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The Investigation of Relationship between Coronary Artery Ectasia, Benign Prostatic Enlargement, and Lower Urinary Tract Symptoms
Prostatic Diseases and Male Voiding Dysfunction The Investigation of Relationship between Coronary Artery Ectasia, Benign Prostatic Enlargement, and Lower Urinary Tract Symptoms _ Mehmet Inci, Numan Baydilli, Adnan Burak Akc¸ay, Abdullah Demirtas¸, lu, Kerem Han Go € zu €r Kaya €kara, and Mehmet Gu €ngo Mehmet Murat Rifaiog OBJECTIVE
METHODS
RESULTS
CONCLUSION
To investigate benign prostatic enlargement (BPE) and lower urinary tract symptoms (LUTS) in patients with coronary artery ectasia (CAE). The relation between CAE, BPE, and LUTS has not been studied so far. We investigated BPE and LUTS symptoms in 47 men with CAE, 45 men with coronary artery disease (CAD), and 47 male controls with normal coronary arteries. LUTS was evaluated by the International Prostate Symptom Score (IPSS). BPE was evaluated with transabdominal ultrasonography. CAD was defined as myocardial infarction and angiographically diagnosed coronary disease. CAE was defined as being without any stenotic lesions with a visual assessment of the coronary arteries showing a luminal dilatation 1.5 fold of the adjacent normal coronary segments. Prostate volume was higher in CAE and CAD patients compared with that of the control subjects, respectively (41.0 10.4 vs 33.5 9.4 cm3; 39.1 10.3 vs 33.5 9.4 cm3; P ¼ .0001); total IPSS was higher in CAD and CAE patients compared with that of the control subjects (P ¼ .0001). Postmictional residual urine volume was higher in CAE and CAD patients compared with that of the control subjects (P ¼ .002). We showed that patients with CAE have higher prostate volume, IPSS, and postmictional residual urine volume compared with those of controls with normal coronary angiograms. This study proposes that BPE, LUTS, and CAE maybe different disorders to a common vascular pathology and endothelial dysfunction. This study showed that BPE and LUTS were frequently seen in CAE at least as much as in CAD. Therefore, LUTS and BPE should be kept in mind for CAE patients in follow-ups. UROLOGY 85: 1436e1440, 2015. 2015 Elsevier Inc.
I
n the aging men, benign prostatic enlargement (BPE)/benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) are the most prevalent health-related conditions, and the prevalence of these disorders increases in elderly men.1-3 In addition, it is estimated that by the year 2018, approximately 1.1 billion men will have BPH-LUTS in the worldwide population.4 BPE secondary to BPH could result in
Financial Disclosure: The authors declare that they have no relevant financial interests. From the Department of Urology, Faculty of Medicine, Mustafa Kemal University, Hatay, Turkey; the Department of Urology, Faculty of Medicine, Erciyes University, Kayseri, Turkey; the Department of Cardiology, Faculty of Medicine, Mustafa Kemal University, Hatay, Turkey; and the Department of Cardiology, Faculty of Medicine, Erciyes University, Kayseri, Turkey Address correspondence to: Numan Baydilli, M.D., Department of Urology, Faculty of Medicine, Erciyes University, Kayseri, Turkey. E-mail: [email protected] Submitted: January 1, 2015, accepted (with revisions): February 27, 2015
1436
ª 2015 Elsevier Inc. All Rights Reserved
LUTS, including storage symptoms, such as increased frequency or urgency and incontinence, and also voiding symptoms, such as slow or intermittent urine stream or straining.5 Prevalence of moderate to severe LUTS is estimated between 18% and 40%.6 There is a strong association between presence of moderate to severe LUTS and decrease in quality of life.2,7,8 Previous studies showed an association between manifestations of atherosclerotic disease, for example, coronary heart disease, noneinsulin-dependent diabetes mellitus, hypertension or dyslipidemia, and inflammatory processes in the development of BPE, LUTS, and coronary artery disease (CAD).9-14 Coronary artery ectasia (CAE) is an abnormal localized or diffuse dilatation of the coronary arteries exceeding 1.5 times that of neighboring normal segments of the coronary arteries. It is a relatively rare entity. In previous http://dx.doi.org/10.1016/j.urology.2015.02.031 0090-4295/15
studies, prevalence has been reported as 1.2% to 4.9% in angiographic series.15 It tends to occur in men with a male-to-female ratio of 3:1. Many studies reported that endothelial dysfunction in patients with CAE was more dominant than those with CAD, and in most cases, atherosclerosis is the primary cause.15 Relations between CAE and benign urologic disorders have not been extensively examined. Hence, we decided to investigate the existence of BPE and LUTS in patients with CAE.
infection, or neurologic disease) that might alter the voiding pattern, and those undergoing treatment with 5a-reductase inhibitors or a-blockers. Patients with indecisive results for prostate cancer on digital rectal examination and/or a total serum PSA concentration of 4-10 ng/mL were not included in this study. Written informed consent was obtained before enrollment from all the participants. The institutional ethics committee approved the study protocol, and the study was conducted in accordance with the Declaration of Helsinki.
