Linking erectile dysfunction and coronary artery disease

Abstract

Coronary artery disease (CAD) and erectile dysfunction (ED) are both highly prevalent conditions that frequently coexist. Additionally, they share mutual vascular risk factors, suggesting that they are both manifestations of systemic vascular disease. The role of endothelial dysfunction in CAD is well established. Normal erectile function is primarily a vascular event that relies heavily on endothelially derived, nitric oxide-induced vasodilation. Accordingly, endothelial dysfunction appears to be a common pathological etiology and mechanism of disease progression between CAD and ED. The risk factors of diabetes mellitus, hypertension, hyperlipidemia, obesity and tobacco abuse contribute to endothelial dysfunction. This article reviews the role of vascular endothelium in health, the abnormalities resulting from vascular risk factors, and clinical trials evaluating the role of endothelial dysfunction in ED.

Introduction

Coronary artery disease (CAD) and erectile dysfunction (ED) are both highly prevalent conditions that frequently occur concomitantly.1, 2, 3, 4, 5, 6 They share mutual risk factors, including diabetes mellitus (DM), hypertension, hyperlipidemia, obesity and tobacco abuse.1, 2, 3, 4 As the number of cardiovascular risk factors increase, so does the incidence of both CAD and ED.3, 4 These similarities have led to a renewed interest in further defining the similarities between these diseases.

Atherosclerosis is a systemic disease, and it is reasonable to expect penile atherosclerosis and resultant ED to occur in patients with CAD. In a review of seven major studies including 700 cardiac patients, Montorsi et al1 found the rate of ED in patients with CAD to be as high as 42–57%. Likewise, Gazzaruso et al2 found the incidence of ED in diabetic patients with silent ischemia to be 33.8%, compared to 4.7% in those without silent ischemia. Other studies have correlated erectile function score with coronary plaque burden and number of diseased coronary arteries.7, 8

Conversely, ED may also be a harbinger of other vascular disease. Montorsi et al's1 review reported that in patients with ED, the incidence of positive exercise stress testing ranged from 5 to 56%. Another study reported that in patients found to have CAD at angiography and clinical ED, 67% reported experiencing symptoms of ED prior to coronary symptoms. Impressively, 100% of type I diabetic patients experienced sexual dysfunction prior to the onset of CAD. In all patients, sexual symptoms occurred a mean of 38.8 months prior to their cardiac symptoms.9 In a study of patients with vasculogenic ED, Shamloul et al10 found that a penile peak systolic velocity <35 cm/s had a specificity of 100% for predicting ischemic heart disease. Men with ED have also been found to be at higher risk of myocardial infarction and peripheral vascular disease.11, 12 These discoveries have created advocates for considering ED as a penile angina.

As CAD and ED overlap in prevalence and risk factors, they are also thought to share pathological basis of etiology and progression.13 The role of endothelial dysfunction is well established in coronary artery disease and its risk factors.14, 15 Normal erectile function is primarily a vascular event that relies heavily on vasodilation, which occurs largely due to endothelially derived nitric oxide (NO).16, 17, 18 Systemic endothelial-dependent vasodilation is decreased in men with ED.19, 20 Accordingly, endothelial dysfunction has been implicated as a common mechanism between CAD and ED. This review will highlight the mechanisms and consequences of endothelial impairment seen in the disease processes associated with CAD and ED.

Normal endothelial function

The luminal surface of blood vessels is lined with a single layer of cells known as the endothelium. It is a semipermeable membrane that interacts with the circulating blood components. The endothelium has a variety of synthetic and metabolic capabilities that enable it to regulate the coagulation cascade, the functions of circulating cells, as well as local vasodilatory and constrictive responses. Through these multiple functions, the endothelium (in its healthy state) is primarily responsible for enabling the arterial system to deliver sufficient tissue perfusion.21 Endothelial disease impairs the regulation of these important events, and thereby jeopardizes the adequacy of tissue oxygen delivery.

Regulation of the coagulation cascade

Endothelial cells have dichotomous functions in regulating the coagulation cascade. In a normal physiologic state, healthy endothelium serves as an anticoagulant membrane, exerting predominantly fibrinolytic, anticoagulant and antiaggragatory effects. These effects occur with the expression of anti-thrombin III (inhibiting fibrinogen to fibrin conversion), heparin-like molecules (which enhance anti-thrombin III activity), and tissue factor pathway inhibitor (which inactivates the extrinsic pathway). They also secrete tissue-type plasminogen activator (tPA). Additionally, endothelial cells bind thrombin, leading to protein C activation and eventually inactivation of plasminogen activator inhibitor 1.21 In a hemostatic response, they produce key components of platelet activation and aggregation, including von Willebrand factor (vWf), fibronectin and thrombospondin, ultimately leading to the initiation of the coagulation cascade.22 These dynamic thrombotic functions are important, as thrombus formation is a key element in atherosclerosis progression.

