The assessment of vascular risk in men with erectile dysfunction: the role of the cardiologist and general physician.

Erectile dysfunction (ED) and cardiovascular disease (CVD) share risk factors and frequently coexist, with endothelial dysfunction believed to be the pathophysiologic link. ED is common, affecting more than 70% of men with known CVD. In addition, clinical studies have demonstrated that ED in men with no known CVD often precedes a CVD event by 2-5 years. ED severity has been correlated with increasing plaque burden in patients with coronary artery disease. ED is an independent marker of increased CVD risk including all-cause and especially CVD mortality, particularly in men aged 30-60 years. Thus, ED identifies a window of opportunity for CVD risk mitigation. We recommend that a thorough history, physical exam (including visceral adiposity), assessment of ED severity and duration and evaluation including fasting plasma glucose, lipids, resting electrocardiogram, family history, lifestyle factors, serum creatinine (estimated glomerular filtration rate) and albumin:creatinine ratio, and determination of the presence or absence of the metabolic syndrome be performed to characterise cardiovascular risk in all men with ED. Assessment of testosterone levels should also be considered and biomarkers may help to further quantify risk, even though their roles in development of CVD have not been firmly established. Finally, we recommend that a question about ED be included in assessment of CVD risk in all men and be added to CVD risk assessment guidelines.

Gender-based cardiometabolic risk evaluation in minority and non-minority men grading the evidence of non-traditional determinants of cardiovascular risk.

Evaluation of cardiometabolic risk has become vital in primary prevention of adverse vascular events (coronary artery disease, heart attack, stroke or congestive heart failure), particularly in younger middle-aged men (40-60 years old). To discern the prevalence of events in these men, clinicians often stratify cardiovascular risk and treat according to traditional Framingham risk criteria. Yet it is evident that the traditional Framingham risk assigned to intermediate- and low-risk men will miss several of these individuals deemed at high 'cardiometabolic risk', also known as residual cardiovascular risk. This review will elaborate the definition of cardiometabolic risk and apply the use of surrogate markers for cardiovascular risk stratification in men in addition to the traditional Framingham-based markers. It will utilise both gender non-specific and gender-specific determinants of cardiometabolic risk. Lastly, it will examine minority men's health and racial differences in these determinants of cardiovascular risk. This analysis includes an electronic literature search utilising PubMed, EMBASE and MEDLINE databases to clarify the level of evidence for the stepwise utility of novel biomarkers for cardiometabolic risk in the male patient. This manuscript generates discussion of the utility of markers of cardiometabolic risk stratification. The following questions are summarised: (i) Are there non-traditional tests that might define this risk better than traditional markers? (ii) Will treatment based on this risk assessment augment present risk stratification and lower cardiovascular risk? (iii) What is known regarding racial differences surrounding cardiometabolic risk assessment? Traditional risk factors including Framingham Risk Score underestimate the overall 10 year and lifetime risk for the intermediate-risk younger middle-aged men<60 years of age. This fact is especially true in the minority population. We have graded the evidence of non-gender specific and gender-specific markers of cardiometabolic risk, thereby, allowing greater clarification of risk in this population. The pragmatic use of these novel markers of cardiometabolic risk may help stratify those individuals at greater lifetime risk than that noted by the Framingham Risk Score.

Erectile dysfunction as a harbinger for increased cardiometabolic risk.

In August 2003, the Minority Health Institute (MHI) convened an Expert Advisory Panel of cardiologists and urologists to design a new practice model algorithm that uses erectile dysfunction (ED) as a clinical tool for early identification of men with systemic vascular disease. The MHI algorithm noted ED as a marker for the presence of cardiovascular disease and suggested that ED may well be a cardiovascular risk equivalent warranting aggressive secondary prevention management strategies, even in the absence of other cardiac or peripheral vascular symptoms. The MHI algorithm stipulates that all men 25 years of age and older should be asked about ED as a routine part of the cardiovascular history during any office visit. The presence of ED should prompt an aggressive assessment for occult vascular disease; many men with erectile difficulty would benefit from early, aggressive management of cardiovascular risk factors with both lifestyle modification and pharmacotherapy to achieve optimal target goals under the existing treatment guidelines. Since publication of the algorithm in 2005, additional research studies have further supported the advisory panel recommendations.

Erectile dysfunction as an early sign of cardiovascular disease.

