ORIGINAL ARTICLE Is endothelial function impaired in erectile dysfunction patients?

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1 (2006) 18, & 2006 Nature Publishing Group All rights reserved /06 $ ORIGINAL ARTICLE Is endothelial function impaired in erectile dysfunction patients? C Kaya 1, Z Uslu 2 and I Karaman 1 1 Department of Urology, Haydarpasa Numune Training and Research Hospital, Bulgurlu mah. Uygarkent sit, Uskudar, Istanbul, Turkey; 2 Department of Radiology, Vakif Gureba Training and Research Hospital, Bulgurlu mah. Uygarkent sit, Uskudar, Istanbul, Turkey Erectile dysfunction (ED) and vascular disease are thought to be linked at the level of the endothelium. Endothelial dysfunction, resulting in the inability of the smooth muscle cells lining the arterioles to relax, prevents vasodilatation. Likewise, penile erection depends on the relaxation of smooth muscle in the corpus cavernosum and the wall of small arteries. The aim was to assess the systemic vascular function in patients with ED. In all, 32 ED patients diagnosed with Doppler Ultrasound and the International Index of Erectile Function-5-item questionnaire and 25 healthy men as a control group enrolled to the study. They all underwent the tests including serum glucose and lipid levels. Echocardiography and exercise stress test was performed routinely. Baseline demographics (body mass index, heart rate and blood pressures), fasting glucose and lipid levels were not significantly different between ED and control groups. Endothelial-dependent brachial artery flow-mediated vasodilatation and brachial artery response to 0.4 mg nitroglycerine (NTG) were measured. Participants were negative on exercise stress test, and echocardiographic parameters including ejection fraction were similar. Endothelial-dependent brachial artery percent diameter change with flow-mediated dilatation ( vs ) and brachial artery response to NTG ( vs ) were significantly different between groups (Po0.001). We found that endothelial function was impaired in ED patients with no apparent cardiovascular disease and diabetes mellitus. This impaired function might be explained by the abnormality in systemic nitric oxide cyclic guanosine monophosphate vasodilator system and suggest that ED and vascular disease may be linked at the level of the endothelium. (2006) 18, doi: /sj.ijir ; published online 28 July 2005 Keywords: endothelium; dilatation; impairment; impotence Introduction The Massachusetts Male Aging Study surveyed 1290 primarily Caucasian men between the ages of 40 and 70 years and found that erectile dysfunction (ED) was present in 52% of this large community sample. 1 ED is commonly associated with a number of other conditions frequently occurring in aging men, including hypertension, ischemic heart disease (IHD), peripheral vascular disease, atherosclerosis, hyperlipidemia and diabetes mellitus (DM). 2 It is now widely accepted that ED in a Correspondence: Dr C Kaya, Department of Urology, Haydarpasa Numune Training and Research Hospital, Bulgurlu mah. Uygarkent sit, A4 blok D17 Uskudar, Istanbul 81190, Turkey. drckaya@hotmail.com Received 3 June 2005; revised 9 June 2005; accepted 16 June 2005; published online 28 July 2005 substantial majority of men is due to underlying vascular causes, especially atherosclerosis. 2,3 Previous studies have shown associations between IHD and ED, and men suffering from IHD have a high prevalence of ED. 4,5 Owing to its prevalence in cardiovascular disease (CVD), ED has traditionally been viewed as a secondary complication of this disorder. However, the cardiac status of patients with ED is unclear. An association between ED and IHD has been suggested as a consequence of vascular lesions of penile arteries. 3 Penile erection is a vascular process, and the small vessels of the penis are very sensitive to functional and structural changes. Rather than being thought of as a late consequence of vascular disease, ED is now beginning to be considered an early manifestation of atherosclerosis and a precursor of systemic vascular disease. In all, 67% of patients with coronary artery disease (CAD) and ED reported ED symptoms that began before CAD symptoms, with a mean time interval of almost

2 56 3 years. 6 It was shown also that the severity of ED correlates with the burden of vascular risk factors and severity of CAD 7,8 and may be a useful indicator of the severity of CAD. Evidence-based data indicated that ED is extremely common in men with chronic CAD, 4 so that patients with CAD or risk factors for CAD should be asked about sexual health and ED. The high frequency of ED in this population made one to assume that the endothelial dysfunction and atherosclerosis are systemic disorders. Damage to the endothelium from smoking, hypertension, lipid abnormalities and diabetes affects not only the coronary arteries but also arteries throughout the body, including those of corpora cavernosa of the penis. 9 Endothelial dysfunction is an important abnormality that contributes to ED and vascular disease. 10,11 Nitric oxide (NO) released by vascular endothelial cells induces smooth muscle cell relaxation and inhibits vascular smooth muscle proliferation. NO exerts many of its effects by activation of soluble guanylate cyclase, resulting in increased production of cyclic guanosine monophosphate (cgmp), which results in lower intracellular calcium levels and, therefore, vasodilatation. 12,13 We designed the present study in order to evaluate whether patients with ED have functional abnormalities of other vascular beds. Materials and methods A total of 32 patients with ED and 25 healthy men were enrolled to participate in this investigation. Patients were recruited into the study after an informed consent was signed. All patients with ED (mean age of 557 years) based on Penile Doppler Ultrasound and International Index of Erectile Function-5 (IIEF-5) questionnaire including questions assessing five domains of sexual function, and the healthy men as a control group (mean age of 577 years) underwent a detailed physical examination including checking the heart rate and blood pressure as well as femoral pulses. Then, blood sample was taken for the laboratory tests including fasting serum glucose and triglyceride, HDL cholesterol and LDL cholesterol levels. All participants to the study were administered the validated Sexual Health Inventory for Men (SHIM) 5-item questionnaire based on IIEF questionnaire. Patients with known CAD, DM, hypertension, malignancy, renal and hepatic insufficiency, and chronic inflammatory disease and patients taking nitrates or treated with selective phosphodiesterase type 5 inhibitors in the last 3 months were excluded from the study. Assessment of flow-mediated dilatation After a light breakfast following overnight fasting, the participants were asked to refrain from alcohol and beverages containing caffeine and strenuous exercise for 24 h prior to the study. Smokers were asked to refrain from smoking at least 8 h before the study. The studies were performed between 0900 and 1200 hours. They rested on beds in supine position at least 15 min and then transthoracic echocardiography was performed by one of the authors, who had no information of the patients clinical data and group, using a Vivid Seven (Vingmed, GE) with a 2.5 MHz phased-array transducer. The right brachial artery systolic and diastolic pressures were taken to be the average of three consecutive measurements made immediately after the echocardiographic study, using conventional sphygmomanometer. And, a maximal exercise stress test was performed to all subjects using the modified Bruce protocol routinely. The patients with abnormal stress test were also excluded from the study. In all patients, endothelial-dependent brachial artery flow-mediated vasodilatation (FMD) and brachial artery response to 400 mg sublingual nitroglycerine (NTG) were measured. The right brachial artery, proximal to the antecubital fossa, was imaged longitudinally using the phased-array transducer. FMD was assessed by measuring the brachial artery diameter at baseline and during reactive hyperemia (with increased flow causing endothelium-dependent dilatation) using a well-described and reproducible method Reactive hyperemia was induced by deflating a cuff previously inflated to 300 mmhg for 4.5 min in the forearm. FMD was assessed at s after deflating the cuff. Arterial flow velocity was measured at baseline and during reactive hyperemia using pulsed-wave Doppler. After 10 min, the endothelium-independent response was assessed by the change in artery diameter at 3 4 min after NTG. The parameters were measured for three consecutive cardiac cycles, and the average was taken. The percentages of diameter and flow changes during reactive hyperemia and after NTG were calculated. Statistical analysis Values were expressed as mean7s.e., and data comparing the FMD values in patients with ED to those of age-matched control group was analyzed using paired Student s t-test. Preocclusion and postocclusion data were also compared using the paired t-test. Po0.01 was considered significant. Results Baseline demographics (age, weight, height, heart rate and blood pressures), fasting glucose and lipid levels as well as risk factors for CAD were not significantly different between patients with ED and healthy subjects (Table 1). Patients had mean

