Type 2 diabetes is associated with a reduction in maximal exercise capacity (V˙O2max) (5,17,18). Abnormal systemic oxygen transport to tissues might contribute to such an alteration in exercise performance. Specific parameters related to cardiac function could be responsible for this diminished V˙O2max (14,19). Among them, the presence of left ventricular diastolic dysfunction (LVDD) has been negatively related to exercise performance in these patients (14).
The impact of exercise training on diabetic cardiomyopathy-more precisely, on LVDD-is not well understood. Even if exercise is considered a component of the therapeutic triad of type 2 diabetes along with diet and hypoglycemic agents, studies that have examined the specific effect of exercise on LVDD in subjects with type 2 diabetes, without associated hypertension or coronary artery disease, are sparse (12,23,24). Interestingly, it has been shown that endurance exercise training could enhance impaired LV diastolic filling in individuals without diabetes (6,11,21), but, to our knowledge, there is no reported study in subjects with well-controlled diabetes. Alterations in heart rate variability (HRV) have been reported in patients with type 2 diabetes and LVDD (16). Of note, aerobic exercise training may also improve HRV (3,27).
Accordingly, the aim of the present study was to evaluate the impact of aerobic exercise training on LVDD and HRV in patients with well-controlled, uncomplicated type 2 diabetes. We hypothesized that aerobic exercise training would improve V˙O2max and positively alter LVDD and HRV in these patients.
Twenty-three sedentary subjects (ages 35-67 yr) with well-controlled type 2 diabetes and LVDD participated in the study. The control of diabetes was confirmed for 3 months before the study, according to standard clinical criteria. All subjects were treated with oral hypoglycemic agents (metformin, glyburide, and/or glyclazide) and/or diet. No subject was on insulin. Exclusion criteria were the presence of cardiovascular disease, documented from a symptom-limited exercise protocol before enrollment in the present study; a documented office blood pressure above 140/90 mm Hg; and the presence of clinically significant comorbidities related to diabetes-that is, renal failure (creatinine above normal upper limit), macroalbuminuria, proliferative retinopathy, and clinically significant sensitive motor or autonomic neuropathies. After initial evaluation, each subject was randomized to either the exercise training or the control group, using a simple randomization table, with age taken into account. The study was approved by the local hospital ethics committee in accordance with the Helsinki declaration, and all subjects gave written informed consent.
At the beginning and end of the exercise training period, a fasting blood profile, cardiac echocardiographic study, HRV evaluation (only in the EX group), and maximal exercise protocol for evaluation of V˙O2max in each subject were performed.
Blood samples were drawn at the beginning and end of the aerobic exercise program for measurement of lipids, glycated hemoglobin (HbA1c), and fasting blood glucose (FBG). FBG was assayed using the hexokinase method (Roche Diagnosis, Indianapolis, IN). Glycated hemoglobin (HbA1c) was assayed using the ion-exchange high-performance liquid chromatography (HPLC) method (Bio-Rad,Hercules, CA). Serum total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol were analyzed as previously described (14,15). Low-density lipoprotein (LDL) cholesterol was calculated using Friedewald‘s formula (7). The cholesterol/HDL ratio was also calculated.
Standard parasternal short-axis, long-axis, and apical views were performed in accordance with the recommendations of the American Society of Echocardiography, with the same observer obtaining all recordings and measurements (Sonos 5500; Hewlet Packard, Andover, MA) (15). Left ventricular mass (LVM) and thickness were evaluated by M-mode Doppler. LVM was calculated using the following formula (9): LVM (g) = 0.8 × 1.04 [(LVEDD + IVST + PWT)3 − (LVEDD)3] + 0.6, where LVEDD is the LV end diastolic dimension, IVST is the interventricular septal thickness, and PWT is the posterior wall thickness. The ejection fraction was evaluated by Simpson‘s method (20).
LVDD was evaluated using standardized criteria (4,15). First, transmitral pulsed Doppler recordings were obtained, and the following parameters were measured: peak E velocity in centimeters per second (peak early transmitral filling velocity during early diastole), peak A velocity in centimeters per second (peak transmitral atrial filling velocity during late diastole), deceleration time in milliseconds (time elapsed between peak E velocity and the point where the extrapolation of the deceleration slope of the E velocity crosses the zero baseline), isovolumetric relaxation time (time elapsed between aortic valve closure and mitral valve opening), and E/A ratio (peak E wave velocity divided by peak A wave velocity). To reduce thehigh filling pressures encountered in the pseudonormalized pattern of left ventricular (LV) filling, the same measurements were repeated during phase II of the Valsalva maneuver (15).
