Erectile-Dysfunction-Cardiovascular-Risk

Summary and Introduction

Summary

Erectile and endothelial dysfunction are common in individuals with multiple cardiovascular risk factors and are longitudinal predictors of cardiovascular events. The pathogenesis of both endothelial and erectile dysfunction is intimately linked through increased expression and activation of endothelial nitric oxide synthase, and the subsequent physiological actions of nitric oxide. Endothelial production of nitric oxide by endothelial nitric oxide synthase in the corpus cavernosum is involved in the maintenance of penile erection. Erectile dysfunction can be detected clinically using systematic questioning and could potentially be employed as an independent predictor of cardiovascular risk to target treatment of cardiovascular risk factors. Both erectile and endothelial dysfunction respond to lifestyle modifications, particularly in individuals with the metabolic syndrome. Drugs that improve endothelial dysfunction can also improve erectile dysfunction, but responses are not always concordant. Phosphodiesterase type 5 inhibitors, however, are powerful agents that commonly improve erectile and endothelial dysfunction, with potential cardiac applications. The recent Princeton consensus requires more extensive implementation and evaluation in clinical practice. The judicious diagnosis of erectile dysfunction, nevertheless, provides a unique opportunity for the prevention of cardiovascular disease.

Introduction

Erectile dysfunction (ED) is the consistent inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance.^[1] Vascular disease is by far the most common cause of ED. Formerly dismissed as a psychological condition, ED has now assumed center stage as a readily treatable disorder and a powerful risk-marker for cardiovascular disease (CVD).^[2,3]

Here, we review the current knowledge of the pathogenesis of vasculogenic ED, with specific reference to abnormalities in the biology of nitric oxide (NO) and the relationship between and the clinical management of ED and CVD. Psychological and neurological aspects of ED have been reviewed elsewhere previously.^[2]

Penile Erection: Central and Peripheral Mechanisms

The unique anatomy of the human penis is customized for producing a complex hemo dynamic response to centrally and peripherally generated psychoneurogenic sexual stimuli. The effective evaluation and application of phosphodiesterase 5 (PDE5) inhibition in the management of ED has significantly elucidated the pathophysiological interrelationship between erectile and generalized endothelial dysfunction, and hence CVD.^[4]

Central control of erectile function resides in the hippocampus and the medial preoptic area and paraventricular nuclei of the hypothalamus.^[5] The signaling of sexual impulses is mediated via the dopaminergic, nitrergic and oxy tocinergic pathways, and is enhanced by bioavailable testosterone.^[5,6] An erection is a coordinated process involving psychoneurogenic stimulation, arterial and cavernosal vasodilatation, increased blood flow and venous occlusion.

Peripheral control of erectile function centers on the interplay between relaxation and contraction of smooth muscle (SM) in the walls of the cavernosal arterioles and the trabeculae of the cavernosal sinuses. Vasodilatation caused by SM relaxation results in increased blood flow, increased intracavernosal pressure and occlusion of the subtunical venous plexus and emissary veins, leading to penile erection. SM cell relaxation is achieved through the cyclic GMP and cyclic AMP pathways, both of which are modulated by various chemomediators (Figure 1).

Figure 1: The physiology of penile erection—peripheral mechanisms.

Figure 1. (click image to zoom) The physiology of penile erection—peripheral mechanisms. Chemomediators such as nitric oxide and endothelin translate effector signals from neuronal impulses into smooth muscle cell relaxation (erection) or smooth muscle contraction (detumescence). Abbreviations: cGMP, cyclic GMP; eNOS, endothelial nitric oxide synthase; nNOS, neuronal nitric oxide synthase; PDE5 phosphodiesterase type 5.