3 Table 1 Baseline demographics of participants of the study Variable ED group (n ¼ 32) (n ¼ 25) P-value 14 Age (years) NS BMI (kg/m 2 ) NS Heart rate (min 1 ) NS Smoking (%) 8 (25%) 6 (30%) NS Plasma glucose level (mg/dl) NS Total cholesterol (mg/dl) NS HDL cholesterol (mg/dl) NS LDL cholesterol (mg/dl) NS Triglyceride (mg/dl) NS IIEF score o0.001 EF (%) NS Systolic BP (mmhg) NS Diastolic BP (mmhg) NS Note that all the parameters between two groups are similar. IIEF ¼ International Index of Erectile Function; NS ¼ not significant ED group Figure 2 Endothelium-dependent dilatation was significantly decreased in patients with ED compared to the healthy participants, Po Values are expressed as mean7s.e ; ED group 12.8 ED group; Figure 1 ED The average IIEF-5 scores of participants of each group Response to NG Figure 3 Brachial artery vasodilatation to NTG (endotheliumindependent dilatation) was significantly reduced in ED patients, Po Values are expressed as mean7s.e. NTG: nitroglycerine. SE systolic and diastolic blood pressure of and 8476 mmhg, respectively. All patients were negative on exercise stress test. Echocardiographic parameters including left ventricular systolic function defined as ejection fraction (65.7 vs 66.2%) were similar in ED and control group, respectively (P40.05). The average SHIM score was 9.2 in ED group, suggesting severe ED, whereas it was 22.3 in healthy men. Of the patients, 20 (62%) had some difficulty maintaining an erection after penetration (Question 3) and 23 (72%) had some difficulty in achieving an erection (Question 2) (Figure 1). FMD (reactive hyperemia response with increased flow causing endothelium-dependent dilatation) was statistically significantly decreased in patients with ED ( %) compared with the healthy men in control group ( %, Po0.001), indicating that impaired vascular response to reactive hyperemia in patients with ED (Figure 2). Brachial artery vasodilatation to NTG (causing endothelium-independent dilatation) ( %) was significantly reduced in ED patients compared with normal subjects ( %) (Po0.001; Figure 3).

4 58 Discussion Endothelial dysfunction, in which damage to the lining of the arterial walls impairs the NO pathway and vasodilation, is an important pathophysiologic factor underlying both ED and CVD. 17 It is found to be the etiologic connection between ED and systemic vascular disease, 18,19 and defined as a functional deterioration of the endothelium characterized by vasospasm, vasoconstriction, alterations in coagulation mechanisms and fibrinolysis, and increased vascular proliferation. It has been related with coronary risk factors, and decreased level has been seen even in early stages in patients with hypercholesterolemia and hypertension, smokers and patients with diabetes. Endothelial dysfunction precedes the development of atherosclerotic lesions. 20 At the cellular level, it results in impaired bioavailability of NO. Oxidative stress that interferes with the NO pathway and also directly toxic to the endothelium is a causal factor in clinically evident occlusive CVD and the vascular damage associated with preclinical disease. 17,21 Recent studies measuring early markers of CVD and endothelial dysfunction demonstrated that damage to the penile vascular bed occurs before systemic vascular illness becomes clinically apparent. 22,23 Kaiser et al. recently revealed that men with ED without clinical CVD had significantly lower brachial artery flowmediated, endothelium-dependent and endothelium-independent vasodilatation that occurs before the development of other overt functional or structural systemic vascular disease, which suggests the presence of a peripheral vascular abnormality in the NO pathway. 