Managing concomitant cardiac disease and erectile dysfunction

Early studies of peak heart rates and blood pressure during coitus led physicians to believe that sexual activity represents a significant risk to patients with cardiovascular disease. Subsequent studies indicated, however, that the heart rate during coitus was no higher than the rate during unaccustomed physical exercise or associated with anger. The absolute risk of myocardial infarction (MI) in a patient with a history of MI has been found to be 10 per million per hour, and the doubling of this risk in the 2 hours following coitus has a negligible impact on annual risk. Coronary artery disease (CAD) is a powerful indicator of the presence of erectile dysfunction (ED), and the risk factors for ED are similar to those for CAD. Studies of sildenafil citrate use in patients with a history of cardiovascular disease have found sildenafil to be safe and effective, except for an absolute contraindication in the concomitant use of nitrates. Physicians should become familiar with the clinical guidelines for classifying ED patients with a history of cardiovascular disease as high risk, intermediate or indeterminate risk, and low risk. The guidelines permit physicians MIlow risk while deferring the resumption of sexual activity among higher risk patients pending further evaluation.     

Diabetes,obesity, and erectile dysfunction

Background: Diabetes mellitus (DM) and obesity affect large parts of the population in the United States and around the world. These disorders are among the most common risk factors for erectile dysfunction (ED), because of their effects on the vasculature and the hormonal milieu.Objective: This article reviews the current literature on the connection between DM, obesity, and ED.Methods: Using the search terms erectile dysfunction, endothelial dysfunction, hypogonadism, diabetes, and obesity, a systematic review of the available literature in the PubMed database was conducted. Relevant English-language publications (to August 2008) were identified.Results: ED is highly prevalent in men with both DM and obesity, and may act as a harbinger for cardiovascular disease (CVD) in this high-risk population. In addition to male hypogonadism and macrovascular disease, endothelial dysfunction is central to the connection between the metabolic syndrome and ED. Conversely, improved glycemic control and weight loss have been found to improve erectile function.Conclusion: ED is very prevalent in men with DM and obesity. It is increasingly being recognized as an early clinical indicator and motivator for patients with CVD. The role of pharmacologic ED treatments in improving endothelial function is currently being investigated.     

La dysfonction érectile, un marqueur précoce d’atteinte cardio-vasculaire

Erectile dysfunction (ED) affects approximately 100 million men in the world and 50% of men between the ages of 40 and 70 years. The commonest cause is a vascular disorder of penile arteries. ED may therefore be a an early marker of cardiovascular disease (CVD). The main arguments in favour of this assertion are primarily epidemiological, but also pathophysiological, as control of cardiovascular risk factors such as smoking, obesity and hypertension may prevent not only CVD, but also ED. This relationship is particularly strong in diabetic patients, in whom ED can be considered to be an element able to identify patients at risk of asymptomatic heart disease. From a pathophysiological point of view, small calibre penile vessels present signs of obstruction earlier than larger vessels because they are more sensitive to even minor haemodynamic changes. There is also a significant correlation between the severity of ED and the number of vessels affected in patients with coronary artery disease. Endothelial dysfunction is the common denominator underlying these diseases and therefore represents a major cause of ED. Preliminary studies have shown that PDE-5 inhibitors can reduce symptoms, improve exercise tolerance, and reduce endothelial dysfunction in patients after cardiac arrest and in diabetics. In the years to come, ED may therefore be added to the classical cardiovascular risk factors and could characterize a population with an increased risk of coronary artery disease.     

