The evidence of a close relationship between cardiovascular disease and erectile dysfunction (ED) is well documented. The aim of this study is to investigate whether there is an early asymptomatic impairment of the peripheral vasculature in young ED patients without obvious cardiovascular disease. We studied a total of 261 ED patients (19–40 years old) and 40 age-matched healthy controls. All participants received questionnaires of cardiovascular risk factors and erectile function assessment, were subjected to lab tests of fasting blood sample, and underwent the ultrasonographic examination of brachial artery flow-mediated dilation (FMD) and carotid intima-media thickness (c-IMT). Insulin resistance (IR) was measured by the homeostasis model assessment of insulin resistance (HOMA-IR). Compared with normal human controls, FMD was significantly lower, whereas the average c-IMT was significantly greater in ED patients. An inverse correlation was found between FMD and mean c-IMT. The ED patients had significantly higher levels of fasting glucose, fasting insulin and HOMA-IR index, but showed relatively lower total testosterone and prolactin levels than the controls. Both FMD and c-IMT showed a significant correlation with International Index of Erectile Function-5 questionnaire (IIEF-5) score, age and HOMA-IR. Multivariate stepwise regression analysis demonstrated that age, HOMA-IR and IIEF-5 score were the risk factors associated with FMD and c-IMT. In conclusion, young ED patients in association with IR display diminished FMD and increased c-IMT. Furthermore, ED, HOMA-IR and age are independent predictors of the two subclinical atherosclerotic markers.
Erectile dysfunction (ED) is defined as the persistent inability to achieve and maintain a sufficient erection to complete intercourse.1 Although the prevalence of ED increases with age, a recent study in Italy showed that 25% new patients are younger than 40 years.2 Cardiovascular disease (CVD) is the worldwide leading cause of death, which is often asymptomatic at early stage, leading to a delay in the diagnosis and treatment. It was reported that more than half of all sudden coronary heart disease deaths occur in patients without prior diagnosis.3 Thus, early detection of subclinical changes, before the serious clinical symptoms arise, is important because it allows early intervention for the high-risk population.
Recently, a close association between ED and CVD has been highlighted in middle-aged and elderly men. ED and CVD are claimed in some studies to share identical pathogenesis of an NO-dependent endothelial and smooth muscle dysfunction caused by their uniform risk factors.4, 5 Both cardiovascular disease and cardiovascular risk factors are more common in patients with ED.6, 7 And the association between the severity of ED and the angiographic extent of coronary atherosclerosis further strengthens the link of ED and CVD.8 Moreover, some clinical studies demonstrated that the appearance of ED showed a couple of years earlier than the coronary artery disease.8, 9 Miner et al.10 believed that identification and characterization of ED may be clinically useful for assessing and managing cardiovascular risk. According to the ‘artery size hypothesis’, when penile arteries are impaired and patients present with ED, other larger vessels may already have entered the subclinical stage.11
Currently, flow-mediated dilation (FMD) of the brachial artery and carotid intima-media thickness (c-IMT), measured by the ultrasonographic technique, are the two valid surrogates in assessing subclinical atherosclerosis. Decreased FMD and increased c-IMT represent functional and morphological markers of generalized subclinical atherosclerosis, respectively. Some studies have assessed subclinical atherosclerosis by FMD and c-IMT in ED patients, but all of them focused on middle-aged and elderly individuals with overt cardiovascular disease and the sample sizes were small.12, 13, 14 Besides, some studies analyzed the effect of phosphodiesterase-5 inhibitor (PDE5i) treatment on ED according to degrees of subclinical atherosclerosis. Javaroni et al.15 found that PDE5i effectiveness positively correlated with brachial FMD. Caretta et al.16 demonstrated that after a PDE5i treatment in alternative days, erectile function improved only in patients with c-IMT less than 1.3 mm.16 Nonetheless, to our knowledge, there is no published evidence regarding the subclinical atherosclerosis and related risk factors in young ED patients without clinical atherosclerosis.
Therefore, this study aimed to assess early functional and structural changes of the vascular system by measuring FMD and c-IMT, and then to explore possible associations between these two surrogates of subclinical atherosclerosis and the underlying risk for developing early atherosclerosis in young ED patients.
