Physical activity, fitness, and vascular health in patients with asthma

Patients with asthma are at an increased risk of cardiovascular disease (CVD),1Iribarren C. Tolstykh I.V. Miller M.K. Sobel E. Eisner M.D. 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: 1014-1024Crossref PubMed Scopus (21) Google Scholar and increased systemic inflammation associated with asthma may play a role. High levels of the proinflammatory cytokines IL-6, C-reactive protein, and tumor necrosis factor-alpha are elevated in asthma, and all are associated with increased CVD risk.2Ridker P.M. Rifai N. Pfeffer M. Sacks F. Lepage S. Braunwald E. Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction.Circulation. 2000; 101: 2149-2153Crossref PubMed Scopus (842) Google Scholar, 3Ridker P.M. Rifai N. Stampfer M.J. Hennekens C.H. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men.Circulation. 2000; 101: 1767-1772Crossref PubMed Scopus (2040) Google Scholar Reduced endothelial vasodilation is seen in early stages of CVD development and is predictive of CVD.4Yeboah J. Folsom A.R. Burke G.L. Johnson C. Polak J.F. Post W. et al.Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosis.Circulation. 2009; 120: 502-509Crossref PubMed Scopus (720) Google Scholar Patients with asthma have reduced endothelial function and increased arterial stiffness than do those without asthma.5Sun W.X. Jin D. Li Y. Wang R.T. Increased arterial stiffness in stable and severe asthma.Respir Med. 2014; 108: 57-62Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 6Yildiz P. Oflaz H. Cine N. Genchallac H. Erginel-Unaltuna N. Yildiz A. et al.Endothelial dysfunction in patients with asthma: the role of polymorphisms of ACE and endothelial NOS genes.J Asthma. 2004; 41: 159-166Crossref PubMed Scopus (20) Google Scholar Systemic inflammation impairs endothelial function7Hingorani A.D. Cross J. Kharbanda R.K. Mullen M.J. Bhagat K. Taylor M. et al.Acute systemic inflammation impairs endothelium-dependent dilatation in humans.Circulation. 2000; 102: 994-999Crossref PubMed Scopus (532) Google Scholar and increases arterial stiffness,8Vlachopoulos C. Dima I. Aznaouridis K. Vasiliadou C. Ioakeimidis N. Aggeli C. et al.Acute systemic inflammation increases arterial stiffness and decreases wave reflections in healthy individuals.Circulation. 2005; 112: 2193-2200Crossref PubMed Scopus (376) Google Scholar but it is unknown whether there is a connection between systemic inflammation, vascular function, and arterial stiffness in subjects with asthma. Importantly, patients with asthma are usually more sedentary than their age-matched counterparts,9Teramoto M. Moonie S. Physical activity participation among adult Nevadans with self-reported asthma.J Asthma. 2011; 48: 517-522Crossref PubMed Scopus (38) Google Scholar and inactivity has been linked to increased inflammation, impaired vascular function, and increased CVD risk.10Williams P.T. Physical fitness and activity as separate heart disease risk factors: a meta-analysis.Med Sci Sports Exerc. 2001; 33: 754-761Crossref PubMed Scopus (558) Google Scholar Accordingly, we evaluated parameters of vascular function and systemic inflammation in patients with and without asthma matched for physical activity and aerobic fitness. We hypothesized that those with asthma would be associated with higher systemic inflammation, impaired endothelial function, and increased arterial stiffness as compared with controls even when matched for physical activity and aerobic fitness. For complete methodology, see this article's Methods section in the Online Repository at www.jacionline.org. Briefly, patients with asthma (18-45 years, n = 16) with a body mass index of 30 kg/m2 or less were recruited and compared with age-, body mass index-, physical activity-, and fitness-matched control subjects (n = 16) without asthma. Asthma diagnosis was based on history and 1) 12% or more and 200 mL improvement in FEV1 postbronchodilator, 2) a positive methacholine challenge (PC20 ≤ 4 mg/mL), or 3) 10% or more decrease in FEV1 after an exercise challenge. Controls demonstrated negative responses to all the 3 tests described above. A cardiopulmonary exercise test was performed to determine aerobic fitness (V.O2max). Physical