The assessment of vascular risk in men with erectile dysfunction: the role of the cardiologist and general physician
- Disclosures Full disclosures are found in Appendix A1.
Erectile dysfunction (ED) and cardiovascular disease (CVD) share risk factors and frequently coexist, with endothelial dysfunction believed to be the pathophysiologic link. ED is common, affecting more than 70% of men with known CVD. In addition, clinical studies have demonstrated that ED in men with no known CVD often precedes a CVD event by 2–5 years. ED severity has been correlated with increasing plaque burden in patients with coronary artery disease. ED is an independent marker of increased CVD risk including all-cause and especially CVD mortality, particularly in men aged 30–60 years. Thus, ED identifies a window of opportunity for CVD risk mitigation. We recommend that a thorough history, physical exam (including visceral adiposity), assessment of ED severity and duration and evaluation including fasting plasma glucose, lipids, resting electrocardiogram, family history, lifestyle factors, serum creatinine (estimated glomerular filtration rate) and albumin:creatinine ratio, and determination of the presence or absence of the metabolic syndrome be performed to characterise cardiovascular risk in all men with ED. Assessment of testosterone levels should also be considered and biomarkers may help to further quantify risk, even though their roles in development of CVD have not been firmly established. Finally, we recommend that a question about ED be included in assessment of CVD risk in all men and be added to CVD risk assessment guidelines.
- We performed a PubMed search for articles pertinent to relationships between erectile dysfunction (ED) and cardiovascular disease (CVD), peripheral arterial disease, stroke, cardiovascular mortality, or all-cause mortality. The evidence-based consensus presented incorporates these articles, published guidelines and the expertise of the multi-specialty author group.
Message for the clinic
- Erectile dysfunction is an independent marker of increased CVD risk, particularly in younger and middle-aged men. A cardiologist or other clinician with relevant expertise plays an important role in evaluating this risk in men with ED, who may have subclinical CVD. Increased recognition of the potential for CVD in men with ED, followed by appropriate preventive or corrective action, can improve and may save lives.
Penile engorgement is a dilatory vascular response to sexual stimulation/arousal that requires sufficient arterial blood inflow. Erectile dysfunction (ED) is the persistent inability to achieve and then maintain an erection to permit satisfactory sexual intercourse. Epidemiologic studies suggest that moderate to severe ED affects 5–20% of men worldwide . ED shares common risk factors with cardiovascular disease (CVD), especially coronary artery disease (CAD), including age , lack of exercise, obesity, smoking, hypercholesterolemia, metabolic syndrome , diabetes , and hypertension . ED and CVD frequently coexist, and a large body of evidence supports ED as a predominantly vascular disease that begins with endothelial dysfunction . Low testosterone is often associated with both ED and CVD [5-8], but the relationship between testosterone and CVD is complex and continues to be investigated in ongoing studies.
The authors of this present review are a group of physicians and scientists who share an interest in sexual and cardiovascular medicine. This article discusses the evidence supporting ED as both consequence and harbinger of CVD and specifically discusses the role of the cardiologist in the characterization and management of cardiovascular risk, particularly among younger men. The role of testosterone in erectile function and cardiovascular health, as well as the utility of testosterone replacement therapy (TRT) is also considered.
Endothelial/vascular dysfunction: the ED/CVD common denominator
The endothelium is a single layer of cells that lines the lumen of the blood vessels. It serves as an interface between blood components and vascular tissues and regulates vascular tone, coagulation, and inflammation . The endothelium, which responds to shear stress, produces and responds to multiple signalling molecules, most notably nitric oxide (NO). Endothelial NO possesses antiatherogenic, antithrombotic, and anti-inflammatory properties and promotes vasodilation of the vascular smooth muscle [4, 10]. Cardiovascular risk factors including dyslipidemia, hypertension, and diabetes are associated with endothelial dysfunction, which is characterised by impaired vasodilation, reduced production of NO, and increased permeability to plasma constituents including low-density lipoproteins. These events cause vasoconstriction, platelet aggregation, and leucocyte adhesion [4, 11]. Impaired endothelial function is an independent predictor of cardiovascular events [12-14].
