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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Objective: Pronounced weight loss after bariatric surgery was demonstrated to have significant beneficial effects on surrogates of early atherosclerosis. The aim of this prospective examination was to investigate whether these improvements of endothelial function and vascular structure are persistent in the long-term.

Design and Methods: A total of 52 obese adults were examined before and 5 years after bariatric surgery. Carotid intima media thickness (IMT), brachial flow-mediated dilation (FMD), abdominal fat distribution, and metabolic parameters were determined. Additional 18 months data were available from 27 patients.

Results: After 5 years, mean weight loss ± SD of 25% ± 12 in all subjects was accompanied by known improvements in metabolism. Change in IMT was −0.02 mm ± 0.007, whereas FMD improved by +1.5% ± 0.5. In the subgroup IMT decreased by 0.04 mm ± 0.06 within the first 18 months, whereas no significant change was observed between 18 month and 5 years. FMD improved by 3.8% ± 0.6 after 18 months followed by a nonsignificant decrease of −1.4% ± 0.9.

Conclusions: These long-term results demonstrate that bariatric surgery-induced weight loss improves both functional and structural markers of early atherosclerosis providing further evidence for the beneficial effects of weight loss on obesity-associated alterations of the vasculature.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Bariatric surgery has consistently been demonstrated to produce effective long-term weight loss and to result in amelioration of most obesity-associated risk factors [1, 2], thereby reducing morbidity and overall mortality [3].

To bridge the multiple beneficial metabolic effects of pronounced weight loss on one side and the data on morbidity and mortality on the other side, we previously investigated the impact of pronounced weight loss on structural and functional surrogate markers of early atherosclerosis [6]. Carotid intima-media thickness (IMT) and flow-mediated vasodilatation of the brachial artery (FMD) are both well-established markers of subclinical atherosclerosis and independent predictors for future vascular events [7, 8]. Both IMT and FMD improved significantly 18 months after bariatric surgery-induced body weight reduction [6]. These results indicate that early atherosclerotic changes can be reversed by weight loss presumably resulting in reduced long-term cardiovascular risk.

Aim of this study was to determine the long-term effects of substantial weight loss after bariatric surgery on markers of early atherosclerosis in severely obese nondiabetic subjects.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Subjects

Patients desiring surgical intervention for the treatment of obesity were initially referred to the surgical department in order to determine the patients' eligibility for surgery. If a subject was eligible, an operation was scheduled after work up at the department for psychosomatic medicine and the outpatient clinic for metabolism, where patients were consecutively screened for eligibility and enrolled when informed consent was given. The total number of patients undergoing bariatric surgery during the recruitment period was 449, of whom 184 were eligible for the study according to our inclusion and exclusion criteria. Written informed consent was obtained by 181 patients, who were examined with regard to anthropometric measures, biochemical parameters of glucose and lipid metabolism, IMT, and FMD.

Inclusion criteria were a BMI > 35 kg/m2 and at least one comorbidity or a BMI > 40 kg/m2. Exclusion criteria were overt diabetes, uncontrolled hypertension (>160/90 mmHg), history of CVD, secondary causes of obesity, pregnancy, lipid lowering or antipsychotic medication, acute or chronic liver diseases, and a history of an average alcohol consumption of more than 20 g alcohol per day. Patients with acute infectious and inflammatory diseases were excluded by taking a medical history and performing physical and laboratory examinations. All baseline procedures were performed on the same day within a 2-month period prior to surgery.

For long-term data 112 patients, enrolled in the years 2003-2006, reached 5 years post-surgery during our follow-up period and were invited for a visit at the outpatient clinic for metabolism, of whom 62 patients could be acquired for participation. Final statistical analysis included 52 subjects, as two patients quit smoking, two patients had been started on lipid-lowering medication, one patient had the gastric band removed, two patients developed T2DM, one patient was not in the fasting state, one patient did not undergo sonographical examination, and one patient was diagnosed prostate cancer. A subpopulation of 25 subjects with 18 months data was constituted by subjects who were included in our previous study on short-term effects of pronounced weight loss on IMT and FMD, who could be contacted (n = 32), agreed to take part (n = 30), and were not lost to follow-up. A thorough history with regard to past and current illnesses, surgeries, change in medications, and smoking habits was taken in all patients to account for confounding factors. The surgical procedures, either Swedish adjustable gastric banding (SAGB) (n = 42) or gastric bypass (GBP) (n = 10), were performed at the Department of Surgery, Medical University Innsbruck, as previously described [9]. Written informed consent was obtained from all subjects. All procedures were performed in accordance with the Declaration of Helsinki and the institutional guidelines of the Department of Internal Medicine I at the Medical University Innsbruck. The study was approved by the local ethical committee.