activity was quantified as the number of steps taken over 3 days by a physical activity monitor. Vascular function was evaluated by flow-mediated dilation (FMD) adjusted for shear stress, and arterial stiffness was evaluated by the pulse wave velocity (PWV) between the radial and the carotid arteries using applanation tonometry. A blood sample was taken for analysis of systemic inflammatory markers (ie, IL-6, C-reactive protein, and tumor necrosis factor-alpha), fasting glucose, and cholesterol levels. The Asthma Control Questionnaire indicated that patients with asthma were within the ranges of controlled to partly controlled asthma. There were no between-group differences in fraction of exhaled nitric oxide, postbronchodilator FEV1, indices of blood pressure, fasting glucose, lipid profiles, or systemic inflammatory markers (see Table I). Although there were no differences in endothelial function (FMD) or microvascular function (velocity time integral) between subjects with and without asthma, subjects with asthma had significantly higher arterial stiffness than did those without asthma (Fig 1). There was no relationship between FMD and markers of systemic inflammation in asthma (see Fig E1, A-C, in this article's Online Repository at www.jacionline.org); however, there was a strong positive correlation between PWV and IL-6 in subjects with asthma, but no associations were observed between PWV and tumor necrosis factor-alpha or C-reactive protein (see Fig E1, E and F).Table ISubjects' characteristicsCharacteristicControlAsthmaP value (2-tailed)Sample size, n (male/female)16 (8/8)16 (10/6).72Age (y)26.6 ± 5.227.8 ± 6.1.58BMI (kg/m2)24.7 ± 3.524.6 ± 4.6.96FEV1 prebronchodilator (% predicted)96.3 ± 12.181.3 ± 15.1.004FEV1 postbronchodilator (% predicted)100.9 ± 13.291.6 ± 12.6.051Feno (ppb)17.9 ± 8.537.3 ± 40.9.16Asthma Control Questionnaire score0.1 ± 0.21.0 ± 0.4<.001Allergies (% yes)18.857.1.03SABA usage (%)0.056.3<.001ICS usage (%)0.018.8<.001Combination ICS + LABA usage (%)0.043.8<.001Physical activity, steps/d10,711 ± 2,67511,125 ± 5,487.79Fitness (relative V.O2max) (mL/kg/min % predicted)106.1 ± 15.997.1 ±23.3.21Mean arterial pressure (mmHg)79 ± 582 ± 10.34Heart rate (bpm)55.7 ± 5.859.3 ± 6.0.10Total cholesterol (mmol/L)3.7 ± 0.93.9 ± 1.4.86HDL (mmol/L)1.4 ± 0.21.4 ± 0.4.92Fasting glucose (mmol/L)3.9 ± 0.43.9 ± 0.4.81CRP (mg/L)2.3 ± 3.833.6 ± 3.5.46IL-6 (pg/mL)8.6 ± 5.96.9 ± 3.5.35TNF-α (pg/mL)16.5 ± 5.116.3 ± 2.8.91Values are mean ± SD unless indicated otherwise.BMI, Body mass index; bpm, beats per minute; CRP, C-reactive protein; Feno, fraction of exhaled nitric oxide; HDL, high-density lipoprotein; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; SABA, short-acting beta-agonist; TNF-α, tumor necrosis factor-alpha; V.O2, rate of oxygen consumption. Open table in a new tab Values are mean ± SD unless indicated otherwise. BMI, Body mass index; bpm, beats per minute; CRP, C-reactive protein; Feno, fraction of exhaled nitric oxide; HDL, high-density lipoprotein; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; SABA, short-acting beta-agonist; TNF-α, tumor necrosis factor-alpha; V.O2, rate of oxygen consumption. When matched for age, body mass index, physical activity, and aerobic fitness, those with asthma and controls had similar endothelial function, microvascular function, and systemic inflammation. Those with asthma had significantly higher arterial stiffness than did those without asthma, suggesting that structural changes within the vessel walls that are independent of physical activity, aerobic fitness, and inflammation occur in asthma. Previous work found that as compared with controls, those with asthma have reduced vascular function6Yildiz P. Oflaz H. Cine N. Genchallac H. Erginel-Unaltuna N. Yildiz A. et al.Endothelial dysfunction in patients with asthma: the role of polymorphisms of ACE and endothelial NOS genes.J Asthma. 2004; 41: 159-166Crossref PubMed Scopus (20) Google Scholar and increased arterial stiffness.5Sun W.X. Jin D. Li Y. Wang R.T. Increased arterial stiffness in stable and severe asthma.Respir Med. 2014; 108: 57-62Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar However, these studies did not report fitness or physical activity levels, and it is likely that those with asthma were less active.9Teramoto M. Moonie S. Physical activity participation among adult Nevadans with self-reported asthma.J Asthma. 