Erectile dysfunction may be classified as predominantly psychogenic, organic, or mixed. Most organic ED is vascular in nature, and endothelial dysfunction is believed to be the aetiologic link between CVD and vasculogenic ED . Because decreased penile vascular flow may reflect underlying endothelial dysfunction , penile blood flow has been suggested as an additional diagnostic test to identify ED patients at risk for CVD . Decreased penile blood flow appears to be sensitive enough to correlate with silent coronary ischaemia before overt manifestations of CAD . Furthermore, reductions in penile blood flow in both the flaccid state or during stimulation with vasodilators have been associated with an increased risk of a major cardiovascular event . Although the literature strongly supports an association between ED and endothelial dysfunction, mechanistic studies have not been performed. Hence, the possibility that these conditions result from a common disease, rather than a cause-and-effect relationship, cannot be ruled out.
A number of studies have demonstrated that endothelial dysfunction leading to ED is rarely limited to the penile vessels. Kaiser et al. reported that patients with ED but without overt systemic vascular disease had impairments in peripheral endothelium-dependent and -independent vasodilation in the absence of traditional cardiovascular risk factors . There was also a significant relationship between the number of circulating endothelial microparticles and the severity of ED in diabetic men . In men with type 2 diabetes and ED, reductions in blood pressure and platelet aggregation in response to intravenous L-arginine were attenuated compared with those without ED . Endothelial cell activation is an important early manifestation of the atherosclerotic process. Bocchio et al.  studied endothelin-1, intercellular adhesion molecules, soluble cell adhesion molecules and P-selectin in men with and without ED. They found that these products were increased in the blood of men with ED, even before penile blood flow was reduced. Vlachopoulos et al.  reported that presence and severity of ED was associated with markers and mediators of subclinical inflammation [e.g. high-sensitivity C-reactive protein (hsCRP), cytokines] and endothelial-prothrombotic activation (e.g. von Willebrand Factor plasminogen activator inhibitor-1, fibrinogen) in men with and without CAD. Additional emerging independent markers of vasculogenic ED presence and severity include endothelial cell-derived factors that participate in the regulation of corporal muscle tone (e.g. endothelin-1, angiotensin II, C natriuretic peptide, asymmetric dimethyl-arginine) or indicate increased endothelial cell damage or repair (e.g. endothelin-1, monocyte oxidative activity, endothelial microparticles, endothelial progenitor cells) . Despite ample published support for endothelial dysfunction as a pathophysiologic link between CVD and vasculogenic ED, the lack of a simple, cost-effective, sensitive, and specific method of assessment limits the utility of endothelial function as a predictor of cardiovascular events.
ED as a predictor of vascular disease, cardiovascular mortality, and all-cause mortality
Men with known CVD , hypertension  or type II diabetes [3, 28] have an ED prevalence of approximately 70%. It follows that clinical enquiries about sexual function should be part of the overall evaluation of cardiac patients and be integral to evidence-based guidelines.
Although large-scale, population-based studies evaluating the incidence of asymptomatic CVD in patients with ED have not been performed, studies in men with clinically evident CVD have confirmed that ED is an independent marker of increased CVD risk [29-34] and commonly precedes clinical CAD [26, 35-38], peripheral arterial disease (PAD)  and stroke . The artery-size hypothesis  may help explain why patients with CAD frequently report ED before CAD detection. Because the lumen of the penile arteries (1–2 mm) is considerably smaller than that of the coronary (3–4 mm), carotid (5–7 mm), and femoral (6–8 mm) arteries, endothelial dysfunction or plaque burden that significantly impairs circulation in the penile arteries may be associated with subclinical plaque disease of the larger vessels. Thus, atherosclerosis sufficient to trigger ED may not be sufficient to cause ischaemic symptoms in other vascular beds (Table 1). This concept has particular prognostic importance in light of evidence that many myocardial infarctions (MIs) result from rupture of non-obstructive, lipid-rich atherosclerotic plaques .
