Stesura Seveso 9Archivio Italiano di Urologia e Andrologia 2014; 86, 1 ORIGINAL PAPER Evaluation of penile cavernosal artery intima-media thickness in patients with erectile dysfunction. A new parameter in the diagnosis of vascular erectile dysfunction. Our experience on 59 cases Domenico Prezioso, Fabrizio Iacono, Umberto Russo, Giuseppe Romeo, Antonio Ruffo, Nicola Russo, Ester Illiano Department of Urology, University Federico II of Naples, Italy. Objective: A precise characterization of erectile dysfunction (ED) of vascu- lar origin has not yet been achieved, although cav- ernous peak systolic velocity (PSV) is generally consid- ered a major parameter. Nevertheless the penile dynamic color Doppler is invasive and linked to sever- al complications. The intima-media thicknesses (IMT) of cavernosal artery would add to the predictive value of vasculogenic ED risk and outcomes. We also hypothesized the existence of a correlation between IMT cavernosal artery and IMT carotid arteries. This study seeks to evaluate these hypotheses with our experience, investigating the predictive accuracy of carotid and cavernosal Doppler ultrasound findings for discriminating patients with vasculogenic ED. Material and methods: A total of 59 subjects (32 vasculo- genic ED patients - group A - and 27 no vasculogenic ED patients - group B) were evaluated in our andrological center from September 2012 to June 2013 and enrolled in the study. All subjects underwent medical history, erectile function domain of the International Index of Erectile Function, physical examination, routine and sex hormone blood tests, and high resolution dynamic color Doppler ultrasound evaluation of carotid and penile districts and valutation of IMT in both districts. Results: The values of cavernosal artery IMT in group A were higher than in group B (0,28 ± 0,06 mm vs 0,17 ± 0,07 mm). Even the values of carotid artery IMT in vas- culogenic ED group were higher than in no vasculogenic ED group (0,74 ± 0,14 mm vs 0,59 ± 0,11 mm). The cav- ernosal IMT showed a moderate (r = 0.61) positive linear correlation (p < 0.001) with the carotid artery IMT. Conclusions: An increased cavernous IMT might predict ED of vascular origin with more accuracy than PSV and could be a sensitive predictor also for systemic athero- sclerosis at an earlier phase. KEY WORDS: Intima media thickness; Vascular erectile dysfunc- tion; Endothelial dysfunction. Submitted 19 August 2013; Accepted 5 October 2013 Summary No conflict of interest declared. INTRODUCTION Erectile dysfunction (ED) is a pervasive disorder that afflicts as many as 30 million men in the United States (1), with an estimated 100 million men affected worldwide (2, 3).The risk of ED is related to many factors, including age, smoking, diabetes, heart disease, depression, and hypertension (4, 5). Vascular disease is by far the most common cause of ED (6) Formerly dismissed as a psy- chological condition, ED has now assumed center stage as a readily treatable disorder and a powerful risk-marker for cardiovascular disease (CVD) (6, 7). Infact because CVD and ED share etiologies as well as pathophysiology (endothelial dysfunction) and because of evidence that degree of ED correlates with severity of CVD, it has been postulated that ED is a sentinel symptom in patients with occult CVD (8). Endothelial dysfunction is intimately linked to atherogenesis and increased CVD risk (9). Dysfunction arises following alteration in the release of several vasoactive factors, mainly nitric oxide (NO), from endothelial cells (9, 10). Endothelial dysfunction due to an abnormality in the release and/or action of NO is characterized by vasoconstriction, coagulation, increased leucocyte adhesion and stimulation of smooth muscle (SM) cell growth, and is, therefore, central to atherogen- esis (9). Several traditional cardiovascular risk factors, such as aging, smoking, hypertension, dyslipidemia and diabetes, and some less traditional risk factors, including inflammation, hypoxia, oxidative stress and homocys- teinemia, are related to endothelial dysfunction (11, 12). Therefore given that endothelial dysfunction predates atherosclerosis development, this possibility is consistent with the so-called ‘artery size’ hypothesis (13). This the- ory posits that atherogenesis is likely