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diabetes research and clinical practice 83 (2009) 249–256
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Diabetes Research and Clinical Practice journal homepage: www.elsevier.com/locate/diabres
Effects of lifestyle modification on central artery stiffness in metabolic syndrome subjects with pre-hypertension and/or pre-diabetes Kunihiko Aizawa a,b, J. Kevin Shoemaker b, Tom J. Overend a,c, Robert J. Petrella a,b,d,* a
Aging, Rehabilitation & Geriatric Care Research Centre, Lawson Health Research Institute at Parkwood Hospital, London, ON, Canada School of Kinesiology, Faculty of Health Sciences, The University of Western Ontario, London, ON, Canada c School of Physical Therapy, Faculty of Health Sciences, The University of Western Ontario, London, ON, Canada d Department of Family Medicine, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada b
article info
abstract
Article history:
Aims: To examine the effects of a 24-week lifestyle intervention prescribed by family
Received 19 August 2008
doctors on carotid artery stiffness in metabolic syndrome (MS) subjects with pre-hyperten-
Received in revised form
sion and/or pre-diabetes.
10 November 2008
Methods: Sixty-three middle-aged and older subjects with pre-hypertension and/or pre-
Accepted 12 November 2008
diabetes were divided into subjects without MS (MS) and with MS (MS+). MS components
Published on line 20 December 2008
and carotid artery stiffness by ultrasound were determined at baseline, at 8 weeks, and following the 24 weeks of lifestyle intervention. Family doctors prescribed an individually
Keywords:
customized lifestyle prescription for aerobic exercise and Mediterranean-style diet.
Ageing
Results: Carotid artery distensibility significantly increased in MS+ following the 24 weeks of
Artery
intervention compared with baseline (0.191 0.012 vs. 0.143 0.011, 1/mmHg 102,
Diet
p < 0.05). Similarly, b stiffness index decreased in MS+ following the 24 weeks of interven-
Exercise
tion (9.8 1.1 vs. 12.5 1.1 AU, p < 0.05). Following the intervention, waist circumference, BP and fasting glucose levels reduced in MS+ (all p < 0.05), and 13 MS+ subjects were free from MS. Conclusions: The results show the reduction of carotid artery stiffness and the improvement of some MS components in MS subjects, suggesting a favorable effect of our lifestyle modification strategy on central artery stiffness as well as MS components in MS subjects. # 2008 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
Metabolic syndrome (MS) is a constellation of cardiovascular disease (CVD) risk factors including atherogenic dyslipidemia, elevated blood pressure (BP), impaired glucose regulation, and abdominal obesity. This highly prevalent condition increases with ageing [1]. Compared to those without MS, individuals with MS have a 61% increased risk of CVD [2]). As the
population ages and the prevalence rate are expected to increase, there is an urgent need to develop a comprehensive strategy to decrease the prevalence and components of MS [1]. First-line therapy for MS is lifestyle modification [3] since the common causes of MS are poor diet and inadequate physical activity [1]. Regular aerobic exercise training has been shown to be associated with reduced development of metabolic risk factors in older adults [4]. Adoption of aerobic
* Corresponding author at: Aging, Rehabilitation, & Geriatric Care Research Centre, Parkwood Hospital, Room B3002, 801 Commissioners Rd., E. London, ON N6C 5J1, Canada. Tel.: +1 519 685 4292x42983; fax: +1 519 685 4060. E-mail address: [email protected] (R.J. Petrella). 0168-8227/$ – see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2008.11.016
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exercise training in healthy and sedentary middle-aged MS subjects has also been shown to be an effective strategy to reduce prevalence of MS [5]. Additionally, a recent study has shown that a 2-year Mediterranean-style diet intervention reduced the prevalence of MS by half [6]. Therefore, implementation of lifestyle modification incorporating both aerobic exercise and a Mediterranean-style diet in MS subjects appears a feasible strategy to delay the progression of MS risk factors and may in turn delay the need for drug therapies [3]. Age-associated central artery stiffness, an independent predictor of all-cause and cardiovascular mortality [7], has been observed to be synergistically increased in MS subjects (see review by Stehouwer et al. [8]). Increased central artery stiffness can be reversed by aerobic exercise in healthy middle-aged and older subjects [9]. In addition, some components of the Mediterranean-style diet have been shown to reduce age-associated central artery stiffness [8]. Hence, it is reasonable to hypothesize that lifestyle modification combining aerobic exercise with a Mediterranean-style diet may decrease age-associated central artery stiffness as well as MS components in MS subjects. The purpose of this study was to examine the effects of lifestyle modification (aerobic exercise and a Mediterraneanstyle diet) on central artery stiffness in MS subjects with prehypertension and/or pre-diabetes. We focused on these subjects because of (1) the results of recent studies showing that BP and glucose levels previously considered ‘‘normal’’ are associated with increased risk for developing CVD [10,11], and (2) the implication that early identification and treatment of these populations with lifestyle modification would be considerable in terms of prevention of hypertension, type 2 diabetes, and CVD.
2.2.
Metabolic syndrome was defined on the basis of the American Heart Association and National Heart, Lung and Blood Institute (AHA-NHLBI) guidelines [3] by the presence of three or more of the following criteria: (1) waist circumference 102 cm in men and 88 cm in women; (2) triglyceride levels 1.69 mmol/L; (3) HDL cholesterol levels <1.04 mmol/L in men and <1.29 mmol/L in women; (4) fasting plasma glucose levels 5.60 mmol/L; and (5) SBP 130 mmHg and/or DBP 85 mmHg.
2.3.
Subjects, materials and methods
2.1.
Subject
This study was a part of the SNAC (Staged Nutrition and Activity Counseling) study whose purpose was to evaluate the effectiveness of lifestyle modification (aerobic exercise and a Mediterranean-style diet) prescribed by family physicians on cardiovascular structure and function in those who had an increased cardiovascular risk (pre-hypertension and/or prediabetes). Sixty-three subjects (31M and 32F, 53.9 8.7 years) with either pre-hypertension (SBP 130–139 mmHg and/or DBP 85–90 mmHg), pre-diabetes (IFG 6.1–7.0 mmol/L and/or IGT 7.8–11.0 mmol/L following an oral glucose tolerance test), or both were studied. All subjects were otherwise healthy (no overt CVD) and none were taking any medications which may have affected BP and blood glucose levels. Eight subjects were on a cholesterol-lowering medication before starting the study and were allowed to continue their same drug regimen throughout the study period. All patients were referred from their own family physicians for this study. The study was approved by The University of Western Ontario Research Ethics Board for Health Sciences Research Involving Human Subjects and all subjects gave written informed consent prior to participation.
Study design
Subjects were studied in the early morning following an overnight fast (including caffeine). The following measures were assessed: blood chemistry (total cholesterol, HDL cholesterol, LDL cholesterol, tryglycerides, and plasma glucose) by routine laboratory methods, anthropometrics (height, weight, waist circumference), resting BP, arterial stiffness of the carotid artery (Doppler ultrasound), and exercise capacity by treadmill exercise test. These measures were repeated at 8 weeks and following the 24-week intervention. Each test was conducted in a temperature-controlled room and at the same time of day for each subject.
