Is erectile dysfunction an early marker of sub-clinical coronary artery disease?

Author(s): Prof. Piero Montorsi, MD Institute of Cardiology, University of Milan, Centro Cardiologico Monzino, IRCCS, Milan and Dr. Th. Roumequère, Brussels

Source: European Urology Today, February 2005, p. 22-23

Erectile function is a psychoneurovascular phenomenon which ultimately culminates in an increase of arterial flow within the hypogastric-penile bed with the subsequent activation of the veno-occlusive mechanism of the corpora cavernosa. When external factors affect either arterial or venous parts of this mechanism or both, erectile dysfunction (ED) ensues. Evidence is accumulating in favour of ED as a vascular disorder in the majority of patients. Firstly, common risk factors for atherosclerosis have been frequently found in patients with ED and the extent of ED has been related to the number and severity of risk factors themselves [1,2]. Secondly, abnormal sexual function has been reported in patients with vascular diseases such as myocardial infarction [3], cerebrovascular disease [4], hypertension and peripheral arterial disease [1,5-6]. Finally, ED and vascular diseases share a similar pathogenic involvement of NOpathway leading to impairment of endothelium- dependent vasodilatation (early phase) and structural vascular abnormalities (late phase) [7,8]. If these observations hold true, ED may be considered as the clinical manifestation of a vascular disease affecting penile circulation as well as angina pectoris is the typical manifestation of a vascular disorder affecting coronary circulation.

The crucial point is: which condition (ED vs. coronary artery disease [CAD]) comes first? In other words, can we consider ED as a early marker of sub-clinical CAD? To answer this question we recently put forward a pathophysiological mechanism, named the ”artery size” hypothesis (Figure 1)[9]. Given the systemic nature of atherosclerosis, all major vascular beds should be affected to the same extent. However, symptoms at different points in the system rarely become evident at the same time in a given patient. This is likely the result of larger vessels being able to better tolerate the same amount of plaque as compared to smaller ones without inducing flow-limiting stenoses. If true, men with early stage ED will rarely have concomitant CAD. When atherosclerosis significantly affects coronary circulation, however, the penile artery will be severely damaged by the same amount of plaque. If true, men with proved CAD will frequently complain of concomitant ED. Thus, ED and CAD should be considered as two different aspects of the same disease with an expected temporal relationship (ED first than CAD) and the risk of latent CAD in ED patients should be low.

A few reports investigating the rate of latent CAD in ED patients have been published [10- 14]. The typical patient enrolled in these studies sought medical attention (i.e. urologist) because of new onset or long-standing ED, had one or more risk factors and no clinical evidence of CAD. Coronary reserve was usually tested by means of standard exercise stress testing (EST). Average prevalence of positive responses was 22.5% (range from 5 to 56%). This figure is somewhat higher than the numbers found in large studies carried out in the Eighties evaluating the rate of positive response to EST (12%) in asymptomatic middleaged men [15-20]. However, comparison between these studies may be misleading due to significant differences in patient numbers, clinical characteristics (including risk factor profile) and criteria adopted to diagnose CAD. Moreover, since no systematic analysis of sexual function was carried out in the Eighties studies, we do not know if they truly represent a normal reference population to compare with. These limitations do not allow to draw definite conclusions about the role of ED as an independent predictor of occult CAD. Thus, given the low rate of detectable CAD in ED patients, no efforts should be spared to identify those at “high risk” according to clinical variables (i.e. age, risk factor background, duration of ED) or non-invasive test (dynamic penile Doppler evaluation). Among the clinical parameters, diabetes is a well known risk factor frequently associated with both ED and CAD. Gazzaruso et al. recently reported on the relationship between ED and silent ischemia in uncomplicated type 2 diabetes [21]. They found those patients with silent ischemia (n=133) as having greater ED prevalence (33.8% vs. 4.7%, p=.000) than those without silent ischemia (n=127). The former group had higher total and LDL-cholesterol levels, microalbuminuria, and lower HDLcholesterol levels as compared to the latter. After adjusting for other confounding variables, ED appeared to be the most efficient independent predictor of silent CAD. Supporting the role of unfavourable risk factor profile as determinant for positive cardiological tests, Prizker et al (10) found 56% prevalence of positive EST response in patients with ED and “aggressive” risk factor background (>2 risk factors in 80% and diabetes in >20%). Patients submitted to coronary angiography had extensive coronary atherosclerosis (2- or 3- vessel disease). Among the non-invasive tests, the role of dynamic penile Doppler evaluation as a tool to identify patients at high risk of occult CAD has been found to be of some help [11-12,14]. Conventionally, patients who showed peak systolic velocity (PSV) <35 cm/sec after pharmacological stimulation (defined as “non-responders”) are thought to have reduced vasodilator response of penile circulation. Although both drug dosages and time of PSV measuring were somewhat different between studies, pooled data were consistently similar. All but one (33/34) patients with positive EST were classified as “non-responders”, whereas nearly half of the cases with negative EST (88/161) were classified as “responders” (i.e. normal vasodilator response). Test sensitivity and specificity were 97% and 55%, respectively. This turned into a negative predictive value of 98% and into a positive predictive value of 31%. In other words, the finding of normal Doppler response in a patient with ED virtually excludes concomitant CAD. Conversely, an abnormal Doppler response is a marker of latent CAD in only 30% of patients.

The issue whether ED or CAD symptoms are manifested first has been addressed by 2 retrospective studies [22-24]. ED symptoms were found to come prior to CAD symptoms in 58% and 67% of CAD patients [22-23]. Montorsi et al. [23] calculated a mean time interval of 39 months (range 1-165 months) between ED onset and CAD onset. The first manifestation of CAD was acute coronary syndrome in 40% (time interval 32 months) or stable effort angina in 60% (time interval 48 months) of cases, respectively. This finding was confirmed by a recent study from our institution - The COBRA Trial - addressing the association between ED and CAD in patients with different types of coronary syndromes (acute vs. chronic coronary syndromes). We found that 77% of patients with chronic angina pectoris had ED symptoms prior to CAD with a mean interval of 25 months. Both prevalence and time interval increased in patients with more extensive disease. Thus, patients with all the 3 major epicardial arteries affected had 94% prevalence of ED prior to CAD with a time interval of 36 months as compared to patients with only one major epicardial artery affected who had 60% and 10 months values, respectively [24]. Although retrospective, these observations suggest that CAD is likely to develop over time in the majority of patients with ED.The length of time will be the result of a balance between adverse (i.e. age, risk factor profile, duration of ED at the time of the first diagnosis) and protective factors (i.e. regular exercise program, treatment of risk factors). Thus, while waiting for prospective studies on this topic, physicians should systematically look for ED in any male with vascular risk factors. If ED is found, strict medical surveillance is mandatory.

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