Advertisement

Systemic vascular health is compromised in both confirmed and unconfirmed asthma

Open AccessPublished:July 14, 2022DOI:https://doi.org/10.1016/j.rmed.2022.106932

      Highlights

      • People with asthma are at increased risk of developing cardiovascular disease.
      • It has been unknown if this risk extends to non-physiologically confirmed asthma.
      • However, markers of cardiovascular risk are present among all with asthma symptoms.
      • Inappropriate medication use may add to the cardiovascular risk in asthma.

      Abstract

      Introduction

      Asthma is associated with increased risk of cardiovascular diseases. Despite many presenting with symptoms of asthma, asthma cannot always be confirmed by physiological assessment. It is thus far unknown if the heightened cardiovascular risk applies to this group. The purpose of this study was to examine markers of cardiovascular risk, including endothelial function, arterial stiffness, and systemic inflammation, in individuals with confirmed asthma, unconfirmed asthma, and healthy controls. As short-acting beta agonist (SABA) use is associated with increased cardiovascular risk, a secondary analysis was conducted to investigate the impact of regular SABA use on vascular outcomes.

      Methods

      Individuals with confirmed asthma (n = 26), unconfirmed asthma (n = 15), and healthy controls (n = 26) were recruited for this cross-sectional study. Asthma was confirmed by FEV1 reversibility, methacholine challenge, or exercise challenge. Endothelial function was assessed using flow-mediated dilation (FMD), arterial stiffness using pulse wave velocity (PWV), and systemic inflammation by C-reactive protein (CRP) levels.

      Results

      FMD was significantly lower in both asthma groups compared to controls (confirmed: 7.7 ± 3.6%, unconfirmed: 7.3 ± 3.5%, controls: 10.4 ± 3.6%, p = 0.02). No difference was found in PWV nor CRP. Asthma participants who used SABA had increased arterial stiffness compared to those without SABA (9.2 ± 2.7 m/s, 7.7 ± 1.1 m/s respectively, p = 0.03). No difference was seen in FMD or CRP between SABA groups.

      Conclusion

      Individuals with a clinical history of asthma symptoms demonstrate vascular impairments regardless of physiological confirmation of disease. Regular SABA use increases arterial stiffness. Avoiding potentially inappropriate SABA use among people without physiologically confirmed asthma may thus be beneficial in curbing cardiovascular risk.

      Keywords

      Abbreviations:

      ACQ (Asthma control questionnaire)

      Abbreviations

      CRP
      C-reactive protein
      FEV1
      Forced expiratory volume in 1 s
      FMD
      Flow-mediated dilation
      PWV
      Pulse wave velocity
      SABA
      Short-acting beta-agonists

      1. Introduction

      Asthma is a chronic disease of the airways characterized by episodes of bronchoconstriction and airway hyper-responsiveness leading to recurrent symptoms of wheezing, tightness of chest, and shortness of breath [
      • Global Initiative for Asthma
      Global Strategy for Asthma Management and Prevention.
      ]. While typically thought of as a disease that primarily affects the pulmonary system, there are considerable cardiovascular consequences associated with asthma including an increased risk of coronary heart disease, cerebrovascular disease, and heart failure [
      • Xu M.
      • Xu J.
      • Yang X.
      Asthma and risk of cardiovascular disease or all-cause mortality: a meta-analysis.
      ]. While numerous large population-based studies investigating the link between asthma and cardiovascular disease have made efforts to untangle the underlying causes [
      • Appleton S.L.
      • et al.
      Asthma is associated with cardiovascular disease in a representative population sample.
      ,
      • Iribarren C.
      • et al.
      Adult asthma and risk of coronary heart disease, cerebrovascular disease, and heart failure: a prospective study of 2 matched cohorts.
      ], the reason for the increased risk of cardiovascular disease in asthma is still largely unknown.
      Despite guidelines recommending that physiological testing should be done before a diagnosis of asthma is made among people presenting with clinical symptoms compatible with asthma [
      • Bateman E.D.
      • et al.
      Global strategy for asthma management and prevention: GINA executive summary.
      ], the diagnosis of asthma is often made based on clinical symptoms alone [
      • LindenSmith J.
      • et al.
      Overdiagnosis of asthma in the community.
      ]. Importantly, most studies reporting on cardiovascular risk in asthma are based on administrative health data that uses a case-finding algorithm to identify patients with asthma based on medical visits and claims. While these studies have great generalizability, they often lack clinical detail on physiological testing confirming airway reversibility on spirometry, airway hyperresponsiveness, or exercise-induced bronchoconstriction seen in accordance with asthma. Until now, it has been unknown if the increased cardiovascular disease risk applies to anyone with a clinical history of asthma symptoms or if the risk is further heightened among those with confirmed asthma pathology.
      Whilst asthma is commonly over- or misdiagnosed [
      • Heffler E.
      • et al.
      Prevalence of over-/misdiagnosis of asthma in patients referred to an allergy clinic.
      ], a large proportion of patients are being treated for asthma despite not having asthma according to objective physiological evaluation [
      • Global Initiative for Asthma
      Global Strategy for Asthma Management and Prevention.
      ,
      • Heffler E.
      • et al.
      Prevalence of over-/misdiagnosis of asthma in patients referred to an allergy clinic.
      ]. Bronchodilators containing short-acting beta agonist (SABA) are frequently prescribed as a first line of treatment among people with clinical symptoms of asthma, even among people without a confirmed diagnosis [
      • Heffler E.
      • et al.
      Prevalence of over-/misdiagnosis of asthma in patients referred to an allergy clinic.
      ]. Acute SABA use has been linked to impaired cardiovascular health [
      • Edgell H.
      • et al.
      Short-term cardiovascular and autonomic effects of inhaled salbutamol.
      ,
      • Moore L.E.
      • et al.
      Acute effects of salbutamol on systemic vascular function in people with asthma.
      ,
      • Cekici L.
      • et al.
      Short-term effects of inhaled salbutamol on autonomic cardiovascular control in healthy subjects: a placebo-controlled study.
      ] and when used chronically, has been associated with increased cardiovascular disease and all-cause mortality [
      • Appleton S.L.
      • et al.
      Asthma is associated with cardiovascular disease in a representative population sample.
      ,
      • Appleton S.L.
      • et al.
      Cardiovascular disease risk associated with asthma and respiratory morbidity might be mediated by short-acting beta2-agonists.
      ]. As such, it is possible that chronic SABA use, potentially prescribed without proper indication, may alter vascular structure and function, leading to increased cardiovascular risk regardless of asthma status. Conversely, other studies have reported associations between respiratory symptoms, beyond what is seen in asthma, and increased cardiovascular risk [
      • Frostad A.
      • et al.
      Respiratory symptoms and long-term cardiovascular mortality.
      ,
      • Jousilahti P.
      • et al.
      Symptoms of chronic bronchitis and the risk of coronary disease.
      ], suggesting respiratory symptomatology alone may be indicative of cardiovascular risk, independent of asthma pathology.
      To further explore the reasons for the heightened cardiovascular risk in asthma and to examine whether the increased cardiovascular risk applies to anyone with asthma-like symptoms, the main purpose of this study was to compare subclinical physiological markers of cardiovascular disease risk, including endothelial function [
      • Brunner H.
      • et al.
      Endothelial function and dysfunction. Part II: association with cardiovascular risk factors and diseases. A statement by the working group on endothelins and endothelial factors of the European society of hypertension.
      ,
      • Green D.J.
      • et al.
      Flow-mediated dilation and cardiovascular event prediction: does nitric oxide matter?.
      ], arterial stiffness [
      • Laurent S.
      • et al.
      Expert consensus document on arterial stiffness: methodological issues and clinical applications.
      ], and systemic inflammation [
      • Pearson T.A.
      • et al.
      Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association.
      ], in individuals with unconfirmed asthma to those with confirmed asthma and to healthy controls. As a secondary aim, the impact of regular SABA usage on the same markers of cardiovascular risk were assessed.