Brachial artery study

FMD was determined as previously described [10]. In brief, the brachial artery was scanned 2-15 cm above the elbow with the use of a 13.0-MHz, linear-array transducer and a standard Acuson Sequoia 512 system (Acuson, Mountain View, CA, USA). After recording a rest scan, a pneumatic cuff was placed around the forearm and inflated to a pressure of 250 mm Hg for 4.5 min. Pressure release resulted in reactive hyperemia, which is the stimulus for flow-mediated endothelium dependent dilation. A scan of the brachial artery was performed within 45-90 s after cuff deflation. FMD was determined as the percentage of diameter change relative to the mean value of the baseline measurement. Variation coefficient in our laboratory was less than 3%, based on measurements taken from the same subjects on separate days. Smokers refrained from smoking on the morning prior to the ultrasound examination.

Carotid artery study

Longitudinal B-mode scans of the common carotid artery were obtained immediately after the brachial artery studies using the same ultrasound system and a 9.0-MHz, linear-array transducer as previously reported [10]. The far wall was assessed just proximal to the carotid bulb (last 2 cm) to identify the maximal CIMT, defined as the distance between the junction of the lumen and the intima and that of the media and adventitia. Three measurements of the right and left carotid artery were averaged to determine the CIMT. In case of atherosclerotic plaques in the carotid arteries indicating an advanced stage of atherosclerosis, these patients (n = 16) were excluded from further FMD analyses.

Abdominal ultrasound study and body composition

Subcutaneous fat diameter (SFD) and visceral fat diameter (VFD) were determined as described by Pontiroli et al. [11]. Measurements were performed in triplicates. Fat mass was determined by body impedance analysis using In Body 3.0 Body Composition Analyzer from Biospace Europe (Dietzenbach, Germany) with an integrated scale. All measurements were taken in the morning in the fasted state.

Laboratory analyses

Blood was drawn after an overnight fast from an antecubital vein into EDTA tubes (1.6 mg/mL) and was centrifuged at 3,000 rpm for 10 min at 4°C immediately after collection. Plasma samples were stored at –80°C until assayed.

Plasma triglycerides, total cholesterol, and high-density lipoprotein (HDL)-C were quantified using a commercially available enzymatic kit (Roche Diagnostic Systems, Basel, Switzerland). Low-density lipoprotein (LDL)-C was calculated using the Friedewald formula. Plasma glucose was measured by the hexokinase method on a Cobas MIRA analyzer. Plasma insulin was determined by a micro particle enzyme immunoassay from Abbott (Wiesbaden, Germany). The homeostasis model of assessment of insulin resistance (HOMA-IR) was calculated by the following formula: fasting serum insulin concentration (μIU/mL) × blood glucose concentration (mg/dL)/405.

C-reactive protein concentration was determined by the CRP (Latex) ultrasensitive assay (Roche Diagnostic Systems).

Statistical analyses

The Shapiro–Wilk test was used to assess normal distribution of variables. Parameters deviating from normal distribution (VFD, systolic and diastolic blood pressure, insulin concentration, HOMA-IR, triglycerides, hs-CRP) were log transformed to approximate a more normal distribution; transformed values were used for further analyses. Homogeneity of variances was tested for by the Levene-Test. The paired-samples T-test was used to determine significant changes before and after bariatric surgery. For analyses regarding the subpopulation with complete data at 0, 18 months, and 5 years, one-way repeated measures analyses of variance with post hoc tests according to Bonferroni were employed. Differences in means between two groups were analyzed using the independent samples T-test. Associations between variables were examined using Pearson's correlation coefficients. Data are expressed as mean ± SD, while not normally distributed data are presented as median and interquartile range. A two-sided P-value smaller or equal to 0.05 was considered statistically significant. All analyses were performed using SPSS 15 for Windows (SPSS, Chicago, IL, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Anthropometric and metabolic measures

