FEMALE UROLOGY Association of Severity of Lower Extremity Arterial Disease and Overactive Bladder Syndrome: A Cross Sectional Study Bahar Yuksel1*, Faruk Ozgor2, Mazlum Sahin3, Metin Savun2,Murat Sahan2 ,Ufuk Caglar2,Omer Sarilar2 INTRODUCTION According to the International Continence Society, overactive bladder syndrome (OAB) is a clinical entity including urgency with or without urgency incon- tinence, frequency and nocturia in the absence of patho- logical and/or metabolic disorder that may clarify these signs (1). According to literature, the prevalence of OAB has been reported in a wide range up to 53% causing significant deterioration in patients sexual function, mental health, and overall life quality. Although, pre- vious reports have reported several factors including aging, central and peripheral sensory, somatic and pe- ripheral neuropathy, and atherosclerosis , the underly- ing mechanism has not been understood clearly yet (2) . Atherosclerosis (AT) is a course that progressive hard- ening and thickening of arteries wall forms as a result of fat deposit plaques on their inner lining. Also, AT is a systemic disorder and small-medium size arteries such as iliac artery branches are more vulnerable to atherosclerotic lesions(3). Capple et al. stated that pelvic ischemia due to AT is trigger point for development of lower urinary system symptoms such as urgency, fre- quency and nocturia(4). On the other hand, AT in the ili- ac artery and distal branches of iliac artery is associated Purpose: The aim of this study aim is to clarify the relationship between Overactive bladder syndrome (OAB) and severity of lower extremity ischemia by using Fontaine classification system. Materials and Methods: Patients who were diagnosed with lower extremity arterial disease were enrolled into the study. The Fontaine score of each patient was taken and all patients completed the validated Turkish version of OAB-V8 questionnaire. Body mass index, serum creatinine, blood urea nitrogen, cholesterol and fasting plasma glucose levels were measured. The patients were divided into two groups. Patients with OAB-V8 score above 8 were enrolled into group 1 and patients with OAB-V8 score under 8 were enrolled into group 2. Results: At the end of study period, 181 patients who met the inclusion criteria were enrolled into the study. Patients with OAB ≥ 8 score (n= 79) were compared with patients with OAB < 8 score (n= 102). The mean age and the mean BMI were significantly higher in patients with OAB ≥ 8 (P = .001 and P = .001, respectively). Also, HDL- cholesterol level was found significantly lower in group 1 patients (P= .001). Multivariate regression anal- ysis showed that presence of Fontaine score ≥ class 2b, age ≥ 60 years, BMI ≥ 30 kg/m2 , and HDL-cholesterol levels < 60 mg/dL were predictive factors for OAB. Conclusion: The present study demonstrated that incidence of OAB is higher in patients with severe lower ex- tremity ischemic symptoms, older age, high BMI, and lower HDL-cholesterol level. Keywords: atherosclerosis, Fontaine classification, OAB-V8 form, overactive bladder, urgency 1Department of Obstetrics and Gynecology, Esenler Maternity and Children’s Hospital, Istanbul, Turkey 2Department of Urology, Haseki Teaching and Research Hospital, Istanbul, Turkey 3Department of Cardiovascular Surgery, Haseki Teaching and Research Hospital, Istanbul, Turkey *Correspondence: Department of Obstetrics and Gynecology, Esenler Maternity and Children’s Hospital, Istanbul, Turkey Tel: +90 [0212] 440 39 00. Fax: +90 [0212] 440 39 00. E-mail: baharyl86 @gmail.com. Received October 2018 & Accepted December 2019 with lower limb ischemia and lead symptoms including sense of fatigue, numbness, muscle pain, and muscle cramp. To determine severity of peripheral artery is- chemia, Fontaine at al. described a classification system including four stages: asymptomatic patients, patients with intermittent claudication, patients with rest pain and patients with ischemic ulcers or gangrene(5). Previous reports have demonstrated the relationship be- tween pelvic ischemia and OAB, however none of these studies has evaluated the presence of OAB in patients with peripheral lower extremity artery ischemia. The aim of this study was to clarify the relationship between OAB and severity of lower extremity ischemia using Fontaine classification system. MATERIALS AND METHODS After obtaining local ethics committee