Introduction:

There is growing evidence that ED is an early sign of cardiovascular disease (CVD). ED is an important marker of vascular disease throughout the arterial tree including coronary artery disease (CAD), stroke and diabetes. Epidemiological studies have confirmed that there is a close association between ED and vascular disease. A recent study in 76 men with chronic stable CAD showed that 75% had ED, to some degree (1). The risk factors for ED –hypertension, smoking, abnormal lipid profile and diabetes – are also risk factors for CAD. The relative risk of ED increases 1.5- fold with hypertension and doubles with hyperlipidemia. The Massachusetts Male Ageing Study, a random-sample cohort study of men aged 40–70, investigated the relationship between baseline risk factors for coronary heart disease (CHD) and subsequent ED, on the premise that subclinical arterial insufficiency might be manifested as ED. Results in 513 men with no ED at baseline revealed that cigarette smoking almost doubled the risk of ED over 8–10 years of follow-up (24 vs. 14%, adjusted for age and covariates). Overweight (body mass index (BMI): >28 kg/m2) and a composite coronary risk score also significantly predicted incident ED.

Associations were also seen for hypertension and dietary intake of cholesterol and saturated fat (2). Additionally, looking at CHD risk factors measured in mid-life could predict the incidence of ED an average of 25 years later. A study, which assessed seven classic CHD risk factors in community dwelling men aged 30–69 from 1972 to 1974 and then again in 1998, found that mean age, BMI, cholesterol and triglycerides were each significantly associated with an increased risk of ED (3). Another study in 215 patients with ED showed that the prevalence of hypercholesterolemia was significantly higher than in matched controls without ED. Nearly three-quarters (70.6%) of the men with ED had hypercholesterolemia (total cholesterol >5.17 mmol/l), compared to 52% of those without ED (p50.06). After exclusion of confounding factors, logistic regression analyses showed that HDL cholesterol and total cholesterol/HDL-cholesterol ratio were significant predictors of ED. Increased 10-year CHD risk was found in more than half (56.6%) of patients with ED, compared to 32.6% in the control group (p<0.05). The researchers concluded that hyperlipidemia was common in men with ED, and their risk of later developing CHD was higher than in those without ED, so they suggested that ED might serve as a sentinel for CHD (4). A prospective study showed that one in four men with ED (aged 40–69) but without known CAD will develop symptomatic CAD in the subsequent 12 years (5). ED is particularly common in patients with diabetes, which triples the risk of ED. The United Kingdom Prevention of Diabetes Study (UKPDS) revealed that 20% of patients had ED at the time their diabetes was diagnosed (6).

Further studies have indicated that between 20 and 85% of men with diabetes develop ED (7). One study of men presenting with ED showed that 17% had previously diagnosed diabetes, 4.7% were previously undiagnosed and 12% had impaired fasting glucose (8). Glycemic control has been shown to correlate with ED – the poorer the glycemic control, the more severe the ED (7).

AETIOLOGICAL Association Between ED And CVD:

ED and CAD overlap in risk factors, pathological basis of disease and disease progression. The common underlying factor is endothelial dysfunction. Endothelial dysfunction measured as impaired vasodilation is prognostic for cardiovascular events, such as myocardial ischemia and stroke (9,10). The endothelium is the single layer of cells that line the luminal surface of blood vessels. Over the past few years, it has become increasingly apparent that it is far more than just a structural lining, with a range of important physiological functions. It acts as a direct interface between the components of circulating blood and local tissue, and regulates numerous local blood vessel functions, including vascular tone, cell adhesiveness, coagulation, inflammation and permeability (11).

The vascular endothelium plays an obligatory role in vasodilation. The role of the arterial vasculature is to provide adequate tissue perfusion and buffer changes in blood pressure and flow that occur with each cardiac cycle and during normal activities. At the tissue capillary level, blood flow remains relatively constant despite rapid changes in the tone of arterioles and venules. Regulation of flow depends on the ability to change the resistance of the vascular bed. The endothelium produces and responds to several potent, locally active mediators.

The most important of these is nitric oxide (NO) – a simple, highly reactive gas. Endothelial NO possesses potent anti-atherogenic properties, in addition to inhibiting platelet aggregation and regulating vascular tone (12). Bioavailable NO can be increased by enhancing its production or reducing its inactivation. NO is also protected against atherosclerosis by other mechanisms. Leucocyte adhesion, an inflammatory process contributing to plaque instability and rupture, is inhibited by NO. NO also has anti-thrombotic properties mediated through the inhibition of platelet aggregation and adhesion. Impaired endothelial function is associated with impaired platelet activation. NO induces endothelial vasodilation by increasing the cyclic guanosine monophosphate content of vascular smooth muscle cells, resulting in relaxation. Defects in the production or action of endothelial NO may explain the increased atherosclerosis seen in diabetes (13). Endothelial dysfunction plays a key part in pathogenesis and progression of atherosclerosis (14) and has been implicated as an early functional alteration that precedes structural changes of the vasculature. Cardiac risk factors – including dyslipidemia, hypertension and type 2 diabetes – are all associated with impaired endothelial function (13).