Pulmonary venous flow recordings were obtained from the four-chamber view directed at the right upper-pulmonary vein. A sample volume was placed 1-2 cm into the pulmonary vein for the measurement of peak A wave velocity in centimeters per second (peak reversed systolic waved during atrial contraction). To distinguish the pseudonormalized pattern of ventricular filling, two of the three following criteria had to be met: 1) the E/A ratio was less than 1 after the Valsalva maneuver; 2) the E/A ratio decreased by ≥ 25% after the Valsalva maneuver; and 3) pulmonary A wave duration was longer than mitral A wave duration (15).
Heart rate variability.
Heart rate variability (HRV) was derived from a 24-h Holter monitoring system (Marquette Electronics, Milwaukee, WI) at baseline and after exercise training in eight subjects from the EX group during activities of normal daily living. HRV derived from 24-h ambulatory monitoring is reproducible and free of placebo effect (25). Using time domains, the standard deviation (SD) of the RR intervals (SDNN), the square root of the mean squared differences of successive RR intervals (rMSSD), and the SD of the average RR intervals calculated for 5-min periods (SDANN) were determined. pNN50 is the proportion of interval differences of successive NN intervals > 50 ms. rMSSD and pNN50 are indices of parasympathetic modulation. NN intervals are the normal-to-normal intervals that include all intervals between adjacent QRS complexes resulting from sinus node depolarizations in the entire 24-h electrocardiogram recording.
Exercise capacity was evaluated in each subject using an incremental protocol of 15 W·min−1 after a warm-up period of 3 min at 25 W, performed on an electromagnetically braked cycle ergometer (Corival, Lode, Netherlands) at a pedaling rate of 50-70 rpm. Expired air was continuously recorded on a breath-by-breath basis for the determination of V˙O2 and carbon dioxide production (V˙O2). The HR was obtained from electrocardiographic monitoring. Blood pressure was measured every 2 min using an automated sphygmomanometer with a headphone circuit option (Model 412, Quinton Instrument Co., Bothell, WA). V˙O2max was defined as the mean V˙O2 recorded in the last 25 s of the incremental exercise protocol. The exercise protocol was always performed in the fasting state at the same time of the day and at 19°C room temperature. The initial V˙O2max measurement was used to prescribe the workload for the aerobic exercise training program, and the second V˙O2max was evaluated to measure the overall improvement in aerobic capacity induced by the exercise training.
Exercise training program.
Aerobic exercise training was performed under the supervision of an exercise specialist. The workload was fixed at 60-70% of V˙O2max and was based on heart rate assessed during the maximal exercise protocol. Exercise was performed on a cycle ergometer three times per week. Within the first 3 wk of the 12-month aerobic exercise training, the duration of each session was rapidly increased from 30 to 60 min. Resistance training was not performed by any subject.
The Student‘s unpaired t-test was used to evaluate differences between groups. Differences within groups were evaluated with the Student‘s paired t-test. The Mann-Whitney test was used for data that were not normally distributed. When appropriate, Pearson‘s correlation coefficient was used for the analysis of associations between variables. All data are presented as means ± SD, unless otherwise specified. A P value < 0.05 was considered statistically significant.
At baseline, anthropometric and hemodynamic data were similar between the groups, except for body mass index (BMI), which was higher in CONT (31 ± 3 vs 28 ± 3 kg·m−2; P < 0.05). The two groups were comparable in terms of glycemic control, lipid profile (Table 1), cardiac structure measurements, functions (Table 2), and HRV parameters (data not shown), as well as maximal oxygen uptake (26.7 ± 5.9 vs 28.6 ± 3.9 mL·kg−1·min−1; P = 0.4). Of note, CONT subjects had a nonsignificantly higher resting systolic blood pressure compared with EX subjects (Table 1).
Impact of exercise training.
V˙O2max increased by 13% in the EX group after exercise training (28.6 ± 3.9 vs 32.7 ± 5.7 mL·kg−1·min−1; P < 0.05), whereas there was no change in the CONT group (26.7 ± 5.9 vs 27.3 ± 6.2 mL·kg−1·min−1; P = 0.58) (Fig. 1). In the EX group, there was a trend for higher maximal workload (143 ± 50 vs 188 ± 46 W; P = 0.06), but there were no significant changes in maximal HR (156 ± 13 vs 157 ± 13 bpm; P = 0.79), maximal systolic blood pressure (224 ± 25 vs 226 ± 16 mm Hg; P = 0.79), and maximal diastolic blood pressure (95 ± 12 vs 88 ± 12 mm Hg; P = 0.26) during the maximal exercise protocol after the exercise training program. There also were no significant changes in these parameters in the CONT group during the period of study (data not shown). An increase in HbA1c and a reduction in LDL cholesterol were observed in both groups after the 12-wk period. A significant reduction in cholesterol was observed in the CONT group only. There were no significant changes in BMI in both the EX and CONT groups (Table 1).