A body of evidence from basic science and clinical research is emerging to provide a compelling argument for endothelial dysfunction as a central etiologic factor in the development of atherosclerosis and vascular disease (ischemic heart disease, stroke, and claudication). Erectile dysfunction (ED) is another prevalent vascular disorder that is now thought to be caused by endothelial dysfunction. In fact, a burgeoning literature is now available that suggests that ED may be an early marker for atherosclerosis and cardiovascular disease (CVD). The emerging awareness of ED as a barometer for CVD represents a unique opportunity to enhance preventive vascular health in men. The diagnosis of ED could become a powerful clinical tool to improve early detection of atherosclerosis and initiate prompt aggressive medical management of associated cardiovascular risk factors.

Relation of C-reactive protein and other cardiovascular risk factors to penile vascular disease in men with erectile dysfunction.

Erectile dysfunction (ED) may be an early sign or symptom of cardiovascular disease (CVD). We examined the relation of traditional and emerging risk factors for CVD to the severity of penile vascular disease in men with ED and without clinical coronary artery disease (CAD). In total, 137 men with ED were evaluated for penile vascular disease severity by penile Doppler ultrasound. These men were divided into the following groups based on ultrasound results: normal, cavernous venous occlusive disease, mild arterial insufficiency, and severe arterial insufficiency. Traditional (fasting lipid panel, fasting glucose, age, BMI, smoking, Framingham coronary artery disease risk score) and emerging (C-reactive protein, Lp(a), homocysteine) risk factors for CVD were correlated to severity of penile vascular disease in men with ED and without clinical CAD. Using univariate analysis, penile Doppler groups showed significant positive correlation to CRP (r=0.21; < or = 0.05) and age (r=0.30; < or = 0.01). For CRP, this correlation remained significant even when adjusted for age (< or = 0.05). Men displaying evidence of penile arterial disease (mild and severe arterial insufficiency) were characterized by elevated CRP levels (0.17 mg/dl) compared to men with no evidence of arterial abnormalities in the penis (0.04 mg/dl). CRP levels correlate significantly with increasing severity of penile vascular disease as measured by penile Doppler.

A new non-pharmacological vacuum therapy for female sexual dysfunction.

Although Female Sexual Dysfunction (FSD) affects 40% of American women, there is no FDA-approved pharmaceutical therapy. The EROS-CTD (Clitoral Therapy Device, UroMetrics, Inc., St. Paul, MN) treatment is the first FDA cleared-to-market therapy for FSD. Clitoral engorgement is believed to play an important role in female sexual arousal and overall sexual satisfaction. The EROS-CTD is a small, battery-powered device designed to enhance clitoral engorgement, increase blood flow to the clitoris, and ultimately improve arousal in women with FSD. The objective of this study was to assess the effectiveness of the EROS-CTD on sexual arousal (genital sensation, vaginal lubrication, ability to reach orgasm, and sexual satisfaction) in normal volunteers and women with FSD.

Treating symptoms of female sexual arousal disorder with the Eros-Clitoral Therapy Device.

OBJECTIVE: The aim of this study was to determine the effect of the Eros-Clitoral Therapy Device (Eros-CTD) on the sexual function of women with and without symptoms of female sexual arousal disorder (FSAD). DESIGN: Periodic survey of sexual function in women using the Eros-CTD over a six-week period. SUBJECTS: A total of 19 women participated in the study--10 with symptoms of FSAD and nine without symptoms of FSAD--ranging in age from 28 to 65 years, with a mean age of 45.2 years. METHODS: Ten patients with symptoms of FSAD and 10 without symptoms were instructed in the use of the small, portable vacuum device, Eros-CTD. One woman without symptoms of FSAD withdrew early in the study for personal reasons. The patients were instructed in the correct use of the device and were asked to complete one Female Intervention Efficacy Index (FIEI) each week. The patients also kept diaries of their use of the device, noting the frequency, length, and strength of vacuum. RESULTS: There was a significant improvement in all symptoms of FSAD (P < .05), including increased sensation, improved vaginal lubrication, enhanced ability to orgasm, and greater overall satisfaction. Patients without FSAD also reported similar changes in sensation, lubrication, ability to orgasm, and overall satisfaction. LIMITATIONS: This study was done on a small sample of self-selected patients, was of limited duration, and had no long-term follow-up. All of these factors should be considered in interpreting the data. CONCLUSION: The Eros-CTD was safe and effective in improving symptoms of FSAD in this group of women. Further studies on the efficacy of the Eros-CTD are indicated.

Trends, rhythms, and aberrations in global climate 65 Ma to present.

