Impact of obesity on venous hemodynamics of the lower limbs

Impact of obesity on venous hemodynamics of the lower limbs Torsten Willenberg, MD,a Anette Schumacher, MD,b Beatrice Amann-Vesti, Prof,b Vincenzo Jacomella, MD,b Christoph Thalhammer, MD,b Nicolas Diehm, MD,a Iris Baumgartner, Prof,a and Marc Husmann,b Bern and Zurich, Switzerland Background: Obesity is a risk factor for chronic venous insufficiency and venous thromboembolism. The aim of this study was to compare venous flow parameters of the lower limbs assessed by duplex ultrasound scanning in obese and nonobese individuals according to body mass index (BMI). Methods: Venous hemodynamics were studied in a prospective cohort study in nonobese (BMI <25 kg/m2) and obese individuals (BMI >30 kg/m2). Diameter, flow volume, peak, mean, and minimum velocities were assessed. Results: The study examined 36 limbs in 23 nonobese individuals and 44 limbs in 22 obese individuals. The diameter of the femoral vein was significantly greater in obese (8.5 ⴞ 2.2 mm) vs nonobese (7.1 ⴞ 1.6 mm; P ⴝ .0009) limbs. Venous peak and minimum velocities differed between nonobese and obese individuals (14.8 ⴞ 7.2 vs 10.8 ⴞ 4.8 cm/s [P ⴝ .0071] and 4.0 ⴞ 3.6 vs 1.7 ⴞ 6.3 cm/s [P ⴝ .056]). Calculation of venous amplitude and shear stress showed significantly higher values in nonobese vs obese (18.8 ⴞ 9.4 vs 12.5 ⴞ 9.3 cm/s [P ⴝ .003] and 2.13 ⴞ 2.2 dyn/cm2 vs 1.6 ⴞ 2.7 dyn/cm2 [P ⴝ .03]). Spearman rank correlation revealed a significant inverse correlation between waist-to-hip ratios and waist circumference and venous peak velocity, mean velocity, velocities amplitude (peak velocity-minimum velocity), and shear stress. Conclusion: Lower limb venous flow parameters differ significantly between healthy obese and nonobese individuals. These findings support the mechanical role of abdominal adipose tissue potentially leading to elevated risk for both venous thromboembolism and chronic venous insufficiency. ( J Vasc Surg 2010;52:664-8.)

Several epidemiologic studies have given strong evidence to the hypothesis that obesity is a risk factor for chronic venous insufficiency (CVI) and venous thromboembolism (VTE).1-3 Obesity can significantly affect the development of metabolic syndrome with a cluster of cardiovascular risk factors. Excess body weight is also related to alterations in the coagulation system, including impaired fibrinolytic activity and elevated plasma concentrations of clotting factors.4 These alterations in endothelial function and coagulation are thought to be relevant not only for arterial but also for venous thrombosis.5 In addition to these mechanisms, obesity is thought to predispose individuals to venous stasis, which is a trigger of both deep vein thrombosis and CVI. Central obesity is thought to be associated with increased intra-abdominal pressure (IAP) caused by abdominal fat.6-8 Arvfidsson et al7 showed that the pressure in the iliofemoral vein in morbidly obese patients was significantly

higher than in nonobese individuals.7 Likewise, surgical weight reduction decreases urinary bladder pressure, a surrogate marker of intra-abdominal pressure.8 The elevated IAP is postulated to be transmitted to the extremities by the femoral veins, leading to venous stasis and distensions of the veins of the lower limbs favoring thrombosis and venous valve dysfunction. To our knowledge, however, no human in vivo studies have confirmed this pathophysiologic assumption. Color-coded duplex ultrasound (CCDU) imaging allows for a noninvasive and accurate flow assessment of the veins of the lower limbs.9 We hypothesized that venous flow characteristics of the lower limb differ between obese and nonobese individuals, inasmuch as obese people exhibit lower flow velocities and a larger vein diameter and that abdominal obesity correlates with venous hemodynamic changes. METHOD