Normalization of LVDD was observed in 5 of 11 EX subjects (P < 0.0001) after exercise training. Among these, four subjects went from a grade 1 LVDD to a normalization of their LV diastolic function, whereas the other subject went from a grade 2 LVDD to normalization of his LV diastolic function (Fig. 2). Aside from these improvements, exercise training had no significant impact on cardiac structures and functions (Table 2) and on HRV (data not shown). No change in LVDD, systolic LV function and cardiac structures were observed in the CONT group, except for a significantly longer IVRT (Table 2). Of note, there were no significant correlations between changes in LVDD and V˙O2max or between changes in LVDD and HRV parameters in the EX group.
The results of this study demonstrate that, along with an important improvement in V˙O2max, aerobic exercise training may normalize LVDD in subjects with well-controlled, uncomplicated type 2 diabetes. To our knowledge, this is the first study to report the positive impact of exercise training on both V˙O2max and LVDD in this population.
In different populations, the presence of LVDD is related to a reduced exercise performance (10,14). In patients with type 2 diabetes, the presence of LVDD, not diabetes per se, could initially affect V˙O2max. This might be triggered by a worsened lipid profile, which, in turn, would affect HRV and the cardiopulmonary function (unpublished observations). In fact, a lower LV diastolic filling, stroke volume, and chronotropic response are likely contributors to such a reduced exercise performance (10). Accordingly, an improvement in LVDD would be therapeutically relevant to enhance the ability of patients with type 2 diabetes to perform exercise and activities of daily living.
In the present study, 45% of patients engaged in an aerobic exercise training program normalized their LVDD, whereas no change was encountered in patients who were not performing aerobic exercise training. This reversal was mostly encountered in patients having LVDD of grade 1 (Fig. 2). Some authors have stressed that improvements in LV diastolic function after exercise training would mostly be present in patients with impaired relaxation, rather than in those with more advanced LVDD, such as pseudonormal or restrictive filling patterns. Smart et al. (22) have recently reported no beneficial impact of 16 wk of aerobic and strength exercise training on LV diastolic function in patients with LVDD. A majority of the patients engaged in the exercise training program had pseudonormal patterns of LVDD (22). Of note, one patient who performed aerobic exercise training in the present study normalized his diastolic function from a grade 2 LVDD. The finding in this study that the patients with a milder form of LVDD improved their diastolic function with exercise training, whereas the majority of patients with more severe LVDD did not, raises the possibility that a longer period of training might be necessary to improve more severe LVDD. We believe this hypothesis merits testing in future studies.
LV diastolic compliance is preserved in older master athletes compared with age-matched and young controls (1). Compared with normally active individuals, endurance-trained athletes have an enhanced ability to increase LV end diastolic volume and stroke volume during exercise (8). Furthermore, the known beneficial influence of exercise training in patients with LV systolic dysfunction might be related to improvements in LVDD (2). More precisely, this improvement would be attributable to a reduction in diastolic wall stress (13). In type 2 diabetes, if the presence of LVDD negatively affects exercise performance as reported (14), it could be argued that a reversal in LVDD to a normalized LV diastolic function should be associated with an increased maximal exercise capacity. In the current study, a 3-month aerobic exercise training program led to a 13% increase in V˙O2max, whereas no change was observed in controls. Because fitness level is positively associated with stroke volume (8), our aerobic exercise training regimen might have triggered an enhanced exercise-induced stroke volume increment, associated with a higher cardiac output and V˙O2max. This beneficial impact of exercise on LV diastolic function and V˙O2max was not associated with BMI, LDL cholesterol, or glycemic control improvements.
This study has some limitations. The number of subjects studied was relatively small, and these results might only be applicable to well-controlled, uncomplicated patients with type 2 diabetes. In addition, no tissue Doppler velocities measurements were acquired. Accordingly, the beneficial impact of aerobic exercise training on LVDD might have been influenced by load-dependent factors. However, this is unlikely, because our EX group experienced an increase in V˙O2max that is compatible with enhanced LVDD.
Future studies might evaluate the prognostic implications of improved diastolic function achieved through exercise training in subjects with type 2 diabetes. Our findings raise the provocative possibility that improved diastolic function through exercise training may be a mechanistic link accounting for the improved prognosis that studies have shown physical activity to confer (26).
This study suggests that, along with a considerable improvement in V˙O2max, aerobic exercise training has the potential to reverse LVDD in patients with well-controlled, uncomplicated type 2 diabetes.
Patrice Brassard is the recipient of a graduate research scholarship in pharmacy (PhD) from the Rx & D Health Research Foundation (HRF) Awards Program, funded in partnership with the Canadian Institutes of Health Research (CIHR). Paul Poirier is a clinician-scientist of the Fonds de la Recherche en Santé du Québec (FRSQ).
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Keywords:©2007The American College of Sports Medicine
AEROBIC EXERCISE; CARDIAC FUNCTION; TYPE 2 DIABETES; V˙O2max