Since 65 million years ago (Ma), Earth's climate has undergone a significant and complex evolution, the finer details of which are now coming to light through investigations of deep-sea sediment cores. This evolution includes gradual trends of warming and cooling driven by tectonic processes on time scales of 10(5) to 10(7) years, rhythmic or periodic cycles driven by orbital processes with 10(4)- to 10(6)-year cyclicity, and rare rapid aberrant shifts and extreme climate transients with durations of 10(3) to 10(5) years. Here, recent progress in defining the evolution of global climate over the Cenozoic Era is reviewed. We focus primarily on the periodic and anomalous components of variability over the early portion of this era, as constrained by the latest generation of deep-sea isotope records. We also consider how this improved perspective has led to the recognition of previously unforeseen mechanisms for altering climate.

Report of the American Foundation for Urologic Disease (AFUD) Thought Leader Panel for evaluation and treatment of priapism.

PURPOSE: Patients with priapism often develop permanent erectile dysfunction and personal sexual distress. This report is intended to help educate the public by reviewing the varied definitions and classifications of priapism and limited literature reports of pathophysiology, diagnosis and treatment outcomes of priapism. The AUA priapism guidelines committee is responsible for creating consensus as to appropriate individual patient management of priapism by physicians. MATERIALS AND METHODS: A multidisciplinary panel, consisting of 19 thought leaders in priapism, was convened by the Sexual Function Health Council of the American Foundation for Urologic Disease to address pertinent issues concerning the role of the urologist, primary care providers and other health care professionals in the education of the public regarding management of men with priapism. The panel utilized a modified Delphi method and built upon the peer review literature on priapism. RESULTS: The Thought Leader Panel recommended adoption of the definition of priapism as a pathological condition of a penile erection that persists beyond or is unrelated to sexual stimulation. Priapism is stressed to be an important medical condition that requires evaluation and may require emergency management. The classification system is categorized into ischemic and non-ischemic priapism. Essential elements of the ischemic classification are the inclusion of: (i) clinical characteristics of pain and rigidity; (ii) diagnostic characteristics of absence of cavernosal arterial blood flow; (iii) pathophysiological characteristics of a closed compartment syndrome; (iv) a time limit of 4 h prior to emergent medical care; and (v) a description of the potential consequences of delayed treatment. Essential elements of the non-ischemic classification are the inclusion of: (i) clinical characteristics of absence of pain and presence of partial rigidity; (ii) diagnostic and pathophysiological characteristics of unregulated cavernosal arterial inflow; and (iii) the need for evaluation but emphasizing the lack of a medical emergency. The panel recommended adoption of a rational management algorithm for the assessment and treatment of priapism where the cornerstone of initial assessment includes a careful clinical history, a focused physical examination and selected laboratory and/or radiologic tests. The panel recommended that specific criteria and clinical profiles requiring specialist referral should be identified. The panel further recommended that patient (and partner) needs and education concerning priapism should be addressed prior to therapeutic intervention, however only in the case of chronic management or post acute presentation evaluation should this delay intervention. Treatment goals to be discussed include management of the priapism with concomitant prevention of permanent and irreversible erectile dysfunction and associated psychosocial consequences. The panel recommended that when specific therapies for priapism are required, a step-care treatment approach based upon reversibility and invasiveness should be followed. CONCLUSIONS: The Thought Leader Panel calls for research to expand our understanding of the prevalence and diagnosis of priapism and education to create awareness among the public of the potential urgency of this condition. Critical areas to be addressed include the multiple pathophysiologies of priapism as well as multi-institutional trials to objectively assess safety and efficacy in the various treatment modalities.

Detection of soluble E-selectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage.

OBJECT: The goal of this study was to explore whether the levels of soluble adhesion molecules were elevated in cerebrospinal fluid (CSF) after subarachnoid hemorrhage (SAH). This association was suggested by the known inflammatory response in vasospasm and the role of vascular adhesion molecules in regulating leukocytic adhesion to, and migration across, vascular endothelium. METHODS: A prospective analysis was performed on CSF samples obtained in 17 patients who had suffered a recent aneurysmal SAH and in 16 control patients by using quantitative enzyme-linked immunosorbent assays for E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and L-selectin. Levels of soluble forms of E-selectin (p=0.0013), ICAM-1 (p=0.0001), and VCAM-1 (p=0.048) were found to be elevated in the CSF of patients after SAH compared with levels in the CSF of norminal controls, patients with unruptured aneurysms, and patients tested months after SAH occurred. In addition, individual patients tested at the time of their initial ictus demonstrated a fall in adhesion molecule levels over time. Levels of E-selectin (p=0.044) were highest in patients who later developed moderate or severe vasospasm. CONCLUSIONS: Adhesion molecules are known to be involved in white cell adherence to the endothelium and subsequent diapedesis and migration in which a role in initiation of tissue damage is postulated. The authors have demonstrated the elevation of three adhesion molecules, with severely elevated levels of E-selectin seen in patients who later develop vasospasm. A correlation with a role of vascular adhesion molecules in the pathogenesis of cerebral vasospasm is suggested.