Cardiovascular risk factors, erection disorders and endothelium dysfunction

Upon sexual stimulation, penile erection, occurring in response to the activation of pro-erectile autonomic pathways, is greatly dependent on adequate inflow of blood to the erectile tissue and requires coordinated arterial endothelium-dependent vasodilatation and sinusoidal endothelium-dependent corporal smooth muscle relaxation. Nitric oxide (NO) is the principal peripheral pro-erectile neurotransmitter which is released by both non-adrenergic, non-cholinergic neurons and the sinusoidal endothelium to relax corporal smooth muscle through the cGMP pathway. Any factors modifying the basal corporal tone, the arterial inflow of blood to the corpora, the synthesis/release of neurogenic or endothelial NO are prime suspects for being involved in the pathophysiology of erectile dysfunction (ED). In fact, conditions associated with altered endothelial function, such as ageing, hypertension, hypercholesterolemia and diabetes, may, by changing the balance between contractant and relaxant factors, cause circulatory and structural changes in penile tissues, resulting in arterial insufficiency and defect in smooth muscle relaxation and thus, ED. There is increasing evidence to suggest that ED is predominantly a vascular disease and may even be a marker for occult cardiovascular disease. Recent results illustrating the importance of endothelial dysfunction in the pathophysiology of different forms of experimental ED are discussed. These pathways may represent new potential treatment targets.     

Total knee replacement surgery is followed by transitory endothelial dysfunction

Acute coronary syndrome (ACS) presents today the leading group of post-operative cardiovascular complications, while endothelial dysfunction (ED) is one of the key elements in its development. The chronic ED represents thus the basis for the gradual development of atherosclerotic changes, while its sudden aggravation leads to ACS. The persistent ED occurs due to the effects of chronic cardiovascular risk factors, while according to the available studies it can also develop or aggravate under the impact of different acute events. We have directed this study to the investigation of the dynamic of endothelial function before and after a major orthopaedic surgical intervention. This randomised prospective study included 19 patients that underwent the intervention of total knee replacement and 20 healthy examinees of the adequate age and gender High-resolution ultrasound test based on the flow mediated dilatation of the brachial artery is what at we carried out at the beginning of the research, respectively 12, 24, 48 and 72 hours, as well as 7 days after the surgical intervention. The starting values of the FMD test were within the normal range in both groups, although the ability of dilatation upon stimulus was significantly lower in the investigated group. The FMD percentage change in the total sample was negatively connected with the body weight, not having shown additional connections with other cardiovascular risk factors. During the early post-operative period, a significant transitory lowering of the FMD percentage change was recorded, having reached the lowest value 24 hours after the surgery. During the seven-day prospective surveillance, no significant cardiovascular complications were recorded. Further research is necessary in order to confirm these results as well as the testing of the possible connection of the described post-operative transitory endothelial dysfunction with the development of cardiovascular complications and the adverse event.     

Farnesoid X receptor activation improves erectile dysfunction in models of metabolic syndrome and diabetes

The metabolic syndrome (MetS) is an insulin-resistant state characterized by a cluster of cardiovascular risk factors, including abdominal obesity, hyperglycemia, elevated blood pressure and combined dyslipidemia. In this review, we discuss the potential of farnesoid X receptor (FXR) agonists in the treatment of erectile dysfunction (ED), a multifactorial disorder often comorbid with MetS. FXR not only regulates lipid and glucose homeostasis but also influences endothelial function and atherosclerosis, suggesting a regulatory role for this hormone nuclear receptor in the cardiovascular complications associated with the MetS, including ED. MetS induces ED via several mechanisms, and in particular through endothelial dysfunction in penile vessels. In a high-fat diet rabbit model of MetS, a 3-month treatment with the potent and selective FXR agonist INT-747 restores endothelium-dependent relaxation in isolated cavernous tissue, normalizing responsiveness to acetylcholine and to electrical field stimulation. Accordingly, eNOS expression in the penis is greatly up-regulated by INT-747 treatment. Experiments in a rat model of chemically-induced type 1 diabetes further demonstrate that INT-747 treatment preserves erectile function induced by electrical stimulation of the cavernous nerve. These results add a new facet to the pleiotropic activities mediated by FXR, and reveal novel beneficial effects of FXR activation with potential clinical relevance. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.     

