Asthma and carotid artery plaques

The article “Persistent asthma is associated with carotid plaque in MESA” by Tattersall et al, which was published in the December 2022 issue of the Journal of the American Heart Association, reports the results of a baseline data analysis of the Multi-ethnic Study of Atherosclerosis (MESA), which was designed to recruit participants of ethnically diverse backgrounds who were free of cardiovascular disease at baseline and monitored for progression.1Tattersall M.C. Dasiewicz A.S. McClelland R.L. Jarjour N.N. Korcarz C.E. Mitchell C.C. et al.Persistent asthma is associated with carotid plaque in MESA.J Am Heart Assoc. 2022; 11e026644Crossref PubMed Scopus (3) Google Scholar In this observational, cross-sectional analysis, Tattersall et al1Tattersall M.C. Dasiewicz A.S. McClelland R.L. Jarjour N.N. Korcarz C.E. Mitchell C.C. et al.Persistent asthma is associated with carotid plaque in MESA.J Am Heart Assoc. 2022; 11e026644Crossref PubMed Scopus (3) Google Scholar investigate the relationship between asthma “subtypes” (intermittent and persistent) and their association with serum inflammatory biomarkers (ie, IL-6 and C-reactive protein [CRP]) and ultrasound-detected carotid arterial plaques by using multivariable regression (Fig 1). This study is an important contribution to the literature on the possible relationship between 2 asthma subtypes and carotid arterial plaques because of its large sample size, adequate racial and ethnic representation, and important covariates. Importantly, the MESA study participants were allegedly free from atherosclerotic cardiovascular disease (ASCVD) as per eligibility criteria, thus raising the potential of using carotid ultrasonography for the early detection or primary prevention of ASCVD among patients with asthma. The results support the possibility of a shared inflammatory pathophysiology between asthma and carotid artery disease. However, important details need to be addressed before recommending paradigmatic conclusions of disease pathobiology. Asthma heterogeneity and nonspecific definitions of asthma subtypes make it difficult to identify the ideal patient with asthma who is likely to benefit from screening carotid ultrasounds. In this study, asthma subtype is dichotomized as persistent (ie, undergoing controller therapy) versus intermittent (ie, not undergoing controller therapy) based on the participant’s self-reporting. These definitions of the terms persistent and intermittent are not those used in asthma treatment guidelines. Additionally, both subtypes are subject to misclassification bias. Controller therapy is prescribed to participants whose disease ranges from mild to severe and, as acknowledged by Tattersall et al,1Tattersall M.C. Dasiewicz A.S. McClelland R.L. Jarjour N.N. Korcarz C.E. Mitchell C.C. et al.Persistent asthma is associated with carotid plaque in MESA.J Am Heart Assoc. 2022; 11e026644Crossref PubMed Scopus (3) Google Scholar is subject to variation in clinician prescription patterns and not underlying pathobiologic asthma severity. The results obtained by Tattersall et al1Tattersall M.C. Dasiewicz A.S. McClelland R.L. Jarjour N.N. Korcarz C.E. Mitchell C.C. et al.Persistent asthma is associated with carotid plaque in MESA.J Am Heart Assoc. 2022; 11e026644Crossref PubMed Scopus (3) Google Scholar would be better substantiated by clarifying whether, for example, a patient with persistent asthma who is receiving step 6 versus step 2 controller therapy (the National Heart, Lung, and Blood Institute’s National Asthma Education and Prevention Program) has worse carotid plaque scores. These data are evidently unavailable because MESA was not a study designed primarily to investigate asthma and therefore does not have the level of detail required to better substantiate the association between carotid plaques and asthma. Furthermore, health care access and other factors determine whether a patient is prescribed controller therapy, further confounding these results. Glucocorticoids are fundamental for controller therapy and may also be implicated in the genesis of atherosclerotic plaques.2Walker B.R. Glucocorticoids and cardiovascular disease.Eur J Endocrinol. 