© Springer-Verlag Berlin Heidelberg 2015Vincenzo Mirone (ed.)Clinical Uro-Andrology10.1007/978-3-662-45018-5_6
6. Editorial on Erectile Dysfunction as Sentinel for Cardiovascular Disease
Department of Urology, Erasme Hospital, University Clinics of Brussels, 808 route de Lennik, Brussels, 1070, Belgium
Erectile dysfunction (ED) affects millions of men worldwide with implications that go far beyond sexual activity. ED is predominantly a vascular disease, frequently coexists with cardiovascular diseases (CVD), and shares common risk factors such as metabolic syndrome, hyperlipidemia, smoking, excessive alcohol consumption, and sedentary behavior (Feldman et al. 2000). ED is now recognized as an early marker of cardiovascular disease, diabetes mellitus, and depression (Tan et al. 2012). It is an important component of the quality of life, but it also confers an independent risk for future cardiovascular events (Araujo et al. 2010; Dong et al. 2011). A usual 2–5-year time period is reported between the onset of ED in men with no known CVD and a cardiovascular event (Gazzaruso et al. 2004; Vlachopoulos et al. 2005; Montorsi et al. 2006). Furthermore, evidence suggests that ED is predictive of peripheral arterial disease and stroke (Polonsky et al. 2009; Ponholzer et al. 2005). It offers to physicians an opportunity for risk assessment (Jackson et al. 2010). Incident ED has a similar or greater predictive value for cardiovascular events as traditional risk factors, such as family history of myocardial infarction, smoking, and hyperlipidemia (Thompson et al. 2005; Araujo et al. 2009). Coronary heart disease is often more severe in patients with ED compared to patients without ED (Montorsi et al. 2003a). For that reason, patients who seek treatment for sexual dysfunction have a high prevalence of CVD that can be live threatening (Salonia et al. 2012).
Management of patient with erectile dysfunction according to the risk for sexual activity and future cardiovascular events is then to be proposed (Gazzaruso et al. 2008; Vlachopoulos et al. 2013).
Vascular problems due to atherosclerosis are a process that begins during childhood and becomes clinically evident from middle age. Endothelial dysfunction has been shown to be a precursor of atherosclerosis lesions (Azadzoi et al. 1996). The main link between ED, CVD, and the risk factors is the vascular endothelium, which plays a fundamental role in the regulation of the circulation. This association is likely to be caused by impairment in the endothelium-dependent relaxation of smooth muscle cells in the corpus cavernosum, which impairs cavernosal perfusion of the penis (Solomon et al. 2003). Endothelial dysfunction can be demonstrated in patients with cardiovascular risk factors and has been found in men with ED and no CVD (Kaiser et al. 2004).
As the endothelial cells recover the sinusoid spaces in the cavernous tissue, it is logical that vascular impotence presents the same pathophysiology than other vascular diseases. This is further substantiated by a similar pathogenic involvement of nitric oxide (NO) pathway (Li et al. 2002). In the oxygen enhancement environment, autonomic dilator nerves and the endothelium are able to stimulate NO formation, mediating trabecular smooth muscle relaxation. Decreased endothelin receptor sites in the corpus cavernosum could reduce NO production and could be one of the explanations for the development of ED. At low oxygen concentrations, measured at the flaccid state of the penis, the synthesis of NO is inhibited (Kim et al. 1993). However, the penis is the only organ which changes from venous to arterial oxygen tensions during the course of its normal function. Lower critical oxygen tension could alter endothelial cells activity but also reduce smooth muscle content and decrease the penile elasticity with higher ratio of penile collagen (Sattar et al. 1995; Raviv et al. 1997).
The link between ED and subsequent cardiac events includes also the artery-size hypothesis. Clinical manifestations of vascular diseases rarely appear simultaneously, because arteries supplying various districts have different sizes. A lumen obstruction of the penile artery would represent a minor abnormality to cause significant obstruction to blood flow in coronary or peripheral arteries due to their larger size (Montorsi et al. 2003b, 2005).
Of particular importance is the increased risk of a cardiac event in men with ED aged 50 years or less with an incidence of atherosclerotic cardiovascular events in men younger than 40 years with ED more than seven times the incidence in a reference population (Chew et al. 2010). Data from the Olmsted County Study also suggested that ED is far more predictive of CVD in men 40–49 years of age than in older men (Inman et al. 2009).
The link is strong enough to justify the statement that men with ED should be considered cardiovascular patients unless proved otherwise. The presence of ED, especially in men aged 30–60 years, should alert the physician to the possibility of increased CVD risk and the workup recommended should, therefore, be used to modify risk. Assessment of ED must include ED severity because more severe ED has been associated with greater risk of major cardiovascular events and extent of CVD (Hall et al. 2010; Salem et al. 2009; Greenstein et al. 1997).
Prevention for arteriosclerosis should be a prime therapeutic target, especially in age-related ED patients, as they are often involved in ischemic heart disease. The interval between the onsets of symptoms is one of the most important factors as it provides an opportunity for early diagnosis, treatment, and prevention.
6.1 Assessment of Endothelial Function
Inflammation is of importance in early atherosclerosis. Several inflammatory markers, such as interleukin-6, tumor necrosis factor-α, or C-reactive protein (CRP), have all been associated with impaired endothelial function, cardiovascular events, and ED. Elevated CRP levels have also been found to significantly correlate with vascular ED as measured by penile Doppler (Billups et al. 2003). But with the exception of CRP, most markers are not commonly run in commercial laboratories, and they can also be elevated in a multitude of other inflammatory processes. Endothelin-1 (ET-1) is a potent vasoconstrictor and proinflammatory peptide associated with endothelial dysfunction, inflammation, and vasoconstriction and of the serum markers studied, ET-1 is probably the one that is closest to achieve clinical relevance (Bohm and Pernow 2007). This underlines the importance of inflammation in early atherosclerosis (Vlachopoulos et al. 2006).
When the endothelium is damaged, circulating endothelial progenitor cells (cEPCs) from the bone marrow are activated in the bloodstream and mature into endothelial cells that help repair the site of injury (Hill et al. 2003). This process, called vasculogenesis, is impaired as documented by low levels of cEPCs in ED and CAD. Circulating markers of endothelial cell damage have been reported in patients with erectile dysfunction, while they have not yet presented any other vascular pathology (Foresta et al. 2005; Baumhakel et al. 2006). Determination of cEPC levels with flow cytometry is not a test that is widely commercially available.
Intima-media thickness (IMT) of the common carotid artery is measured after visualization by ultrasonography. IMT has been found to correlate with other measures of endothelial function and is firmly correlated with ED, but interpretation is hampered by discordant measurements hailing from operator variability (Bocchio et al. 2005).
Flow-mediated dilation of the brachial artery (FMD)
FMD of the brachial artery with ultrasonographic assessment has become the most widely published standard in the assessment of endothelial dysfunction. Briefly, arterial occlusion with a blood pressure cuff for 5 min and subsequent release leads to reactive hyperemia and local endothelial activation. When this is performed on the patient’s arm, increased shear stress leads to endothelium-dependent dilation of the brachial artery, which can be measured and quantified by ultrasound. The results can then be contrasted to endothelium-independent dilation provoked by administration of nitroglycerin. Endothelial function of the brachial artery as measured by FMD has long been firmly linked to coronary endothelial function (Wu et al. 2005). Numerous studies have solidly connected impaired FMD with ED even without manifest CVD (Chiurlia et al. 2005; Yavuzgil et al. 2005; Kaya et al. 2006). Although FMD is noninvasive and the most widely published method to evaluate endothelial function, problems with reproducibility persist. Results are highly operator dependent and can be confounded by changes in baseline diameter of the brachial artery. A more recent method of assessing endothelial function is peripheral arterial tonometry measuring reactive hyperemia (RH-PAT). This office-based technique uses a finger probe to assess digital volume changes accompanying pulse waves after inducing reactive hyperemia with a blood pressure cuff on the upper arm (Kuvin et al. 2007). Nevertheless, assessment of endothelial dysfunction may be used in the future to replace the more invasive penile Doppler to help determine ED etiology.
Modifications of reversible causes or risk factors at the base of the pathogenesis of atherosclerosis remain the first approach toward improving endothelial function and associated with chronic exposure to PDE5-I; they could improve or even cure ED and could avoid fatal cardiovascular attacks in the future (Gupta et al. 2011). As the first point of medical contact for men with erectile dysfunction symptoms, the primary care physician or urologist has a unique opportunity to identify those who require early intervention to prevent cardiovascular disease (Nehra et al. 2013).
The Princeton Consensus expert panel focused on the evaluation and management of cardiovascular risk in men with erectile dysfunction (ED) and no known cardiovascular disease (CVD), with particular emphasis on identification of men with ED who may require additional cardiologic workup (Nehra et al. 2012).
It is of interest to consider the whole patient management in men presenting ED. Patients with ED have a higher risk to develop cardiovascular diseases. ED is often of vascular origin and should be considered as a sentinel symptom of a cardiovascular pathology. An appropriate clinical and biological evaluation for cardiovascular risk factors should be considered. The dietary reduction of serum lipids and physical activity are probably the first-line treatment. An early adoption of a healthy life style may be the best approach to reduce the burden of erectile dysfunction on the health and well-being of men. As endothelial dysfunction is one important feature of both ED and cardiovascular disease, inhibition of PDE5 as first-line therapy of ED may enhance endothelial function by amplifying the response of vascular smooth muscles to NO.
This may encourage men with erection problems to consult and help practitioners to identify patients with ED with the opportunity for the diagnosis of other serious conditions clearly named cardiovascular disease of which ED could be a symptom. This would allow earlier intervention and improve treatment outcomes, reducing morbidity and mortality of cardiovascular disease. ED is a window of opportunities for cardiac diseases.