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European Heart Journal Advance Access originally published online on October 20, 2006
European Heart Journal 2006 27(22):2640-2648; doi:10.1093/eurheartj/ehl341
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Unfavourable endothelial and inflammatory state in erectile dysfunction patients with or without coronary artery disease

Charalambos Vlachopoulos*, Konstantinos Aznaouridis, Nikolaos Ioakeimidis, Konstantinos Rokkas, Carmen Vasiliadou, Nikolaos Alexopoulos, Elli Stefanadi, Athanasios Askitis and Christodoulos Stefanadis

Cardiovascular Diseases and Sexual Health Unit, 1st Department of Cardiology, Athens Medical School, Hippokration Hospital, Kerassoundos 17, Athens 11528, Greece

Received 16 April 2006; revised 3 October 2006; accepted 5 October 2006; online publish-ahead-of-print 20 October 2006.

* Corresponding author. Tel: +30 697 2272727; fax: +30 210 7485039. E-mail address: cvlachop{at}otenet.gr


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 
Aims Erectile dysfunction (ED) confers an independent cardiovascular risk. We investigated the role of low-grade inflammation and endothelial dysfunction in ED patients with or without coronary artery disease (CAD).

Methods and results We evaluated 141 men (age 58.8 years) for ED and CAD through a rigourous investigation (including coronary angiography to reveal occult CAD). Blood levels of inflammatory (hsCRP, IL-6, IL-1ß, and TNF-{alpha}) and endothelial-prothrombotic markers/mediators (vWF, tPA, PAI-1, and fibrinogen) were significantly increased in ED patients and correlated negatively with sexual performance. ED was associated with higher levels of these substances (except for IL-6) on top of CAD alone. For most substances, the unfavourable impact of ED alone was not significantly different than the impact of CAD alone. In multivariable models, these markers/mediators predicted independently ED presence. In our population, the negative predictive value of the combination of fibrinogen <225 mg/dL with IL-6 <1.24 pg/mL for excluding ED was 91.7% (95% CI: 61.5–99.8).

Conclusion ED is associated with increased inflammatory and endothelial-prothrombotic activation in men with or without CAD. ED confers an incremental unfavourable impact on the circulating levels of these markers/mediators when combined with CAD. These findings have implications for increased cardiovascular risk in ED patients.

Key Words: Coagulation • Coronary artery disease • Endothelial dysfunction • Erectile dysfunction • Inflammation


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 References
 
Erectile dysfunction (ED) is a highly prevalent disorder that affects to a varying severity almost 50% of men aged 40–70 years.1,2 Recent studies3 show that ED is independently related to increased cardiovascular events. ED and coronary artery disease (CAD) are closely related by sharing common risk factors1,4 and having endothelial dysfunction as a common denominator in their pathophysiology.5–7 At the clinical level, ED is common in patients with subclinical or symptomatic CAD8–12 and, conversely, recent studies suggest that ED may occur before either a chronic disease presentation or an acute coronary event.3,8,13–15

Inflammation may promote endothelial dysfunction16–18 and is a cardiovascular risk factor.19–22 Furthermore, altered prothrombotic state is associated with increased risk of cardiovascular events.23,24 The aim of this study was to assess the association between endothelial dysfunction, altered prothrombotic state and low-grade inflammation and ED in patients with and without CAD. For this purpose, a wide range of inflammatory [high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumour necrosis factor-{alpha} (TNF-{alpha})], and endothelial-prothrombotic [fibrinogen, von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1), and tissue type plasminogen activator (tPA)] markers/mediators were comprehensively evaluated in such patients.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 References
 
Study population
From January 2004 to June 2006, we enrolled consecutive patients with known CAD who were referred to the Cardiovascular Diseases and Sexual Health Unit of our Department for evaluation of ED, or consecutive patients presenting with ED symptoms of recent onset without known CAD. These latter patients were evaluated comprehensively with non-invasive tests (exercise stress test and stress echocardiography) and coronary angiography to reveal occult CAD.15 Control subjects (no ED, no CAD) were recruited from a large cohort followed in our department for arterial function studies and they were matched for age and risk factors with the other subgroups. In the control group, CAD was excluded with medical history, examination, and a negative exercise treadmill test. Initially, 158 men were assessed for inclusion in the study. The flow of participants in the study is shown schematically in Figure 1. Finally, 141 men (mean age 58.8) were analysed. CAD was documented with coronary arteriography in all CAD patients.