to present earlier with clinical symptoms in arteries of a smaller diameter, such as in the penis, than in larger sized arteries, such as in the coronary circulation (14). In as much as the vas- cular disease is the most common cause of ED, after an intracavernosal injection of a vasodilatory agent, color Doppler sonography is performed to evaluate cavernosal arteries and dorsal vessels, and to demonstrate both arte- rial insufficiency (primary diagnostic criteria for arterial DOI: 10.4081/aiua.2014.1.9 Prezioso_Stesura Seveso 26/03/14 10:11 Pagina 9 Archivio Italiano di Urologia e Andrologia 2014; 86, 1 D. Prezioso, F. Iacono, U. Russo, G. Romeo, A. Ruffo, N. Russo, E. Illiano 10 insufficiency include a peak systolic velocity (PSV) of less than 25 cm/sec and waveform dampening) (15) and venous incompetence (most investigators used to diag- nose venous leakage when arterial end-diastolic velocity is greater than 5 cm/sec) (15). That makes it a valuable tool in the diagnostic evaluation of ED (15). Color Doppler ultrasonography is a valuable, informative and minimally invasive tool in the diagnosis of ED (16). Color Doppler imaging offers several advantages over duplex imaging, including rapid localization of the cav- ernosal artery and accurate angle correction; depiction of cavernosal artery and dorsal vein flow progression; and demonstration of venous flow and arterial variants (15). However, due to the common pathogenesis that charac- terizes ED and CVD, the classical color Doppler could be complemented with a new method in use in the study of atherosclerosis of the carotid arteries, the intima-media thickness (IMT). Carotid-wall IMT infact is a surrogate measure of atherosclerosis (17) associated with cardio- vascular risk factors (18) and with cardiovascular out- comes (19-22). It is the distance from the lumen-intima interface to the media-adventitia interface of the artery wall, as measured on noninvasively acquired ultrasono- graphic images of the carotid arteries (20). The IMT is increasingly used as a surrogate end point of vascular outcomes in clinical trials aimed at determining the suc- cess of interventions that lower risk factors for athero- sclerosis and associated diseases (stroke, myocardial infarction and peripheral artery diseases, like disease of cavernosal artery). We hypothesized that the IMT of cav- ernosal artery would add to the predictive value of vas- culogenic ED risk and outcomes. We also hypothesized the existence of a correlation between IMT cavernosal artery and IMT carotid arteries. This study seeks to eval- uate these hypotheses with our experience, investigating the predictive accuracy of carotid and cavernosal Doppler ultrasound (CDU) findings for discriminating patients with vasculogenic ED. MATERIAL AND METHODS The study design consisted of a observational trial con- duced from September 2012 to June 2013. The study was conducted according to the Helsinki Declaration. Written informed consent was obtained from all patients. We enrolled 59 patients, mean age was 55,3 ± 3,7 years. Inclusion criteria were: over 51,6 years of age, male patients with stable marital relations and affected by ED. Exclusion criteria were: International Index of Erectile Function (IIEF) score ! 26, alcoholism, smoking, hyper- tension, CVD, neurogenic syndrome (multiple sclerosis, multiple atrophy, Parkinson’s disease, tumors, stroke, disk disease, spinal cord disorders, polyneuropathy, uraemia), Peyronie’s disease, penile fracture, congenital curvature of penis, micropenis, hypospadias, epispadias, hyperprolat- tinemia, hyper- and hypothyroidism, Cushing’s disease, drug assumption (PDE5 inhibitors, intracavernous administration of vasoactive drugs, antihypertensives, antidepressants, antipsychotics, antiandrogens, antihista- mines, heroin, cocaine and methadone), radiotherapy (pelvis or retroperitoneum) and lower pelvic surgery (oncological pelvic surgery, lower urinary and genital tract surgery). We enrolled 59 patients presenting at the Andrology Department of our Clinic. At visit patients were evaluated by means of a detailed medical and sexual his- tory. A general (including assessment of Body Mass Index - BMI - and blood pressure) and urological objective exam- ination was carried out to identify the presence of any dis- eases