Pharmaco-écho-doppler pénien: méthodologie, critères diagnostiques et indications actuelles dans l’exploration d’une dysfonction érectile

Erectile dysfunction (ED) is a common multifactorial disease, whose organic or mixed origin is currently considered as dominant in men aged 50 years and older. Most ED classified as arterial are linked to endothelial dysfunction in relation to the key factors of cardiovascular risk. ED is an indicator of vascular health in general. It is also a predictor of cardiovascular events, including coronary heart disease. It has also been associated with lower peripheral arterial disease and stroke. The penile doppler ultrasound examination is actually used relatively infrequently in the management of ED, the etiologic factors being considered most often not necessary for the therapeutic management, but also because of the absence of standardization. Nonetheless, large recent studies have shown that the vascular nature of ED, basis on doppler parameters recorded after intracavernous injection of vasoactive drugs, strengthened the predictive value of ED on events and cardiovascular mortality, justifying a highest interest in this test.     

Advanced glycation end-products: a common pathway in diabetes and age-related erectile dysfunction

Abstract

Reactive derivatives of non-enzymatic glucose-protein condensation reactions integrate a heterogeneous group of irreversible adducts called advanced glycation end-products (AGEs). Numerous studies have investigated the role of the AGEs in cardiovascular system; however, its contribution to erectile dysfunction (ED) that is an early manifestation of cardiovascular disease has been less intensively investigated. This review summarizes the most recent advances concerning AGEs effects in the cavernous tissue of the penis and in ED onset, particularly on diabetes and aging, conditions that not only favor AGEs formation, but also increase risk of developing ED. The specific contribution of AGE on intra- and extracellular deposition of insoluble complexes, interference in activity of endothelial nitric oxide (NO) synthase, NO bioavailability, endothelial-dependent vasodilatation, as well as molecular pathways activated by receptor of AGEs are presented. Finally, the interventional actions that prevent AGEs formation, accumulation or activity in the cavernous tissue and that include nutritional pattern modulation, nutraceuticals, exercise, therapeutic strategies (statins, anti-diabetics, inhibitors of phosphodiesterase-5, anti-hypertensive drugs) and inhibitors of AGEs formation and crosslink breakers, are discussed. From this review, we conclude that despite the experiments conducted in animal models pointing to the AGE/RAGE axis as a potential interventional target with respect to ED associated with diabetes and aging, the clinical data have been very disappointing and, until now, did not provide evidence of benefits of treatments directed to AGE inactivation.     

Erectile dysfunction and diabetes mellitus

Background: Erectile dysfunction (ED) is highly prevalent, affecting ≥50% of men with diabetes mellitus (DM) worldwide.Objective: This article reviews current knowledge on the epidemiology and underlying pathophysiology of ED in men with DM, diagnostic modalities, and treatment options.Methods: A MEDLINE literature search was conducted for articles published in English from inception of the database through November 2008, using the terms erectile dysfunction, diabetes, epidemiology, pathophysiology, phosphodiesterase inhibitors, intracavernosal injection, and penile prosthesis. Data on the epidemiology, diagnosis, and treatment of ED were extracted from all relevant articles.Results: The literature search revealed 685 original articles and reviews, 67 of which were selected for inclusion in this review. DM may cause ED through a number of pathophysiologic changes, including neuropathy, endothe-lial dysfunction, cavernosal smooth muscle structural/functional changes, hormonal changes, and psychological effects. The diagnosis of ED in men with DM is based on their sexual and medical histories and results of validated questionnaires such as the International Index of Erectile Function. Laboratory examinations are usually limited to testosterone and prolactin levels that may independently contribute to ED because specialized examinations are not necessary in most diabetic men with ED. The first step in the treatment of ED in men with DM includes glycemic control and treatment of diabetic comorbidities. The associated hypogonadism must also be treated; otherwise, pharmacologic treatment may be less efficacious or not efficacious at all. Phosphodiesterase type-5 (PDE-5) inhibitors have revolutionized the treatment of ED, and they are considered first-line treatment, with a mean efficacy rate of 50% and a favorable safety profile. Intracavernous administration of vasoactive drugs is the second-line medical treatment when PDE-5 inhibitors have failed. Alprostadil is the most widely used drug for this condition, but the combination of papaverine, phentolamine, and alprostadil represents the most efficacious pharmacologic treatment option for patients whose ED does not respond to monotherapy. Excellent functional and safety results have been reported for penile prosthesis implantation, and this approach, along with proper counseling, can be considered for selected patients with treatment-refractory ED.Conclusions: ED is common in men with DM, who represent one of the most difficult-to-treat subgroups of ED patients. PDE-5 inhibitors are the first-line treatment option, followed by intracavernosal injections and implantation of a penile prosthesis.     