NO, the principal chemomediator, is synthesized and released at the endings of non adrenergic noncholinergic (NANC) parasympathetic nerves and by the vascular and sinusoidal endothelial cells, inducing SM relaxation.^[7] Noradrenaline and other sympathomimetic agents, on the other hand, cause SM contraction and vaso constriction, hence penile detumescence and flaccidity.^[5] Other endothelialderived molecules that help regulate penile blood flow include prostaglandins, bradykinin, hyperpolarizing factor, endothelin and angiotensin.^[8,9] The physiology of the NANC parasympathetic nerve terminals and SM and endothelial cells of the cavernosal arterioles and trabeculae is pivotal to the peripheral mechanism of erectile function. Endothelial and neuronal dysfunction are, therefore, critical in the pathogenesis of ED.^[7]

The Role of Nitric Oxide in Penile Erection

Penile tumescence and erection is critically reliant on the release of NO by both cavernosal nerve terminals and endothelial cells.^[8,9] NO activates guanylyl cyclase in penile SM cells, thereby converting GTP to cyclic GMP, with subsequent activation of protein kinase G and accelerated efflux of calcium and potassium from SM cells, ultimately increasing penile blood flow (Figure 1). The synthesis and release of NO by neuronal NO synthase (nNOS) in the cavernosal NANC nerve terminals is calcium-dependent and responsible for the initiation of penile erection following sexual stimulation.^[10,11] Penile engorgement and shear stress activate a phosphoinositide 3 kinase/Akt signaling pathway, leading to further NO release by endothelial NO synthase (eNOS), which maintains the erection.^[10] These mechanisms are part of a feed-forward system (Figure 2). A defect in this system results in ED. The role of the endothelial cells in the maintenance of penile erection underscores the close association of ED with endothelial dysfunction in the peripheral circulation,^[12] and with the presence of cardio vascular risk factors^[13] and coronary artery disease.^[3] Although we acknowledge that nNOS initiates penile erection and is involved in the neurogenic causes of ED, here we focus on the role of eNOS as the link between vasculogenic ED and cardiovascular risk.

Figure 2: The roles of two forms of nitric oxide synthase in cavernosal smooth muscle relaxation and the initiation and maintenance of penile erection.

Figure 2. (click image to zoom) The roles of two forms of nitric oxide synthase in cavernosal smooth muscle relaxation and the initiation and maintenance of penile erection. Abbreviations: Akt, protein kinase B; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; nNOS, neuronal nitric oxide synthase; P, phosphorylated; PI3K, phosphoinositide 3 kinase. Permission obtained from National Academy of Sciences © Hurt KJ et al. (2002) Proc Natl Acad Sci USA 99: 4061–4066.

Endothelial Dysfunction: Beyond the Corpus Cavernosum

Endothelial dysfunction is intimately linked to atherogenesis and increased CVD risk.^[14] Dysfunction arises following alteration in the release of several vasoactive factors, principally NO, from endothelial cells.^[14,15] NO is formed from l-arginine and molecular oxygen by eNOS, a reaction that in endothelial cells is triggered by a G-protein-coupled signaling pathway activated by shear stress or circulating bioactive agents, such as acetylcholine and 5-hydroxytryptamine. NO is released both subluminally, where it has vasodilatory and antiproliferative properties,^[15] and abluminally, where it exerts anticoagulant, antiadhesive and antiplatelet effects.

Endothelial dysfunction due to an abnormality in the release and/or action of NO is characterized by vasoconstriction, coagulation, increased leucocyte adhesion and stimulation of SM cell growth, and is, therefore, central to athero genesis.^[14] Several traditional cardiovascular risk factors, such as aging, smoking, hyper tension, dyslipidemia and diabetes, and some less- traditional risk factors, including inflammation, hypoxia, oxidative stress and homocysteinemia, are related to endothelial dysfunction.^[16,17] It is also a feature of acute coronary syndromes, heart failure, reperfusion injury, renal failure, systemic inflammatory disorders and ED.^[14,17]

