-body plethysmography was used to continuously monitor ventilation in conscious animals. SH rats had higher blood pressure, lower BRS and increased frequency of AV block as evidence by non-conducted p-waves when compared with WKY rats. A single exposure to acrolein caused a decrease in BRS and increased incidence of arrhythmia in both WKY and SH rats. There were minimal ECG differences between the strains, whereas only SH rats experienced irregular breathing during acrolein. These results demonstrate that acrolein causes immediate cardiovascular reflexive dysfunction and persistent arrhythmia in both normal and hypertensive animals. As such, homeostatic imbalance may be one mechanism by which air pollution increases risk 24 h after exposure, particularly in people with underlying cardiovascular disease.

Hypoxia stress test reveals exaggerated cardiovascular effects in hypertensive rats after exposure to the air pollutant acrolein.

Exposure to air pollution increases the risk of cardiovascular morbidity and mortality, especially in susceptible populations. Despite increased risk, adverse responses are often delayed and require additional stress tests to reveal latent effects of exposure. The goal of this study was to use an episode of "transient hypoxia" as an extrinsic stressor to uncover latent susceptibility to environmental pollutants in a rodent model of hypertension. We hypothesized that exposure to acrolein, an unsaturated aldehyde and mucosal irritant found in cigarette smoke, diesel exhaust, and power plant emissions, would increase cardiopulmonary sensitivity to hypoxia, particularly in hypertensive rats. Spontaneously hypertensive and Wistar Kyoto (normotensive) rats, implanted with radiotelemeters, were exposed once for 3h to 3 ppm acrolein gas or filtered air in whole-body plethysmograph chambers and challenged with a 10% oxygen atmosphere (10min) 24h later. Acrolein exposure increased heart rate, blood pressure, breathing frequency, and minute volume in hypertensive rats and also increased the heart rate variability parameter LF, suggesting a potential role for increased sympathetic tone. Normotensive rats only had increased blood pressure during acrolein exposure. The hypoxia stress test after acrolein exposure revealed increased diastolic blood pressure only in hypertensive rats and increased minute volume and expiratory time only in normotensive rats. These results suggest that hypertension confers exaggerated sensitivity to air pollution and that the hypoxia stress test is a novel tool to reveal the potential latent effects of air pollution exposure.

Diesel exhaust inhalation increases cardiac output, bradyarrhythmias, and parasympathetic tone in aged heart failure-prone rats.

Acute air pollutant inhalation is linked to adverse cardiac events and death, and hospitalizations for heart failure. Diesel engine exhaust (DE) is a major air pollutant suspected to exacerbate preexisting cardiac conditions, in part, through autonomic and electrophysiologic disturbance of normal cardiac function. To explore this putative mechanism, we examined cardiophysiologic responses to DE inhalation in a model of aged heart failure-prone rats without signs or symptoms of overt heart failure. We hypothesized that acute DE exposure would alter heart rhythm, cardiac electrophysiology, and ventricular performance and dimensions consistent with autonomic imbalance while increasing biochemical markers of toxicity. Spontaneously hypertensive heart failure rats (16 months) were exposed once to whole DE (4h, target PM(2.5) concentration: 500 µg/m(3)) or filtered air. DE increased multiple heart rate variability (HRV) parameters during exposure. In the 4h after exposure, DE increased cardiac output, left ventricular volume (end diastolic and systolic), stroke volume, HRV, and atrioventricular block arrhythmias while increasing electrocardiographic measures of ventricular repolarization (i.e., ST and T amplitudes, ST area, T-peak to T-end duration). DE did not affect heart rate relative to air. Changes in HRV positively correlated with postexposure changes in bradyarrhythmia frequency, repolarization, and echocardiographic parameters. At 24h postexposure, DE-exposed rats had increased serum C-reactive protein and pulmonary eosinophils. This study demonstrates that cardiac effects of DE inhalation are likely to occur through changes in autonomic balance associated with modulation of cardiac electrophysiology and mechanical function and may offer insights into the adverse health effects of traffic-related air pollutants.

