Abstract
Introduction. The aim of this study was to investigate the blood pressure (BP) response to exercise in normotensive patients with type II diabetes mellitus (DM). Materials and methods. A cross-sectional study was carried out on 75 normotensive subjects with type 2 DM (group 1), and 70 age-gender matched normotensive healthy volunteers (group 2). Treadmill exercise test, 24-h ambulatory BP monitoring (ABPM) were performed for each patients and healthy volunteers. Results. There were 67 patients (mean age 52 ± 9 years and 42% male) in group 1 and 68 healthy volunteers (mean age 51 ± 7 years and 43% male) in group 2. Eight patients from group 1 and 2 subjects from group 2 were excluded because of high BP on ABPM. Groups were similar for systolic BP (SBP) and diastolic BP (DBP) on office measurements and on ABPM. Groups were similar for rest SBP, DBP, heart rate, exercise duration on exercise test. Peak SBP was significantly higher in group 1 than in group 2, but peak DBP was not (196.9 ± 18 vs 165.9 ± 18.6 mmHg, p 0.001; 88.1 ± 11.6 vs 86.2 ± 8.7 mmHg, p = 0.283, respectively). Hypertensive response to exercise (HRE) was more frequent in group 1 than in group 2 [39 (58%) vs 6 (9%), p 0.001]. Independent predictors of peak SBP were DM, office SBP and male gender, while independent predictors of HRE were DM, office SBP and age in multivariate analysis. Conclusions. SBP response to exercise is exaggerated in normotensive diabetic patients compared with non-diabetic subjects. DM, office SBP and male gender are independent predictors of peak SBP. DM, office SBP and age are independent predictors of HRE.
Introduction
The hemodynamic changes during exercise may be a predictor of cardiovascular diseases or give hints about the current cardiovascular status of patients. An abnormal rise in blood pressure (BP) response to exercise, called the hypertensive response to exercise (HRE) was determined as a predictor of development of unborn hypertension (HT) in subjects with normal BP at resting (Citation1), as an indicator of endothelial dysfunction, which has an important role in the pathophysiology of cardiovascular diseases (Citation2), as a marker of left ventricular hypertrophy and remodeling (Citation3,Citation4) and also mortality (Citation5).
The incidence of HT is higher in patients with diabetes mellitus (DM) than the normal population. Elevation of BP indicates higher cardiovascular mortality in patients with DM (Citation6–8). However, diabetic patients with normal BP have also high cardiovascular mortality. Scott et al. (Citation3) showed that up to half of diabetic patients with normal office BP have HRE. Furthermore, patients with HRE and normal BP at the office were evaluated in a study, and it was found that 58% of the patients had high BP on ambulatory BP monitoring (ABPM) (Citation4). This finding shows that many patients with HRE have also masked HT. HRE frequency has not been evaluated in diabetic patients with normal BP on ABPM previously. Therefore, we aimed to investigate the BP responses to the exercise and its relevance in patients with type 2 DM who have normal BP on ABPM.
Materials and methods
Study population and protocol
Seventy-five consecutive type 2 diabetic patients without history of HT and with normal BP on ABPM (group 1) were included to the study. The control group consisted of 70 healthy volunteers without DM, with normal BP on ABPM (group 2). Type 2 DM was defined as fasting plasma glucose (FPG) higher than 125 mg/dl and/or a 2-h post-glucose challenge higher than 200 mg/dl and using antidiabetic medication history. Office BP, ABPM, treadmill exercise test, electrocardiography and blood sampling for laboratory analyses were performed for each subjects. Detailed history was recorded. Exclusion criteria were HT, cardiovascular disease including coronary artery disease, congestive heart failure, congenital heart disease, mild or moderate valvular heart disease, peripheric vascular disease, established chronic renal failure or serum creatinine levels 1.5 mg (132 μmol/l), chronic obstructive pulmonary disease, thyroid dysfunction, anemia, history of an implanted pacemaker, pre-excitation syndrome, left bundle branch block, atrial fibrillation, frequent ventricular premature beat and any other medication that would affect BP such as nasal decongestants, and having incomplete exercise or orthopedic problems that would preclude maximal effort on the treadmill. Also, patients with masked HT were excluded after ABPM. They gave informed consent after the nature of the procedures had been explained. The local ethics committee approved the study.
Blood pressure measurements
Office BP was measured three times in the seated position by a cardiologist using a mercury sphygmomanometer after 10 min resting. The average of the three measurements was used for the representative examination value. Proper cuff size was determined based on arm circumference. The measurement was performed under controlled conditions in a quiet room.
