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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Vasc Med. Author manuscript; available in PMC 2010 August 3.
Published in final edited form as:
PMCID: PMC2914468
NIHMSID: NIHMS216206

Endothelium-dependent vasodilation is associated with exercise capacity in smokers and non-smokers

Kevin S. Heffernan, PhD,1,2 Richard H. Karas, MD PhD,1,2 Eshan A. Patvardhan, MBBS,1 and Jeffrey T. Kuvin, MD1, From the Vascular Function Study Group

Abstract

Objectives

Smoking is an established cardiovascular risk factor that impairs endothelial function and reduces exercise capacity. Peripheral vascular endothelial function correlates with exercise capacity, but whether this association prevails in smokers is unknown. The purpose of this investigation was to examine the association between endothelial function and exercise capacity in chronic smokers and non-smoking controls.

Methods

Brachial artery flow mediated dilation (FMD, endothelium-dependent) following 5-minutes of upper arm occlusion was compared in 26 smokers (age 58±1 yrs; 15 female; BMI = 28±1) and 39 non-smokers (age 58±1 yrs; 24 female; BMI = 28±1) using ultrasound. Exercise treadmill time (ETT) was recorded from a standard Bruce protocol during symptom limited stress testing.

Results

There was a significant positive association between FMD and ETT in smokers (r = 0.60, p<0.05) and non-smokers (r = 0.28, p<0.05). FMD was significantly lower in smokers vs. non-smokers (8.9 ± 0.9 vs. 12.6 ± 0.7%, p<0.05). ETT was significantly lower in smokers (425 ± 35 sec) versus non-smokers (522 ± 25 sec, p<0.05). After adjusting for FMD, there were no longer group differences in ETT. When patients were matched according to FMD, there were no differences in ETT between smokers and non-smokers.

Conclusion

Peripheral endothelial dysfunction is a correlate of low exercise capacity in smokers and non-smokers alike. Future research is needed to examine if improving endothelial function will lead to concomitant increases in exercise capacity in chronic smokers.

Keywords: flow mediated vasodilation, exercise testing, smoking, vascular function

Smokers have lower exercise capacity when compared to their non-smoking peers and this is independent of physical activity levels and/or clustering of common cardiovascular risk factors 1,2. Moreover, exercise capacity increases very shortly after smoking cessation, arguing for a direct role of smoking in the diminution of exercise capacity 3. Impaired exercise capacity is related to poor quality of life, reduced physical function, inability to complete activities of daily living and increased dependence 4,5. Numerous studies have demonstrated that impaired exercise capacity is predictive of increased risk/mortality even after controlling for standard risk factors 6,7. Endothelial dysfunction has been shown to correlate with exercise capacity in various populations 810. Cigarette smoking causes peripheral vascular endothelial dysfunction and as such, smokers present with impaired endothelium-dependent vasodilation 1114. Whether vascular endothelial function is a correlate of exercise capacity in smokers has yet to be investigated.

Vascular responsiveness to exercise may be impaired in smokers. Gaenzer et al. has noted impaired femoral vascular responsiveness during exercise in smokers compared to non-smokers and this blunted exercise-induced femoral flow mediated dilation (FMD) was highly correlated with brachial artery FMD induced by 5-minutes of local occlusion (a traditional measure of conduit artery endothelium-dependent vasodilation)13. Moreover, the vasculature of smokers appears impervious to modulation by select therapies known to improve vascular function in other clinical cohorts (e.g. ischemic preconditioning, vitamin C, vitamin E)1517. Therefore, it is possible that resting endothelium-dependent vasodilation may not be associated with exercise capacity in this unique cohort due to the severity of vascular dysfunction.

The purpose of this study was to examine the association between vascular endothelial function and exercise capacity in smokers. We hypothesized that endothelium-dependent vasodilation would be a correlate of exercise capacity in smokers and non-smokers. To comprehensively test this hypothesis, several statistical and methodological approaches were employed. First we examined the statistical association between endothelium-dependent vasodilation and exercise capacity in smokers and non-smokers. Second, we examined whether statistically adjusting for group differences in endothelium-dependent vasodilation would abolish differences in exercise capacity between smokers and nonsmokers. Third, we matched smokers and non-smokers for endothelium-dependent vasodilation and examined whether exercise capacity would be similar between groups when this factor is held constant. Finally, we examined whether exercise capacity is higher in smokers on statin therapy, a pharmacological intervention known to improve endothelium-dependent vasodilation.