2.4.
Resting blood pressure and heart rate
Following a 10-min seated rest, brachial SBP and DBP, and heart rate (HR) were measured with an automated oscillometric device (BpTRUTM, VSM MedTech Ltd., Coquitlam, BC). All measurements were repeated after a further 5min rest.
2.5.
2.
Definition of metabolic syndrome
Arterial stiffness of the carotid artery
The measurement of arterial stiffness indices of the carotid artery was performed using a 10 MHz linear array transducer attached to a high-resolution ultrasound machine (VingMed System 5, GE Ultrasound A/S, Horton, Norway) as previously described [12]. All scans were performed by the same investigator and made under similar conditions. The longitudinal B-mode internal diameter of the right common carotid artery 1–2 cm proximal to the carotid bifurcation was imaged with simultaneous BP measurements of the left brachial artery. Images were recorded to S-VHS tape for later offline analysis. All images were analyzed by the same investigator. To characterize arterial stiffness, arterial distensibility and b stiffness index of the carotid artery were calculated [13]. Intima-media thickness (IMT) of the right common carotid artery was also assessed by the same device. The longitudinal B-mode images of the carotid artery IMT were assessed while subjects were in a supine position with the head turned approximately 458 away from the side examined. IMT was examined at a straight portion of the artery 1–2 cm proximal to the bifurcation. Carotid artery intima-media thickness was defined as the distance between the lumen–intima interface and media–adventitia interface of the far wall.
diabetes research and clinical practice 83 (2009) 249–256
2.6.
Maximal treadmill exercise
Subjects performed a graded exercise treadmill test (Bruce protocol) to volitional fatigue. Their exercise capacity was expressed as VO2max estimated from metabolic equivalents (METs) where 1 MET is 3.5 ml O2/(kg min).
2.7.
Lifestyle interventions
The lifestyle intervention incorporated in this study contained four components: Aerobic exercise, Mediterranean-style diet, Activity Diet Prescription, and Stage of Change. The intervention was delivered by each subject’s family physician.
2.7.1.
Aerobic exercise
Exercise capacity and training intensity were determined using the Step Test Exercise Prescription (STEP). Briefly, the STEP is a clinic-setting exercise counseling and prescription tool validated previously [14] and endorsed by the College of Family Physicians of Canada as part of an accredited Continuing Health Education strategy to improve physical activity education among family physicians. Each subject’s family physician administered the step test, which included stepping up and down two small (9.5 cm) steps at a comfortable pace 20 times. The stepping time (in seconds) and post exercise heart rate were recorded, followed by conversion to predicted maximal oxygen uptake (VO2max) and an exercise heart rate based on 75% of predicted VO2max [14]. Following the STEP, subjects were provided with a detailed aerobic exercise prescription based on the American College of Sports Medicine’s guideline [15], including frequency (most days of the week), intensity (moderate intensity), and duration (either 30 min or 3 bout of 10 min). Intensity of exercise during training was determined by radial artery palpation. Subjects were instructed to palpate the pulse for 10 s and multiply by 6 (for beats per minute).
2.7.2.
Mediterranean-style diet
Subjects were instructed to incorporate a Mediterranean-style diet characterized by an increased consumption of vegetables, legumes, fruits, and whole grains, the use of olive oil/ margarine as a main source of fat, and the intake of fish instead of red meat [16]. Moderate intake of red wine is allowed but limited only with meals and within the recommended standard drink servings per day. Water is considered the most appropriate beverage. To optimize familiarization with the diet and facilitate long-term adherence, during first 8 weeks, subjects received one dinner meal per day (5 meals per week) from the laboratory (prepared by The University of Western Ontario Food Services) as well as sample menus for breakfast and lunch. From week 9 on, subjects received only sample menus for all meals.
2.7.3.
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groups (grain products, fruits and vegetables, milk products, and meat and alternatives mainly coming from fish, poultry or legumes) that the patient should be eating per day.
2.7.4.
Stage of change
Prochaska and DeClemente’s ‘‘stage of change’’ model [17] was used to assist subjects to change their physical activity and nutritional behavior. Briefly, by administering the Stage of Change Questionnaires for Physical Activity and a Mediterranean-style Diet and using the algorithms for Physical Activity and a Mediterranean-style Diet, family physicians determined at what stage (precontemplation, contemplation, preparation, action, and maintenance) the patient was for both physical activity and diet. The physician then counseled subjects based on their change stage for both physical activity and diet using an appropriate stage-based counseling.
2.8.
Statistical analysis
Data are expressed as means S.D., unless otherwise stated. Baseline data between subjects without MS (MS) and with MS (MS+) were tested using an independent-samples t-test and one-way analysis of variance (ANOVA) for continuous variables, and a x2 test for categorical variables. Variables with skewed distribution were log-transformed before statistical analysis. Repeated measures ANOVA tests were used to compare differences at baseline, at 8 weeks and following the 24 weeks of SNAC intervention. When a significant main effect was observed, a Bonferroni post hoc test was performed. As arterial stiffness is influenced by changes in mean arterial pressure (MAP), analysis of covariance (ANCOVA) was performed with MAP as a covariate. Because of the concern that eight subjects who had been taking a cholesterollowering medication might have caused a significant confounding, separate analyses were performed by (1) comparing the difference in central artery stiffness between those who were on a medication and those who were not, and (2) excluding those eight subjects from the entire cohort. As no indication was found that the use of a lipid-lowering medication had a significant impact on central artery stiffness in either analysis, those eight subjects were included in the final analysis. Intention-to-treat analysis with the lastobservation-carry-forward method was used for those who did not complete the measurements following the 24 weeks of SNAC intervention (6 MS and 8 MS+ subjects). In most cases, the reason for attrition was difficulty of scheduling lab visits due to work-related time constraints. In those subjects, data at 8 weeks were imputed. Significance for all statistical tests was set at p < 0.05. All analyses were performed using SPSS for Windows (version 14.0).
3.
Results
3.1.
