Penile and Systemic Endothelial Function in Men with and without Erectile Dysfunction

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1 european urology 55 (2009) available at journal homepage: Sexual Medicine Penile and Systemic Endothelial Function in Men with and without Erectile Dysfunction Yoram Vardi *, Lior Dayan, Boaz Apple, Ilan Gruenwald, Yaron Ofer, Giris Jacob Neuro-Urology Unit and Recanati Autonomic Dysfunction Center, Rambam Health Campus, and Faculty of Medicine, Technion-IIT, Haifa, Israel Article info Article history: Accepted July 17, 2008 Published online ahead of print on August 8, 2008 Keywords: Erectile dysfunction Endothelial function Veno-occlusive plethysmography Blood flow Abstract Background: Assessment of endothelial function can provide essential information about the mechanisms of cardiovascular disease. Emerging data show that erectile dysfunction (ED) can precede the symptoms of ischemic heart disease, and this suggests that endothelial dysfunction is the link between these two clinical entities. Objective: To evaluate penile and systemic endothelial function in subjects with and without ED. Design, setting, and participants: Fifty-nine subjects were enrolled in the study. According to their International Index of Erectile Function (IIEF) ED domain scores, they were divided into two groups: 40 patients with ED and 19 men without ED (control group). Hemodynamic measurements, penile endothelial function, and forearm endothelial function were assessed in all participants using veno-occlusive plethysmography. Measurements: We measured baseline blood flow in both the forearm and the penis and calculated the corresponding vascular resistances. Postischemic changes in blood flow were recorded serially in both organs for the evaluation of endothelial function. Area under the flow-time curve (AUC), and maximal blood flow after ischemia were considered to be the indices of endothelial function. Results and limitations: General characteristics of the two groups of participants were comparable except for age ( yr in the control group vs yr in the ED group). Baseline forearm blood flow was similar in the two groups, but the penile blood flow was significantly lower in men with ED compared with that in the men without ED: versus ml/min per 100 ml of tissue ( p = 0.006). Penile vascular resistance was higher in the ED group compared with the control group. The indices of forearm endothelial function were comparable in both groups ( p = 0.70 for the AUCs). However, indices of penile endothelial function were significantly higher in the control group compared with those of the ED group (AUC: 950 units 130 vs units, p = 0.001). Conclusions: The use of veno-occlusive plethysmography for evaluating penile endothelial function is simple and reliable and provides new information on the pathophysiology of ED at the level of penile vasculature. This is the first study that provides evidence of impaired penile endothelial function without the presence of a significant peripheral endothelial dysfunction. Furthermore, these results provide further support for the notion that the development of ED could predict the future onset of cardiovascular disease. # 2008 Published by Elsevier B.V. on behalf of European Association of Urology. * Corresponding author. Neuro-Urology Unit, Rambam Health Campus, Bat-Galim, Haifa, Israel. Tel ; Fax: address: yvardi@rambam.health.gov.il (Y. Vardi) /$ see back matter # 2008 Published by Elsevier B.V. on behalf of European Association of Urology. doi: /j.eururo

2 980 european urology 55 (2009) Introduction 2. Methods Erectile dysfunction (ED) is observed, most frequently, in pathologies involving vascular function, such as diabetes mellitus, hypertension, atherosclerosis and smoking [1 3]. Current data suggest that the endothelial dysfunction is the link between ED and the aforementioned diseases [4 7] and that endothelial dysfunction results in reduced ability of the endothelial cells to release vasorelaxants (eg, nitric oxide [NO]) [8,9]. Consequently, the ability of the arteriolar smooth muscle cells to relax efficiently is impaired, and ED occurs as a result of inadequate endothelialdependent vasodilation and insufficient blood flow to the corpora. Inadequate endothelialdependent vasodilation occurs also in the anginal syndrome in which there is insufficient blood flow to the myocardium [10]. ItisnoteworthythatED generally precedes the appearance of the coronary artery disease by 2 3 yr, and thus can be an early marker for latent ischemic heart disease [11,12]. Endothelial function in the peripheral vasculature can be assessed either by invasive or noninvasive techniques. However, the interpretation of the results is controversial. Intra-arterial catheterization and local drug infusion is the gold standard for assessing endothelial function, but the invasive nature of the procedure limits its widespread use clinically [13,14]. The results from noninvasive techniques to assess endothelial function are indirect because they rely on postischemic flow-mediated dilatation (FMD) and reactive hyperemia that develop