that could interfere with erectile function such as Peyronie's disease, cancer of the penis, hypospadias, epis- padias, signs and symptoms suggestive of hypogonadism (small testes, alterations in secondary sexual characteris- tics, decreased libido), neurological disorders. In all patients in whom an autonomic neuropathy was suspect- ed, especially in patients with diabetes, it was assessed by the evocation of the bulbo-cavernous reflex. Each patient finally performed a rectal examination to search for a pos- sible benign prostatic hypertrophy (BPH) to be associated with the presence of lower urinary yract symptoms (LUTS). In each patient lipid and metabolic levels (triglycerides, total cholesterol, HDL cholesterol, fasting blood glucose), hormone levels (testosterone (T), dihydrotestosterone (DHT), luteinizing hormone (LH), follicle-stimulating hor- mone (FSH), estradiol, prolactin), clinical examination were evaluated. We asked all patients to complete the International Index of erectile function (IIEF) questionnaire: the IIEF domain was calculated and ED grading was so determined: absence of ED (EF score 26 to 30), mild ED (EF score 17 to 25), moderate ED (EF score 11 to16) and severe ED (EF score < 10) (23). All patients were evaluat- ed with gray scale ultrasound and color Doppler ultra- sound just before injection and 1, 5, 15, 20 minutes after injection and the images were recorded. A 7.5 mHz linear transducer with a mechanical standoff wedge to produce a favorable insonating angle throughout the entire field of view was used for the Doppler ultrasound examinations. The degree of erection was classified into flask erection, tumescence, full erection, rigid erection and detumes- cence phases by an urologist. Spectrum pattern, peak sys- tolic velocity (PSV), end diastolic velocity (EDV) values and compliance were measured with conventional penile Doppler ultrasound 5 minutes after pharmacological stimulation for each subject. According to the reference levels given in the recommendations of the European Association of Urology (EAU) guidelines, a positive test is a rigid erectile response (unable to bend the penis) that appears within 10 min after the intracavernous injection and lasts for 30 min, and a peak systolic blood flow high- er than 30 cm/s and a resistance index higher than 0.8 are generally considered normal in a duplex ultrasound of penile arteries (24). Patients were divided in 2 groups: vasculogenic ED (group A) and no vasculogenic ED (group B) according to color Doppler image findings. The group A was com- posed of 32 patients, while the group B was composed of 27 patients. IMT values of common carotid artery and of cavernosal artery were calculated in all patients. Intima- media interface lines were manually traced as continuous lines by a certified reader, and IMT values were calculat- ed (25). The mean IMT of the common carotid artery was measured over a segment of the common carotid artery that was 1 cm long, located approximately 0.5 cm below the carotid-artery bulb, and considered not to contain any plaque (i.e., not to have any perceivable protrusion of the Prezioso_Stesura Seveso 26/03/14 10:11 Pagina 10 artery wall into the lumen) (26). In each individual patient, the measurement was made bilaterally while for the statistical study was considered the media of the two values obtained. IMT of cavernosal artery was measured in the proximal artery, choosing the straight portion that offered the best visualization. Also in this case the meas- urement was bilateral and the average of the values obtained was used for the study. The measurement was made by the same skilled operator for each patient, using a scanner Philips iU22 xmatrix ultrasound system and a probe L12-5 50 mm Broadband Linear Array Transducer with a frequency range from 12 to 5 MHz. The results of both groups were compared by Student t test (p < 0.05). RESULTS At initial evalutation in the group A the IIEF total score was 10.8 ± 3.2, moderate ED, while in the second group the IIEF total score was 17.4 ± 4.1, mild ED, (p < 0.001). This result was expected and is obviously in agreement with the belief that hemodynamic alterations of the penile vasculature are the factors that can mostly impair erectile function.In the group A the diastolic blood pressure was 92.3 ± 5.1 mmHg versus 86,9 ± 6,1 in group B, while the systolic blood pressure was 143.2 ± 7.5 mmHg and 134,4 ± 9,2 respectively (p < 0.001). Furthermore in the group A glucose (p = 0.021) and triglycerides (p = 0.013) levels were higher than those in group B, while cholesterol lev- els were lower.