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.

Emotional stressors trigger cardiovascular events.

AIMS: To describe the relation between emotional stress and cardiovascular events, and review the literature on the cardiovascular effects of emotional stress, in order to describe the relation, the underlying pathophysiology, and potential therapeutic implications. MATERIALS AND METHODS: Targeted PUBMED searches were conducted to supplement the authors' existing database on this topic. RESULTS: Cardiovascular events are a major cause of morbidity and mortality in the developed world. Cardiovascular events can be triggered by acute mental stress caused by events such as an earthquake, a televised high-drama soccer game, job strain or the death of a loved one. Acute mental stress increases sympathetic output, impairs endothelial function and creates a hypercoagulable state. These changes have the potential to rupture vulnerable plaque and precipitate intraluminal thrombosis, resulting in myocardial infarction or sudden death. CONCLUSION: Therapies targeting this pathway can potentially prevent acute mental stressors from initiating plaque rupture. Limited evidence suggests that appropriately timed administration of beta-blockers, statins and aspirin might reduce the incidence of triggered myocardial infarctions. Stress management and transcendental meditation warrant further study.

Bone marrow-derived cell transplantation therapy for myocardial infarction: lessons learned and future questions.

Over the last decade, many investigators have utilized bone marrow-derived cells for cell transplantation therapy in animal studies and in patients with acute myocardial infarction and chronic heart failure. In those experimental and clinical studies, various doses and types of bone marrow-derived cells have been transplanted to the injured myocardium using a variety of approaches, such as intracoronary infusion or catheter-based direct endomyocardial injection, and at different time points after successful coronary reperfusion. The reported treatment effects are variable, which may be related to differences in cell type and quantity of transplanted cells, timing and approach of cell transplantation and patient selection. In this review, we summarize and discuss the controversies and questions related to the clinical use of bone marrow-derived cells.

Erectile dysfunction and coronary artery disease prediction: evidence-based guidance and consensus.

* A significant proportion of men with erectile dysfunction (ED) exhibit early signs of coronary artery disease (CAD), and this group may develop more severe CAD than men without ED (Level 1, Grade A). * The time interval among the onset of ED symptoms and the occurrence of CAD symptoms and cardiovascular events is estimated at 2-3 years and 3-5 years respectively; this interval allows for risk factor reduction (Level 2, Grade B). * ED is associated with increased all-cause mortality primarily due to increased cardiovascular mortality (Level 1, Grade A). * All men with ED should undergo a thorough medical assessment, including testosterone, fasting lipids, fasting glucose and blood pressure measurement. Following assessment, patients should be stratified according to the risk of future cardiovascular events. Those at high risk of cardiovascular disease should be evaluated by stress testing with selective use of computed tomography (CT) or coronary angiography (Level 1, Grade A). * Improvement in cardiovascular risk factors such as weight loss and increased physical activity has been reported to improve erectile function (Level 1, Grade A). * In men with ED, hypertension, diabetes and hyperlipidaemia should be treated aggressively, bearing in mind the potential side effects (Level 1, Grade A). * Management of ED is secondary to stabilising cardiovascular function, and controlling cardiovascular symptoms and exercise tolerance should be established prior to initiation of ED therapy (Level 1, Grade A). * Clinical evidence supports the use of phosphodiesterase 5 (PDE5) inhibitors as first-line therapy in men with CAD and comorbid ED and those with diabetes and ED (Level 1, Grade A). * Total testosterone and selectively free testosterone levels should be measured in all men with ED in accordance with contemporary guidelines and particularly in those who fail to respond to PDE5 inhibitors or have a chronic illness associated with low testosterone (Level 1, Grade A). * Testosterone replacement therapy may lead to symptomatic improvement (improved wellbeing) and enhance the effectiveness of PDE5 inhibitors (Level 1, Grade A). * Review of cardiovascular status and response to ED therapy should be performed at regular intervals (Level 1, Grade A).

The endothelial cell in health and disease: its function, dysfunction, measurement and therapy.

