Alterations in functional connectivity (FC) have been observed in individuals with Alzheimer’s disease (AD) with elevated amyloid (Aβ) and tau. However, it is not yet known whether directed FC is already influenced by Aβ and tau load in cognitively healthy (CH) individuals. A 21-channel electroencephalogram (EEG) was used from 46 CHs classified based on cerebrospinal fluid (CSF) Aβ tau ratio: pathological (CH-PAT) or normal (CH-NAT). Directed FC was estimated with Partial Directed Coherence in frontal, temporal, parietal, central, and occipital regions. We also examined the correlations between directed FC and various functional metrics, including neuropsychology, cognitive reserve, MRI volumetrics, and heart rate variability between both groups. Compared to CH-NATs, the CH-PATs showed decreased FC from the temporal regions, indicating a loss of relative functional importance of the temporal regions. In addition, frontal regions showed enhanced FC in the CH-PATs compared to CH-NATs, suggesting neural compensation for the damage caused by the pathology. Moreover, CH-PATs showed greater FC in the frontal and occipital regions than CH-NATs. Our findings provide a useful and non-invasive method for EEG-based analysis to identify alterations in brain connectivity in CHs with a pathological versus normal CSF Aβ/tau. This study reveals disrupted brain functional connectivity as an early biomarker in cognitively healthy individuals with pathological CSF amyloid/tau, aiding early Alzheimer’s detection.

The effect of electronic cigarette (E-cig) vaping on cardiac and vascular function during the healing phase of myocardial infarction (MI), and post-MI remodeling was investigated. Sprague Dawley rats were subjected to left coronary artery ligation to induce MI. One week later, rats were randomized to receive either 12 weeks of exposure to purified air ( n = 37) or E-cig vapor (15 mg/ml of nicotine) ( n = 32). At 12 weeks, cardiac and vascular function, and post-MI remodeling were assessed. Baseline blood flow in the femoral artery did not differ between groups, but peak reperfusion blood flow was blunted in the E-cig group (1.59 ± 0.15 ml/min) vs. the air group (2.11 ± 0.18 ml/min; p = 0.034). Femoral artery diameter after reperfusion was narrower in the E-cig group (0.54 ± 0.02 mm) compared to the air group (0.60 ± 0.02 mm; p = 0.023). Postmortem left ventricular (LV) volumes were similar in the E-cig (0.69 ± 0.04 ml) and air groups (0.73 ± 0.04 ml; p = NS); and myocardial infarct expansion index did not differ between groups (1.4 ± 0.1 in E-cig group versus 1.3 ± 0.1 in air group; p = NS). LV fractional shortening by echo did not differ between groups at 12 weeks (E-cig at 29 ± 2% and air at 27 ± 1%; p = NS). Exposure to E-cig during the healing phase of MI was associated with altered vascular function with reduced femoral artery blood flow and diameter at reperfusion, but not with worsened LV dilation or worsened cardiac function.

Background Electronic cigarettes have gained popularity as a nicotine delivery system, which has been recommended by some as an aid to help people quit traditional smoking. The potential long‐term effects of vaping on the cardiovascular system, as well as how their effects compare with those from standard cigarettes, are not well understood. The intrinsic frequency (IF) method is a systems approach for analysis of left ventricle and arterial function. Recent clinical studies have demonstrated the diagnostic and prognostic value of IF. Here, we aim to determine whether the novel IF metrics derived from carotid pressure waveforms can detect effects of nicotine (delivered by chronic exposure to electronic cigarette vapor or traditional cigarette smoke) on the cardiovascular system. Methods and Results One hundred seventeen healthy adult male and female rats were exposed to purified air (control), electronic cigarette vapor without nicotine, electronic cigarette vapor with nicotine, and traditional nicotine‐rich cigarette smoke, after which hemodynamics were comprehensively evaluated. IF metrics were computed from invasive carotid pressure waveforms. Standard cigarettes significantly increased the first IF (indicating left ventricle contractile dysfunction). Electronic cigarettes with nicotine significantly reduced the second IF (indicating adverse effects on vascular function). No significant difference was seen in the IF metrics between controls and electronic cigarettes without nicotine. Exposure to electronic cigarettes with nicotine significantly increased the total IF variation (suggesting adverse effects on left ventricle‐arterial coupling and its optimal state), when compared with electronic cigarettes without nicotine. Conclusions Our IF results suggest that nicotine‐containing electronic cigarettes adversely affect vascular function and left ventricle‐arterial coupling, whereas standard cigarettes have an adverse effect on left ventricle function.