2011; 48: 517-522Crossref PubMed Scopus (38) Google Scholar As a result, subjects with asthma would probably have exhibited lower fitness and impaired vascular health. In addition, previous work6Yildiz P. Oflaz H. Cine N. Genchallac H. Erginel-Unaltuna N. Yildiz A. et al.Endothelial dysfunction in patients with asthma: the role of polymorphisms of ACE and endothelial NOS genes.J Asthma. 2004; 41: 159-166Crossref PubMed Scopus (20) Google Scholar had not normalized vascular reactivity to its stimulus (ie, shear stress). Our findings indicate that when matched for fitness or physical activity, those with asthma do not appear to have reduced vascular function as compared with healthy controls. However, the increase in arterial stiffness in those with asthma is related to lung disease, and not secondary to reduced physical activity or fitness. Although increased levels of systemic inflammation are known to adversely affect vascular function and arterial stiffness,7Hingorani A.D. Cross J. Kharbanda R.K. Mullen M.J. Bhagat K. Taylor M. et al.Acute systemic inflammation impairs endothelium-dependent dilatation in humans.Circulation. 2000; 102: 994-999Crossref PubMed Scopus (532) Google Scholar, 8Vlachopoulos C. Dima I. Aznaouridis K. Vasiliadou C. Ioakeimidis N. Aggeli C. et al.Acute systemic inflammation increases arterial stiffness and decreases wave reflections in healthy individuals.Circulation. 2005; 112: 2193-2200Crossref PubMed Scopus (376) Google Scholar systemic inflammation was similar in both those with asthma and controls. These findings indicate that the increase in PWV in those with asthma relative to controls occurred independent of systemic inflammation. There was an association between IL-6 and arterial stiffness within those with asthma, suggesting that systemic inflammation may be related to arterial stiffness in those with asthma; however, it does not explain the elevation in PWV relative to controls. All subjects in the present study were carefully screened, and it could be argued that these stringent inclusion criteria may have resulted in a sample inadequate to detect between-group differences in FMD. Our study was powered to detect a 10% difference in FMD between those with asthma and controls,6Yildiz P. Oflaz H. Cine N. Genchallac H. Erginel-Unaltuna N. Yildiz A. et al.Endothelial dysfunction in patients with asthma: the role of polymorphisms of ACE and endothelial NOS genes.J Asthma. 2004; 41: 159-166Crossref PubMed Scopus (20) Google Scholar corresponding to a large increase in the relative risk of CVD (for more details, see this article's Online Repository at www.jacionline.org). More importantly, the mean value for vascular function between those with asthma and controls was very similar, and a power calculation indicates that 340 subjects would have been required to detect a difference, which would have been well below any clinical significance. Beta agonists may modify sympathetic nerve activity, which could affect PWV and may explain the difference observed between those with asthma and controls. In the present study, all subjects with asthma withheld beta agonists for 12 hours before testing, and thus acute effects were controlled; however, chronic effects of asthma medication on vascular health are mostly still unknown. Furthermore, the age criteria in the present study did not allow for the evaluation of the influence of age or asthma duration on vascular health and further research is needed in this area. In conclusion, stiffening of the systemic arteries appears to occur independently of physical activity, inflammation, and fitness in those with asthma. However, endothelial function and systemic inflammation are similar between physical activity and fitness-matched subjects with and without asthma, suggesting that mild controlled asthma alone does not contribute to increased systemic inflammation and/or impaired vascular function and that previous results showing impaired endothelial function and systemic inflammation in those with asthma may be explained by differences in baseline fitness