Cardiac Catheterization
METHODS The study population was selected from a series of 1752 consecutive patients who underwent coronary angiography between November 2009 and February 2012 in the Erciyes University because of the presence of chest pain or positive or equivocal results of noninvasive screening tests for myocardial ischemia. Nine hundred ninety-six patients were >40 years old and were men. Because of exclusion criteria and irregular documents, 438 patients were excluded from the study. The remaining 558 patients were divided into 3 groups (CAD, CAE, and control) and invited to hospital by phone-calling. Fortyseven patients with CAE, 45 patients with CAD, and 47 patients from the control group, a total amount of 139, accepted to be involved in the study. The CAE subjects (mean age, 55.9 12.5 years) who had irregularities with ectatic coronaries were without any stenotic lesions. CAD was defined as myocardial infarction, and angiographically diagnosed coronary disease.16,17 The CAD group (mean age, 55.7 11.7 years) had CAD with stenotic lesions >20%. Age- and sex-matched individuals constituted the control group (mean age, 53.5 13.0 years) that were selected in a consecutive manner from catheterized patients during the same study period and who proved to have normal coronary angiograms. All subjects were evaluated by detailed medical history, physical examination, and biochemical analysis. Special emphasis was put on cardiovascular risk factors and diseases. Blood was analyzed with respect to concentrations of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, total cholesterol, total serum prostatespecific antigen (PSA), and total testosterone. All subjects were questioned for any cardiovascular drug use, smoking habits, and alcohol consumption, and underwent transthoracic echocardiography for left ventricular (LV) ejection fraction assessment. Image acquisition was performed in the left lateral decubitus position using a Vingmed System Vivid 7 (GE Vingmed Ultrasound, Horten, Norway) with a standard 2D transducer. Exclusion criteria included the following: refusal to participate in the study; known CAD; LV dysfunction (LV ejection fraction <50%) and hypertrophy; unstable ischemic conditions (unstable angina pectoris and myocardial infarction); valvular heart disease; congenital heart disease; collagenosis, connective tissue diseases, and vasculitis; and diabetes mellitus and patients taking antidiabetic treatment (such as oral hypoglycemic agents and/or insulin). Those with diabetes insipidus, metabolic syndrome, neoplasm, impaired kidney failure (creatinine clearance <60 mL/min), nephrotic syndrome, abnormality in thyroid function tests, and liver disease were not included in this study. Patients were excluded if they had a history of lower urinary tract surgery, prostate or bladder carcinoma, bladder calculi, previous radiotherapy to the pelvic region, or concomitant disease (eg, cystitis, prostatitis, acute urinary tract UROLOGY 85 (6), 2015
All patients in the study underwent selective coronary artery angiography. The femoral artery, and sometimes radial cannulation, was used for the arterial access site, and a Judkins system was applied for cannulation of the left and the right coronary arteries. Two experienced physicians who were blinded to the study evaluated all angiograms. Angiograms with localized and/or diffuse dilatation with a stenotic lesion not exceeding 1.5 times the normal segment of the artery were diagnosed as a CAE. Ectasia diameter was calculated by quantitative angiography on digital angiograms. When there was no identifiable adjacent normal segment, the mean diameter of the corresponding coronary segment in the control group served as the normal value. Angiograms without stenotic lesions in any major epicardial coronary arteries were considered as normal angiograms.
Lower Urinary Tract Symptoms and Benign Prostatic Enlargement Assessment All patients were initially evaluated by an assessment of their medical histories, with subjective symptoms determined using the International Prostate Symptom Score (IPSS). The subjects answered the native language 7-item validated version of the IPSS in Turkish. Each question was scored from 0 to 5. In addition, all subjects underwent a physical examination, including a digital rectal examination, urinalysis, PSA measurement, and assessments of the free uroflowmetry analysis to determine the mean peak urinary flow rate (Qmax), prostate volume (PV), postmictional residual urine volume (PMR), and biochemical analysis. PV and PMR were evaluated with transabdominal ultrasonography (TAUS). All TAUS scans were performed by the same sonographer. TAUS was performed in the supine position, both before and immediately after uroflowmetry. In each patient, the PV and PMR were measured. The volume estimation was an ellipsoidal volume calculation; the prostate was considered ellipsoidal in shape and the volume (mL) was calculated as 0.523 width (cm) height (cm) length (cm). The widths and heights were measured on axial planes and craniocaudal lengths on sagittal planes at their greatest diameter. An Acuson Sequoia 512 (Siemens Medical Solution, Mountain View, CA) US scanner with either a 3.5-MHz-curved or a 7.5-MHz endocavitary probe was used for all examinations.
Statistical Analysis The Statistical Package for the Social Sciences (SPSS) statistical software package, version 15.0, for Windows (SPSS Inc., Chicago, IL) was used for statistical analyses. Kruskal-Wallis and Mann-Whitney U tests were used in the comparison of groups. Continuous variables were given as mean standard deviation, and categorical variables were defined as a percentage. A P value of <.05 was considered significant. 1437
Table 1. Comparison of baseline demographic, clinical, and laboratory characteristics of the between groups in the study population Variables Age (y) Hypertension, n (%) Smoking habit, n (%) Alcohol consumption, n (%) Body mass index (kg/m2) Acetylsalicylic acid use, n (%) ACE-I use, n (%) ARB use, n (%) ACE-I plus diuretic use, n (%) ARB plus diuretic use, n (%) Calcium antagonist use, n (%) Statin use, n (%) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) LVEF (%) Ectasia diameter (mm) tPSA (ng/dL) TT (ng/mL)
CAE (N ¼ 47)
CAD (N ¼ 45)
Controls (N ¼ 47)
P Value
55.9 12.5 18 (38) 25 (53) 19 (40) 24.0 2.4 5 (11) 3 (6) 2 (4) 2 (4) 3 (6) 3 (6) 3 (6) 183 48 114 35 42 21 178 48 62.7 4.3 5.07 0.44 1.9 0.4 3.8 0.1
55.7 11.7 18 (41) 21 (45) 15 (34) 23.9 2.3 3 (7) 2 (5) 3 (7) 1 (2) 6 (14) 3 (7) 8 (18) 181 48 113 29 39 7 179 49 62.6 4.3
53.5 13.0 20 (43) 21 (45) 18 (38) 23.7 2.3 4 (9) 2 (4) 1 (2) 1 (2) 3 (6) 2 (4) 2 (4) 170 38 109 20 40 8 169 41 64.2 4.6
NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS
2.0 0.2 3.6 0.3
2.1 0.1 3.7 0.2
NS NS
ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CAD, coronary artery disease; CAE, coronary artery ectasia; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LVEF, left ventricle ejection fraction; NS, nonsignificant; tPSA, total serum prostate-specific antigen; TT, total testosterone. Continuous variables were given as mean standard deviation, and categorical variables were defined as a percentage.