From the Swiss Cardiovascular Centre, Division of Clinical and Interventional Angiology, University Hospital, Berne;a and the Department of Angiology, University Hospital Zurich, Zurich.b This study was supported by the Swiss Society of Phlebology (SGP) and the Swiss Heart Foundation. Competition of interest: none. Correspondence: Torsten Willenberg, MD, Clinical and Interventional Angiology, Bern University Hospital and University of Bern, Freiburgstrasse, 3010 Bern, Switzerland (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a competition of interest. 0741-5214/$36.00 Copyright © 2010 by the Society for Vascular Surgery. doi:10.1016/j.jvs.2010.04.023

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The local Ethics Committee of the University Hospital of Zurich approved this study (No. 1709). All participants gave written informed consent. Participants and study protocol. Venous hemodynamics of the lower limbs were studied in 46 limbs of nonobese individuals and in 44 limbs of obese individuals in a prospective cohort design from April 2007 to March 2008 at a tertiary center for vascular disease. Inclusion criteria were a body mass index (BMI) ⬍25 kg/m2 or ⬎30 kg/m2. Excluded were individuals with clinical signs of CVI, DU evidence of venous valve dysfunction or outflow obstruction, prior limb surgery or sclerotherapy, history

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and clinical signs of arterial disease, connective tissue disorders, leg trauma or swelling, clinical signs of lymphedema, history of chronic obstructive pulmonary disease, and cardiac failure. The protocol entailed that participants provide a medical history and undergo a clinical examination and DU imaging to exclude venous incompetence or thrombosis. Medical staff and students volunteered as study participants. BMI and waist-to-hip ratio. BMI was calculated as the patient’s weight (kg)/height (m2). Waist circumference was measured at a point midway between the costal margin and iliac crest and in line with the mid-axilla. To measure hip circumference, the greater trochanter was located as the widest part of the hips at the level of the buttock line. Waist and hip circumference were assessed with the patient standing. The waist-to-hip ratio (WHR) was calculated at the waist circumstance divided by hip circumstance. CCDU imaging. DU assessments were performed in a tertiary referral hospital vascular laboratory by experienced vascular physicians (T. W. and A. S.). Participants were placed in a standardized supine position for all DU scan measurements, with an upper body elevation of 10°. CCDU was performed using the Accuson Sequioa 512 (Siemens AG, Medical Solutions, Zurich, Switzerland), fitted with an 8-MHz linear scan head. The technical settings (gain, contrast, and rejection) were optimized after an initial evaluation and were maintained. Real-time gated Doppler superimposed on B-mode imaging was used in the evaluation of flow. Signals representing artefacts due to erratic movement or forced breathing were discarded and measurements repeated. Doppler flow velocity tracings representing periods of 7 seconds were stored in memory and processed using automated wave form-enveloping DU software. Flow was studied at the femoral vein, 2 cm caudad to the confluence with the deep femoral vein. Peak (PeakV), mean (MeanV), and minimum (MinV) velocities were obtained. Vein diameter was measured by placing the B-mode callipers over the proximal and distal intimal-luminal interfaces. The cross-sectional area calculated as ␲ ⫻ diameter2/4. This calculation enabled estimation of venous volume flow [Qvenous ⫽ MeanV ⫻ cross-sectional area]. Pulsatility index of venous flow [PIvenous] was calculated [PIvenous ⫽ (PeakV ⫺ MinV)/MeanV], in keeping with its estimation in arterial flow.10 The velocity amplitude (Vamp) was calculated as the difference between PeakV – MinV. At least four measurements were performed for each of the evaluated parameters and then averaged. Venous wall shear stress was calculated as 8 ⫻ ␮ ⫻ Vmean/diameter, where blood viscosity (␮) was assumed to be constant (0.035 dyn/s/cm2).11 The applied method’s reproducibility for estimating flow in smaller veins, such as perforators, has been reported.12 Validation and reproducibility of this automatic method have been described previously.9 Statistical analysis. Data are expressed as mean and standard deviations. Data were analyzed with the Mann-

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Table I. Baseline characteristics of control and obese participants Variable Female, No. Age Weight, kg Height, m Body mass index, kg/m2 Waist circumference, cm Hip circumference, cm Waist-to-hip ratio

Controls (n ⫽ 23)

Obese (n ⫽ 22)

10 Mean (SD) 49.7 (15.6) 69 (10) 1.75 (0.08) 22.4 (2.1) 88 (10) 93 (5) 0.94 (0.07)

10 Mean (SD) 53.5 (15.5) 106 (18) 1.71 (0.1) 36.2 (5.9) 122 (11) 114 (11) 1.08 (0.07)

Pa ⬎.99 .013 ⬍.0001 .2700 ⬍.0001 ⬍.0001 ⬍.0001 ⬍.0001

SD, Standard deviation. a Mann-Whitney U test.