Downregulation of endothelial NO synthase (eNOS) with disease results in reduced bioavailability of NO which results in endothelial dysfunction. Hyperglycemia may additionally impair endothelial function by promoting release of free radicals. One potent free radical, superoxide anion, inactivates NO resulting in the production of peroxynities – a potent oxidant that stimulates the production of vasoconstrictor prostanoids. NO production is also reduced in the presence of free radicals. Oxidative stress leads to the upregulation of anti-oxidation enzymes, such as superoxide dismutase, producing hydrogen peroxide. Overall, a reduction in NO results in endothelial dysfunction (13).

ED As A Surrogate Marker For CAD:

There is growing evidence that ED can be considered as a useful surrogate marker for CAD, with studies showing that a large proportion of men develop the problem before cardiac symptoms become evident. One study showed that ED symptoms occurred before symptoms of CAD in 67% of men in a consecutive series presenting with chest pain and angiographically documented CAD. Note, all patients with type 1 diabetes and ED developed sexual dysfunction before CAD onset (p<0.001) (15).

The obvious reason why ED may present before other signs of CVD is because penile artery diameter is smaller (1–2mm) than the coronary artery (3–4mm) or carotid artery (5–7mm), so symptoms associated with atherosclerosis occur sooner (16). The degree of plaque sufficient to cause ED – blocking blood flow through the penile artery – causes only 30–40% stenosis in arteries of greater diameter. Detecting atherosclerosis this early stage could potentially prevent life-threatening events by facilitating appropriate intervention. Several studies have demonstrated that cardiovascular assessment of men with ED enables the detection of CVD. One study showed that ED presented well before anginal symptoms of CAD in 67% of men with a mean time interval of almost 3 years (15,16). Another study revealed that 45% of men with ED had previously undiagnosed hyperlipidemia, 5% had undiagnosed diabetes and 7% had undiagnosed hypertension (17).

ED as A Sentinel For Type 2 Diabetes:

ED is a very clear sentinel for type 2 diabetes and patients presenting with ED should be tested for diabetes. One study estimated that 12% of patients with diabetes were diagnosed during the evaluation of ED (19). Another study of 129 men presenting with ED revealed that 17% had previously diagnosed diabetes, 4.7% had previously undiagnosed diabetes and a further 12% had impaired fasting glucose. Disturbingly, urine dipstick testing would have missed 80% of these (8). The UKPDS clearly illustrated the potential for preventing complications by earlier diagnosis – in addition to 20% having ED, 35% had hypertension, 1% had an MI, 18% had abnormal ECG and 21% had retinopathy (20). Gazzaruso et al. also evaluated the presence of ED in 133 uncomplicated type 2 diabetic men with angiographically verified silent CAD and in 127 type 2 diabetic men without myocardial infarction at exercise ECG, 48-h ambulatory ECG and stress echocardiography. The findings showed a strong, independent association between ED and silent CAD in apparently uncomplicated type 2 diabetic patients (21).

There is a clear rationale for detecting diabetes as early as possible, because this has been shown to offer the potential for preventing long-term complications. If a patient with impaired fasting glucose or undiagnosed diabetes could be picked up earlier by checking glucose levels in men presenting with ED, it would be possible to achieve prompt control of glucose levels and make efforts to correct hypertension, abnormal lipid levels and reduce body weight, where appropriate. Patients could also be encouraged to make lifestyle changes, including reducing weight and increasing exercise levels, to reduce the risk of progressing to type 2 diabetes. Earlier detection would also be cost-effective, as 50% of the total costs of diabetes have been estimated to be the result of complications (22).

Practical Ways Of Detecting CVD And Diabetes In Patients With ED:

The clear evidence for ED as an ‘early warning sign’ or subclinical marker of CVD, including diabetes, supports improved efforts to find patients with ED and then to investigate them further for CVD. The possibility that patients might have silent CVD should be considered – and investigated – in men who present with ED, particularly when they have other cardiovascular risk factors (23). Primary care practitioners and nurses have a particularly important role in achieving early detection of ED by asking patients about the problem and then requesting further investigations into diabetes and CVD. Models in secondary care – such as male cardiovascular health clinics – have illustrated the feasibility and importance of considering ED and CVD at the same time. Patients referred to a urologist for investigation of ED could also be checked for signs of early cardiac disease.

Can We Treat ED In The Same Way As CVD?

Treatments that reduce damage to the endothelium will provide protection throughout vasculature, with potential benefits for preventing CVD as well as treating ED. A study in 400 hypertensives (mean BP: 154/94mmHg) treated with a range of antihypertensives showed that patients who showed improved flow-mediated dilation – indicating improved endothelial function – suffered fewer events (27). Treatments that can restore endothelial dependent vasodilation include antioxidants. Improvement has also been seen with L-arginine, although results have been variable. In the coronary circulation, statins improve endothelial function. Statins achieve multiple effects, in addition to reducing cholesterol. They increase NO formation in endothelial cells and increase eNOS expression. They also have anti-inflammatory effects (28–30).

Treatments that reduce damage to the endothelium will improve the entire vascular system – including the cardiovascular system and the vascular system of the penis – thus potentially improving both CVD and ED. Research has shown that PDE-5 inhibitors, such as sildenafil citrate, improve endothelial dysfunction significantly (31–33). It would be expected that this would reduce CVD, as well as providing effective treatment for ED (34). In addition, a less explained effect of PDE-5 inhibitors is that, in patients with diabetes, treating with a PDE-5 inhibitor to restore nocturnal erections and controlling other risk factors achieves a better clinical response in those patients achieving improved control of hypertension and lipid profile (35, 36, 37, 38).