Table 2. Comparison of BPE and LUTS parameters of the between groups in the study population Variables
CAE (N ¼ 47)
PV (cm3) IPSS total Storage IPSS Volume IPSS PMR (cc) Qmax (mL/sn)
41.0 11.8 5.7 6.1 11.4 14.2
10.4*y 7.1*y 3.2*y 4.6*y 9.0*y 4.9*y
CAD (N ¼ 45) 39.1 11.9 5.8 6.0 12.2 14.4
10.3** 7.1** 3.2** 4.6** 9.8** 4.8**
Controls (N ¼ 47)
P Value
.0001 .0001 .0001 .0001 .002 .0001
33.5 5.1 3.0 2.1 6.4 18.2
9.4 2.7 1.8 1.2 4.9 3.0
BPE, benign prostatic enlargement; IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms; PMR, postmictional residual urine volume; PV, prostate volume; Qmax, maximum mean peak urinary flow rate; other abbreviations as in Table 1. Variables were given as mean standard deviation. * P <.01 (coronary artery ectasia compared with control). ** P <.01 (coronary artery disease compared with control). y P >.05 (coronary artery ectasia compared with coronary artery disease).
RESULTS There were not statistically significant differences between the 3 groups with respect to age, presence of hypertension, smoking, and alcohol consumption (P >.05). The laboratory findings of all the groups were not statistically different (Table 1). Comparison of BPE and LUTS parameters between the groups, in the study population, is given in (Table 2). PV was higher in CAE and CAD patients compared with that of the control subjects, respectively (41.0 10.4 vs 33.5 9.4 cm3; 38.1 10.3 vs 33.5 9.4 cm3; P ¼ .0001); total IPSS was higher in CAE and CAD patients compared with that of the control subjects, respectively (11.8 7.1 vs 5.1 2.7; 11.9 7.1 vs 5.1 2.7; P ¼ .0001). Mean storage IPSS, respectively (5.7 3.2 vs 5.8 3.2 vs 3.0 1.8; P ¼ .0001); mean volume IPSS, respectively (6.1 4.6 vs 6.0 4.6 vs 2.1 1.2; P ¼ .0001); and PMR, respectively (11.4 9.0 vs 12.2 9.8 vs 6.4 4.9 cc; P ¼ .002), were 1438
higher in CAE and CAD patients compared with those of the control subjects (Table 2). In the CAE and CAD groups, Qmax was found to be lower than that in the control group, respectively (14.2 4.9 vs 18.2 3.0; 12.2 9.8 vs 18.2 3.0; P ¼ .0001; Table 2).
COMMENT The main findings of the study are as follows: first, PV was significantly higher in CAE and CAD patients compared with that of the control subjects. Second, IPSS was significantly higher in CAD and CAE patients compared with that of the control subjects. Extensive atherosclerotic changes and damage in the media of the vessel wall have been found in histologic specimens of coronary artery with CAE and CAD.18 Specifically, recent attention has been focused on arterial atherosclerosis as one of the important risk factors UROLOGY 85 (6), 2015
for BPH or BPE. Berger et al9 reported that an atherosclerosis-dependent increase in the recessive index for blood vessels in the transitional zone of the prostate resulted in vascular damage. In this regard, they claimed that perfusion disorder was responsible for prostate hyperplasia. In one study, it was reported that the levels of vascular endothelial growth factor (VEGF) were higher in CAE than in normal arteries.19 In the prostate tissue, hypoxia may occur in patients presenting with generalized or localized vascular damage. Hypoxia induces expression not only of hypoxia-inducible factor 1 but also of angiogenic growth factors such as VEGF, fibroblast growth factors 2 and 7, and transforming growth factor b, as well as cytokines such as interleukin 8 (IL-8), which suggests that hypoxia might trigger prostatic growth.20,21 In a recent study, PV and PMR were found to be significantly higher in the CAE and CAD groups than in the control group. Moreover, Qmax was found to be significantly lower than that in the control group. With this background in mind, in CAE and CAD patients, we speculated that perfusion disorder in the prostate may be responsible for BPE, which might be cause diminution of Qmax and elevated PMR in clinically due to hypoxia-induced factors. Sezen et al22 reported an increase both in serum total oxidant levels and oxidative stress and a decrease in total antioxidant level in CAE and CAD patients when compared with those in the normal subjects. This study revealed oxidative stress leading to endothelial dysfunction. There is increasing evidence that oxidative stress may have a role in the induction of cell growth. This is supported by observations suggesting that there may be a common pathogenic mechanism responsible for vascular smooth muscle cell growth and remodeling, as well as prostate smooth muscle proliferation.20 Pace et al23 found that high plasma peroxides and decreased total equivalent antioxidant capacity levels were measured in patients affected by BPH. In our study, in the CAE and CAD groups, PV and PMR were found to be significantly higher than those in the control group. In addition, Qmax was found to be statistically lower than that in the control group. With this background in mind, we believed that oxidative stress may trigger prostatic growth that might cause impairment of Qmax and increase PMR in CAE and CAD patients. In the study by Li et al,24 elevated plasma C-reactive protein (CRP) and IL-6 levels of patients with CAE and CAD were compared with those of angiographically normal controls. However, the independent variable most strongly associated with CAE was CRP. Mengus et al25 showed that inflammation played an important role in the development of LUTS by increasing expression of IL-6, IL-7, and IL-15 genes in BPH tissues. Liao et al26 found higher serum CRP levels were significantly associated with residual urgency in BPH patients. In the present study, IPSS and PMR was found to be statistically significantly elevated in the CAE and CAD patients than in the control group. In light of these studies, we consider UROLOGY 85 (6), 2015
