American Journal of Cardiology
Volume 104, Issue 9 , Pages 1251-1255, 1 November 2009

Effects of Bariatric Surgery on Inflammatory, Functional and Structural Markers of Coronary Atherosclerosis

Department of Internal Medicine, Section of Cardiology, Northeastern Ohio Universities College of Medicine, Youngstown, Ohio

Received 16 February 2009; received in revised form 19 June 2009; accepted 19 June 2009.

Article Outline

This study was designed to assess the effects of bariatric weight loss surgery on structural, functional, and inflammatory markers of coronary atherosclerosis. Obesity is a worldwide epidemic and an independent risk factor for coronary atherosclerosis. It remains unclear whether surgically induced weight loss reduces cardiovascular risk. This prospective study enrolled 50 consecutive subjects with morbid obesity who underwent Roux-en-Y gastric bypass surgery (GBS) after failed attempts at medical weight loss. Subjects were recruited through a comprehensive weight loss center affiliated with an academic tertiary care hospital. All subjects had body mass indexes ≥40 kg/m2 or body mass indexes of 35 to 40 kg/m2 with ≥2 co-morbid obesity-related conditions. Markers of coronary atherosclerosis, including brachial artery flow-mediated dilation, carotid intima-media thickness, and high-sensitivity C-reactive protein, were measured before GBS and 6, 12, and 24 months after GBS. There were statistically significant improvements in all measured markers of coronary atherosclerosis after GBS. The mean body mass index decreased from 47 to 29.5 kg/m2 at 24 months (p <0.001), the mean carotid intima-media thickness regressed from 0.84 to 0.50 mm at 24 months (p <0.001), mean flow-mediated dilation improved from 6.0% to 14.9% at 24 months (p <0.05), and mean high-sensitivity C-reactive protein decreased from 1.23 to 0.65 mg/dl at 6 months (p <0.001) and to 0.35 mg/dl at 24 months (p <0.001). In conclusion, GBS results in significant improvements in inflammatory, structural, and functional markers of coronary atherosclerosis.

 

Obesity is associated with an inflammatory state that generates prothrombosis, dyslipidemia, and insulin resistance.1 The cytokine interleukin-6, produced by adipocytes, stimulates liver genesis of C-reactive protein (CRP),2 which can be used concomitantly with the ratio of total cholesterol to high-density lipoprotein (HDL) to more strongly predict the risk for a first coronary atherosclerotic event.3, 4 Early atherosclerotic development is associated with endothelial damage, endothelial dysfunction, and carotid intima-media thickening.5, 6, 7, 8 The ultrasonographic assessment of brachial artery flow mediated dilation (FMD) and carotid intima-media thickness (CIMT) can thus be used to assess cardiovascular risk and the severity of coronary atherosclerosis.9 The purpose of this study was to measure the effect of Roux-en-Y gastric bypass surgery (GBS), and its associated weight loss, on known markers of coronary atherosclerosis.

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Methods 

Subjects were recruited through a comprehensive weight loss center and consecutively enrolled in the study from December 2004 to January 2006. Body mass index (BMI), total cholesterol, low-density lipoprotein, HDL, triglycerides, high-sensitivity CRP (hsCRP), FMD, and CIMT data were collected from 50 subjects before GBS and 6 months after GBS. The same data were collected from 46 patients 12 months after GBS. The study design was approved by the institutional review board, and all subjects gave written consent for participation. Subjects were considered for Roux-en-Y GBS in a multidisciplinary fashion after failed attempts at medical weight loss. All subjects had BMIs ≥40 kg/m2 or BMIs of 35 to 40 kg/m2 with ≥2 co-morbid obesity-related conditions. Subjects were excluded for age <21 years or known chronic inflammatory disorder. Tabulated co-morbid conditions included hypertension, diabetes mellitus, and dyslipidemia. Before GBS, 20 subjects were defined as having diabetes mellitus, 34 as having hypertension, and 38 as having dyslipidemia on the basis of medical history. Although the acquisition of 24-month follow-up data after GBS was not part of the study design protocol, subject interest in the study was high, and 28 subjects agreed to 2-year follow-up data acquisition, with institutional review board approval.

