Anatomy, Pathophysiology, Molecular Mechanisms, and Clinical Management of ED in Patients Affected by CAD

[madman]

Abstract

Erectile dysfunction (ED) has been defined as the inability to attain or maintain a penile erection sufficient for successful sexual intercourse. ED carries a notable influence on life quality, with significant implications for family and social relationships. Because atherosclerosis of penile arteries represents one of the most frequent ED causes, patients presenting with it should always be investigated for potential coexistent coronary or peripheral disease. Up to 75% of ED patients have a stenosis of the iliac-pudendal-penile arteries, supplying the male genital organ’s perfusion. Recently, pathophysiology and molecular basis of male erection have been elucidated, giving the ground to pharmacological and mechanical revascularization treatment of this condition. This review will focus on the normal anatomy and physiology of erection, the pathophysiology of ED, the relation between ED and cardiovascular diseases, and, lastly, on the molecular basis of erectile dysfunction.




1. Introduction

The Fourth International Consultation on Sexual Medicine has defined erectile dysfunction (ED) as the consistent or recurrent inability to attain and maintain penile erection sufficient for sexual satisfaction [1] ED is classified as organic, psychological, or resulting from several simultaneous (mixed) factors, the most frequent form. Today, it is still problematic to accurately estimate the impact and the incidence of ED because of social, ethical, cultural, and religious reasons. Moreover, many men are convinced that sexual impairment is an inevitable feature of late age [2,3] leading to reduced and delayed medical advice.

The global mean ED prevalence ranges from 14% to 48%, with higher rates in the US and South East Asia than European rates [1,4]. In the U.S., at least 12 million men between 40 and 79 years of age have ED. In contrast, Italy has reported a prevalence of ED (complete and incomplete) of 12.8% and a significant incidence of age-related ED (2% between 18 and 30 years and 48% over 70 years) [5]. Based on the Massachusetts Male Aging Study (MMAS) data, over a population range between 40 and 70 years, ED increased with age from 5.1% to 15% and from 17% to 34% for complete and moderate ED, respectively; mild ED remained stable at about 17% over the years. Furthermore, the prevalence of ED worldwide will be estimated to reach 322 million men by 2025 [6]. Perhaps, this percentage is significantly underestimated.

Increasing evidence suggested an association between ED and cardiovascular diseases (CVD) [7] with an increased prevalence of ED in cardiovascular patients and an increased prevalence of CVD in patients with ED [8]. However, among clinical manifestations of atherosclerotic disease, ED usually proceeds by approximately five years the onset of coronary diseases, such as coronary disease, begins five years early the onset of carotid and peripheral disease with claudication [9].

Performance anxiety and relationship issues are commonly recognized psychological causes of ED. Still, its prevalence is also related to several age-independent comorbidities, such as congestive heart diseases, atherosclerosis, blood hypertension, and other vascular disorders, psychiatric disorders (depression), endocrine disorders (diabetes, reduction of testosterone), neurological disorders, and concomitant other genitourinary disease-related to surgery [10].

*This review will summarize the mechanism of men’s erection, focusing on pathophysiology and molecular mechanisms of erectile dysfunction, with a glimpse of the clinical linkage between cardiovascular disease and ED.




2. Anatomy of Erection

3. Vascular Events of Erection

4. Molecular Basis of Erectile Dysfunction

5. Erectile Dysfunction and Cardiovascular Diseases

6. Guidelines for Therapeutic Management of Erectile Dysfunction

7. New on the Horizon: Regeneration Strategies for ED
7.1. Platelet-Rich Plasma and ED
7.2. Stem Cell Therapy and ED




8. Conclusions

Erectile dysfunction is common in CVD patients, and it is clear that it may represent a significant earlier predictor of cardiovascular events and cardiovascular death. Usually, there is a 3 to 5 years-time interval between the onset of ED and cardiovascular event. Thus, sexual function assessment should be incorporated into CVD risk stratification for all men since it is tightly associated with the same risk factors and share several common molecular and pathogenetic mechanisms related to endothelial dysfunction and atherosclerotic plaque formation. It should be considered that a comprehensive reduction of major cardiovascular risk factors improves overall vascular health, including sexual function.