Baseline characteristics
Activity diet prescription
This prescription was designed to link the STEP and a Mediterranean-style diet together. Based on each subject’s cardiovascular fitness (low/fair, average, and good/high) determined by the STEP, family physicians determined the appropriate number of servings for each of the four food
Baseline characteristics of the two groups are shown in Table 1. There were no differences between the groups in terms of age and gender ratio. Subjects with MS were heavier
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MS
Age, years Gender, M/F Height, cm Weight, kg (Changes) BMI, kg/m2 (Changes) Wc, cm (Changes) SBP, mmHg (Changes) DBP, mmHg (Changes) FG, mmol/L (Changes) HDL, mmol/L (Changes) TG, mmol/L (Changes) T-chol, mmol/L (Changes) LDL, mmol/L (Changes) Heart rate, beats/min (Changes) VO2max, ml/kg/min (Changes)
Baseline
8 weeks
169.6 7.5 84.6 16.3 29.3 5.0 94.4 12.2 127.6 17.4 82.0 9.8 5.53 0.72 1.63 0.44 1.24 0.46 5.27 0.88 3.14 0.68 73.0 10.5 36.1 9.5
54.3 8.2 15/14 169.6 7.5 84.0 16.6 (0.5 2.6) 29.1 5.1 (0.2 1.0) 93.9 11.3 (0.4 4.1) 124.9 14.0 (2.7 13.2) 80.2 7.5 (1.9 9.2) 5.29 0.65 1.48 0.39 (0.16 0.37) 1.42 0.54 (0.18 0.45) 5.13 0.70 (0.13 0.56) 2.98 0.55 (0.16 0.44) 72.3 11.6 (0.8 9.5) 38.3 10.9 (2.2 6.8)
MS+ 24 weeks
169.6 7.5 83.9 16.4 (0.7 3.6) 29.0 5.0 (0.3 1.4) 92.1 11.5 (2.3 5.8) 124.1 11.9 (3.5 13.3) 78.9 8.2 (3.1 8.5) 5.57 0.82 1.56 0.40 (0.06 0.33) 1.39 0.58 (0.14 0.47) 5.21 0.85 (0.06 0.56) 3.01 0.74 (0.13 0.41) 71.5 8.6 (1.5 8.7) 40.9 10.9* (4.7 6.5)
Baseline
8 weeks
169.1 11.3 96.3 18.0y 33.7 5.9y 105.7 13.4y 137.4 15.3y 85.6 10.0 6.12 0.98y 1.29 0.34y 2.18 1.31y 5.77 0.98 3.57 0.93y 77.0 12.7 32.6 8.3
53.5 9.1 15/19 169.1 11.3 94.9 17.6*y (1.4 2.8) 33.2 5.8*y (0.5 1.0) 104.4 11.8y (1.3 5.1) 132.0 14.9y (5.4 15.6) 81.9 9.2 (3.7 8.7) 5.81 0.76*y 1.27 0.34y (0.02 0.13) 2.15 1.46y (0.05 0.71) 5.65 0.95 (0.13 0.60) 3.46 0.83y (0.11 0.61) 74.2 10.8 (2.8 9.5) 35.5 8.4* (2.8 5.2)
24 weeks
169.1 11.3 94.0 17.6*y (2.3 3.8) 32.9 6.1*y (0.8 1.3) 102.5 12.0*y (3.3 5.8) 130.4 17.3*y (6.9 16.1) 80.0 8.7* (5.6 9.2) 5.81 0.67*y 1.29 0.34y (0.00 0.14) 1.94 1.03y (0.25 1.14) 5.41 0.84* (0.36 0.70) 3.26 0.76*y (0.15 0.18) 70.6 11.7* (6.4 11.9) 37.6 8.9* (5.0 7.4)
Data are means S.D. In each variable, changes from baseline are shown in parentheses. MS, subjects without metabolic syndrome. MS+, subjects with metabolic syndrome. BMI, body mass index. Wc, waist circumference. SBP, systolic blood pressure. DBP, diastolic blood pressure. FG, fasting glucose. HDL, high-density lipoprotein cholesterol. TG, triglyceride. T-chol, total cholesterol. LDL, low density lipoprotein cholesterol. VO2max, maximal oxygen uptake. * p < 0.05 vs. within group baseline value. y p < 0.05 vs. corresponding between-group value.
diabetes research and clinical practice 83 (2009) 249–256
Table 1 – Subjects’ baseline characteristics and effects of 24 weeks of lifestyle modification on anthropometrics, components of metabolic syndrome, metabolic parameters, and exercise capacity.
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Table 2 – Subjects’ baseline and effects of 24 weeks of lifestyle modification on carotid artery parameters. MS
Dd, mm IMT, mm Strain, % MAP, mmHg
MS+
Baseline
8 weeks
24 weeks
Baseline
8 weeks
6.14 0.58 0.61 0.11 5.53 2.28 92.4 9.1
6.16 0.53 0.60 0.09 5.67 1.56 91.2 9.1
6.14 0.59 0.59 0.09 5.40 1.86 91.3 9.6
6.11 0.61 0.61 0.10 5.13 1.44 97.1 8.0y
6.04 0.54 0.61 0.11 5.95 1.95 94.3 9.2*
24 weeks 6.07 0.59 0.62 0.12 6.27 1.88* 93.4 9.2*
Data are means S.D. MS, subjects without metabolic syndrome. MS+, subjects with metabolic syndrome. Dd, carotid artery diameter at diastole. IMT, carotid artery intima-media thickness. MAP, mean arterial pressure. * p < 0.05 vs. within group baseline value. y p < 0.05 vs. corresponding between-group value.
than MS subjects, and BMI was greater in MS+ than in MS (all p < 0.05, Table 1). As expected, MS+ subjects had greater waist circumference, and elevated BP, fasting glucose, triglycerides levels and LDL cholesterol levels compared to MS subjects (all p < 0.05, Table 1). In addition, HDL cholesterol levels were also lower in MS+ subjects ( p < 0.05).
3.2. Effects of SNAC intervention on carotid artery parameters Baseline carotid artery structures and function were not different between the groups (Table 2). Carotid artery distensibility tended to be lower in MS+ than MS but did not reach statistical significance. b stiffness index was similar between the groups. Fig. 1 shows the effects of the 24-week SNAC intervention on carotid artery distensibility
and b stiffness index. Carotid artery distensibility significantly increased in MS+ at 8 weeks (0.179 0.012 1/ mmHg 102) and following the 24-week intervention (0.191 0.012 1/mmHg 102) compared with baseline (0.143 0.011 1/mmHg 102, p < 0.05). Similarly, b stiffness index decreased in MS+ following the 24-week intervention compared with baseline (9.8 1.1 vs. 12.5 1.1 AU, p < 0.05). While carotid artery diameter and intima-media thickness remained the same, strain significantly increased in MS+ at 8 weeks and following the 24-week intervention ( p < 0.05, Table 2). Neither index changed in MS throughout the study period.
3.3. Effects of SNAC intervention on the components of metabolic syndrome Effects of the 24 weeks of SNAC intervention on the components of MS are shown in Table 1. We observed the reduction of waist circumference, SBP, DBP, and fasting glucose levels in MS+ (all p < 0.05). HDL cholesterol and triglycerides levels remained unchanged in MS+. No changes in the MS components were observed in MS following the intervention. All the MS components were still different between the groups ( p < 0.05). Following the 24-week intervention, 13 subjects were free from MS in MS+, whereas 5 MS subjects developed MS.
3.4.
Effects of SNAC intervention on other parameters
Weight, BMI and heart rate significantly decreased in MS+ following the intervention (all p < 0.05, Table 1). In addition, total and LDL cholesterol levels dropped in MS+ following the intervention compared to baseline (both p < 0.05, Table 1). VO2max increased in both groups following the intervention ( p < 0.05, Table 1).
4.
Fig. 1 – Effects of 24 weeks of lifestyle modification on carotid artery distensibility (upper) and b stiffness index (lower). Data are means W S.E. *p < 0.05 vs. within group baseline.