BACKGROUND:While the acute exposure to electronic cigarette (E-cig) vapor has been associated with an increase in blood pressure, the chronic effect of E-cig vapor on blood pressure compared to standard cigarette smoke has not been extensively studied. We determined the effect of E-cig exposure on blood pressure and other measures of cardiac function in both young and old rats. METHODS:Young Sprague Dawley rats (6 weeks old, both sexes) were randomly exposed to air (n = 34), E-cig with nicotine (E-cig Nic+; n = 30), E-cig without nicotine (E-cig Nic-; n = 28) or standard cigarette smoke (n = 27). Old Fischer 344 rats (25 months old, both sexes) were randomized into 2 groups: (1) 26 rats in the purified air (negative control) group and (2) 17 rats in the electronic cigarette vapor plus nicotine group (E-cig Nic+). After 12 weeks of exposure, hemodynamics were determined by Millar catheter, echocardiography, and thermodilution catheter, a few days after their last exposure. RESULTS:In young rats, cigarette smoke was associated with higher systolic, diastolic and mean blood pressures and peak LV systolic pressure, compared to air or E-cig Nic + or E-cig Nic- groups. Neither fractional shortening nor cardiac output differed among the groups. Absolute value for dp/dt min, a measure of diastolic LV function, was lowest in the E-cig Nic- group. Tau, a measure of LV relaxation was worse in this group as well. In old rats, E-cig vaping did not change heart rate, blood pressure, and cardiac function. However, E-cig Nic + exposure was associated with a greater heart weight/BW and LV weight/BW compared to air exposure in old rats. CONCLUSIONS:Chronic exposure to E-cig vaping did not cause an increase in blood pressure or heart rate, nor did it change cardiac function compared to air in young rats after 12 weeks of exposure, while standard cigarette smoking was associated with an increase in blood pressure. E-cig vaping was associated with a greater heart weight/BW and LV weight/BW compared to air exposure in old rats, suggested that older animals might be more vulnerable to E-cig stimulus than younger ones.

Purpose: We investigated the effects of exposure to electronic cigarettes (E-cig) vapor on the sizes of the no-reflow and myocardial infarction regions, and cardiovascular function compared to exposure to purified air and standard cigarette smoke. Methods and Results: Sprague Dawley rats (both male and female, 6 weeks old) were successfully exposed to filtered air (n = 32), E-cig with nicotine (E-cig Nic + , n = 26), E-cig without nicotine (E-cig Nic − , n = 26), or standard cigarette smoke (1R6F reference, n = 31). All rats were exposed to inhalation exposure for 8 weeks, prior to being subjected to 30 minutes of left coronary artery occlusion followed by 3 hours of reperfusion. Exposure to E-cig vapor with or without nicotine or exposure to standard cigarettes did not increase myocardial infarct size or worsen the no-reflow phenomenon. Exposure to E-cig Nic + reduced the body weight gain, and increased the LV weight normalized to body weight and LV wall thickness and enhanced the collagen deposition within the LV wall. E-cig exposure led to cardiovascular dysfunction, such as reductions in cardiac output, LV positive and negative dp/dt, suggesting a reduction in contractility and relaxation, and increased systemic arterial resistance after coronary artery occlusion and reperfusion in rats compared to air or cigarette exposure. Conclusions: E-cig exposure did not increase myocardial infarct size or worsen the no-reflow phenomenon, but induced deleterious changes in LV structure leading to cardiovascular dysfunction and increased systemic arterial resistance after coronary artery occlusion followed by reperfusion.