that inflammation may be related to the development of LUTS, elevated PMR, and IPSS in patients with CAE and CAD. Endothelial dysfunction occurs secondary to a decrease in production of nitric oxide (NO) or an increase in oxidation. Endothelium-dependent vasodilatation diminishes as a result of decreased NO levels in cardiovascular diseases.27 The bioavailability of NO was decreased by the production of reactive oxygen species such as superoxide and peroxynitrite in subjects with cardiovascular risk factors.28 In the human prostate, the NOecyclic guanosine monophosphate signal pathway is considered to have important functional roles.29 A reduction in the local nitrergic innervation of the prostate in men with BPH and, thus, a decrease in the NOmediated relaxation of prostatic smooth muscle could impact the pathophysiology of LUTS.30 In our study, total IPSS, mean storage IPSS, and mean volume IPSS were found to be significantly higher in the CAE and CAD patients than those in the control group. According to these studies, in our opinion, a decreased level of NO might be the other pathologic development of LUTS with an increased IPSS in CAE and CAD patients. Relatively small size owing to less participation might be the first limitation of this study. The second limitation was that transrectal ultrasonography was not used. For PV measurement, TAUS was considered to have an equal value, and also, the less-invasive method such as transrectal ultrasonography. The last limitation was VEGF, NO, CRP, serum total oxidant, oxidative stress and total antioxidant levels, and so forth as inflammation markers were not evaluated.
CONCLUSION We showed that patients with CAE have higher PV, IPSS, and PMR compared with those of controls with normal coronary angiograms. This study proposes that BPE, LUTS, and CAE may be different disorders to a common vascular pathology and endothelial dysfunction. This study showed that BPE and LUTS were frequently seen in CAE at least as much as in CAD. Therefore, LUTS and BPE should be kept in mind in CAE patients in follow-ups. Further studies are required to explore the exact mechanisms. References 1. Robertson C, Link CL, Onel E, et al. The impact of lower urinary tract symptoms and comorbidities on quality of life: the BACH and UREPIK studies. BJU Int. 2007;99:347-354. 2. Wei JT, Schottenfeld D, Cooper K, et al. The natural history of lower urinary tract symptoms in black American men: relationships with aging, prostate size, flow rate and bothersomeness. J Urol. 2001; 165:1521-1525. 3. Garraway WM, Collins GN, Lee RJ. High prevalence of benign prostatic hypertrophy in the community. Lancet. 1991;338:469-471. 4. Casabe A, Roehrborn CG, Da Pozzo LF, et al. Efficacy and safety of the coadministration of tadalafil once daily with finasteride for 6 months in men with lower urinary tract symptoms and prostatic
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6.
7.
8.
9. 10.
11. 12.
13.
14.
15.
16.
enlargement secondary to benign prostatic hyperplasia. J Urol. 2014; 191:727-733. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Am J Obstet Gynecol. 2002;187:116-126. Wei JT, Calhoun EA, Jacobsen SJ. Benign prostatic hyperplasia. In: Litwin MS, Saigal CS, eds. Urologic Diseases in America US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Washington, DC: US Government Publishing Office; 2004:43-67; NIH Publication No. 04-5512. Girman CJ, Jacobsen SJ, Rhodes T, et al. Association of healthrelated quality of life and benign prostatic enlargement. Eur Urol. 1999;35:277-284. Girman CJ, Jacobsen SJ, Tsukamoto T, et al. Health-related quality of life associated with lower urinary tract symptoms in four countries. Urology. 1998;51:428-436. Berger AP, Bartsch G, Deibl M, et al. Atherosclerosis as a risk factor for benign prostatic hyperplasia. BJU Int. 2006;98:1038-1042. Michel MC, Mehlburger L, Schumacher H, et al. Effect of diabetes on lower urinary tract symptoms in patients with benign prostatic hyperplasia. J Urol. 2000;163:1725-1729. Ivleva A, Sivkov AV. Treatment of arterial hypertension in patients with benign prostatic hyperplasia. Urologiia. 2000:6-11. St Sauver JL, Jacobson DJ, McGree ME, et al. Protective association between nonsteroidal antiinflammatory drug use and measures of benign prostatic hyperplasia. Am J Epidemiol. 2006;164:760-768. Rohrmann S, Smit E, Giovannucci E, et al. Association between markers of the metabolic syndrome and lower urinary tract symptoms in the Third National Health and Nutrition Examination Survey (NHANES III). Int J Obes. 2005;29:310-316. Joseph MA, Harlow SD, Wei JT, et al. Risk factors for lower urinary tract symptoms in a population-based sample of African-American men. Am J Epidemiol. 2003;157:906-914. Hartnell GG, Parnell BM, Pridie RB. Coronary artery ectasia. Its prevalence and clinical significance in 4993 patients. Br Heart J. 1985;54:392-395. Roger VL, Killian J, Henkel M, et al. Coronary disease surveillance in Olmsted County objectives and methodology. J Clin Epidemiol. 2002;55:593-601.