Discussion
In the present study, we examined the effects of lifestyle modification (an individually customized Mediterranean-style diet with physical activity) on carotid artery stiffness in MS subjects with pre-hypertension and/or pre-diabetes, who were previously considered ‘‘normal’’ but are at increased risk for CVD. We observed a reduction in carotid artery stiffness following the 24 weeks of SNAC intervention in MS subjects and the reduction was accompanied by the improvements of
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diabetes research and clinical practice 83 (2009) 249–256
some MS components (waist circumference, BP, and fasting glucose). Because the common causes of MS are poor diet and inadequate physical activity [1], lifestyle modification is advocated as the first-line therapy of MS [3]. Aerobic exercise and some components of Mediterranean-style diet, the primary components of our lifestyle modification program, have been shown to have a favorable effect not only on reducing the prevalence of MS [4–6] but also on reducing ageassociated central artery stiffness [8,9]. Despite these individual effects, the combined effect of aerobic exercise and a Mediterranean-style diet on central artery stiffness was less clear. To our knowledge, this study is the first to have shown that the 24 weeks of aerobic exercise and a Mediterraneanstyle diet prescribed by family physicians effectively reduced carotid artery stiffness in MS subjects. The participants of this study had pre-hypertension and/or pre-diabetes at the time of enrolment. Increased cardiovascular morbidity and mortality associated with these conditions may in part be related to increased central artery stiffness [7]. Recently, the coexistence of pre-hypertension and impaired fasting glucose in middle-aged Japanese men has been shown to synergistically increase the brachial-ankle pulse wave velocity [18]. Thus, it appears that the presence of MS in addition to pre-hypertension and/or pre-diabetes would further exacerbate age-associated central artery stiffness, and several studies have supported this notion. However, a recent study revealed that while the presence of MS without type 2 DM was associated with marginally higher carotid artery stiffness, the presence of MS with type 2 DM was associated with a marked increase in carotid artery stiffness in patients with manifestations of arterial disease [19]. In agreement with their results, we have recently shown that the presence of MS did not synergistically increase carotid artery stiffness in MS subjects with pre-hypertension and/or pre-diabetes [12]. Although the discrepancy among the studies might be due to the different populations studied, these findings would in part indicate that the contribution of type 2 DM and probably hypertension to central artery stiffness in MS may be greater than that of either pre-diabetes, pre-hypertension, or both. Preventing the progression to type 2 DM from pre-diabetes and to hypertension from pre-hypertension may be of great importance in MS. From this perspective, the results of this study that showed the decrease in not only carotid artery stiffness but also in both BP and fasting glucose levels following the 24-week intervention would suggest the usefulness of our lifestyle modification program in terms of preventing type 2 DM and hypertension as well as the possibility of reducing CVD derived from the reduction in central artery stiffness. Although we can only speculate on them, there are several possible mechanisms by which our lifestyle modification program reduced central artery stiffness in MS subjects. It is well known that the advanced glycosylation end-products (AGE)-induced collagen cross-linking increases with ageing that leads to increased age-associated central artery stiffness [20]. Although we do not know if inhibition of AGE-induced collagen cross-linking formation occurred in this study, it may be possible that increased arterial wall deformation during exercise might have occurred in this study [9]. The increase in
BP and HR during exercise may ‘‘stretch’’ collagen fibers and their cross-linking occurring as a result of ageing and increased glucose concentrations. With the repeated exposures of this stretch-like exercise training, there may be a reduction in arterial stiffness and the absence of carotid artery remodeling (Table 2) observed in this study could partly explain this possibility. Another possibility is that altered autonomic regulation of the heart indicated by the reduction in HR in MS subjects in this study may have accounted for the decrease in carotid artery stiffness. The increase in HR has been shown to stiffen a central artery in humans [21]. Interestingly, increased fish consumption, a component of a Mediterranean-style diet, is associated with decreased HR in men without coronary heart disease [22]. Thus, the reduction of HR observed in our MS subjects may in part be responsible for the reduction in central artery stiffness following the intervention in this study. Finally, endothelial function that modulates arterial stiffness [23] may have been enhanced following this 24-week intervention. Enhanced endothelial function has been observed following aerobic exercise training [24]. Additionally, a Mediterranean-style diet as a whole [6] has been shown to enhance endothelial function. The study showed that a reduction of inflammatory markers (hsCRP and IL-6) was associated with enhanced endothelial function, suggesting an anti-inflammatory effect of a Mediterraneanstyle diet. These mechanisms may in part explain the reduction in carotid artery stiffness in our subjects. We acknowledge several limitations in our study. First, the use of brachial pulse pressure (PP) (instead of carotid PP) may introduce an error in the calculation of arterial stiffness indices because of PP amplification from central to distal arteries [13]. While PP amplification becomes less with ageing (meaning PP of both central and peripheral arteries becomes similar), it is still desirable to measure PP at the same site and thus the use of brachial PP may have overestimated carotid PP in this study. A second limitation is that the lack of timecontrol data and/or a control group might have impacted on the changes observed in this study. Although it is preferable to have a control group, given the powerful effects of our lifestyle modification in subjects with MS as well as the lack of effect in subjects without MS even if they were under the same intervention as MS subjects, we believe that the effects of our lifestyle modification are valid. A third limitation is that we were not able to determine whether an individual component of our lifestyle modification program (aerobic exercise and each component of the Mediterranean-style diet) accounted for the changes in central artery stiffness we observed following the study. However, in terms of diet interventions, the clinical usefulness of a whole diet approach (Mediterranean-style diet) on cardiovascular events as well as the synergistic effects of individual components of Mediterranean-style diet on total mortality has been reported [16]. Thus, it appears that individual components of the Mediterranean-style diet in addition to aerobic exercise employed in this study may have cumulative effects on central artery stiffness. Despite these limitations, there are important clinical implications in this study. First, our MS subjects had prehypertension and/or pre-diabetes which were considered ‘normal’ but are at increased risk for developing CVD
diabetes research and clinical practice 83 (2009) 249–256
[10,11]. For instance, 30–40% of BP-related CVD events occur in the BP range previously considered normal [10]. In this context, the reduction of age-associated central artery stiffness observed in this study is expected to reduce CVD risk. Second, all exercise and diet prescriptions in this study were delivered by each subject’s family physician who is the first point of entry to the Canadian health-care system for many, and thus ideally positioned to provide health information including lifestyle counseling. Hence, there is great potential for family physicians to interact with a large population at risk in terms of implementing lifestyle changes. Previous studies with lifestyle modification programs have clearly shown the benefit of those lifestyle changes for reducing the incidence of type 2 DM by nearly 60% [25]. From this point of view, the results of this study are encouraging and also show a tremendous window of opportunity for family physicians who could give their at-risk patients individually customized lifestyle advice (instead of vague general advice such as ‘‘you should eat right and exercise more’’) using this lifestyle modification program. Certainly, additional studies are warranted to examine the long-term feasibility of this lifestyle modification program and determine whether this program will reduce CVD burden in the long term. In conclusion, the results of this study show the reduction of carotid artery stiffness following the 24 weeks of SNAC intervention in MS subjects, and that the reduction was accompanied by improvements of some MS components (waist circumference, BP, and fasting glucose). These results suggest a favorable effect of our lifestyle modification strategy on central artery stiffness as well as the components of MS in subjects with MS.
Conflicts of interest There are no conflicts of interest.