Materials and methods
Written informed consents were obtained prior to data collection and the study was approved by The Ethics Committee of the First Affiliated Hospital of Sun Yat-Sen University, and informed consent was obtained. The study was conducted in accordance with the Declaration of Helsinki to protect the personal data. Each participant was assigned a number for keeping his privacy.
A total of 261 male ED patients were recruited from the andrology outpatient section of our hospital from October 2012 to July 2013. The ED was defined by a score of <22 in the International Index of Erectile Function-5 questionnaire (IIEF-5).17 Forty age-matched healthy subjects were recruited from the medical center in accordance with the inclusion and exclusion criteria. The general information including demography, medical history and smoking habit were collected via a validated questionnaire by fully trained interviewers. Anxiety and depression were assessed using the validated Hospital Anxiety and Depression Scale. All subjects underwent a complete physical examination including height, weight and blood pressure measurements according to a standard protocol. Body mass index (BMI) was calculated by the following formula:18 BMI=weight (kg)/height2 (m2). The homeostasis model was used to assess insulin resistance (HOMA-IR) according to the following formula:19 HOMA-IR= (fasting insulin (μU ml−1) × fasting glucose (mmol l−1))/22.5.
The inclusion criteria consisted of individuals with age between 18 and 40 years and having a stable marital relationship, complaining of ED of at least 6 months in the absence of any questionable/clinical symptom of cardiovascular disease (chest tightness, chest pain, etc.) or a history of cardiovascular disease including ischemic heart disease (angina or myocardial infarction), heart failure or peripheral vascular disease, or cerebrovascular disease (transient ischemic attacks or strokes).
Exclusion criteria were the patients having low testosterone levels (serum total testosterone <300 ng dl−1); cardiovascular disease (established or suspected); chronic inflammatory or autoimmune diseases; sleep apnea syndrome; diabetes, hypertension, drugs usage that may affect endothelial and erectile function such as statins, vitamin E or PDE5i for the last 3 months, smoking, urogenital abnormalities, overt liver and kidney insufficiency, psychiatric disorder, or drug/alcohol abuse.
Overnight fasting blood samples were drawn from each patient between 0800 to 1000 hours. After centrifugation (3000 r.p.m. at 4 °C for 15 min), the serum samples were stored at −80 °C until analysis. Fasting glucose, fasting insulin, total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, high-sensitivity C-reactive protein, uric acid, prolactin and total testosterone levels were determined by using commercial assay kits in the Clinical Testing Center of our hospital. The laboratory technicians were blinded to the clinical characteristics of the patients.
Ultrasound measurements of FMD and c-IMT
A fully trained technician who was blinded to the inclusion group of each patient performed the assessment of the ultrasound of the brachial artery FMD and IMT of carotid arteries. In addition, penile duplex ultrasonography was conducted only in the flaccid state, without intracorporeal injection to dilate the cavernosal arteries, to evaluate the organic factors derived from anatomic abnormalities affecting penile erection, and no patient with obvious tunical thickening, septal fibrosis, cavernous fibrosis, calcified plaques or vascular malformations was found among our subjects.
FMD of brachial artery
All subjects had fasted for at least 8 h and stopped drinking coffee for at least 2 h before the ultrasound examination. After at least 15 min rest in a quiet environment, FMD was evaluated in the right brachial artery using a high-resolution ultrasound machine equipped with a high frequency and linear array ultrasound probe (5–12 MHz; VIVID7 GE, GE Healthcare, Milwaukee, WI, USA). The probe was positioned approximately 2–5 cm proximal to the elbow. Diameter and blood flow velocity of brachial artery were recorded by R-wave gating of the synchronic electrocardiogram (ECG). Baseline parameters were obtained before reactive hyperemia, and then an arterial occlusion cuff was placed around the arm and inflated above 250 mm Hg for 5 min before deflating. After cuff deflation, the greatest diameter was recorded at end diastole (tip of ECG R-wave). FMD was calculated as the percentage change in diameter before and after cuff inflation. Because the measured FMD value was decimal, the form of FMD percentage was used in the present study. It is accepted that the value of ⩾10% dilatation was normal and that of <10% dilatation was abnormal.20 Endothelial-independent dilatation of the brachial artery was not performed as part of the FMD.