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17. Goraya TY, Jacobsen SJ, Belau PG, et al. Validation of death certificate diagnosis of out-of-hospital coronary heart disease deaths in Olmsted County, Minnesota. Mayo Clin Proc. 2000;75: 681-687. 18. Akcay AB, Inci M, Bilen P, et al. Assessment of the relationship between coronary artery ectasia and erectile function score. Int J Impot Res. 2011;23:128-133. 19. Savino M, Parisi Q, Biondi-Zoccai GG, et al. New insights into molecular mechanisms of diffuse coronary ectasiae: a possible role for VEGF. Int J Cardiol. 2006;106:307-312. 20. Berger AP, Kofler K, Bektic J, et al. Increased growth factor production in a human prostatic stromal cell culture model caused by hypoxia. Prostate. 2003;57:57-65. 21. Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38-47. 22. Sezen Y, Bas M, Polat M, et al. The relationship between oxidative stress and coronary artery ectasia. Cardiol J. 2010;17:488-494. 23. Pace G, Di Massimo C, De Amicis D, et al. Oxidative stress in benign prostatic hyperplasia and prostate cancer. Urol Int. 2010;85: 328-333. 24. Li JJ, Nie SP, Qian XW, et al. Chronic inflammatory status in patients with coronary artery ectasia. Cytokine. 2009;46:61-64. 25. Mengus C, Le Magnen C, Trella E, et al. Elevated levels of circulating IL-7 and IL-15 in patients with early stage prostate cancer. J Transl Med. 2011;9:162. 26. Liao CH, Chung SD, Kuo HC. Serum C-reactive protein levels are associated with residual urgency symptoms in patients with benign prostatic hyperplasia after medical treatment. Urology. 2011;78: 1373-1378. 27. Gratzke C, Angulo J, Chitaley K, et al. Anatomy, physiology, and pathophysiology of erectile dysfunction. J Sex Med. 2010;7:445-475. 28. El Melegy NT, Ali ME, Awad EM. Plasma levels of endothelin-1, angiotensin II, nitric oxide and prostaglandin E in the venous and cavernosal blood of patients with erectile dysfunction. BJU Int. 2005;96:1079-1086. 29. Uckert S, Kuthe A, Jonas U, et al. Characterization and functional relevance of cyclic nucleotide phosphodiesterase isoenzymes of the human prostate. J Urol. 2001;166:2484-2490. 30. Klotz T, Mathers MJ, Bloch W, et al. Nitric oxide based influence of nitrates on micturition in patients with benign prostatic hyperplasia. Int Urol Nephrol. 1999;31:335-341.
UROLOGY 85 (6), 2015
METHODS
RESULTS
CONCLUSION
To investigate benign prostatic enlargement (BPE) and lower urinary tract symptoms (LUTS) in patients with coronary artery ectasia (CAE). The relation between CAE, BPE, and LUTS has not been studied so far. We investigated BPE and LUTS symptoms in 47 men with CAE, 45 men with coronary artery disease (CAD), and 47 male controls with normal coronary arteries. LUTS was evaluated by the International Prostate Symptom Score (IPSS). BPE was evaluated with transabdominal ultrasonography. CAD was defined as myocardial infarction and angiographically diagnosed coronary disease. CAE was defined as being without any stenotic lesions with a visual assessment of the coronary arteries showing a luminal dilatation 1.5 fold of the adjacent normal coronary segments. Prostate volume was higher in CAE and CAD patients compared with that of the control subjects, respectively (41.0 10.4 vs 33.5 9.4 cm3; 39.1 10.3 vs 33.5 9.4 cm3; P ¼ .0001); total IPSS was higher in CAD and CAE patients compared with that of the control subjects (P ¼ .0001). Postmictional residual urine volume was higher in CAE and CAD patients compared with that of the control subjects (P ¼ .002). We showed that patients with CAE have higher prostate volume, IPSS, and postmictional residual urine volume compared with those of controls with normal coronary angiograms. This study proposes that BPE, LUTS, and CAE maybe different disorders to a common vascular pathology and endothelial dysfunction. This study showed that BPE and LUTS were frequently seen in CAE at least as much as in CAD. Therefore, LUTS and BPE should be kept in mind for CAE patients in follow-ups. UROLOGY 85: 1436e1440, 2015. 2015 Elsevier Inc.