Dobutamine "stress" test and latent cardiac susceptibility to inhaled diesel exhaust in normal and hypertensive rats.

BACKGROUND: Exercise "stress" testing is a screening tool used to determine the amount of stress for which the heart can compensate before developing abnormal rhythm or ischemia, particularly in susceptible persons. Although this approach has been used to assess risk in humans exposed to air pollution, it has never been applied to rodent studies. OBJECTIVE: We hypothesized that a single exposure to diesel exhaust (DE) would increase the risk of adverse cardiac events such as arrhythmia and myocardial ischemia in rats undergoing a dobutamine challenge test, which can be used to mimic exercise-like stress. METHODS: Wistar-Kyoto normotensive (WKY) and spontaneously hypertensive (SH) rats implanted with radiotelemeters and a chronic intravenous catheter were whole-body exposed to 150 µg/m3 DE for 4 hr. Increasing doses of dobutamine, a ß1-adrenergic agonist, were administered to conscious unrestrained rats 24 hr later to elicit the cardiac response observed during exercise while heart rate (HR) and electrocardiogram (ECG) were monitored. RESULTS: A single exposure to DE potentiated the HR response of WKY and SH rats during dobutamine challenge and prevented HR recovery at rest. During peak challenge, DE-exposed SH rats had lower overall HR variability when compared with controls, in addition to transient ST depression. All DE-exposed animals also had increased arrhythmias. CONCLUSIONS: These results are the first evidence that rats exhibit stress-induced cardiac dysrhythmia and ischemia sensitivity comparable to humans after a single exposure to a toxic air pollutant, particularly when in the presence of underlying cardiovascular disease. Thus, exposure to low concentrations of air pollution can impair the heart's ability to respond to stress and increase the risk of subsequent triggered dysfunction.

Whole and particle-free diesel exhausts differentially affect cardiac electrophysiology, blood pressure, and autonomic balance in heart failure-prone rats.

Epidemiological studies strongly link short-term exposures to vehicular traffic and particulate matter (PM) air pollution with adverse cardiovascular (CV) events, especially in those with preexisting CV disease. Diesel engine exhaust is a key contributor to urban ambient PM and gaseous pollutants. To determine the role of gaseous and particulate components in diesel exhaust (DE) cardiotoxicity, we examined the effects of a 4-h inhalation of whole DE (wDE) (target PM concentration: 500 µg/m(3)) or particle-free filtered DE (fDE) on CV physiology and a range of markers of cardiopulmonary injury in hypertensive heart failure-prone rats. Arterial blood pressure (BP), electrocardiography, and heart rate variability (HRV), an index of autonomic balance, were monitored. Both fDE and wDE decreased BP and prolonged PR interval during exposure, with more effects from fDE, which additionally increased HRV triangular index and decreased T-wave amplitude. fDE increased QTc interval immediately after exposure, increased atrioventricular (AV) block Mobitz II arrhythmias shortly thereafter, and increased serum high-density lipoprotein 1 day later. wDE increased BP and decreased HRV root mean square of successive differences immediately postexposure. fDE and wDE decreased heart rate during the 4th hour of postexposure. Thus, DE gases slowed AV conduction and ventricular repolarization, decreased BP, increased HRV, and subsequently provoked arrhythmias, collectively suggesting parasympathetic activation; conversely, brief BP and HRV changes after exposure to particle-containing DE indicated a transient sympathetic excitation. Our findings suggest that whole- and particle-free DE differentially alter CV and autonomic physiology and may potentially increase risk through divergent pathways.

Divergent electrocardiographic responses to whole and particle-free diesel exhaust inhalation in spontaneously hypertensive rats.