A total of 40 female and 12 male subjects with a mean age of 35.3 years (range 18-59 years) were included in the 5-year analysis. The subpopulation with additional 18 months data constituted of 19 female and 9 male subjects (mean age 33.7 years, range 20-51 years). Assessed anthropometric and metabolic parameters before and 5 years after bariatric surgery including mean relative changes are presented in Table 1. Weight loss was not significantly different between sexes or surgery groups (−10.9 kg/m2 ± 6.1 after SAGB vs. −14.0 kg/m2 ± 4.6 after GBP). Sixty percent of patients had hypertension at baseline, which improved in 42 percent after 5 years. Impaired fasting glucose, defined as fasting plasma glucose levels above 100 mg/dL and below 126 mg/dL, was present in 42% of all subjects before surgery and 19% at follow-up.

Table 1. Anthropomorphometric and metabolic parameters before and 5 years after bariatric surgery in all subjects
n = 52Baseline5 yearsP-value
  1. BMI, body mass index; WHR, waist-to-hip ratio; SFD, subcutaneous fat diameter; VFD, visceral fat diameter; BP, blood pressure; HOMA-IR, homeostasis model of insulin resistance; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; hs-CRP, high sensitive C-reactive protein. Values are given as mean ± SD, except a are given as median and interquartile range. P-value determined by paired-samples T-test.

Weight (kg)124.5 ± 18.392.1 ± 17.5<0.001
BMI (kg/m2)43.6 ± 4.932.2 ± 5.3<0.001
Fat mass (kg)54.7 ± 10.330.3 ± 11.2<0.001
Waist (cm)117.5 ± 15.1102.8 ± 15.4<0.001
Hip (cm)134.6 ± 11.0116.4 ± 10.7<0.001
WHR0.87 ± 0.100.88 ± 0.110.435
SFD (cm)4.1 ± 1.22.8 ± 1.2<0.001
VFD (cm)a7.5 (4.6)2.3 (3.4)<0.001
BP systolic (mm Hg)a130 (15)127 (26)0.006
BP diastolic (mm Hg)a85 (10)80 (17)0.077
Glucose (mmol/L)5.54 ± 0.625.21 ± 0.670.001
Insulin (μIU/mL)a118 (99)61 (49)<0.001
HOMA-IRa4.30 (3.60)1.88 (1.82)<0.001
Total cholesterol (mmol/L)4.94 ± 0.914.78 ± 0.960.105
HDL-C (mmol/L)1.25 ± 0.291.3 ± 0.310.056
LDL-C (mmol/L)3.04 ± 0.832.94 ± 0.780.207
Triglycerides (mmol/L)a1.24 (0.77)1.01 (0.68)0.003
hs-CRPa0.68 (0.58)0.17 (0.32)<0.001

Measures of atherosclerosis

Results of IMT and FMD measurements are listed in Table 2. IMT decreased in 67.3% of patients, whereas FMD improved in 72.2% of all subjects with FMD measurements. Individual changes of IMT and FMD are depicted in Panel A of Figures 1 and 2. After 5 years 73.1% of subjects with improved FMD also had reduced IMT. Change in IMT was −0.012 mm ± 0.053 in the SAGB group as compared to −0.058 mm ± 0.044 in the GBP cohort (P = 0.014). IMT was decreased in all patients after GBP surgery compared to 59.5% after SAGB. No significant gender-specific differences with regard to weight loss or change in IMT were observed.

image

Figure 1. IMT before and 5 years after bariatric surgery. (A) Individual changes of IMT in total study population (n = 52). (B) Individual changes of IMT in subpopulation with additional 18 months visits (n = 27). Asterisks indicate level of significance (**P < 0.01; n.s., not significant) as calculated by (A) Students paired samples t-test and (B) repeated measures ANOVA followed by Bonferroni post hoc adjustment.

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Table 2. IMT and FMD before and 5 years after bariatric surgery in all subjects
n = 52Baseline5 yearsP-value
  1. IMT, intima media thickness; FMD, flow-mediated vasodilation.

  2. Values are given as mean ± SD, except ais given as median and interquartile range. P-value determined by paired-samples T-test.