following temporary occlusion of an artery. Rapid cessation of the induced ischemia in the tested vessel (or organ) provokes an increased release of NO and possibly other endothelial-dependent vasorelaxant factors [8,14], and the magnitude of the resultant increase in vascular diameter or local blood flow is considered to be a measure of endothelial function. Two noninvasive techniques are widely used to assess endothelial function: Doppler ultrasonography and veno-occlusive strain-gauge plethysmography [14]. Recently, we were able to adapt and validate the use of veno-occlusive plethysmography to assess penile blood flow and endothelial function in a group of normal male healthy volunteers without ED [15]. The aim of the present study was to compare systemic and penile endothelial function in subjects with and without ED using the veno-occlusive plethysmography Subjects Fifty-nine men participated in the present study. These patients were recruited from the Neuro-Urology Clinic, Rambam Health Campus, and the control group (men without ED) was recruited through advertisements in local media. The participants were men whose ages ranged between 20 yr and 70 yr and who had not used a phosphodiesterase type 5 inhibitor (PDE5-I) during the past 6 mo. Individuals were excluded if they had symptoms of peripheral vascular disease (ie, claudication) or suffered from uncontrolled hypertension, end-stage renal failure, congestive heart failure (New York Heart Association score >II), or moderate-to-severe anginal syndrome. The severity of ED was assessed according to the International Index of Erectile Function (IIEF) ED domain score. Any participant whose IIEF score was 26 was considered to have normal erectile function. Accordingly, 19 men were found to have normal erectile function (control group) and 40 men were found to have ED. The study was approved by the local institutional review board as required by the Declaration of Helsinki, and each participant gave his signed, informed consent Study protocol Prior to the study, each participant was examined by a urologist and was asked to describe his sexual history as part of the full IIEF assessment. Throughout the entire study period, a three-lead electrocardiogram and cuff blood pressure (BP) (Datex-Engstrom, Helsinki, Finland) were recorded continuously. After instrumentation and being at rest for 20 min, baseline measurements of penile and forearm blood flow were made and the corresponding endothelial function was assessed. All measurements were made at the Recanati Autonomic Dysfunction Center at our hospital in a quiet, darkened room whose ambient temperature was approximately 24 8C. On the day of study, the participants were not permitted to smoke or drink beverages that contained alcohol and monoamines Procedures for evaluating forearm and penile endothelial function Procedures for evaluating forearm and penile endothelial function were performed according to Dayan et al [15] Forearm study A sphygmomanometer cuff was applied to the right arm, and then inflated to 50 mm Hg for 7 s to prevent venous egress. During this period, forearm blood flow was measured by a strain-gauge plethysmograph (ECR5, DE Hokanson Inc, Bellevue, WA, USA). A 7-s deflation period was allowed before the subsequent measurement. Cutaneous flow of the hand was excluded from the forearm blood flow measurements by inflating a wrist cuff to a pressure level greater than the systolic BP. The baseline forearm blood flow was determined from the average of at least four stable repeated flow measurements [15].

3 european urology 55 (2009) Reactive hyperemia was induced by inflating a pneumatic cuff (S300 Aneroid sphygmomanometer, DE Hokanson Inc, Bellevue, WA, USA) above the sphygnomanometric cuff to a pressure level that was greater than the systolic BP and maintaining it for 5 min. The cuff was then rapidly deflated and measurements of postischemic forearm blood flow were made serially until the forearm blood flow returned to baseline values. Flow was expressed as millilitres per minute for 100 ml of tissue Penile study The penis was stabilized throughout the entire study period using an ad hoc device that was especially designed for this purpose. A specialized sphygnomanometric cuff (DP 2.5 disposable penile cuff, DE Hokanson Inc, Bellevue, WA, USA) wasplacedaroundthebaseofthepenisandtheninflatedto 50 mm Hg. This pressure was maintained for 5 s to induce venous filling of the penis. Thereafter, the cuff was deflated for 10 s. A mercury strain gauge (DE Hokanson Inc, Bellevue, WA, USA) of varying circumference ( cm, the circumference of an average penis) was placed at least 1 2 cm above the distal edge of the penile cuff. The baseline penile blood flow was determined from the average of at least four stable repeated flow determinations that were obtained after 15 min of instrumentation. Reactive hyperemia in the penis was induced by inflating a pneumatic cuff (PC 3.3 penile cuff, DE Hokanson Inc, Bellevue, WA, USA) that was placed around the base of the penis and coating the veno-occlusive cuff to a pressure level that was greater than