All subjects underwent brachial artery ultrasonography for the evaluation of endothelial function. Brachial artery images were obtained using a high-resolution (7.5-MHz) transducer (Acuson Cypress; Siemens Medical Solutions, Mountain View, California) approximately 3 to 5 cm above the right antecubital fossa. Twelve hours before ultrasound imaging, subjects were asked to abstain from vasoactive medications and smoking because of their potential to alter vascular reactivity. Subjects were placed in a supine position, and baseline images of brachial artery diameter were obtained in the longitudinal plane. A blood pressure cuff was then inflated to 50 mm Hg suprasystolic for 5 minutes to occlude arterial flow. Subsequently, the blood pressure cuff was deflated, and the brachial artery was reimaged at 1 minute after deflation, at which time peak vasodilation occurs.10 FMD is expressed as a percentage using the following formula: (maximum diameter − baseline diameter)/baseline diameter × 100.10 The measurements were made from the near intimal interface to the far wall at end-systole using continuous gated electrocardiography. FMD measurements were conducted in a blinded fashion with the consensus of 3 investigators.

Images of CIMT using the right carotid artery were obtained in the longitudinal plane with subjects in the supine position. The carotid bulb was visualized, and CIMT was measured 1 cm proximal to the bifurcation of the artery. Images of the far wall were obtained to enhance reproducibility, and measurements of maximal CIMT were made in plaque-free areas using software integrated calipers.11, 12 CIMT measurements were conducted in a blinded fashion with the consensus of 3 investigators.

On the day of ultrasonographic testing, subjects underwent laboratory evaluations for hsCRP and fasting lipid profiles, which included total cholesterol, low-density lipoprotein, HDL, and triglycerides.

Statistical analysis was performed using 2-tailed paired Student's t tests (SPSS version 14, SPSS, Inc., Chicago, Illinois), and results are expressed as mean ± SEM. For purposes of statistical analysis, subjects were divided into 2 groups: early effects of GBS at 6 months and long-term effects of GBS at 24 months. To ensure that the group of subjects followed for 24 months was similar to the cohort that began the study, baseline characteristics of the subjects completing 24 months of data acquisition were compared to those of the subjects who did not complete 24 months of data acquisition.

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Results 

The study population consisted of 50 subjects, 38 women and 12 men. Follow-up was carried out at 6-month intervals for 1 year. Additional data were acquired on 28 subjects at 24 months after GBS. Before GBS, 34 of 50 subjects (68%) required antihypertensive medications, 19 of 50 subjects (38%) required lipid-lowering medications, and 20 of 50 subjects (40%) were taking diabetic medications. At 6 months after GBS, only 10 of 49 subjects (20%) were still taking blood pressure–lowering agents, only 2 of 49 subjects (4%) were prescribed lipid-lowering agents, and only 3 of 49 subjects (6%) were still taking diabetic medications. Prescriptions of antihypertensive, lipid-lowering, and diabetic medications were controlled not by the study investigators but by the subjects' primary care physicians. The 2 surgeons who performed the GBS required that all subjects stop smoking before being accepted to undergo surgery.

Preoperatively, the baseline mean BMI was 47 kg/m2. Postoperatively, the mean BMIs at 6, 12, and 24 months were 32.4, 28.3, and 29.5 kg/m2, respectively (Figure 1). Mean hsCRP decreased from 1.23 mg/dl before GBS to 0.65, 0.39, and 0.35 mg/dl at 6, 12, and 24 months, respectively, after GBS (Figure 2). Mean FMD was 6.0% before GBS and improved to 13.2% at 6 months, 15.8% at 1 year, and 14.9% at 2 years after GBS (Figure 3). The mean CIMT decreased from 0.84 mm at baseline to 0.52 mm at 6 and 12 months and to 0.50 mm at 2 years (Figure 4). In subjects in the group (n = 50) assessing the early effects of GBS on markers of coronary atherosclerosis, there were statistically significant reductions in total cholesterol, triglycerides, and low-density lipoprotein at 6 months after GBS (Table 1). In subjects in the group (n = 28) representative of the long-term effects of GBS on markers of coronary atherosclerosis, there were statistically significant reductions in total cholesterol, triglycerides, and low-density lipoprotein and a statistically significant increase in HDL at 24 months after GBS (Table 2). Except for HDL and FMD, the subjects with 24-month follow-up data did not significantly differ from those without 24-month follow-up data (Table 3).