Endothelial dysfunction can be tested in vivo using several techniques that rely principally on measuring change in arterial diameter or flow in response to stimuli, such as acetylcholine, 5-hydroxytryptamine or l-arginine, which increase the endothelial release and action of NO.^[18] Circulating biomarkers, such as high-sensitivity C-reactive protein (hsCRP), P-selectin, adhesion molecules and endo thelial progenitor cells, have also been employed to assess endothelial dysfunction in clinical studies.^[18] Longitudinal observations confirmed that dysfunction of the endothelium of the coronary and peripheral circulation is predictive of cardiovascular events, the sensitivity and specificity being greater for coronary artery endothelial dysfunction than for peripheral dysfunction.^[19] Impaired NO- mediated vasodilatation of forearm resistance arteries reflects decreased total-body production of NO, supporting the link with ED.^[20]

The mechanism underlying endothelial dysfunction induced by cardiovascular risk factors, such as diabetes, hypertension, smoking and dyslipidemia, involves two processes: the inhibition of dimethylarginine dimethylaminohydrolase, which catalyses the hydrolysis of asymmetric dimethyl arginine, an inhibitor of eNOS; and the uncoupling of eNOS activity. Both processes increase oxidative stress in the endothelial cells.^[21,22] This increase in oxidative stress leads to further oxidative catabolism of NO, formation of peroxynitrite, and activation of the proinflammatory nuclear factor kappa B, which in turn induces cellular inflammation and adhesion molecule production.^[15,21] These mechanisms, and reduction in bone-marrowderived endothelial progenitor cells, could underpin a common pathogenesis for both erectile and endothelial dysfunction.^[23,24] In individuals with established ED, elevated asymmetric dimethyl arginine level has been shown to correlate with the severity of various cardiovascular risk factors, indicating the impact they could have on endothelial function.^[25]

Clinical Assessment of Erectile Dysfunction

A patient with ED provides a unique clinical opportunity to detect cardiovascular risk factors and disease. Comprehensive investigation of medical, social and sexual history should be undertaken routinely, in addition to a physical examination and relevant laboratory and ancillary investigations. Initially, testing should include arterial blood pressure, waist circumference, fasting plasma lipids, glucose, glycated hemoglobin (HbA_1C), renal biochemistry, testosterone, hsCRP and resting 12-lead electrocardiography. Standard criteria should be used to identify the metabolic syndrome.^[26]

Although the diagnosis of ED per se relies heavily on the patient's perception and description of the problem, confirmation and assessment of its severity should be conducted with the internationally validated 5-item International Index of Erectile Function (IIEF-5) or the erectile function section of the 15-item IIEF.^[27,28] The IIEF-5 (also known as the Sexual Health Inventory for Men [SHIM]) has been the preferred investigational instrument in ED studies. ED and various grades of ED severity, indicated by IIEF-5 scores, correlate significantly with CVD risk factors such as hyper tension, diabetes, hyperlipidemia and obesity.^[29–31] Although not specifically reflective of nNOS and eNOS activity, question 3 of the Sexual Encounter Profile ("Did your erection last long enough for you to have successful intercourse?") and questions 3 ("How often were you able to maintain your erection after you had penetrated your partner?") and 4 ("How difficult was it to maintain your erection to completion of intercourse?") of the IIEF-5 are indicative of maintenance of erectile function. They could, therefore, be useful in identifying ED as a clinical manifestation of endothelial dysfunction.

The presence of significant psychogenic factors in the etiology of ED can be confirmed by the presence of adequate nocturnal penile tumescence. Duplex ultrasonographic imaging of the corpora cavernosa, dynamic infusion cavernosometry and cavernosography, and pharmacological stimuli can yield hemodynamic data that support a vasculogenic cause of ED.