The heart and brain have bi-directional influences on each other, including autonomic regulation and hemodynamic connections. Heart rate variability (HRV) measures variation in beat-to-beat intervals. New findings about disorganized sinus rhythm (erratic rhythm, quantified as heart rate fragmentation, HRF) are discussed and suggest overestimation of autonomic activities in HRV changes, especially during aging or cardiovascular events. When excluding HRF, HRV is regulated via the central autonomic network (CAN). HRV acts as a proxy of autonomic activity and is associated with executive functions, decision-making, and emotional regulation in our health and wellbeing. Abnormal changes of HRV (e.g., decreased vagal functioning) are observed in various neurological conditions including mild cognitive impairments, dementia, mild traumatic brain injury, migraine, COVID-19, stroke, epilepsy, and psychological conditions (e.g., anxiety, stress, and schizophrenia). Efforts are needed to improve the dynamic and intriguing heart-brain interactions.

Exposure to traffic-related air pollution consisting of particulate matter (PM) is associated with cognitive decline leading to Alzheimer's disease (AD). In this study, we sought to examine the neurotoxic effects of exposure to ultrafine PM and how it exacerbates neuronal loss and AD-like neuropathology in wildtype (WT) mice and a knock-in mouse model of AD (App(NL-G-F/+)-KI) when the exposure occurs at a prepathologic stage or at a later age with the presence of neuropathology. App(NL-G-F/+)-KI and WT mice were exposed to concentrated ultrafine PM from local ambient air in Irvine, California, for 12 weeks, starting at 3 or 9 months of age. Particulate matter-exposed animals received concentrated ultrafine PM up to 8 times above the ambient levels, whereas control animals were exposed to purified air. Particulate matter exposure resulted in a marked impairment of memory tasks in prepathologic App(NL-G-F/+)-KI mice without measurable changes in amyloid-beta pathology, synaptic degeneration, and neuroinflammation. At aged, both WT and App(NL-G-F/+)-KI mice exposed to PM showed a significant memory impairment along with neuronal loss. In App(NL-G-F/+)-KI mice, we also detected an increased amyloid-beta buildup and potentially harmful glial activation including ferritin-positive microglia and C3-positive astrocytes. Such glial activation could promote the cascade of degenerative consequences in the brain. Our results suggest that exposure to PM impairs cognitive function at both ages while exacerbation of AD-related pathology and neuronal loss may depend on the stage of pathology, aging, and/or state of glial activation. Further studies will be required to unveil the neurotoxic role of glial activation activated by PM exposure.

IntroductionResting heart rate (HR) and heart rate variability (HRV) have been linked with cognition in the general population and in older individuals. The knowledge of this aspect of heart-brain relationship is relatively absent in older individuals with early Alzheimer's disease (AD) pathology. This study explores relationships of the HR, HRV, and cognition in cognitively healthy individuals with pathological amyloid/tau ratio (CH-PATs) in cerebral spinal fluid (CSF) compared to those with normal ratio (CH-NATs).MethodsWe examined the relationships between 1) resting HR and Mini‐Mental State Examination (MMSE); 2) resting HR and brain processing during Stroop interference; and 3) resting vagally mediated HRV (vmHRV) and task switching performance.ResultsOur studies showed that compared to CH-NATs, those CH-PATs with higher resting HR presented with lower MMSE, and less brain activation during interference processing. In addition, resting vmHRV was significantly correlated with task switching accuracy in CH-NATs, but not in CH-PATs.DiscussionThese three different tests indicate dysfunctional heart-brain connections in CH-PATs, suggesting a potential cardio-cerebral dysfunctional integration.

Air pollution poses a significant threat to human health, though a clear understanding of its mechanism remains elusive. In this study, we sought to better understand the effects of various sized particulate matter from polluted air on Alzheimer's disease (AD) development using an AD mouse model. We exposed transgenic Alzheimer's mice in their prodromic stage to different sized particulate matter (PM), with filtered clean air as control. After 3 or 6 months of exposure, mouse brains were harvested and analyzed. RNA-seq analysis showed that various PM have differential effects on the brain transcriptome, and these effects seemed to correlate with PM size. Many genes and pathways were affected after PM exposure. Among them, we found a strong activation in mRNA Nonsense Mediated Decay pathway, an inhibition in pathways related to transcription, neurogenesis and survival signaling as well as angiogenesis, and a dramatic downregulation of collagens. Although we did not detect any extracellular Aβ plaques, immunostaining revealed that both intracellular Aβ1-42 and phospho-Tau levels were increased in various PM exposure conditions compared to the clean air control. NanoString GeoMx analysis demonstrated a remarkable activation of immune responses in the PM exposed mouse brain. Surprisingly, our data also indicated a strong activation of various tumor suppressors including RB1, CDKN1A/p21 and CDKN2A/p16. Collectively, our data demonstrated that exposure to airborne PM caused a profound transcriptional dysregulation and accelerated Alzheimer's-related pathology.