      2. Methods

      2.1 Ethics, consent, and permissions

      This study was approved by the University of Alberta Health Research Ethics Boards (Pro00083372, Pro00047054). All participants provided written informed consent prior to participating in the study.

      2.2 Participants

      Participants with self-reported or physician-diagnosed asthma were recruited from the general population and community pulmonary clinics from the Edmonton metropolitan area. Healthy controls matched for age, sex, and body mass index were recruited from the general population. All participants were between 18 and 45 years old and current non-smokers with less than a 10 pack-years smoking history. People with known cardiovascular disease, pulmonary disease other than asthma, or current pregnancy were excluded from the study.
      All participants completed a full pulmonary function test followed by complete evaluation for asthma according to current guidelines at the time of the study [
      • Bateman E.D.
      • et al.
      Global strategy for asthma management and prevention: GINA executive summary.
      ]. Briefly, physiological confirmation of asthma was based on clinical history of asthma symptoms, including recurrent episodes of wheezing, cough, and/or chest tightness, and at least one of the following: reversibility in forced expiratory volume in 1 s (FEV1) of ≥12% and 200 mL; ≥20% reduction in FEV1 following a methacholine challenge; or ≥10% reduction in FEV1 following an exercise challenge [
      American thoracic, S. And P. American college of chest, ATS/ACCP statement on cardiopulmonary exercise testing.
      ]. Individuals with a clinical history of asthma symptoms and physiological evidence of asthma were labelled as confirmed asthma. Individuals with a clinical history of asthma symptoms but no physiological evidence of asthma, as outlined above, were labelled unconfirmed asthma. Individuals who did not report asthma symptoms and showed no evidence of reversibility or airway hyperreactive to methacholine or exercise were categorized as healthy controls.