Fig 1. Mean values of peak (PeakV), minimal venous (MinV) and mean venous (MeanV) blood flow velocities in the femoral vein of nonobese and obese participants. Error bars show the standard deviation.

Whitney U test for intergroup comparison between obese and nonobese participants. Correlations between WHR/ waist circumference and venous flow parameters were calculated by Spearman rank test. We did not test BMI and flow parameters because BMI was used to differentiate between obese and nonobese volunteers and was not a continuous variable because overweight volunteers (BMI 25 to 29) were not included. Data analysis was performed using SPSS software (SPSS Inc, Chicago, IL). A value of P ⬍ .05 was considered to be significant. RESULTS All of the 46 control limbs and 44 limbs of obese participants that were assessed were included in the analyses. Baseline characteristics are reported in Table I. Obesity and venous diameter and hemodynamics. PeakV was significantly higher in controls (14.8 ⫾ 7.2 cm/s) than in obese participants (10.8 ⫾ 4.8 cm/s, P ⫽ .0070; Fig 1). MinV tended to be lower in nonobese participants (– 4.0 ⫾ 3.6 cm/s) vs obese (–1.7 ⫾ 6.3 cm/s, P ⫽ .056; Fig 1). Obesity did not affect MeanV (4.8 ⫾ 5.1 in controls vs 3.8 ⫾ 3.5 in obese, P ⫽ .239; Fig 1). The femoral vein diameter was significantly smaller in the con-

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Fig 4. Mean of calculated venous shear stress in the femoral vein of nonobese and obese participants. Error bars show the standard deviation. Fig 2. Mean of calculated venous pulsatility index in the femoral vein of nonobese and obese participants. Error bars show the standard deviation.

Table II. Waist-to-hip ratio and waist circumference in correlation to lower limb venous flow characteristics in 22 obese and 23 nonobese individuals Parameters

Fig 3. Mean of calculated venous velocity amplitudes in the femoral vein of nonobese and obese participants. Error bars show the standard deviation.

Waist-to-hip ratio Peak velocity Minimum velocity Mean velocity Peak⫺minimum velocity Pulsatility amplitude Diameter Volume flow Shear stress Waist Peak velocity Minimum velocity Mean velocity Peak⫺minimum velocity Pulsatility amplitude Diameter Volume flow Shear stress

Ra

Pa

⫺0.44 0.429 ⫺0.294 ⫺0.533 ⫺0.197 0.458 0.093 ⫺0.413

⬍.0001 ⬍.0001 .0084 ⬍.0001 .0768 ⬍.0001 .4057 .0002

⫺0.378 0.314 ⫺0.25 ⫺0.428 ⫺0.153 0.456 0.143 ⫺0.369

.0007 .0050 .0247 .0001 .168 ⬍.0001 .2031 .0009

a

trol (7.1 ⫾ 1.6 mm) than in obese participants (8.5 ⫾ 2.2 mm, P ⫽ .0009). No significant difference of the flow volume was found between the groups (controls, 89.5 ⫾ 81.5 mL/min; obese, 99.4 ⫾ 54.7 mL/min, P ⫽ .12). There were no significant differences between the left and right leg for all assessed and calculated flow parameters (PeakV, MinV, MeanV, diameter, Qvenous, PIvenous, PeakV – MinV) for each group (data not shown). Obesity and outflow resistance and shear stress. Pulsatility index, indicating outflow resistance, was significantly higher in obese participants (7.24 ⫾ 2.3) than in controls (5.99 ⫾ 0.86; P ⫽ .02; Fig 2). Velocities amplitude (PeakV – MinV) was significantly higher in controls (18.8 ⫾ 9.4 cm/s) than in obese participants (12.5 ⫾ 9.3 cm/s, P ⫽ .003; Fig 3). Lower mean velocities and greater diameter results in a lower wall shear stress in obese people, which was 1.2 ⫾ 0.0 dyn/cm2 vs 2.13 ⫾ 2.2 dyn/cm2 in controls (P ⫽ .03; Fig 4).