Erectile Dysfunction and Cardiovascular Risk

Several epidemiological studies in selected patient populations have clearly shown that the major cardiovascular risk factors—aging, smoking, diabetes, hyperlipidemia and hypertension— have raised prevalence in individuals with ED.^[13,32] The prevalence of ED is also directly related to the number of cardiovascular risk factors present, being highest in individuals with more than three. Patients with coronary artery disease have a high frequency of ED,^[33,34] which correlates with the number of stenotic and calcified arteries and predates symptomatic disease.^[35–37] Notably, a patient with vasculogenic ED is likely to have one coronary artery with a 50% stenosis.^[33,34,38]

Cardiometabolic risk in abdominally obese subjects is now well-defined by the metabolic syndrome rubric.^[26] ED prevalence increases with the number of components of the metabolic syndrome, being as high as 40% in individuals with four components, and is especially prevalent in those with diabetes (Figure 3).^[39] In individuals with the metabolic syndrome, ED has a linear relationship with evidence of endothelial dysfunction, as reflected by increased circulating plasma levels of hsCRP.^[40] Obstructive sleep apnea, a feature of the metabolic syndrome, can also contribute to both endothelial and ED via several mechanisms, including hypoxia, hypogonadism and hyperadrenergic activity.^[41,42] De Angelis et al. showed that in patients with type 2 diabetes and ED, the response of blood pressure to and degree of platelet aggregation following l-arginine administration—a surrogate test for endo thelial dysfunction—is impaired when compared with those with type 2 diabetes and no ED.^[43] In this analysis, the independent predictors of ED were HbA_1C, blood pressure response to l-arginine, circulating P-selectin levels and autonomic neuropathy. ED development in those with type 2 diabetes is principally related to both vasculopathy and neuropathy.^[2,9]

Figure 3: The prevalence of erectile dysfunction, estimated by the IIEF-5 score, and serum highsensitivity CRP levels in relation to components of the metabolic syndrome, as defined by the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.

Figure 3. (click image to zoom) The prevalence of erectile dysfunction, estimated by the IIEF-5 score, and serum highsensitivity CRP levels in relation to components of the metabolic syndrome, as defined by the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Abbreviations: CRP, C-reactive protein; IIEF-5, 5-item International Index of Erectile Function. Permission obtained from American Diabetes Association © Esposito K et al. (2005) Diabetes Care 28: 1201–1203.

A plausible theoretical link between erectile and endothelial dysfunction posits that cardiovascular risk factors could induce ED by impairing NO release from endothelial cells following neuronal activation and initiation of a penile erection. A residual, important question, however, is whether ED reflects endothelial dysfunction independent of traditional cardiovascular risk factors.

Erectile Dysfunction: Predictor of Cardiovascular Risk?

That CVD and its associated risk factors predict ED is now well accepted.^[3] New observational data, however, indicate that ED may inde pendently predict CVD.^[44–46] Data from the placebo group of a large clinical trial indicate that prevalent or incident ED predicted the occurrence of cardiovascular events over a follow-up period of 9 years, with a hazard ratio of 1.45.^[44] This association was independent of conventional cardiovascular risk factors, including age, hypertension, diabetes, hyperlipidemia and smoking. Over 5 years the incidence of ED was 57% and its presence predicted subsequent cardio vascular events to a degree either equal to or greater than that of cigarette smoking, hyperlipidemia or family history of myocardial infarction. These data are consistent with smaller studies showing that ED predates the development of sympto matic coronary disease.^[36]

In a cross-sectional study of patients with type 2 diabetes, analysis showed that ED, assessed by questionnaire, was the most- significant indepen dent predictor of silent coronary artery disease (defined by angio graphy or stress testing) compared with other parameters, such as smoking, HbA_1C, micro albuminuria, hypertension and dyslipidemia.^[47] In other studies, ED also independently correlated with coronary artery calcification^[37] and left ventricular diastolic dysfunction.^[45]

In a case–control study, younger men with vasculogenic ED and no traditional cardio vascular risk factors or clinical CVD were shown to have impaired endotheliumdependent and endothelium-independent vasodilatation of the brachial artery^[48]—also an indicator for SM cell dysfunction in the peripheral circulation. An independent association between erectile and endothelial dysfunction, including increased plasma levels of endothelin-1 and adhesion molecules, and a reduction in circulating endothelial progenitor cells, has been confirmed by others.^[24,46,49] Our studies have shown an independent association between erectile and endothelial dysfunction, particularly in the resistance arteries, as demonstrated by impaired forearm plethysmography and increased pulse pressure in men with ED.^[50] There is a possibility, however, that unmeasured risk factors, such as homocysteine level, insulin resistance and oxidative stress, could provide the missing link between erectile and endothelial dysfunction.^[17]