Background: The impact of long-term electronic cigarettes (E-cig) vaping on cardiovascular function in rats were investigated. Methods: Sprague Dawley rats (both sex, 6 weeks old) were randomly exposed to filtered air (n=32), E-cig with nicotine (E-cig Nic + , n=26), E-cig without nicotine (E-cig Nic - , n=26), or standard cigarette smoke (n=31). After exposure to inhalation exposure for 8 weeks, the rats were subjected to 30 minutes of left coronary artery occlusion followed by 3 hours of reperfusion. Cardiovascular function was measured with intracavitary Millar catheters and echocardiography during the surgical procedure. Results: As the data shown in the Table, at 2.5 hours after coronary artery reperfusion, heart rate, cardiac output and positive/negative LV dp/dt were lower in the E-cig Nic + group compared to the air and/or cigarette group. LVFS in the cigarette group was higher than compared to E-cig Nic + or air group. There was a significantly higher systemic arterial resistance in the E-cig Nic + group compared to the cigarette group. Conclusions: Chronic E-cig Nic + exposure impairs the cardiovascular function recovery during the phase of coronary artery reperfusion after heart attack, indicated by reductions of heart rate, cardiac output, LV positive and negative dp/dt (suggesting a reduction in contractility and relaxation); and increase in systemic arterial resistance in the setting of experimental acute myocardial infarction compared to air and/or standard cigarette smoke.

Purpose: We investigated the effects of chronic exposure to electronic cigarettes (e-cig) on myocardial infarct size and the size of the no-reflow zone in a rat model of both sexes. Methods and Results: Sprague Dawley rats (6 weeks old) were randomized to 4 exposure groups: (1) Purified air (n=16 male/16 female); (2) e-cig vapor with 15mg/mL nicotine (n=13 male/15 female); (3) e-cig vapor without nicotine (n=16 male/12 female); and (4) Standard nicotine-containing combustion cigarette smoke (n=16 male/16 female). All rats were exposed to inhalation exposure for 8 weeks, prior to being subjected to 30 minutes of left coronary artery occlusion followed by 3 hours of reperfusion. Two-way analysis of variance (that factors sex and treatment) demonstrated that chronic exposure to e-cig vapor (with or without nicotine) or to standard cigarettes did not alter myocardial infarct or no-reflow size compared to air. However, as shown in the figure, infarct size was significantly smaller (40.7 ± 2.7% vs 54.5 ± 2.6%; p=0.0004) and no-reflow size was smaller (18.1 ± 2.0% vs 26.8 ± 2.2%; p=0.0042) in female rats compared to male rats. Conclusions: Long-term e-cig exposure did not affect the cardiac sensitivity to ischemia/reperfusion injury in young rats. Female rats are more tolerance to ischemia/reperfusion injury than males. This sex difference phenomena was not observed in our previous study [Li et al. J Thromb Thrombolysis. 1995;2(3):221-225.] that examined the tolerance between males and females subjected to 90 mins of left coronary artery occlusion followed by 4 hours of reperfusion in 1-year-old SD rats and found the myocardial infarct size to be similar between the sexes. The different findings between the 2 studies may be due to the age difference (which implies possible hormonal effects in the younger rats) or different coronary artery occlusion and reperfusion times.

