e-Cigarette Aerosol Reduces Left Ventricular Function in Adolescent Mice
2022; Lippincott Williams & Wilkins; Volume: 145; Issue: 11 Linguagem: Espanhol
10.1161/circulationaha.121.057613
ISSN1524-4539
AutoresEvan W. Neczypor, Ty Saldaña, Matthew J. Mears, David M. Aslaner, Yael-Natalie H. Escobar, Matthew W. Gorr, Loren E. Wold,
Tópico(s)Climate Change and Health Impacts
ResumoHomeCirculationVol. 145, No. 11e-Cigarette Aerosol Reduces Left Ventricular Function in Adolescent Mice Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBe-Cigarette Aerosol Reduces Left Ventricular Function in Adolescent Mice Evan W. Neczypor, BS, Ty A. Saldaña, BS, Matthew J. Mears, BS, David M. Aslaner, BS, Yael-Natalie H. Escobar, PhD, Matthew W. Gorr, PhD and Loren E. Wold, PhD Evan W. NeczyporEvan W. Neczypor https://orcid.org/0000-0002-2969-3758 Dorothy M. Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, College of Medicine and Wexner Medical Center, and College of Nursing, Ohio State University, Columbus. , Ty A. SaldañaTy A. Saldaña Dorothy M. Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, College of Medicine and Wexner Medical Center, and College of Nursing, Ohio State University, Columbus. , Matthew J. MearsMatthew J. Mears https://orcid.org/0000-0003-3833-5634 Dorothy M. Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, College of Medicine and Wexner Medical Center, and College of Nursing, Ohio State University, Columbus. , David M. AslanerDavid M. Aslaner https://orcid.org/0000-0001-9650-346X Dorothy M. Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, College of Medicine and Wexner Medical Center, and College of Nursing, Ohio State University, Columbus. , Yael-Natalie H. EscobarYael-Natalie H. Escobar Dorothy M. Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, College of Medicine and Wexner Medical Center, and College of Nursing, Ohio State University, Columbus. , Matthew W. GorrMatthew W. Gorr https://orcid.org/0000-0001-7561-6481 Dorothy M. Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, College of Medicine and Wexner Medical Center, and College of Nursing, Ohio State University, Columbus. and Loren E. WoldLoren E. Wold Correspondence to: Loren E. Wold, PhD, FAHA, FAPS, 603 Dorothy M. Davis Heart and Lung Research Institute, Colleges of Medicine and Nursing, Ohio State University, 473 W 12th Avenue, Columbus, OH 43210. Email E-mail Address: [email protected] https://orcid.org/0000-0001-8155-0204 Dorothy M. Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, College of Medicine and Wexner Medical Center, and College of Nursing, Ohio State University, Columbus. Originally published21 Feb 2022https://doi.org/10.1161/CIRCULATIONAHA.121.057613Circulation. 2022;145:868–870Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: February 21, 2022: Ahead of Print Electronic cigarette (EC) use (vaping) has grown at an alarming rate in recent years. Originally used as a cessation aid for combustible cigarette smoking, vaping has grown exponentially in popularity in adolescents and teenagers.1 Although there are clear pulmonary consequences of EC use,2 adolescent cardiac health has not been examined despite the well-documented impact of particulate matter (found in EC aerosol) on the heart.3 Therefore, the cardiovascular system may encounter significant detriment after EC exposure throughout the sensitive period of adolescence. To investigate this, we used a mouse model of adolescent EC exposure.All animal use was approved and conducted in accordance with institutional guidelines. FVB (mice susceptible to the Friend leukemia virus B) mice (3–5 weeks old) were exposed to EC aerosol (50:50 mixture of propylene glycol and vegetable glycerin) with nicotine (20.2 mg/mL) or vehicle alone at relevant levels (one 70-mL puff per minute for 4 h/d, 5 d/wk) or to high-efficiency particulate air–filtered air as control (FA) for 3 weeks or 3 months. EC aerosol was produced from a third-generation EC device attached to an exposure chamber (SCIREQ; Montreal, Canada). Data supporting the findings from this study are available from the corresponding author.Heart weight/tibia length ratio was not altered after 3 months of exposure in male or female mice (Figure [A]). Male mice displayed reduced fractional shortening and impaired diastolic function using echocardiography after exposure to EC aerosol with nicotine for 3 months but not in response to vehicle alone (Figure [B]). These changes were not found in mice exposed at adulthood (3 months old), adolescent female mice (Figure [B]), adolescent mice exposed to a "casual-use" timeframe (1 h/d, 3 d/wk), or adolescent mice exposed for only 3 weeks in duration. Systolic and diastolic blood pressure were unchanged as measured by tail cuff. On euthanization after 3 months of exposure, pressure-volume loop recordings of the left ventricle revealed that the male, adolescent EC, and EC with nicotine (EC[+Nic]) groups had reduced end-systolic elastance, and the EC(+Nic) group had reduced preload-recruitable