Figure 3411
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  		Figure 1 Flow chart of study participants. EST, exercise stress test.

 
These patients were classified into four subgroups according to the presence or absence of ED and CAD: (1) no-ED/no-CAD (n=32), (2) ED/no-CAD (n=46), (3) no-ED/CAD (n=25), and (4) ED/CAD (n=38) (Table 1). Cardiovascular drugs were not discontinued prior to the study. The study complies with the Declaration of Helsinki, the protocol was approved by our Institutional Research Ethics Committee, and all subjects gave written informed consent.


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  		Table 1 Clinical characteristics of the study subjects according to the presence of ED and CAD

 
Evaluation of ED
ED of vasculogenic origin was diagnosed according to comprehensive medical and sexual history, score of the five-item form of the International Index of Erectile Function, the Sexual Health Inventory for Men (SHIM score <21 indicates ED),25,26 hormonal testing (total testosterone and prolactin), and penile Doppler ultrasonography. Doppler studies were performed using 20 mg intracavernous prostaglandin E1 and audiovisual stimulation.15 Vasculogenic ED was diagnosed when the peak systolic velocity (PSV) was less than 35 cm/s, and/or when the end-diastolic velocity (EDV) was greater than 5 cm/s. Through these evaluations, patients were excluded if their ED was secondary to hormonal, psychological, neurological, or anatomic abnormalities, pelvic surgery, or trauma.

Measurement of inflammatory and endothelial-prothrombotic markers
Immediately after acquisition of venous blood (between 08:00–09:00 a.m. after an overnight fast), plasma or serum were separated by centrifugation (3000g at 4°C for 15 min), then placed in aliquots and stored at –70°C for the measurement of inflammatory and endothelial-prothrombotic markers. hsCRP and fibrinogen were measured by immunonephelometry (Dade Behring, Marburg, Germany). High-sensitivity IL-1ß and TNF-{alpha} (R&D Systems, Minneapolis, MN, USA) and high-sensitivity IL-6 (BioSource, Camarillo, CA, USA) were measured using ELISA. PAI-1, vWF, and tPA were also measured with ELISA (Asserachrom, Diagnostica Stago, Asnieres, France).

Statistical analysis
Sample size calculation was based on the hypothesis that ED would be associated with an increase in the level of each inflammatory or endothelial-prothrombotic marker/mediator of at least 0.6 of 1 SD. Therefore, we estimated that a minimum of 45 subjects per group (90 in total) would provide 80% power at the 5% level of significance to detect such a difference between groups with and without ED. However, to provide better confidence, we recruited much more subjects.

Continuous variables are expressed as mean value±SD. Normality was tested using the Kolmogorov–Smirnov criterion. Logarithmic transformation was performed for skewed distributions before any parametric analysis. Skewed variables are expressed as median value (interquartile range).

The main comparisons were done between men with ED vs. those without ED within the CAD and no-CAD subgroups. For numerical clinical parameters and for the endothelial-prothrombotic and inflammatory variables of interest, two-way ANOVA was used to analyse the effect of ED and CAD (independent factors) on each variable (dependent factor). We focused on the following two null hypotheses in this procedure: (1) ED does not influence the level of the variable and (2) the effect of ED on the level of each variable does not depend on CAD (i.e. there is no interaction of ED and CAD). The association of ED with binary clinical variables was assessed with logistic regression analysis, with ED and CAD as the independent variables. Correlations between SHIM score and continuous variables were evaluated by calculation of the Spearman's correlation coefficient.

