Number 28, 2005
Sex and the Heart

Erectile dysfunction as an early indicator of cardiovascular and metabolic disease

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Kevin L. Billups
The EpiCenter for Sexual Health & Medicine, Edina and Department of Laboratory Medicine & Pathology, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA
Correspondence: Dr Kevin L. Billups, 7455 France Avenue South, Suite 362, Edina, MN 55435, USA.
Tel: +1 (612) 202 9082, fax: +1 (952) 226 3808, e-mail: klbillups@earthlink.net

Introduction
Over the past decade, the cascade of events that occur between the development of cardiovascular risk factors and the onset of symptomatic clinical cardiovascular disease has been intensively investigated and well characterized on a cellular and molecular level. Cardiovascular risk factors are known to lead to the development of asymptomatic subclinical cardiovascular disease (CVD), followed by symptomatic clinical CVD and organ damage as an endstage event (Figure 1).

Unique aspects of penile anatomy and erectile physiology
It is now widely accepted that organic erectile dysfunction in a substantial majority of men is attributable to underlying vascular causes, especially atherosclerosis [9–14]. Many men will note the onset of erectile dysfunction – specifically, difficulty being able to maintain a firm erection – before they are diagnosed with cardiovascular disease. The anatomic structure of the penis and the physiology of achieving and maintaining an erection provide clues as to why the penile vascular bed has some unique properties that facilitate early detection of systemic vascular disease.
Penile erection is the result of a complex and coordinated series of events involving vascular response, neuronal pathways, and psychosomatic stimulation. The nitric oxide pathway is activated upon sexual stimulation, and nitric oxide is released into penile smooth muscle from both the vascular endothelium of the penis and the autonomic, cavernous nerve terminals. Within the penile smooth muscle, nitric oxide activates guanylyl cyclase, which increases the concentration of the second messenger, cyclic guanosine monophosphate (cGMP). The increased concentrations of cGMP result in relaxation of arterial smooth muscle in the penis and increased inflow of blood. In addition, cGMP relaxes trabecular smooth muscle, which facilitates engorgement of the sinusoidal spaces and compression of the subtunical venules (Figure 3). The net result is complete occlusion of penile venous outflow and trapping of blood within the corpus cavernosa [9]. A functioning nitric oxide pathway is therefore a primary determinant of smooth muscle tone, arterial inflow, and restricted venous outflow in the physiology of erection. Disruption of any of these factors can lead to erectile dysfunction. Endothelial dysfunction, which is associated with impaired release and activity of nitric oxide, underlies the pathophysiology of vascular erectile dysfunction [5,6,8].

Clinical research studies supporting the idea of erectile dysfunction as an early marker of cardiovascular disease
Recently conducted studies that measured early markers of cardiovascular disease and endothelial dysfunction demonstrated that damage to the penile vascular bed occurs before clinically apparent CVD [17,18]. In one study, 30 men with Doppler-proven erectile dysfunction and no clinical evidence of cardiovascular disease (mean age 46 years) were compared with 27 healthy, age-matched controls across a number of measures for peripheral vascular structure and function (rapid computed axial tomography scan imaging for coronary calcification, aortic pulse wave velocity, and carotid intima media thickness [IMT]) and were not found to differ. However, they differed with respect to measures that assessed systemic endothelial function using flow-mediated brachial artery vasodilatation studies: when compared with controls, the men with erectile dysfunction exhibited significantly lower brachial artery flow-mediated, endothelium-dependent vasodilatation (P ≤ 0.05) and endothelium-independent vasodilatation (blunted response to 0.4 mg sublingual nitroglycerin; P = 0.02) [17].
In another study, biochemical markers of endothelial cell activation were used to compare 45 men with erectile dysfunction but no clinical cardiovascular disease with 25 age-matched normal individuals. Biochemical and structural markers compared between the erectile dysfunction and normal men included carotid IMT, soluble P-selectin, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and endothelin-1. Results revealed no difference in carotid IMT scores between the two groups, but soluble P-selectin, ICAM-1, VCAM-1, and endothelin-1 concentrations were significantly greater in the men with erectile dysfunction and no cardiovascular disease [18].
Results from these two clinical studies support the idea that erectile dysfunction precedes overt structural occlusion of larger blood vessels and is often an early manifestation of atherosclerosis and CVD. Erectile dysfunction probably begins as a nonobstructive, functional process caused by endothelial and smooth muscle dysfunction. As atherosclerosis and CVD progress, erectile dysfunction becomes more of a structural disease caused by occlusion of the penile cavernosal and helicine arteries.

Conclusions
Results from clinical research studies are suggesting that erectile dysfunction must now be considered an early marker of subclinical or undiagnosed cardiovascular and metabolic disease. The symptom of erectile difficulty occurs at all stages of the CVD cascade (Figure 2). Erectile dysfunction should be considered, not only as an early symptom of cardiovascular disease, but also as an emerging risk factor that significantly influences overall global cardiovascular risk and aggressive risk factor management strategies in men aged 25 years and older [19]. Such a fundamental shift in thinking could profoundly affect preventive vascular medicine.

FUNDING
Kevin L. Billups receives research and grant support from the Speakers’ bureau, and is a Consultant for Pfizer Inc. Speakers’ bureau and for Eli Lilly/ICOS.

REFERENCES