the systolic pressure and maintaining it for 5 min. The postischemic penile blood flow was then recorded immediately after the deflation and serially until the flow rate returned to baseline levels. The highest blood flow (maximal flow) and the area under the time-flow curve (AUC) of the reactive hyperemic response were then calculated and were considered to be the indices of penile and forearm endothelial function (Fig. 1). Organ-specific vascular resistance, as a measure of vascular tone, was Fig. 1 A schematic illustration of the sequential measurement of organ blood flow plotted over time (seconds) shows baseline blood flow, then the maximal blood flow obtained after the release of the arterial occlusion and the corresponding calculation of the area under the curve of flow-time curve (AUC). calculated by dividing individual mean BP (systolic BP diasdiastolic BP/3 + diastolic BP) by the correspondent local basal blood flow Statistical analysis of the data Data are presented as mean standard error of the mean. A two-sided, nonpaired student t test was used to compare the study parameters between the two groups. The chisquare test was used to compare binary data. A multivariate analysis (general linear model) was performed to detect variables that can affect endothelial function (SPSS version 15 for Windows, Chicago, IL, USA). The level for statistical significance was set at p < Results As shown in Table 1, the general characteristics of the participants are comparable except for the lower IIEF ED domain score (due to the selection criteria) and the higher age of participants in the ED group compared with those of the control group. Basal penile blood flow was significantly lower in the ED group compared with that of control group: ml/min per 100 ml of tissue versus ml/min per 100 ml of tissue ( p = 0.006), respectively (Fig. 2, lower panel). It is noteworthy that the baseline penile blood flow was 3-fold higher than that in the forearm in the control group. However, baseline forearm blood flows were comparable in both groups: ml/min per 100 ml of tissue (control group) versus ml/min per 100 ml of tissue (ED group). Indices of endothelial function, namely maximal blood flow rate and AUC in the forearm and penis of both groups are displayed in Fig. 3. In the forearm, maximal blood flow and AUC of the control group were comparable to those in the ED group (blood flow, ml/min per 100 ml of tissue vs 22 2 ml/min per 100 ml of tissue, p < 0.7; AUC: units vs units, p = 0.19). However, penile endothelial indices were significantly higher in the control group compared with the ED group (blood flow, 27 4 ml/min per 100 ml of tissue vs ml/min per 100 ml of tissue, p = 0.05; AUC: units vs units, p = 0.001) (Fig. 3, lower panel). Penile vascular resistance was significantly lower ( p < ) compared with that of the forearm. Forearm vascular resistance was 29 3 mm Hg/ml per min per 10 ml of tissue in the control group and 26 2 mm Hg/ml per min per 10 ml of tissue in the ED group, p = 0.27 (Fig. 4). However, penile vascular resistance was significantly higher in the ED group than that in the control group: mm Hg/ml

4 982 european urology 55 (2009) Table 1 General characteristics of the study participants Control n = 19 ED group n =40 p-values Age, years Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, beats per minute Ischemic heart disease, no. (%) 5 (18%) 8 (20%) 0.90 Hypertension, no. (%) 4 (21%) 15 (38%) 0.20 Diabetes mellitus, no. (%) 3 (16%) 10 (25%) 0.40 Smokers, no. (%) 7 (36%) 10 (25%) 0.8 IIEF <0.000 ED, erectile dysfunction; IIEF, International Index of Erectile Function; BP, blood pressure. per min per 10 ml of tissue versus mm Hg/ ml per min per 10 ml of tissue ( p = 0.055). A multivariate analysis, which was performed using a generalized linear model (GLM) (R 2 = 0.4), revealed that the only variable that could influence the presence of endothelial dysfunction (AUC, independent variable, which reflects the endothelial function) in our study population is the group (ED vs non-ed) ( p = 0.014). However, age of the participants was not a determinant for the presence of penile endothelial dysfunction ( p = 0.25). Fig. 3 Forearm and penile vascular resistance in the control group and the erectile dysfunction (ED) group. 4. Discussion Fig. 2 Resting forearm and penile blood flow in millilitres per minute for 100 ml of organ tissue in the control group and the erectile dysfunction (ED) group. Abbreviation: NS, not significant. Penile erection is a complex neurovascular event that is modulated by psychological and organic factors [16]. The latter requires an intact parasympathetic nervous system and normal vascular function [17]. The vascular component of penile erection has two cardinal constituents: a myogenic constituent and an endothelial one. Preservation of endothelial function is fundamental to the complicated process of penile erection [18 20]. Therefore, assessment of penile endothelial function is of interest in determining the etiology of ED-specific drug effects (namely organic vs psychogenic) and follow-up in patients with sexual dysfunction.