Mechanisms of endothelial dysfunction in rheumatoid arthritis: lessons from animal studies

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by articular and extra-articular manifestations involving cardiovascular diseases (CVDs), which account for 30% to 50% of all deaths. In patients with RA, atherosclerosis lesions occur earlier and have a more rapid evolution than in the general population. Beyond mortality, the impact of CVD on quality of life, combined with the associated increase in health-care costs, renders CVD in RA a major public health problem. Recent studies showed that patients with RA are characterized by the presence of endothelial dysfunction (ED), which is recognized as a key event in the development of atherosclerosis. By definition, ED is a functional and reversible alteration of endothelial cells, leading to a shift of the actions of the endothelium toward reduced vasodilation, proinflammatory state and proliferative and prothrombotic properties. Although the improvement of endothelial function is becoming an important element of the global management of patients with RA, the mechanistic determinants of ED in RA are still poorly understood. Animal models of RA provide the unique opportunity to unravel the pathophysiological features of ED in RA. The present review summarizes the available data on mechanisms underlying ED in animal models of RA and proposes attractive prospects in order to discover novel therapeutic strategies of RA-associated ED.     

Relationship between testosterone and erectile dysfunction

Although erectile function is clearly androgen dependent, is it just as clear at what level of testosterone erectile dysfunction (ED) begins? Does the decline in testosterone that occurs with aging always produce ED? Are exogenous androgens the answer to ED? The answers range from clear to complex.     

Erectile dysfunction in patients with cardiovascular disease

Erectile dysfunction is a highly prevalent disease, especially in cardiovascular-compromised men. Many of the well-established risk factors for cardiovascular disease are also risk factors for erectile dysfunction. A correlation between erectile dysfunction and endothelial dysfunction is well established. It is postulated that erectile dysfunction with an arteriovascular aetiology can predate and be an indicator of potential coronary artery disease. In this paper we will attempt to increase awareness among cardiologists for the predictive value of erectile dysfunction for future cardiovascular disease in order to optimise cardiovascular risk management. The treatment of erectile dysfunction and cardiovascular interactions is also discussed in detail.     

The role of prostaglandins in the aetiology and treatment of erectile dysfunction.

Both animal and human penile tissue synthesize prostaglandins (PGs). Furthermore, intracavernous injection of certain PGs elicits erection in men with erectile dysfunction (ED). It is also well established that PGs are involved in the pathophysiology of atherosclerosis and diabetes mellitus (DM). Since atherosclerosis and DM are major risk factors for ED, it has been suggested that the disruption of PG synthesis in penile tissues and related vasculature may play a role in the pathogenesis of ED. In this review, we discuss the role of PGs in normal penile erection as well as on the pathophysiology and treatment.     