approval, pa- tients diagnosed with lower extremity AT between Jan- uary 2017 to January 2018 in the cardiovascular unit of a tertiary academic center were enrolled into the study. The research was managed in accordance with Helsinki Declaration and informed consent was obtained from all patients. To achieve indiscrete study population, patients younger than 18 years old, patients with be- nign prostate hyperplasia, uncontrolled diabetes melli- Urology Journal/Vol 17 No. 2/ March-April 2020/ pp. 180-184. [DOI: 10.22037/uj.v0i0.4886] Vol 17 No 02 March-April 2020 181 tus, uncontrolled hypertension, neurological disorders, urinary system cancers, and history of pelvic radiation were excluded from the study. Moreover, patients with residual volume > 100 ml and maximum flow rate < 15 ml/s were also excluded. History of incontinence sur- gery and pelvic organ prolapse surgery, and presence of pelvic organ prolapse at the time of enrollment were other exclusion criteria. Asymptomatic patients with lower extremity AT and patients with ischemic symptoms (fatigue, numbness, muscle pain, muscle cramp, skin ulcers and tissue loss) due to lower extremity AT were evaluated by a single cardiovascular surgeon in an outpatient setting. De- tailed medical history was obtained and physical exami- nation was performed in all patients. The Fontaine score of each patient was evaluated and all patients completed the validated Turkish version of 8- item validated over- active bladder (OAB) questionnaire (OAB-V8) . Smoking history and body mass index (BMI) were noted. Also, serum creatinine, blood urea nitrogen, cholesterol, HDL- cholesterol, LDL- choles- terol, triglyceride and fasting plasma glucose levels were measured. Moreover, urine culture, urinalysis, sonography of the urinary tract, uroflowmetry, and bladder diary were performed routinely. The patients were divided into two groups based on se- verity of OAB symptoms evaluated by OAB-V8 ques- tionnaire. Patients with OAB-V8 score above 8 were enrolled into group 1 and patients with OAB-V8 score under 8 were enrolled into group 2, respectively. The groups were compared according to patients’ medical history, severity of lower extremity ischemic symp- toms, OAB-V8 scores, serum blood test results, sonog- raphy of the urinary tract and uroflowmetry findings. 8- Item Validated Overactive Bladder (OAB) Question- naire The form OAB-V8 is a self-reported questionnaire, including 8 queries that evaluate severity of irritative symptoms including urgency, frequency, nocturia and urgency urinary incontinence. A score of 8 and above of the OAB shows significant association with OAB and a score under 8 indicates that diagnosis of OAB is questionable or absent. In this questionnaire, urgency and frequency are accepted as a sudden urge to pass urine and eight or more micturition per day. The noc- turia is defined as waking at night to void ≥ 2 times and involuntary leakage with urgency is described urgency urinary incontinence(6). Fontaine Classification The Fontaine classification is a clinical classification method to evaluate the severity of peripheral artery disease which includes four stages. Patients with sub- clinical peripheral artery disease without any symptoms are enrolled in class 1. Patients with intermittent clau- dication after walking are considered class 2 (2a: Inter- mittent claudication after more than 200 meters of pain free walking and 2b: intermittent claudication after less than 200 meters of walking). Patients with rest pain and patients with ischemic ulcers or gangrene are grouped in stage III and stage IV, respectively. Statistical Analysis The Statistical Package of Social Sciences for Windows (SPSS) version 20 was used for statistical analysis. We divided patients into 2 groups based on their OAB-V8 score. Categorical variables were presented as num- bers and percentages and compared with Chi Square test. Continuous variables were presented as means and standard deviations and compared with independ- ent sample t-test. Logistic regression analysis was used to examine the possible association between age, BMI, HDL and Fontaine Score. Statistical significance was considered as a two-tailed p value < 0.05. Lower extremity arterial disease and veractive Bladder-Yuksel et al. Table 1. Comparison of patients’ characteristics Groups OAB Non-OAB p value [Group 1] [Group 2] Number 79 102 Gender [Male/Female] 66/13 81/21 .483 Age [years]* 