2007; 157: 545-559Crossref PubMed Scopus (403) Google Scholar But asthma treatments have changed since the MESA study was initiated, and there are likely fewer patients taking maintenance oral corticosteroids now than there were then, which may make their results less relevant today. Tattersall et al1Tattersall M.C. Dasiewicz A.S. McClelland R.L. Jarjour N.N. Korcarz C.E. Mitchell C.C. et al.Persistent asthma is associated with carotid plaque in MESA.J Am Heart Assoc. 2022; 11e026644Crossref PubMed Scopus (3) Google Scholar also found that participants with persistent asthma had the highest levels of IL-6 and CRP compared with those with intermittent or no asthma. They note that “the high-IL-6 asthma phenotype may be at higher risk for carotid plaques and future ASCVD events.” Indeed, type (T) 1 (T1) and T17 inflammation, but not T2, are associated with atherosclerotic disease.3Libby P. Lichtman A.H. Hansson G.K. Immune effector mechanisms implicated in atherosclerosis: from mice to humans.Immunity. 2013; 38: 1092-1104Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar,4Gao Q. Jiang Y. Ma T. Zhu F. Gao F. Zhang P. et al.A critical function of Th17 proinflammatory cells in the development of atherosclerotic plaque in mice.J Immunol. 2010; 185: 5820-5827Crossref PubMed Scopus (177) Google Scholar Both T1 and T17 inflammation are also associated with severe asthma subtypes.5Raundhal M. Morse C. Khare A. Oriss T.B. Milosevic J. Trudeau J. et al.High IFN-gamma and low SLPI mark severe asthma in mice and humans.J Clin Invest. 2015; 125: 3037-3050Crossref PubMed Scopus (241) Google Scholar,6Irvin C. Zafar I. Good J. Rollins D. Christianson C. Gorska M.M. et al.Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma.J Allergy Clin Immunol. 2014; 134 (e7): 1175-1186Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar Furthermore, IL-6 is necessary for T17 inflammation and is associated with an exacerbation-prone severe asthma phenotype.7Peters M.C. Mauger D. Ross K.R. Phillips B. Gaston B. Cardet J.C. et al.Evidence for exacerbation-prone asthma and predictive biomarkers of exacerbation frequency.Am J Respir Crit Care Med. 2020; 202: 973-982Crossref PubMed Scopus (81) Google Scholar This suggests that if a common pathophysiologic inflammatory mechanism underlies both asthma and carotid plaque formation, it will be relevant to some but not all patients with asthma. However, the mean difference in serum IL-6 levels between participants with persistent asthma and those without it is 0.37 pg/mL, which is below the upper limit of the normal reference range (3.16 pg/mL) used by Peters et al in the National Heart Lung and Blood Institute’s Severe Asthma Research Program-3 study and perhaps clinically insignificant.8Peters M.C. McGrath K.W. Hawkins G.A. Hastie A.T. Levy B.D. Israel E. et al.Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts.Lancet Respir Med. 2016; 4: 574-584Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar Furthermore, inclusion of both IL-6 and CRP in fully adjusted models in the study by Tattersall et al1Tattersall M.C. Dasiewicz A.S. McClelland R.L. Jarjour N.N. Korcarz C.E. Mitchell C.C. et al.Persistent asthma is associated with carotid plaque in MESA.J Am Heart Assoc. 2022; 11e026644Crossref PubMed Scopus (3) Google Scholar did not change the magnitude of the association between asthma subtypes and carotid plaque scores. This suggests that the association is likely mediated by factors other than IL-6 and CRP and that residual confounding may be at stake. One additional point that may support the association of IL-6 and CRP levels with carotid artery plaques is that rheumatologic diseases are also characterized by these elevations and patients with them have greater risk of ASCVD. This study identified the presence of carotid plaques in 50.5% of participants without asthma versus in 67% of participants with persistent asthma, respectively, in a population with a mean age 62 to 63 years. The difference in mean plaque scores between these groups (1.29 vs 2.08 on a scoring scale of 0-12) was relatively small and unlikely to result in an increase in the hazard of ASCVD.9Gepner A.D. Young R. Delaney J.A. Budoff M.J. Polak J.F. Blaha M.J. et al.Comparison of carotid plaque score and coronary artery calcium score for predicting cardiovascular disease events: the multi-ethnic study of atherosclerosis.J Am Heart Assoc. 