Recently it has been reported that there is a strict correlation between erectile dysfunction (ED) and cardiovascular diseases, but the importance of such relationship still needs to be addressed. Ultrasonographic peak systolic velocity (PSV), is considered a reliable parameter for the diagnosis of arteriogenic ED. However, the cut-off value of PSV<30 cm/s has sufficient sensitivity only in the diagnosis of advanced arteriogenic ED and it is not representative of peripheral vascular alterations. In the present study, we set up an age-adjustment of PSV – calculated with the formula PSV <6.73+age × 0.7 – that permits a more accurate diagnosis of vascular aetiology in ED patients and may predict the presence of carotid wall alterations. We studied 179 consecutive subjects (mean age 52 years, range 23–79 years), with a history of ED of at least 6 months, by means of penile colour doppler ultrasonography (P-CDU) and common carotid arteries colour doppler ultrasonography (CCA-CDU) between June 2003 and September 2004. Statistical analysis was carried out with the statistical software R. PSV and CCAD values showed a statistically significant negative correlation. Age adjustment further improved this relationship permitting to identify an age-dependent PSV cut-off given by the formula PSV <6.73+age × 0.7. The age-adjusted PSV cut-off allows an accurate interpretation of vascular aetiology in ED patients and predicts the presence of carotid wall alterations, from the intima-media pathologic thickness to the plaque formation, with high values of both sensitivity and specificity.
Erectile dysfunction (ED) is a significant male health problem affecting approximately 150 million men all over the world. The incidence of ED increases sharply with age affecting 19–64% of men aged 40 to 80 years.1 Furthermore, epidemiological studies on the prevalence and incidence of ED have demonstrated a strict correlation between this condition and cardiovascular diseases.2 It is now well established that risk factors for ED including diabetes mellitus, lipid abnormalities, hypertension, cigarette smoking, are also risk factors for systemic vascular disease. Recently, it has been confirmed that a significant number of patients with an angiographic diagnosis of coronary arterial disease have ED and that in almost 70% of these patients ED may become evident prior to angina.3 Other authors observed that among patients older than 45 years with ED of probable vascular pathogenesis, in the absence of any cardiac symptomatology, 15.7% showed electrocardiographic alterations during a dynamic ergometric test4 and that among patients showing an impaired (<30 cm/s) PSV with the P-CDU, 41.9% had a silent ischaemic cardiac disease.5
The age-related increased incidence of ED and its strong correlation with vascular diseases suggest that ED is an early clinical manifestation of peripheral vascular damage. Mean intima-media thickness (m-IMT) of common carotid arteries (CCA) analysed by high resolution carotid ultrasonography correlates with brachial endothelial function,6 and is strongly associated with the risk of myocardial infarction and stroke in asymptomatic older adults.7 Therefore, an increased carotid artery m-IMT is considered an important predictive parameter of cardiovascular diseases and development of atherosclerosis.
The present study was designed to verify, in a large number of ED patients, the existence of a possible correlation between penile PSV and carotid m-IMT. We also set up a PSV stratified for patients' age, in order to detect arteriogenic ED and carotid wall alterations in ED population with high sensitivity and specificity. In fact, the proposed PSV cut-off value <30 cm/s has sufficient sensitivity only in the diagnosis of advanced arteriogenic ED, and does not correlate with peripheral vascular alterations.
Patients and methods
The study was approved by the Hospital Ethics Committee and all patients supplied an informed consent. From June 2003 to September 2004, we selected 179 consecutive subjects aged 23 to 79 years, with a history of at least 6 months of ED, defined as the consistent inability to obtain and maintain an erection for satisfactory sexual intercourse, assessed by IIEF-5 (questionnaire score <21 was considered ED).
Patients evaluation included complete medical and sexual history, physical examination, routine (glucose, HbA1c, total cholesterol, creatinin, AST, ALT) and hormonal (LH, FSH, prolactin, total testosterone, estradiol) blood analysis, penile colour doppler ultrasonography and common carotid arteries colour doppler ultrasonography (P-CDU and CCA-CDU, respectively). Patients with diagnosis of traumatic ED (pelvic or perineal trauma/surgery) or penile fibrosis (La Peyronie's disease) were excluded from the study.
CCA-CDU and P-CDU were carried out using a high-resolution colour doppler ultrasound (Esaote AU5, Genoa, Italy) equipped with a linear 7.5 MHz probe (axial resolution <0.2 mm). CCA were studied with a longitudinal scansion at 20 mm from the bulbar dilation and image recording was carried out at the end of diastole. For each carotid three measurements of IMT (defined as the distance between the vessel lumen and the adventitia margin) were performed and the mean value of measurements carried out was considered as the m-IMT.8 Common carotid artery diseases (CCAD) were divided into five stages, from 0 to 4. CCAD equal to 0 corresponds to the absence of carotid alterations, whereas CCAD values between 1 and 4 denote increasing carotid wall alterations (Table 1). We are mainly interested in the classification of patients according to the presence/absence of carotid wall damage (from thickness to plaque). For this reason, we defined ‘carotid wall alteration’ CCAD>1 and, conversely, ‘absence of carotid wall alteration’ CCAD=0.