Methods

Patient Selection

Sixty-five patients reporting to the outpatient Preventive Cardiology Center at Tufts Medical Center for clinically-indicated stress testing due to chest pain were investigated in this study. All patients were community dwelling individuals residing in the greater Boston area. Exclusion criteria included patients with uncontrolled hypertension, uncontrolled diabetes mellitus, known coronary artery disease (CAD), severe valvular disease, recent myocardial infarction (within three months) or unstable cardiac symptoms, congestive heart failure or left ventricular ejection fraction <40%, renal insufficiency (serum creatinine > 2 mg/dL), active liver disease, chronic obstructive pulmonary disease, known peripheral artery disease, or Raynaud’s disease.

Exercise Testing

Patients completed a symptom limited exercise treadmill test using a standard Bruce protocol with continuous 12-lead ECG assessment. Exercise test time (ETT) was recorded in seconds and taken as a measure of exercise capacity. Prior to the completion of exercise, intravenous technetium-99m sestamibi was administered for subsequent myocardial perfusion imaging via single photon emission computed tomography (SPECT). Patients were considered CAD− if no perfusion abnormalities were detected and only these patients were retrospectively selected for final data analysis. Patients with fixed or reversible perfusion defects (CAD+) were excluded to avoid the potential confounding influence of ischemia on exercise test time.

Subjects were instructed to fast overnight (at least 12-hours) and refrain from caffeine or alcohol intake, smoking and vasoactive medications on the day of testing. All vascular measures were made with the subject in the supine position in a dimly lit, temperature-controlled room following a ten-minute acclimatization period. All vascular examinations were conducted in the morning to reduce potential influence of diurnal variation on measurement of endothelial function. All subjects gave written informed consent and this study was approved by the institutional review board at Tufts Medical Center.

Brachial artery endothelium dependent and independent vasodilation

Endothelium-dependent vasodilation of the brachial artery was assessed using high resolution ultrasonography as previously described 9. Briefly, the brachial artery was longitudinally imaged 2-cm above the antecubital fossa using a 10mHz linear array vascular ultrasound transducer. Diameters were measured during end-diastole (gated with ECG R-waves) using ultrasonic calipers. The average of 5 evenly spaced measures (distance between the anterior and posterior intima-blood interfaces) obtained within a 5 cm segment of the vessel was used for subsequent analysis. Following baseline brachial artery diameter (BAD) measurement, reactive hyperemia was induced by an ischemic stimulus (rapid inflation of a blood pressure cuff around the upper arm to a supra-systolic pressure for 5 minutes). Immediately post cuff release, reactive hyperemia was confirmed by qualitatively assessing blood velocity for 10 seconds using spectral Doppler. Sixty seconds following release of the occlusion cuff, brachial diameter was once again measured as aforementioned. Responses were calculated as percentage change in brachial artery diameter from baseline (flow mediated dilation, FMD).

Endothelium-independent vasodilation was assessed 10-min after reactive hyperemia testing. Brachial artery diameters were assessed before and 5-min following administration of sublingual nitroglycerine (nitroglycerin-mediated dilation, NMD). Intraobserver and interobserver variability in our clinic has previously been established to be low (1.8% and 2.8% respectively) 18. These methods conform to the guidelines set out for the ultrasound measurement of endothelium-dependent and -independent dilation of the brachial artery 19.