Background Fine particulate matter (PM 2.5 ) exposure accelerates atherosclerosis and contains known ovotoxic chemicals. However, effects of exposure to PM 2.5 on the finite ovarian follicle pool have hardly been investigated, nor have interactions between ovarian and cardiovascular effects. We hypothesized that subchronic inhalation exposure to human-relevant concentrations of PM 2.5 results in destruction of ovarian follicles via apoptosis induction, as well as accelerated recruitment of primordial follicles into the growing pool. Further, we hypothesized that destruction of ovarian follicles enhances the adverse cardiovascular effects of PM 2.5 in females. Results Hyperlipidemic apolipoprotein E ( Apoe ) null ovary-intact or ovariectomized female mice and testis-intact male mice were exposed to concentrated ambient PM 2.5 or filtered air for 12 weeks, 5 days/week for 4 h/day using a versatile aerosol concentration enrichment system. Primordial, primary, and secondary ovarian follicle numbers were decreased by 45%, 40%, and 17%, respectively, in PM 2.5 -exposed ovary-intact mice compared to controls ( P < 0.05). The percentage of primary follicles with granulosa cells positive for the mitosis marker Ki67 was increased in the ovaries from PM 2.5 -exposed females versus controls ( P < 0.05), consistent with increased recruitment of primordial follicles into the growing pool. Exposure to PM 2.5 increased the percentages of primary and secondary follicles with DNA damage, assessed by γH2AX immunostaining ( P < 0.05). Exposure to PM 2.5 increased the percentages of apoptotic antral follicles, determined by TUNEL and activated caspase 3 immunostaining ( P < 0.05). Removal of the ovaries and PM 2.5 -exposure exacerbated the atherosclerotic effects of hyperlipidemia in females ( P < 0.05). While there were statistically significant changes in blood pressure and heart rate variability in PM 2.5 -compared to Air-exposed gonad-intact males and females and ovariectomized females, the changes were not consistent between exposure years and assessment methods. Conclusions These results demonstrate that subchronic PM 2.5 exposure depletes the ovarian reserve by increasing recruitment of primordial follicles into the growing pool and increasing apoptosis of growing follicles. Further, PM 2.5 exposure and removal of the ovaries each increase atherosclerosis progression in Apoe-/- females. Premature loss of ovarian function is associated with increased risk of osteoporosis, cardiovascular disease and Alzheimer’s disease in women. Our results thus support possible links between PM 2.5 exposure and other adverse health outcomes in women.

Introduction: We have recently shown (Alavi et al. Circulation, (2021)144: A13745-A13745) that adverse effects of nicotine delivered chronically by electronic cigarette (EC) vapor or standard cigarettes on left ventricular systolic function can be captured using intrinsic frequency (IF) method applied on carotid waveforms. Here, we propose a hybrid IF-machine learning (ML) method to detect nicotine effect on cardiovascular system using a carotid waveform. Methods: Total number of n=117 young healthy adult male and female Sprague Dawley rats (49% (n=57) female, weight ~200-250 g) were randomized and exposed to: 1) purified air, n=32; 2) EC vapor without nicotine (EC NIC-), n=26; 3) EC vapor plus nicotine (EC NIC+), n=27; and 4) standard cigarette smoke from reference combustion cigarettes (3R4F), n=32. All the exposures (nose-only) took place for duration of 5 hours/day, 4 days/week for total of 8 weeks. Third-generation type EC from VaporFi, tank model: Volt 2 was used. E-liquid was tobacco flavored with a 50/50 propylene glycol/glycerin ratio. Similar nicotine amount as the standard cigarette was delivered to the rats of EC NIC+ group. After 8 weeks of exposure, IFs were computed from invasively measured carotid waveforms. A support vector machine (SVM) classifier with radial basis function kernel was trained using IF data from 83 rats to detect (non)-nicotine groups. The k -fold cross-validation ( k =10) was used to avoid overfitting. The remaining rats were used for generalization test (n=14) and stratified blind test (n=20). Results: Our SVM model showed positive and negative predictive values of 66.7% and 76.9%, respectively. Sensitivity and specificity were 82.4% and 58.8% for test data (Fig1). Conclusions: Our results suggest that nicotine delivered by ECs or cigarettes can be detected by a physics-based ML model from a single carotid waveform. This method can potentially be used for detecting adverse effect of nicotine on cardiovascular system noninvasively.