Multivariable logistic regression analysis was used to estimate the adjusted odds ratio (OR) for ED (dependent variable) according to levels of each inflammatory or endothelial-prothrombotic biochemical parameter (independent variable). Considering that such models require a minimum of 10 patients for each independent variable and for each modality of the dependent variable (no ED and ED), our sample size (84 patients with ED and 57 patients without ED) was sufficient for including five or six independent variables in each model. Among the clinical variables that correlated with ED with P<0.15 in univariate analysis, we observed collinearity of total cholesterol with LDL-cholesterol (r=0.87) and of systolic BP with pulse pressure (r=0.86). Thus, the independent variables of each of these models comprised age, systolic pressure, total cholesterol, and glucose because of statistical correlation, and body-mass index because of biological relevance, plus one inflammatory or prothrombotic factor. The overall significance of these models was evaluated with likelihood ratio tests. As assessed with Hosmer and Lemeshow's goodness of fit tests, the estimates generated by these models fitted the data adequately.

Receiver-operator characteristics (ROC) analysis was used to assess the diagnostic performance of the endothelial-prothrombotic and inflammatory variables to predict presence of ED over the entire range of their values. The area under the ROC curve (AUC) was used as an estimate of global performance, considering that an AUC of 0.5 indicates no ability to discriminate ED. The efficacy of a variable as a test to diagnose ED was assessed with estimation of sensitivity, specificity, positive, and negative predictive value and their corresponding 95% confidence intervals (CI) according to two cut-off values: (1) the value that maximizes sensitivity and specificity, corresponding to the point of ROC curve that is closest to the left upper angle and (2) the value that corresponds to a sensitivity of about 95%, thus allowing only a 5% of false negative results; this high sensitivity would evaluate the ability of the examined biochemical variables to ‘rule out’ ED (see Discussion for rationale). The 95% CIs were calculated from the binomial distribution.

All tests were two-tailed and exact P-values <0.05 were considered statistically significant. Data analysis was performed with SPSS software, version 10.1 (Chicago, IL, USA) and MedCalc software (Mariakerke, Belgium).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 References
 
Subject characteristics
Clinical characteristics of the study population according to the presence of ED within the CAD subgroups are shown in Table 1. Overall, two-way ANOVA accounting for ED and CAD showed that the 84 patients with ED were marginally older (59.9±9.4 vs. 57.1±8.3 years, P=0.07) and they had higher systolic BP (135±16 vs. 129±14 mmHg, P=0.01), pulse pressure (54±13 vs. 48±10 mmHg, P=0.01), total cholesterol (213±38 vs. 195±37 mg/dL, P=0.004), and LDL cholesterol (139±32 vs. 124±36 mg/dL, P=0.004) compared with the 57 subjects without ED. In logistic regression accounting for ED and CAD, we observed no differences between men with ED and men without ED in the frequency of use of drugs that might affect erectile function, such as ß-blockers (33 vs. 30%, P=0.71) or diuretics (17 vs. 9%, P=0.20), or use of drugs with potential effects on the level of endothelial prothrombotic or inflammatory markers/mediators, such as angiotensin converting enzyme inhibitors (31 vs. 23%, P=0.32), angiotensin II receptor type-1 blockers (10 vs. 11%, P=0.83), statins (33 vs. 41%, P=0.29), or antiplatelet agents (38 vs. 43%, P=0.47). The extent of CAD as expressed by the number of the diseased coronary arteries was not different in men with ED compared with men with normal erectile function within the CAD subgroup.

Association of endothelial-prothrombotic and inflammatory markers/mediators with ED and CAD
In the whole study population, SHIM score was inversely associated with age (r=–0.27, P=0.001), systolic BP (r=–0.29, P=0.001), pulse pressure (r=–0.27, P=0.001), total cholesterol (r=–0.15, P=0.07), triglycerides (r=–0.16, P=0.06), and inflammatory and endothelial-prothrombotic markers/mediators (Figure 2).


Figure 3412
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  		Figure 2 Spearman's correlations of biochemical markers of inflammation (top 4 panels) and endothelial function-prothrombotic state (bottom 4 panels) with sexual performance as assessed by the SHIM score in the whole study population.