IMT of carotid arteries
The c-IMT was evaluated using a high-resolution, B-mode ultrasound machine equipped with a high frequency and linear array ultrasound probe (5–12 MHz; VIVID7 GE) mainly according to previous description.21, 22 Both sides of the c-IMT were measured by longitudinal view in the common carotid artery approximately 1 cm proximal to the carotid bifurcation. The c-IMT was measured as the distance between the leading edge of the first bright line on the far wall (lumen–intima interface) and the leading edge of the second bright line (media and the adventitia). The average of the sum of the maximal IMT on both sides was defined as the mean carotid IMT. Because currently there are no standardized diagnostic criteria to define elevated c-IMT in different ethnic and age groups, and a study from Taiwan reported that the value of IMT over the cut point of 0.68 mm correlated with obviously increased risk of carotid atherosclerosis,22 we took 0.68 mm as the limit of the normal c-IMT in our subjects.
The distribution of all the variables was firstly determined using the Kolmogorov–Smirnov test. The data were presented as median (interquartile range) or as mean±s.d. according to the results of Kolmogorov–Smirnov test. Continuous variables with a normal distribution were compared using the Student's t-test and those with an asymmetric distribution by the Mann–Whitney U-test. The χ2 test was used to compare categorical variables. The raw relationship between c-IMT or FMD and specific variables was assessed using the Pearson’ correlation analysis for continuous variables and Spearman correlation was used for categorical variables. In addition, a stepwise multivariate linear regression analysis was carried out using FMD and c-IMT as the dependent variable and IIEF-5 score, age, BMI, systolic blood pressure, diastolic blood pressure, HOMA-IR, serum cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, uric acid, high-sensitivity C-reactive protein, total testosterone and prolactin as independent variables. Statistical significance was defined as two-sided P<0.05. All the data were analyzed by using the SPSS 13.0 software (version 13.0, Chicago, IL, USA).
The baseline characteristics and clinical data of the study population are shown in Table 1. The ED group had significantly higher fasting glucose (P<0.001) and fasting insulin levels (P=0.02), lower total testosterone (P=0.014) and prolactin levels (P<0.001), and greater HOMA-IR value (P<0.001) compared with controls. The two groups did not differ in terms of age, BMI, blood pressure, uric acid, serum lipid profiles and high-sensitivity C-reactive protein levels.
The FMD% was significantly reduced in the ED group compared with the control group (9.44±2.70 vs 13.00±2.89, P<0.001) (Figure 1a). According to the standard cutoff value (FMD% <10), 148 ED patients (56.7%) and 4 controls (10.0%) had abnormal FMD%. There was a significantly higher incidence of low FMD% in ED patients than in controls (OR=1.79, P<0.001) (Table 2).
The mean c-IMT value was significantly higher in the ED group than in the control group (0.66 (0.60, 0.75) vs 0.59 (0.50, 0.68) mm, P<0.001) (Figure 1b). Taking the 75th percentile (0.68 mm) of the control group as the normal c-IMT, 122 ED patients (46.7%) and 10 controls (25.0%) had abnormal mean c-IMT. ED patients had a higher incidence of abnormal c-IMT values as estimated by odds ratio (OR=2.63, P=0.010) as shown in Table 2.
The FMD% exhibited a significant positive correlation with IIEF-5 score (r=0.261, P<0.001), prolactin level (r=0.200, P<0.001) and negative correlation with age (r=−0.127, P=0.028), fasting insulin (r=−0.130, P=0.024), HOMA-IR (r=−0.211, P<0.001) and total cholesterol (r=−0.129, P=0.025). Conversely, the mean c-IMT exhibited significant positive correlation with age (r=0.283, P<0.001), BMI (r=0.227, P<0.001), HOMA-IR (r=0.242, P<0.001), fasting glucose (r=0.162, P=0.005), fasting insulin (r=0.153, P=0.008), total cholesterol (r=0.147, P=0.011), triglycerides levels (r=0.168, P=0.003), high-sensitivity C-reactive protein (r=0.183, P=0.001) and negative correlation with IIEF-5 score (r=−0.143, P=0.013), high-density lipoprotein cholesterol (r=−0.150, P=0.009), total testosterone (r=−0.186, P=0.001) and prolactin levels (r=−0.192, P=0.001) (Table 3). Furthermore, a contrary correlation was established between FMD% and mean c-IMT (r=−0.241, P<0.001) (Figure 2).