Diesel exhaust (DE) is a major contributor to traffic-related fine particulate matter (PM)(2.5). Although inroads have been made in understanding the mechanisms of PM-related health effects, DE's complex mixture of PM, gases, and volatile organics makes it difficult to determine how the constituents contribute to DE's effects. We hypothesized that exposure to particle-filtered DE (fDE; gases alone) will elicit less cardiac effects than whole DE (wDE; particles plus gases). In addition, we hypothesized that spontaneously hypertensive (SH) rats will be more sensitive to the electrocardiographic effects of DE exposure than Wistar Kyoto rats (WKY; background strain with normal blood pressure). SH and WKY rats, implanted with telemeters to monitor electrocardiogram and heart rate (HR), were exposed once for 4 h to 150 µg/m(3) or 500 µg/m(3) of wDE (gases plus PM) or fDE (gases alone) DE, or filtered air. Exposure to fDE, but not wDE, caused immediate electrocardiographic alterations in cardiac repolarization (ST depression) and atrioventricular conduction block (PR prolongation) as well as bradycardia in SH rats. Exposure to wDE, but not fDE, caused postexposure ST depression and increased sensitivity to the pulmonary C fiber agonist capsaicin in SH rats. The only notable effect of DE exposure in WKY rats was a decrease in HR. Taken together, hypertension may predispose to the potential cardiac effects of DE and components of DE may have divergent effects with some eliciting immediate irritant effects (e.g., gases), whereas others (e.g., PM) trigger delayed effects potentially via separate mechanisms.

Overt and latent cardiac effects of ozone inhalation in rats: evidence for autonomic modulation and increased myocardial vulnerability.

BACKGROUND: Ozone (O3) is a well-documented respiratory oxidant, but increasing epidemiological evidence points to extrapulmonary effects, including positive associations between ambient O3 concentrations and cardiovascular morbidity and mortality. OBJECTIVE: With preliminary reports linking O3 exposure with changes in heart rate (HR), we investigated the hypothesis that a single inhalation exposure to O3 will cause concentration-dependent autonomic modulation of cardiac function in rats. METHODS: Rats implanted with telemeters to monitor HR and cardiac electrophysiology [electrocardiography (ECG)] were exposed once by whole-body inhalation for 4 hr to 0.2 or 0.8 ppm O3 or filtered air. A separate cohort was tested for vulnerability to aconitine-induced arrhythmia 24 hr after exposure. RESULTS: Exposure to 0.8 ppm O3 caused bradycardia, PR prolongation, ST depression, and substantial increases in atrial premature beats, sinoatrial block, and atrioventricular block, accompanied by concurrent increases in several HR variability parameters that were suggestive of increased parasympathetic tone. Low-O3 exposure failed to elicit any overt changes in autonomic tone, heart rhythm, or ECG. However, both 0.2 and 0.8 ppm O3 increased sensitivity to aconitine-induced arrhythmia formation, suggesting a latent O3-induced alteration in myocardial excitability. CONCLUSIONS: O3 exposure causes several alterations in cardiac electrophysiology that are likely mediated by modulation of autonomic input to the heart. Moreover, exposure to low O3 concentrations may cause subclinical effects that manifest only when triggered by a stressor, suggesting that the adverse health effects of ambient levels of air pollutants may be insidious and potentially underestimated.

Dietary salt exacerbates isoproterenol-induced cardiomyopathy in rats.

Spontaneously hypertensive heart failure rats (SHHFs) take longer to develop compensated heart failure (HF) and congestive decompensation than common surgical models of HF. Isoproterenol (ISO) infusion can accelerate cardiomyopathy in young SHHFs, while dietary salt loading in hypertensive rats induces cardiac fibrosis, hypertrophy, and--in a minority-congestive HF. By combining ISO with dietary salt loading in young SHHFs, the authors sought a nonsurgical model that is more time--and resource-efficient than any of these factors alone. The authors hypothesized that salt loading would enhance ISO-accelerated cardiomyopathy, promoting fibrosis, hypertrophy, and biochemical characteristics of HF. SHHFs (lean male, 90d) were infused for 4 wk with ISO (2.5 mg/kg/day) or saline. After 2 wk of infusion, a 6-wk high-salt diet (4%, 6%, or 8% NaCl) was initiated. Eight percent salt increased heart weight, HF markers (plasma B-type natriuretic peptide, IL-6), lung lymphocytes, and indicators of lung injury and edema (albumin and protein) relative to control diet, while increasing urine pro-atrial natriuretic peptide relative to ISO-only. High salt also exacerbated ISO-cardiomyopathy and fibrosis. Thus, combining ISO infusion with dietary salt loading in SHHFs holds promise for a new rat HF model that may help researchers to elucidate HF mechanisms and unearth effective treatments.