Acknowledgements This study was supported by a grant from the Heart and Stroke Foundation of Ontario.
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Contents lists available at ScienceDirect
Diabetes Research and Clinical Practice journal homepage: www.elsevier.com/locate/diabres
Effects of lifestyle modification on central artery stiffness in metabolic syndrome subjects with pre-hypertension and/or pre-diabetes Kunihiko Aizawa a,b, J. Kevin Shoemaker b, Tom J. Overend a,c, Robert J. Petrella a,b,d,* a
Aging, Rehabilitation & Geriatric Care Research Centre, Lawson Health Research Institute at Parkwood Hospital, London, ON, Canada School of Kinesiology, Faculty of Health Sciences, The University of Western Ontario, London, ON, Canada c School of Physical Therapy, Faculty of Health Sciences, The University of Western Ontario, London, ON, Canada d Department of Family Medicine, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada b
article info
abstract
Article history:
Aims: To examine the effects of a 24-week lifestyle intervention prescribed by family
Received 19 August 2008
doctors on carotid artery stiffness in metabolic syndrome (MS) subjects with pre-hyperten-
Received in revised form
sion and/or pre-diabetes.
10 November 2008
Methods: Sixty-three middle-aged and older subjects with pre-hypertension and/or pre-
Accepted 12 November 2008
diabetes were divided into subjects without MS (MS) and with MS (MS+). MS components
Published on line 20 December 2008
and carotid artery stiffness by ultrasound were determined at baseline, at 8 weeks, and following the 24 weeks of lifestyle intervention. Family doctors prescribed an individually
Keywords:
customized lifestyle prescription for aerobic exercise and Mediterranean-style diet.
Ageing
Results: Carotid artery distensibility significantly increased in MS+ following the 24 weeks of
Artery
intervention compared with baseline (0.191 0.012 vs. 0.143 0.011, 1/mmHg 102,
Diet
p < 0.05). Similarly, b stiffness index decreased in MS+ following the 24 weeks of interven-
Exercise
tion (9.8 1.1 vs. 12.5 1.1 AU, p < 0.05). Following the intervention, waist circumference, BP and fasting glucose levels reduced in MS+ (all p < 0.05), and 13 MS+ subjects were free from MS. Conclusions: The results show the reduction of carotid artery stiffness and the improvement of some MS components in MS subjects, suggesting a favorable effect of our lifestyle modification strategy on central artery stiffness as well as MS components in MS subjects. # 2008 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
Metabolic syndrome (MS) is a constellation of cardiovascular disease (CVD) risk factors including atherogenic dyslipidemia, elevated blood pressure (BP), impaired glucose regulation, and abdominal obesity. This highly prevalent condition increases with ageing [1]. Compared to those without MS, individuals with MS have a 61% increased risk of CVD [2]). As the
population ages and the prevalence rate are expected to increase, there is an urgent need to develop a comprehensive strategy to decrease the prevalence and components of MS [1]. First-line therapy for MS is lifestyle modification [3] since the common causes of MS are poor diet and inadequate physical activity [1]. Regular aerobic exercise training has been shown to be associated with reduced development of metabolic risk factors in older adults [4]. Adoption of aerobic
* Corresponding author at: Aging, Rehabilitation, & Geriatric Care Research Centre, Parkwood Hospital, Room B3002, 801 Commissioners Rd., E. London, ON N6C 5J1, Canada. Tel.: +1 519 685 4292x42983; fax: +1 519 685 4060. E-mail address: [email protected] (R.J. Petrella). 0168-8227/$ – see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2008.11.016
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exercise training in healthy and sedentary middle-aged MS subjects has also been shown to be an effective strategy to reduce prevalence of MS [5]. Additionally, a recent study has shown that a 2-year Mediterranean-style diet intervention reduced the prevalence of MS by half [6]. Therefore, implementation of lifestyle modification incorporating both aerobic exercise and a Mediterranean-style diet in MS subjects appears a feasible strategy to delay the progression of MS risk factors and may in turn delay the need for drug therapies [3]. Age-associated central artery stiffness, an independent predictor of all-cause and cardiovascular mortality [7], has been observed to be synergistically increased in MS subjects (see review by Stehouwer et al. [8]). Increased central artery stiffness can be reversed by aerobic exercise in healthy middle-aged and older subjects [9]. In addition, some components of the Mediterranean-style diet have been shown to reduce age-associated central artery stiffness [8]. Hence, it is reasonable to hypothesize that lifestyle modification combining aerobic exercise with a Mediterranean-style diet may decrease age-associated central artery stiffness as well as MS components in MS subjects. The purpose of this study was to examine the effects of lifestyle modification (aerobic exercise and a Mediterraneanstyle diet) on central artery stiffness in MS subjects with prehypertension and/or pre-diabetes. We focused on these subjects because of (1) the results of recent studies showing that BP and glucose levels previously considered ‘‘normal’’ are associated with increased risk for developing CVD [10,11], and (2) the implication that early identification and treatment of these populations with lifestyle modification would be considerable in terms of prevention of hypertension, type 2 diabetes, and CVD.
2.2.
Metabolic syndrome was defined on the basis of the American Heart Association and National Heart, Lung and Blood Institute (AHA-NHLBI) guidelines [3] by the presence of three or more of the following criteria: (1) waist circumference 102 cm in men and 88 cm in women; (2) triglyceride levels 1.69 mmol/L; (3) HDL cholesterol levels <1.04 mmol/L in men and <1.29 mmol/L in women; (4) fasting plasma glucose levels 5.60 mmol/L; and (5) SBP 130 mmHg and/or DBP 85 mmHg.
2.3.
Subjects, materials and methods
2.1.
Subject
This study was a part of the SNAC (Staged Nutrition and Activity Counseling) study whose purpose was to evaluate the effectiveness of lifestyle modification (aerobic exercise and a Mediterranean-style diet) prescribed by family physicians on cardiovascular structure and function in those who had an increased cardiovascular risk (pre-hypertension and/or prediabetes). Sixty-three subjects (31M and 32F, 53.9 8.7 years) with either pre-hypertension (SBP 130–139 mmHg and/or DBP 85–90 mmHg), pre-diabetes (IFG 6.1–7.0 mmol/L and/or IGT 7.8–11.0 mmol/L following an oral glucose tolerance test), or both were studied. All subjects were otherwise healthy (no overt CVD) and none were taking any medications which may have affected BP and blood glucose levels. Eight subjects were on a cholesterol-lowering medication before starting the study and were allowed to continue their same drug regimen throughout the study period. All patients were referred from their own family physicians for this study. The study was approved by The University of Western Ontario Research Ethics Board for Health Sciences Research Involving Human Subjects and all subjects gave written informed consent prior to participation.
Study design
Subjects were studied in the early morning following an overnight fast (including caffeine). The following measures were assessed: blood chemistry (total cholesterol, HDL cholesterol, LDL cholesterol, tryglycerides, and plasma glucose) by routine laboratory methods, anthropometrics (height, weight, waist circumference), resting BP, arterial stiffness of the carotid artery (Doppler ultrasound), and exercise capacity by treadmill exercise test. These measures were repeated at 8 weeks and following the 24-week intervention. Each test was conducted in a temperature-controlled room and at the same time of day for each subject.
