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A Simple Noninvasive Test to Detect Vascular Disease in Patients with Erectile Dysfunction: A Novel Method
jsm_112.fm Page 331 Monday, February 13, 2006 8:24 PM Blackwell Science, LtdOxford, UKJSMJournal of Sexual Medicine1743-6095Journal of Sexual Medicine 2005200632331336Original ArticleErectile Dysfunction and Cardiovascular DiseaseAlkhayal et al.
331
A Simple Noninvasive Test to Detect Vascular Disease in Patients with Erectile Dysfunction: A Novel Method Shawket Alkhayal, MB ChB, MRCS, MSc (Urol.), Victoria Lehmann, Dip. (Human Sexuality), and Philip Thomas, FRCS (Urol.) Royal Sussex County Hospital, Urology Department, Brighton, UK DOI: 10.1111/j.1743-6109.2005.00112.x
ABSTRACT
Introduction. The association between erectile dysfunction (ED) and cardiovascular disease (CVD) is becoming increasingly evident. Both conditions are thought to share a common denominator, which is endothelial dysfunction. Therefore, testing endothelial function in ED patients may serve to detect vascular disease in this cohort of patients. Aims. To investigate whether measuring the reactive hyperemic response (RHR) of the forearm vessels through a simple noninvasive method could identify vascular disease in patients with ED. Patients and Methods. Forty-eight male subjects were recruited into the study, 35 of whom presented to the sexual dysfunction clinic with a complaint of ED, and 13 healthy subjects served as a control group. The ED patients were subdivided into two groups, according to the presence or absence of CVD or its risk factors. The RHR of the forearm vessels was measured noninvasively in all subjects by using a handheld Doppler device. Results. Significant reduction in the peak systolic velocity ration was observed in ED patients with concomitant CVD or risk factors in comparison with the other ED patients with no CVD or risk factors and the control group. Results were highly significant on both occasions (P < 0.001). The 50% recovery time was not significantly different between any of the groups (P > 0.05). Conclusion. Our results suggest that those patients with impaired RHR have an abnormality in their vascular system, which is likely to be the cause of their ED and CVD. Using this simple noninvasive method can help to identify vascular disease in ED patients. It can also be used to suggest vascular disease in any patient, where further tests might be indicated. Alkhayal S, Lehmann V, and Thomas P. A simple noninvasive test to detect vascular disease in patients with erectile dysfunction: A novel method. J Sex Med 2006;3:331–336. Key Words. Erectile Dysfunction; Endothelial Dysfunction; Reactive Hyperaemic Response
Introduction
I
t is increasingly recognized that there is an association between erectile dysfunction (ED) and cardiovascular disease (CVD). Both conditions are thought to be linked at the level of the endothelium of blood vessels, because loss of the functional integrity of the endothelium plays a major role in the pathogenesis of ED in this cohort of patients [1]. The vascular endothelium regulates vascular tone by releasing a variety of factors that affect the contractile and relaxatory behavior of the underlying vascular smooth muscle [2]. There are several neurotransmitters and biochemical factors that may either be released from the endothelium
© 2005 International Society for Sexual Medicine
or act upon it to release other mediators in the process of erection. Most researchers now agree that nitric oxide (NO) is the principal, but not the only neurotransmitter mediating penile erection. There are other factors that might also play a role in this process. Acetylcholine, prostaglandins, and the recently investigated endotheliumderived hyperpolarizing factor, among others, all appear to have a role in vascular smooth muscle relaxation in the penis and in other vascular beds [3,4]. Endothelial dysfunction results in impaired vascular reactivity and impaired relaxation of the smooth muscle cells lining the arteries and arterioles, which may lead to ischemic heart disease and/or ED. J Sex Med 2006;3:331–336
jsm_112.fm Page 332 Monday, February 13, 2006 8:24 PM