Background:Electronic cigarettes (eC) may not be entirely benign. There is a lack of data on the effect of a single acute exposure of eC vapor using various heating sources and power settings upon lung injury. The purpose of this study was to determine if an acute exposure with eC vapor heated with different heating elements and power levels induced inflammatory changes in the lungs and heart. Methods:Rats were exposed to pure air or received a single, 4-h exposure to eC vapor. The devices used either a stainless steel (SS) or nichrome (NC) heating element randomized to a low or high atomization power (45 versus 70 W). Rats were euthanized within 48 h of exposure. Results:The eC groups showed accumulation of inflammatory cells in bronchial lumen, near the pleura, and within the alveolar spaces. The numbers of inflammatory cells per field in the lung parenchyma were significantly greater in the rats exposed to eC groups vs. the air group. There were significantly higher inflammatory gene expression changes in the lungs of animals assigned to 70 W power. We observed that eC vapor generated using burnt coils were toxic and could cause acute respiratory distress and myocarditis. Conclusion:In conclusion, one 4-h exposure to eC vapor, in the absence of vitamin E oil or nicotine, significantly increased lung inflammation. Effects were seen after exposures to vapor generated using SS and NC heating elements at either high or low power. Vapor from devices with burnt coils can negatively affect the heart and lung.

Despite advancements in the radiotherapeutic management of brain malignancies, resultant sequelae include persistent cognitive dysfunction in the majority of survivors. Defining the precise causes of normal tissue toxicity has proven challenging, but the use of preclinical rodent models has suggested that reductions in neurogenesis and microvascular integrity, impaired synaptic plasticity, increased inflammation, and alterations in neuronal structure are contributory if not causal. As such, strategies to reverse these persistent radiotherapy-induced neurological disorders represent an unmet medical need. AM251, a cannabinoid receptor 1 reverse agonist known to facilitate adult neurogenesis and synaptic plasticity, may help to ameliorate radiation-induced CNS impairments. To test this hypothesis, three treatment paradigms were used to evaluate the efficacy of AM251 to ameliorate radiation-induced learning and memory deficits along with disruptions in mood at 4 and 12 weeks postirradiation. Results demonstrated that acute (four weekly injections) and chronic (16 weekly injections) AM251 treatments (1 mg/kg) effectively alleviated cognitive and mood dysfunction in cranially irradiated mice. The beneficial effects of AM251 were exemplified by improved hippocampal- and cortical-dependent memory function on the novel object recognition and object in place tasks, while similar benefits on mood were shown by reductions in depressive- and anxiety-like behaviors on the forced swim test and elevated plus maze. The foregoing neurocognitive benefits were associated with significant increases in newly born (doublecortin+) neurons (1.7-fold), hippocampal neurogenesis (BrdU+/NeuN+mature neurons, 2.5-fold), and reduced expression of the inflammatory mediator HMGB (1.2-fold) in the hippocampus of irradiated mice. Collectively, these findings indicate that AM251 ameliorates the effects of clinically relevant cranial irradiation where overall neurological benefits in memory and mood coincided with increased hippocampal cell proliferation, neurogenesis, and reduced expression of proinflammatory markers.

Introduction: Cardiovascular intrinsic frequency (IF) is a systems approach for the analysis of left ventricle (LV) function, arterial dynamics, and LV-arterial coupling. It was shown in a recent Framingham Heart Study (Hypertension 2021, 77(2):338-346) that higher values of the first IF (ω 1 ) (derived from carotid pressure waveforms) are associated with higher risk for incident heart failure and composite CVD events. Here, we examined the effect of chronic exposure to E-cigarette and standard cigarette on ω 1 in rats. Methods: Adult male and female Sprague Dawley rats were exposed to: 1) Purified air ( n =6); 2) E-cigarette vapor without nicotine ( n =6); 3) E-cigarette vapor plus nicotine (similar amount of nicotine as the standard cigarette, n =6); and 4) Standard nicotine-containing cigarette smoke ( n =9). E-cigarette was a 3rd generation type E-cigarette from VaporFi, tank model: Volt 2. Rats were placed into a nose-only exposure system. The exposures took place for 5 hours/day, 4 days/week for a total of 8 weeks. The E-liquid was a 50/50 propylene glycol/glycerin mixture with a tobacco flavor additive. After 8 weeks of exposure, the rats were anesthetized to measure the hemodynamics including invasive carotid pressure waveforms. IF parameters were computed from pressure waveforms with similar cardiac cycles. Results: There was no difference in ω 1 between purified air and E-cigarette vapor without nicotine; there was no significant difference in ω 1 between E-cigarette vapor with nicotine versus standard nicotine-containing cigarette smoke. ω 1 was significantly higher (P<0.005) in the nicotine-containing groups versus the non-nicotine containing groups (Fig.1). Conclusions: Our results suggest that nicotine delivered either by standard cigarette smoke or E-cigarette vapor adversely affects the LV systolic function, and ω 1 measured from the carotid waveform alone (that can be measured non-invasively with an iPhone app), can capture these negative effects.