 

[madman]

Figure 1. Pathways of penile erection: Dilation of cavernosal arteries and smooth muscle cells (SMCs) of cavernosal spaces is mediated by the nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) pathway. NO is derived from nonadrenergic, noncholinergic nerves (nNOS, NOS type I), and the endothelium (eNOS or NOS type III) of cavernosal sinuses (both calcium2+/calmodulin-dependent isoforms). NO crosses plasma membranes to enter vascular smooth muscle cells (VSMCs) and promotes the synthesis and accumulation of cGMP, which induces a cascade reaction, leading to smooth muscle relaxation by reducing intracellular calcium levels. NNOS = neuronal nitric oxide. ENOS = endothelial nitric oxide. See the text for details. A physiological penile erection requires normal vascular, neurological, and tissue responses. Penile erection is initiated after the central stimulus and integration of tactile, visual, olfactory, and imaginative triggers. Different observations demonstrate a network of afferent fibers from the genitals, spinal interneurons, and sympathetic, parasympathetic, and somatic nuclei, receiving stimulus from the periphery at the spinal cord level triggering reflexive erections. This network seems to receive also supraspinal information. At the level of the central nervous tissue, afferent data is processed in the forebrain and hypothalamus. In this latter area, the medial preoptic center, paraventricular nucleus, and anterior hypothalamic regions regulate erections and modulate autonomic events associated with sexual response. Different efferent pathways are present between the hypothalamus and sacral autonomic centers represented by the thoracolumbar and sacral autonomic nuclei. The erectile activity is finally coordinated by autonomic fibers network to the penis and somatic fibers pathways to the perineal striated muscles, responsible, in turn, for penis sensation. The cavernosal nerves originate from the autonomic system and are made of both sympathetic and parasympathetic fibers. These fibers travel along the prostate and enter the corpus spongiosum and the corpora cavernosa to regulate the blood flow during erection. The central regulation of penile erection involves many transmitters, but their specific function is unknown [19,20]. Nerve impulses trigger neurotransmitters’ release and relaxing factors from the endothelial cells, resulting in smooth muscle cells’ Figure 1. Pathways of penile erection: Dilation of cavernosal arteries and smooth muscle cells (SMCs) of cavernosal spaces is mediated by the nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) pathway. NO is derived from nonadrenergic, noncholinergic nerves (nNOS, NOS type I), and the endothelium (eNOS or NOS type III) of cavernosal sinuses (both calcium2+/calmodulin-dependent isoforms). NO crosses plasma membranes to enter vascular smooth muscle cells (VSMCs) and promotes the synthesis and accumulation of cGMP, which induces a cascade reaction, leading to smooth muscle relaxation by reducing intracellular calcium levels. NNOS = neuronal nitric oxide. ENOS = endothelial nitric oxide. See the text for details.

 

[madman]

Figure 2. Molecular basis of nitric oxide (NO) reduction in erectile dysfunction. (Bullet 1) Superoxide (O2 −) inactivates NO to form peroxynitrite (ONOO−). Peroxynitrite attacks and destroys tetrahydrobiopterin (BH4), a critical cofactor in NO synthesis. (Bullet 2) Advanced glycation end products (AGEs) promote superoxide formation, as well as directly inactivate NO. (Bullet 3) Arginase II degrades L-arginine, a substrate required for NO synthesis. (Bullet 4) Androgen deficiency reduces the expression of the endothelial isoform of NO synthase (eNOS). (Bullet 5) Rho-kinase reduces the expression and phosphorylation of eNOS, which is required for its full activation. P = eNOS phosphorylation.

 

[madman]

Table 1. Etiologies of Erectile Dysfunction (ED).

 

[madman]

Figure 3. Luminal narrowing due to atherosclerotic burden will manifest clinically earlier in penile arteries (smaller caliper) than in coronary, carotid, or iliac district (larger caliper). This explains why ED represents the “tip of the iceberg” of systemic atherosclerotic disease, and it is usually the first “alert sign” to manifest before a major cardiovascular event (Modified from Reference [9]). TIA, transient ischaemic attack.

 

[madman]

Figure 4. Cardioprotective effects of PDE5i in patients affected by acute myocardial infarction. Reduction of infarct size related to decrease myocardial cells’ apoptosis, decrease in afterload due to increase vasodilatation and increase in systolic function has been demonstrated (Modified from Ref. [70]).