TRPA1 and sympathetic activation contribute to increased risk of triggered cardiac arrhythmias in hypertensive rats exposed to diesel exhaust.

BACKGROUND: Diesel exhaust (DE), which is emitted from on- and off-road sources, is a complex mixture of toxic gaseous and particulate components that leads to triggered adverse cardiovascular effects such as arrhythmias. OBJECTIVE: We hypothesized that increased risk of triggered arrhythmias 1 day after DE exposure is mediated by airway sensory nerves bearing transient receptor potential (TRP) channels [e.g., transient receptor potential cation channel, member A1 (TRPA1)] that, when activated by noxious chemicals, can cause a centrally mediated autonomic imbalance and heightened risk of arrhythmia. METHODS: Spontaneously hypertensive rats implanted with radiotelemeters were whole-body exposed to either 500 µg/m³ (high) or 150 µg/m³ (low) whole DE (wDE) or filtered DE (fDE), or to filtered air (controls), for 4 hr. Arrhythmogenesis was assessed 24 hr later by continuous intravenous infusion of aconitine, an arrhythmogenic drug, while heart rate (HR) and electrocardiogram (ECG) were monitored. RESULTS: Rats exposed to wDE or fDE had slightly higher HRs and increased low-frequency:high-frequency ratios (sympathetic modulation) than did controls; ECG showed prolonged ventricular depolarization and shortened repolarization periods. Rats exposed to wDE developed arrhythmia at lower doses of aconitine than did controls; the dose was even lower in rats exposed to fDE. Pretreatment of low wDE-exposed rats with a TRPA1 antagonist or sympathetic blockade prevented the heightened sensitivity to arrhythmia. CONCLUSIONS: These findings suggest that a single exposure to DE increases the sensitivity of the heart to triggered arrhythmias. The gaseous components appear to play an important role in the proarrhythmic response, which may be mediated by activation of TRPA1, and subsequent sympathetic modulation. As such, toxic inhalants may partly exhibit their toxicity by lowering the threshold for secondary triggers, complicating assessment of their risk.

ST depression, arrhythmia, vagal dominance, and reduced cardiac micro-RNA in particulate-exposed rats.

Recently, investigators demonstrated associations between fine particulate matter (PM)-associated metals and adverse health effects. Residual oil fly ash (ROFA), a waste product of fossil fuel combustion from boilers, is rich in the transition metals Fe, Ni, and V, and when released as a fugitive particle, is an important contributor to ambient fine particulate air pollution. We hypothesized that a single-inhalation exposure to transition metal-rich PM will cause concentration-dependent cardiovascular toxicity in spontaneously hypertensive (SH) rats. Rats implanted with telemeters to monitor heart rate and electrocardiogram were exposed once by nose-only inhalation for 4 hours to 3.5 mg/m(3), 1.0 mg/m(3), or 0.45 mg/m(3) of a synthetic PM (dried salt solution), similar in composition to a well-studied ROFA sample consisting of Fe, Ni, and V. Exposure to the highest concentration of PM decreased T-wave amplitude and area, caused ST depression, reduced heart rate (HR), and increased nonconducted P-wave arrhythmias. These changes were accompanied by increased pulmonary inflammation, lung resistance, and vagal tone, as indicated by changes in markers of HR variability (increased root of the mean of squared differences of adjacent RR intervals [RMSSD], low frequency [LF], high frequency [HF], and decreased LF/HF), and attenuated myocardial micro-RNA (RNA segments that suppress translation by targeting messenger RNA) expression. The low and intermediate concentrations of PM had less effect on the inflammatory, HR variability, and micro-RNA endpoints, but still caused significant reductions in HR. In addition, the intermediate concentration caused ST depression and increased QRS area, whereas the low concentration increased the T-wave parameters. Thus, PM-induced cardiac dysfunction is mediated by multiple mechanisms that may be dependent on PM concentration and myocardial vulnerability (this abstract does not reflect the policy of the United States Environmental Protection Agency).