While conclusive evidence is lacking, preliminary studies indicate that ED is a significant independent predictor of coronary events. Given that endothelial dysfunction predates atherosclerosis development, this possibility is consistent with the so-called 'artery size' hypo thesis (Figure 4). This theory posits that atherogenesis is likely to present earlier with clinical symptoms in arteries of a smaller diameter, such as in the penis, than in larger sized arteries, such as in the coronary circulation.^[51] This hypothesis could be extended to the symptomatic manifestations of endothelial dysfunction in different arterial beds.

Figure 4. (click image to zoom) The 'artery size' hypothesis. This theory posits that luminal narrowing due to atherogenesis will manifest clinically earlier (A) in penile arteries (as erectile dysfunction), for example, than in (B) coronary arteries (as angina pectoris). Abbreviation: TIA, transient ischemic attack. Permission obtained from Elsevier Ltd © Montorsi P et al. (2005) Am J Cardiol 96 (Suppl): 19M–23M.

Reversal of Endothelial and Erectile Dysfunction

Two key questions need to be asked. First, can therapies proven to improve endothelial function and reduce cardiovascular risk improve ED? Second, can agents used to treat ED improve cardiovascular outcomes?

Several treatments improve endothelial dysfunction. Lifestyle changes, vitamin and food supplements, and a wide spectrum of pharmacotherapies can improve endotheliumdependent vasodilatation of the peripheral circulation in patients at risk of CVD, including those with multiple risk factors, insulin resistance and type 2 diabetes.^[52,53] Some but not all of these therapies can also improve ED.

Lifestyle Modification

In a 2-year randomized controlled trial, a weight loss and exercise program improved ED in 30% of obese male participants compared with nonobese controls.^[54] Reversal of ED was paralleled by improvement in inflammatory marker levels, such as interleukin 6 (IL-6), and endothelial function, as estimated by the response of blood pressure and platelet aggregation following intravenously administered l-arginine. Lifestyle changes can, therefore, not only improve endothelial function and cardiovascular risk but also ED.^[54,55] Notably, continuous positive air pressure can improve ED in obese patients with severe obstructive sleep apnea.^[56]

Cardiovascular Drugs

Statins, fibrates and glitazones might have divergent effects on erectile and endothelial dysfunction. Several case reports and one lipidclinic- based study have implicated statins and particularly fibrates in ED development.^[57,58] Reports of recovery after drug withdrawal have varied. A recent prospective study has indicated that statins are more likely to induce ED in individ uals with multiple cardiovascular risk factors and established endothelial dysfunction than in those at lower risk of CVD.^[59] Whether this effect is neurogenic and related to statin lipo philicity is unclear. Only one large statin trial reported ED as an adverse event, although data were based on self-reporting and not IIEF scores.^[57,60] A small study, however, has shown improved erectile function in men treated with the combination of atorvastatin and the PDE5 inhibitor sildenafil compared with sildenafil alone.^[61]

Although a possible protective role of angiotensin- converting-enzyme (ACE) inhibition in ED was not confirmed in a recent placebo-controlled trial,^[62] a prospective study has indicated that combined ACE inhibitor and angiotensin-II-receptor antagonist therapy could benefit ED in patients at high risk of CVD.^[59] Use of nonselective β-adrenergic blockers, however, could be a reason for ED in patients with hypertension.^[63] Valsartan can improve, whereas carvedilol can aggravate ED in newly diagnosed patients with hyper tension.^[64] There is clearly a need for further investigation, especially appropriately designed studies of erectile function with newer anti hypertensive therapies, which are known to have a beneficial effect on endothelial function.