      2.3 Study design

      This cross-sectional study compared endothelial function, arterial stiffness, and systemic inflammation between individuals with a) a diagnosis of asthma confirmed by physiological testing, b) those with an asthma diagnosis that could not be confirmed by physiological testing, and c) healthy controls without asthma.
      Participants completed two to four days of testing determined by the research team according to the required physiological assessments. Vascular assessments and pulmonary function testing were performed on Day 1. On Day 2 (optional) the participant conducted a cardiopulmonary exercise test (CPET) to evaluate cardiopulmonary fitness and screen for unknown cardiovascular morbidity. On day 3 a methacholine inhalation challenge was conducted, and on Day 4 an exercise challenge was performed. If the result from the reversibility test was negative, participants with a clinical history of asthma symptoms were asked to do the methacholine inhalation challenge (Day 3) and/or the exercise challenge (Day 4). Controls performed all challenge tests and had to demonstrate a negative result on each test. Prior to each study visit, participants were asked to withhold SABA, food, caffeine, alcohol, and exercise for at least 12 h, as well as long-acting controller medications including corticosteroids for at least 48 h prior to each test day, as applicable. Additionally, participants were asked to refrain from acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs for three days prior to testing when possible. To reduce circadian variances, all vascular measurements were conducted at the same time of the day in the morning, when possible. All study visits were separated by a minimum of 7 days.
      On Day 1, all participants signed informed consent and had their medical history, including SABA use in the last year (yes/no) and allergies (any), reviewed together with a researcher. All participants with any history of asthma symptoms completed the Asthma Control Questionnaire (ACQ) [
      • Juniper E.F.
      • et al.
      Identifying 'well-controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire.
      ] to assess symptom control.
      Following 10 min of rest in the supine position in a dark, quiet, temperature-controlled room, blood pressure was measured using an automatic blood pressure monitor (BpTRU Medical Devices, Coquitlam, BC) and vascular measurements were obtained. A venous blood sample was taken, followed by a full pulmonary function test (Vmax, CareFusion, Yorba Linda, CA, USA), including spirometry before and after the administration of 400 μg of salbutamol.
      Individuals with an asthma diagnosis that could not be confirmed by a significant improvement in FEV1 [
      • Bateman E.D.
      • et al.
      Global strategy for asthma management and prevention: GINA executive summary.
      ] following salbutamol administration were scheduled for a follow-up exercise challenge (Day 3) and/or methacholine challenge (Day 4). Standardized protocols were followed for these challenges [
      American thoracic, S. And P. American college of chest, ATS/ACCP statement on cardiopulmonary exercise testing.
      ]. Reduced physical fitness and activity are associated with increased cardiovascular risk [
      • Kodama S.
      • et al.
      Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis.
      ,
      • Ross R.
      • et al.
      Importance of assessing cardiorespiratory fitness in clinical practice: a case for fitness as a clinical vital sign: a scientific statement from the American heart association.
      ,
      • Sui X.
      • LaMonte M.J.
      • Blair S.N.
      Cardiorespiratory fitness as a predictor of nonfatal cardiovascular events in asymptomatic women and men.
      ]. As such, peak oxygen consumption (VO2peak) was assessed via CPET in a subset of participants using a progressive incremental protocol (Day 2, optional) [
      American thoracic, S. And P. American college of chest, ATS/ACCP statement on cardiopulmonary exercise testing.
      ]. Physical activity was evaluated in a subset of participants by 5-day average step count using a Fitbit (Fitbit Inc., San Francisco, CA, USA) activity monitor.

      2.4 Measurements

      2.4.1 Endothelial function

      Brachial endothelial function was assessed as flow-mediated dilation following 5 min of supra-systolic forearm occlusion distal to the imaging site using Doppler ultrasonography (8L-RS 4.0–13.0 MHz probe, Vivid q, GE Healthcare, Mississauga, ON) [
      • Harris R.A.
      • et al.
      Ultrasound assessment of flow-mediated dilation.
      ,
      • Thijssen D.H.J.
      • et al.
      Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans.
      ]. Baseline brachial diameter and flow data were obtained over 1 min prior to occlusion. Following release of the 5-min occlusion, brachial diameter and flow were assessed for 3.5 min to evaluate changes. Diameter change from baseline was analysed in 8 s averages using Carotid Analyzer (Medical Imaging Applications, LLC, Coralville, IA, USA). Brachial artery blood velocity was averaged in two 8-s time increments for every 16 s sweep, using EchoPAC PC software (version 110.x.x, GE Healthcare, Horten, Norway), and was used to calculate flow (Flow =blood velocityπr ∗60). Shear stress following reactive hyperemia was calculated as SSRH = 8 x flow/diameter. Flow mediated dilation (FMD) was calculated as %FMD = [(max diameterbaseline diameter)/baseline diameter] x100 and was statistically adjusted by AUC SSRH (area under the curve i.e. sum of all SSRH post release values up to and including the peak diameter) [
      • Harris R.A.
      • et al.
      Ultrasound assessment of flow-mediated dilation.
      ,
      • Thijssen D.H.J.
      • et al.
      Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans.
      ]. A 1% decrease in FMD corresponds to a 7% increase in cardiovascular risk [
      • Green D.J.
      • et al.
      Flow-mediated dilation and cardiovascular event prediction: does nitric oxide matter?.
      ].

      2.4.2 Arterial stiffness

      Arterial stiffness [
      • Laurent S.
      • et al.
      Expert consensus document on arterial stiffness: methodological issues and clinical applications.
      ] was assessed as the pulse wave velocity (PWV) using applanation tonometry (Complior, Alam Medical, Saint Quentin Fallavier, France) between the carotid and radial artery. Briefly, PWV was calculated as the distance between the measuring sites (Δd) divided by the average time between of the arrival of the pulse at the measuring sites (Δt) over 10 consecutive beats (PWV = Δd/Δt). A 1 m/s increase in PWV corresponds to an approximate 16% increase in cardiovascular risk [
      • Vlachopoulos C.
      • Aznaouridis K.
      • Stefanadis C.
      Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis.
      ].