Table 1. Artery size and atherothrombosis. A significant restriction to flow in the penile arteries may be subclinical in larger vessels 
|Coronary||3–4||Ischaemic heart disease|
Several studies suggest that ED has a predictive value for cardiovascular events that is comparable to or better than traditional risk factors. For example, in a population-based study of 1709 men aged 40–70 years, multivariate-adjusted analysis showed that moderate or complete ED was associated with hazard ratios (HRs) of 1.26 (95% CI, 1.01–1.57) for all-cause mortality and 1.43 (95% CI, 1.00–2.05) for CVD mortality . Similarly, hypertension was associated with HRs of 1.43 (95% CI, 1.15–1.78) and 1.43 (95% CI, 1.00–2.05), respectively. In multivariate-adjusted analyses of data obtained from men enrolled in the Prostate Cancer Prevention Trial, incident ED was associated with an HR for cardiovascular events [1.27 (95% CI, 1.05–1.55)] that was similar to those for smoking and family history of MI . Among 1549 men with known CVD who participated in the ONTARGET/TRANSCEND trial, ED was significantly predictive of all-cause death and a composite of cardiovascular death, MI, stroke, and hospitalisation for heart failure after adjustment for confounding characteristics . A meta-analysis of 12 prospective studies involving 36,744 men (Table 2) confirmed a statistically increased overall risk for CVD, CAD risk, stroke risk and increase in all-cause mortality in men with ED and no cardiac symptoms . In this study and a study of men with known CVD , ED was found to be an independent marker for cardiovascular events and all-cause mortality additional to conventional risk factors.
Table 2. Relative risks for men with ED vs. no ED 
|Overall CVD||1.48||1.25–1.74||< 0.001|
Results of three different studies suggest that the predictive strength of ED for CVD events is stronger in younger than in older men. Data from the Olmstead County Study demonstrated that ED in men 40–49 years of age was far more predictive of CAD than ED in older men (Table 3) . Younger age (20–29 and 30–39 years age groups) at first manifestation of ED also increased predictive value for cardiovascular events sevenfold in a retrospective study by Chew et al. . Most recently, a case–control study involving 242 men (mean age, 58 years) referred for elective coronary angiography showed that men < 60 years with CAD were significantly more likely to have ED than those without CAD. CAD was not associated with increased likelihood of ED in men ≥ 60 years . These data support ED as a powerful marker of cardiovascular risk in men in their 3rd, 4th, 5th and 6th decades, with markedly weakened prognostic potential in older men.
Table 3. Age-stratified associations between erectile dysfunction and incident coronary artery disease 
|40–49||21||2655||2.7 (0.9–8.1)||0.08||2.1 (0.7–6.4)||0.19|
|50–59||33||2882||1.3 (0.5–3.1)||0.62||1.1 (0.5–2.8)||0.79|
|60–69||57||1834||1.5 (0.9–2.6)||0.15||1.4 (0.8–2.4)||0.22|
|≥ 70||43||904||0.7 (0.3–1.2)||0.19||0.6 (0.3–1.2)||0.17|
Although the aforementioned studies provide ample support for ED as a predictor of CVD events in younger and middle-aged men, only one study has assessed the potential of ED to improve CVD prediction beyond traditional risk factors. In a population-based study of men 40–70 years of age, addition of ED status to the Framingham Risk Score (FRS) in a multivariate statistical model resulted in reclassification of 5 of 78 (6.4%) low-risk patients to intermediate risk . However, the net reclassification improvement (3.1%) for ED was not statistically significant. Addition of ED to other risk calculations or templates has not been performed.
Temporal relationship between onset of ED symptoms and clinical CVD
Several reports have shown that ED symptoms are likely to precede cardiovascular events, particularly CAD. Montorsi et al. found that 49% of 300 consecutive men with acute chest pain (admitted to coronary care) and angiographically confirmed CAD (i.e. acute c