Statistical analysis

All data are reported as means ± SEM. A priori significance was set at p < 0.05. Normality of distribution was assessed using Kolmogorov-Smirnof and Shapiro-Wilk tests. Pearson’s correlation coefficients were used to assess relationships between variables of interest. Stepwise multiple regression analysis was performed to examine predictors of exercise test time in our cohort. Variables entered into the model included traditional cardiovascular risk factors (age, gender, presence/absence of hypertension, diabetes, hyperlipidemia, family history of CVD, and BMI), BAD, FMD and NMD. Analysis of variance (for parametric data) was used to assess differences in continuous outcome variables between groups. Analysis of co-variance (ANCOVA) was used to statistically remove the effect of FMD on ETT. In addition, we also performed ANCOVA, adjusting for the potential influence of traditional risk factors (age, gender, presence of hypertension, presence of diabetes, hypercholesterolemia) and medication use (statins, beta-blockers, ACE-inhibitors, calcium channel blockers, aspirin) on ETT. Smokers and non-smokers were then matched for FMD using previously defined clinically relevant cut-points 9 and compared using ANOVA. FMD and ETT in smokers/non-smokers on statin therapy were compared to smokers/non-smokers not on statin therapy using ANOVA. For all ANOVA, when a group effect was detected, post hoc comparisons were made with t-tests. Data analysis was carried out using SPSS (SPSS, Inc., Chicago, IL).

Results

Smoking and non-smoking groups were similar in age, BMI, and prevalence of cardiovascular risk factors (Table 1). According to results from stepwise multiple regression, predictors of ETT for the group as a whole included age (standardized β = −0.431, p<0.05), FMD (standardized β = 0.373, p<0.05), and female gender (standardized β = −0.352, p<0.05). For smokers, the regression equation for FMD as a predictor of ETT was: y = 21.5x + 233.8. For controls, the regression equation for FMD as a predictor of ETT was: y = 8.43x + 416.4. There was a significant association between FMD and ETT in smokers (r=0.60, p<0.05) and non-smokers (r=0.28, p<0.05).

Table 1
Patient characteristics.

FMD and ETT were significantly lower in smokers versus non-smokers (Table 1). When ANCOVA was performed with traditional risk factors entered as covariates, group differences remained (adjusted means: smokers 437±29 sec vs. non-smokers 516±23 sec; p<0.05). When ANCOVA was performed with FMD entered as the covariate, group differences in ETT were no longer significant (adjusted means: smokers 456±31 sec vs. non-smokers 502±25 sec; p>0.05). There were no differences in NMD between smokers (21.3 ± 1.6%) and non-smokers (18.9 ± 0.9 %, p>0.05). There was no association between NMD and ETT in smokers (r=0.21, p>0.05) and non-smokers (r=−0.04, p>0.05).

Smokers and non-smokers with low FMD (< 10%) had similar ETT (Figure 1, p>0.05). Similarly, smokers and non-smokers with high FMD (≥ 10%) had similar ETT (Figure 1, p>0.05). Smokers and non-smokers with FMD ≥ 10% had greater ETT compared to smokers and non-smokers with FMD < 10% (Figure 1, p<0.05).

Figure 1
Exercise capacity in smokers and nonsmokers with low (<10%) versus high (≥10%) brachial artery flow mediated dilation (FMD).

ETT and FMD were higher in smokers taking statins versus smokers not taking statins (Table 3, Figure 2; p<0.05). ETT and FMD were higher in non-smokers taking statins versus non-smokers not taking statins (Table 3, Figure 2; p<0.05). In smokers and non-smokers, there were no differences in FMD or ETT between those taking anti-hypertensives (ACE inhibitors, calcium channel blockers and β blocker) or aspirin therapy versus those not taking anti-hypertensives or aspirin therapy (p>0.05).

Figure 2
Exercise capacity in smokers and nonsmokers taking statins versus those not taking statins.
Table 3
Patient characteristics according to statin use.

Discussion

The findings of the present study were as follows: 1) chronic smokers have lower exercise capacity and lower endothelium-dependent vasodilation compared to non-smokers 2) a positive association was noted between endothelium-dependent vasodilation and exercise capacity in smokers and non-smokers; 3) statistically adjusting for endothelium-dependent vasodilation abolished group differences in exercise capacity; 4) when smokers and non-smokers were matched for endothelial function, exercise capacity was not different between groups; 5) smokers and non-smokers on statin therapy had higher endothelium-dependent vasodilation and higher exercise capacity than their counterparts not on statin therapy.