      2.4.3 Systemic inflammation

      Systemic inflammation was assessed as level of C-reactive protein in serum. Venous blood was collected by a certified phlebotomist following vascular assessments using standardized and sterile procedures [
      • World Health Organisation international
      Guidelines on Drawing Blood: Best Practices in Phlebotomy.
      ]. Whole blood underwent serum preparation and was stored in a −80C freezer until time of analysis. Analysis of serum was done at the University of Alberta using an enzyme linked immunosorbent assay (ELISA) protocol [
      • Faul F.
      • et al.
      G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences.
      ]. High sensitivity human CRP (Catalog # DY1707, R&D Systems, Inc.) ELISA kits were used as per manufacturers' protocols []. Levels of CRP levels have previously been associated with cardiovascular risk in people with and without known underlying cardiovascular morbidity [
      • Koosha P.
      • et al.
      High sensitivity C-reactive protein predictive value for cardiovascular disease: a nested case control from isfahan cohort study (ICS).
      ,
      • Ridker P.M.
      • Glynn R.J.
      • Hennekens C.H.
      C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction.
      ].

      2.5 Statistical analysis

      Descriptive characteristics were summarized as means and 95% confidence interval (95% Cl) or counts and percentages (%) and compared across groups using one-way analysis of variance (ANOVA) or chi-square test for continuous and categorical variables, respectively. Vascular health, including endothelial function, arterial stiffness, and systemic inflammation, were assessed across groups using a one-way ANOVA, followed by Bonferroni-corrected multiple comparisons when a main effect was present. Participants currently using SABA >1x per month over the past 12 months were classified as regular SABA users, and those with <1x per month were classified as non-SABA users. Unpaired Student's t-tests for continuous variables and the chi-square test for categorical variables were used to conduct comparisons in baseline characteristics and vascular outcomes and between SABA users and non-SABA users, regardless of asthma confirmation.
      Previous work has demonstrated an impairment in endothelial function in people with varying severity of asthma [
      • Yildiz P.
      • et al.
      Endothelial dysfunction in patients with asthma: the role of polymorphisms of ACE and endothelial NOS genes.
      ], therefore we utilized these data to complete an a priori power calculation (G* Power) [
      • Faul F.
      • et al.
      G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences.
      ] to determine sufficient sample size for this study. Based on the calculated large effect size (1.03), a minimum of fifteen participants in each group would reach eighty percent power (α = 0.05, β = 0.20) to detect between-group differences in flow-mediated dilation.
      Statistical analysis was completed using the Statistical Package for Social Sciences (SPSS) for Windows version 26.0 (SPSS Inc., Chicago, IL). For all inferential analyses, statistical significance was considered as p < 0.05.