332 There are little data available on the systemic vasculature of patients with ED, but it is well known that patients with risk factors for CVD or overt CVD are at risk of developing ED––in fact, it has been increasingly recognized that ED could be an early marker of coronary artery disease [5]. Common risk factors associated with vascular disease and ED include hypertension, hyperlipidemia, diabetes mellitus, and cigarette smoking. Therefore, an assessment of the endothelial function of the peripheral circulation in ED patients may serve to detect undiagnosed vascular disease in those patients, which can also be a contributing or major factor in their ED. Therefore, testing vascular endothelial function in ED patients may uncover hidden or undiagnosed vascular disease or provide a clue to the general vascular condition of those patients, thus alerting the physician to perform more sophisticated tests. Current tests to diagnose vascular disease relate to history, examination, serum lipid profile, electrocardiogram, and exercise treadmill testing or other invasive methods such as angiography and other contrast cardiac studies. A simple noninvasive method that can be used to detect vascular disease would therefore be very useful. A simple and novel method, using a handheld Doppler device, was evaluated in our study as a test for vascular function in ED patients. Patients and Methods
Thirty-five patients and 13 healthy volunteers were recruited to the study. The patients were either existing follow-up or newly referred patients by their general practitioner with a complaint of ED. All patients were evaluated at the ED clinic by a history and general physical examination and followed standard clinic investigation protocol, including blood pressure measurement, fasting serum lipid profile, and blood glucose as well as urine dipstick testing. Free and total testosterone levels were measured in patients with clinical suspicion of hypogonadism from their history or examination. All subjects completed an International Index of Erectile Function-5 questionnaire to confirm and record the degree of their erectile function. Those with a score of 22–25 had no ED, 17–21 mild ED, 12–16 mild to moderate ED, 8–11 moderate ED, and 1–7 severe ED as validated by Rosen et al. [6]. Patients with diagnosis of carcinoma of the prostate, hypogonadism, and penile injuries or abnormalities and patients J Sex Med 2006;3:331–336
Alkhayal et al. with history of pelvic surgery or irradiation were excluded from the study. All 48 individuals underwent measurements of the reactive hyperemic response (RHR) of their right brachial artery as described below, with the investigator blinded to the patients’ condition. To induce RHR, a sphygmomanometer with its cuff applied to the distal forearm and wrist was used to interrupt the blood flow to the distal forearm and hand. The cuff was inflated to 280 mm Hg for 120 seconds, as was performed and validated by Hirono et al in their study of patients with coronary artery disease [7]. All tests were performed in the morning between 9:00 AM and 12:00 PM in a temperature-controlled environment (20–22∞C). The peak systolic velocity ratio (PSVR) and 50% recovery time (50% RT), which are defined as the ratio of maximal to baseline peak systolic velocity and the interval from resumption of arterial blood flow to 50% decline of the increased systolic velocity, respectively, were used to measure reactive hyperemia at the brachial artery noninvasively with a handheld continuous Doppler device (Multi Dopplex II), with an 8 MHz probe (EZ8) (Huntleigh Technology plc, Luton, Bedfordshire, UK). Recordings were made at baseline before cuff inflation and immediately after release of the occlusion for 90 seconds. The probe was held in constant position with an angle of 45 degrees over the right brachial artery with a specially devised probe holding apparatus made of hard foam. The best audible and visible Doppler signal was used in locating the probe. Huntleigh Diagnostics Doppler reporter software (version 3.1) was used to display, store, and make calculations on the displayed and recorded waveforms with the aid of a connected laptop computer (Figure 1). To test for intraobserver variability, measurements were repeated on 10 of the subjects in the same setting and under the same conditions of measurement after settlement of normal vascular hemodynamics. To test for interobserver variability, 10 recordings were selected randomly, and the same calculations were made by another observer, who was blinded to the original calculations made by the first observer, using the same software. ED patients were divided into two groups according to the presence or absence of CVD or cardiovascular risk factors (CVR). Group A consisted of 19 patients who all had ED with either an established CVD or one or more CVR. Group B consisted of 16 patients who all had ED but no history or clinical evidence of CVD or CVR. A
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Erectile Dysfunction and Cardiovascular Disease
Figure 1 Trace of recorded blood flow waveforms, at baseline and during reactive hyperemia.
third group (group C) consisting of 13 healthy volunteer subjects with no history or evidence of ED or CVD or CVR and who all had normal lipid profile, normal blood sugar, and normal blood pressure were recruited into the study to serve as a control group. The presence of CVD was defined as history of previous myocardial infarction, history of angioplasty, coronary artery bypass graft surgery, or angina. CVR was defined as history or clinical evidence of hypertension, diabetes mellitus on oral hypoglycemic or insulin therapy, or evidence of hypercholesterolemia. Diabetes was defined as a fasting blood glucose >7.00 mmol/L (126 mg/dL), or use of hypoglycemic agents or insulin. Hypertension was defined as systolic blood pressure >140 mm Hg, or diastolic >90 mm Hg on more than two occasions, or use of antihypertensive medications. Any fasting total serum cholesterol level above 5.5 mmol/L was considered hypercholesterolemia. Fourteen patients in group A and 12 patients in group B have already tried phosphodiesterase type 5 (PDE5) inhibitor (sildenafil citrate) on on-demand treatment, with different doses and variable responses. In group A, nine patients tried 50 mg and five were on 100 mg,
while in group B, 10 patients had 50 mg and two had 100 mg doses. None of the patients in group C had any medication. The main outcome measures of this study were to measure and compare the PSVR and 50% RT as variables of RHR in the three groups of patients and to test for validity and reliability of measuring the RHR with Multi Dopplex II device. Results
Variables of Reactive Hyperemia Summary statistics for the measured variables of the three groups are shown in (Table 1). Results
Table 1
Number Age (year) IIEF PSVR 50% RT
Summary statistics of the three groups Group A (ED + CVD)
Group B (ED - CVD)
Group C (Controls)
19 61 (7) 11 (4.7) 1.285 (0.088) 17.5 (7.91)
16 49 (11) 12 (4) 1.44 (0.132) 13.2 (4.96)
13 41 (11) 24 (1) 1.441 (0.145) 13.2 (4.64)
Results are presented as mean ± standard deviation. IIEF = International Index of Erectile Function; PSVR = peak systolic velocity ratio; 50% RT = 50% of the recovery time.
J Sex Med 2006;3:331–336
jsm_112.fm Page 334 Monday, February 13, 2006 8:24 PM
334 are expressed as mean ± standard deviation. Analysis of variance (ANOVA) was performed to detect variability between the groups and unpaired Student’s t-test was used for the evaluation of difference between the groups. A probability of P < 0.05 was considered significant. The PSVR was significantly lower in group A patients––1.285 (0.088), 95% confidence interval (1.113–1.457)––in comparison with group B patients––1.44 (0.132), 95% CI (1.182–1.698) (P = 0.0002)––and the control group––1.441 (0.145), 95% CI (1.157–1.725) (P = 0.0008). There was no statistically significant difference in the PSVR between group B patients and the control group C (P = 0.99). No further calculations of the 50% RT were performed, as there was no significant difference between the groups on ANOVA. Regression analysis revealed no significant correlation between PSVR and age of the patients (r = 0.28) (P > 0.05). PSVR was therefore not affected by the age of the patients.
Validity and Reliability For intraobserver variability in measuring the RHR at the brachial artery, the correlation between measurements was analyzed and the repeatability coefficient was calculated by using Bland and Altman’s statistical method [8]. The mean PSVR measured by the first observer in 10 patients was 1.332 and by the second observer in the same patients was 1.380. The mean difference in the PSVR between the two observers was 0.11 ± 0.1, with 95% limits of agreement of -0.09 to 0.31. The repeatability coefficient was 20%. The mean PSVR measured by the first observer in 10 patients was 1.390 and the mean PSVR measured by a second observer from the same traces was 1.369. The mean difference between the two sets of measurements was 0.038 ± 0.05 with a 95% CI (-0.06 to 0.136). This was not statistically significantly different (paired Student’s t-test, P = 0.20). Discussion
The main finding of this study is that patients with ED and CVD have impaired RHR, in comparison with the other two groups who have no evidence of CVD or CVR. Those patients in the first group clearly have impaired endothelial function, which could affect both peripheral and penile vascular beds and which was revealed by blunting of their RHR, as measured by the PSVR. J Sex Med 2006;3:331–336
Alkhayal et al. All patients in group A suffered from ED and had developed either a CVD or one or more of its risk factors. In addition, 90% (17 out of 19 patients) in this group had no nocturnal erections and there were no other elements in their history that could otherwise have contributed to their ED other than CVD or CVR. In group B, all patients complained of ED, with 88% (14 out of 16) having normal nocturnal erections. None of those patients had any evidence of overt CVD or CVR from their history, examination, and laboratory investigations, and 14 patients had psychological elements in their history, in the form of either depression or performance anxiety. This indicates that their ED is more likely to be psychological in origin rather than a result of endothelial dysfunction, and this was also confirmed by their measured PSVR, which was not statistically significantly different from the healthy control group. Only two patients in group A had psychological elements in their history. Although a PDE5 inhibitor (sildenafil) was used by some of the patients, it was unlikely to have affected our results of measuring the RHR, as 14 of the patients in group A and 12 in group B were on sildenafil on-demand treatment and none of the patients had more than four doses in total or had any dose within 24 hours of the test. The RHR was tested as a measure of endothelial and vascular reactivity, as evidence suggests a key role of endothelial function along resistance vessels in the formation of reactive hyperemia [9]. Reactive hyperemia is a protective adaptation that has evolved in mammals to ensure prompt restoration of blood flow when interrupted abruptly with resulting ischemia. Vascular physiologists have considered the mechanisms responsible for this response for many years and have invoked a role for both direct myogenic responses and local vasoactive substances, which include prostaglandins, adenosine, adenosine triphosphate (ATP)-sensitive potassium channels, adenosine 5¢triphosphate, oxygen, and pH, as well as hydrogen peroxide [10,11]. In addition to pressure changes, after release of an occlusion, a sudden increase of blood flow could also activate shear stresssensitive mechanisms eliciting the release of endothelium-derived dilator factors, such as NO, which may limit myogenic constriction and modify the duration of reactive hyperemia [12]. Recently, one study demonstrated that endothelial dysfunction in ED patients, detected noninvasively in the arm using the flow-mediated dilatation (FMD) to reactive hyperemia method,
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335
Erectile Dysfunction and Cardiovascular Disease correlated well with abnormalities detected in the penile vasculature detected by penile dopplex studies in the same patients [13]. Another study has demonstrated impaired peripheral endothelial vascular function in patients with coronary artery disease by impaired RHR of the brachial artery, using a pulsed Doppler device and imaging of the studied vessels [7]. The most widely used noninvasive test for arterial endothelial health has been the ultrasoundbased measurement of FMD in systemic vessels, such as the brachial artery, which was established by Celermajer et al. [14]. The magnitude of the change in vessel diameter from the baseline period to the peak observed during reactive hyperemia is indicative of the degree of endothelial function. Nevertheless, measuring FMD is technically difficult and therefore somewhat operatordependent. Our method of measuring the RHR using Multi Dopplex II Doppler device, was inspired from the method used by Hirono et al., which used the same principle of measuring the RHR in the brachial artery but used a pulsed Doppler machine with the region of interest guided by two-dimensional images from a 7.0 MHz linear array transducer [7]. Our method of using a simple handheld continuous Doppler device is much simpler, takes little time to perform, requires little training, is easy to use in an outpatient clinic setting, and most importantly is noninvasive. It has also proved to be a valid and reproducible method, because both variables of RHR could be measured in all patients and produced a nonsignificant difference when measured twice in the same patients or by a second observer. The PSVR could be used to give significant results, while the 50% RT was not different between the groups and therefore could not be used as a measure of the RHR in our study. Proper positioning of the probe and fixation of the arm in one position is essential in obtaining accurate measurements, as in all methods. Although both methods are elicited by a similar transient occlusion of the brachial blood flow, noninvasive investigation of reactive hyperemia in the humeral circulation differs from assessment of endothelial function with the flow-mediated arterial dilation. Indeed, whereas NO plays the key role in the latter, several mediators are involved in the former, including myogenic and metabolic factors, prostaglandins, K+ ATP channels, adenosine, and NO, which is only one of the many components of this complex regulation mechanism [15]. Further studies to compare our method with other
tests that are used to detect vascular disease would be valuable. Conclusion
As endothelial dysfunction affects both ED and CVD patients, testing endothelial function in the peripheral circulation of ED patients by using this simple noninvasive method could identify vascular abnormalities, which might have contributed to the ED. Furthermore, it can also be used as a screening tool to detect occult vascular disease, which might therefore require further tests. Corresponding Author: Shawket Alkhayal, MRCS, MSc (Urol.), Royal Sussex County Hospital, Urology Department, Sussex House 1 Abbey Road, Brighton BN2 1ES, UK. Tel: +44 1273-696955; Fax: +44 1273664798; E-mail: [email protected] Conflict of Interest: None. References
1 Solomon H, Man JW, Jackson G. Erectile dysfunction and the cardiovascular patient: Endothelial dysfunction is the common denominator. Heart 2003;89:251–3. 2 Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288:373–6. 3 Busse R, Edwards G, Feletou M, Fleming I, Vanhoutte PM, Weston AH. EDHF: Bringing the concepts together. Trends Pharmacol Sci 2002;23: 374–80. 4 Saenz de Tejada I, Goldstein I, Azadzoi K, Krane RJ, Cohen RA. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med 1989;320:1025–30. 5 Morley JE, Korenman SG, Kaiser FE, Mooradian AD, Viosca SP. Relationship of penile brachial pressure index to myocardial infarction and cerebrovascular accidents in older men. Am J Med 1988;84:445–8. 6 Rosen RC, Cappelleri JC, Smith MD, Lipsky J, Pena BM. Development and evaluation of an abridged, 5item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res 1999;11:319–26. 7 Hirono O, Kubota I, Shiga R, Abe S, Terashita K, Tomoike H. Impaired hyperaemic response of forearm vessels in patients with coronary artery disease, a non invasive evaluation. Jpn Heart J 1996;6:837– 46. 8 Bland JM, Altman DG. Applying the right statistics: Analyses of measurement studies. Ultrasound Obstet Gynecol 2003;22:85–93. J Sex Med 2006;3:331–336
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336 9 Casino PR, Kilcoyne CM, Quyyumi AA, Hoeg J, Panza JA. The role of nitric oxide in endothelium dependent vasodilation of hypercholestrolemic patients. Circulation 1993;88:2541–7. 10 Sparks HV Jr, Belloni FL. The peripheral circulation: Local regulation. Annu Rev Physiol 1978; 40:67–92. 11 Wolin MS, Rodenburg JM, Messina EJ, Kaley G. Similarities in the pharmacologic modulation of reactive hyperemia and vasodilation to hydrogen peroxide in rat skeletal muscle arterioles: Effects of probes for endothelium-derived mediators. J Pharmacol Exp Ther 1990;253:508–12. 12 Koller A, Sun D, Huang A, Kaley G. Corelease of nitric oxide and prostaglandins mediates flowdependent dilation of rat gracilis muscle arterioles.
J Sex Med 2006;3:331–336
Alkhayal et al. Am J Physiol Heart Circ Physiol 1994;267:H326– 32. 13 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; 43:179–84. 14 Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111–5. 15 Monsuez JJ. Mediators of reactive hyperemia. Arch Mal Coeur Vaiss 2001;94:591 (Abstract).
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A Simple Noninvasive Test to Detect Vascular Disease in Patients with Erectile Dysfunction: A Novel Method Shawket Alkhayal, MB ChB, MRCS, MSc (Urol.), Victoria Lehmann, Dip. (Human Sexuality), and Philip Thomas, FRCS (Urol.) Royal Sussex County Hospital, Urology Department, Brighton, UK DOI: 10.1111/j.1743-6109.2005.00112.x
ABSTRACT
Introduction. The association between erectile dysfunction (ED) and cardiovascular disease (CVD) is becoming increasingly evident. Both conditions are thought to share a common denominator, which is endothelial dysfunction. Therefore, testing endothelial function in ED patients may serve to detect vascular disease in this cohort of patients. Aims. To investigate whether measuring the reactive hyperemic response (RHR) of the forearm vessels through a simple noninvasive method could identify vascular disease in patients with ED. Patients and Methods. Forty-eight male subjects were recruited into the study, 35 of whom presented to the sexual dysfunction clinic with a complaint of ED, and 13 healthy subjects served as a control group. The ED patients were subdivided into two groups, according to the presence or absence of CVD or its risk factors. The RHR of the forearm vessels was measured noninvasively in all subjects by using a handheld Doppler device. Results. Significant reduction in the peak systolic velocity ration was observed in ED patients with concomitant CVD or risk factors in comparison with the other ED patients with no CVD or risk factors and the control group. Results were highly significant on both occasions (P < 0.001). The 50% recovery time was not significantly different between any of the groups (P > 0.05). Conclusion. Our results suggest that those patients with impaired RHR have an abnormality in their vascular system, which is likely to be the cause of their ED and CVD. Using this simple noninvasive method can help to identify vascular disease in ED patients. It can also be used to suggest vascular disease in any patient, where further tests might be indicated. Alkhayal S, Lehmann V, and Thomas P. A simple noninvasive test to detect vascular disease in patients with erectile dysfunction: A novel method. J Sex Med 2006;3:331–336. Key Words. Erectile Dysfunction; Endothelial Dysfunction; Reactive Hyperaemic Response
Introduction
I
t is increasingly recognized that there is an association between erectile dysfunction (ED) and cardiovascular disease (CVD). Both conditions are thought to be linked at the level of the endothelium of blood vessels, because loss of the functional integrity of the endothelium plays a major role in the pathogenesis of ED in this cohort of patients [1]. The vascular endothelium regulates vascular tone by releasing a variety of factors that affect the contractile and relaxatory behavior of the underlying vascular smooth muscle [2]. There are several neurotransmitters and biochemical factors that may either be released from the endothelium
© 2005 International Society for Sexual Medicine
or act upon it to release other mediators in the process of erection. Most researchers now agree that nitric oxide (NO) is the principal, but not the only neurotransmitter mediating penile erection. There are other factors that might also play a role in this process. Acetylcholine, prostaglandins, and the recently investigated endotheliumderived hyperpolarizing factor, among others, all appear to have a role in vascular smooth muscle relaxation in the penis and in other vascular beds [3,4]. Endothelial dysfunction results in impaired vascular reactivity and impaired relaxation of the smooth muscle cells lining the arteries and arterioles, which may lead to ischemic heart disease and/or ED. J Sex Med 2006;3:331–336
jsm_112.fm Page 332 Monday, February 13, 2006 8:24 PM
332 There are little data available on the systemic vasculature of patients with ED, but it is well known that patients with risk factors for CVD or overt CVD are at risk of developing ED––in fact, it has been increasingly recognized that ED could be an early marker of coronary artery disease [5]. Common risk factors associated with vascular disease and ED include hypertension, hyperlipidemia, diabetes mellitus, and cigarette smoking. Therefore, an assessment of the endothelial function of the peripheral circulation in ED patients may serve to detect undiagnosed vascular disease in those patients, which can also be a contributing or major factor in their ED. Therefore, testing vascular endothelial function in ED patients may uncover hidden or undiagnosed vascular disease or provide a clue to the general vascular condition of those patients, thus alerting the physician to perform more sophisticated tests. Current tests to diagnose vascular disease relate to history, examination, serum lipid profile, electrocardiogram, and exercise treadmill testing or other invasive methods such as angiography and other contrast cardiac studies. A simple noninvasive method that can be used to detect vascular disease would therefore be very useful. A simple and novel method, using a handheld Doppler device, was evaluated in our study as a test for vascular function in ED patients. Patients and Methods
Thirty-five patients and 13 healthy volunteers were recruited to the study. The patients were either existing follow-up or newly referred patients by their general practitioner with a complaint of ED. All patients were evaluated at the ED clinic by a history and general physical examination and followed standard clinic investigation protocol, including blood pressure measurement, fasting serum lipid profile, and blood glucose as well as urine dipstick testing. Free and total testosterone levels were measured in patients with clinical suspicion of hypogonadism from their history or examination. All subjects completed an International Index of Erectile Function-5 questionnaire to confirm and record the degree of their erectile function. Those with a score of 22–25 had no ED, 17–21 mild ED, 12–16 mild to moderate ED, 8–11 moderate ED, and 1–7 severe ED as validated by Rosen et al. [6]. Patients with diagnosis of carcinoma of the prostate, hypogonadism, and penile injuries or abnormalities and patients J Sex Med 2006;3:331–336
Alkhayal et al. with history of pelvic surgery or irradiation were excluded from the study. All 48 individuals underwent measurements of the reactive hyperemic response (RHR) of their right brachial artery as described below, with the investigator blinded to the patients’ condition. To induce RHR, a sphygmomanometer with its cuff applied to the distal forearm and wrist was used to interrupt the blood flow to the distal forearm and hand. The cuff was inflated to 280 mm Hg for 120 seconds, as was performed and validated by Hirono et al in their study of patients with coronary artery disease [7]. All tests were performed in the morning between 9:00 AM and 12:00 PM in a temperature-controlled environment (20–22∞C). The peak systolic velocity ratio (PSVR) and 50% recovery time (50% RT), which are defined as the ratio of maximal to baseline peak systolic velocity and the interval from resumption of arterial blood flow to 50% decline of the increased systolic velocity, respectively, were used to measure reactive hyperemia at the brachial artery noninvasively with a handheld continuous Doppler device (Multi Dopplex II), with an 8 MHz probe (EZ8) (Huntleigh Technology plc, Luton, Bedfordshire, UK). Recordings were made at baseline before cuff inflation and immediately after release of the occlusion for 90 seconds. The probe was held in constant position with an angle of 45 degrees over the right brachial artery with a specially devised probe holding apparatus made of hard foam. The best audible and visible Doppler signal was used in locating the probe. Huntleigh Diagnostics Doppler reporter software (version 3.1) was used to display, store, and make calculations on the displayed and recorded waveforms with the aid of a connected laptop computer (Figure 1). To test for intraobserver variability, measurements were repeated on 10 of the subjects in the same setting and under the same conditions of measurement after settlement of normal vascular hemodynamics. To test for interobserver variability, 10 recordings were selected randomly, and the same calculations were made by another observer, who was blinded to the original calculations made by the first observer, using the same software. ED patients were divided into two groups according to the presence or absence of CVD or cardiovascular risk factors (CVR). Group A consisted of 19 patients who all had ED with either an established CVD or one or more CVR. Group B consisted of 16 patients who all had ED but no history or clinical evidence of CVD or CVR. A
jsm_112.fm Page 333 Monday, February 13, 2006 8:24 PM
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Erectile Dysfunction and Cardiovascular Disease
Figure 1 Trace of recorded blood flow waveforms, at baseline and during reactive hyperemia.
third group (group C) consisting of 13 healthy volunteer subjects with no history or evidence of ED or CVD or CVR and who all had normal lipid profile, normal blood sugar, and normal blood pressure were recruited into the study to serve as a control group. The presence of CVD was defined as history of previous myocardial infarction, history of angioplasty, coronary artery bypass graft surgery, or angina. CVR was defined as history or clinical evidence of hypertension, diabetes mellitus on oral hypoglycemic or insulin therapy, or evidence of hypercholesterolemia. Diabetes was defined as a fasting blood glucose >7.00 mmol/L (126 mg/dL), or use of hypoglycemic agents or insulin. Hypertension was defined as systolic blood pressure >140 mm Hg, or diastolic >90 mm Hg on more than two occasions, or use of antihypertensive medications. Any fasting total serum cholesterol level above 5.5 mmol/L was considered hypercholesterolemia. Fourteen patients in group A and 12 patients in group B have already tried phosphodiesterase type 5 (PDE5) inhibitor (sildenafil citrate) on on-demand treatment, with different doses and variable responses. In group A, nine patients tried 50 mg and five were on 100 mg,
while in group B, 10 patients had 50 mg and two had 100 mg doses. None of the patients in group C had any medication. The main outcome measures of this study were to measure and compare the PSVR and 50% RT as variables of RHR in the three groups of patients and to test for validity and reliability of measuring the RHR with Multi Dopplex II device. Results
Variables of Reactive Hyperemia Summary statistics for the measured variables of the three groups are shown in (Table 1). Results
Table 1
Number Age (year) IIEF PSVR 50% RT
Summary statistics of the three groups Group A (ED + CVD)
Group B (ED - CVD)
Group C (Controls)
19 61 (7) 11 (4.7) 1.285 (0.088) 17.5 (7.91)
16 49 (11) 12 (4) 1.44 (0.132) 13.2 (4.96)
13 41 (11) 24 (1) 1.441 (0.145) 13.2 (4.64)
Results are presented as mean ± standard deviation. IIEF = International Index of Erectile Function; PSVR = peak systolic velocity ratio; 50% RT = 50% of the recovery time.
J Sex Med 2006;3:331–336
jsm_112.fm Page 334 Monday, February 13, 2006 8:24 PM
334 are expressed as mean ± standard deviation. Analysis of variance (ANOVA) was performed to detect variability between the groups and unpaired Student’s t-test was used for the evaluation of difference between the groups. A probability of P < 0.05 was considered significant. The PSVR was significantly lower in group A patients––1.285 (0.088), 95% confidence interval (1.113–1.457)––in comparison with group B patients––1.44 (0.132), 95% CI (1.182–1.698) (P = 0.0002)––and the control group––1.441 (0.145), 95% CI (1.157–1.725) (P = 0.0008). There was no statistically significant difference in the PSVR between group B patients and the control group C (P = 0.99). No further calculations of the 50% RT were performed, as there was no significant difference between the groups on ANOVA. Regression analysis revealed no significant correlation between PSVR and age of the patients (r = 0.28) (P > 0.05). PSVR was therefore not affected by the age of the patients.
Validity and Reliability For intraobserver variability in measuring the RHR at the brachial artery, the correlation between measurements was analyzed and the repeatability coefficient was calculated by using Bland and Altman’s statistical method [8]. The mean PSVR measured by the first observer in 10 patients was 1.332 and by the second observer in the same patients was 1.380. The mean difference in the PSVR between the two observers was 0.11 ± 0.1, with 95% limits of agreement of -0.09 to 0.31. The repeatability coefficient was 20%. The mean PSVR measured by the first observer in 10 patients was 1.390 and the mean PSVR measured by a second observer from the same traces was 1.369. The mean difference between the two sets of measurements was 0.038 ± 0.05 with a 95% CI (-0.06 to 0.136). This was not statistically significantly different (paired Student’s t-test, P = 0.20). Discussion
The main finding of this study is that patients with ED and CVD have impaired RHR, in comparison with the other two groups who have no evidence of CVD or CVR. Those patients in the first group clearly have impaired endothelial function, which could affect both peripheral and penile vascular beds and which was revealed by blunting of their RHR, as measured by the PSVR. J Sex Med 2006;3:331–336