Regulation of inflammatory cells

The endothelium regulates transmigration of circulating cells through a complex interplay of trans-signaling molecules. Endothelial cells recruit inflammatory cells via expression of cell adhesion molecules such as selectin and immunoglobulin superfamily adhesion molecules, and by responding to proadhesion signals from circulating cytokines.23 Platelets also have a range of endothelial signaling abilities, including the release of vasodilating agents (such as ADP and serotonin), as well as vasoconstricting and procoagulant factors (such as endothelin-1 and vWf). The effects of these circulating cell signals can further be attenuated by some endothelially derived substances such as NO and prostacyclin.21

Regulation of vasodilation/vasoconstriction

The endothelium produces and reacts to several vasodilator and vasoconstrictor mediators. Vascular flow regulation results from local coordination of these influences to maintain steady and adequate tissue perfusion.24 One of the key contributors to vascular tone is NO, which is produced by endothelial nitric oxide synthase (eNOS).25 As a freely diffusible gas, NO acts not only within the lumen but also on the surrounding smooth muscle cells where it increases cyclic guanosine monophosphate (cGMP)-mediated vasodilation.21 Endothelial cells also produce a number of prostaglandins, most notably prostacyclin (PGI2) and thromboxane A2 (TXA2). PGI2 initiates cyclic adenosine monophosphate (cAMP)-mediated smooth muscle relaxation, while TXA2 causes vasoconstriction. In normal physiologic conditions, PGI2 exerts the predominate vascular effects.26 Another endothelially released factor with variable vascular influences is angiotensin II. This peptide has vasoconstricting, prothrombotic, oxidant and atherogenic effects, as well as the ability to counteract these effects depending on the receptor (subtype AT1 or AT2) activated. The endothelium also stimulates the production of bradykinin, which further results in the release of the vasodilating agents NO and endothelium-derived hyperpolarizing factor (EDHF). In contrast, the endothelium also produces the vasoconstricting hormones known as the endothelins.21

As the exact roles of each of these agents in health and disease are delineated, it is clear that the endothelium has a diverse role in maintaining vascular tone as well as arterial flow through a variety of mechanisms. Furthermore, a disruption in these regulatory functions at any level could lead to impaired and insufficient tissue perfusion.

Endothelial dysfunction

Endothelial dysfunction has gained increasing notoriety as a key player in the pathogenesis of atherosclerosis.27 As atherosclerosis is the commonest cause of vasculogenic erectile dysfunction in older men, it is frequently considered another manifestation of vascular disease.1, 28 The mutual risk factors shared by ED and CAD each contribute to endothelial dysfunction. Just as the presence of these risk factors overlaps within patient populations, so do their effects on the endothelium. The mechanisms and manifestations of endothelial dysfunction are outlined here.

Diabetes mellitus

Diabetic men with impotence have dysfunctional neurogenic and endothelium-dependent penile smooth muscle relaxation.29 On a cellular level, there may be impairment of the L-arginine NO pathway at a number of sites. While the precise mechanisms have not been clearly defined, endothelial damage may either decrease basal release of NO, or may lead to increased breakdown. Furthermore, eNOS activity may be attenuated by accumulation of NOS inhibitors.15 Proposed mechanisms of altered NO bioactivity include lack of cofactors essential for NOS activity,30, 31 overproduction of NOS inhibitors such as asymmetric and symmetric dimethylarginine (ADMA and SDMA),32 and altered NO formation due to adverse effects of advanced end-product glycosylation.33, 34 In addition to endothelial alterations, vascular smooth muscle cells appear to have a blunted response to NO.15, 35 Additionally, increased plasma and corporal body endothelin levels have been seen in diabetic men with ED.36, 37 This appears to be important in the pathogenesis of ED, as ET-1 is a key factor in maintaining corpus cavernosal smooth muscle tone.38, 39

While not completely defined, manifestations of endothelial dysfunction may differ between type I and II DM.15

Type I

Studies on endothelial dysfunction in type I DM have been conflicting, and may be related to degree of glycemic control and disease duration. Several (but not all) studies have demonstrated forearm endothelial dysfunction, as well as impaired endothelial-dependent microvascular responses. Most studies reveal preserved responses to endothelium-independent agonists, suggesting decreased NO bioactivity.15 Endothelial function may also be related to microalbuminuria, which appears to influence endothelium-dependent and -independent vasodilation.40, 41