(p = 0.016). Infact the glucose levels in group A were 114,7 ± 20,3 mg/dl versus 103,4 ± 21,2 mg/dl in group B. Triglycerides levels were 175,3 ± 30,6 mg/dl in vasculogenic ED group , and 160,2 ± 17,0 mg/dl in no vasculogenic group. Different trend showed the cho- lesterol levels infact they were higher in group B (43,9 ± 10,2 mg/dl – group A – vs 49,3 ± 8,4 mg/dl – group B). There were not statistically significant differences between the groups in BMI values (28.1 ± 3.1 vs 26.5 ± 4.5). Table 1 shows the characteristics of the two groups. These findings supported the association of ED with CVD, ath- erosclerosis and cardiovascular risk. Table 2 shows the findigs of carotid and cavernosal artery IMT. The values of cavernosal artery IMT in group A were higher than in group B (0,28 ± 0,06 mm vs 0,17 ± 0,07 mm).This sug- gested that hemodynamic functional alterations evaluated in penile color Doppler image were correlated with mor- phological alterations of cavernosal artery evaluated by ultrasound. Even the values of carotid artery IMT in vas- culogenic ED group were higher than in no vasculogenic ED group (0,74 ± 0,14 mm vs 0,59 ± 0,11 mm). This result is in complete agreement with the association between carotid atherosclerosis and polydistrectual ath- erosclerosis like cavernosal atherosclerosis. Lastly we wanted to analyze the possibility of a correlation between the values of cavernous IMT and carotid IMT in our study population. As graphically represented in Figure 1, the cavernosal IMT showed a moderate (r = 0.61) posi- tive linear correlation (p < 0.001) with the carotid artery IMT. The explanation of these results was that the same risk factors and pathogenesis of vascular injury caused simultaneously endothelial damage in different distrects. 11Archivio Italiano di Urologia e Andrologia 2014; 86, 1 Evaluation of penile cavernosal artery intima-media thickness in patients with erectile dysfunction Vasculogenic ED No vasculogenic ED P (n = 32) (n = 27) Age mean (SD) 53,2 ± 8,2 49,6 ± 7,6 NS IIEF-5 mean (SD) 10,8 ± 3,2 17,4 ± 4,1 p < 0,001 BMI mean (SD) 28,1 ± 3,1 26,5 ± 4,5 NS Systolic blood pressure (mmHg) mean (SD) 143,2 ± 7,5 134,4 ± 9,2 p < 0,001 Diastolic blood pressure (mmHg) mean (SD) 92,3 ± 5,1 86,9 ± 6,1 p < 0,001 Glycemia (mg/dl) mean (SD) 114,7 ± 20,3 103,4 ± 21,2 p = 0,021 Total cholesterol (mg/dl) mean (SD) 193,3 ± 42,0 176,0 ± 24,8 NS Cholesterol HDL (mg/dl) mean (SD) 43,9 ± 10,2 49,3 ± 8,4 p = 0,016 Triglycerides (mg/dl) mean (SD) 175,3 ± 30,6 160,2 ± 17,0 p = 0,013 BMI: Body mass index; ED: Erectile dysfunction; HDL: High-density lipoprotein; IIEF-5: International Index of erectile function. Table 1. Characteristics of patients: Vasculogenic ED (group A) and No vasculogenic ED (group B). Vasculogenic ED No vasculogenic ED P (n = 32) (n = 27) IMT cavernosal artery mean (SD) 0,28 ± 0,06 0,17 ± 0,07 p < 0,001 IMT carotid artery mean (SD) 0,74 ± 0,14 0,59 ± 0,11 p < 0,001 BED: Erectile dysfunction; IMT: Intima–media thickness.. Table 2. Intima-media thickness (IMT) values of common carotid artery and of cavernosal artery. Prezioso_Stesura Seveso 26/03/14 10:11 Pagina 11 Archivio Italiano di Urologia e Andrologia 2014; 86, 1 D. Prezioso, F. Iacono, U. Russo, G. Romeo, A. Ruffo, N. Russo, E. Illiano 12 DISCUSSION The association between ED and CVD has previously been recognized (27). Patients with CVD frequently describe preexisting ED (28).These patients must be clearly distinguished from those who have neither CVD nor cardiovascular risk factors and have a defect in the generating NO-3-5-cyclic guanosine monophosphate peripheral vascular system in SM that is independent of other systemic vascular diseases (29). It has been sug- gested, but never demonstrated, that early treatment of coronary heart disease risk factors may reduce the later risk of ED (30). Furthermore, it has been hypothesized that ED is a harbinger of CVD (31, 32). In a study of men with diabetes with vs without ED, ED was the most effi- cient predictor of coronary