In healthy human and animal models devoid of clinical manifestations of CAD, limitations in exercise capacity have been historically ascribed to two factors, reduced convective properties or O2 delivery (i.e. reduced cardiac output and blood flow) and/or reduced diffusive properties or O2 extraction at the level of the muscle mitochondria-capillary boundary 20. Recent evidence has also implicated endothelial dysfunction as a causative factor in reducing exercise capacity 21. With aging and disease, limitations in oxygen and nutrient delivery limit contractile work and age-associated impairment in endothelium-dependent vasodilation contributes to lower exercise hyperemia 21,22. Endothelial dysfunction will result in a state of heightened vasoconstriction and blunted vasodilation, reducing blood flow into the capillary bed and preventing efficient oxygen extraction by muscle mitochondria, ultimately reducing exercise capacity. A reduction in blood flow to working skeletal muscle (i.e. reduced perfusion) may also limit the ability to perform functional tasks 23. Peripheral vascular endothelial function has been shown to correlate with exercise capacity and physical function in various populations 810,23. Although we do not have measures of endothelial function during exercise, conduit artery FMD following 5-min of occlusion (as used in the present study) is highly correlated with exercise-induced FMD in smokers and non-smokers 13. Therefore, reduced endothelium-dependent vasodilation may contribute to reductions in exercise capacity in both smokers and non-smokers. Given the profound level of vascular dysfunction in smokers compared to non-smokers, the impact of endothelial dysfunction on blunted exercise capacity may be more pronounced.

Exercise capacity increases very shortly (7 days) after smoking cessation, arguing for a direct role of smoking in the diminishment of exercise capacity 3. Smoking cessation induces rapid reversal of endothelial dysfunction and the time course is similar to improvements noted in exercise capacity 24. Therapies that improve endothelial function have beneficial effects on exercise capacity in other clinical cohorts. In patients with heart failure, improving endothelial function with either atorvastatin 25,26 or sildenafil is correlated with improvements in exercise capacity 2729. Statin therapy has been shown to improve endothelial function in smokers 30,31 and this can occur in as little as 24-hours from the initial dose 32. In support of this, we noted that endothelial function was higher in smokers (and non-smokers) using statins compared their non-statin using counterparts. Smokers taking statins had endothelial function comparable to that of non-smokers. Thus it would appear that statin therapy may be able to restore endothelial function in smokers to levels rivaling non-smokers. Interestingly, exercise capacity was also higher in smokers using statins compared to smokers not using statins and levels were comparable to those witnessed in non-smokers. These findings raise the intriguing possibility that therapies that improve endothelial function may be associated with concomitant improvements in exercise capacity and this may be particularly beneficial in smokers, a cohort with established endothelial dysfunction. Additional studies are needed to demonstrate this empirically.

An alternative interpretation of the present findings is that higher exercise capacity (secondary to a more physically active lifestyle) may have a favorable effect on vascular endothelial function in smokers33. Highly endurance trained smokers have improved peripheral blood flow34. Given that smoking cessation remains a very difficult task for many, physical activity may be an important lifestyle modification to preserve peripheral endothelial function in chronic smokers. This may have important implications for overall vascular health and primary/secondary disease prevention in this cohort.

Limitations to this study should be noted. These data are cross sectional. As such, cause-and-effect cannot be directly ascertained. We do not have data pertaining to the duration and magnitude of cigarette smoking in our smokers. However there does not appear to be a dose-dependent association between number of cigarettes smoked/pack-years of exposure and cardiovascular events 35,36. Also, light smokers have similar impairments in endothelial function as heavy smokers 12. Therefore, the possibility that smokers with attenuated decrements in endothelial function were lighter smokers or smoked for less duration remains unlikely. Finally, we did not control for shear stress when measuring FMD and this may affect interpretation of our findings37,38. We do not have measures of pulmonary function. Impaired pulmonary function in smokers may reduce exercise capacity and this may hamper the interpretation of our findings2. Overall, it should be stressed that the current findings are preliminary and further research is necessary to substantiate them.

In conclusion, there is an association between endothelium-dependent vasodilation and exercise capacity in chronic smokers and non-smokers. Endothelial dysfunction may be an important, previously unrecognized determinant of exercise capacity in chronic smokers. Future research is needed to prospectively examine if interventions that specifically target endothelial dysfunction in smokers concomitantly improves exercise capacity.

Table 2
Patient characteristics according to FMD < 10% versus FMD ≥ 10%.

Footnotes

Disclosures: None

References

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