Particulate matter inhalation exacerbates cardiopulmonary injury in a rat model of isoproterenol-induced cardiomyopathy.

Ambient particulate matter (PM) exposure is linked to cardiovascular events and death, especially among individuals with heart disease. A model of toxic cardiomyopathy was developed in Spontaneously Hypertensive Heart Failure (SHHF) rats to explore potential mechanisms. Rats were infused with isoproterenol (ISO; 2.5 mg/kg/day subcutaneous [sc]), a beta-adrenergic agonist, for 28 days and subsequently exposed to PM by inhalation. ISO induced tachycardia and hypotension throughout treatment followed by postinfusion decrements in heart rate, contractility, and blood pressures (systolic, diastolic, pulse), and fibrotic cardiomyopathy. Changes in heart rate and heart rate variability (HRV) 17 days after ISO cessation indicated parasympathetic dominance with concomitantly altered ventilation. Rats were subsequently exposed to filtered air or Harvard Particle 12 (HP12) (12 mg/m(3))--a metal-rich oil combustion-derived PM--at 18 and 19 days (4 h/day) after ISO infusion via nose-only inhalation to determine if cardio-impaired rats were more responsive to the effects of PM exposure. Inhalation of PM among ISO-pretreated rats significantly increased pulmonary lactate dehydrogenase, serum high-density lipoprotein (HDL) cholesterol, and heart-to-body mass ratio. PM exposure increased the number of ISO-pretreated rats that experienced bradyarrhythmic events, which occurred concomitantly with acute alterations of HRV. PM, however, did not significantly affect mean HRV in the ISO- or saline-pretreated groups. In summary, subchronic ISO treatment elicited some pathophysiologic and histopathological features of heart failure, including cardiomyopathy. The enhanced sensitivity to PM exposure in SHHF rats with ISO-accelerated cardiomyopathy suggests that this model may be useful for elucidating the mechanisms by which PM exposure exacerbates heart disease.

A single exposure to particulate or gaseous air pollution increases the risk of aconitine-induced cardiac arrhythmia in hypertensive rats.

Epidemiological studies demonstrate an association between arrhythmias and air pollution. Aconitine-induced cardiac arrhythmia is widely used experimentally to examine factors that alter the risk of arrhythmogenesis. In this study, Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats acutely exposed to synthetic residual oil fly ash (s-ROFA) particles (450 mug/m(3)) were "challenged" with aconitine to examine whether a single exposure could predispose to arrhythmogenesis. Separately, SH rats were exposed to varied particulate matter (PM) concentrations (0.45, 1.0, or 3.5 mg/m(3) s-ROFA), or the irritant gas acrolein (3 ppm), to better assess the generalization of this challenge response. Rather than directly cause arrhythmias, we hypothesized that inhaled air pollutants sensitize the heart to subsequent dysrhythmic stimuli. Twenty-four hour postexposure, urethane-anesthetized rats were monitored for heart rate (HR), electrocardiogram, and blood pressure (BP). SH rats had higher baseline HR and BP and significantly longer PR intervals, QRS duration, QTc, and JTc than WKY rats. PM exposure caused a significant increase in the PR interval, QRS duration, and QTc in WKY rats but not in SH rats. Heart rate variability was significantly decreased in WKY rats after PM exposure but increased in SH rats. Cumulative dose of aconitine that triggered arrhythmias in air-exposed SH rats was lower than WKY rats and even lower for each strain postexposure. SH rats exposed to varied concentrations of PM or acrolein developed arrhythmia at significantly lower doses of aconitine than controls; however, there was no PM concentration-dependent response. In conclusion, a single exposure to air pollution may increase the sensitivity of cardiac electrical conduction to disruption. Moreover, there seem to be host factors (e.g., cardiovascular disease) that increase vulnerability to triggered arrhythmias regardless of the pollutant or its concentration.