Phosphodiesterase Type 5 Inhibitors

The development and clinical introduction of PDE5 inhibitors has revolutionized the management of patients with ED. By inhibiting PDE5, these agents enhance the bioeffectiveness of NO in SM cells by increasing signaling from cGMP to protein kinase G, and hence the maintenance of penile blood flow (Figure 5).^[65] Preclinical studies in healthy individuals showed that the PDE5 inhibitor sildenafil had a mild hypotensive effect and also improved arterial stiffness.^[66] Several studies have now shown that PDE5 inhibitors improve coronary endothelial function in patients with ischemic heart disease and heart failure.^[67,68]

Figure 5. (click image to zoom) Mechanism of action of phosphodiesterase type 5 inhibitors in inducing smooth-muscle relaxation in cavernosal arteries and in the peripheral circulation. Abbreviations: cGMP, cyclic GMP; PDE5, phosphodiesterase type 5.

The benefits of treating pulmonary hypertension by enhancing the NO pathway in the local vasculature with sildenafil have also been identified, but the efficacy of this treatment remains to be confirmed in controlled clinical trials.^[69] More recently, controlled observations have clearly shown that both sildenafil and the longer-acting tadalafil improve brachial artery flow-mediated dilatation in men at increased risk of CVD, including those with type 2 diabetes.^[70,71] Improvements have also been reported in patients with type 2 diabetes within 1 h of 25 mg sildenafil being admini stered orally, with sustained improvement after continuing therapy for 4 weeks.^[70] Similarly, significant improvements in endothelial function in the brachial artery remained 2 weeks after stopping tadalafil in men at increased risk of CVD.^[71] This finding was corroborated by increased plasma concentration of NO and reduced endothelin-1 levels.^[71] A recent study has also indicated there could be an inter active benefit from adding a PDE5 inhibitor to an ACE inhibitor in patients with heart failure.^[72]

Agents that increase the expression of eNOS either directly or via risk-factor modification can, therefore, potentially have an additive or synergistic effect in improving endothelial function when coadministered with a PDE5 inhibitor, since the latter operates downstream of eNOS. This notion has also been shown to extend to improvement in erectile function.^[73] Whether lifestyle interventions work in synergy with PDE5 inhibitors in improving coronary and peripheral endothelial function remains unknown. Other agents that have been known to improve endothelial function as well as ED include l-arginine, tetrahydrobiopterin and antioxidant supplements.^[53]

The Princeton Consensus: Erectile Dysfunction and Cardiology

In 1999, the first Princeton consensus addressed the cardiac safety of drug treatment for ED.^[74] The 2006 revised guidelines expand upon this issue, recommending stratification of the risk, ideally including exercise electro cardiography, before resuming sexual activity.^[38] In men with coronary artery disease, no adverse effect on cardiac ischemia has been observed with PDE5 inhibitors alone.^[75] The randomized controlled trials of sildenafil identified no excess risk for myocardial infarction in those men randomized to active medication.^[76] The interaction between PDE5 inhibitors and NO donors—typically nitrates—is, however, again highlighted for its potential high risk of precipitating hypo tension.^[76]

In the setting of angina, alternatives to nitrates should be used after PDE5 inhibitor therapy. For the minority of patients whose cardiac risk from sexual activity is high, tadalafil should not be the PDE5 inhibitor of first choice, because of its long half-life. Although the second Princeton consensus contains recommendations as to how soon nitrate therapy can be used after the use of PDE5 inhibitors, no recommendations were made for the situation in reverse. Ongoing therapy with nitrates, especially long-acting nitrates, remains an absolute contraindication to the use of PDE5 inhibitors. If the patient's need for short-acting sublingual nitrate is infrequent, however, it can be argued that the judicious use of PDE5 inhibitors is reasonable, provided there has been an interval of at least 24 h from previous nitrate use.^[77]

Consistent with this Review, the revised guidelines recognize the role of endothelial dysfunction as the 'common denominator' for both ED and CVD. ED is highlighted as a risk marker for CVD in men with no cardiac symptoms and as an opportunity to institute cardiovascular preventative therapy. Recommendations state that any man presenting with ED should have estimation of correctable cardiovascular risk markers—lipids, glucose and blood pressure—with or without an exercise stress test for risk stratifi cation. These guidelines are a major development in the recognition of the significance of ED, and establish a new precedent and challenge for CVD prevention.