64.2 ± 8.1 56.0 ± 7.9 .001 BMI [kg/m2]* 32.3 ± 3.9 27.5 ± 3.9 .001 OAB-V8* 18.7 ± 5.8 3.8 ± 2.1 .001 OAB WET/OAB DRY 28/ 51 NA NA Total water intake (mL) 1750 ± 680 1320 ± 430 .001 Total caffeine intake (mL) 440 ± 280 280 ± 120 .001 Total alcohol intake (mL) 50 ± 15 35 ± 10 .127 Fontaine Score .001 Class 1 1 [1.3%] 47 [46.1%] Class 2a 32 [40.5%] 55 [53.9%] Class 2b 29 [36.7%] 0 Class 3 15 [19.0%] 0 Class 4 2 [2.5%] 0 HT 26 [32.9%] 32 [31.4%] .827 Smoking 29 [36.7%] 32 [31.4%] .454 LDL, mg/ml* 130.4 ± 35.8 127.1 ± 36.2 .546 HDL, mg/dl* 45.1 ± 5.8 76.6 ± 32.2 .001 Cholesterol, mg/dl* 265.7 ± 89.1 243.2 ± 87.8 .091 Trigliseride, mg/dl* 163.6 ± 44.2 172.0 ± 49.2 .238 Glucose, mg/dl* 136.8 ± 28.7 137.8 ± 30.0 .819 Creatinine, mg/dl* 1.2 ± 0.7 1.4 ± 0.9 .195 * Mean ± standard deviation Abbreviations: NA : not available; P < 0.05 : statistically significant difference; OAB: over active bladder; OAB V8: 8- item validated over active bladder syndrome questionnaire score; BMI: Body mass index; mg/dL: milligram per deciliter; HT: hypertension; LDL: low density lipoprotein; HDL: high density lipoprotein Female Urology 182 RESULTS At the end of one-year study period, 322 patients were enrolled into the study out of which 181 patients met the study inclusion criteria and where included in the final analysis. Due to benign prostate hyperplasia, un- controlled diabetes mellitus, neurological disease, his- tory of pelvic radiation, history of pelvic organ surgery and usage of medication for OAB, 71, 12, 15, 9, 6 and 19 patients were excluded from the study, respectively. Also, 9 patients were excluded due to other reasons in accordance with study exclusion criteria. The patients with OAB ≥ 8 score (n = 79) and the pa- tients with OAB < 8 score (n = 102) were compared. The mean age and the mean BMI were significantly higher in patients with OAB≥ 8 (p = 0.001 and p = .001, respectively). The mean age of patients with wet OAB was higher although the difference was not statistically significant (66.2 vs 62.7, p = .114). On the other hand, gender, presence of hypertension and smoking history were comparable between two groups (p = .483, p = .827 and p = .454, respectively). Moreover, levels of serum creatinine, fasting plasma glucose, LDL- cho- lesterol and triglyceride did not show statistical differ- ence between patients with OAB ≥ 8 and patients with OAB < 8 score. However, HDL- cholesterol levels were found significantly lower in patients in group 1 (45.1 mg/dL vs 76.6 mg/dL, p = .001). When groups were compared according to Fontaine classification system, the patients with OAB ≥ 8 score had higher scores (p = .001). The mean post voiding volume was 42.5 ml in group 1 and 41.9 ml in group 2 (p =.887). Also, the mean maximum flow rate and the mean average flow rate were similar between two groups (p = .660 and p = .784, respectively). The patient number according to Fontaine classification is listed in Table 1. Multivariate regression analysis showed that presence of Fontaine score ≥ class 2b is an independent risk fac- tor for OAB and increases the risk of OAB upto 4 fold . Additionally, age ≥60 years, BMI ≥ 30 kg/m2 and lower HDL-cholestrol level (60 mg/dL) were predictive fac- tors for OAB (Table 3). DISCUSSION Atherosclerosis is a multifocal, smoldering and im- mune inflammatory disorder that leads to endothelial dysfunction affecting all arteries of the body. It’s well known that small and medium sized arteries like penile and vesical arteries are more vulnerable to AT due to their relatively small lumen diameter compared to wid- er sized arteries. In accordance with this hypothesis, au- thors showed that the significant relationship between coronary artery disease and erectile dysfunction indi- cates the possible role of OAB(7,8). The severity of lower extremity ischemia has been re- ported in a wide range according the literature due to the subjective examination finding and different interpreta- tion of imaging modalities. Thus, classification systems have been created for more objective evaluation of is- chemia, better surgical planning and comprehensive patient counseling. Additionally, using classification system has led to further scientific reporting(9). The Fontaine classification system is the first determined tool to clarify severity of lower extremity ischemia by European Society of Cardiovascular Surgery. The sys- tem is solely based on physical examination and