22 In the present study, we examined vascular endothelial and smooth muscle function in the large vessels of patients with ED using a simple noninvasive method, which enabled accurate and reproducible assessment of the vascular response to flow increase and nitrates. Anderson et al. 24 found that coronary artery endothelium-dependent vasomotor responses to acetylcholine and flow-mediated vasodilatation in the brachial artery were similar. Thus, endothelial function in peripheral vessels such as the brachial artery can be measured noninvasively and inferentially correlated to responses within the coronary vasculature. In animals, flow-dependent dilatation is endothelium dependent and mediated by NO; 25 the same mechanism is essential for flow-mediated dilatation of large human arteries. Hence, this test can be used as an estimate of the capacity of human endothelial cells to release NO in response to a physiological stimulus as well as an estimate of endothelial dysfunction in diseased states. To distinguish endothelial from intrinsic smooth muscle dysfunction, we used NTG, an endothelium-independent vasodilator; nitrates cause smooth muscle to relax, acting directly by increasing cgmp levels of smooth muscle cells. We preferred to use this noninvasive and accurate method to test endothelial function of conduit arteries, instead of using intraarterial infusion of acetylcholine, which is an invasive method, and in the forearm is usually used in conjunction with venous occlusion plethysmography to assess endothelial function of small resistance vessels. However, some limitations on the measurement of blood flow in human brachial artery have been reported. 14,26 29 The magnitude of FMD appears to be related to many factors in addition to artery studied, including the method of measurement (e.g. echo wall tracking vs echo Doppler imaging), site of occlusion (either proximal or distal to the measurement site), duration of occlusion and presence or absence of exercise. In a study evaluating the FMD in human brachial artery after different circulatory occlusion conditions revealed that the type of occlusion (proximal vs distal) had an effect on FMD. 28 These studies demonstrated that there are important betweenmethod differences in the FMD response of the brachial artery. The result of the present study in brachial artery clearly indicates the presence of endothelial dysfunction in patients with ED. The reduced productions of NO by dysfunctional endothelial cells lining the penile arterial system and the corpus have a negative impact on erection, since perivascular smooth muscle tissue and other cells are often rich in the PDE enzymes that degrade cgmp, limiting the duration of the vasodilatation produced by a given quantity of cgmp. 30,31 The response to nitrates was normal in patients with ED. The mechanism underlying reduced NO bioavailability in ED are multifactorial; however, there is a substantial evidence that NO bioavailability is reduced because of oxidative inactivation by excessive production of superoxide anions. There is sufficient evidence that impairment of endothelium-dependent vasodilatation is an early phenomenon of atherogenesis and it is present in humans before the anatomic evidence of atherosclerosis. 20,32 In the vascular wall, an increase in oxidative stress is thought to modify several important physiological functions. Regulation of vascular tone and blood flow, increased platelet and monocyte adhesion to the endothelium, and control of cellular growth are strongly influenced by reactive oxygen species. These phenomena ultimately modulate vessel diameter and remodeling and formation of atherosclerotic lesions. Our findings imply that there is a decreased bioavailability of NO in patients with ED either decreased NO formation or increased NO inactivation. Apparently, the observed endothelial dysfunction in our patients reflects an early atherosclerotic process of large vessels. 17,21

5 The initial assessment of patients with ED in the urologist office may represent a unique opportunity to identify undiagnosed CVD. It has been suggested that ED may be a sentinel for IHD. 33 Unfortunately, we currently lack guidelines to identify patients with ED who are asymptomatic from a cardiovascular point of view, and still might need to be assessed by a cardiologist. A cardiological consultation including a stress ECG is recommended in ED patients with a negative cardiac history, if there are two or more positive vascular risk factors available. 23 Although further studies are warranted, our data suggest that noninvasive measurement of endothelial function is deteriorated significantly in patients with ED patients with no apparent CVD and DM. Endothelium-dependent and endotheliumindependent dilatation is impaired in the systemic arteries of males with ED. 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