      3. Results

      A total of 67 participants were recruited and included in the study. Of these, 26 were healthy controls, 15 with unconfirmed asthma, and 26 with confirmed asthma. As outlined in Table 1, there were no differences in age or body mass index between the groups. Although no statistically significant difference was seen, the proportion of male vs. females appeared to be disturbed in favour of females in the unconfirmed asthma group, but it was evenly split in the confirmed asthma and control-groups. People with confirmed asthma had lower FEV1 (84 ± 14 vs 99 ± 11 and 101 ± 9 %predicted, respectively, p < 0.05) and higher reversibility in FEV1 following bronchodilator (11 ± 9 vs 3 ± 5 and 5 ± 3%, respectively, p < 0.05) than both healthy controls and unconfirmed asthma. There were more people with self-reported allergies in the asthma groups, regardless of confirmation, than among healthy controls (73% in each asthma group vs 19% in healthy controls, p < 0.05). People with confirmed asthma had a ACQ score indicative of less controlled asthma compared to unconfirmed asthma (0.8 ± 0.7 vs 0.4 ± 0.5, p < 0.05). There were no statistically differences in smoking history, cardiopulmonary fitness, or physical activity levels between groups. Regular SABA usage was reported in roughly half of all people in each asthma group (47% and 46% for unconfirmed and confirmed asthma, respectively, p = 0.98). Approximately 67% of those with unconfirmed asthma were prescribed two or more asthma medications compared to 46% of those with confirmed asthma (p = 0.61 [Table 1],).
      Table 1Participant characteristics.
      Healthy controls n = 26Unconfirmed asthma n = 15Confirmed asthma n = 26p
      Sex, Male/female, count13/133/1213/130.12
      Age, years24 ± 327 ± 726 ± 60.33
      Height m1.7 ± 0.11.7 ± 0.11.7 ± 0.10.51
      Weight kg68.6 ± 13.769.5 ± 17.575.4 ± 22.60.37
      BMI kg/m223.7 ± 3.824.2 ± 3.925.1 ± 5.00.50
      FEV1 pre -bronchodilator, % predicted99 ± 11101 ± 984 ± 14*¥0.00
      FEV1 reversibility, %3 ± 55 ± 311 ± 9*¥0.00
      Smoking history, pack years0.0 ± 0.10.3 ± 1.00.5 ± 1.80.37
      Allergies, %1973*73*0.00
      ACQ, score0.4 ± 0.50.8 ± 0.7¥0.02
      VO2 peak, mL/min/kg45.3 ± 9.037.7 ± 6.241.3 ± 10.20.09
      Physical Activity, steps/day8358 ± 64777566 ± 35566442 ± 31400.71
      SABA usage1, %47460.98
      ≥2 medications for asthma prescribed2, %67460.61
      BMI = body mass index; FEV1 = forced expiratory volume in 1 s; ACQ = asthma control questionnaire; VO2 peak = peak oxygen consumption; SABA = short-acting beta-agonist.1Regular use in the past year. 2Including SABA and controller medications. Data are presented as mean ± standard deviations or percentage of participants. *p < 0.05 compared to healthy control group. ¥ p < 0.05 compared to unconfirmed asthma group.
      Compared to healthy controls, endothelial function was significantly lower among both people with unconfirmed and confirmed asthma (FMD: 10.4 ± 3.6 vs 7.3 ± 3.5 and 7.7 ± 3.6, respectively, p < 0.05 [Fig. 1]) but there was no difference between unconfirmed and confirmed asthma. Neither arterial stiffness (PWV: 7.9 ± 1.8 vs 8.5 ± 1.0 vs 8.2 ± 2.5 m/s for healthy controls, unconfirmed asthma, and confirmed asthma, respectively, p = 0.58) nor systemic inflammation (CRP: 4.38 ± 7.03 vs 6.66 ± 7.46 vs 4.09 ± 6.35 for healthy controls, unconfirmed asthma, and confirmed asthma, respectively, p = 0.53) were different between groups (Fig. 1). Data on PWV were unavailable in five participants and CRP was unavailable in eight participants. As outlined in Table 2, no differences were found in other baseline vascular parameters, including heart rate, blood pressure, and brachial parameters, evaluated together with the main vascular outcomes.
      Fig. 1
      Fig. 1Vascular outcomes compared between healthy controls, unconfirmed asthma, and confirmed asthma. FMD: Flow-mediated dilation; PWV: pulse wave velocity; CPR: C-reactive protein. *p < 0.05 compared to healthy controls.
      Table 2Vascular characteristics.
      Healthy controls n = 26Unconfirmed asthma n = 15<Confirmed asthma n = 26p
      Baseline diameter, mm3.7 ± 0.63.5 ± 0.53.6 ± 0.60.65
      Baseline flow, ml/min79.2 ± 54.560.8 ± 33.868.8 ± 42.20.45
      Baseline SSRH163.3 ± 85.9134.3 ± 60.2143.6 ± 67.60.43
      AUC SSRH3788 ± 13773314 ± 14053574 ± 15640.60
      Baseline HR, beats/min57 ± 1064 ± 1260 ± 90.08
      Systolic BP, mmHg105 ± 9108 ± 9106 ± 90.73
      Diastolic BP, mmHg67 ± 871 ± 766 ± 60.12
      SSRH = shear stress reactive hyperemia; AUC SSRH = area under the curve shear stress reactive hyperemia; HR = heart rate; BP = blood pressure. Data are presented as mean ± standard deviations.
      Table 3 provides data on selected baseline characteristics for the sub-analysis investigating vascular differences among people with asthma (both unconfirmed and confirmed) grouped based on no SABA (n = 22) vs SABA (n = 19) use in the last year. The groups were well matched for age, sex, and FEV1, and resting blood pressure was similar between groups. A higher proportion of those who had been using SABA in the last year had self-reported allergies (95 vs 55%, p < 0.05) and less controlled asthma (ACQ score: 1.0 ± 0.7 vs 0.4 ± 0.5, p < 0.05) compared to those with no SABA. Furthermore, while there were no statistical difference in endothelial function (FMD: 7.8 ± 2.8 vs 7.3 ± 2.6%, p = 0.53) or systemic inflammation (CRP: 4.69 ± 6.48 vs 5.40 ± 7.33 mg/L, p = 0.76) between no SABA and SABA users, people who had been using SABA regularly had higher arterial stiffness by on average 1.5 m/s compared to those with no SABA (9.2 ± 2.7 vs 7.7 ± 1.1 m/s, p < 0.05) (Fig. 2).
      Table 3Selected characteristics of participants with asthma (unconfirmed and confirmed) grouped according to SABA use in the previous year.
      No SABA n = 22SABA n = 19p
      Age, years25 ± 727 ± 50.27
      Sex, Male/female9/137/120.79
      BMI, kg/m224.9 ± 5.524.7 ± 3.40.89
      FEV1 pre, % predicted92 ± 1288 ± 180.27
      Allergies, %5595*0.00
      ACQ, score0.4 ± 0.51.0 ± 0.7*0.01
      Systolic BP, mmHg107 ± 10106 ± 80.78
      Diastolic BP, mmHg69 ± 667 ± 70.56
      BMI = body mass index; FEV1 = forced expiratory volume in 1 s; ACQ = asthma control questionnaire; BP = blood pressure. Data are presented as mean ± standard deviations or percentage of participants. *p < 0.05 between groups.
      Fig. 2
      Fig. 2Vascular outcomes among people with asthma (confirmed or unconfirmed) grouped based on short-acting beta-agonist (SABA) usage within the last year. FMD: Flow-mediated dilation; PWV: pulse wave velocity; CPR: C-reactive protein. *p < 0.05 between groups.