Conclusions and Implications for Clinical Practice

Erectile and endothelial dysfunction are common abnormalities that coexist in individuals with multiple cardiovascular risk factors and in those with established CVD. The mechanisms for erectile and endothelial dysfunction are closely related to the pathobiology of NO as a consequence of disturbances in the expression and activation of eNOS. Both erectile and endothelial dysfunction can be readily identified, although currently this is seldom routine clinical practice. Both conditions are predictive of cardiovascular events. The 'artery size' hypothesis is based on a structural notion, but is still consistent with generalized endothelial dysfunction underpinning these clinical disorders. ED has been associated with endo thelial dysfunction of conduit vessels, increased coronary artery calcification and silent angina independent of traditional cardiovascular risk factors.

ED could potentially be employed as an indepen dent predictor of cardiovascular risk to guide a targeted approach to identifying and modifying established and less well-established cardiovascular risk factors. Both erectile and endothelial dysfunction are responsive to lifestyle modification, particularly in patients who are obese and have the metabolic syndrome. Many drugs that improve endothelial function can also improve ED, but the effects are not universal. Correction of multiple cardiovascular risk factors, particularly with lifestyle changes, could be required to improve both conditions. PDE5 inhibitors also provide a powerful therapeutic tool for improving both erectile and endothelial dysfunction, with several cardiac applications.^[78] Further studies should explore the efficacy of combination therapies with other agents used to modify cardiovascular risk status.

As recommended by the revised Princeton consensus, the strong link between erectile and endothelial dysfunction indicates that all patients complaining of ED, judged likely to be vasculogenic, should be screened for modifiable cardiovascular risk factors, and possibly subclinical atherosclerosis, using carotid ultrasonography, coronary calcium scores and an exercise stress test. Increased carotid intimalmedial thickness could be used to guide the intensity of risk factor intervention.^[79] In patients with diabetes, the presence of ED can also provide a rationale for screening for silent coronary artery disease.^[47] Clinicians need to consider and detect ED in their patients, and in so doing seize a unique opportunity for preventing CVD.

Sidebar: Key Points

Endothelial and erectile dysfunction are intimately associated; both disorders arise from disturbance in the release and action of nitric oxide from endothelial cells.
Erectile and endothelial dysfunction can be readily detected clinically and are associated with a wide spectrum of cardiovascular risk factors, and are also independently predictive of cardiovascular events.
Both conditions can be improved by lifestyle modifications and by several pharmacological agents.
Phosphodiesterase type 5 inhibitors improve both endothelial and erectile dysfunction by potentiating the action of nitric oxide from endothelial cells.
The Princeton consensus offers practical guidelines for assessing cardiovascular risk in patients with erectile dysfunction and managing erectile dysfunction in patients with established coronary artery disease.

Reprint Address

Gerald F Watts, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia gerald.watts@uwa.edu.au

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Authors and Disclosures

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Author

Gerald F. Watts

GF Watts is Professor of Medicine and Head of Internal Medicine at Royal Perth Hospital, School of Medicine and Pharmacology.

Disclosure: Gerald F. Watts has disclosed no relevant financial relationships.

Kew-Kim Chew

K-K Chew is Senior Clinical Fellow and Clinical Specialist in Men's Health and Sexual Medicine, the Keogh Institute for Medical Research Sir Charles Gairdner Hospital.

Disclosure: Kew-Kim Chew has disclosed no relevant financial relationships.

Bronwyn G.A. Stuckey

BGA Stuckey is Clinical Associate Professor and Medical Director of the Keogh Institute for Medical Research and Consultant Endocrinologist, Department of Endocrinology and Diabetes, University of Western Australia, Perth, Australia.

Disclosure: Bronwyn G.A. Stuckey has disclosed no relevant financial relationships.