stroke work compared with FA (Figure [C]), collectively indicating a reduced contractile capacity as a result of exposure. Pressure-volume loop analysis also revealed no change in Tau in the EC(+Nic) compared with FA, indicating the transmitral early to late ventricular filling peak velocity ratio alteration observed via echocardiography may not accurately depict the diastolic function of these mice (Figure [C]). Trichrome staining of cardiac tissue revealed increased perivascular fibrosis in the male adolescent vehicle group relative to control and the nicotine group, implicating a protective effect of nicotine (Figure [D]). Similarly, ELISA targeting type I collagen (Novus Biologicals; Centennial, CO) showed a slight, nonsignificant increase in the vehicle group (P=0.14 by ANOVA; Figure [D], bottom right). Reverse-transcription quantitative polymerase chain reaction demonstrated that adolescent EC exposure with nicotine increased cardiac COL1A1 and COL3A1 expression in males after 3 weeks of exposure, which was reversed by 3 months (Figure [E]). This inverted response may be a result of timing of exposure in mouse development, or a protective effect of nicotine after prolonged exposure. We performed RNA sequencing on the left ventricle of male mice (National Center for Biotechnology Information Gene Expression Omnibus accession no. GSE183614) and found that when comparing FA with EC(+Nic), expression of many genes was altered in adolescent mice (71) and few altered in adult mice (4) (Figure [F]). Further, gene ontology analyses revealed that the genes changes included those involved in the inflammatory response, stress response, fibroblast signaling, and endothelial cell signaling.Download figureDownload PowerPointFigure. Cardiac and systemic effects of adolescent e-cigarette aerosol exposure.Male and female mice were exposed to filtered air (FA), electronic cigarette aerosol without nicotine (EC), or with nicotine (EC[+Nic]). Data are expressed as mean±SEM. *P<0.05 by unpaired Student t test, or 1- or 2-way ANOVA with post hoc Tukey multiple comparison test. Statistical tests for reverse-transcription quantitative polymerase chain reaction data were conducted on change in cycle thresholds values. A, Heart weight/tibia length ratio of male and female mice (n=8–19) after 3 months of exposure. B, Echocardiographic analysis of the left ventricle of male (n=24–30) and female (n=14–22) mice after 3 months of exposure. Male EC(+Nic) mice had reduced fractional shortening (%FS) and reduced transmitral early (E) to late (A) ventricular filling peak velocity ratio (E/A ratio; *P<0.05 by ANOVA). C, Pressure-volume loops from male mice exposed for 3 months: slope of the end-systolic pressure-volume relationship curve is lowered in EC and EC(+Nic) mice as indicated by reduced Ees, preload recruitable stroke work is also reduced in EC(+Nic) mice compared to FA, and Tau is unchanged (*P<0.05 by ANOVA). D, Representative perivascular images from male mice exposed for 3 months. Sections were subject to Masson's trichrome staining and imaged using a bright-field light microscope at 60× magnification (top). Percent fibrosis was quantified as percent area of blue staining region averaged across at least 3 images per mouse (n=5) using ImageJ software (bottom left). ELISA targeting type I collagen in the left ventricle of male mice exposed for 3 months (n=5, *P<0.05, by ANOVA; bottom right). E, Gene expression of COL1A1 and COL3A1 in the left ventricle of male mice exposed for either 3 weeks (3wk, top) or 3 months (3mo, bottom; n=4, *P<0.05 by ANOVA). F, Volcano plots from deseq2 analysis of RNA sequencing of left ventricle from hearts of adolescent and adult male mice; each dot represents a gene. Blue or red color indicates the gene was downregulated or upregulated, respectively, with a cutoff value of 2-fold change and adjusted P<0.05. G, Concentration of biomarkers in the serum of mice exposed to FA, EC, and EC(+Nic; n=3–6) for 3 months collected by cardiac puncture within 24 hours of exposure (*P<0.05 by ANOVA). H, Concentration of nicotine and metabolites in serum of male (blue) and female (red) EC(+Nic) mice exposed for 3 months (n=10) collected by submandibular bleed within 4 hours of exposure (top; *P<0.05 by ANOVA). 3HC indicates 3-hydroxycotinine; CCL2, chemokine C-C motif chemokine ligand 2; cot, cotinine; Ees, end-systolic elastance; IL-18, interleukin 18; MIP-1β, macrophage inflammatory protein 1β; SCF, stem cell factor; and VEGF-A, vascular endothelial growth factor A.To examine systemic changes manifested by EC, serum was analyzed for biomarkers using immunoassay (Ampersand Biosciences; Saranac Lake, NY). Adolescent male mice exposed to EC aerosol had significantly elevated serum IL-18 (interleukin 18), CCL2 (chemokine C-C motif chemokine ligand 2), MIP-1β (macrophage inflammatory protein 1β), SCF (stem cell factor), and VEGF-A (vascular endothelial growth factor A) (Figure [G]). Although several of these alterations were nicotine-dependent, vehicle alone was sufficient to cause some alterations, including MIP-1β, SCF, and VEGF-A. Females exhibited a different serum biomarker profile, because only IFN-γ (interferon γ) was increased compared with FA and vehicle. Thus, EC promoted systemic inflammation, which may cause further downstream changes to organ systems including the heart.To investigate for sex-dependent differences, we examined nicotine metabolism using liquid chromatography-mass spectrometry. Although nicotine concentrations in the serum of male and female mice exposed to EC with nicotine were similar, concentrations of metabolites including cot (cotinine) and 3HC (3-hydroxycotinine) were significantly lower in female compared with male mice. Further, the 3HC/cot ratio, a measure of cytochrome P450 2A6 (Cyp2A5 in mice) activity, a critical enzyme in nicotine metabolism,4 was significantly and substantially increased in female mice compared with male mice (Figure [H]). Reverse-transcription quantitative polymerase chain reaction of liver tissue targeting CYP2A5 also showed increased expression in females compared with males, further supporting a more rapid nicotine metabolism in female mice (3-fold increase, P<0.05 by t test). Because reductions in cardiac function and body weight were only observed in male mice exposed to EC aerosol with nicotine, this finding could suggest that females exhibit some degree of protection against EC aerosol from enhanced nicotine metabolism.To our knowledge, this is the first study to evaluate cardiac function in adolescent mice exposed to EC aerosol. Our results heighten the concern for the dangers of EC use, specifically in youth, and call for further work detailing the mechanistic contributions to the observed cardiac dysfunction. Although EC aerosol alone appeared to have a more mild effect on cardiac function, a synergistic effect of nicotine and its metabolites with reactive by-products of combustion, such as various aldehydes,5 could account for the more pronounced consequences after nicotine exposure. Regardless, the novel results of this study demonstrate that EC aerosol exposure can reduce cardiac function in developing male mice.Article InformationAcknowledgmentsThe authors thank Drew Miller, Jacob Grimmer, and Michael Muffler for their assistance with mouse exposures and Drs Gang Chen and Philip Lazarus for their nicotine metabolite analysis.Sources of FundingThis work was supported by salary support for Dr Escobar (T32HL149637), the National Institutes of Health (R01 HL139348, R01 AG057046), and the American Heart Association (20YVNR35490079) to Dr Wold.Disclosures None.FootnotesFor Sources of Funding and Disclosures, see page 870.Circulation is available at www.ahajournals.org/journal/circCorrespondence to: Loren E. Wold, PhD, FAHA, FAPS, 603 Dorothy M. Davis Heart and Lung Research Institute, Colleges of Medicine and Nursing, Ohio State University, 473 W 12th Avenue, Columbus, OH 43210. Email loren.[email protected]eduReferences1. Miech R, Johnston L, O'Malley PM, Bachman JG, Patrick ME. Trends in adolescent vaping, 2017-2019.N Engl J Med. 2019; 381:1490–1491. doi: 10.1056/NEJMc1910739CrossrefMedlineGoogle Scholar2. Chun LF, Moazed F, Calfee CS, Matthay MA, Gotts JE. Pulmonary toxicity of e-cigarettes.Am J Physiol Lung Cell Mol Physiol. 2017; 313:L193–L206. doi: 10.1152/ajplung.00071.2017CrossrefMedlineGoogle Scholar3. Nelin TD, Joseph AM, Gorr MW, Wold LE. Direct and indirect effects of particulate matter on the cardiovascular system.Toxicol Lett. 2012; 208:293–299. doi: 10.1016/j.toxlet.2011.11.008CrossrefMedlineGoogle Scholar4. Tanner J-A, Novalen M, Jatlow P, Huestis MA, Murphy SE, Kaprio J, Kankaanpää A, Galanti L, Stefan C, George TP, et al.. Nicotine metabolite ratio (3-hydroxycotinine/cotinine) in plasma and urine by different analytical methods and laboratories: implications for clinical implementation.Cancer Epidemiol Biomarkers Prev. 2015; 24:1239–1246. doi: 10.1158/1055-9965.EPI-14-1381.CrossrefMedlineGoogle Scholar5. Lee YO, Morgan-Lopez AA, Nonnemaker JM, Pepper JK, Hensel EC, Robinson RJ. Latent class analysis of e-cigarette use sessions in their natural environments.Nicotine Tob Res. 2019; 21:1408–1413. doi: 10.1093/ntr/nty164CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Whitehead A, Fried N, Li Z, Neelamegam K, Pearson C, LaPenna K, Sharp T, Lefer D, Lazartigues E, Gardner J and Yue X (2022) Alpha7 nicotinic acetylcholine receptor mediates chronic nicotine inhalation-induced cardiopulmonary dysfunction, Clinical Science, 10.1042/CS20220083, 136:12, (973-987), Online publication date: 30-Jun-2022. March 15, 2022Vol 145, Issue 11Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.121.057613PMID: 35184570 Originally publishedFebruary 21, 2022 Keywordsvapingheart functione-cigaretteadolescentPDF download Advertisement SubjectsAnimal Models of Human DiseaseBasic Science ResearchCell Biology/Structural BiologyContractile FunctionPathophysiology
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