Stem cell therapy and diabetic erectile dysfunction: A critical review

Erectile dysfunction (ED) has been identified as one of the most frequent chronic complications of diabetes mellitus (DM). The prevalence of ED is estimated to be about 67.4% in all DM cases worldwide. The pathophysiological process leading to ED involves endothelial, neurological, hormonal, and psychological factors. In DM, endothelial and neurological factors play a crucial role. Damages in the blood vessels and erectile tissue due to insulin resistance are the hallmark of ED in DM. The current treatments for ED include phosphodiesterase-5 inhibitors and penile prosthesis surgery. However, these treatments are limited in terms of just relieving the symptoms, but not resolving the cause of the problem. The use of stem cells for treating ED is currently being studied mostly in experimental animals. The stem cells used are derived from adipose tissue, bone, or human urine. Most of the studies observed an improvement in erectile quality in the experimental animals as well as an improvement in erectile tissue. However, research on stem cell therapy for ED in humans remains to be limited. Nevertheless, significant findings from studies using animal models indicate a potential use of stem cells in the treatment of ED.     

阴茎勃起及勃起功能障碍的研究进展

勃起功能障碍的基础研究须近十年来取得了较大进展,一氧化氮－cGMP(NO-cGMP)通路的发现使得阴茎平滑肌松驰的机制进一步阐明。一氧化氮合酶（NOS）、磷酸二酯酶（PDEs）的研究为勃起功能障碍的临床治疗提供了坚实的基础,进而促使了万艾可的问世。目前,勃起功能障碍的基因治疗停留在实验室阶段,但随着分子生物学的深入研究,转基因疗法可能成为临床上治疗勃起功能障碍的有效方法之一。     

Nonpharmacologic treatment of erectile dysfunction

Nonpharmacologic treatment for erectile dysfunction (ED) includes sex therapy, the use of vacuum erection devices, penile prosthesis implantation, and penile vascular surgery. Sex therapy is indicated for psychogenic ED and is at times a useful adjunct for other treatments in men with mixed psychogenic and organic ED. Vacuum erection devices produce usable erections in over 90% of patients; however, patient and partner acceptability is an issue. Three-piece inflatable penile prostheses create flaccidity and an erection that comes close to that which occurs naturally. Penile vascular surgery has shown greatest efficacy in young men with vasculogenic ED resulting from pelvic or perineal trauma.     

Purinergic receptors mediate endothelial dysfunction and participate in atherosclerosis

Atherosclerosis is the main pathological basis of cardiovascular disease and involves damage to vascular endothelial cells (ECs) that results in endothelial dysfunction (ED). The vascular endothelium is the key to maintaining blood vessel health and homeostasis. ED is a complex pathological process involving inflammation, shear stress, vascular tone, adhesion of leukocytes to ECs, and platelet aggregation. The activation of P2X4, P2X7, and P2Y2 receptors regulates vascular tone in response to shear stress, while activation of the A2A, P2X4, P2X7, P2Y1, P2Y2, P2Y6, and P2Y12 receptors promotes the secretion of inflammatory cytokines. Finally, P2X1, P2Y1, and P2Y12 receptor activation regulates platelet activity. These purinergic receptors mediate ED and participate in atherosclerosis. In short, P2X4, P2X7, P2Y1, and P2Y12 receptors are potential therapeutic targets for atherosclerosis.     

Low serum insulin-like growth factor-1 in patients with erectile dysfunction

Objective

Endothelial dysfunction and microvascular damage play a crurical role in the pathogenesis of erectile dysfunction (ED). Insulin-like growth factor-1 (IGF-1) is one of the growth factors that have a wide range of biologic effects. IGF-1 is an important mediator of cell growth, differentiation and transformation in various tissues. The purpose of the current study was to determine the association between IGF-1 levels and ED.

Materials and methods

All men were evaluated for ED and divided into two groups: 80 patients suffering from ED for >?1 year and 80 subjects without ED were enrolled as a control group in this study. Diagnosis of ED was based on the International Index of Erectile Function Score-5. IGF-1 levels were measured in serum by an automated chemiluminescence immunoassay. The relationship between IGF-1 levels and ED scores in patients was statistically evaluated.

