Role of endothelial dysfunction

Endothelial dysfunction is an integral component of the pathogenesis of CVD and ED, and has been shown to be an independent predictor of future cardiovascular events. Kaiser et al6 was the first to demonstrate abnormal endothelial function in men with ED and no documented CAD.


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To date, all four published studies on the subject have demonstrated that men with ED and no clinical manifestations of CAD demonstrate abnormal endothelial function compared with controls who did not have ED. Detecting endothelial dysfunction in “healthy” men with ED further strengthens the concept that ED is an early marker of CVD that is independent of the more traditional risk factors. 


In light of these compelling epidemiologic and scientific data link-ing ED, endothelial dysfunction and CAD, there is a need to define and use tests that will further stratify and identify ED patients at high risk for previously undetected CAD. The Princeton consensus panel reviewed the safety and drug interaction data for all three PDE-5 inhibitors (sildenafil, tadalafil, vardenafil), with emphasis on the safety of these agents in men with ED and concomitant CVD. The Princeton II consensus guidelines highlighted that ED is an early symptom or harbinger of CVD, due to the common risk factors and pathophysiology mediated through endothelial dysfunction.7


They recommended that all men with ED should undergo a full medical assessment and concluded that any asymptomatic man who presents with ED that does not have an obvious cause should be treated as a cardiac (or vascular) patient until proven otherwise. As such, these men should be screened for vascular disease and undergo blood glucose, lipid, and BP measurements. Their recommendations also include that ideally, all patients at risk, but asymptomatic, for coronary disease should undergo an elective stress test to facilitate risk stratification.


The Minority Health Institute (MHI) convened an expert advisory panel of cardiologists and urologists to design a new practice model algorithm that uses ED as a clinical tool for early identification of men with systemic vascular disease.8 The MHI algorithm stipulates that all men aged 25 years and older, regardless of sexual dysfunction complaints, should be asked about ED. The presence of ED should prompt an aggressive assessment for cardiovascular risk and occult systemic vascular disease.


Montorsi et al3 recommended additional noninvasive tests for those men with intermediate cardiac risk. This intermediate risk group, which is estimated to represent almost 40% of the U.S. population, is defined utilizing the standardized Framingham risk score as having a 10% to 20% risk of developing a heart attack or die from coronary disease in the next 10 years. Additional testing aimed to better define CAD risk should be considered in this population and include tests to assess both obstructive and non-obstructive CVD.


Tests to assess obstructive CAD include: coronary calcium score by electron-beam computed tomography, electrocardiographic stress test, nuclear imaging, and coronary angiography. To ascertain non-obstructive diffuse cardiovascular risk, assessment of endothelial function, carotid intima-media thickness, ankle brachial index, and penile duplex Doppler were discussed by the authors.


It is apparent that urologists need to implement cardiovascular risk stratification to identify ED patients at high risk for previously undetected CAD. To broaden the urologist’s role in identification of occult CVD, several diagnostic techniques can be incorporated including standardized CVD risk questionnaires such as the Framingham risk score, BP, glucose, and lipid measurements, and an initial physical examination focusing on detecting peripheral vascular disease. For some men with ED, consideration of in-office, non-invasive assessment of endothelial function and or penile duplex Doppler ultrasound can be considered.


Doppler evaluation

In the ED population, the penile duplex Doppler evaluation has been considered a screening tool for previously undetected CAD. In a pooled analysis of all published studies, the results of this evaluation have a negative predictive value of 84% and a positive predictive value of 32%. In other words, the finding of a normal Doppler response defined as a PSV greater than 35 cm/s in a patient with ED makes obstructive CAD unlikely.


Conversely, an abnormal Doppler response indicates previously undiagnosed obstructive CAD in approximately 30% of cases, which may statistically reflect a poor predictive value but arguably may be clinically significant. Use of this diagnostic modality has been in decline, however, because it requires an intracavernosal injection and it is not recommended prior to initiating first line oral therapy for ED.


Assessment of endothelial dysfunction has been used to replace penile Doppler and help determine ED etiology. Recently, Mazo et al9 and Ucar et al10 have demonstrated that the severity of the endothelial dysfunction correlated with ED etiology. Endothelial function was significantly lower in patients with arteriogenic ED as demonstrated by penile Doppler than in patients with other forms of ED (psychogenic, venous occlusive dysfunction).


Recently, numerous urology and men’s health centers in the United States and Europe have incorporated endothelial function assessment of their ED population using the FDA-approved, noninvasive, computer based EndoPAT-2000 unit (Itamar Medical Ltd., Caesarea, Israel).


At the recent annual meeting of the Sexual Medicine Society of North America, Khera et al11 reported that in the ED population screening with the EndoPAT-2000 unit is useful in establishing cardiovascular risk in the urology office setting and it holds promise for differentiating arteriogenic ED from venous occlusive dysfunction. Prospective scientific as well as epidemiological studies using this technology are ongoing at numerous medical facilities.

PDE-5 inhibitors are first line therapy for ED. They have revolutionized the perception of this disease entity and are the mainstay of the global treatment of ED. The medications are being used in other therapeutic areas, such as pulmonary hypertension and lower urinary tract symptoms (LUTS). In addition, all three PDE-5 inhibitors have demonstrated improvement in endothelial function.


Furthermore, it appears that the benefit of the drugs on endothelial function persists even after patients discontinue use of the medications, suggesting a sustained physiological impact. Rosano et al12 demonstrated that the improvement on endothelial function following chronic tadalafil use persisted for up to two weeks following cessation of therapy.

Familiarity by the urological community for chronic PDE-5 inhibitor therapy has been established primarily for penile rehabilitation following prostate cancer treatments, LUTS, and salvage treatment for non-responders to on-demand PDE-5 inhibitor use. Chronic dosing for tadalafil is currently approved in Europe and was recently approved by the FDA. It appears that chronic PDE-5 inhibitor therapy is required to achieve improvement in endothelial function.


In a prospective crossover study, Aversa et al13 demonstrated that improvement in endothelial function was noted only in men on chronic tadalafil therapy and not in those only using the drug on demand for sexual function. One can foresee the possibility of a new algorithm whereby an ED patient with endothelial dysfunction will not only be referred for a more aggressive cardiologic evaluation but the treating urologist will consider initiating chronic PDE-5 therapy to treat ED as well as achieve overall improvement in endothelial function.