Twenty-four-hour ABPM was performed for all subjects with the Space-Labs 90207 (Redmond, WA, USA). The cuff was mounted on the non-dominant arm between 08:00 and 09:00 h, and removed 24 h later. Cuff size was chosen according to arm circumference. The device was programmed to register BP at 15-min intervals in the daytime and at 30-min intervals at night-time for the 24-h period. The majority of records were performed on working days. The subjects were instructed to maintain their usual activities and keep their arm immobile at the time of each cuff inflation. Valid records had to fulfill a series of pre-established criteria, including at least 80% of SBP and DBP successful recordings during the daytime and night-time periods, 24-h duration, and at least one BP measurement per hour. Evaluation was performed taking the mean values of day and night BPs into account. Daytime and night-time periods were defined individually according to the patient's self-reported data. Subjects were classified as hypertensive if the daytime value of SBP was 140 mmHg or DBP was 90 mmHg, or night-time value of SBP was 125 mmHg or DBP was 75 mmHg on ABPM (Citation6,Citation9). Each reading was edited by the computer and manually, and outliers (SBP 80 mmHg or 260 mmHg; or diastolic BP 40 mmHg or 150 mmHg; and HR 40 or 150 beats/min) were deleted.
Exercise test assessment
The exercise test was processed on all subjects by treadmill according to the Bruce protocol. A 12-lead electrocardiogram was obtained throughout the test. Resting SBP and DBP were the average of three measurements taken in a seated position by a cardiologist. Exercise BP values were measured during the last minute of each 3-min stage and at peak exercise, and within 1 and 3 min after the cessation of exercise, using by indirect arm-cuff oscillometric sphygmomanometer in the right arm according to guidelines. Exercise capacity was recorded as peak exercise time in minutes. Peak exercise workload was estimated on the basis of the speed and grade of the treadmill and recorded as metabolic equivalents (1 MET equals 3.5 ml of oxygen uptake per kilogram of body weight per minute). Target heart rate was determined as 85% of predicted heart rate. Predicted heart rate was defined as 220 − age. Subjects were encouraged to exercise until achieving target heart rate in the absence of symptoms or other indicators of ischemia. The highest SBP value achieved during the exercise stress test was the peak exercise SBP. The HRE was defined as a peak exercise SBP ≥ 210 mmHg in men, or SBP ≥ 190 mmHg in women or DBP ≥ 105 mmHg in all subjects, in line with the Framingham criteria (Citation10).
Statistical analysis
Continuous variables were tested for normal distribution by the Kolmogorov–Smirnov test. We report continuous data as mean and standard deviation or median. We compared continuous variables using the Student t-test or Mann–Whitney U test between groups. Categorical variables were summarized as percentages and compared with the χ2 test. Correlation analyses between parametric variables were tested by Pearson's and non-parametric variables with Spearman's correlation coefficient. Linear regression analysis was performed to estimate the contribution proportion of the peak SBP predictors. Logistic regression analysis was performed to estimate predictors of HRE. A two-sided p-value 0.05 was considered significant and confidence interval (CI) was 95%. All statistical analyses were performed with the SPSS version 15 (SPSS, Inc., Chicago, IL).
Results
Eight patients from group 1 and 2 subjects from group 2 were excluded because of high BP on ABPM. The data from 67 patients from group 1 and 68 of group 2 were analyzed. There were 67 patients (mean age 52 ± 9 and 42% male) in group 1 and 68 healthy volunteers (mean age 51 ± 7 and 43% male) in group 2. Comparisons of baseline and ABPM characteristics between groups are shown in . The mean DM duration of group 1 was 5.2 ± 4.1 years. Except one patient newly diagnosed, all patients were on at least one oral antidiabetic drug (78%) and insulin therapy (22%). Levels of fasting plasma glucose (FPG) and HbA1C were higher in group 1 than in group 2, but not significantly different.
Table I. Baseline characteristics.
shows hemodynamic data of both groups during exercise test. Onset heart rates, SBP and diastolic BPs, and exercise time and workloads were not different. After beginning to exercise, SBP was significantly higher in group 1 at all stages, especially at peak exercise (). However, diastolic BP showed no difference. HRE was significantly higher in group 1 than in group 2 (58% vs 9%, p 0.001). At first minute of recovery, SBP was higher in group 1 than group 2, but diastolic BP (DBP) levels in all stage of recovery were similar between the groups. Pulse pressures were similar among the groups at rest, but peak pulse pressure of group 1 was higher than group 2. ΔSBP (peak SBP − rest SBP) was also significantly higher in group 1 than in group 2, but ΔDBP (peak DBP − rest DBP) was similar among the groups ().
Table II. Exercise test results of groups.
Figure 1. Blood pressures in patients with type 2 diabetes mellitus (group 1) compared with healthy volunteers (group 2) at rest, during exercise and in 24-h ambulatory blood pressure monitoring. DM, diabetes mellitus; HV, healthy volunteers.