artery disease (33). A large- scale study of 25 650 men found a 75% increased risk of peripheral vascular disease in men with preexisting ED (34). Ian M. Thompson demonstrated the substantial association between incident as well as prevalent ED and subsequent CVD, including angina, myocardial infarc- tion, stroke, and transient ischemic attack (35). Several epidemiological studies in selected patient populations have clearly shown that the major cardiovascular risk factors – aging, smoking, diabetes, hyperlipidemia and hypertension – have raised prevalence in individuals with ED (36, 37). The prevalence of ED is also directly related to the number of cardiovascular risk factors pres- ent, being highest in individuals with more than three. Patients with coronary artery disease have a high fre- quency of ED (38, 39) which correlates with the number of stenotic and calcified arteries and predates sympto- matic disease (40). Notably, a patient with vasculogenic ED is likely to have one coronary artery with a 50% stenosis (38, 39). Cardiometabolic risk in abdominally obese subjects is now well-defined as the metabolic syn- drome (41). ED prevalence increases with the number of components of the metabolic syndrome, being as high as 40% in individuals with four components, and is espe- cially prevalent in those with diabetes (42). In individu- als with the metabolic syndrome, ED has a linear rela- tionship with evidence of endothelial dysfunction (43). A plausible theoretical link between erectile and endothelial dysfunction posits that cardiovascular risk factors could induce ED by impairing NO release from endothelial cells following neuronal activation and initi- ation of a penile erection. A residual, important question, however, is whether ED reflects endothelial dysfunction independent of traditional cardiovascular risk factors (43). Carotid-artery IMT, measured noninvasively with the use of carotid-artery ultrasonography, is an inde- pendent predictor of new cardiovascular events in per- sons without a history of CVD (43). A review of eight epidemiologic studies showed that the IMT of the com- mon carotid artery by itself (in all eight studies) or com- bined with the IMT of the internal carotid artery and pre- sented as a score (in one of the eight studies) had inde- pendent predictive power with respect to cardiovascular events (44) .The presence of plaque (defined as an inter- nal-carotid artery IMT ! 1.9 mm) has been shown to be associated with increased event rates (45). Gokkaya investigated the predictive accuracy of carotid and CDU findings for discriminating patients with vascu- logenic erectile dysfunction (EDV). Of total 50 patients, 29 (58%) were included in vasculogenic ED group and 21 (42%) in non-vasculogenic ED group according to P-CDU findings. There was a significant difference between groups for cavernosal IMT (P = 0.012) but not for carotid IMT (P = 0.601). When patients were reclassi- fied according to carotid IMT values (IMT of the first group < 0.9 mm and the second > = 0.9 mm), carotid PSV and EDV values were different (P = 0.033 and 0.018, respectively). Cavernosal PSV and EDV displayed no dif- ference (P = 0.816 and 0.123) while cavernosal IMT and percent change of cavernosal caliper were significantly different (P = 0.014 and 0.018) (46). Caretta performed a high magnification ultrasonographic study in order to compare functional and morphological parameters of the cavernous artery to PSV and their relation with penile and systemic atherosclerosis (47). A total of 109 subjects (84 ED patients and 25 controls) were evaluated. Cavernous parameters were significantly different between ED and controls. Multivariate model showed that IMT was the only predicting parameter for ED of vascular origin. Cavernous IMT showed a strong direct correlation with carotid and femoral IMT. ED patients with two or more cardiovascular risk factors had a significantly higher cav- ernous IMT (47). Ucar investigated the relationship between penile color Doppler sonography (CDS) findings and sonographic endothelial parameters in patients with ED, including IMT of common carotid arteries (CCA) and flow-mediated dilatation (FMD) of brachial artery (48). Fifty-six ED patients were included in the study. IMT val- ues were higher in arterial/combined