      4. Discussion

      This study found that people with a clinical history of asthma symptoms, regardless of whether the diagnosis of asthma could be objectively confirmed based on physiological testing at the time of the study, had impaired endothelial function compared to healthy controls. Furthermore, people with a clinical history of asthma symptoms who used SABA medications regularly in the previous year were found to have an increased arterial stiffness, well within the range of clinical importance, compared to those with no SABA use. These results suggest that cardiovascular risk is increased among people with symptoms of asthma regardless of physiological confirmation, and that this may be partly due to the impact of regular SABA use on the systemic vasculature.
      Asthma has been linked to increased risk of cardiovascular disease in numerous large population-level studies [
      • Xu M.
      • Xu J.
      • Yang X.
      Asthma and risk of cardiovascular disease or all-cause mortality: a meta-analysis.
      ,
      • Appleton S.L.
      • et al.
      Asthma is associated with cardiovascular disease in a representative population sample.
      ,
      • Iribarren C.
      • et al.
      Adult asthma and risk of coronary heart disease, cerebrovascular disease, and heart failure: a prospective study of 2 matched cohorts.
      ] and despite efforts to identify the underlying causes, the reason for the increased risk of cardiovascular disease in asthma is still largely unknown. Previous studies have used case-finding algorithms based on medical visits and claims for asthma in administrative health data rather than objective physiological testing that reported increased risk of cardiovascular disease. In accordance with these studies, we found that those with a clinical history of asthma symptoms had approximately 3% worse endothelial function compared to healthy controls, corresponding to an estimated 21% increase in cardiovascular risk [
      • Green D.J.
      • et al.
      Flow-mediated dilation and cardiovascular event prediction: does nitric oxide matter?.
      ].
      In the current study, no differences in vascular outcomes between asthmatics with physiologically confirmed vs unconfirmed asthma were found, suggesting that the association between asthma and cardiovascular disease risk may be inherent to asthma symptomatology rather than its pathophysiology. However, participants with confirmed asthma reported greater asthma symptoms, had lower baseline FEV1 and greater post-bronchodilator reversibility compared to unconfirmed asthma participants. Previous studies have indicated there may be a direct link between respiratory morbidity and cardiovascular risk [
      • Frostad A.
      • et al.
      Respiratory symptoms and long-term cardiovascular mortality.
      ,
      • Jousilahti P.
      • et al.
      Symptoms of chronic bronchitis and the risk of coronary disease.
      ], and reduced endothelial function, elevated arterial stiffness, and systemic inflammation has been associated with worse asthma disease severity and declining control [
      • Yildiz P.
      • et al.
      Endothelial dysfunction in patients with asthma: the role of polymorphisms of ACE and endothelial NOS genes.
      ,
      • Sun W.X.
      • et al.
      Increased arterial stiffness in stable and severe asthma.
      ,
      • Zietkowski Z.
      • et al.
      High-sensitivity C-reactive protein in the exhaled breath condensate and serum in stable and unstable asthma.
      ]. Conversely, the lack of differences between unconfirmed and confirmed asthma in our study would indicate that the impaired endothelial function is unlikely due to common causes of respiratory symptoms, reduced lung function, or airway reversibility alone, but rather suggests that other important contributing factors may be present.
      It has been suggested that low physical activity and fitness levels commonly observed in people with asthma [
      • Ford E.S.
      • et al.
      Leisure-time physical activity patterns among US adults with asthma.
      ,
      • Teramoto M.
      • Moonie S.
      Physical activity participation among adult Nevadans with self-reported asthma.
      ] could be the source of impaired endothelial function [
      • Moore L.E.
      • et al.
      Physical activity, fitness, and vascular health in patients with asthma.
      ,
      • Williams P.T.
      Physical fitness and activity as separate heart disease risk factors: a meta-analysis.
      ]. However, VO2peak was similar across the three groups. Further, average daily step count was very similar between groups. These data suggest that fitness or physical activity is unlikely to be the primary driver of the observed reduction in FMD in people with asthma compared to controls.
      As previous studies have indicated that the use of SABA may have detrimental cardiovascular effects [
      • Edgell H.
      • et al.
      Short-term cardiovascular and autonomic effects of inhaled salbutamol.
      ,
      • Moore L.E.
      • et al.
      Acute effects of salbutamol on systemic vascular function in people with asthma.
      ,
      • Appleton S.L.
      • et al.
      Cardiovascular disease risk associated with asthma and respiratory morbidity might be mediated by short-acting beta2-agonists.
      ], this study further investigated if there are vascular differences among all people with asthma symptoms grouped based on history of SABA usage within the year prior to the study. We found that people with regular SABA use had 1.5 m/s higher PWV than those without SABA (Fig. 2), which according to a large meta-analysis [
      • Vlachopoulos C.
      • Aznaouridis K.
      • Stefanadis C.
      Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis.
      ] corresponds to an estimated 24% heighted risk of cardiovascular events. Although guidelines recommend objective assessment to confirm diagnosis [
      • Bateman E.D.
      • et al.
      Global strategy for asthma management and prevention: GINA executive summary.
      ], it is common practice to prescribe asthma medication based on respiratory symptoms alone [
      • Heffler E.
      • et al.
      Prevalence of over-/misdiagnosis of asthma in patients referred to an allergy clinic.
      ]. Our lab has previously shown that acute use of SABA was associated with increased muscle sympathetic nerve activity (MSNA) [
      • Edgell H.
      • et al.
      Short-term cardiovascular and autonomic effects of inhaled salbutamol.
      ], decreased endothelial function, and increased arterial stiffness [
      • Moore L.E.
      • et al.
      Acute effects of salbutamol on systemic vascular function in people with asthma.
      ]. In the current study, regular SABA users demonstrated increased arterial stiffness compared to non regular SABA users, regardless of asthma confirmation. Increased MSNA can modulate arterial stiffness independent of hemodynamics [
      • Nardone M.
      • Floras J.S.
      • Millar P.J.
      Sympathetic neural modulation of arterial stiffness in humans.
      ], and therefore it may be that chronic SABA use results in arterial remodelling and increased arterial stiffness secondary to increased MSNA, though this requires further investigation. Furthermore, SABA users had less controlled asthma than non-SABA users, as evident by the differences in ACQ scores, and less asthma control has been associated with elevated arterial stiffness previously [
      • Sun W.X.
      • et al.
      Increased arterial stiffness in stable and severe asthma.
      ]. As such, further research on the interaction between level of control and SABA use in relation to cardiovascular risk in asthma is warranted.