5 european urology 55 (2009) Fig. 4 Vascular endothelial function indices, namely maximal blood flow and area under the flow-time curve of the control group and the erectile dysfunction (ED) group. Endothelial function can be affected by a myriad of factors that include age, hypercholesterolemia, smoking habits, hypertension, and diabetes mellitus [21]. These cardiovascular risk factors affect the function of vascular endothelial cells by reducing the ability of the vasculature to relax and could lead to the development of diseases such as ischemic heart disease and eventually ED. The commonly used methodology for assessing endothelial function in the peripheral vasculature (eg, forearm and leg) relies upon postischemic reactive hyperemia. In this method, the vascular endothelium releases NO and other vasodilatory mediators, such as adenosine and prostaglandins [8,9,22]. The resultant changes in blood flow (or artery diameter) are thus considered to be a reflection of endothelial function. Recently, we were able to apply and validate this methodology to assess penile endothelial function and reported that the baseline penile blood flow was 3-fold higher than the baseline forearm blood flow in healthy males without ED. Moreover, individual penile endothelial indices (AUCs and maximal flow) positively correlated with those of the corresponding forearm, thereby providing further support for the validity of our novel methodology [15]. The results of the present study confirmed our previous findings only in the men without ED. However, the men with ED had lower baseline penile blood flow than those without ED, which probably indicates the presence of a corporal vasculopathy. Although both groups had comparable mean systemic blood pressures, the penile vascular resistance in the ED group was higher than that of the control group. This finding indicates that local vascular compliance is reduced in men with ED. This lends additional support for the existence of a selective corporal vasculopathy in men with ED, despite their similarity in cardiovascular profile and in systemic hemodynamics [13,23]. Penile, but not forearm, indices of endothelial function (AUC and maximal blood flow) were found to be significantly different between the two groups of men. This result suggests that men with ED may have also impaired endothelial function in the cavernous arteries compared with that in men without ED. The differences in the level of endothelial damage between the peripheral and penile vasculatures may imply that endothelial damage in men with ED could be organ-specific. This feature suggests that assessment of corporal endothelial function in men with ED could detect penile endothelial dysfunction before the appearance of endothelial dysfunction on the forearm [2,24]. Therefore, the assessment of forearm endothelial function alone in patients with ED, as suggested by different investigators, could miss the presence of localized penile vascular pathology.

6 984 [1] Solomon H, Wierzbicki AS, Lumb PJ, Lambert-Hammill M, Jackson G. Cardiovascular risk factors determine erectile and arterial function response to sildenafil. Am J Hypertens 2006;19: [2] Stuckey BG, Walsh JP, Ching HL, et al. Erectile dysfunction predicts generalised cardiovascular disease: evidence from a case-control study. Atherosclerosis 2007;194: [3] Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts male aging study. J Urol 1994;151: [4] Kaya C, Uslu Z, Karaman I. Is endothelial function impaired in erectile dysfunction patients? Int J Impot Res 2006;18: [5] Fonseca V, Jawa A. Endothelial and erectile dysfunction, diabetes mellitus, and the metabolic syndrome: common pathways and treatments? Am J Cardiol 2005;96:13M 8M. [6] Elesber AA, Solomon H, Lennon RJ, et al. Coronary endothelial dysfunction is associated with erectile dyseuropean urology 55 (2009) Alternative explanations for the aforementioned findings could be inherent in the methodology that we used for the assessment of endothelial function, namely veno-occlusive plethysmography. The size and tissue composition of the penis is different from the forearm: it is smaller and is almost exclusively composed of vascular tissue. Using reactive hyperemia in a small and chiefly vascular organ may have different physiologic and mechanistic interpretations that can alter the clinical significance of the obtained results. In this regard, we may not have measured the vascular response to endothelial stimulation only when doing veno-occlusive plethysmography on the penis, but other penile functions, such as nonvascular compliance. Nevertheless, our data clearly showed that men with ED have a compromised penile hemodynamic profile that includes a low resting penile blood flow rates with a high vascular resistance. This suggests that the vascular component (eg, endothelial function) is the main contributor to our results, as already previously demonstrated in healthy subjects. It is well known that age can affect systemic and eventually penile endothelial function [15]. Therefore, in order to clarify further the effect of age on our results, we performed a subanalysis of the data that excluded the young participants in both