Type II

Patients with type II DM have impaired vasodilation in response to both endothelium-dependent and -independent agonists.20 These patients also have increased generation of reactive oxygen species (ROS),42 which damage endothelial cells either directly, or indirectly via effects on lipid peroxidation and by scavenging NO to produce peroxynitrite, a potent oxidant.15 Patients with type II DM also tend to have smaller LDL particles that are more susceptible to oxidation; oxidized LDL, in turn, damages the endothelium, and has been shown in animals to inhibit endothelium-dependent vasodilation to a greater degree than native LDL.43

It should be noted that DM can adversely affect erectile function through a number of other mechanisms. Significant neurologic alterations also appear to play an important role. Peripheral and autonomic neuropathy decreased release of acetylchoine by cholinergic nerves, and sparse penile noradrenergic nervous innervation are a few of the proposed neurologic derangements contributing to ED.44, 45, 46, 47

Hypertension

The hallmarks of primary hypertension are increased peripheral sympathetic activity, increased vasoconstrictor tone and decreased endothelium-dependent vasodilation.48, 49, 50 Some cases of hypertension-associated endothelial dysfunction may be related to eNOS gene variations.51, 52 Changes in the cyclooxygenase pathway also appear to play a major role, as increased COX activity can lead to increased ROS, with further disruption of ‘normal’ endothelial activity.50, 53, 54 Decreased NOS levels in essential hypertension have been reported, as well as muted vasoconstrictor response to L-NMMA, although this is not a universal finding.55 It should be emphasized that dysfunctional endothelium-dependent vasodilation is not merely a cause of hypertension; it exists in several disease states (as outlined here), and degree of endothelial dysfunction does not correlate with blood pressure values.15

Hypertension plays an etiologic role in ED beyond its correlation with endothelial dysfunction. Structural alterations with vascular and corporal remodeling occur that reduce vasodilatory capacity.56 Animal studies have also revealed vascular smooth muscle proliferation and fibrosis.57 Clearly, endothelial dysfunction is one of many vascular disturbances that occur in hypertension and appears to contribute to ED.

Dyslipidemia

Hypercholesterolemia has a well-established link to endothelial dysfunction, with oxidized low-density lipoprotein being a key mediator. In familial hypercholesterolemia, endothelial dysfunction is seen prior to clinical arterial disease.15 Even in the setting of angiographically normal coronary arteries, reduced endothelium-derived NO bioavailability has been seen in the setting of hypercholesterolemia.58 Endothelial dysfunction is not only related to LDL concentration but also to LDL size, with smaller particles being associated with such dysfunction. In general, however, there does not appear to be an alteration in endothelial NO, tPA or ET-1 levels.15 There are emerging data suggesting that high-density lipoprotein may independently and favorably effect endothelial function.59, 60, 61 The effects of hypertriglyceridemia, however, are less clear.

Obesity

Disturbed endothelial function has been seen in both resistance and conductance arteries of the obese patient, independent of other vascular comorbidities.15 One mechanism may be the apparent relationship between obesity and a chronic inflammatory state. Elevated levels of the circulating intercellular adhesion molecules-1 (ICAM-1), vascular adhesion molecule (VCAM-1), E and P selectins, tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6) have been reported in obese men and women.62, 63 These cytokines have been demonstrated to influence endothelial function,64 and are key contributors in the early atherogenic process.65 Additionally, this inflammatory process can be a source of oxidative stress, leading to free radical formation and thereby secondarily decreasing NO bioavailability. It has been suggested that COX and ROS may be contributors to endothelial dysfunction in obesity.66 Finally, obese patients appear to have greater basal ET-1 vascular tone that contributes to impaired endothelium-dependent vasodilation.67

Smoking

Tobacco smoke has direct toxicities to endothelial cells, causing architectural and functional changes. These include decreased eNOS activity, increased adhesion expression and impaired regulation of important thrombotic factors. These adverse effects are related in part to ROS endothelial damage, and seem to be dose-related.15

Implications of endothelial dysfunction in CAD

Endothelial dysfunction plays a key role in the progression of atherosclerosis, contributing to exaggerated intimal proliferation and malregulation of the inflammatory processes that can lead to arterial plaque destabilization. When coupled with paradoxical vasoconstriction and improper ‘policing’ of vascular thrombosis, this can lead to catastrophic events such as seen with acute coronary syndromes and myocardial infarctions.14 Impaired endothelium-dependent vasomotion has been correlated with increased myocardial ischemia and events,68, 69 independent of traditional associated cardiac risk factors.70

