although the exercise tolerance test ( ett ) has been widely used in clinical practice , the value of blood pressure ( bp ) response to ett remains unclear , especially regarding the relationship between bp response during exercise and future cardiovascular events . the current guidelines include exercise - induced hypertension as a marker for future hypertension but not for cardiovascular morbidity and mortality outcomes . several recent studies have shown that bp response at submaximal rather than at maximal workload was associated with future cardiovascular disease ( cvd ) in normotensive patients , but the prognostic value of bp response during ett in hypertensive patients has not yet been determined . at our center , a diagnosis of hypertension is based on 24-h ambulatory blood pressure monitoring ( abpm ) , with ett using the naughton / balke protocol utilized for cardiac rehabilitation and risk stratification . because almost all the patients in our registry , the asan - abpm registry , underwent ett at initial evaluation , we assessed the prognostic value of submaximal systolic bp ( sbp ) response during exercise for future cardiovascular events in patients with mild - to - moderate sustained hypertension ( sht ) diagnosed by 24-h abpm . we enrolled patients aged 18 years who were registered in the asan - abpm registry between may 2002 and october 2005 . patients were excluded if they had a history of coronary artery disease or stroke at the time of hospital visit , symptomatic congestive heart failure or failed to achieve the target heart rate . of the 1017 patients screened , 886 ( 87.1% ) were taking antihypertensive medications at the time of ett , whereas 131 ( 12.9% ) were not . we excluded 190 patients who had not achieved target heart rate , 42 with previous ischemic heart disease ( ihd ) or stroke and 9 with stage 3 hypertension . therefore , our study population consisted of 300 patients with sht ( figure 1 ) . all the patients receiving antihypertensive medications were asked to discontinue them for at least five half - lives of the drug . clinical bps were measured by the physician investigators using a mercury sphygmomanometer , with sbp and diastolic bp ( dbp ) at rest measured in the left brachial artery after at least 510  min of rest , with two readings taken 5  min apart . ambulatory bp was measured using 24-h abpm with a portable spacelabs 90207 ( issaquah , wa , usa ) noninvasive recorder with a bp cuff fitted on the nondominant arm . the unit was programmed to record bp and heart rate at 15-min intervals from 0600 to 2200 hours ( daytime period ) and at 30-min intervals from 2200 to 0600 hours ( night period ) ; awake and asleep periods were calculated from diary entries . sht was defined as a daytime bp 135/85  mm  hg and a night bp 120/70  mm  hg . we also assessed the clinical and family history of each patient , as well as the results of physical examination , laboratory parameters , echocardiography and exercise treadmill tests . attainment of 85% of target heart rates ( age- and sex - predicted maximal heart rate ) was considered adequate . target heart rates were not considered predetermined end points , rather subjects underwent symptom - limited treadmill tests . throughout the ett , bp and heart rate were measured using a suntech medical tango bp monitoring system ( raleigh , nc , usa ) , with baseline measurements taken with the subject at rest in a sitting position prior to exercise sbp and dbp were measured by auscultation for 30  s before the end of each 2-min incremental stage . multi - lead ecg recordings were taken at rest and at the same interval until the end of the recovery period to exclude ischemia or arrhythmia . all the patients were categorized into quartiles based on their absolute value of sbp response at stage 4 of the naughton / balke treadmill protocol ( 7.4 metabolic equivalent tasks ) . we also assessed dbp at stage 4 and sbp and dbp at the maximal workload for each individual . if a patient was unable to reach stage 4 , the highest sbp through stage 3 the primary outcome of this study was the composite of all - cause death , new - onset ihd and stroke . the cause and date of death were confirmed by information gathered from the national population registry of the korean national statistical office , together with a review of all the available clinical records . follow - up data were also collected by direct telephone interview and a review of medical records . ihd was diagnosed in patients with typical angina symptoms and positive results on at least one stress test ( ett , thallium scan or dobutamine stress echocardiography ) . stroke was diagnosed by an independent neurologist based on brain imaging . the patients were followed for a median of 66 months ( interquartile range 3479 months ) . all the statistical analyses were performed using spss ( version 18.0 ; spss inc , chicago , il , usa ) . summary statistics are presented as frequencies and percentages , means.d . or medians with interquartile ranges . between - group differences in continuous variables were assessed by analysis of variance and turkey 's tests , whereas between - group differences in the frequency of categorical variables were assessed using the chi - square or fisher 's exact tests , as appropriate . relationship between bp variables measured during ett was evaluated by calculation of spearman 's rank correlation coefficient . cumulative survival and event - free rate curves were calculated by the kaplan  meier method and compared using the log - rank test . we used three - step adjustment using cox proportional hazard models to adjust for confounding variables . in model 1 , unadjusted hr hr was further adjusted for framingham general cardiovascular risk score and other confounding variables were adjusted in model 3 . all p - values were two - sided , and p<0.05 was considered statistically significant . the study participants were middle aged ( mean 50.411.17 years old ) with more men ( 56.7% ) included ( table 1 ) . the 300 participants showing sbp increases during exercise were divided into quartiles based on their bp responses at stage 4 of the ett . the clinical and exercise characteristics of the study population are shown in table 2 . compared with participants who had the lowest quartile of sbp increases , those with increases in the highest quartile were older , had higher body mass index and framingham scores , as well as had higher clinical sbp , dbp and night sbp . during ett , patients in quartile 4 showed the earliest target - hr achievement and lowest exercise capacity . there was no significant difference in alcohol consumption , smoking history and lipid profile across the quartiles . participants in the highest quartile showed a greater increase in sbp and a lesser decrease in dbp at submaximal and maximal exercise bp . in the correlation matrix ( table 4 ) , the absolute value of stage 4 sbp showed strong positive correlation with the change of sbp at stage 4 ( r=0.791 , p=0.001 ) and the absolute sbp value at maximal workload ( r=0.680 , p=0.001 ) , whereas relationship with the dbp variables were weaker . unadjusted survival analysis using the kaplan  meier method showed that the 5-year overall survival rate did not differ significantly among quartiles 14 ( 100% vs. 96.6% vs. 94.4% vs. 98.3% , p=0.211 ) . however , there was a trend of lower 5-year event - free survival rate in a higher quartile ( 98.3% vs. 95.0% vs. 88.2% vs. 86.9% , p=0.064 ) . compared with patients in quartile 1 , the 5-year event - free survival rate was significantly lower for patients in quartiles 3 ( 86.9% vs. 98.3% , p=0.022 ) and 4 ( 88.2% vs. 98.3% , p=0.023 ) . , more cardiovascular events occurred in a higher quartile ( 1.3% vs. 3.9% vs. 10.3% vs. 9.9% , p=0.028 ) and the difference in event - free survival was mainly driven by new - onset ihd . results of multivariable models relating exercise bp to the composite risk of death , ihd and stroke are shown in table 6 . after adjusting for resting sbp and dbp , we found that , compared with patients in quartiles 1 and 2 , those in quartiles 3 ( hr 4.52 , 95% confidence interval ( ci ) 1.3315.29 , p=0.015 ) and 4 ( hr 5.16 , 95% ci 1.4218.88 , p=0.013 ) were at significantly higher risk of composite outcomes ( see table 6 ) . these differences remained significant after adjusting for framingham risk scores . in model 3 , even after adjustment for known risk factors , exercise capacity and abpm data , patients in quartiles 3 and 4 tended to have higher risks of composite outcomes than those in quartile 1 , however , the difference was not significant for those in quartile 4 . however , when assessing quartiles as a continuous variable , multivariate analysis models showed that each 8-min sbp increment was associated with an increase in hr of 1.76 ( 95% ci 1.122.78 , p=0.010 ) , which remained significant after adjusting for resting sbp , dbp , framingham score and all the other variables . ( hr 1.74 , 95% ci 1.042.89 , p=0.035 ) . further analysis comparing 8-min sbp > 180 ( upper 50% of total population ) and 180  mm  hg ( lower 50% of total population ) showed that the former group was at significantly increased risk of composite end points ( hr 3.74 , 95% ci 1.2411.28 , p=0.019 ) , even after adjustment for all the other variables ( hr 4.00 , 95% ci 1.1913.44 , p=0.025 ) . the most important finding of this study of patients with uncomplicated mild - to - moderate sht was that those in higher quartiles were associated with higher risk of the composite end point in unadjusted analysis . during ett , patients in higher quartiles showed greater incremental increases in sbp and lower decrements in dbp . clinically , patients in higher quartiles had higher daytime and night sbp during abpm , as well as more risk factors for cvd , including higher framingham score and body mass index and lower exercise capacity . moreover , patients in higher quartiles were at high risk of the composite end point , even after adjustment for known cvd risk factors . although most prior studies focused on peak sbp at maximal workload , we considered sbp at submaximal workload in the naughton / balke protocol as more valuable for several reasons . first , because submaximal workload was easily achieved by patients with lower exercise capacity , we could include representative data from more patients . second , because the naughton / balke protocol used smaller increments in workload , this protocol could more accurately portray functional capacity than the bruce protocol , as well as minimizing contamination by mental factors . third , we regarded data from a treadmill test as more valuable than data from a bicycle ergometer because maximal oxygen uptake is generally lower on the latter . moreover , because the legs of individuals from east asia are usually shorter than those of caucasians , a bicycle ergometer may underestimate the exact workload of exercise . in addition , all of our patients underwent abpm monitoring at the beginning of treatment , thus , confirming sht and allowing abpm data to be integrated into multivariate analysis models . as a result , our study included a homogeneous group of patients with mild - to - moderate sht relevant to clinical practice , allowing the independent prognostic value of ett results to be determined . large population studies have shown an association between sbp response during submaximal ett and cvd . for example , the relationship between submaximal sbp and cardiovascular mortality was assessed in normotensive patients using a bicycle ergometer . that study showed that 6-min sbp , representing 55% of the mean exercise capacity of the entire population , was