groups. The results of this subanalysis involved two agematched (51 2) groups of 20 men with ED and a control group of ten men and showed that the indices of endothelial function remained statistically different in the ED group compared with the controls (penile AUC was units vs units for controls and ED respectively, p = 0.004). Moreover, the results of the multivariate analysis excluded any effect of age on the obtained results. These results suggest that age is not a dominant determinant of endothelial dysfunction in our group of men with ED. 5. Conclusions We have shown that the use of veno-occlusive plethysmography for evaluation of penile endothelial function is simple and reliable and can provide new information on the pathophysiology of ED at the level of penile vasculature. The results of the present study demonstrate differences in indices of endothelial function between the systemic (forearm) and penile vasculature in patients with ED compared with patients without ED. This is the first study that provides evidence of impaired penile endothelial function, without a significant systemic vasculopathy, thereby providing further support for the notion that the development of ED could predict the future onset of symptomatic cardiovascular disease. Potentially, we will be able to study effects of various pharmacological interventions whose aims are to improve penile endothelial function using this method of veno-occlusive plethysmography. Author contributions: Yoram Vardi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Vardi, Apple, Ofer, Gruenwald, Dayan, Jacob. Acquisition of data: Vardi, Apple, Ofer, Dayan, Jacob. Analysis and interpretation of data: Vardi, Apple, Gruenwald, Dayan, Jacob. Drafting of the manuscript: Vardi, Apple, Gruenwald, Jacob. Critical revision of the manuscript for important intellectual content: Vardi, Gruenwald, Jacob. Statistical analysis: Vardi, Jacob. Obtaining funding: Vardi, Jacob. Administrative, technical, or material support: Apple, Ofer, Gruenwald, Dayan, Jacob. Supervision: Vardi, Gruenwald, Jacob. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: Pfizer Ltd provided a nonrestricted grant for this study. Pfizer Ltd provided funds for laboratory equipment only. References

7 european urology 55 (2009) function and elevated asymmetric dimethylarginine in patients with early atherosclerosis. Eur Heart J 2006;27: [7] Solomon H, Man JW, Jackson G. Erectile dysfunction and the cardiovascular patient: endothelial dysfunction is the common denominator. Heart 2003;89: [8] Meredith IT, Currie KE, Anderson TJ, Roddy MA, Ganz P, Creager MA. Postischemic vasodilation in human forearm is dependent on endothelium-derived nitric oxide. Am J Physiol 1996;270:H [9] Joannides R, Haefeli WE, Linder L, et al. Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation 1995;91: [10] Kern JM. Coronary blood flow and myocardial ischemia. In: Zipes PD, Lippy P, Bonow OR, Braunwald E, editors. Braunwald s heart disease. Philadelphia, PA: Elsevier Saunders; p [11] Montorsi P, Ravagnani PM, Galli S, et al. Association between erectile dysfunction and coronary artery disease: a case report study. J Sex Med 2005;2: [12] Montorsi P, Ravagnani PM, Galli S, et al. Association between erectile dysfunction and coronary artery disease: role of coronary clinical presentation and extent of coronary vessels involvement: the COBRA trial. Eur Heart J 2006;27: [13] Kuvin JT, Karas RH. Clinical utility of endothelial function testing: ready for prime time? Circulation 2003;107: [14] Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation 2007;115: [15] Dayan L, Gruenwald I, Vardi Y, Jacob G. A new clinical method for the assessment of penile endothelial function using the flow mediated dilation with plethysmography technique. J Urol 2005;173: [16] Saenz de Tejada I, Angulo J, Cellek S, et al. Physiology of erectile function. J Sex Med 2004;1: [17] Carrier S, Brock G, Kour NW, Lue TF. Pathophysiology of erectile dysfunction. Urology 1993;42: [18] Guay AT. ED2: erectile dysfunction = endothelial dysfunction. Endocrinol Metab Clin North Am 2007;36: [19] Chiurlia E, D Amico R, Ratti C, Granata AR, Romagnoli R, Modena MG. Subclinical coronary artery atherosclerosis in patients with erectile dysfunction. J Am Coll Cardiol 2005;46: [20] Angulo J, Cuevas P, Fernandez A, et al. Diabetes impairs endothelium-dependent relaxation of human penile vascular tissues mediated by NO and EDHF. Biochem Biophys Res Commun 2003;312: [21] Seftel AD, Sun P, Swindle R. The prevalence of hypertension, hyperlipidemia, diabetes mellitus and depression in men with erectile dysfunction. J Urol 2004; 171: [22] Duffy SJ, New G, Tran BT, Harper RW, Meredith IT. Relative contribution of vasodilator prostanoids and NO to metabolic vasodilation in the human forearm. Am J Physiol 1999;276:H [23] Landmesser U, Hornig B, Drexler H. Endothelial function: a critical determinant in atherosclerosis? Circulation 2004;109:II [24] Kaiser DR, Billups K, Mason C, Wetterling R, Lundberg JL, Bank AJ. Impaired brachial artery endothelium-dependent and -independent vasodilation in men with erectile dysfunction and no other clinical cardiovascular disease. J Am Coll Cardiol 2004;43: