- Email: [email protected]
The Effect of Vascular Risk Factors on Penile Vascular Status in Men With Erectile Dysfunction
Sexual Function/Infertility The Effect of Vascular Risk Factors on Penile Vascular Status in Men With Erectile Dysfunction Muammer Kendirci,* Landon Trost,* Suresh C. Sikka* and Wayne J. G. Hellstrom†,‡ From the Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana
Purpose: The cause of erectile dysfunction is mostly organic in nature and is most commonly associated with a vasculogenic etiology. This study evaluates the relationship between penile hemodynamic parameters and vascular risk factors in men with erectile dysfunction. Materials and Methods: A total of 1,216 patients with erectile dysfunction were evaluated regarding the relationship between vascular risk factors and penile vascular parameters. The patients were stratified according to the type and number of risk factors present. Each patient underwent a penile duplex Doppler ultrasound study after injections of intracavernous prostaglandin E1 with accompanying visual sexual stimulation to evaluate penile blood flow parameters. Specific criteria were used to categorize patients according to varying definitions of vascular status. The odds ratio for selected vascular risk factors was calculated. The rates of arterial insufficiency, venoocclusive dysfunction, mixed vascular disease and nonvascular etiologies were also evaluated. These results were statistically compared to those from patients with erectile dysfunction without vascular risk factors. Results: The poorest blood flow parameters were observed in patients with erectile dysfunction with coronary artery disease and diabetes. Arterial insufficiency was most prevalent in patients with coronary artery disease, followed by diabetes. Paradoxically, it was least likely to occur in the smoking group. Venoocclusive dysfunction was observed most often in hypertensive patients with erectile dysfunction. The odds ratio for having abnormal penile blood flow parameters correlated with the number of vascular risk factors present. Conclusions: This study demonstrates that vascular risk factors are associated with abnormalities in the hemodynamics of blood vessels. Moreover, the number of vascular risk factors correlates with an increased likelihood of having abnormal penile vascular parameters. Key Words: impotence; risk factors; ultrasonography, Doppler, duplex; diabetes mellitus
rectile dysfunction is defined as the persistent inability to achieve or maintain an erection sufficient for sexual intercourse.1 The Massachusetts Male Aging Study estimates that 52% of men 40 to 70 years old experience some degree of ED, with 10% having severe ED.2 ED has been independently associated with poorer general health and with a lower quality of life for patient and partner. Penile erection is the end result of a series of events that involves neurogenic and vasculogenic responses to the integration of central and peripheral sensual stimulation. The proper function of the vascular endothelium is essential to achieving and maintaining penile erection. Recent data reveal that more than 80% of ED has an organic basis, with
E
Submitted for publication December 1, 2006. Presented at annual meeting of American Urological Association, Atlanta, Georgia, May 20 –25, 2006. * Nothing to disclose. † Correspondence: Department of Urology, Tulane University School of Medicine, 1430 Tulane Ave., SL-42, New Orleans, Louisiana 70112 (telephone: 504-988-7308; FAX: 504-988-5059; e-mail: [email protected]). ‡ Financial interest and/or other relationship with King Pharmaceuticals/Palatin Technologies, Indevus, Vivus, Mentor, American Medical Systems, Sanofi-Aventis, Lilly ICOS, Solvay, Auxilium, Johnson & Johnson, Pfizer and Bayer.
See Editorial on page 2250.
0022-5347/07/1786-2516/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION
vascular disease being the most common etiology. Similarly the presence of ED has been shown to correlate with coronary artery disease, hypertension, atherosclerosis, hyperlipidemia, smoking and diabetes mellitus.3 Arterial insufficiency as an etiology for ED may result from decreased cardiac output, increased systemic resistance, decreased vascular compliance or vessel narrowing secondary to arteriosclerosis. The association between ED and VRFs serves as an important sentinel indicator for underlying vascular disease and a stimulus for early screening and preventative measures. Although ED is a natural consequence of aging, its severity is directly related to vascular risk factors, all of which are associated with endothelial dysfunction.3 The vascular endothelium of the penis has a pivotal role in modulating vascular tone and blood flow into the penis in response to humoral, neural and mechanical stimuli. The endothelium releases various factors that affect the contractile and relaxatory activity of the underlying vascular smooth muscle. In addition, physical hemodynamic changes caused by alter-
Editor’s Note: This article is the fifth of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 2706 and 2707.
2516
Vol. 178, 2516-2520, December 2007 Printed in U.S.A. DOI:10.1016/j.juro.2007.08.001
VASCULAR RISK FACTORS IN ERECTILE DYSFUNCTION
2517
ations in penile blood flow and shear stress release various mediators that modulate the underlying smooth muscle tone. In endothelial dysfunction the regulatory role of the endothelium is hindered, resulting in decreased responsiveness to vasodilatory mediators and/or increased sensitivity to various vasoconstricting agents. The term endothelial dysfunction implies a decrease in endothelial dependent corpora cavernous smooth muscle relaxation, for the most part secondary to increased destruction or total loss of nitric oxide bioactivity in the vascular tree. Epidemiological studies provide evidence for the association between the presence of VRFs and the subsequent development of ED. However, limited data exist on the impact of vascular risk factors on penile blood flow parameters. In this study we evaluate the relationship between penile vascular parameters using PDDU and each of the various vascular risk factors in men with ED, and predict the impact each vascular risk factor has on penile blood flow.
and nonvascular etiology—PSV more than 30 cm per second with EDV 5 cm per second or less and RI more than 0.8.5 Patients with ED with selected vascular risk factors (diabetes mellitus, coronary artery disease, hypertension, dyslipidemia and smoking) were compared to those with no vascular risk factors in terms of penile blood flow parameters including PSV, EDV and RI. The percentage of men in each vascular risk factor group who met the criteria for AI, VOD, mixed vascular or nonvascular causes of ED were calculated and summarized. In addition, the odds ratio for having an abnormal penile blood flow was determined for each risk factor individually as well as in combination. Study parameters were compared among groups using Pearson’s chi-square test (SAS® version 9.0). Analysis of covariance was used to assess the impact of comorbidities. Values were given as mean ⫾ SEM.
MATERIALS AND METHODS
In our study population 131 patients had no vascular risk factors, 224 patients had 1 vascular risk factor and 861 participants had 2 or more vascular risk factors. The most common single vascular risk factor in the study population was smoking (27%), followed by hypertension (24%) and dyslipidemia (19%), while diabetes mellitus (18%) and coronary artery disease (12.5%) were the least common. The percentage of subjects who had zero, 1, or 2 or more vascular risk factors were 11%, 18% and 71%, respectively. Patients with ED with no risk factors and those with smoking as a sole risk factor were found to be the youngest, while patients with dyslipidemia and coronary artery disease were on average the oldest (table 1). Mean PSV in patients with ED with no vascular risk factors was 32.4 ⫾ 0.89 cm per second. The poorest blood flow was found in patients with ED with coronary artery disease (PSV 18.47 ⫾ 1.32 cm per second) followed by diabetes (PSV 24.14 ⫾ 2.06 cm per second). Mean EDV in patients with ED with no vascular risk factors was 5.0 ⫾ 0.48 cm per second. The highest mean EDV values were documented in men with ED with coronary artery disease (8.1 ⫾ 2.42 cm per second) followed by hypertension (7.8 ⫾ 2.03 cm per second) (table 1). Arterial insufficiency was most prevalent in men with ED with coronary artery disease (40%) followed by diabetes (32.8%), while it was least likely to be present in the smoking group (23.3%) (table 1). VOD was most commonly observed in the hypertensive group patients with ED (36.5%). Men with ED and no associated vascular risk factors were found by PDDU to have a nonvascular etiology 58% of the time, while those with coronary artery disease demonstrated the lowest rate of nonvascular etiology (4%), followed by hypertension (16%) and diabetes (18%) (table 2).
A total of 1,216 consecutive patients with ED were evaluated using PDDU in regard to the impact of the type and number of associated VRFs on penile vascular function. All patients underwent a detailed sexual and medical history, focused physical examination, and laboratory testing, including blood glucose and serum lipid levels. Patients with ED with single vascular risk factors were categorized into hypertension, coronary artery disease, dyslipidemia, diabetes mellitus and smoking groups. Patients who had 2 or more vascular risk factors were not included in individual groups but were used to determine the correlational strength between increased numbers of vascular risk factors and exhibiting abnormal penile blood flow parameters. Patients with ED without any vascular risk factors served as a control group. Erectile function was assessed via administration of a questionnaire addressing sexual function (1992 to 1997) or by administration of the IIEF questionnaire (1997 onward).4 The sum of questions 1 to 5 and 15 of the IIEF was calculated based on a maximum score of 30. Patients who had a total erectile score of less than 25 were identified as having ED. Each patient underwent a PDDU after intracorporal injection of prostaglandin E1 with accompanying visual sexual stimulation in privacy to evaluate penile blood flow for a baseline assessment. Several parameters were used for different vascular status definitions such as pure AI—PSV less than 25 cm per second, borderline AI—PSV 25 to 30 cm per second, pure venoocclusive dysfunction—EDV more than 5 cm per second and RI less than 0.8 (with the condition that PSV is more than 30 cm per second), mixed vascular disorder—PSV less than 25 cm per second and EDV more than 5 cm per second,
RESULTS
TABLE 1. Characteristics of men with ED with selected vascular risk factors
No./total No. (%) Mean pt age ⫾ SEM Mean PSV ⫾ SEM Mean EDV ⫾ SEM % AI % VOD % Nonvascular state
No VRFs
Hypertension
Diabetes
Dyslipidemia
Smoking
CAD
131/1,216 (11) 46.8 ⫾ 0.74 32.4 ⫾ 0.89 5.0 ⫾ 0.48 12 18 58
54/224 (24) 55.9 ⫾ 0.74 25.3 ⫾ 3.47 7.8 ⫾ 2.03 20 36 16
39/224 (18) 50.13 ⫾ 1.79 24.1 ⫾ 2.06 7.2 ⫾ 2.11 33 34 18
42/224 (19) 58.75 ⫾ 4.52 25.8 ⫾ 1.27 7.0 ⫾ 1.21 13 27 28
61/224 (27) 46.19 ⫾ 0.99 31.9 ⫾ 1.56 5.8 ⫾ 0.74 23 29 22
28/224 (12.5) 57.8 ⫾ 0.91 18.4 ⫾ 1.32 8.1 ⫾ 2.42 40 33 4
2518
VASCULAR RISK FACTORS IN ERECTILE DYSFUNCTION
TABLE 2. Odds ratios for abnormal cavernosal blood flow in men with ED with a single vascular risk factor or a combination of factors VRF
Odds Ratio
Dyslipidemia Smoking Diabetes Hypertension Hypertension ⫹ smoking Diabetes ⫹ hypertension Diabetes ⫹ smoking CAD Diabetes ⫹ hypertension ⫹ smoking
1.12 1.14 1.46 1.78 2.41 3.15 3.94 5.66 6.58
The odds ratio for having an abnormal penile blood flow correlated with an increasing number of vascular risk factors. The odds ratio for having abnormal cavernous blood flow was found to be 1.81 for a single vascular risk factor, 3.40 for 2 risk factors, 5.60 for 3 risk factors, 7.92 for 4 risk factors and 10.7 for 5 vascular risk factors (see figure). DISCUSSION This study demonstrates that vascular risk factors are associated with abnormalities in penile vascular function. Men with ED and either coronary artery disease or diabetes as sole vascular risk factors exhibit the lowest levels of cavernous blood flow. Moreover, the number of vascular risk factors directly correlates with an increased likelihood of having abnormal penile vascular parameters. Results from this study further strengthen the correlation that exists between vascular risk factors and penile hemodynamics. Because vascular disease is the most common etiology for ED, it is important to further classify which risk factors are associated with abnormal cavernous blood flow and, thus, with vascular compromise. To date, to our knowledge no prior study has directly compared vascular risk factors side by side to examine the degree of alteration in PSV and EDV on PDDU as well as proposed associations between the number of vascular risk factors and ED. Results derived from this study indicate that compared to patients with ED with no vascular risk factors, PSV values as measured by PDDU are decreased in men with hypertension, diabetes, dyslipidemia and coronary artery disease but not with smoking. Likewise, EDV values are increased in patients with all vascular risk factors with coronary artery disease exhibiting the highest value. When examining contributing etiologies to ED, patients with no vascular risk factors had a higher percentage of nonvascular causes of ED, whereas patients with vascular risk factors showed a much higher rate of AI and VOD and a much lower degree of nonvascular etiologies. An increased number of vascular risk factors was associated with a higher odds ratio for having an abnormal PDDU with coronary artery disease showing the greatest value for an individual factor. ED may be predictive of subclinical cardiovascular disease. A recent study evaluating aortic flow mediated dilatation and distensibility found decreased flow rates and compliance in ED cases compared to controls, indicating the presence of more generalized vascular disease.6 Using Doppler imaging another study demonstrated the presence of impaired endothelial and left ventricular function in men with ED compared to age matched controls.7 Recently
Shamloul et al studied 40 patients with ED older than 40 years to see if PSV values obtained on PDDU correlated with abnormal stress electrocardiograms.8 Findings of a PSV of 35 cm per second or less were 50% sensitive and 100% specific in predicting the presence of ischemic heart disease, while the presence of an abnormal stress electrocardiogram had a 100% positive predictive value for a PSV of 35 cm per second or less. Similarly, Elesber et al reported that coronary endothelial dysfunction was independently associated with ED in men with early coronary atherosclerosis.9 Data from the current study demonstrating that ED cases with established coronary artery disease have the lowest PSV and highest EDV on PDDU among vascular risk factors are not surprising. While hypertension, diabetes, dyslipidemia and smoking are associated with vascular damage over time, diseased coronary vessels indicate that damage has already occurred to vessels throughout the body including the penile vasculature. Our data indicate that 40% of men with ED and established coronary artery disease have documented AI as a contributing factor to their ED. The mechanism of vascular insufficiency in the penis is likely similar to that observed in the coronary vessels, namely a decrease in blood flow secondary to lumenal narrowing and associated loss of vascular compliance. This mechanism could also partly account for the high percentage of VOD observed because decreased cavernous blood flow results in lower cavernous pressures that may be insufficient to compress subtunical venules. Damage to endothelial cells lining corporal lacunar sinuses may also contribute to ED through decreased synthesis of endothelially derived nitric oxide. When comparing PSV and EDV values among risk factors, the data appear to indicate that smoking is associated with higher peak flows and lower EDV values compared to hypertension, diabetes and hyperlipidemia. However, in this study patients with ED with smoking as their only vascular risk factor were younger on average than those with hypertension, diabetes and dyslipidemia. This fact could account for the disparity, because younger patients with similar risk factors are not as likely to have the same degree of vascular damage as older patients. A recent study of 109 patients with ED comparing ED in smoking vs nonsmoking patients failed to find a statistical significance between measured PSV values but concluded that VOD had a substantial role in the development of ED in smokers.10 Similarly, data from our study indicate that VOD was present in 29% of patients with smoking as a vascular risk factor.
Correlation between number of vascular risk factors and abnormal cavernous blood flow.
VASCULAR RISK FACTORS IN ERECTILE DYSFUNCTION The presence of diabetes in men increases the likelihood of having ED and is associated with impairment in penile blood flow parameters. A recent study demonstrated a statistically significant association between the presence of diabetes and a poor response to intracavernous injections including decreased PSV values.11 In another study by Kadioglu et al sexually active diabetic patients had a significantly lower cavernous PSV and a higher average EDV compared to nondiabetics.12 These results are consistent with the significant alterations that occur in the penile vascular system with diabetes.13 In our study patients with diabetes as a sole vascular risk factor experienced similar decreases in PSV and increases in EDV compared to those with no vascular risk factors. Additionally, men with diabetes were found to have a nonvascular cause for ED only 18% of the time. This further supports the finding that ED in diabetic men is due in large measure to a compromised vascular supply. Epidemiological studies have documented the correlation between hypertension and the incidence of ED. The Massachusetts Male Aging Study reported that 30% of men 40 to 70 years old with hypertension had ED.2 Although hypertension as a direct cause of ED has not been proven to date, it has been hypothesized that it impairs vascular function via shear stress damage.3 Rat models of hypertension have documented significant increases in cavernous and vascular smooth muscle proliferation as well as cavernous fibrosis and other morphological changes.14 Our study has shown that the presence of hypertension increases the likelihood of having an abnormal penile blood flow 1.78 times. In addition, men with ED with hypertension exhibited a significantly reduced PSV and increased EDV compared to men without vascular risk factors. Furthermore, the rates of AI and VOD were significantly higher in hypertensive men compared to controls while a nonvascular state was found in only 16% of these patients. Similar to hypertension, recent studies have documented an association between dyslipidemia and increased ED prevalence and severity.15,16 The effect of hyperlipidemia on erectile function has been partially attributed to atherosclerosis in the hypogastric-cavernous arterial vascular bed, which results in decreased penile blood flow. Additionally, impairment of endothelium dependent relaxation in various vascular beds of men with hypercholesterolemia has been well established.17,18 Our study further defines the relationship between dyslipidemia and impaired penile blood flow. Patients with ED with hyperlipidemia exhibited significantly lower PSV and higher EDV compared to controls, and were associated with a significantly higher rate of AI and VOD and a lower rate of nonvascular causes. These hemodynamic data suggest that hyperlipidemia as a sole vascular risk factor is associated with an increased rate of abnormal penile blood flow parameters in men with ED. The presence of 2 or more vascular risk factors is associated with a higher odds ratio of having an abnormal cavernous blood flow, except the presence of established coronary artery disease. Additional risk factors appear to have a synergistic rather than an additive effect on the odds ratio for abnormal cavernous blood flow. This association underscores the importance of minimizing risk factors when possible.
vasculature. Coronary artery disease as an associated vascular risk factor in men with ED contributes significantly to poor cavernous blood flow. Other vascular risk factors such as diabetes, dyslipidemia, hypertension and smoking are associated with impaired penile blood flow in men with ED as assessed by PDDU compared to those with no risk factors. Moreover, the number of vascular risk factors correlates with an increased likelihood of having abnormal penile vascular parameters.
Abbreviations and Acronyms AI CAD ED EDV IIEF
⫽ ⫽ ⫽ ⫽ ⫽
PDDU PSV RI VOD VRF
⫽ ⫽ ⫽ ⫽ ⫽
arterial insufficiency coronary artery disease erectile dysfunction end-diastolic velocity International Index of Erectile Dysfunction penile duplex Doppler ultrasound peak systolic velocity resistive index venoocclusive dysfunction vascular risk factor
REFERENCES 1. 2.
3.
4.
5.
6.
7.
8.
9.
10.
CONCLUSIONS 11.
This study demonstrates that vascular risk factors are associated with abnormalities in the hemodynamics of penile
2519
NIH Consensus Conference. Impotence. NIH Consensus Development Panel on Impotence. JAMA 1993; 270: 83. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ and McKinlay JB: Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151: 54. Kendirci M, Nowfar S and Hellstrom WJ: The impact of vascular risk factors on erectile function. Drugs Today (Barc) 2005; 41: 65. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J and Mishra A: The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997; 49: 822. Kendirci M, Nowfar S, Gur S, Jabren GW, Sikka SC and Hellstrom WJ: The relationship between the type of penile abnormality and penile vascular status in patients with Peyronie’s disease. J Urol 2005; 174: 632. Uslu N, Gorgulu S, Alper AT, Eren M, Nurkalem Z, Yildirim A et al: Erectile dysfunction as a generalized vascular dysfunction. J Am Soc Echocardiogr 2006; 19: 341. Uslu N, Eren M, Gorgulu S, Alper AT, Orhan AL, Yildirim A et al: Left ventricular diastolic function and endothelial function in patients with erectile dysfunction. Am J Cardiol 2006; 97: 1785. Shamloul R, Ghanem HM, Salem A, Elnashaar A, Elnaggar W, Darwish H et al: Correlation between penile duplex findings and stress electrocardiography in men with erectile dysfunction. Int J Impot Res 2004; 6: 235. Elesber AA, Solomon H, Lennon RJ, Mathew V, Prasad A, Pumper G et al: Coronary endothelial dysfunction is associated with erectile dysfunction and elevated asymmetric dimethylarginine in patients with early atherosclerosis. Eur Heart J 2006; 27: 824. Elhanbly S, Abdel-Gaber S, Fathy H, El-Bayoumi Y, Wald M and Niederberger CS: Erectile dysfunction in smokers: a penile dynamic and vascular study. J Androl 2004; 25: 991. El-Sakka AI: Penile axial rigidity and Doppler ultrasonography parameters in patients with erectile dysfunction: association with type 2 diabetes. Urology 2003; 62: 525.
2520 12.
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16. 17. 18.
VASCULAR RISK FACTORS IN ERECTILE DYSFUNCTION
Kadioglu A, Erdogru T, Karsidag K, Dinccag N, Satman I, Yilmaz MT et al: Evaluation of penile arterial system with color Doppler ultrasonography in nondiabetic and diabetic males. Eur Urol 1995; 27: 311. Chung WS, Shim BS and Park YY: Hemodynamic insult by vascular risk factors and pharmacologic erection in men with erectile dysfunction: Doppler sonography study. World J Urol 2000; 18: 427. Toblli JE, Stella I, Inserra F, Ferder L, Zeller F and Mazza ON: Morphological changes in cavernous tissue in spontaneously hypertensive rats. Am J Hypertens 2000; 13: 686. Seftel AD, Sun P and Swindle R: The prevalence of hypertension, hyperlipidemia, diabetes mellitus and depression in men with erectile dysfunction. J Urol 2004; 171: 2341. El-Sakka AI: Characteristics of erectile dysfunction in Saudi patients. Int J Impot Res 2004; 6: 13. Rosenfeld ME: Oxidized LDL affects multiple atherogenic cellular responses. Circulation 1991; 83: 2137. Kugiyama K, Kerns SA, Morrisett JD, Roberts R and Henry PD: Impairment of endothelium-dependent arterial relaxation by lysolecithin in modified low-density lipoproteins. Nature 1990; 344: 160.
EDITORIAL COMMENT Penile erection is a vascular event under neural control, and is determined by the balance between arterial inflow and venous outflow. Therefore, vascular arterial abnormalities will affect erectile function and vasculogenic ED.1 Endothe-
lial dysfunction is the fundamental problem, and as the endothelium is the same throughout the arterial tree ED and CAD often coexist although the CAD may be silent.2 The sharing of risk factors between ED and CAD, while not surprising given the endothelial common denominator, has led to the concept of ED in the absence of cardiac symptoms being a target for aggressive risk reduction to reduce the chances of a subsequent symptomatic cardiac event.3 In this retrospective study of 1,216 men with ED, even allowing for changing risk definitions during 15 years, the link between CAD and penile vascular hemodynamic abnormalities is clearly documented. With increasing risk factors abnormal cavernosal flow increases (as does the risk of CAD), cementing the penile/ED/CAD link and the need for risk reduction intervention. Graham Jackson Department of Cardiology Guy’s & St Thomas’ NHS Foundation Trust London, United Kingdom 1.
Sullivan ME, Keoghane SR and Miller MAW: Vascular risk factors and erectile dysfunction. BJU Int 2001; 87: 838. 2. Solomon H, Man JW and Jackson G: Erectile dysfunction and the cardiovascular patient: endothelial dysfunction is the common denominator. Heart 2003; 89: 251. 3. Jackson G, Rosen RC, Kloner RA and Kostis JB: The second Princeton consensus on sexual dysfunction and cardiac risk: new guidelines for sexual medicine. J Sex Med 2006; 3: 28.
Purpose: The cause of erectile dysfunction is mostly organic in nature and is most commonly associated with a vasculogenic etiology. This study evaluates the relationship between penile hemodynamic parameters and vascular risk factors in men with erectile dysfunction. Materials and Methods: A total of 1,216 patients with erectile dysfunction were evaluated regarding the relationship between vascular risk factors and penile vascular parameters. The patients were stratified according to the type and number of risk factors present. Each patient underwent a penile duplex Doppler ultrasound study after injections of intracavernous prostaglandin E1 with accompanying visual sexual stimulation to evaluate penile blood flow parameters. Specific criteria were used to categorize patients according to varying definitions of vascular status. The odds ratio for selected vascular risk factors was calculated. The rates of arterial insufficiency, venoocclusive dysfunction, mixed vascular disease and nonvascular etiologies were also evaluated. These results were statistically compared to those from patients with erectile dysfunction without vascular risk factors. Results: The poorest blood flow parameters were observed in patients with erectile dysfunction with coronary artery disease and diabetes. Arterial insufficiency was most prevalent in patients with coronary artery disease, followed by diabetes. Paradoxically, it was least likely to occur in the smoking group. Venoocclusive dysfunction was observed most often in hypertensive patients with erectile dysfunction. The odds ratio for having abnormal penile blood flow parameters correlated with the number of vascular risk factors present. Conclusions: This study demonstrates that vascular risk factors are associated with abnormalities in the hemodynamics of blood vessels. Moreover, the number of vascular risk factors correlates with an increased likelihood of having abnormal penile vascular parameters. Key Words: impotence; risk factors; ultrasonography, Doppler, duplex; diabetes mellitus
rectile dysfunction is defined as the persistent inability to achieve or maintain an erection sufficient for sexual intercourse.1 The Massachusetts Male Aging Study estimates that 52% of men 40 to 70 years old experience some degree of ED, with 10% having severe ED.2 ED has been independently associated with poorer general health and with a lower quality of life for patient and partner. Penile erection is the end result of a series of events that involves neurogenic and vasculogenic responses to the integration of central and peripheral sensual stimulation. The proper function of the vascular endothelium is essential to achieving and maintaining penile erection. Recent data reveal that more than 80% of ED has an organic basis, with
E
Submitted for publication December 1, 2006. Presented at annual meeting of American Urological Association, Atlanta, Georgia, May 20 –25, 2006. * Nothing to disclose. † Correspondence: Department of Urology, Tulane University School of Medicine, 1430 Tulane Ave., SL-42, New Orleans, Louisiana 70112 (telephone: 504-988-7308; FAX: 504-988-5059; e-mail: [email protected]). ‡ Financial interest and/or other relationship with King Pharmaceuticals/Palatin Technologies, Indevus, Vivus, Mentor, American Medical Systems, Sanofi-Aventis, Lilly ICOS, Solvay, Auxilium, Johnson & Johnson, Pfizer and Bayer.
See Editorial on page 2250.
0022-5347/07/1786-2516/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION
vascular disease being the most common etiology. Similarly the presence of ED has been shown to correlate with coronary artery disease, hypertension, atherosclerosis, hyperlipidemia, smoking and diabetes mellitus.3 Arterial insufficiency as an etiology for ED may result from decreased cardiac output, increased systemic resistance, decreased vascular compliance or vessel narrowing secondary to arteriosclerosis. The association between ED and VRFs serves as an important sentinel indicator for underlying vascular disease and a stimulus for early screening and preventative measures. Although ED is a natural consequence of aging, its severity is directly related to vascular risk factors, all of which are associated with endothelial dysfunction.3 The vascular endothelium of the penis has a pivotal role in modulating vascular tone and blood flow into the penis in response to humoral, neural and mechanical stimuli. The endothelium releases various factors that affect the contractile and relaxatory activity of the underlying vascular smooth muscle. In addition, physical hemodynamic changes caused by alter-
Editor’s Note: This article is the fifth of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 2706 and 2707.
2516
Vol. 178, 2516-2520, December 2007 Printed in U.S.A. DOI:10.1016/j.juro.2007.08.001
VASCULAR RISK FACTORS IN ERECTILE DYSFUNCTION
2517
ations in penile blood flow and shear stress release various mediators that modulate the underlying smooth muscle tone. In endothelial dysfunction the regulatory role of the endothelium is hindered, resulting in decreased responsiveness to vasodilatory mediators and/or increased sensitivity to various vasoconstricting agents. The term endothelial dysfunction implies a decrease in endothelial dependent corpora cavernous smooth muscle relaxation, for the most part secondary to increased destruction or total loss of nitric oxide bioactivity in the vascular tree. Epidemiological studies provide evidence for the association between the presence of VRFs and the subsequent development of ED. However, limited data exist on the impact of vascular risk factors on penile blood flow parameters. In this study we evaluate the relationship between penile vascular parameters using PDDU and each of the various vascular risk factors in men with ED, and predict the impact each vascular risk factor has on penile blood flow.
and nonvascular etiology—PSV more than 30 cm per second with EDV 5 cm per second or less and RI more than 0.8.5 Patients with ED with selected vascular risk factors (diabetes mellitus, coronary artery disease, hypertension, dyslipidemia and smoking) were compared to those with no vascular risk factors in terms of penile blood flow parameters including PSV, EDV and RI. The percentage of men in each vascular risk factor group who met the criteria for AI, VOD, mixed vascular or nonvascular causes of ED were calculated and summarized. In addition, the odds ratio for having an abnormal penile blood flow was determined for each risk factor individually as well as in combination. Study parameters were compared among groups using Pearson’s chi-square test (SAS® version 9.0). Analysis of covariance was used to assess the impact of comorbidities. Values were given as mean ⫾ SEM.
MATERIALS AND METHODS
In our study population 131 patients had no vascular risk factors, 224 patients had 1 vascular risk factor and 861 participants had 2 or more vascular risk factors. The most common single vascular risk factor in the study population was smoking (27%), followed by hypertension (24%) and dyslipidemia (19%), while diabetes mellitus (18%) and coronary artery disease (12.5%) were the least common. The percentage of subjects who had zero, 1, or 2 or more vascular risk factors were 11%, 18% and 71%, respectively. Patients with ED with no risk factors and those with smoking as a sole risk factor were found to be the youngest, while patients with dyslipidemia and coronary artery disease were on average the oldest (table 1). Mean PSV in patients with ED with no vascular risk factors was 32.4 ⫾ 0.89 cm per second. The poorest blood flow was found in patients with ED with coronary artery disease (PSV 18.47 ⫾ 1.32 cm per second) followed by diabetes (PSV 24.14 ⫾ 2.06 cm per second). Mean EDV in patients with ED with no vascular risk factors was 5.0 ⫾ 0.48 cm per second. The highest mean EDV values were documented in men with ED with coronary artery disease (8.1 ⫾ 2.42 cm per second) followed by hypertension (7.8 ⫾ 2.03 cm per second) (table 1). Arterial insufficiency was most prevalent in men with ED with coronary artery disease (40%) followed by diabetes (32.8%), while it was least likely to be present in the smoking group (23.3%) (table 1). VOD was most commonly observed in the hypertensive group patients with ED (36.5%). Men with ED and no associated vascular risk factors were found by PDDU to have a nonvascular etiology 58% of the time, while those with coronary artery disease demonstrated the lowest rate of nonvascular etiology (4%), followed by hypertension (16%) and diabetes (18%) (table 2).
A total of 1,216 consecutive patients with ED were evaluated using PDDU in regard to the impact of the type and number of associated VRFs on penile vascular function. All patients underwent a detailed sexual and medical history, focused physical examination, and laboratory testing, including blood glucose and serum lipid levels. Patients with ED with single vascular risk factors were categorized into hypertension, coronary artery disease, dyslipidemia, diabetes mellitus and smoking groups. Patients who had 2 or more vascular risk factors were not included in individual groups but were used to determine the correlational strength between increased numbers of vascular risk factors and exhibiting abnormal penile blood flow parameters. Patients with ED without any vascular risk factors served as a control group. Erectile function was assessed via administration of a questionnaire addressing sexual function (1992 to 1997) or by administration of the IIEF questionnaire (1997 onward).4 The sum of questions 1 to 5 and 15 of the IIEF was calculated based on a maximum score of 30. Patients who had a total erectile score of less than 25 were identified as having ED. Each patient underwent a PDDU after intracorporal injection of prostaglandin E1 with accompanying visual sexual stimulation in privacy to evaluate penile blood flow for a baseline assessment. Several parameters were used for different vascular status definitions such as pure AI—PSV less than 25 cm per second, borderline AI—PSV 25 to 30 cm per second, pure venoocclusive dysfunction—EDV more than 5 cm per second and RI less than 0.8 (with the condition that PSV is more than 30 cm per second), mixed vascular disorder—PSV less than 25 cm per second and EDV more than 5 cm per second,
RESULTS
TABLE 1. Characteristics of men with ED with selected vascular risk factors
No./total No. (%) Mean pt age ⫾ SEM Mean PSV ⫾ SEM Mean EDV ⫾ SEM % AI % VOD % Nonvascular state
No VRFs
Hypertension
Diabetes
Dyslipidemia
Smoking
CAD
131/1,216 (11) 46.8 ⫾ 0.74 32.4 ⫾ 0.89 5.0 ⫾ 0.48 12 18 58
54/224 (24) 55.9 ⫾ 0.74 25.3 ⫾ 3.47 7.8 ⫾ 2.03 20 36 16
39/224 (18) 50.13 ⫾ 1.79 24.1 ⫾ 2.06 7.2 ⫾ 2.11 33 34 18
42/224 (19) 58.75 ⫾ 4.52 25.8 ⫾ 1.27 7.0 ⫾ 1.21 13 27 28
61/224 (27) 46.19 ⫾ 0.99 31.9 ⫾ 1.56 5.8 ⫾ 0.74 23 29 22
28/224 (12.5) 57.8 ⫾ 0.91 18.4 ⫾ 1.32 8.1 ⫾ 2.42 40 33 4
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VASCULAR RISK FACTORS IN ERECTILE DYSFUNCTION
TABLE 2. Odds ratios for abnormal cavernosal blood flow in men with ED with a single vascular risk factor or a combination of factors VRF
Odds Ratio
Dyslipidemia Smoking Diabetes Hypertension Hypertension ⫹ smoking Diabetes ⫹ hypertension Diabetes ⫹ smoking CAD Diabetes ⫹ hypertension ⫹ smoking
1.12 1.14 1.46 1.78 2.41 3.15 3.94 5.66 6.58
The odds ratio for having an abnormal penile blood flow correlated with an increasing number of vascular risk factors. The odds ratio for having abnormal cavernous blood flow was found to be 1.81 for a single vascular risk factor, 3.40 for 2 risk factors, 5.60 for 3 risk factors, 7.92 for 4 risk factors and 10.7 for 5 vascular risk factors (see figure). DISCUSSION This study demonstrates that vascular risk factors are associated with abnormalities in penile vascular function. Men with ED and either coronary artery disease or diabetes as sole vascular risk factors exhibit the lowest levels of cavernous blood flow. Moreover, the number of vascular risk factors directly correlates with an increased likelihood of having abnormal penile vascular parameters. Results from this study further strengthen the correlation that exists between vascular risk factors and penile hemodynamics. Because vascular disease is the most common etiology for ED, it is important to further classify which risk factors are associated with abnormal cavernous blood flow and, thus, with vascular compromise. To date, to our knowledge no prior study has directly compared vascular risk factors side by side to examine the degree of alteration in PSV and EDV on PDDU as well as proposed associations between the number of vascular risk factors and ED. Results derived from this study indicate that compared to patients with ED with no vascular risk factors, PSV values as measured by PDDU are decreased in men with hypertension, diabetes, dyslipidemia and coronary artery disease but not with smoking. Likewise, EDV values are increased in patients with all vascular risk factors with coronary artery disease exhibiting the highest value. When examining contributing etiologies to ED, patients with no vascular risk factors had a higher percentage of nonvascular causes of ED, whereas patients with vascular risk factors showed a much higher rate of AI and VOD and a much lower degree of nonvascular etiologies. An increased number of vascular risk factors was associated with a higher odds ratio for having an abnormal PDDU with coronary artery disease showing the greatest value for an individual factor. ED may be predictive of subclinical cardiovascular disease. A recent study evaluating aortic flow mediated dilatation and distensibility found decreased flow rates and compliance in ED cases compared to controls, indicating the presence of more generalized vascular disease.6 Using Doppler imaging another study demonstrated the presence of impaired endothelial and left ventricular function in men with ED compared to age matched controls.7 Recently
Shamloul et al studied 40 patients with ED older than 40 years to see if PSV values obtained on PDDU correlated with abnormal stress electrocardiograms.8 Findings of a PSV of 35 cm per second or less were 50% sensitive and 100% specific in predicting the presence of ischemic heart disease, while the presence of an abnormal stress electrocardiogram had a 100% positive predictive value for a PSV of 35 cm per second or less. Similarly, Elesber et al reported that coronary endothelial dysfunction was independently associated with ED in men with early coronary atherosclerosis.9 Data from the current study demonstrating that ED cases with established coronary artery disease have the lowest PSV and highest EDV on PDDU among vascular risk factors are not surprising. While hypertension, diabetes, dyslipidemia and smoking are associated with vascular damage over time, diseased coronary vessels indicate that damage has already occurred to vessels throughout the body including the penile vasculature. Our data indicate that 40% of men with ED and established coronary artery disease have documented AI as a contributing factor to their ED. The mechanism of vascular insufficiency in the penis is likely similar to that observed in the coronary vessels, namely a decrease in blood flow secondary to lumenal narrowing and associated loss of vascular compliance. This mechanism could also partly account for the high percentage of VOD observed because decreased cavernous blood flow results in lower cavernous pressures that may be insufficient to compress subtunical venules. Damage to endothelial cells lining corporal lacunar sinuses may also contribute to ED through decreased synthesis of endothelially derived nitric oxide. When comparing PSV and EDV values among risk factors, the data appear to indicate that smoking is associated with higher peak flows and lower EDV values compared to hypertension, diabetes and hyperlipidemia. However, in this study patients with ED with smoking as their only vascular risk factor were younger on average than those with hypertension, diabetes and dyslipidemia. This fact could account for the disparity, because younger patients with similar risk factors are not as likely to have the same degree of vascular damage as older patients. A recent study of 109 patients with ED comparing ED in smoking vs nonsmoking patients failed to find a statistical significance between measured PSV values but concluded that VOD had a substantial role in the development of ED in smokers.10 Similarly, data from our study indicate that VOD was present in 29% of patients with smoking as a vascular risk factor.
Correlation between number of vascular risk factors and abnormal cavernous blood flow.
VASCULAR RISK FACTORS IN ERECTILE DYSFUNCTION The presence of diabetes in men increases the likelihood of having ED and is associated with impairment in penile blood flow parameters. A recent study demonstrated a statistically significant association between the presence of diabetes and a poor response to intracavernous injections including decreased PSV values.11 In another study by Kadioglu et al sexually active diabetic patients had a significantly lower cavernous PSV and a higher average EDV compared to nondiabetics.12 These results are consistent with the significant alterations that occur in the penile vascular system with diabetes.13 In our study patients with diabetes as a sole vascular risk factor experienced similar decreases in PSV and increases in EDV compared to those with no vascular risk factors. Additionally, men with diabetes were found to have a nonvascular cause for ED only 18% of the time. This further supports the finding that ED in diabetic men is due in large measure to a compromised vascular supply. Epidemiological studies have documented the correlation between hypertension and the incidence of ED. The Massachusetts Male Aging Study reported that 30% of men 40 to 70 years old with hypertension had ED.2 Although hypertension as a direct cause of ED has not been proven to date, it has been hypothesized that it impairs vascular function via shear stress damage.3 Rat models of hypertension have documented significant increases in cavernous and vascular smooth muscle proliferation as well as cavernous fibrosis and other morphological changes.14 Our study has shown that the presence of hypertension increases the likelihood of having an abnormal penile blood flow 1.78 times. In addition, men with ED with hypertension exhibited a significantly reduced PSV and increased EDV compared to men without vascular risk factors. Furthermore, the rates of AI and VOD were significantly higher in hypertensive men compared to controls while a nonvascular state was found in only 16% of these patients. Similar to hypertension, recent studies have documented an association between dyslipidemia and increased ED prevalence and severity.15,16 The effect of hyperlipidemia on erectile function has been partially attributed to atherosclerosis in the hypogastric-cavernous arterial vascular bed, which results in decreased penile blood flow. Additionally, impairment of endothelium dependent relaxation in various vascular beds of men with hypercholesterolemia has been well established.17,18 Our study further defines the relationship between dyslipidemia and impaired penile blood flow. Patients with ED with hyperlipidemia exhibited significantly lower PSV and higher EDV compared to controls, and were associated with a significantly higher rate of AI and VOD and a lower rate of nonvascular causes. These hemodynamic data suggest that hyperlipidemia as a sole vascular risk factor is associated with an increased rate of abnormal penile blood flow parameters in men with ED. The presence of 2 or more vascular risk factors is associated with a higher odds ratio of having an abnormal cavernous blood flow, except the presence of established coronary artery disease. Additional risk factors appear to have a synergistic rather than an additive effect on the odds ratio for abnormal cavernous blood flow. This association underscores the importance of minimizing risk factors when possible.
vasculature. Coronary artery disease as an associated vascular risk factor in men with ED contributes significantly to poor cavernous blood flow. Other vascular risk factors such as diabetes, dyslipidemia, hypertension and smoking are associated with impaired penile blood flow in men with ED as assessed by PDDU compared to those with no risk factors. Moreover, the number of vascular risk factors correlates with an increased likelihood of having abnormal penile vascular parameters.
Abbreviations and Acronyms AI CAD ED EDV IIEF
⫽ ⫽ ⫽ ⫽ ⫽
PDDU PSV RI VOD VRF
⫽ ⫽ ⫽ ⫽ ⫽
arterial insufficiency coronary artery disease erectile dysfunction end-diastolic velocity International Index of Erectile Dysfunction penile duplex Doppler ultrasound peak systolic velocity resistive index venoocclusive dysfunction vascular risk factor
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This study demonstrates that vascular risk factors are associated with abnormalities in the hemodynamics of penile
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EDITORIAL COMMENT Penile erection is a vascular event under neural control, and is determined by the balance between arterial inflow and venous outflow. Therefore, vascular arterial abnormalities will affect erectile function and vasculogenic ED.1 Endothe-
lial dysfunction is the fundamental problem, and as the endothelium is the same throughout the arterial tree ED and CAD often coexist although the CAD may be silent.2 The sharing of risk factors between ED and CAD, while not surprising given the endothelial common denominator, has led to the concept of ED in the absence of cardiac symptoms being a target for aggressive risk reduction to reduce the chances of a subsequent symptomatic cardiac event.3 In this retrospective study of 1,216 men with ED, even allowing for changing risk definitions during 15 years, the link between CAD and penile vascular hemodynamic abnormalities is clearly documented. With increasing risk factors abnormal cavernosal flow increases (as does the risk of CAD), cementing the penile/ED/CAD link and the need for risk reduction intervention. Graham Jackson Department of Cardiology Guy’s & St Thomas’ NHS Foundation Trust London, United Kingdom 1.
Sullivan ME, Keoghane SR and Miller MAW: Vascular risk factors and erectile dysfunction. BJU Int 2001; 87: 838. 2. Solomon H, Man JW and Jackson G: Erectile dysfunction and the cardiovascular patient: endothelial dysfunction is the common denominator. Heart 2003; 89: 251. 3. Jackson G, Rosen RC, Kloner RA and Kostis JB: The second Princeton consensus on sexual dysfunction and cardiac risk: new guidelines for sexual medicine. J Sex Med 2006; 3: 28.