Spearman rank correlation.

Correlation between abdominal obesity and hemodynamic parameters. Spearman rank correlation revealed a significant inverse correlation between WHR or waist circumference and PeakV, MeanV, velocities amplitude (PeakV – MinV), and shear stress. Furthermore, a significant positive correlation was found between WHR/waist circumference for MinV and diameter (Table II). No significant correlations were found for WHR and pulsatility index and volume flow. However, the similar inverse and positive correlations and lack of correlation, respectively, were found when waist circumference only was taken as the independent factor. DISCUSSION The results of the present study suggest that obesity affects lower limb venous hemodynamic properties. The

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femoral vein diameter was significantly greater in obese compared with nonobese participants. This could be interpreted as a result of elevated IAP transmitted to the femoral veins and leading to vein wall distension. Increased stasis and reduced forward flow velocity might be a consequence. Indeed, we also found significant different hemodynamic properties between the obese and nonobese participants. PeakV was lower and MinV higher in the obese group. Outflow obstruction caused by elevated IAP that results from abdominal fat could explain these findings. Likewise, pulsatility index, which is derived from peak, minimum, and mean venous flow velocities, indicated a higher outflow resistance in obese participants in our study. The lower amplitude between peak and minimum venous velocities in obese participants indicates a continuous flow. This is in agreement with the greater vein diameter in the obese group and previous reports on intravenous pressures in obese people that is greater compared with nonobese people.6-8 Abdominal obesity increases the IAP that is transmitted to the veins of the lower limbs. This leads to greater tension on the venous vessel wall, and hence, greater diameter. Minimum venous velocity is usually slightly negative because venous valves close due to backflow. Although one might expect higher venous backflow in obese participants, our data indicate the opposite. It seems more likely that through the greater pressure, the venous vessel wall is permanently under greater tension in obese people; hence, venous elasticity is attenuated. This potentially results in venous valve dysfunction over time and might explain the higher incidence of CVI in obese people.13 The significantly lower venous shear stress in obese individuals supports that IAP in obesity results in venous stasis of the lower limb given by the correlation between WHR or waist circumference with velocity parameters and diameter. We used the BMI for obese vs nonobese group definition because this marker of overweight and obesity is established and correlates well with total body fat content in adults.14 BMI, however, fails to consider the distribution of fat.15 In view of the relationship between centrally located fat and coronary heart disease, waist circumference and WHR are accepted. We therefore used WHR and waist circumference because this considers the abdominal fat distribution. Our data show a significantly lower value of shear stress at the femoral vein in obese vs nonobese participants. Lower shear stress might promote the release of factors that reduce inflammation and the formation of reactive free radicals.16 As described by Bergan et al16 decreased shear stress might support development of CVI. In addition, these alterations of inflammation and coagulation at the venous endothelium are further enhanced by systemic changes in these parameters, which in addition to CVI favor a VTE event. Although there are only a few reports on human in vivo assessment of venous flow properties, abundant studies have shown that obesity is among other intrinsic factors, such as previous VTE, CVI, chronic heart failure, immobility, and cancer that increase the like-