Results

The mean age of patients in ED group was 60.4?±?11.3 years and 55.4?±?9.6 in control group. The plasma IGF-1 levels were significantly lower in ED than in control group (96.5?±?38.3 and 132.5?±?53.3 ng/ mL, respectively, P?<?0.001). The IGF-1 levels were positively correlated with ED score (r?=?0.623, P?<?0.01).

Conclusion

In this study serum IGF-1 levels were found to be associated with endothelial dysfunction that predicts ED. Serum IGF-1 level appears to be a specific predictor of ED, and it might be used in early prediction of ED in male population.

     

Management of Erectile Dysfunction in the Hypogonadal Man: A Case-Based Review

Erectile dysfunction (ED) has emerged as an important marker of cardiovascular and overall health, independent of other known conventional risk factors. ED often precedes coronary artery disease in half of affected subjects, and could indicate the presence of cardiovascular pathology. The pathophysiology and role of androgens in sexual function are described, along with the relevant literature on the effects of aging in erectile and gonadal function. The concept of testosterone supplementation (TST) in men with ED is reviewed. The authors utilize clinical vignettes to discuss the appropriate management of two clinical cases of men at different life stages who have ED in the setting of hypogonadism and propose a treatment algorithm. In patients of all ages, proper identification of the underlying pathophysiology of decreased libido and erectile function is paramount in choosing between the use of TST, phosphodiesterase type 5 inhibitors, or both, in the management of these disorders.Key words: Erectile dysfunction, Testosterone supplementation, Hypogonadism, Phosphodiesterase type 5 inhibitorsErectile dysfunction (ED) has emerged as an important marker of cardiovascular and overall health, independent of other known conventional risk factors. Because ED often precedes coronary artery disease (CAD) in half of affected subjects, it may be considered a harbinger of indolent cardiovascular pathology.^1,2 The modulation of erectile function by testosterone is well known,^3,4 and in men with both hypogonadism and ED a treatment strategy necessitating management of both conditions is required.Phosphodiesterase type 5 inhibitors (PDE5i) and testosterone supplementation therapy (TST) are established treatment strategies for ED and hypogonadism, respectively. Using a PDE5i in combination with TST has the potential for improving efficacy in men with concurrent ED and hypogonadism compared with the use of either agent alone. However, in light of the recent evidence associating testosterone with cardiovascular risk in elderly men,^5,6 TST should be used judiciously in the management of ED in older men.     

Circulating miRNA as novel markers for diastolic dysfunction

MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression. Though their significance is unclear, pioneer profiling studies have attributed specific serum miRNA signatures to different disease conditions. The diagnostic potential of miRNA detection in human plasma for cardiovascular disorders is beginning to be recognized as important. In this study, we examined miRNA profiling in isolated diastolic dysfunction (DD) with preserved systolic function to identify promising candidate miRNAs. The presence of these miRNAs was tested in stable patients with isolated DD, patients with stable compensated dilated cardiomyopathy (DCM—systolic plus diastolic dysfunction) and those with decompensated congestive heart failure secondary to dilated cardiomyopathy (DCM–CHF—systolic plus diastolic dysfunction). We identified new circulating miRNAs (miR-454, miR-500, miR-1246, miR-142-3p) which showed distinct patterns of expression in patients with diastolic dysfunction. The presence or absence of systolic dysfunction does not seem to affect this trend. MiR-454 and miR-500 are downregulated in diastolic dysfunction. MiR-1246 is upregulated in diastolic dysfunction. MiR-142-3p is downregulated in DCM and DCM–CHF groups but not in the DD group. The expression of miR-124-5p is highly upregulated in DCM but not in DD and DCM–CHF groups. We therefore propose that these circulating miRNAs may serve as novel biomarkers for diastolic dysfunction because in all of these patients the only common factor was diastolic dysfunction.