Impaired endothelium-independent vasodilation in ED

Men with ED also appear to have impaired endothelial-dependent and -independent vasodilation beyond that accounted for by vascular risk factors. Yavuzgil et al compared brachial artery flow-mediated dilation (FMD) and nitroglycerine-mediated dilation (NMD) in three sets of patients: those with presumed vasculogenic ED and cardiac risk factors, those with similar risk factors but no ED, and a control population without cardiac risk factors or ED. They found that brachial artery FMD and NMD were significantly reduced in patients with ED compared to healthy controls. Patients without ED but who had similar risk factors had decreased FMD, but not NMD compared with healthy controls. This suggests impairment in endothelial-independent vasodilation.19 This study confirmed earlier findings by Kaiser et al, who also compared patients with ED and no known CAD to a healthy control group. They too discovered patients with ED to have impaired FMD and NMD compared with controls.20 It remains to be seen whether this discrepancy in endothelial-independent vasodilation may confer additional cardiovascular risk beyond that of the traditional cardiac risk factors.

Hormone therapy

Little is known about the effects of hormone therapy in patients with CAD and ED. The beneficial effects of the hormone replacement therapy in non-elderly hormone-deficient individuals raised the hope that hormone substitutes might reverse symptoms of ED as well.

The three male endocrine axes are characterized by age-related changes in the concentrations of circulatory hormones:71

  1. 1)

    Hypothalamic–pituitary–testicular axis with lower serum level of testosterone.

  2. 2)

    Hypothalamic–adrenal axis with gradual decline in dehydroepiandrosterone (DHEA).

  3. 3)

    The growth hormone (GH) insulin-like growth factor (IGF).

The debate on the role of testosterone is still ongoing. Testosterone replacement definitely should be used in men who have deficiency in their male hormone levels, occasionally in men with borderline low levels of testosterone and never used in men who have normal or elevated levels of androgens.72

Human GH has become an important topic in the field of anti-aging medicine.

GH may play an important role in maintenance of penile erection function perhaps by promotion of the NO-cGMP pathway, stimulating the regeneration of the NO containing nerve fibers and the augmentation of the androgenic action.73

Lis et al74 found in an animal study that GH can improve erectile function of internal iliac ligation rats, which can be explained by the increase in the number of neuronal NOS-containing nerve fibers in corpus carvosum of rats.

However, due to the insulin antagonistic effect of GH as well as its IGF-I-mediated mitogenic effect, there is a question about its safety.75

Gene therapy

Gene and growth factor and stem cell therapy might provide future options in the management of patients with CAD and ED.

Nitric oxide (NOS) is synthesized by eNOS and neuronal NOS (nNOS) in the penis. Recently, the role of gene therapy has been studied in different animal models.76 In a study by Bivalacques et al, the effects of combination eNOS synthase gene therapy and sildenafil on erectile function in diabetic rats were studied. The study showed that the cavernosal cGMP levels were significantly decreased in diabetic rats but increased after transfection with AD CMV eNOS compared with controls. Overexpression of eNOS and cGMP in combination with sildenafil significantly increased both peak intracavernosal pressure (ICP) and total ICP to CNS of diabetic rats, similar to controls. The overall erectile response was greater in diabetic rats receiving eNOS gene therapy and sildenafil than rats receiving sildenafil or eNOS gene alone.77, 78, 79

Another in vivo study used adenovirally mediated transfer of eNOS gene with or without cGMP PDE, showing promising results as a future treatment for ED.80

Myoblast-mediated gene therapy was tested in vivo and was more superior in delivering inducible NOS into the corpus cavernosum than direct adenovirus or a plasmid transfection method.81 Future therapy may also involve augmentation of K+ channel expression by gene transfer or increasing channel function by using PDE-5.82 Currently, however, direct vaso-active therapy by use of PDE-5 inhibition seems to be the most realistic option for the treatment of ED, in particular also in patients with endothelial dysfunction and stable CAD.

Conclusion

CAD and ED are common diseases that frequently coexist. In addition to sharing common risk factors, they appear to share a common pathological basis: endothelial dysfunction. Altered inflammatory and vasodilator endothelial regulation appears to carry clinical implications independent of the associated vascular risk factors. Symptoms of ED may precede clinical cardiac manifestations, and should prompt a cardiac risk assessment. Understanding the etiology and role of endothelial dysfunction at a cellular level may provide insight into common screening and treatment modalities.

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Correspondence to E R Schwarz.

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Rodriguez, J., Al Dashti, R. & Schwarz, E. Linking erectile dysfunction and coronary artery disease. Int J Impot Res 17, S12–S18 (2005). https://doi.org/10.1038/sj.ijir.3901424

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Keywords

  • endothelial dysfunction
  • coronary artery disease
  • erectile dysfunction
  • atherosclerosis
  • vascular disease
  • sexual function

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