2.4.
Resting blood pressure and heart rate
Following a 10-min seated rest, brachial SBP and DBP, and heart rate (HR) were measured with an automated oscillometric device (BpTRUTM, VSM MedTech Ltd., Coquitlam, BC). All measurements were repeated after a further 5min rest.
2.5.
2.
Definition of metabolic syndrome
Arterial stiffness of the carotid artery
The measurement of arterial stiffness indices of the carotid artery was performed using a 10 MHz linear array transducer attached to a high-resolution ultrasound machine (VingMed System 5, GE Ultrasound A/S, Horton, Norway) as previously described [12]. All scans were performed by the same investigator and made under similar conditions. The longitudinal B-mode internal diameter of the right common carotid artery 1–2 cm proximal to the carotid bifurcation was imaged with simultaneous BP measurements of the left brachial artery. Images were recorded to S-VHS tape for later offline analysis. All images were analyzed by the same investigator. To characterize arterial stiffness, arterial distensibility and b stiffness index of the carotid artery were calculated [13]. Intima-media thickness (IMT) of the right common carotid artery was also assessed by the same device. The longitudinal B-mode images of the carotid artery IMT were assessed while subjects were in a supine position with the head turned approximately 458 away from the side examined. IMT was examined at a straight portion of the artery 1–2 cm proximal to the bifurcation. Carotid artery intima-media thickness was defined as the distance between the lumen–intima interface and media–adventitia interface of the far wall.
diabetes research and clinical practice 83 (2009) 249–256
2.6.
Maximal treadmill exercise
Subjects performed a graded exercise treadmill test (Bruce protocol) to volitional fatigue. Their exercise capacity was expressed as VO2max estimated from metabolic equivalents (METs) where 1 MET is 3.5 ml O2/(kg min).
2.7.
Lifestyle interventions
The lifestyle intervention incorporated in this study contained four components: Aerobic exercise, Mediterranean-style diet, Activity Diet Prescription, and Stage of Change. The intervention was delivered by each subject’s family physician.
2.7.1.
Aerobic exercise
Exercise capacity and training intensity were determined using the Step Test Exercise Prescription (STEP). Briefly, the STEP is a clinic-setting exercise counseling and prescription tool validated previously [14] and endorsed by the College of Family Physicians of Canada as part of an accredited Continuing Health Education strategy to improve physical activity education among family physicians. Each subject’s family physician administered the step test, which included stepping up and down two small (9.5 cm) steps at a comfortable pace 20 times. The stepping time (in seconds) and post exercise heart rate were recorded, followed by conversion to predicted maximal oxygen uptake (VO2max) and an exercise heart rate based on 75% of predicted VO2max [14]. Following the STEP, subjects were provided with a detailed aerobic exercise prescription based on the American College of Sports Medicine’s guideline [15], including frequency (most days of the week), intensity (moderate intensity), and duration (either 30 min or 3 bout of 10 min). Intensity of exercise during training was determined by radial artery palpation. Subjects were instructed to palpate the pulse for 10 s and multiply by 6 (for beats per minute).
2.7.2.
Mediterranean-style diet
Subjects were instructed to incorporate a Mediterranean-style diet characterized by an increased consumption of vegetables, legumes, fruits, and whole grains, the use of olive oil/ margarine as a main source of fat, and the intake of fish instead of red meat [16]. Moderate intake of red wine is allowed but limited only with meals and within the recommended standard drink servings per day. Water is considered the most appropriate beverage. To optimize familiarization with the diet and facilitate long-term adherence, during first 8 weeks, subjects received one dinner meal per day (5 meals per week) from the laboratory (prepared by The University of Western Ontario Food Services) as well as sample menus for breakfast and lunch. From week 9 on, subjects received only sample menus for all meals.
2.7.3.
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groups (grain products, fruits and vegetables, milk products, and meat and alternatives mainly coming from fish, poultry or legumes) that the patient should be eating per day.
2.7.4.
Stage of change
Prochaska and DeClemente’s ‘‘stage of change’’ model [17] was used to assist subjects to change their physical activity and nutritional behavior. Briefly, by administering the Stage of Change Questionnaires for Physical Activity and a Mediterranean-style Diet and using the algorithms for Physical Activity and a Mediterranean-style Diet, family physicians determined at what stage (precontemplation, contemplation, preparation, action, and maintenance) the patient was for both physical activity and diet. The physician then counseled subjects based on their change stage for both physical activity and diet using an appropriate stage-based counseling.
2.8.
Statistical analysis
Data are expressed as means S.D., unless otherwise stated. Baseline data between subjects without MS (MS) and with MS (MS+) were tested using an independent-samples t-test and one-way analysis of variance (ANOVA) for continuous variables, and a x2 test for categorical variables. Variables with skewed distribution were log-transformed before statistical analysis. Repeated measures ANOVA tests were used to compare differences at baseline, at 8 weeks and following the 24 weeks of SNAC intervention. When a significant main effect was observed, a Bonferroni post hoc test was performed. As arterial stiffness is influenced by changes in mean arterial pressure (MAP), analysis of covariance (ANCOVA) was performed with MAP as a covariate. Because of the concern that eight subjects who had been taking a cholesterollowering medication might have caused a significant confounding, separate analyses were performed by (1) comparing the difference in central artery stiffness between those who were on a medication and those who were not, and (2) excluding those eight subjects from the entire cohort. As no indication was found that the use of a lipid-lowering medication had a significant impact on central artery stiffness in either analysis, those eight subjects were included in the final analysis. Intention-to-treat analysis with the lastobservation-carry-forward method was used for those who did not complete the measurements following the 24 weeks of SNAC intervention (6 MS and 8 MS+ subjects). In most cases, the reason for attrition was difficulty of scheduling lab visits due to work-related time constraints. In those subjects, data at 8 weeks were imputed. Significance for all statistical tests was set at p < 0.05. All analyses were performed using SPSS for Windows (version 14.0).
3.
Results
3.1.
Baseline characteristics
Activity diet prescription
This prescription was designed to link the STEP and a Mediterranean-style diet together. Based on each subject’s cardiovascular fitness (low/fair, average, and good/high) determined by the STEP, family physicians determined the appropriate number of servings for each of the four food
Baseline characteristics of the two groups are shown in Table 1. There were no differences between the groups in terms of age and gender ratio. Subjects with MS were heavier
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MS
Age, years Gender, M/F Height, cm Weight, kg (Changes) BMI, kg/m2 (Changes) Wc, cm (Changes) SBP, mmHg (Changes) DBP, mmHg (Changes) FG, mmol/L (Changes) HDL, mmol/L (Changes) TG, mmol/L (Changes) T-chol, mmol/L (Changes) LDL, mmol/L (Changes) Heart rate, beats/min (Changes) VO2max, ml/kg/min (Changes)
Baseline
8 weeks
169.6 7.5 84.6 16.3 29.3 5.0 94.4 12.2 127.6 17.4 82.0 9.8 5.53 0.72 1.63 0.44 1.24 0.46 5.27 0.88 3.14 0.68 73.0 10.5 36.1 9.5
54.3 8.2 15/14 169.6 7.5 84.0 16.6 (0.5 2.6) 29.1 5.1 (0.2 1.0) 93.9 11.3 (0.4 4.1) 124.9 14.0 (2.7 13.2) 80.2 7.5 (1.9 9.2) 5.29 0.65 1.48 0.39 (0.16 0.37) 1.42 0.54 (0.18 0.45) 5.13 0.70 (0.13 0.56) 2.98 0.55 (0.16 0.44) 72.3 11.6 (0.8 9.5) 38.3 10.9 (2.2 6.8)
MS+ 24 weeks
169.6 7.5 83.9 16.4 (0.7 3.6) 29.0 5.0 (0.3 1.4) 92.1 11.5 (2.3 5.8) 124.1 11.9 (3.5 13.3) 78.9 8.2 (3.1 8.5) 5.57 0.82 1.56 0.40 (0.06 0.33) 1.39 0.58 (0.14 0.47) 5.21 0.85 (0.06 0.56) 3.01 0.74 (0.13 0.41) 71.5 8.6 (1.5 8.7) 40.9 10.9* (4.7 6.5)
Baseline
8 weeks
169.1 11.3 96.3 18.0y 33.7 5.9y 105.7 13.4y 137.4 15.3y 85.6 10.0 6.12 0.98y 1.29 0.34y 2.18 1.31y 5.77 0.98 3.57 0.93y 77.0 12.7 32.6 8.3
53.5 9.1 15/19 169.1 11.3 94.9 17.6*y (1.4 2.8) 33.2 5.8*y (0.5 1.0) 104.4 11.8y (1.3 5.1) 132.0 14.9y (5.4 15.6) 81.9 9.2 (3.7 8.7) 5.81 0.76*y 1.27 0.34y (0.02 0.13) 2.15 1.46y (0.05 0.71) 5.65 0.95 (0.13 0.60) 3.46 0.83y (0.11 0.61) 74.2 10.8 (2.8 9.5) 35.5 8.4* (2.8 5.2)
24 weeks
169.1 11.3 94.0 17.6*y (2.3 3.8) 32.9 6.1*y (0.8 1.3) 102.5 12.0*y (3.3 5.8) 130.4 17.3*y (6.9 16.1) 80.0 8.7* (5.6 9.2) 5.81 0.67*y 1.29 0.34y (0.00 0.14) 1.94 1.03y (0.25 1.14) 5.41 0.84* (0.36 0.70) 3.26 0.76*y (0.15 0.18) 70.6 11.7* (6.4 11.9) 37.6 8.9* (5.0 7.4)
Data are means S.D. In each variable, changes from baseline are shown in parentheses. MS, subjects without metabolic syndrome. MS+, subjects with metabolic syndrome. BMI, body mass index. Wc, waist circumference. SBP, systolic blood pressure. DBP, diastolic blood pressure. FG, fasting glucose. HDL, high-density lipoprotein cholesterol. TG, triglyceride. T-chol, total cholesterol. LDL, low density lipoprotein cholesterol. VO2max, maximal oxygen uptake. * p < 0.05 vs. within group baseline value. y p < 0.05 vs. corresponding between-group value.
diabetes research and clinical practice 83 (2009) 249–256
Table 1 – Subjects’ baseline characteristics and effects of 24 weeks of lifestyle modification on anthropometrics, components of metabolic syndrome, metabolic parameters, and exercise capacity.
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Table 2 – Subjects’ baseline and effects of 24 weeks of lifestyle modification on carotid artery parameters. MS
Dd, mm IMT, mm Strain, % MAP, mmHg
MS+
Baseline
8 weeks
24 weeks
Baseline
8 weeks
6.14 0.58 0.61 0.11 5.53 2.28 92.4 9.1
6.16 0.53 0.60 0.09 5.67 1.56 91.2 9.1
6.14 0.59 0.59 0.09 5.40 1.86 91.3 9.6
6.11 0.61 0.61 0.10 5.13 1.44 97.1 8.0y
6.04 0.54 0.61 0.11 5.95 1.95 94.3 9.2*
24 weeks 6.07 0.59 0.62 0.12 6.27 1.88* 93.4 9.2*
Data are means S.D. MS, subjects without metabolic syndrome. MS+, subjects with metabolic syndrome. Dd, carotid artery diameter at diastole. IMT, carotid artery intima-media thickness. MAP, mean arterial pressure. * p < 0.05 vs. within group baseline value. y p < 0.05 vs. corresponding between-group value.
than MS subjects, and BMI was greater in MS+ than in MS (all p < 0.05, Table 1). As expected, MS+ subjects had greater waist circumference, and elevated BP, fasting glucose, triglycerides levels and LDL cholesterol levels compared to MS subjects (all p < 0.05, Table 1). In addition, HDL cholesterol levels were also lower in MS+ subjects ( p < 0.05).
3.2. Effects of SNAC intervention on carotid artery parameters Baseline carotid artery structures and function were not different between the groups (Table 2). Carotid artery distensibility tended to be lower in MS+ than MS but did not reach statistical significance. b stiffness index was similar between the groups. Fig. 1 shows the effects of the 24-week SNAC intervention on carotid artery distensibility
and b stiffness index. Carotid artery distensibility significantly increased in MS+ at 8 weeks (0.179 0.012 1/ mmHg 102) and following the 24-week intervention (0.191 0.012 1/mmHg 102) compared with baseline (0.143 0.011 1/mmHg 102, p < 0.05). Similarly, b stiffness index decreased in MS+ following the 24-week intervention compared with baseline (9.8 1.1 vs. 12.5 1.1 AU, p < 0.05). While carotid artery diameter and intima-media thickness remained the same, strain significantly increased in MS+ at 8 weeks and following the 24-week intervention ( p < 0.05, Table 2). Neither index changed in MS throughout the study period.
3.3. Effects of SNAC intervention on the components of metabolic syndrome Effects of the 24 weeks of SNAC intervention on the components of MS are shown in Table 1. We observed the reduction of waist circumference, SBP, DBP, and fasting glucose levels in MS+ (all p < 0.05). HDL cholesterol and triglycerides levels remained unchanged in MS+. No changes in the MS components were observed in MS following the intervention. All the MS components were still different between the groups ( p < 0.05). Following the 24-week intervention, 13 subjects were free from MS in MS+, whereas 5 MS subjects developed MS.
3.4.
Effects of SNAC intervention on other parameters
Weight, BMI and heart rate significantly decreased in MS+ following the intervention (all p < 0.05, Table 1). In addition, total and LDL cholesterol levels dropped in MS+ following the intervention compared to baseline (both p < 0.05, Table 1). VO2max increased in both groups following the intervention ( p < 0.05, Table 1).
4.
Fig. 1 – Effects of 24 weeks of lifestyle modification on carotid artery distensibility (upper) and b stiffness index (lower). Data are means W S.E. *p < 0.05 vs. within group baseline.