I
n the aging men, benign prostatic enlargement (BPE)/benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) are the most prevalent health-related conditions, and the prevalence of these disorders increases in elderly men.1-3 In addition, it is estimated that by the year 2018, approximately 1.1 billion men will have BPH-LUTS in the worldwide population.4 BPE secondary to BPH could result in
Financial Disclosure: The authors declare that they have no relevant financial interests. From the Department of Urology, Faculty of Medicine, Mustafa Kemal University, Hatay, Turkey; the Department of Urology, Faculty of Medicine, Erciyes University, Kayseri, Turkey; the Department of Cardiology, Faculty of Medicine, Mustafa Kemal University, Hatay, Turkey; and the Department of Cardiology, Faculty of Medicine, Erciyes University, Kayseri, Turkey Address correspondence to: Numan Baydilli, M.D., Department of Urology, Faculty of Medicine, Erciyes University, Kayseri, Turkey. E-mail: [email protected] Submitted: January 1, 2015, accepted (with revisions): February 27, 2015
1436
ª 2015 Elsevier Inc. All Rights Reserved
LUTS, including storage symptoms, such as increased frequency or urgency and incontinence, and also voiding symptoms, such as slow or intermittent urine stream or straining.5 Prevalence of moderate to severe LUTS is estimated between 18% and 40%.6 There is a strong association between presence of moderate to severe LUTS and decrease in quality of life.2,7,8 Previous studies showed an association between manifestations of atherosclerotic disease, for example, coronary heart disease, noneinsulin-dependent diabetes mellitus, hypertension or dyslipidemia, and inflammatory processes in the development of BPE, LUTS, and coronary artery disease (CAD).9-14 Coronary artery ectasia (CAE) is an abnormal localized or diffuse dilatation of the coronary arteries exceeding 1.5 times that of neighboring normal segments of the coronary arteries. It is a relatively rare entity. In previous http://dx.doi.org/10.1016/j.urology.2015.02.031 0090-4295/15
studies, prevalence has been reported as 1.2% to 4.9% in angiographic series.15 It tends to occur in men with a male-to-female ratio of 3:1. Many studies reported that endothelial dysfunction in patients with CAE was more dominant than those with CAD, and in most cases, atherosclerosis is the primary cause.15 Relations between CAE and benign urologic disorders have not been extensively examined. Hence, we decided to investigate the existence of BPE and LUTS in patients with CAE.
infection, or neurologic disease) that might alter the voiding pattern, and those undergoing treatment with 5a-reductase inhibitors or a-blockers. Patients with indecisive results for prostate cancer on digital rectal examination and/or a total serum PSA concentration of 4-10 ng/mL were not included in this study. Written informed consent was obtained before enrollment from all the participants. The institutional ethics committee approved the study protocol, and the study was conducted in accordance with the Declaration of Helsinki.
Cardiac Catheterization
METHODS The study population was selected from a series of 1752 consecutive patients who underwent coronary angiography between November 2009 and February 2012 in the Erciyes University because of the presence of chest pain or positive or equivocal results of noninvasive screening tests for myocardial ischemia. Nine hundred ninety-six patients were >40 years old and were men. Because of exclusion criteria and irregular documents, 438 patients were excluded from the study. The remaining 558 patients were divided into 3 groups (CAD, CAE, and control) and invited to hospital by phone-calling. Fortyseven patients with CAE, 45 patients with CAD, and 47 patients from the control group, a total amount of 139, accepted to be involved in the study. The CAE subjects (mean age, 55.9 12.5 years) who had irregularities with ectatic coronaries were without any stenotic lesions. CAD was defined as myocardial infarction, and angiographically diagnosed coronary disease.16,17 The CAD group (mean age, 55.7 11.7 years) had CAD with stenotic lesions >20%. Age- and sex-matched individuals constituted the control group (mean age, 53.5 13.0 years) that were selected in a consecutive manner from catheterized patients during the same study period and who proved to have normal coronary angiograms. All subjects were evaluated by detailed medical history, physical examination, and biochemical analysis. Special emphasis was put on cardiovascular risk factors and diseases. Blood was analyzed with respect to concentrations of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, total cholesterol, total serum prostatespecific antigen (PSA), and total testosterone. All subjects were questioned for any cardiovascular drug use, smoking habits, and alcohol consumption, and underwent transthoracic echocardiography for left ventricular (LV) ejection fraction assessment. Image acquisition was performed in the left lateral decubitus position using a Vingmed System Vivid 7 (GE Vingmed Ultrasound, Horten, Norway) with a standard 2D transducer. Exclusion criteria included the following: refusal to participate in the study; known CAD; LV dysfunction (LV ejection fraction <50%) and hypertrophy; unstable ischemic conditions (unstable angina pectoris and myocardial infarction); valvular heart disease; congenital heart disease; collagenosis, connective tissue diseases, and vasculitis; and diabetes mellitus and patients taking antidiabetic treatment (such as oral hypoglycemic agents and/or insulin). Those with diabetes insipidus, metabolic syndrome, neoplasm, impaired kidney failure (creatinine clearance <60 mL/min), nephrotic syndrome, abnormality in thyroid function tests, and liver disease were not included in this study. Patients were excluded if they had a history of lower urinary tract surgery, prostate or bladder carcinoma, bladder calculi, previous radiotherapy to the pelvic region, or concomitant disease (eg, cystitis, prostatitis, acute urinary tract UROLOGY 85 (6), 2015
All patients in the study underwent selective coronary artery angiography. The femoral artery, and sometimes radial cannulation, was used for the arterial access site, and a Judkins system was applied for cannulation of the left and the right coronary arteries. Two experienced physicians who were blinded to the study evaluated all angiograms. Angiograms with localized and/or diffuse dilatation with a stenotic lesion not exceeding 1.5 times the normal segment of the artery were diagnosed as a CAE. Ectasia diameter was calculated by quantitative angiography on digital angiograms. When there was no identifiable adjacent normal segment, the mean diameter of the corresponding coronary segment in the control group served as the normal value. Angiograms without stenotic lesions in any major epicardial coronary arteries were considered as normal angiograms.