We determined the effects of chronic exposure to e‐cigarette vapor (with and without nicotine) and standard cigarette smoke on the myocardial infarct size and the size of the no‐reflow zone (microvascular injury) following re‐ establishment of patency of the large epicardial coronary artery occlusion in the setting of acute myocardial infarction, compared to exposure to purified air.

Introduction: lectronic cigarette (eC) or Vaping induced Lung Injury (EVALI) was first described in the summer of 2019 in patients presenting with acute respiratory distress. Several factors contributing to EVALI are suspected, including use of oil carriers, and heating and power elements. This study examined whether a single acute exposure to eC smoke using two popular heating elements on high or low power levels would induce inflammatory gene expression and proteins, and changes in alveolar macrophage function. Hypothesis: We hypothesize that nichrome, but not stainless-steel atomizers and high power wattage used in the eC device contribute to the extent of changes in pulmonary inflammatory response and alveolar macrophage activity. Methods: Adult Sprague Dawley rats were exposed to clean air (n=8) or eC vapor (50% propylene glycol, 50% vegetable glycerin, tobacco flavoring, no nicotine, n=8) for a single four hour period using devices equipped with stainless steel (SS) or nichrome (NC) heating elements at 45 or 70 wattage power (5 exposure conditions per sex group). Rats were euthanized and bronchoalveolar lavage was performed to collect alveolar macrophages for ex-vivo cell studies. The remaining lung tissue was homogenized for inflammatory protein and gene expression analyses. Results: Significant changes were observed in animals assigned to 70 watts. Increases ranging from 1.5-fold to 2-fold change in expression of the inflammation related genes IL-6, TNF-α and CRP occurred in rats assigned to NC atomizers (p ≤ 0.05), predominantly in males. While the concentration of CRP protein was significantly increased in females, CRP gene expression was decreased at the time point examined. Other proteins were not significantly elevated. Significant (p ≤ 0.05) changes in phagocytic activity were only observed in males exposed to 70 watts NC vapor, which generated exaggerated superoxide production by 4-fold during ex-vivo incubation. Evidence of depressed phagocytic activity was observed in other exposure groups, although not statistically significant. Conclusions: These results demonstrate that a single 4-hr exposure to e-cigarettes can initiate increased gene expression of inflammatory markers IL-6, TNF-α and CRP and oxidative changes in the lung.

Electronic cigarettes (E-cigs) generate nicotine containing aerosols for inhalation and have emerged as a popular tobacco product among adolescents and young adults, yet little is known about their health effects due to their relatively recent introduction. Few studies have assessed the long-term effects of inhaling E-cigarette smoke or vapor. Here, we show that two months of E-cigarette exposure causes suppression of bone marrow hematopoietic stem and progenitor cells (HSPCs). Specifically, the common myeloid progenitors and granulocyte-macrophage progenitors were decreased in E-cig exposed animals compared to air exposed mice. Competitive reconstitution in bone marrow transplants was not affected by two months of E-cig exposure. When air and E-cig exposed mice were challenged with an inflammatory stimulus using lipopolysaccharide (LPS), competitive fitness between the two groups was not significantly different. However, mice transplanted with bone marrow from E-cigarette plus LPS exposed mice had elevated monocytes in their peripheral blood at five months post-transplant indicating a myeloid bias similar to responses of aged hematopoietic stem cells (HSC) to an acute inflammatory challenge. We also investigated whether E-cigarette exposure enhances the selective advantage of hematopoietic cells with myeloid malignancy associated mutations. E-cigarette exposure for one month slightly increased JAK2V617F mutant cells in peripheral blood but did not have an impact on TET2−/− cells. Altogether, our findings reveal that chronic E-cigarette exposure for two months alters the bone marrow HSPC populations but does not affect HSC reconstitution in primary transplants.