      4.1 Strength and limitations

      This observational study evaluated a sample of well-characterized participants which involved considerable effort to recruit and evaluate each participant. As such, the sample size was relatively small; however, ninety-five percent power was achieved for the main outcome (i.e. between-group difference in FMD) of this study.
      Asthma is a heterogenous disease with a wide array of possible triggers, among them seasonal changes or events. This was a cross-sectional study, and as such, any potential seasonal fluctuations in asthma symptoms and control were not accounted for; asthma assessment and vascular evaluations were done in proximity to each other to reflect the relationship between the current asthma status and vascular health of the participants. It is thus plausible that individuals with both confirmed and unconfirmed asthma, according to the testing done for this study, may have exhibited different results if they had been tested during a different time of the year.
      There are many confounding variables that can influence vascular outcomes. This study did not adjust for risk factors such as lipid profile, assessment of lifestyle factors (stress, nutrition), and undiagnosed co-morbidities. There was also large variability between groups in the number of participants that completed the fitness and physical activity testing, which makes these data difficult to interpret.
      The current study examined CRP, a non-specific marker of systemic inflammation, because of its documented association with cardiovascular risk [
      • Koosha P.
      • et al.
      High sensitivity C-reactive protein predictive value for cardiovascular disease: a nested case control from isfahan cohort study (ICS).
      ,
      • Ridker P.M.
      • Glynn R.J.
      • Hennekens C.H.
      C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction.
      ,
      • Ridker P.M.
      Clinical application of C-reactive protein for cardiovascular disease detection and prevention.
      ]. Other inflammatory markers more specific to asthma may have strengthened the study further.‬‬‬‬‬‬ Considering the high presence of allergic disease among the participants with asthma (73%), the involvement of inflammatory mediators linked to allergic disease such as eosinophils and platelets should also be taken into consideration in future studies. Medication use was assessed through recall which is a potential source of reporting bias. Only the effect of salbutamol was evaluated in the current study and further studies assessing the systemic vascular impacts of other common asthma medications are also warranted. Longitudinal studies of individuals naïve to asthma medication with a recent diagnosis of asthma prior to beginning treatment are needed to better understand the progression of vascular dysfunction and inflammation associated with asthma and asthma medications.

      5. Conclusion

      Individuals with a clinical history of asthma symptoms have reduced vascular function, a predictor of cardiovascular risk, regardless of physiological confirmation of disease, as compared to healthy controls. This suggests factors external to disease pathology may be responsible for the increased cardiovascular risk associated with asthma. Importantly, arterial stiffness was increased among people with asthma who regularly use SABA, regardless of asthma confirmation. As such, this study highlights the importance of proper asthma management to avoid potentially inappropriate SABA use among people without physiologically confirmed asthma.

      Availability of data and materials

      Data supporting this study can be made available upon request to [email protected]

      Author agreement

      All authors have seen and approved the final version of the manuscript being submitted. This article is the authors' original work, has not received prior publication and is not under consideration for publication elsewhere.

      Funding source

      This work was supported by the Canadian Institutes of Health Research (CIHR) [grant number 407589, 2018].

      CRediT authorship contribution statement

      Shelby L. Henry: Conceptualization, Methodology, Investigation, Formal analysis, Resources, Data curation, Writing – original draft, Visualization, Project administration. Linn E. Moore: Conceptualization, Methodology, Investigation, Resources, Writing – original draft, Writing – review & editing, Funding acquisition. Andrew R. Brotto: Investigation, Formal analysis, Resources, Data curation, Writing – review & editing. Samira Rowland: Investigation, Formal analysis, Data curation, Writing – review & editing. Desi Fuhr: Investigation, Resources, Data curation, Writing – review & editing. Michael K. Stickland: Conceptualization, Methodology, Resources, Data curation, Writing – review & editing, Supervision, Funding acquisition, All authors approve of the final version of the manuscript.