Lower Urinary Tract Symptoms and Benign Prostatic Enlargement Assessment All patients were initially evaluated by an assessment of their medical histories, with subjective symptoms determined using the International Prostate Symptom Score (IPSS). The subjects answered the native language 7-item validated version of the IPSS in Turkish. Each question was scored from 0 to 5. In addition, all subjects underwent a physical examination, including a digital rectal examination, urinalysis, PSA measurement, and assessments of the free uroflowmetry analysis to determine the mean peak urinary flow rate (Qmax), prostate volume (PV), postmictional residual urine volume (PMR), and biochemical analysis. PV and PMR were evaluated with transabdominal ultrasonography (TAUS). All TAUS scans were performed by the same sonographer. TAUS was performed in the supine position, both before and immediately after uroflowmetry. In each patient, the PV and PMR were measured. The volume estimation was an ellipsoidal volume calculation; the prostate was considered ellipsoidal in shape and the volume (mL) was calculated as 0.523 width (cm) height (cm) length (cm). The widths and heights were measured on axial planes and craniocaudal lengths on sagittal planes at their greatest diameter. An Acuson Sequoia 512 (Siemens Medical Solution, Mountain View, CA) US scanner with either a 3.5-MHz-curved or a 7.5-MHz endocavitary probe was used for all examinations.
Statistical Analysis The Statistical Package for the Social Sciences (SPSS) statistical software package, version 15.0, for Windows (SPSS Inc., Chicago, IL) was used for statistical analyses. Kruskal-Wallis and Mann-Whitney U tests were used in the comparison of groups. Continuous variables were given as mean standard deviation, and categorical variables were defined as a percentage. A P value of <.05 was considered significant. 1437
Table 1. Comparison of baseline demographic, clinical, and laboratory characteristics of the between groups in the study population Variables Age (y) Hypertension, n (%) Smoking habit, n (%) Alcohol consumption, n (%) Body mass index (kg/m2) Acetylsalicylic acid use, n (%) ACE-I use, n (%) ARB use, n (%) ACE-I plus diuretic use, n (%) ARB plus diuretic use, n (%) Calcium antagonist use, n (%) Statin use, n (%) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) LVEF (%) Ectasia diameter (mm) tPSA (ng/dL) TT (ng/mL)
CAE (N ¼ 47)
CAD (N ¼ 45)
Controls (N ¼ 47)
P Value
55.9 12.5 18 (38) 25 (53) 19 (40) 24.0 2.4 5 (11) 3 (6) 2 (4) 2 (4) 3 (6) 3 (6) 3 (6) 183 48 114 35 42 21 178 48 62.7 4.3 5.07 0.44 1.9 0.4 3.8 0.1
55.7 11.7 18 (41) 21 (45) 15 (34) 23.9 2.3 3 (7) 2 (5) 3 (7) 1 (2) 6 (14) 3 (7) 8 (18) 181 48 113 29 39 7 179 49 62.6 4.3
53.5 13.0 20 (43) 21 (45) 18 (38) 23.7 2.3 4 (9) 2 (4) 1 (2) 1 (2) 3 (6) 2 (4) 2 (4) 170 38 109 20 40 8 169 41 64.2 4.6
NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS
2.0 0.2 3.6 0.3
2.1 0.1 3.7 0.2
NS NS
ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CAD, coronary artery disease; CAE, coronary artery ectasia; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LVEF, left ventricle ejection fraction; NS, nonsignificant; tPSA, total serum prostate-specific antigen; TT, total testosterone. Continuous variables were given as mean standard deviation, and categorical variables were defined as a percentage.
Table 2. Comparison of BPE and LUTS parameters of the between groups in the study population Variables
CAE (N ¼ 47)
PV (cm3) IPSS total Storage IPSS Volume IPSS PMR (cc) Qmax (mL/sn)
41.0 11.8 5.7 6.1 11.4 14.2
10.4*y 7.1*y 3.2*y 4.6*y 9.0*y 4.9*y
CAD (N ¼ 45) 39.1 11.9 5.8 6.0 12.2 14.4
10.3** 7.1** 3.2** 4.6** 9.8** 4.8**
Controls (N ¼ 47)
P Value
.0001 .0001 .0001 .0001 .002 .0001
33.5 5.1 3.0 2.1 6.4 18.2
9.4 2.7 1.8 1.2 4.9 3.0
BPE, benign prostatic enlargement; IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms; PMR, postmictional residual urine volume; PV, prostate volume; Qmax, maximum mean peak urinary flow rate; other abbreviations as in Table 1. Variables were given as mean standard deviation. * P <.01 (coronary artery ectasia compared with control). ** P <.01 (coronary artery disease compared with control). y P >.05 (coronary artery ectasia compared with coronary artery disease).
RESULTS There were not statistically significant differences between the 3 groups with respect to age, presence of hypertension, smoking, and alcohol consumption (P >.05). The laboratory findings of all the groups were not statistically different (Table 1). Comparison of BPE and LUTS parameters between the groups, in the study population, is given in (Table 2). PV was higher in CAE and CAD patients compared with that of the control subjects, respectively (41.0 10.4 vs 33.5 9.4 cm3; 38.1 10.3 vs 33.5 9.4 cm3; P ¼ .0001); total IPSS was higher in CAE and CAD patients compared with that of the control subjects, respectively (11.8 7.1 vs 5.1 2.7; 11.9 7.1 vs 5.1 2.7; P ¼ .0001). Mean storage IPSS, respectively (5.7 3.2 vs 5.8 3.2 vs 3.0 1.8; P ¼ .0001); mean volume IPSS, respectively (6.1 4.6 vs 6.0 4.6 vs 2.1 1.2; P ¼ .0001); and PMR, respectively (11.4 9.0 vs 12.2 9.8 vs 6.4 4.9 cc; P ¼ .002), were 1438
higher in CAE and CAD patients compared with those of the control subjects (Table 2). In the CAE and CAD groups, Qmax was found to be lower than that in the control group, respectively (14.2 4.9 vs 18.2 3.0; 12.2 9.8 vs 18.2 3.0; P ¼ .0001; Table 2).