IMT (mm)a0.57 (0.17)0.56 (0.15)0.004
FMD (%) [n = 36]5.2 ± 3.36.6 ± 3.40.001

Bivariate correlation analysis before surgery revealed significant associations between IMT and age (r = 0.589, P < 0.001), VFD (r = 0.313, P = 0.024), systolic blood pressure (r = 0.504, P < 0.001), diastolic blood pressure (r = 0.336, P = 0.018), HbA1c (r = 0.486, P < 0.001), and glucose (r = 0.311, P = 0.026). After surgery IMT was significantly correlated with FMD (r = −0.573, P < 0.001), weight (r = 0.278, P = 0.046), BMI (r = 0.275, P = 0.049), VFD (r = 0.439, P = 0.001), systolic blood pressure (r = 0.591, P < 0.001), diastolic blood pressure (r = 0.475, P = 0.001), and HDL-C (r = −0.301, P = 0.03). No significant association was found between change of IMT, calculated as 5-year value minus baseline value, and change of other assessed parameters.

Preoperative FMD was negatively associated with baseline weight (r = −0.463, P = 0.005), waist (r = −0.458, P = 0.005), WHR (r = −0.433, P = 0.008), VFD (r = −0.539, P = 0.001), IMT (r = −0.402, P = 0.015), and HbA1c (r = −0.408, P = 0.015). After surgery FMD was associated with weight (r = −0.611, P < 0.001), BMI (r = −0.532, P = 0.001), fat mass (r = −0.493, P = 0.002), waist (r = −0.432, P = 0.010), hip (r = −0.519, P = 0.001), VFD (r = −0.493, P = 0.002), systolic blood pressure (r = −0.656, P < 0.001), diastolic blood pressure (r = −0.427, P = 0.015), IMT (r = −0.573, P < 0.001), and plasma glucose (r = −0.419, P = 0.011). Prospective correlation analysis revealed significant associations between change of FMD and change of weight (r = −0.407, P = 0.014), BMI (r = −0.376, P = 0.024), and fat mass (r = −0.351, P = 0.036), whereas an association with VFD failed to reach statistical significance (r = −0.324, P = 0.054).

Analysis of subpopulation

Analysis of the subpopulation with additional 18-month data (n = 27) revealed that a significant improvement of IMT and FMD occurs during the first 18 months after bariatric surgery, whereas after this period both parameters stabilize despite a continuing, albeit less-pronounced, weight loss: Initial weight loss in these subjects was −8.9 kg/m2 ± 4.8 (P < 0.001), followed by −2.7 kg/m2 ± 5.4 (P < 0.05). Concomitantly, IMT decreased by 0.03 mm ± 0.05 mm within the first 18 months (P < 0.01), while no significant change was observed between examinations after 18 months and 5 years (Figure 1B). FMD improved by 3.9% ± 2.4 after 18 months (P < 0.001), followed by a nonsignificant decrease of −1.2% ± 2.9 (Figure 2B).

image

Figure 2. FMD before and 5 years after bariatric surgery. (A) Individual changes of FMD in total study population (n = 36). (B) Individual changes of FMD in subpopulation with additional 18 months visits (n = 14). Asterisks indicate level of significance (*P < 0.05, *** P < 0.001; n.s., not significant) as calculated by (A) Students paired samples t-test and (B) repeated measures ANOVA followed by Bonferroni post hoc adjustment.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Bariatric surgery has become the most efficient treatment option for severely obese subjects by inducing substantial and sustained weight loss with beneficial effects on classical and nonclassical cardiovascular risk factors. On the basis of the findings of our previous study indicating a positive effect of bariatric surgery-induced pronounced weight loss on atherosclerosis, this study was aimed at examining the long-term effects of a marked weight reduction on IMT and FMD, showing that functional and structural alterations of the vasculature were significantly improved 5 years after surgical intervention, however less than after 18 months. Thus, the current finding of a sustained improvement of IMT and FMD 5 years after bariatric surgery lends further support to the hypothesis of a beneficial effect of bariatric surgery-induced substantial weight loss on atherosclerosis.

Habib and colleagues [12] reported significant regression of IMT starting at 6 months after bariatric surgery with further prevention of progression until the 2-year follow-up. In a subgroup of the Swedish Obese Subjects study, IMT progression rate in the carotid bulb was lower in subjects undergoing weight loss after bariatric surgery compared to subjects with persistent obesity [13]. Moderate weight loss during a dietary intervention trial resulted in no significant change of carotid IMT after 2 years [14]. The fact that weight loss in this study not only resulted in slowed IMT progression but even in significant regression after 5 years further indicates a durable positive effect of pronounced weight loss after bariatric surgery on subclinical atherosclerosis in the long term. Additional analysis of subjects with intermediate 18 months visits revealed that the observed effect was predominantly because of a significant IMT regression within the first 18 months and subsequent halt of IMT progression.

In the METEOR-trial evaluating the effect of high-dose rosuvastatin on IMT in low-risk individuals with mild atherosclerosis slowed IMT progression without significant regression was observed [15]. Owing to the restriction to obese, but otherwise healthy, subjects our study population was considerably younger (mean 35 years vs. 57 years) and thus exhibited a relatively low median IMT of 0.55 mm before surgery. It could be assumed that because of such low IMT values, the current observation is of limited validity with regard to patients with a more advanced stage of atherosclerosis and consequently greater IMT. However, in a post hoc subgroup analysis of the METEOR data determining whether the effect of rosuvastatin treatment varied according to baseline IMT levels no significant differences in benefit across levels of baseline IMT could be detected [16].

In statin trials using IMT to assess medication efficacy, positive effects on IMT progression are conferred by amelioration of the proatherogenic lipid profile, particularly lowering of LDL-C. In contrast, no improvement in cholesterol levels including LDL-C and HDL-C was observed in our study after 5 years. It is thus unlikely that an improvement of cholesterol levels is accountable for the observed effect. In a dietary intervention study, regression of IMT after 2 years was considered to be mediated by the weight loss-induced decline in blood pressure [14], which is also a primary contributor to intima media thickening [17]. However, systolic and diastolic blood pressure were only marginally improved compared to baseline examinations. Similarly to our previous observation, VFD and IMT were significantly correlated before and after bariatric surgery, but showed no association in prospective analysis. This may be due to the fact that after 5 years the patients' weight course shows great inter-individual differences, that is, continuing weight loss, weight stabilization, or weight regain, which is largely dependent upon the bariatric procedure employed. As IMT “lags” behind during weight loss and subsequent weight regain by 3-12 months as indicated in a recent study [18], determination of significant prospective associations may be hampered.

As IMT and FMD provide distinct independent information about atherosclerosis [19], we analyzed FMD as a surrogate measure of early functional changes of the endothelium in patients without atherosclerotic plaques in the carotid arteries. FMD was significantly improved after 5 years indicating a long-term benefit of weight loss after bariatric surgery on endothelial function in obese adults without manifest atherosclerosis. Improvement of FMD after weight loss in the short term is frequently reported in both dietary and bariatric surgery intervention studies [20]. Although Lind et al. [23] observed rapid improvement of vasoreactivity after GBP, no significant change in FMD was observed after 1 or 12 months. In comparison to similar studies, the authors attributed this divergent finding to a higher mean FMD before surgery, which was also not different from lean controls [23]. However, in a randomized controlled study on the effect of fat gain on endothelial function, a modest mean weight gain of 4.1 kg resulted in decreased FMD after 8 weeks compared to nonweight gainers but recovered to baseline values after the restoration of normal weight [24]. Furthermore, the deterioration of endothelial function was significantly correlated with the increase in visceral fat but not subcutaneous fat [24].

Limitations of this study are the lack of a control group and the relatively small sample size. Additionally, the fact that only 62 subjects out of 112 examined at baseline participated in the 5-year follow-up study may pose a potential selection bias.

This study provides novel long-term data on the effects of pronounced weight loss after bariatric surgery on surrogate measures of atherosclerosis suggesting a sustained positive impact of bariatric surgery on atherosclerosis, which could potentially reduce future cardiovascular risk. These observations merit further investigation in more comprehensive controlled trials and mechanistic studies to gain more insights on the beneficial effects of bariatric surgery-induced weight loss on cardiovascular health.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

We highly appreciate the expert technical assistance of Karin Salzmann and Simone Wühl.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References