Increased non-conducted P-wave arrhythmias after a single oil fly ash inhalation exposure in hypertensive rats.

BACKGROUND: Exposure to combustion-derived fine particulate matter (PM) is associated with increased cardiovascular morbidity and mortality especially in individuals with cardiovascular disease, including hypertension. PM inhalation causes several adverse changes in cardiac function that are reflected in the electrocardiogram (ECG), including altered cardiac rhythm, myocardial ischemia, and reduced heart rate variability (HRV). The sensitivity and reliability of ECG-derived parameters as indicators of the cardiovascular toxicity of PM in rats are unclear. OBJECTIVE: We hypothesized that spontaneously hypertensive (SH) rats are more susceptible to the development of PM-induced arrhythmia, altered ECG morphology, and reduced HRV than are Wistar Kyoto (WKY) rats, a related strain with normal blood pressure. METHODS: We exposed rats once by nose-only inhalation for 4 hr to residual oil fly ash (ROFA), an emission source particle rich in transition metals, or to air and then sacrificed them 1 or 48 hr later. RESULTS: ROFA-exposed SH rats developed non-conducted P-wave arrhythmias but no changes in ECG morphology or HRV. We found no ECG effects in ROFA-exposed WKY rats. ROFA-exposed SH rats also had greater pulmonary injury, neutrophil infiltration, and serum C-reactive protein than did ROFA-exposed WKY rats. CONCLUSIONS: These results suggest that cardiac arrhythmias may be an early sensitive indicator of the propensity for PM inhalation to modify cardiovascular function.

Continuous electrocardiogram reveals differences in the short-term cardiotoxic response of Wistar-Kyoto and spontaneously hypertensive rats to doxorubicin.

Electrocardiography (ECG) is one of the standard technologies used to monitor and assess cardiac function, and provide insight into the mechanisms driving myocardial pathology. Increased understanding of the effects of cardiovascular disease on rat ECG may help make ECG assessments in rat toxicology studies routine, thus facilitating continuous measurement of functional decrements associated with cardiotoxicant exposure. These studies seek to test the hypothesis that hypertensive rats are more susceptible to the short-term cardiotoxic effects of doxorubicin (DOX) when compared with normotensive rats with respect to continuously measured ECG endpoints. Male Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats surgically implanted with radiotelemeters were treated once a week for three weeks with either vehicle, 1.25 (low), 2.5 (medium), or 5 (high) mg/kg DOX (i.p.). ECG, heart rate (HR), and core body temperature (T(co)) were continuously monitored during the 1-week baseline and throughout the experimental period until rats were sacrificed 24 h after the third injection. DOX prevented normal body weight gain in both strains and significantly decreased diurnal HR and T(co) of high DOX SH rats. In the ECG, SH rats had prolonged baseline PR intervals and QT(c) when compared with WKY rats. All DOX-treated WKY rats subsequently developed PR interval prolongation; however only those treated with high DOX had increased QT(c). DOX caused an increase in ST interval in SH rats, and resulted in ECG morphology changes. The number of arrhythmias due to DOX was increased in both strains. In conclusion, ECG analysis can reveal underlying cardiovascular disease as a risk factor in the heart's response to toxicant-induced injury in the rat; and be a valuable tool to evaluate baseline vulnerability and assess cardiotoxicity.

A hyperlipidemic rabbit model provides new insights into pulmonary zinc exposure effects on cardiovascular health.