Long-term follow-up of patients receiving injection therapy for erectile dysfunction.

OBJECTIVES: During the last decade, vasoactive intracavernosal pharmacotherapy (VIP) has been used extensively for the treatment of erectile dysfunction. However, there is concern about high discontinuation rates and the possibility of long-term complications. Because of few long-term studies on VIP, we investigated efficacy, side effects, satisfaction index, and drop-out rate for injection therapy in patients who started treatment more than 5 years ago. METHODS: Questionnaires were mailed to 108 patients who were started on VIP more than 5 years ago, between November 1984 and July 1989. The hospital records and data from the 100 responders (93%) were reviewed. RESULTS: Only 32% of the patients continue to use VIP. Most (56%) of those who discontinued did so during the first year. The patients cited one or more of the following reasons for discontinuation: desire for a permanent modality of therapy (29%), lack of a suitable partner (26%), fear of needles (23%), poor response (23%), fear of complications (22%), and lack of sexual spontaneity (21%). This study, which has one of the longest follow-up periods in the literature, has significant new findings in three areas: discontinuation rates fall after 2 years, long-term complications are relatively minor, and patients who discontinue therapy are significantly older or have a poor initial impression of VIP. Paradoxically, discontinuing VIP was apparently unrelated to side effects or etiology of erectile dysfunction, and 82% of patients would still recommend VIP to a friend. CONCLUSIONS: This study conclusively shows that because of high initial satisfaction and relatively minor side effects, VIP should remain as one of the initial options for long-term treatment of erectile dysfunction. However, despite seemingly doing well, patients often discontinue therapy, and therefore should be followed closely so that alternative therapy can be offered.

Evidence for E-selectin complement regulatory domain mRNA splice variants in the rat.

The adhesion protein E-selectin is one mediator of endothelial cell-leukocyte interaction during acute inflammation. To investigate the molecular regulation of E-selectin function, we have examined the expression of E-selectin mRNA in target rat tissues after administration of lipopolysaccharide, a potent inducer of acute inflammation. In the course of these studies we isolated two unique rat E-selectin cDNA fragments. Both cDNA fragments show extensive nucleotide sequence homology to previously isolated mouse and human E-selectin cDNAs. However, they differ for the presence of sequences that encode complement regulatory domain-5 (CR5). Previous studies have shown that different animal species express E-selectin mRNAs that encode different numbers of CR domains. The isolation of these two rat E-selectin cDNA fragments, which differ only for the presence of CR5, represents the first direct evidence for the existence of E-selectin CR-variant mRNAs in the same species. Moreover, the sequence of the CR5(-) cDNA is consistent with its origin from an mRNA splice variant of a CR5(+) mRNA. We have demonstrated the presence of the two predicted mRNA species in rat heart tissue and have investigated their expression in response to lipopolysaccharide. Although both mRNA variants were greatly induced by lipopolysaccharide, the CR5(-) form was more abundant in both treated and control tissues. This difference in mRNA abundance may indicate different levels of CR5 variant proteins that perform functionally distinct tasks in E-selectin dependent inflammatory processes.

Expression of E-selectin mRNA during ischemia/reperfusion injury.

To better understand molecular and cellular processes involved in tissue inflammation, we have examined expression of endothelial leukocyte adhesion molecule 1 (E-selectin) mRNA in adult male rats after ischemia/reperfusion (I/R) injury and after intravenous injection of lipopolysaccharide (LPS). The polymerase chain reaction was used to generate a rat E-selectin cDNA fragment by using heart total RNA from rats exposed to LPS. This partial cDNA fragment spanned sequences from complement repeat region-5 to the second cytoplasmic tail domain. Comparison of the predicted amino acid sequence from the rat cDNA fragment to mouse and human E-selectin protein sequences showed significant conservation. The rat E-selectin cDNA fragment was used as a probe to examine the regulation of E-selectin mRNA expression by Northern blot analysis. As previously described in other animal species, E-selectin mRNA expression was induced after intravenous injection of LPS. In contrast, ischemia did not induce E-selectin mRNA expression, except in the setting of I/R injury. I/R injury triggered expression of E-selectin mRNA in the kidney. These experiments represent a first in vivo examination of E-selectin mRNA expression after I/R injury and constitute an initial step in characterizing a model system for investigating inflammation in the setting of acute ischemic injury.