2017; 6e005179Crossref PubMed Scopus (102) Google Scholar Therefore, that these data should be used to change current practice to identify which patients with asthma should undergo carotid ultrasound remains uncertain. However, this article1Tattersall M.C. Dasiewicz A.S. McClelland R.L. Jarjour N.N. Korcarz C.E. Mitchell C.C. et al.Persistent asthma is associated with carotid plaque in MESA.J Am Heart Assoc. 2022; 11e026644Crossref PubMed Scopus (3) Google Scholar should also be an impetus for continued efforts to characterize the patients at risk and to understand a potential shared pathobiology between asthma subsets and carotid artery disease. Some of the results obtained by Tattersall et al1Tattersall M.C. Dasiewicz A.S. McClelland R.L. Jarjour N.N. Korcarz C.E. Mitchell C.C. et al.Persistent asthma is associated with carotid plaque in MESA.J Am Heart Assoc. 2022; 11e026644Crossref PubMed Scopus (3) Google Scholar may also be related to the variable definitions used in the study. For example, smoking is a known risk factor for ASCVD and is the strongest predictor in terms of beta coefficients in fully adjusted models. Smoking is categorized as “never, former, or current.” Therefore, this study did not capture the risk exposure variation between heavy and light smokers. Additionally, the fully adjusted model of Tattersall et al1Tattersall M.C. Dasiewicz A.S. McClelland R.L. Jarjour N.N. Korcarz C.E. Mitchell C.C. et al.Persistent asthma is associated with carotid plaque in MESA.J Am Heart Assoc. 2022; 11e026644Crossref PubMed Scopus (3) Google Scholar included components or their proxies of the metabolic syndrome, which are all risk factors for carotid plaque formation. These include body mass index, total and high-density lipoprotein levels, cholesterol level, systolic blood pressure, statin use, hypertension medications, and diabetes. But insulin resistance, a feature of but distinct from diabetes mellitus, was not studied as one of the metabolic syndrome components that increases the risk of both asthma and ASCVD among obese patients.10Cardet J.C. Ash S. Kusa T. Camargo Jr., C.A. Israel E. Insulin resistance modifies the association between obesity and current asthma in adults.Eur Respir J. 2016; 48: 403-410Crossref PubMed Scopus (73) Google Scholar Exercise, sedentary lifestyle, diet, alcohol use, and drug use also may be important unmeasured confounders. Of the 6 recruitment centers for MESA, 4 are from major metropolitan centers; therefore, some associations may be related to exposures unique to city living. Having a small population with persistent asthma (n = 109) compared with the population with intermittent asthma (n = 388) and population of individuals without asthma s (n = 4532) is another limitation of the study by Tattersall et al. Important future directions include taking advantage of the racial and ethnic inclusiveness in MESA and conducting analyses stratified by these entities. As noted in the supplement to the article by Tattersall et al,1Tattersall M.C. Dasiewicz A.S. McClelland R.L. Jarjour N.N. Korcarz C.E. Mitchell C.C. et al.Persistent asthma is associated with carotid plaque in MESA.J Am Heart Assoc. 2022; 11e026644Crossref PubMed Scopus (3) Google Scholar age and sex remain important covariates also calling for stratified analyses for these characteristics. As this was an observational, cross-sectional study, causation cannot be determined, and therefore, longitudinal associations are needed to address temporality. Asthma is a chronic disease with associated comorbidities. Tattersall et al1Tattersall M.C. Dasiewicz A.S. McClelland R.L. Jarjour N.N. Korcarz C.E. Mitchell C.C. et al.Persistent asthma is associated with carotid plaque in MESA.J Am Heart Assoc. 2022; 11e026644Crossref PubMed Scopus (3) Google Scholar have identified carotid plaques as another possible comorbid condition of asthma. Optimal patient care requires identifying coexisting problems that can influence asthma and other important health outcomes through a detailed history and physical examination, carefully ordering appropriate tests, educating the patient, and following the patient longitudinally. Encouraging people living with asthma to modify their behaviors and improve control of comorbid conditions known to increase cardiovascular risk should be an important part of any treatment plan.