sever- ity of ischemic symptoms classified into stage 1 to 4 (5). According to artery size hypothesis, patients cate- gorized within a higher Fontaine class, are expected to face bladder ischemia, including OAB syndrome more often. In accordance with that hypothesis, we found sig- nificantly higher OAB-V8 score in patients categorized within higher Fontaine class and multivariate analysis Table 2. Comparison of patients according to OAB symptoms and uroflow parameters between groups Groups OAB [Group 1] Non-OAB [Group 2] p value Number 79 102 Urgency 70 [88.6%] 22 [21.6%] .001 Frequency 41 [51.9%] 20 [19.6%] .001 Nocturia 43 [54.4%] 29 [28.4%] .001 Urgency urinary incontinence 42 [53.2%] 7 [6.9%] .001 Postvoiding urinary residue, ml* 42.5 ± 18.4 41.9±18.7 .887 Max flow rate, mL/s* 20.4 ± 3.4 20.7±3.9 .660 Average flow rate, mL/s* 13.6 ± 2.4 13.5±2.4 .784 Voided volume, mL* 200.1 ± 43.8 213.1±67.1 .135 * Mean ± standart deviation P < 0.05 : statistically significant difference Abbreviation: OAB: over active bladder Odds Ratio* p* Odds Ratio** p** Agea 1.9 (1.4-2.6) 0.001 2.5 (1.1-5.6) .027 BMIb 2.6 (1.9-3.7) 0.001 4.2 (1.8-9.5) .001 HDLc 17.5 (4.5-68.3) 0.001 30.9 (6.7-142.3) .001 Fontain Scored 1.3 (0.9-1.9) 0.002 4.0 (1.2-13.5) .023 * univariate analysis **multivariate analysis a: < 60 years vs ≥ 60 years b: < 30 kg/m2 vs ≥ 30 kg/m2 c: < 60 mg/dl vs ≥ 60 m/dL d: < Grade 2b vs ≥ Grade 2b Table 3. Univariate and Multivariant Analysis Lower extremity arterial disease and veractive Bladder-Yuksel et al. Vol 17 No 02 March-April 2020 183 revealed classification as Fontaine 2b or higher is an independent risk factor for OAB development. The incidence of atherosclerosis increases with age, it reduces blood flow and corrupts oxygenation of tissues. Pinggera et al. compared bladder perfusion of 32 elder- ly patients which have lower urinary tract symptoms and 20 young healthy volunteers with transrectal col- our Doppler ultrasonography. They found significant- ly lower bladder perfusion rate in symptomatic elderly patients than in the younger healthy volunteers(10). In a more recent study by Kilinc et al. age was identified as independent risk factor for OAB development in multi- variate regression analysis(11). In accordance with stud- ies mentioned above, we also determined a statistically significant relation with age and OAB in the present study. Several authors had stated that prevalence of OAB syndrome has a positive correlation with obesity due to increased intraabdominal and intravesical pressure that leads overactivity of detrusor muscle. Richter et al. claimed high abdominal pressure may deteriorate inner- vations of pelvic floor(12). In another possible hypothe- sis, ghrelin-A peptide hormone that regulates metabolic activity and reach higher levels in obese patients may be the other trigger causing an increase on contractile activity of the bladder through its receptors on pregan- glionic neurons(13). Moreover, relationship between obe- sity and AT risk factors such as dyslipidemia, hyperten- sion, insulin resistance is well known. In this present study, we found significantly higher BMI in patients who were diagnosed OAB syndrome and BMI ≥ 30 kg/ m2 increased OAB syndrome risk 4.2 fold times. How- ever, we did not find any association between other AT risk factors and OAB syndrome. Our study sample may justify these results since only patients whose diabe- tes mellitus and hypertension were under control were included into study. We found higher LDL- cholester- ol levels in patients with OAB. However, univariate analysis did not predict LDL-cholesterol as risk factor for OAB development. However, we did not evaluate the possible effect of dyslipidemia duration and central obesity in the OAB development. These may be a sub- ject of another study. Plasma lipids have crucial role in AT development. The one of cholesterol subtype called as HDL cholesterol facilitates promotion of reverse cholesterol transport, accelerates plaque regression, and leads to endotheli- al function improvement. Moreover, HDL has anti-in- flammatory and anti-thrombotic characteristics. Thus, some authors hypothesize that increase in HDL levels may be associated with reduction of AT events(14). In accordance with that knowledge, we found significant higher HDL- cholesterol levels in patients without OAB (76.6 mg/dL vs 45.1 mg/dL, P = 0001, respectively). Moreover, multivariate regression analysis