 
The main effects of ED and the ED–CAD interaction on the level of the endothelial-prothrombotic and inflammatory variables were analysed with two-way ANOVA tests that included ED and CAD as the independent factors and each biochemical parameter as the dependent factor. In these models, ED was associated with increased levels of all examined endothelial-prothrombotic and inflammatory variables (Figure 3). Additionally, except for IL-6, no interaction of ED and CAD was observed on the levels of any variable, thus implying that the effect of ED on these substances does not depend on the presence or absence of CAD (Figure 3). Regarding IL-6, a significant interaction of ED and CAD appeared (P=0.025, Figure 3), since ED was related to higher IL-6 level in patients without CAD (P<0.001) but not in subjects with CAD (P=0.6).


Figure 3413
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  		Figure 3 Box-and-whisker plots of levels of inflammatory and endothelial-prothrombotic markers/mediators according to ED and CAD. The centreline of the box denotes the median value; the extremes of the box, the interquartile range; and the bars, the upper and lower limits of 95% of the data. The circles represent outlying data (between 1.5 times the interquartile range and 3.0 times the interquartile range beyond the 25th or 75th percentile) and the asterisks extreme values (more than 3.0 times the interquartile range beyond the 25th or 75th percentile). Probability values for ED, CAD, and EDxCAD interaction by two-way analysis of variance tests, including ED and CAD as independent variables and each biochemical marker as dependent variable.

 
ED-only vs. CAD-only patients
Interestingly, when patients with ED only (ED/no-CAD) were compared with patients with CAD only (no-ED/CAD), no significant differences were found in hsCRP, IL-1ß, TNF-{alpha}, vWF, fibrinogen, and t-PA (Figure 3, P-values by unpaired t-test were 0.27, 0.24, 0.69, 0.20, 0.28, and 0.85 respectively). Men with CAD alone had mildly increased IL-6 levels (P=0.046) and decreased PAI-1 level (P=0.019) compared with men with ED alone.

In multivariable logistic regression models adjusting for age, systolic BP, total cholesterol, glucose, and body-mass index, all endothelial prothrombotic and inflammatory variables remained independent predictors for presence of ED. Adjusted ORs for ED according to the levels of the examined variables are shown in Table 2.


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  		Table 2 Adjusted (multivariable) OR and 95% CI for ED according to the levels of inflammatory and endothelial-prothrombotic parameters

 
Diagnostic performance of endothelial-prothrombotic and inflammatory markers for ED prediction
Overall test accuracy
Table 3 shows the AUCs and 95% CIs of the ROC curves for the examined endothelial-prothrombotic and inflammatory markers/mediators for prediction of ED presence. The AUCs for all the inflammatory variables (hsCRP, IL-1ß, IL-6, and TNF-{alpha}) and t-PA were less than 0.7. On the other hand, fibrinogen was associated with a fair to good performance (AUC 0.79).


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  		Table 3 Diagnostic performance of endothelial-prothrombotic and inflammatory parameters: AUCs and 95% CI for identifying ED in the study population

 
Discrimination limits for identifying ED
When cut-off limits that maximized the sum of sensitivity and specificity were used, fibrinogen had the best diagnostic performance for ED among all the markers. In particular, a fibrinogen level of 273 mg/dL (95% CI: 269–281 mg/dL) was associated with a sensitivity of 72.6% (95% CI: 61.8–81.8), and a specificity of 71.9% (58.5%–83.0%). Given the prevalence of ED in our population, this cut-off corresponded to a positive predictive value of 79.2% (68.5–87.6). However, the negative predictive value was only 64.1% (51.1–75.7) for this fibrinogen value, and notably, regarding the rest of the inflammatory and endothelial substances, the rates of false-negative results were even higher when such cut-off values were used.