COMMENT The main findings of the study are as follows: first, PV was significantly higher in CAE and CAD patients compared with that of the control subjects. Second, IPSS was significantly higher in CAD and CAE patients compared with that of the control subjects. Extensive atherosclerotic changes and damage in the media of the vessel wall have been found in histologic specimens of coronary artery with CAE and CAD.18 Specifically, recent attention has been focused on arterial atherosclerosis as one of the important risk factors UROLOGY 85 (6), 2015
for BPH or BPE. Berger et al9 reported that an atherosclerosis-dependent increase in the recessive index for blood vessels in the transitional zone of the prostate resulted in vascular damage. In this regard, they claimed that perfusion disorder was responsible for prostate hyperplasia. In one study, it was reported that the levels of vascular endothelial growth factor (VEGF) were higher in CAE than in normal arteries.19 In the prostate tissue, hypoxia may occur in patients presenting with generalized or localized vascular damage. Hypoxia induces expression not only of hypoxia-inducible factor 1 but also of angiogenic growth factors such as VEGF, fibroblast growth factors 2 and 7, and transforming growth factor b, as well as cytokines such as interleukin 8 (IL-8), which suggests that hypoxia might trigger prostatic growth.20,21 In a recent study, PV and PMR were found to be significantly higher in the CAE and CAD groups than in the control group. Moreover, Qmax was found to be significantly lower than that in the control group. With this background in mind, in CAE and CAD patients, we speculated that perfusion disorder in the prostate may be responsible for BPE, which might be cause diminution of Qmax and elevated PMR in clinically due to hypoxia-induced factors. Sezen et al22 reported an increase both in serum total oxidant levels and oxidative stress and a decrease in total antioxidant level in CAE and CAD patients when compared with those in the normal subjects. This study revealed oxidative stress leading to endothelial dysfunction. There is increasing evidence that oxidative stress may have a role in the induction of cell growth. This is supported by observations suggesting that there may be a common pathogenic mechanism responsible for vascular smooth muscle cell growth and remodeling, as well as prostate smooth muscle proliferation.20 Pace et al23 found that high plasma peroxides and decreased total equivalent antioxidant capacity levels were measured in patients affected by BPH. In our study, in the CAE and CAD groups, PV and PMR were found to be significantly higher than those in the control group. In addition, Qmax was found to be statistically lower than that in the control group. With this background in mind, we believed that oxidative stress may trigger prostatic growth that might cause impairment of Qmax and increase PMR in CAE and CAD patients. In the study by Li et al,24 elevated plasma C-reactive protein (CRP) and IL-6 levels of patients with CAE and CAD were compared with those of angiographically normal controls. However, the independent variable most strongly associated with CAE was CRP. Mengus et al25 showed that inflammation played an important role in the development of LUTS by increasing expression of IL-6, IL-7, and IL-15 genes in BPH tissues. Liao et al26 found higher serum CRP levels were significantly associated with residual urgency in BPH patients. In the present study, IPSS and PMR was found to be statistically significantly elevated in the CAE and CAD patients than in the control group. In light of these studies, we consider UROLOGY 85 (6), 2015
that inflammation may be related to the development of LUTS, elevated PMR, and IPSS in patients with CAE and CAD. Endothelial dysfunction occurs secondary to a decrease in production of nitric oxide (NO) or an increase in oxidation. Endothelium-dependent vasodilatation diminishes as a result of decreased NO levels in cardiovascular diseases.27 The bioavailability of NO was decreased by the production of reactive oxygen species such as superoxide and peroxynitrite in subjects with cardiovascular risk factors.28 In the human prostate, the NOecyclic guanosine monophosphate signal pathway is considered to have important functional roles.29 A reduction in the local nitrergic innervation of the prostate in men with BPH and, thus, a decrease in the NOmediated relaxation of prostatic smooth muscle could impact the pathophysiology of LUTS.30 In our study, total IPSS, mean storage IPSS, and mean volume IPSS were found to be significantly higher in the CAE and CAD patients than those in the control group. According to these studies, in our opinion, a decreased level of NO might be the other pathologic development of LUTS with an increased IPSS in CAE and CAD patients. Relatively small size owing to less participation might be the first limitation of this study. The second limitation was that transrectal ultrasonography was not used. For PV measurement, TAUS was considered to have an equal value, and also, the less-invasive method such as transrectal ultrasonography. The last limitation was VEGF, NO, CRP, serum total oxidant, oxidative stress and total antioxidant levels, and so forth as inflammation markers were not evaluated.
CONCLUSION We showed that patients with CAE have higher PV, IPSS, and PMR compared with those of controls with normal coronary angiograms. This study proposes that BPE, LUTS, and CAE may be different disorders to a common vascular pathology and endothelial dysfunction. This study showed that BPE and LUTS were frequently seen in CAE at least as much as in CAD. Therefore, LUTS and BPE should be kept in mind in CAE patients in follow-ups. Further studies are required to explore the exact mechanisms. References 1. Robertson C, Link CL, Onel E, et al. The impact of lower urinary tract symptoms and comorbidities on quality of life: the BACH and UREPIK studies. BJU Int. 2007;99:347-354. 2. Wei JT, Schottenfeld D, Cooper K, et al. The natural history of lower urinary tract symptoms in black American men: relationships with aging, prostate size, flow rate and bothersomeness. J Urol. 2001; 165:1521-1525. 3. Garraway WM, Collins GN, Lee RJ. High prevalence of benign prostatic hypertrophy in the community. Lancet. 1991;338:469-471. 4. Casabe A, Roehrborn CG, Da Pozzo LF, et al. Efficacy and safety of the coadministration of tadalafil once daily with finasteride for 6 months in men with lower urinary tract symptoms and prostatic
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