The overall effect of cardiovascular risk factors on the dependent variables FMD% and c-IMT was analyzed using a stepwise multiple linear regression model. The variables predicting FMD% in the regression model were age, HOMA-IR and IIEF-5 score, while the variables predicting c-IMT were age, HOMA-IR, IIEF-5 score and BMI. When IIEF-5 score was added to the model, it was a significant and independent predictor of both FMD% and c-IMT and the predictive ability improved. Regardless of whether IIEF-5 score was included in the model, HOMA-IR was always a significant predictor of both FMD% and c-IMT in the model. The final regression models are summarized in Tables 4 and 5.
To our knowledge, the relationship between ED and subclinical atherosclerotic markers has not been reported in young ED men. The current study finds that even young ED patients without overt clinical atherosclerosis have early subclinical atherosclerosis changes, which presented as decreased FMD and increased c-IMT. Furthermore, IIEF-5 scores, HOMA-IR and age are independent predictors of subclinical atherosclerosis, indicating that ED, insulin resistance and age are the potential risks of suffering cardiovascular disease.23, 24
Endothelial dysfunction appears to be the earliest stage of atherosclerosis.25 Brachial artery FMD is a useful surrogate reflecting endothelial function and is widely used in clinical studies. Decreased brachial FMD has been associated with increased incidence of cardiovascular events in healthy or CVD patients.26 So far, only a few studies have investigated the relationship of ED and FMD. Chiurlia et al.12 found that FMD was more impaired in diagnosed vascular ED patients. Bhatia et al.27 reported that patients with ED have impaired FMD independent of other risk factors. Kaiser et al.5 demonstrated that both endothelium-dependent and -independent vasodilatation were significantly impaired in ED patients. But most of these studies focused on the elderly with established cardiovascular disease, or the sample size was small. Although our target population was young (30.40±4.86 years), we found that FMD% was significantly decreased in the ED group and the impairment of endothelial function is more likely to occur in ED patients, as confirmed by odds ratio. Our results support the view that the presence of ED may simultaneously indicate the early functional impairment of the peripheral vasculature, which has nothing to do with age.
Carotid IMT is another useful noninvasive marker of subclinical atherosclerosis. The measurement of c-IMT provides an assessment of early structural vascular abnormalities, also known to be a strong predictor of future cardiovascular events.28 Previous studies have assessed c-IMT by ultrasound in men diagnosed with ED. Ucar et al.13 reported that c-IMT values of vasculogenic ED patients were higher than non-vasculogenic ED patients. Vlachopoulos et al.29 found that in hypertensive patients, patients with ED had higher c-IMT than those without ED. Conversely, two studies found no differences in c-IMT between ED patients and control subjects.5, 30 In our study, c-IMT was higher in young ED patients and increased c-IMT was more likely to occur in these ED patients, as confirmed by odds ratio. However, we could not find that c-IMT correlated with the severity of ED. It may be due to the fact that the c-IMT thickness is so thin that the tiny changes cannot be detected in varying degrees of ED by the current ultrasonic equipment. In addition, atherosclerosis usually occurs in the medium-sized and large arteries rather than in the microvessels. One study showed that atherosclerosis was found in only 13% of penile autopsy tissue whereas coronary and peripheral atherosclerosis was present in 87 and 77% of cases, which suggested that not necessarily systemic atherosclerosis would be associated with atherosclerosis of the penile vasculature.31 Anyway, more direct evidences are needed to clarify the relationships of ED or penile vasculature with atherosclerosis or peripheral vascular.