Discussion
In the present study, we examined the effects of lifestyle modification (an individually customized Mediterranean-style diet with physical activity) on carotid artery stiffness in MS subjects with pre-hypertension and/or pre-diabetes, who were previously considered ‘‘normal’’ but are at increased risk for CVD. We observed a reduction in carotid artery stiffness following the 24 weeks of SNAC intervention in MS subjects and the reduction was accompanied by the improvements of
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some MS components (waist circumference, BP, and fasting glucose). Because the common causes of MS are poor diet and inadequate physical activity [1], lifestyle modification is advocated as the first-line therapy of MS [3]. Aerobic exercise and some components of Mediterranean-style diet, the primary components of our lifestyle modification program, have been shown to have a favorable effect not only on reducing the prevalence of MS [4–6] but also on reducing ageassociated central artery stiffness [8,9]. Despite these individual effects, the combined effect of aerobic exercise and a Mediterranean-style diet on central artery stiffness was less clear. To our knowledge, this study is the first to have shown that the 24 weeks of aerobic exercise and a Mediterraneanstyle diet prescribed by family physicians effectively reduced carotid artery stiffness in MS subjects. The participants of this study had pre-hypertension and/or pre-diabetes at the time of enrolment. Increased cardiovascular morbidity and mortality associated with these conditions may in part be related to increased central artery stiffness [7]. Recently, the coexistence of pre-hypertension and impaired fasting glucose in middle-aged Japanese men has been shown to synergistically increase the brachial-ankle pulse wave velocity [18]. Thus, it appears that the presence of MS in addition to pre-hypertension and/or pre-diabetes would further exacerbate age-associated central artery stiffness, and several studies have supported this notion. However, a recent study revealed that while the presence of MS without type 2 DM was associated with marginally higher carotid artery stiffness, the presence of MS with type 2 DM was associated with a marked increase in carotid artery stiffness in patients with manifestations of arterial disease [19]. In agreement with their results, we have recently shown that the presence of MS did not synergistically increase carotid artery stiffness in MS subjects with pre-hypertension and/or pre-diabetes [12]. Although the discrepancy among the studies might be due to the different populations studied, these findings would in part indicate that the contribution of type 2 DM and probably hypertension to central artery stiffness in MS may be greater than that of either pre-diabetes, pre-hypertension, or both. Preventing the progression to type 2 DM from pre-diabetes and to hypertension from pre-hypertension may be of great importance in MS. From this perspective, the results of this study that showed the decrease in not only carotid artery stiffness but also in both BP and fasting glucose levels following the 24-week intervention would suggest the usefulness of our lifestyle modification program in terms of preventing type 2 DM and hypertension as well as the possibility of reducing CVD derived from the reduction in central artery stiffness. Although we can only speculate on them, there are several possible mechanisms by which our lifestyle modification program reduced central artery stiffness in MS subjects. It is well known that the advanced glycosylation end-products (AGE)-induced collagen cross-linking increases with ageing that leads to increased age-associated central artery stiffness [20]. Although we do not know if inhibition of AGE-induced collagen cross-linking formation occurred in this study, it may be possible that increased arterial wall deformation during exercise might have occurred in this study [9]. The increase in
BP and HR during exercise may ‘‘stretch’’ collagen fibers and their cross-linking occurring as a result of ageing and increased glucose concentrations. With the repeated exposures of this stretch-like exercise training, there may be a reduction in arterial stiffness and the absence of carotid artery remodeling (Table 2) observed in this study could partly explain this possibility. Another possibility is that altered autonomic regulation of the heart indicated by the reduction in HR in MS subjects in this study may have accounted for the decrease in carotid artery stiffness. The increase in HR has been shown to stiffen a central artery in humans [21]. Interestingly, increased fish consumption, a component of a Mediterranean-style diet, is associated with decreased HR in men without coronary heart disease [22]. Thus, the reduction of HR observed in our MS subjects may in part be responsible for the reduction in central artery stiffness following the intervention in this study. Finally, endothelial function that modulates arterial stiffness [23] may have been enhanced following this 24-week intervention. Enhanced endothelial function has been observed following aerobic exercise training [24]. Additionally, a Mediterranean-style diet as a whole [6] has been shown to enhance endothelial function. The study showed that a reduction of inflammatory markers (hsCRP and IL-6) was associated with enhanced endothelial function, suggesting an anti-inflammatory effect of a Mediterraneanstyle diet. These mechanisms may in part explain the reduction in carotid artery stiffness in our subjects. We acknowledge several limitations in our study. First, the use of brachial pulse pressure (PP) (instead of carotid PP) may introduce an error in the calculation of arterial stiffness indices because of PP amplification from central to distal arteries [13]. While PP amplification becomes less with ageing (meaning PP of both central and peripheral arteries becomes similar), it is still desirable to measure PP at the same site and thus the use of brachial PP may have overestimated carotid PP in this study. A second limitation is that the lack of timecontrol data and/or a control group might have impacted on the changes observed in this study. Although it is preferable to have a control group, given the powerful effects of our lifestyle modification in subjects with MS as well as the lack of effect in subjects without MS even if they were under the same intervention as MS subjects, we believe that the effects of our lifestyle modification are valid. A third limitation is that we were not able to determine whether an individual component of our lifestyle modification program (aerobic exercise and each component of the Mediterranean-style diet) accounted for the changes in central artery stiffness we observed following the study. However, in terms of diet interventions, the clinical usefulness of a whole diet approach (Mediterranean-style diet) on cardiovascular events as well as the synergistic effects of individual components of Mediterranean-style diet on total mortality has been reported [16]. Thus, it appears that individual components of the Mediterranean-style diet in addition to aerobic exercise employed in this study may have cumulative effects on central artery stiffness. Despite these limitations, there are important clinical implications in this study. First, our MS subjects had prehypertension and/or pre-diabetes which were considered ‘normal’ but are at increased risk for developing CVD
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[10,11]. For instance, 30–40% of BP-related CVD events occur in the BP range previously considered normal [10]. In this context, the reduction of age-associated central artery stiffness observed in this study is expected to reduce CVD risk. Second, all exercise and diet prescriptions in this study were delivered by each subject’s family physician who is the first point of entry to the Canadian health-care system for many, and thus ideally positioned to provide health information including lifestyle counseling. Hence, there is great potential for family physicians to interact with a large population at risk in terms of implementing lifestyle changes. Previous studies with lifestyle modification programs have clearly shown the benefit of those lifestyle changes for reducing the incidence of type 2 DM by nearly 60% [25]. From this point of view, the results of this study are encouraging and also show a tremendous window of opportunity for family physicians who could give their at-risk patients individually customized lifestyle advice (instead of vague general advice such as ‘‘you should eat right and exercise more’’) using this lifestyle modification program. Certainly, additional studies are warranted to examine the long-term feasibility of this lifestyle modification program and determine whether this program will reduce CVD burden in the long term. In conclusion, the results of this study show the reduction of carotid artery stiffness following the 24 weeks of SNAC intervention in MS subjects, and that the reduction was accompanied by improvements of some MS components (waist circumference, BP, and fasting glucose). These results suggest a favorable effect of our lifestyle modification strategy on central artery stiffness as well as the components of MS in subjects with MS.
Conflicts of interest There are no conflicts of interest.
Acknowledgements This study was supported by a grant from the Heart and Stroke Foundation of Ontario.
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