insufficiency group when compared to cavernous veno-occlusive disease but the difference was not statistically significant. The com- bined use of IMT and FMD established the diagnosis of vasculogenic ED with 100% sensitivity and 59.2% speci- ficity. The positive predictive value was 72%, negative predictive value 100% and accuracy 80%. The combined use of brachial artery FMD and carotid arteries IMT meas- urements may be suggested as an alternative method to evaluate vasculogenic ED (48). Vlachopoulos evaluated Figure 1. Correlation between carotid artery IMT and cavernosal artery IMT. IMT: Intima–media thickness. Prezioso_Stesura Seveso 26/03/14 10:11 Pagina 12 arterial structural and functional characteristics and measured systemic endothelial/inflammatory markers in 52 hypertensive men with vasculogenic ED and in 34 hypertensive men with normal erectile function, matched for age, blood pressure, risk factors and treatment (49). Hypertensive patients with ED had higher common carotid IMT (0.95 ±.19 vs. 0.83 ± 0.18 mm, P = 0.003) and carotid-femoral pulse-wave velocity (8.89 ± 1.38 vs. 8.11 ± 1.10 m/s, P = 0.007), lower flow-mediated dilation of the brachial artery (absolute values of 2.96 ± 1.64 vs. 4.07 ± 1.68%, P = 0.003). In hypertensive men, the pres- ence but not the severity of vasculogenic ED is associated with subclinical atherosclerosis, impairment of arterial function and systemic endothelial and inflammatory acti- vation (49). CONCLUSION The increase of IMT is an expression of morphological and structural alterations of the vessel wall due to ather- osclerotic phenomena. Both the carotid and cavernous IMT proved significantly higher in patients suffering from ED vasculogenic, in association with the classical risk factors for CVD. In particular, the evaluation of IMT cavernous arteries could be done, together with the color-Doppler evalua- tion of PSV, by EDV, a new sonographic parameter useful in identifying those cases of vasculogenic ED in a more precise way than what can not be done with the alone assessment of PSV. The penile color Doppler with intracavernous injection of vasoactive substances is a diagnostic method for a long time widely used in the evaluation of patients with ED. However, it is invasive and linked to several complica- tions such as bruising, hematoma and penile priapism, not to mention that this method is considered embar- rassing by most of the patients. In addition, the anxiety that comes from intracavernous injection can induce an abnormal response in the patient who may have adren- ergic inhibitory effect, in fact decreasing the sensitivity of this test. Further studies should be aimed at understanding if the assessment of cavernous IMT is a reliable screening test for those subjects with multiple cardiovascular risk fac- tors at risk of vasculogenic ED, or even if it can com- pletely replace the more invasive and less tolerated color- Doppler investigation with intracavernous injection in the instrumental assessment of erectile function. REFERENCES 1. Lewis RW. Epidemiology of erectile dysfunction. Urol Clin North Am. 2001; 28:209-216. 2. NIH Consensus Development Panel on Impotence. Impotence. JAMA. 1993; 270:83-90. 3. Zusman RM, Morales A, Glasser DB, Osterloh IH. Overall cardio- vascular profile of sildenafil citrate. Am J Cardiol. 1999; 83:35C-44C. 4. Johannes CB, Araujo AB, Feldman HA, Derby CA, et al. 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The combined use of brachial artery flow-mediat- ed dilatation and carotid artery intima-media thicknessmeasure- ments may be a method to determine vasculogenic erectile dysfunc- tion. Int J Impot Res. 2007; 19:577-83. 49. Vlachopoulos C, Aznaouridis, et al. Arterial function and inti- ma-media thickness in hypertensive patients with erectile dysfunc- tion. J Hypertens. 2008; 26:1829-36. Correspondence Domenico Prezioso, MD dprezioso@libero.it Fabrizio Iacono, MD fiacon@tin.it Umberto Russo, MD umberto.russo@libero.it Giuseppe Romeo, MD giuseppe.romeo85@gmail.com Antonio Ruffo, MD antonio.ruffo7@gmail.com Nicola Ruffo, MD stoiconk@hotmail.com Ester Illiano, MD (Corresponding Author) ester.illiano@inwind.it Department of Urology - University Federico II of Naples via Pansini 5 - 80131 Naples, Italy Prezioso_Stesura Seveso 26/03/14 10:11 Pagina 14