When values corresponding to a sensitivity of ~95% were used as cut-off limits, the false-negative results decreased (negative predictive value was increased), but with the trade-off of low specificities and low positive predictive values. Fibrinogen had again the highest ability to ‘rule out’ ED compared with the rest of the markers. Figure 4 shows that a cut-off of 225 mg/dL (95% CI: 213–237 mg/dL) for fibrinogen and of 1.24 pg/mL (95% CI: 1.02–1.46 pg/mL) for IL-6 were associated with a negative predictive value (ability to ‘rule out’ ED) of 85.2% (66.3–95.8) and 81.0% (58.1–94.6), respectively. When these two cut-off limits were combined, the negative predictive value was 91.7% (61.5–99.8), meaning that subjects who had fibrinogen<225 mg/dL and IL-6 <1.24 pg/mL had a 0.917 probability of being free of ED.


Figure 3414
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  		Figure 4 Charts showing the diagnostic performance of fibrinogen and IL-6 for ED at cut-off values associated with 95% sensitivity.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 References
 
Our study is the first to evaluate the association between low-grade inflammation and altered endothelial-prothrombotic state on one side and ED on the other, in patients with and without CAD through a thorough approach that integrates a wide spectrum of circulating markers and mediators. According to our findings, the level of these inflammatory and endothelial-prothrombotic parameters is inversely associated with erectile performance. Moreover, ED is related to increased circulating levels of such variables, both in patients with or without CAD. This implies that the combination of ED and CAD is associated with higher levels of such markers (except for IL-6) on top of CAD alone. Notably, for most markers, we did not observe significant differences on these variables between men with ED alone and men with CAD alone. Finally, low levels of IL-6 and fibrinogen may satisfactorily exclude the presence of ED in patients with CAD or with an unfavourable risk factor profile. These findings elucidate pathophysiological links and have important clinical implications.

Endothelium, inflammation, and ED: pathophysiological considerations
The increased markers/mediators of endothelial damage found in our study underscore the involvement of endothelial dysfunction in the pathogenesis of ED, which also comprises a pathophysiological link between this entity and cardiovascular disorders.5,7,12 Our study corroborates recent findings that endothelial dysfunction in ED is a systemic arterial defect not confined to the penile vasculature,5,27 and offers a humoural basis for this association. Furthermore, some of these variables may have a direct involvement in inducing endothelial dysfunction in the penile vasculature beyond their role as markers of ED. For example, fibrinogen may migrate into the arterial intima and form fibrin and microthrombi, which in turn activate the inflammatory cascade and impair endothelial function.24

We17 and others18 have shown that inflammatory stimuli may acutely impair arterial function. Furthermore, on a chronic basis, inflammatory markers are strongly related to endothelial dysfunction.16,22 Accordingly, our results provide a pathophysiological link between inflammation, altered endothelial function, and ED, although the nature of our study does not substantiate a causal relationship. Our findings are in line with previous sporadic reports showing increased inflammatory and endothelial dysfunction substances in men with ED and vascular risk factors but without clinical evidence of CAD.27–32

In the present study, concentrations of endothelial procoagulant and inflammatory variables correlated inversely with the level of sexual performance in subjects with or without ED. Our findings are in line with previous reports showing that the severity of ED is associated with endothelium-dependent vasoreactivity,27 activation of subclinical inflammation,30 and carotid intima–media thickness.33 These data further evidence the mechanistic involvement of endothelial dysfunction and inflammation in the ED phenotype.

Prognostic implications of ED in patients with or without CAD
Our study has important clinical implications. ED is a health disorder with a significant impact not only because it affects a large part of the male population, but also because it appears to carry an independent risk for cardiovascular events. Indeed, a recent large epidemiological study has shown that ED is independently related to increased cardiovascular events in the long-term.3 Given that inflammatory and endothelial-prothrombotic biochemical variables are predictive of future cardiovascular outcomes in the general population,21–24,34–36 the present study supports the hypothesis that increased levels of such variables in subjects free of overt cardiovascular disease may be associated with the independently increased risk of cardiovascular events attributed to ED. Particular strengths of our study are that, first, we elaborated a broad profile of markers and mediators targeting different stages of the inflammatory and thrombotic cascades, and, secondly, we classified our sub-populations strictly by meticulously seeking for occult CAD in asymptomatic subjects both in the normal population and within patients with ED. The latter is particularly important since we have recently shown that almost 1 out of 5 patients without known atherosclerotic disease who present with vasculogenic ED may have occult CAD documented by coronary arteriography.15