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lihood for an adverse event.17 Numerous studies have shown a clear relationship between obesity and the risk of idiopathic VTE and pulmonary embolism, independent of other recognized risk factors, with odds ratios of 2.42 in two separate studies comparing BMI ⬎30 with BMI ⬍25.5,14,18,19 Even more striking is that a waist circumference ⬎100 cm confers up to a fourfold increased risk of venous thromboembolism.18,20 Likewise, postthrombotic syndrome is more likely to develop in obese individuals after VTE.1 Excess body weight is a risk factor not only for a first VTE event but also for recurrent VTE events, as recently reported.21 Many researches in this field have focused on changes in coagulation and reported that levels of D-dimer, fibrinogen, factor VIII, and factor IX significantly increased according to categories of BMI. Interestingly, stasis as a third factor in the Virchow triad has not been as extensively assessed in a human in vivo study. Invasive human in vivo studies have investigated the effect of abdominal obesity on IAP and intravenous iliac pressure.7,8 These studies require venous access or a bladder catheter. CCDU imaging, in contrast, is noninvasive and allows for an assessment of flow patterns. Fronek et al22 used CCDU imaging to investigate the effect of aging on lower limb venous hemodynamics.22 Delis et al9,12 used CCDU scans in the assessment of venous hemodynamics of perforators and to determine the effect of posture on deep vein flow patterns. Although we studied a rather small group of obese and nonobese individuals, the findings are striking considering the limited numbers of legs investigated and underline that abdominal obesity is associated with lower limb outflow impairment. Our study sample is too limited to stratify venous flow impairment for categories of BMI. Furthermore, it does not allow conclusions about venous velocities in patients with moderate overweight (BMI, 25-30 kg/m2). Our data only indicate that an impairment of lower limb venous outflow is observed in obese individuals, but not whether this translates into an increased risk for VTE or CVI. This link has recently been reported by larger, event-driven cohort studies.17,18,20,21 However, other factors such ambulatory activity, ankle-joint function, and gait pattern might be involved as well. The nonblinded manner of data assessment by DU must be considered a shortcoming in our study protocol. Blinding the observer in our study setting was impossible, and measurements were strictly standardized to overcome this. This standardization and the applied exclusion criteria were also needed to minimize the effect of other factors that might affect venous flow, such as movements, posture, or respiration pattern. We found no differences between the right and the left leg regarding the assessed DU hemodynamic direct and indirect parameters (data not shown). Iliac vein compression is much more prevalent in women than in men.23 Of course, it would have been interesting to provide more precise information about the venous system of the participants in our trial, such as by means of venous pressure

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measurements, plethysmography, and abdominal computed tomography scanning. Nevertheless, our data indicate that a simple, noninvasive assessment by DU imaging is sufficient to detect differences in flow patterns with respect to obesity, although there was no matching for age between obese and nonobese individuals. We cannot exclude this as a possible confounder even if this does not seem very likely. CONCLUSIONS Our findings support the hypothesis that obesity has a relevant influence on lower limb venous hemodynamic parameters. Whether this may explain the increased risk for CVI and VTE in obese participants remains speculative and should be further investigated. AUTHOR CONTRIBUTIONS Conception and design: TW, MH Analysis and interpretation: MH, TW, ND Data collection: TW, AS Writing the article: TW, MH Critical revision of the article: IB, BA, ND, VJ, CT Final approval of the article: TW, MH, IB, BA Statistical analysis: MH, TW Obtained funding: MH, TW Overall responsibility: TW REFERENCES 1. Ageno W, Piantanida E, Dentali F, Steidl L, Mera V, Squizzato A, et al. Body mass index is associated with the development of the postthrombotic syndrome. Thromb Haemost 2003;89:305-9. 2. Danielsson G, Eklof B, Grandinetti A, Kistner RL. The influence of obesity on chronic venous disease. Vasc Endovascular Surg 2002;36: 271-6. 3. Hansson PO, Eriksson H, Welin L, Svardsudd K, Wilhelmsen L. Smoking and abdominal obesity: risk factors for venous thromboembolism among middle-aged men: “the study of men born in 1913.” Arch Intern Med 1999;159:1886-90. 4. Darvall KA, Sam RC, Silverman SH, Bradbury AW, Adam DJ. Obesity and thrombosis. Eur J Vasc Endovasc Surg 2007;33:223-33. 5. Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Polak JF, Folsom AR. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med 2002;162:1182-9. 6. Padberg F Jr, Cerveira JJ, Lal BK, Pappas PJ, Varma S, Hobson RW 2nd. Does severe venous insufficiency have a different etiology in the morbidly obese? Is it venous? J Vasc Surg 2003;37:79-85.

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