ED is associated with an increase in the risk of CV disease and events,7, 32 and the increase is independent of conventional cardiovascular risk factors.32 Moreover, the prognostic value of ED for cardiovascular events is greater at younger ages and in the intermediate CVD risk population.33, 34, 35 However, studies about the warning role of ED on subclinical atherosclerosis, especially in young ED patients, are few. Kaiser et al.5 have drawn the conclusion that ED in patients without clinical cardiovascular disease is independently associated with endothelial dysfunction in a study on a small sample population. In our study, ED was associated with a hazard ratio of 11.79 for endothelial dysfunction and 2.63 for increased c-IMT. In addition, multiple regression analysis confirmed IIEF-5 score is an independent predictor of both FMD% and c-IMT after adjusting other CVFs. When IIEF-5 score was included in the model, it significantly improved subclinical atherosclerosis prediction beyond traditional risk factors. Our results suggest that ED itself is a sentinel symptom for subclinical atherosclerosis even in young patients without overt clinical atherosclerosis. ED usually occurs several years in advance of clinical CVD,8, 9 and the interval of ED and the onset of subsequent CVD suggests that the latter may be preceded by a stage of subclinical CVD. So the symptoms of ED arise provide the opportunity for an early intervention to prevent the possible future CVD.
On the other side, previous studies have examined the relationship between IR and subclinical atherosclerosis. Graziana et al.36 found that HOMA-IR but not BMI is the major determinant of early vascular impairment in morbidly obese subjects. In addition, the Insulin Resistance and Atherosclerosis Study found an independent correlation between IR and the c-IMT.37 IR is considered as a pre-diabetic state and the progression of IR to diabetes parallels the progression of endothelial dysfunction to atherosclerosis.38 In the present study, HOMA-IR is significantly higher in ED patients than that in healthy controls, which to some extent reflects the value of ED to find underlying cardiovascular risk factors. In addition, HOMA-IR was independently associated with both FMD% and c-IMT in the regression model regardless of the IIEF-5 score. Combined with previous studies, it is reasonable to conclude that IR may take part in the impairment of endothelial function and vascular wall histology, being the common pathogenesis of ED and atherosclerosis. The findings are consistent with a previous study, which confirmed a direct atherosclerotic effect of IR independent of glucose control and other components of the metabolic syndrome.39 However, it is still too early to say whether the improvement of insulin sensitivity may counteract ED, although one study has reported that treatment with metformin in patients with ED and poor response to sildenafil reduced the IR and improved erectile function.40 This may be also because metformin treatment could improve erectile function by an increased eNOS phosphorylation.41
There were several limitations in the present study. First, although the significantly diminished FMD value was able to reflect the impairment of endothelial-dependent vasodilation function in young ED adults, we could not be sure whether endothelial-independent function was also impaired due to the lack of nitroglycerine-induced vasodilation measurement. Therefore, further research is needed to determine the decreased FMD primarily derived from endothelial or myogenic etiology. Second, the higher HOMA-IR value in the ED group suggested they may be in pre-diabetic state, and the results may not be generalizable. However, their fasting glucose and insulin levels were in normal reference range and all the participants in our study were recruited randomly according to the inclusion and exclusion criteria. Third, our study is limited by its cross-sectional nature, the relatively small control population (n=40) and indeterminate etiology of ED, although the findings were not equivocal, and careful matching of participants with and without ED. However, the relatively young age, good quality spontaneous erections and the strict inclusion and exclusion criteria suggested they were probably psychogenic or mixed ED. In addition, the diagnosis of men without clinical atherosclerosis lacks objective evidence and was mainly based on a careful questioning and meticulous physical examination.
In summary, the current study suggests that the complaint of ED, even at young age, patients with IR may recommend the c-IMT and/or FMD determinations, therefore acting as sentinel of subclinical vascular disease. However, whether the treatment of ED, including elimination of cardiovascular risk factors, is conductive to prevent the onset of, or arrest the development to, an overt cardiovascular disease needs further research.
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The work is supported by grants from the National Natural Science Foundation of China (Grant No. 81070488, 81270696, 81302223), Guangdong Natural Science Fund ((Grant No.S2013010015356, S2011010005282, 2015A030310083) and Science and Technology Planning Project of Guangzhou, China (Grant No. 201300000094, 2012B 031800288, 2011B032000003). The funder had no role in study design, data collection and analysis,decision to publish,or preparation of the manuscript.
The authors declare no conflict of interest.
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Chen, SF., Yao, FJ., Sun, XZ. et al. Brachial artery flow-mediated dilatation and carotid intima-media thickness in young ED patients with insulin resistance. Int J Impot Res 28, 194–199 (2016). https://doi.org/10.1038/ijir.2016.30
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