This study ascertains the effects of zinc, a major component of particulate matter, on pulmonary and systemic endpoints using hyperlipidemic rabbits to model diet-induced human atherosclerosis. New Zealand White rabbits were fed a normal or cholesterol-enriched diet and then were intratracheally instilled 1x/week for 4 weeks with saline or 16 microg/kg of zinc, equal parts sulfate and oxide. Physiologic responses, blood after each exposure, and terminal bronchoalveolar lavage (BAL) were assessed. Rabbits fed a cholesterol-rich diet developed hyperlipidemia and had consistently higher circulating leukocyte counts than rabbits fed normal chow. Within minutes after zinc instillation, saturation of peripheral oxygen was decreased in hyperlipidemic rabbits and heart rate was increased in hyperlipidemic rabbits with total serum cholesterol levels greater than 200 mg/dl. Total circulating leukocytes levels were increased 24 h after the first zinc instillation, but upon repeated exposures this effect was attenuated. After repeated zinc exposures, BAL fluid (BALF) N-acetylglucosaminidase activity was increased regardless of hyperlipidemic state. Hyperlipidemic rabbits had an increase in BALF-oxidized glutathione and a decrease in serum nitrite. The study elucidates mechanisms by which the zinc metal component of PM drives cardiovascular health effects, as well as the possible susceptibility induced by hyperlipidemia. Furthermore, the study exemplifies the benefits of monitoring circulatory physiology during exposure as well as after exposure.

Potentiation of pulmonary reflex response to capsaicin 24h following whole-body acrolein exposure is mediated by TRPV1.

Pulmonary C-fibers are stimulated by irritant air pollutants producing apnea, bronchospasm, and decrease in HR. Chemoreflex responses resulting from C-fiber activation are sometimes mediated by TRPV1 and release of substance P. While acrolein has been shown to stimulate C-fibers, the persistence of acrolein effects and the role of C-fibers in these responses are unknown. These experiments were designed to determine the effects of whole-body acrolein exposure and pulmonary chemoreflex response post-acrolein. Rats were exposed to either air or 3 ppm acrolein for 3 h while ventilatory function and HR were measured; 1-day later response to capsaicin challenge was measured in anesthetized rats. Rats experienced apnea and decrease in HR upon exposure to acrolein, which was not affected by either TRPV1 antagonist or NK(1)R antagonist pretreatment. Twenty-four hours later, capsaicin caused apnea and bronchoconstriction in control rats, which was potentiated in rats exposed to acrolein. Pretreatment with TRPV1 antagonist or NK(1)R antagonist prevented potentiation of apneic response and bronchoconstriction 24h post-exposure. These data suggest that although potentiation of pulmonary chemoreflex response 24h post-acrolein is mediated by TRPV1 and release of substance P, cardiopulmonary inhibition during whole-body acrolein exposure is mediated through other mechanisms.

Agonist-mediated airway challenge: cardiopulmonary interactions modulate gas exchange and recovery.

Diverse agonists used for airway challenges produce a stereotypic sequence of immediate functional responses (e.g., bronchoconstriction, gas trapping, hypoxemia, etc.) at the time such reactions are triggered. The reaction incorporates both pulmonary and cardiac changes that clearly interact in an orchestrated fashion taking the subject (or animal model) through the response generally to ultimate recovery. We hypothesize that despite differences in the initiation of the response, diverse airway provocations lead to a cascade of events that converge through a common physiologic pathway. To better understand the sequence of events and the counterbalanced cardiopulmonary responses, we examined histamine, methacholine, and ovalbumin (OVA) challenges in the awake guinea pig model and assessed ventilatory and breathing mechanics in the context of associated cardiac parameters. With the histamine response as the prototype, we evaluated the role of beta-adrenoreceptors using propranolol (1.0-10 mg/kg i.p.) and found that beta-adrenoreceptors are critical in reducing challenge-induced gas trapping in the lungs. The disposition of the circulatory response to agonist challenge (the OVA model) was reflected in a significant absolute shunting of blood through poorly ventilated regions of the lung. The methacholine challenge revealed that gasping enhanced lung inflation and reversed the diminished Pa(O2). Moreover, beta-sympathetic function was critical to recovery. Collectively, the response profiles of these disparate models of airway challenge suggest a highly integrated balance to maintain gas exchange among the pulmonary airways and vasculature, modulated in recovery by beta-adrenoreceptors.