and/or physical activity. This study (protocol no. Pro00029773) was approved by the University of Alberta Health Research Ethics Board. Written consent was obtained from all subjects before participation in the study. Men and women with asthma (n = 16) between the ages of 18 and 45 years and with a body mass index of 30 kg/m2 or less were recruited from the University of Alberta Asthma Clinic and The Lung Health Clinic, Edmonton, Alberta, Canada. Asthma diagnosis was based on history of asthma symptoms such as recurrent episodes of wheezing, chest tightness, shortness of breath, and 1) 12% or less and 200 mL improvement in FEV1 postbronchodilator,E1Bateman E.D. Hurd S.S. Barnes P.J. Bousquet J. Drazen J.M. FitzGerald M. et al.Global strategy for asthma management and prevention: GINA executive summary.Eur Respir J. 2008; 31: 143-178Crossref PubMed Scopus (2380) Google Scholar, E2Lougheed M.D. Leniere C. Ducharme F.M. Licskai C. Dell S.D. Rowe B.H. et al.Canadian Thoracic Society 2012 guideline update: diagnosis and management of asthma in preschoolers, children and adults: executive summary.Can Respir J. 2012; 19: e81-e88PubMed Google Scholar 2) a positive methacholine challenge (PC20 ≤ 4 mg/mL2), or 3) 10% or more decrease in FEV1 after an exercise challenge.E2Lougheed M.D. Leniere C. Ducharme F.M. Licskai C. Dell S.D. Rowe B.H. et al.Canadian Thoracic Society 2012 guideline update: diagnosis and management of asthma in preschoolers, children and adults: executive summary.Can Respir J. 2012; 19: e81-e88PubMed Google Scholar, E3Crapo R.O. Casaburi R. Coates A.L. Enright P.L. Hankinson J.L. Irvin C.G. et al.Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999.Am J Respir Crit Care Med. 2000; 161: 309-329Crossref PubMed Scopus (2219) Google Scholar Asthma control was evaluated according to the Asthma Control QuestionnaireE4Juniper E.F. Bousquet J. Abetz L. Bateman E.D. Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire.Respir Med. 2006; 100: 616-621Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar, E5Juniper E.F. O'Byrne P.M. Guyatt G.H. Ferrie P.J. King D.R. Development and validation of a questionnaire to measure asthma control.Eur Respir J. 1999; 14: 902-907Crossref PubMed Scopus (1857) Google Scholar at the time of the first visit and only those with controlled (Asthma Control Questionnaire score of <0.75) and partly controlled (Asthma Control Questionnaire score of 0.75-1.5) asthma were included. Age, body mass index, and physical activity/fitness-matched control subjects (n = 16) without asthma (asymptomatic and as demonstrated by negative responses to all 3 the tests described above) were recruited from the general population. Subjects were excluded if demonstrating the following cardiovascular risk factors: hypertension (defined as resting systolic blood pressure of 140 mmHg or more and/or diastolic blood pressure of 90 mmHg or more),E6Roger V.L. Go A.S. Lloyd-Jones D.M. Benjamin E.J. Berry J.D. 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Go A.S. Lloyd-Jones D.M. Benjamin E.J. Berry J.D. Borden W.B. et al.Heart disease and stroke statistics–2012 update: a report from the American Heart Association.Circulation. 2012; 125: e2-e220Crossref PubMed Scopus (0) Google Scholar or 1 or more reason(s) to withhold from physical activity according to the Physical Activity Readiness Questionnaire (PAR-Q) and You Questionnaire.E7The American College of Sport Medicine, American College of Sport Medicine's guideline for exercise testing and prescription; Preparticipation Health Screening; 2009; Chapter 2; p 24.Google Scholar Because coexisting allergies do not increase the risk of CVD in asthmaE9Iribarren C. Tolstykh I.V. Miller M.K. Sobel E. Eisner M.D. 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: 1014-1024Crossref PubMed Scopus (142) Google Scholar but may influence the systemic inflammatory profile,E10Wood L.G. Baines K.J. Fu J. Scott H.A. Gibson P.G. The neutrophilic inflammatory phenotype is associated with systemic inflammation in asthma.Chest. 2012; 142: 86-93Crossref PubMed Scopus (210) Google Scholar, E11Olafsdottir I.S. Gislason T. Thjodleifsson B. Olafsson I. Gislason D. Jogi R. et al.C reactive protein levels are increased in non-allergic but not allergic asthma: a multicentre epidemiological study.Thorax. 