associated with cardiovascular mortality after multivariate adjustment , a finding consistent with our results despite our inclusion of only hypertensive patients . in addition , a study of > 6000 patients found an association between bruce stage 2 sbp 180  mm  hg and future cvd in non - hypertensive patients . in extending these findings to hypertensive patients , we found that a greater increase in bp was associated with higher morbidity and mortality rates and was a clinical risk factor for cvd . the mechanism underlying the association between exercise sbp response and cvd has not yet been determined . in healthy patients , an increase in cardiac output is usually accompanied by an increase in sbp , but may be attenuated by adaptive vasodilatation of peripheral vessels . an exaggerated sbp response during ett has been regarded as a consequence of mismatching between these two mechanisms . interestingly , outcomes in our patients were exactly the opposite of that in patients with known ihd , in that exaggerated exercise sbp had protective effects on outcomes , which may be associated with better cardiac output augmentation . because we excluded patients with impaired cardiac output augmentation , this mechanism may be reflected in the characteristics of the bp response in the patients in higher quartiles of the present study , including greater sbp increment and reduced dbp decrement , despite lower exercise capacity , higher daytime and night sbp during abpm monitoring . a continuous exposure to high bp during daily activity may lead to a high cvd rate for patients in the upper quartiles . in addition to their differing sbp response , the differences in baseline characteristics among patients in different quartiles may have affected the clinical outcomes . patients in higher quartiles were older , had higher body mass index and clinical and abpm bp , and lower exercise capacity than those in lower quartiles . in particular , the framingham general cvd score , a strong prognostic factor , was significantly higher for patients in quartile 4 . the submaximal ett response among our patients was well correlated with their general cvd risk factors , resulting in differences in primary outcomes on unadjusted survival analysis . thus , in addition to being an independent prognostic factor , higher sbp response during ett may itself be a marker of future cvd risk . the primary limitations of our study were the relatively small patient cohort and short follow - up period , resulting in a relatively low incidence of clinical events . the limitation in cohort size was mainly due to the exclusion of patients with pre - existing cvd and those at high risk of cvd . a follow - up period of 5 years may be too short to show the clinical significance in patients at mild - to - moderate risk . to overcome the limited numbers of patients and observed events , we had to use the framingham risk score as a surrogate marker of many cardiovascular risk factors such as age , sex , smoking status and lipid profiles . as a result , age and sex itself were not included in our three - step models because of the limited number of observed events and multicollinearity . and we had to summate the quartiles 1 and 2 as a reference to calculate the hr of quartiles 3 and 4 . however , our exclusion criteria enabled our assessment of new cvd in a homogeneous patient group , and these patients could be intensively followed - up because the study was performed in a single center . because some of our patients may have become fatigued before reaching their maximal exercise capacities , we may have underestimated maximal bp . however , the submaximal sbp we observed was likely correct because almost all of the patients exercised for more than stage 4 . in conclusion , the submaximal sbp response at stage 4 ( 8  min ) of the naughton / balke protocol may be a good predictor of future cardiovascular events in patients with mild - to - moderate sht . and patients with stage 4 sbp > 180  mm  hg were at significantly higher cardiovascular risk , even after adjustment for other risk factors , than those with lower sbp .
the relationship between blood pressure ( bp ) response during exercise and future cardiovascular events remains unclear . 
 we assessed the association between an increase in early systolic bp ( sbp ) during exercise tests and future cardiovascular events in patients with sustained hypertension ( sht ) . between 2002 and 2005 , we enrolled 300 patients newly diagnosed with mild - to - moderate sht without complications from the asan ambulatory blood pressure monitoring registry . 
 all the patients successfully performed treadmill tests , achieving target heart rate according to the naughton / balke protocol . 
 the patients were divided into quartiles according to their sbp at 8  min ( 7.4 metabolic equivalent tasks ) . 
 the primary outcome was the composite of all - cause death , new - onset ischemic heart disease and stroke . 
 the 5-year survival rates did not differ significantly among quartiles 14 ( 100% vs. 96.6% vs. 94.4% vs. 98.3% , p=0.211 ) . 
 relative to quartile 1 , the 5-year event - free survival rates were significantly lower in patients in quartiles 3 ( 86.9% vs. 98.3% , p=0.023 ) and 4 ( 88.2% vs. 98.3% , p=0.023 ) . 
 after multivariable adjustment for covariates , the risk for the composite end point was higher for patients in quartiles 3 ( hazard ratio ( hr ) 4.69 , 95% confidence interval ( ci ) 1.2817.13 , p=0.020 ) and 4 ( hr 3.65 , 95% ci 0.9214.50 , p=0.065 ) than in quartiles 1 and 2 . 
 cardiovascular risk was significantly higher in patients with stage 4 sbp ( > 180  mm  hg ) even after adjustment ( hr 4.00 , 95% ci 1.1913.44 , p=0.025 ) 
 . increased submaximal sbp response to exercise may be a predictor of future cardiovascular events in patients with mild - to - moderate sht .