Our study has two important key findings regarding the association between ED and CAD. First, this study is the first to show that ED is accompanied by an incremental endothelial-prothrombotic and inflammatory activation (higher levels of all markers except IL-6) on top of a disorder known to damage the endothelium, such as CAD. This finding has pathophysiological and, most importantly clinical relevance, given that some of these biochemical factors have been related to cardiovascular outcomes in patients with CAD.37,38 Secondly, for most of the endothelial-prothrombotic and inflammatory substances, we did not observe significant differences in men with ED alone compared with men with CAD but normal erectile function. Although this finding does not substantiate equivalence between ED and CAD in terms of endothelial or inflammatory activation, it indicates that ED may comprise an alternative phenotype in patients with generalized vascular disease and provides further pathophysiological insights into the independent value of ED as a marker and prognosticator of cardiovascular disease.3,12–15

According to ‘artery-size hypothesis’ of Montorsi et al.,6 since penile arteries have smaller diameter compared with coronary arteries, luminary obstruction may lead to the development of ED prior to the development of flow-limiting coronary lesions. However, given the important role of inflammation for the rupture of unstable (and not necessarily obstructive) plaques,19,20,22 our findings suggest that the lack of obstructive coronary atherosclerotic lesions does not preclude an increased risk of acute coronary events in patients with ED and no clinical evidence of CAD.

The diagnosis of vasculogenic ED is clinically relevant, because (1) ED is a marker of additional risk, (2) nowadays treatment with phosphodiesterase-5 inhibitors is effective, safe, and relatively inexpensive, and, importantly, (3) such a treatment may be associated with beneficial effects on the overall cardiovascular performance.39–42 In our population, simple biochemical substances such as fibrinogen or IL-6 had a satisfactory negative predictive value for ED (few false negative results), and perhaps they may comprise a useful tool to rule out ED in high-risk profile patients.

Specific comments
No patient had received phosphodiesterase-5 inhibitors in the last 6 months so as to avoid the confounding effect of a possible improvement in endothelial and arterial function that we and others have shown.39–42

Drugs were not discontinued prior to the study including these with potential effects on the levels of the target biochemical markers/mediators. However, there was not any difference in the use of drugs when patients with or without ED were compared.

The present study was not specifically designed to investigate the role of the examined markers/mediators as tests for ED diagnosis. The proposed cut-off values of variables, like fibrinogen, for excluding ED may be of value for other populations as well, given that the prevalence of ED in our study (59%) was not considerably higher than the almost 50% prevalence that was recently reported in a large cohort of men older than 40 years.2 However, larger studies are warranted in order to examine the performance of these cut-off values in other populations.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
References
 
ED is associated with increased circulating levels of systemic inflammatory and endothelial-prothrombotic markers/mediators in men with or without CAD. The coexistence of ED and CAD is associated with higher levels of such markers on top of CAD alone. Moreover, the inflammatory and endothelial activation observed in men with ED alone is not significantly different compared with men with CAD alone. These findings emphasize the pathophysiological involvement of inflammation and endothelial dysfunction in the pathogenesis of ED and provide a potential explanation for the increase of cardiovascular risk in such patients. Men seeking medical advice for ED may benefit from measurement of parameters such as fibrinogen or IL-6, for better disease assessment and cardiovascular risk determination. Further studies are needed to establish causal relationships and to evaluate the relative importance of each inflammatory and endothelial-prothrombotic marker and mediator on the development of ED and the risk that it confers.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 

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Is erectile dysfunction a low-grade systemic inflammatory condition?
Eur. Heart J., March 1, 2007; 28(5): 642 - 643.
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