For evaluation, the correlates of multiple variables with exercises peak SBP, univariate and multivariate linear regression analyses was performed (). The variables for which the unadjusted p-value was 0.05 in univariate analysis were adjusted to the full model. At multivariate linear regression analysis, type 2 DM (r = 0.61, p 0.001), office SBP (r = 0.28, p = 0.033) and male sex (r = 0.12, p = 0.046) were independently correlated with exercise peak SBP. Also, we performed the logistic regression analyses to identify the independent predictors of HRE in the study population and DM (odds ratio, OR = 20.699, 95% CI 6.538–66.157; p 0.001), office SBP (OR = 1.106, 95% CI 1.055–1.160; p 0.001) and age (OR = 0.067, 95% CI 0.044–0.108; p = 0.025) were independent predictors of HRE ().
Table III. Independent correlates of exercise peak systolic blood pressure in linear regression analysis.
Table IV. Independent predictors of hypertensive response to exercise in logistic regression analysis.
Discussion
This study showed that SBP response and HRE frequency are higher in type 2 DM patients compared with non-diabetics who were normotensive on ABPM. In addition, type 2 DM, office SBP and male gender were independently correlated with exercise peak SBP, and type 2 DM, office SBP and age were independent predictors of HRE.
Previous studies showed the increased BP response to exercise in patients with insulin resistance (Citation11) and overt diabetes (Citation3). However, subjects could be normotensive on office measurements but hypertensive on ABPM, which is called masked HT (Citation12,Citation13). In a previous study, 14.5% of these subjects were hypertensive on ABPM, when their office BPs were normal (Citation14). Another study showed this situation was as frequent as 30% in patients with type 2 DM (Citation15). Leitao et al. (Citation16) showed that HT could not be diagnosed optimally in 38% of diabetic patients with borderline BP via office measurements and ABPM was recommended to the patients whose BP is between 120/70 and 140/90 mmHg. In the present study, we diagnosed HT in 11% of diabetic patients and 3% of control subjects via ABPM whose office BPs were normal. We excluded these subjects from the study and evaluated the HRE in diabetic patients who are normotensive on office measurements and ABPM.
The frequency of HRE variation in previous studies (Citation3,Citation10,Citation15) might be related to discrepancies in study populations like demographic properties, office BP, and the chosen cut-off value for HRE. There was an exaggerated BP response to exercise, including some based solely on SBP (Citation17,Citation18) and others on SBP and DBP together (Citation19). Additionally, it has been indicated that the cut-off point separating normal from abnormal responses should be determined according to gender, age, and physical fitness (Citation20). We used the Framingham study criteria for HRE definition (Citation10); also we used quantitative BP measurements for comparison, and we observed higher peak SBP and HRE frequency in normotensive diabetic patients comparing control subjects.
HRE might be caused by DM-related situations like hyperinsulinemia (Citation21), increased aortic stiffness (Citation22), vascular dysfunction (Citation22), increased sympathetic activity (Citation23), nephropathy (Citation23) and increased rennin–angiotensin–aldosterone system activity (Citation24) in diabetic patients. Also, endothelial dysfunction, which is frequently seen in diabetics, was shown to have an impact on exercise BP (Citation22). Masked HT and HRE might be similar in pathophysiology. Office BP is in the normal range in both situations. Hypertensive response is seen in masked HT with usual daily physical activities, and HRE is seen in more than usual daily physical activities. Morbidity and mortality are increased in both of them. Kramer et al. (Citation24) showed BP response to exercise was more exaggerated in patients with masked HT comparing the truly normotensive patients with type 2 DM (Citation24).
HRE was studied and shown to be a predictor for morbidity and mortality in healthy subjects (Citation5), mild to moderate hypertensive men (Citation25), adults with coronary artery disease (Citation26), and non-diabetic hypertensives with insulin resistance (Citation9). This relation may be partially responsible for morbidity and mortality in diabetic patients. Also, this finding is supported by increased LV hypertrophy incidence in patients with HRE (Citation3,Citation10). Unfortunately, there is no guidance on follow-up and management of HRE. Target BP values for diabetics were arranged lower than for non-diabetics (Citation6,Citation27). This proposal might be useful for management of HRE, but some evidence does not support this. More recently, Schultz et al. (Citation28) showed that lifestyle modification including weight loss, dietary composition tailoring, and exercise training might attenuated the HRE developing in diabetic patients with normal exercise BP (Citation28). Close clinical follow-up and lifestyle modification might be recommendable for these patients. We need prompt prospective studies, which evaluate the anti- hypertensive treatment effects on HRE.
A possible limitation of the present study may be represented by the small number of patients.
Conclusions
SBP response to exercise increased in type II DM patients who were normotensive on ABPM. Type 2 DM and higher office SBP were found to be independent predictors for peak SBP and HRE. An increased SBP response to exercise may be explain the increased cardiovascular mortality in DM. Anti-hypertensive therapy necessity and the significance of other management options might be revealed by prospective studies for this population.
Conflict of interest: None.
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