P-CDU was performed after an intracavernous injection of alprostadil 10 μg. Evaluation of intracavernous blood flow was assessed at the level of the peno-scrotal junction in the following 20 min and the peak systolic velocity (PSV) parameter was measured. A new dose of alprostadil 10 μg was injected in combination with 1 mg of phentolamine if the erection obtained by patients was not comparable to the one present during sexual activity at home.9
All ultrasound examinations were performed in a blinded fashion by the same doctor, expert in vascular diagnostics.
The results are given as mean+s.d. P-values of <0.05 and <0.01 were regarded as significant and highly significant, respectively. Statistical discriminant analysis, in which variables PSV and age are used to classify patients into different degrees of carotid thickness, was performed by means of the logistic regression model.10 The analysis was carried out with the statistical software R.
The mean age of the 179 patients was 52+12 years (range 23–79 years). Overall, 24 patients out of 179 (13.4%) had decreased PSV, if we considered a PSV value <30 cm/s to be abnormal, and 90 (50.8%) had different degrees of CCAD. PSV and CCAD values showed a statistically significant negative correlation (Figure 1) with a correlation coefficient of r=−0.65 (P<0.001). These data show that the proposed PSV cut-off of 30 cm/s does not correlate with carotid wall damage.
Therefore, a statistical discriminant analysis was performed in order to investigate which PSV values might correlate with carotid wall damage. The optimal PSV cut-off that strongly correlates with the presence of m-IMT pathologic thickness, (i.e. CCAD>1) resulted in PSV<47 cm/s (sensitivity=0.81, specificity=0.87) with a highly significant (P<0.001) regression coefficient (Figure 2). We then analysed the contribution of the other risk factors in the correlation between PSV and CCAD. The regression coefficient of aging was the only one significantly different from zero: the graphic represented in Figure 3 shows that CCAD is related to age with a correlation coefficient of r=0.45 (P<0.001).
Therefore, a logistic regression with ‘age’ and ‘PSV’ as explanatory variable and ‘presence/absence of carotid thickness or plaque’ as response variable was performed. All the regression coefficients were highly significant with P<0.001. Such a logistic regression was then used to derive the linear classification rule set in Figure 4 (PSV<6.73+0.7 × age) which constitutes a cut-off that detects both arteriogenic ED and carotid wall alterations with very high values of sensitivity (0.88) and specificity(0.89) (Figure 5). Some examples of this stratification are given in Table 2.
Recent literature suggests a possible role of PSV, assessed by P-CDU, in predicting patients at risk for cardiovascular diseases or peripheral vascular damage.5 Furthermore, ultrasonographic evaluation of CCA IMT is a good marker of generalized atherosclerosis, increased cardiovascular risk and does correlate with endothelial function assessed by flow-mediated dilation of the brachial artery.6, 7, 8 Anyway, the association between carotid and penile vascular ultrasonographic alterations is not yet well defined, as well as PSV cut-off values are still debatable.
In the present study, 50.8% of patients with ED had different degrees of carotid wall damage. However, with the proposed PSV cut-off value <30 cm/s, only 13.4% of these men were identified, suggesting that other PSV cut-off values could be more appropriate. In fact, PSV and CCAD were inversely related (Figures 1 and 4) and the analysis of our data allowed us to find a more predictive cut-off (PSV<47 cm/s) in order to detect both arteriogenic ED and the presence of early carotid wall alterations with high values of sensitivity and specificity (0.81 and 0.87, respectively). PSV cut-off value of 30 cm/s is based on 10 year-old studies11 that compared PSV with selective arteriography, thus detecting only overt stenosis of cavernous arteries.
However, in the last years, growing evidence showed that the pathogenesis of arteriogenic ED begins with endothelial dysfunction, which occurs much before overt stenosis of arteries. In this way, an appropriate PSV cut-off may light up an early alteration of both cavernous flow and carotid artery wall.
According to recent literature loss of smooth muscle cells for increased apoptosis and concomitant increase of deposition of collagen fibres in the arterial media, are thought to lead to arterial stiffness and, later, to atherosclerosis in arteries with normal or slightly increased IMT in aged rats.12 For this reason we included in the analysis the variable ‘age’ that was found to be directly related to the presence of CCAD (Figure 3) and ED. This analysis showed that age influenced significantly the PSV cut-off values. Therefore, the best predictive cut-off value of PSV, in order to state an arteriogenic aetiology of ED and to detect carotid atherosclerotic lesions, was derived by the following formula: PSV<6.73+0.7 × age. According to this formula, the predictive power of PSV increases to very high sensitivity and specificity (0.88 and 0.89, respectively). A possible explanation for the effectiveness of this formula is that, with the age-related intrinsic modifications of arteries and cavernous structures, higher penile flow values are required in the elderly in comparison to the young to obtain a valid erection. Considering that ED occurs much more frequently with aging, the formula-derived PSV cut-off may help physicians to better interpret PSV values according to patient's age, and to investigate the carotid health of these patients when appropriate (i.e. when formula-derived PSV values are low).
In conclusion, age-adjusted PSV cut-off permits to recognize, at a very early stage, an arteriogenic pathogenesis of ED and detects carotid wall alterations in the ED population with high sensitivity and specificity.
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Caretta, N., Palego, P., Roverato, A. et al. Age-matched cavernous peak systolic velocity: a highly sensitive parameter in the diagnosis of arteriogenic erectile dysfunction. Int J Impot Res 18, 306–310 (2006). https://doi.org/10.1038/sj.ijir.3901413
- erectile dysfunction
- peak systolic velocity
- carotid thickness