revealed higher HDL- cholesterol level as a predictive factor to prevent OAB. However, some studies emphasized the HDL- cholesterol functionality is more important to prevent AT event beyond plasma HDL-cholesterol con- centration. Correlation between OAB and HDL- cho- lesterol functionality may be a subject of another study. The present study has some limitations. First, our study was a cross sectional study with a relatively small pa- tient number. Additionally, this study included patients from only a single center and represented only single center experience. However, all patients were evaluated by a single cardiovascular surgeon and urologist that improve internal validity of the study. Also, we could not evaluate the interval time between the beginning of ischemic symptoms and OAB symptoms. Lastly, we did not analyze the treatment response and treatment cost of patients who referred to outpatient urology clin- ic from the cardiovascular unit. The present study demonstrated that incidence of OAB was higher in patients with severe lower extremity is- chemic symptoms. Additionally, patients with older age, high BMI and lower HDL-cholesterol level face OAB symptoms more frequently. Our study supported that investigating bladder function is advisable in pa- tients with severe leg ischemia. Our findings must be supported by further prospective studies with a larger patient volume. CONFLICT OF INTEREST None declared by the authors. REFERENCES 1. Azurı J, Kafri R, Ziv-Baran T, Stav K. Outcomes of different protocols of pelvic floor physical therapy and anti‐cholinergics in women with wet over‐active bladder: A 4‐year follow‐up. Neurourol Urodyn , 2017; 36.3: 755-8. 2. Bykoviene L, Kubilius R, Aniuliene R,Bartuseviciene E, Bartusevicius A. Effects on The Overactive Bladder. A Randomized Clinical Trial. Urol J. 2018;15: 186-192. 3. Herrington W, Lacey B, Sherliker P. Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease. Circ Res 2016; 118:535–46 4. Chapple C (2014) Chapter 2: Pathophysiology of neurogenic detrusor overactivity and the symptom complex of “overactive bladder”. Neurourol Urodyn 33(Suppl 3): S6–S13. 5. Novo S., Coppola G. Milio G. Critical limb ischemia: definition and natural history. Current Drug Targets-Cardiovascular & Hematological Disorders, 2004; 4.3: 219-25. 6. Tarcan T, Mangir N, Ozgur MO et al. OAB-V8 overactive bladder questionnaire validation study. Üroloji Bülteni 2012; 21:113–6 7. Montorsi P, Ravagnani PM, Galli S. Association between erectile dysfunction and coronary artery disease: matching the right target with the right test in the right patient. Eur Urol, 2006; 50:721–31 8. Acquadro C, Kopp Z, Coyne KS, Corcos J, Tubaro A, Choo MS. Translating overactive bladder questionnaires in 14 languages. Urology, 2006; 67: 536-40. 9. Ozgor F, Yanaral F, Savun M, Ozdemir H, Sarilar O, Binbay M. Comparison of STONE, CROES and Guy’s nephrolithometry scoring systems for predicting stone-free status and complication rates after percutaneous nephrolithotomy in obese patients. Lower extremity arterial disease and veractive Bladder-Yuksel et al. Urolithiasis, 2017; 1-7. 10. Pinggera G, Mitterberger M, Steiner E et al Association of lower urinary tract symptoms and chronic ischaemia of the lower urinary tract in elderly women and men: assessment using colour Doppler ultrasonography. BJU Int 2008; 102:470–4 11. Kilinc MF, Yasar E, Aydin HI, Yildiz Y, Doluoglu OG. Association between coronary artery disease severity and overactive bladder in geriatric patients. World J Urol, 2018; 36:35-40. 12. Richter HE, Creasman JM, Myers DL, Wheeler TL, Burgio KL, Subak LL. Urodynamic characterization of obese women with urinary incontinence undergoing a weight loss program: the Program to Reduce Incontinence by Diet and Exercise (PRIDE) trial. International Urogynecology Journal, 2008; 19:1653-8. 13. Ferens, D. M., Yin, L., Ohashi‐Doi, K., Habgood, M., Bron, R., Brock, J. A.,Furness, J. B. . Evidence for functional ghrelin receptors on parasympathetic preganglionic neurons of micturition control pathways in the rat. Clinical and Experimental Pharmacology and Physiology, 2010;37 :926-932. 14. Zhou P, Li B, Liu B, Chen T, Xiao J. Prognostic role of serum total cholesterol and high-density lipoprotein cholesterol in cancer survivors: A systematic review and meta- analysis. 2018; 477:94-104. Lower extremity arterial disease and veractive Bladder-Yuksel et al. Female Urology 184