2005; 60: 451-454Crossref PubMed Scopus (119) Google Scholar both atopic and nonatopic subjects were recruited and previously known allergies noted. Fractions of exhaled nitric oxide (NIOX MINO, Aerocrine, Inc, Solna, Sweden) were used for the evaluation of pulmonary inflammation, and the risk of obstructive sleep apnea was defined as having 3 or more risk factors occurring on the F. R. P. E. C. Y. High score indicates a of obstructive sleep J 2012; 108: PubMed Scopus Google Scholar, F. B. P. S. S. et a to patients for obstructive sleep 2008; 108: PubMed Scopus Google Scholar A cardiopulmonary exercise test was performed to determine the rate of oxygen at exercise (V.O2max). The test was performed on a at stages of analysis of pulmonary was performed the test using the The subjects were to rate their of at the on the from 1 at to The time was as as a of cardiopulmonary M.K. M. exercise using cardiopulmonary exercise Med. 2012; PubMed Scopus Google Scholar Physical activity was quantified as the number of steps taken and the of physical activity have previously been to measure J. W. of for in healthy Sci Sports Exerc. PubMed Scopus Google Scholar, validation of the and using the PubMed Scopus Google Scholar and have been used in research with patients with F. A.D. D. et between pulmonary function and physical activity in in patients with Med. 2008; 102: Full Text Full Text PDF PubMed Scopus Google Scholar The subjects were to the activity on the of their for the for a of 3 2 and 1 of the from the were using All endothelial function and arterial stiffness were at the time of in the after a fasting of flow-mediated PubMed Scopus Google Scholar, J. et of flow-mediated dilation in a and J Heart 2011; PubMed Scopus Google Scholar When the subjects were to withhold any long-acting beta agonists and/or for a of hours before the test and short-acting beta agonists for 12 hours before the subjects were for than asthma, and were not taken within days before the study. The endothelial function of the brachial was evaluated at after of in the using of the brachial was and the blood of the was of the for a duration of The blood velocity and the brachial were for before and 3 after and function was evaluated as the velocity time of the first of reactive E. S. J. F. et of new of vascular function to dilatation as a measure of cardiovascular risk J 2009; Full Text Full Text PDF PubMed Scopus Google Scholar The shear after reactive was as mean velocity of flow-mediated PubMed Scopus Google Scholar All FMD tests were by the within the vessel were evaluated by 2 independent The correlation for and % baseline were = and stiffness was evaluated by the PWV between the radial and the carotid arteries using applanation Inc, The carotid and radial were obtained after of at PWV was over the 2 30 were from and were for analysis The between was by the difference in time between corresponding as per S. J. L. P. C. D. et on arterial and clinical Heart J. 2006; PubMed Scopus Google Scholar Blood was an after the vascular function resting glucose and cholesterol levels were and the blood was to at for a of 30 before at for at were to Alberta, for analysis of inflammatory markers (ie, IL-6, C-reactive protein, and tumor necrosis are as mean ± SD unless For all the of was at and vascular parameters were compared between those with asthma and controls using independent were compared between those with asthma and controls using the The between levels of tumor necrosis IL-6, and C-reactive protein, and shear after reactive and PWV were evaluated in those with asthma using the correlation on previous P. Oflaz H. Cine N. Genchallac H. Erginel-Unaltuna N. Yildiz A. et al.Endothelial dysfunction in patients with asthma: the role of polymorphisms of ACE and endothelial NOS genes.J Asthma. 2004; 41: 159-166Crossref PubMed Scopus Google Scholar a sample of in was to detect a 10% difference in FMD between those with asthma and controls, corresponding to a more than increase in the relative risk of H. D. dilation and cardiovascular does nitric oxide 2011; PubMed Scopus Google Scholar = = All were performed using for the

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