  • View full-size image.
  • Figure 2. 

    Effect of GBS on hsCRP. Graphic plot of the decrease in mean hsCRP over 24 months after GBS, measured preoperatively and 6, 12, and 24 months postoperatively.

  • View full-size image.
  • Figure 3. 

    Effect of GBS on brachial FMD. Graphic plot of the increase in mean brachial FMD over 24 months after GBS, measured preoperatively and 6, 12, and 24 months postoperatively.

Table 1. Early effects of gastric bypass surgery on markers of coronary atherosclerosis
Time PointBMI (kg/m2)Total Cholesterol (mg/dl)Triglycerides (mg/dl)HDL (mg/dl)Low-Density Lipoprotein (mg/dl)hsCRP (mg/dl)CIMT (mm)FMD (%)
Before surgery47.0±1.0188±6170±1349±1105±51.23±0.130.84±0.036.0±1.7
6 months after surgery32.4±0.9154±5101±650±184±40.65±0.080.52±0.0213.2±2.1
p value (before surgery vs 6 months after surgery)<0.001<0.001<0.0010.9510.002<0.001<0.0010.004

Data are expressed as mean ± SEM.

Table 2. Long-term effects of gastric bypass surgery on markers of coronary atherosclerosis
Time PointBMI (kg/m2)Total Cholesterol (mg/dl)Triglycerides (mg/dl)HDL (mg/dl)Low-Density Lipoprotein (mg/dl)hsCRP (mg/dl)CIMT (mm)FMD (%)
Before surgery47.2±1.4188±8169±1652±2101±71.39±0.220.86±0.042.9±2.2
24 months after surgery29.5±0.9164±691±962±384±60.35±0.030.50±0.0215.2±2.1
p value (before surgery vs 24 months after surgery)<0.0010.005<0.001<0.0010.020<0.001<0.001<0.001

Data are expressed as mean ± SEM.

Table 3. Comparison of baseline markers of coronary atherosclerosis
VariableSubjects With 24-Month Follow-UpSubjects With Only 6-Month Follow-Uptp Value
(n = 28)(n = 22)
Age (years)44.8±1.844.5±2.4−0.1120.911
Body mass index (kg/m2)47.2±1.446.7±1.6−0.2560.799
Total cholesterol (mg/dl)189±8188±10−0.0670.947
Triglycerides (mg/dl)168±15172±240.1540.878
High-density lipoprotein (mg/dl)52±245±2−2.4660.017
Low-density lipoprotein (mg/dl)102±7110±80.7030.485
hsCRP (mg/dl)1.36±0.211.06±0.10−1.1860.241
CIMT (mm)0.86±0.040.81±0.04−0.9730.335
Flow mediated dilation (%)3.0±2.19.9±2.72.0610.045

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Discussion 

Bariatric surgery is an established method of achieving long-term and meaningful weight loss. Recently, the Swedish Obese Subjects Study, a large prospective trial, showed that GBS was associated with decreased overall mortality.13 Roux-en-Y GBS appears to have a more substantial degree and duration of weight loss compared to other variants of GBS.13, 14 It remains unclear from the Swedish Obese Subjects Study whether the effect on mortality is due to weight loss surgery.13

Our study substantiates the results of previous studies with marked and continued improvements in BMI after bariatric surgery. Additionally, we observed that there was a trend toward a decreased number of subjects requiring glucose-lowering medications, antihypertensive medications, and lipid-lowering medications.