Variability of ischemia during spermatic cord torsion in the rat.

Testicular torsion affects prepubertal males and causes testicular infarction and subfertility. Animal models of spermatic cord torsion have been used in an attempt to study the mechanism of testicular injury from torsion. Although standardized animal models of torsion have been proposed, their reliability in producing testicular ischemia has not been documented. Dynamic enhanced magnetic resonance imaging (MRI) of the testis was used in a rat model with surgically induced, unilateral, 720 degrees torsion to quantify the severity of ischemia. Intravenous dysprosium diethylenetriaminepentaacetic acid-bis methylamide (Dy-DTPA-BMA) was injected as a bolus followed by serial dynamic Turbo GRASS images. Region of interest (ROI) measurements were obtained within the testicular parenchyma during contrast enhancement and washout. Perfusion abnormalities ranging from minimal delay in contrast enhancement in the torqued testicle to complete absence of intraparenchymal blood flow were documented with dynamic enhanced MRI. Reperfusion scans 1 hour after surgical reduction of torsion showed normalization of testicular blood flow in all animals. Dynamic enhanced MRI appears to be a useful method of documenting the perfusion deficit arising from torsion of the testis. Standard animal models of torsion produce inconsistent results because they do not reliably reproduce testicular ischemia. The ability of MRI to quantify perfusion abnormalities in the testis may provide additional information in the evaluation of human patients with symptoms of testicular torsion.

Dynamic enhanced magnetic resonance imaging of testicular perfusion in the rat.

Magnetic Resonance Imaging (MRI) has several theoretical advantages in the evaluation of spermatic cord torsion and testicular ischemia. The technique uses no ionizing radiation, has both excellent spatial and temporal resolution and, when used with an intravenous bolus of a paramagnetic contrast agent, provides a semiquantitative assessment of tissue perfusion and vascular injury. In clinical instances of testicular torsion, accurate estimates of tissue perfusion are desirable since testicular salvage is inversely related to the duration of torsion and the degree of tissue ischemia. Perfusion imaging of the rat testis was used as a model to demonstrate the potential use of MRI in the experimental and clinical analysis of disorders that affect blood flow to the testis.

Reduction of epididymal sperm motility after ablation of the inferior mesenteric plexus in the rat.

Surgical ablation of the inferior mesenteric plexus in the rat results in an excessive accumulation of sperm within the cauda epididymidis. The present study examined the effect of ablation of the inferior mesenteric plexus on the motility of cauda epididymal spermatozoa. One to 8 weeks after ablation of the inferior mesenteric plexus, sperm curvilinear and straight line swimming velocities were reduced significantly compared with sperm curvilinear and straight line swimming velocities from sham-operated controls. Sperm swimming linearity also changed significantly versus controls after inferior mesenteric plexus ablation. Additional experiments using a vasectomy model suggested that the reductions in sperm curvilinear and straight swimming velocities after inferior mesenteric plexus ablation were not primarily the result of tubal obstruction. These data suggest that the sympathetic nervous system may influence epididymal sperm function.

Ablation of the inferior mesenteric plexus in the rat: alteration of sperm storage in the epididymis and vas deferens.

The involvement of the sympathetic nervous system in the transport and storage of spermatozoa in the male reproductive tract was examined by surgically ablating the inferior mesenteric plexus (IMP). One to eight weeks after ablation of the IMP, epididymal weight and the total number of spermatozoa present in the cauda epididymidis were significantly greater in IMP-ablated rats than in sham-operated rats. By contrast, the number of spermatozoa present in the initial segment of the vas deferens was significantly greater than in sham operated controls one week after IMP ablation but returned to control levels at two, four, six and eight weeks. Throughout the experiment, no differences were observed between IMP-ablated and control rats in the percentage of motile cauda epididymal spermatozoa, testicular weight, testicular sperm number or serum testosterone. These data demonstrate that the sympathetic nervous system differentially regulates sperm transport and storage in the male reproductive tract and suggest that the IMP may influence the epididymal maturation of spermatozoa.