Alkhayal et al. All patients in group A suffered from ED and had developed either a CVD or one or more of its risk factors. In addition, 90% (17 out of 19 patients) in this group had no nocturnal erections and there were no other elements in their history that could otherwise have contributed to their ED other than CVD or CVR. In group B, all patients complained of ED, with 88% (14 out of 16) having normal nocturnal erections. None of those patients had any evidence of overt CVD or CVR from their history, examination, and laboratory investigations, and 14 patients had psychological elements in their history, in the form of either depression or performance anxiety. This indicates that their ED is more likely to be psychological in origin rather than a result of endothelial dysfunction, and this was also confirmed by their measured PSVR, which was not statistically significantly different from the healthy control group. Only two patients in group A had psychological elements in their history. Although a PDE5 inhibitor (sildenafil) was used by some of the patients, it was unlikely to have affected our results of measuring the RHR, as 14 of the patients in group A and 12 in group B were on sildenafil on-demand treatment and none of the patients had more than four doses in total or had any dose within 24 hours of the test. The RHR was tested as a measure of endothelial and vascular reactivity, as evidence suggests a key role of endothelial function along resistance vessels in the formation of reactive hyperemia [9]. Reactive hyperemia is a protective adaptation that has evolved in mammals to ensure prompt restoration of blood flow when interrupted abruptly with resulting ischemia. Vascular physiologists have considered the mechanisms responsible for this response for many years and have invoked a role for both direct myogenic responses and local vasoactive substances, which include prostaglandins, adenosine, adenosine triphosphate (ATP)-sensitive potassium channels, adenosine 5¢triphosphate, oxygen, and pH, as well as hydrogen peroxide [10,11]. In addition to pressure changes, after release of an occlusion, a sudden increase of blood flow could also activate shear stresssensitive mechanisms eliciting the release of endothelium-derived dilator factors, such as NO, which may limit myogenic constriction and modify the duration of reactive hyperemia [12]. Recently, one study demonstrated that endothelial dysfunction in ED patients, detected noninvasively in the arm using the flow-mediated dilatation (FMD) to reactive hyperemia method,
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Erectile Dysfunction and Cardiovascular Disease correlated well with abnormalities detected in the penile vasculature detected by penile dopplex studies in the same patients [13]. Another study has demonstrated impaired peripheral endothelial vascular function in patients with coronary artery disease by impaired RHR of the brachial artery, using a pulsed Doppler device and imaging of the studied vessels [7]. The most widely used noninvasive test for arterial endothelial health has been the ultrasoundbased measurement of FMD in systemic vessels, such as the brachial artery, which was established by Celermajer et al. [14]. The magnitude of the change in vessel diameter from the baseline period to the peak observed during reactive hyperemia is indicative of the degree of endothelial function. Nevertheless, measuring FMD is technically difficult and therefore somewhat operatordependent. Our method of measuring the RHR using Multi Dopplex II Doppler device, was inspired from the method used by Hirono et al., which used the same principle of measuring the RHR in the brachial artery but used a pulsed Doppler machine with the region of interest guided by two-dimensional images from a 7.0 MHz linear array transducer [7]. Our method of using a simple handheld continuous Doppler device is much simpler, takes little time to perform, requires little training, is easy to use in an outpatient clinic setting, and most importantly is noninvasive. It has also proved to be a valid and reproducible method, because both variables of RHR could be measured in all patients and produced a nonsignificant difference when measured twice in the same patients or by a second observer. The PSVR could be used to give significant results, while the 50% RT was not different between the groups and therefore could not be used as a measure of the RHR in our study. Proper positioning of the probe and fixation of the arm in one position is essential in obtaining accurate measurements, as in all methods. Although both methods are elicited by a similar transient occlusion of the brachial blood flow, noninvasive investigation of reactive hyperemia in the humeral circulation differs from assessment of endothelial function with the flow-mediated arterial dilation. Indeed, whereas NO plays the key role in the latter, several mediators are involved in the former, including myogenic and metabolic factors, prostaglandins, K+ ATP channels, adenosine, and NO, which is only one of the many components of this complex regulation mechanism [15]. Further studies to compare our method with other
tests that are used to detect vascular disease would be valuable. Conclusion
As endothelial dysfunction affects both ED and CVD patients, testing endothelial function in the peripheral circulation of ED patients by using this simple noninvasive method could identify vascular abnormalities, which might have contributed to the ED. Furthermore, it can also be used as a screening tool to detect occult vascular disease, which might therefore require further tests. Corresponding Author: Shawket Alkhayal, MRCS, MSc (Urol.), Royal Sussex County Hospital, Urology Department, Sussex House 1 Abbey Road, Brighton BN2 1ES, UK. Tel: +44 1273-696955; Fax: +44 1273664798; E-mail: [email protected] Conflict of Interest: None. References
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