Regression of the mean CIMT began at 6 months and continued at the 2-year mark, indicating sustained risk reduction. In the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) trial, the effects of atorvastatin and pravastatin on CIMT were compared at 12 months.15 Although low-density lipoprotein cholesterol was significantly decreased in the atorvastatin arm of the ARBITER trial, there was no significant reduction in CIMT, but prevention of progression was demonstrated over a 12-month period.15 The ARBITER trial data, in conjunction with our study, suggest that post-GBS CIMT reduction is not explainable only by reductions in cholesterol levels. The Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS) concluded that fluvastatin slowed the progression of mean CIMT only after treatment for 36 months.16 It is thus unlikely that the use of lipid-lowering agents in the subjects in our study had a substantial impact on CIMT, especially considering that only 4% of patients continued taking lipid-lowering agents 6 months after GBS.

Far-wall CIMT was evaluated as opposed to near-wall CIMT. It has been reported that the near wall has greater intima-media thickness, averaging 0.2 mm greater because of accelerated atherosclerotic progression compared to the far wall.5 The far wall in our experience, as with other groups, was more consistently visualized, allowing for better reproducibility.12

Hs-CRP levels decreased with statistical significance, suggesting a lessened state of cardiovascular risk. Concomitantly, low-density lipoprotein and total cholesterol levels improved, with most subjects no longer requiring lipid-lowering therapy. At 6 months after GBS, HDL improvement was not significant. However, with sustained weight loss, HDL improvement was statistically significant at 1 and 2 years after GBS. In nonobese patients, the combined improvement in hs-CRP and cholesterol predicts a greater degree of cardiovascular risk reduction than either risk factor alone.3, 4 Whether or not elevated hs-CRP levels directly promote atherosclerosis remains controversial. Jialal et al17, 18 described the possible role of elevated CRP in the pathogenesis of unstable angina with its participation in atherothrombosis. Gotto19 indicated that CRP can be isolated from a variety of tissues and is secreted in association with myocardial infarction. It is established that the adipocyte, as an endocrine cell, promotes a state of inflammation mediated through various cytokines, which results in elevated levels of CRP in obese subjects.2 Previous trials have demonstrated CRP reduction after GBS.20, 21 This study affirms that reduced hsCRP levels after GBS are also accompanied by early and late improvements in cholesterol levels, potentially further reducing cardiovascular risk. However, it remains unknown whether improvements in these markers of coronary atherosclerotic risk will translate into actual reductions in adverse cardiovascular clinical outcomes.

Impaired FMD is considered a marker of early atherosclerosis causing endothelial dysfunction.6, 7, 8 There is some debate, however, as to whether it adds additional risk information beyond traditional risk factors, particularly in subjects without known coronary atherosclerotic disease.6 Stratification tertiles have been delineated in a population-based cohort study, noting that a value <7.5% was associated with a significantly higher risk for cardiovascular events.6 The mean baseline FMD in our study was 6.0%, a value that would be associated with a higher cardiovascular risk. Postoperatively, a substantial improvement in mean FMD from baseline was observed at 6 months after GBS (6.0% to 13.2%). Similarly, a significant improvement in mean FMD was evident in the group followed for 24 months after GBS (2.9% to 15.2%). Gokce et al22 studied changes in FMD after weight loss, comparing medical to surgically induced weight loss therapy, noting similar FMD levels at baseline (surgical 6.8%, medical 7.3%), with an improvement to 10.2% 3 months after surgery.22 To date, our study demonstrates the largest and most sustained improvement in FMD after weight reduction, suggesting reversal of endothelial dysfunction after GBS.

Limitations of this study include the small sample size and a higher than expected rate of attrition. There was difficulty in maintaining subject follow-up longitudinally, mainly because subjects had achieved the desired weight loss and were less inclined to pursue post-GBS clinic visits. However, the additional data from the 2-year group confirms sustained weight loss and improvements in all measured markers of cardiovascular risk. Other possibly significant variables include change in diet and/or exercise habits over the course of the follow-up period, which were not quantified in this study.

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Acknowledgment 

We would like to thank Michele Catania, Diane Evans, Cathy Engartner, and David J. Gemmel, PhD, for their assistance with this study.

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PII: S0002-9149(09)01271-5

doi:10.1016/j.amjcard.2009.06.042

American Journal of Cardiology
Volume 104, Issue 9 , Pages 1251-1255, 1 November 2009

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