      Declaration of competing interest

      None.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

      References

        • Global Initiative for Asthma
        Global Strategy for Asthma Management and Prevention.
        2021
        • Xu M.
        • Xu J.
        • Yang X.
        Asthma and risk of cardiovascular disease or all-cause mortality: a meta-analysis.
        Ann. Saudi Med. 2017; 37: 99-105
        • Appleton S.L.
        • et al.
        Asthma is associated with cardiovascular disease in a representative population sample.
        Obes. Res. Clin. Pract. 2008; 2: 71-142
        • Iribarren C.
        • et al.
        Adult asthma and risk of coronary heart disease, cerebrovascular disease, and heart failure: a prospective study of 2 matched cohorts.
        Am. J. Epidemiol. 2012; 176: 1014-1024
        • Bateman E.D.
        • et al.
        Global strategy for asthma management and prevention: GINA executive summary.
        Eur. Respir. J. 2008; 31: 143-178
        • LindenSmith J.
        • et al.
        Overdiagnosis of asthma in the community.
        Cancer Res. J. 2004; 11: 111-116
        • Heffler E.
        • et al.
        Prevalence of over-/misdiagnosis of asthma in patients referred to an allergy clinic.
        J. Asthma. 2015; 52: 931-934
        • Edgell H.
        • et al.
        Short-term cardiovascular and autonomic effects of inhaled salbutamol.
        Respir. Physiol. Neurobiol. 2016; 231: 14-20
        • Moore L.E.
        • et al.
        Acute effects of salbutamol on systemic vascular function in people with asthma.
        Respir. Med. 2019; 155: 133-140
        • Cekici L.
        • et al.
        Short-term effects of inhaled salbutamol on autonomic cardiovascular control in healthy subjects: a placebo-controlled study.
        Br. J. Clin. Pharmacol. 2009; 67: 394-402
        • Appleton S.L.
        • et al.
        Cardiovascular disease risk associated with asthma and respiratory morbidity might be mediated by short-acting beta2-agonists.
        J. Allergy Clin. Immunol. 2009; 123: 124-130 e1
        • Frostad A.
        • et al.
        Respiratory symptoms and long-term cardiovascular mortality.
        Respir. Med. 2007; 101: 2289-2296
        • Jousilahti P.
        • et al.
        Symptoms of chronic bronchitis and the risk of coronary disease.
        Lancet. 1996; 348: 567-572
        • Brunner H.
        • et al.
        Endothelial function and dysfunction. Part II: association with cardiovascular risk factors and diseases. A statement by the working group on endothelins and endothelial factors of the European society of hypertension.
        J. Hypertens. 2005; 23: 233-246
        • Green D.J.
        • et al.
        Flow-mediated dilation and cardiovascular event prediction: does nitric oxide matter?.
        Hypertension. 2011; 57: 363-369
        • Laurent S.
        • et al.
        Expert consensus document on arterial stiffness: methodological issues and clinical applications.
        Eur. Heart J. 2006; 27: 2588-2605
        • Pearson T.A.
        • et al.
        Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association.
        Circulation. 2003; 107: 499-511
      1. American thoracic, S. And P. American college of chest, ATS/ACCP statement on cardiopulmonary exercise testing.
        Am. J. Respir. Crit. Care Med. 2003; 167: 211-277
        • Juniper E.F.
        • et al.
        Identifying 'well-controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire.
        Respir. Med. 2006; 100: 616-621
        • Kodama S.
        • et al.
        Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis.
        JAMA. 2009; 301: 2024-2035
        • Ross R.
        • et al.
        Importance of assessing cardiorespiratory fitness in clinical practice: a case for fitness as a clinical vital sign: a scientific statement from the American heart association.
        Circulation. 2016; 134: e653-e699
        • Sui X.
        • LaMonte M.J.
        • Blair S.N.
        Cardiorespiratory fitness as a predictor of nonfatal cardiovascular events in asymptomatic women and men.
        Am. J. Epidemiol. 2007; 165: 1413-1423
        • Harris R.A.
        • et al.
        Ultrasound assessment of flow-mediated dilation.
        Hypertension. 2010; 55: 1075-1085
        • Thijssen D.H.J.
        • et al.
        Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans.
        Eur. Heart J. 2019; 40: 2534-2547
        • Vlachopoulos C.
        • Aznaouridis K.
        • Stefanadis C.
        Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis.
        J. Am. Coll. Cardiol. 2010; 55: 1318-1327
        • World Health Organisation international
        Guidelines on Drawing Blood: Best Practices in Phlebotomy.
        2010 (Geneva)
        • Faul F.
        • et al.
        G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences.
        Behav. Res. Methods. 2007; 39: 175-191
        • R&D Systems
        Human C-reactive protein/CRP DuoSet.
        • Koosha P.
        • et al.
        High sensitivity C-reactive protein predictive value for cardiovascular disease: a nested case control from isfahan cohort study (ICS).
        Global Heart. 2020; 15: 3
        • Ridker P.M.
        • Glynn R.J.
        • Hennekens C.H.
        C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction.
        Circulation. 1998; 97: 2007-2011
        • Yildiz P.
        • et al.
        Endothelial dysfunction in patients with asthma: the role of polymorphisms of ACE and endothelial NOS genes.
        J. Asthma. 2004; 41: 159-166
        • Sun W.X.
        • et al.
        Increased arterial stiffness in stable and severe asthma.
        Respir. Med. 2014; 108: 57-62
        • Zietkowski Z.
        • et al.
        High-sensitivity C-reactive protein in the exhaled breath condensate and serum in stable and unstable asthma.
        Respir. Med. 2009; 103: 379-385
        • Ford E.S.
        • et al.
        Leisure-time physical activity patterns among US adults with asthma.
        Chest. 2003; 124: 432-437
        • Teramoto M.
        • Moonie S.
        Physical activity participation among adult Nevadans with self-reported asthma.
        J. Asthma. 2011; 48: 517-522
        • Moore L.E.
        • et al.
        Physical activity, fitness, and vascular health in patients with asthma.
        J. Allergy Clin. Immunol. 2015; 136: 809-811 e3
        • Williams P.T.
        Physical fitness and activity as separate heart disease risk factors: a meta-analysis.
        Med. Sci. Sports Exerc. 2001; 33: 754-761
        • Nardone M.
        • Floras J.S.
        • Millar P.J.
        Sympathetic neural modulation of arterial stiffness in humans.
        Am. J. Physiol. Heart Circ. Physiol. 2020; 319: H1338-H1346
        • Ridker P.M.
        Clinical application of C-reactive protein for cardiovascular disease detection and prevention.
        Circulation. 2003; 107: 363-369