Endothelial cells have numerous endocrine functions and contribute to a variety of processes, including penile erection and vasodilation. Endothelial dysfunction is associated with cardiovascular risk factors and has been implicated in the pathogenesis of atherosclerosis and ED. This study reviews endothelial function, in addition to endothelial dysfunction and its role in atherosclerosis and ED. Measurement of endothelial function is reviewed, including catheter-based methods, venous occlusion plethysmography, high-frequency ultrasound, peripheral arterial tonometry, digital pulse amplitude tonometry, digital thermal monitoring, the L-arginine test and measurement of compounds released by endothelial cells. Therapy and medications that improve endothelial function are reviewed. As the scientific community learns more about the importance of the endothelium, it is increasingly important for the clinician to understand endothelial function, dysfunction, measurement of endothelial function and therapies that affect this remarkable cell type.

How to save a life during a clinic visit for erectile dysfunction by modifying cardiovascular risk factors.

Erectile dysfunction (ED) is an early marker for systemic atherosclerosis and is a predictor for coronary artery disease and cardiac events. The aim of this paper is to convey the importance of addressing cardiovascular risk factors in patients with ED and to inform urologists as well as other physicians who are not specialized in cardiology how to carry out a basic cardiovascular evaluation, including history, physical examination and objective data. We review the evidence and pathophysiology linking ED to cardiovascular disease, and then describe how to carry out a basic cardiovascular evaluation. We present data from the literature showing that appropriate use of lifestyle modifications and medical therapy has a positive effect on mortality, on numerous cardiovascular end points and on ED. Suggestions of when to refer the ED patient to an internist or cardiologist are provided. Identifying and treating cardiovascular risk factors may not only benefit the patient's ED, but it might also save the patient's life.

Erectile dysfunction and heart failure: the role of phosphodiesterase type 5 inhibitors.

The phosphodiesterase type 5 (PDE-5) inhibitors are effective in treating erectile dysfunction (ED). ED and heart failure (HF) share similar risk factors, and commonly present together. This association has led to questions ranging from the safety and efficacy of PDE-5 inhibitors in HF patients to a possible role for this class of medication to treat HF patients with or without ED. In addition to endothelial dysfunction, there are causes of ED specific to patients with HF including low exercise tolerance, depression and HF medications. Before treating HF patients with PDE-5 inhibitors, patients should be assessed for their risk of a cardiac event during sexual activity. PDE-5 inhibitors are safe and effective in treating ED in HF patients. An improvement in erectile function by PDE-5 inhibitors was associated with an improvement in quality of life and reduction in depression. Several studies demonstrated the effect of PDE-5 inhibitors on HF per se. PDE-5 inhibitors improved endothelial dysfunction, increased exercise tolerance, decreased pulmonary vascular resistance and pulmonary artery pressure, and increased cardiac index. Several mechanisms whereby PDE-5 inhibitors improve HF have been proposed. PDE-5 inhibitors already have a role in treating primary pulmonary hypertension; however additional studies are needed to determine if they will become a standard therapy for HF patients.

Erectile dysfunction as a predictor of cardiovascular disease.

Although it has been recognized that erectile dysfunction (ED) and coronary artery disease share many of the same risk factors--smoking, dyslipidemia, diabetes and hypertension--just in the past few years several new studies now suggest that ED is an important early marker of the presence of coronary artery disease. Recent analyses suggest that ED symptoms occur prior to coronary artery disease symptoms and may be a predictor of future major cardiovascular events. Some of these new studies also suggest that ED is an independent risk factor for predicting cardiovascular events--that is independent of other well-established risk factors. Taken together, these new studies suggest that when a patient presents with ED, the patient should be questioned about cardiac health and cardiovascular risk factors. If cardiovascular risk factors are identified, they should be worked up and aggressively treated--as treatment of these risk factors may be life-saving.

The phosphodiesterase-5 inhibitor tadalafil reduces myocardial infarct size.

The aim of this study was to determine, in an animal model, the effects of tadalafil on myocardial infarct size (IS), hemodynamics and regional myocardial blood flow after myocardial ischemia and reperfusion. Patients with erectile dysfunction (ED) often have risk factors for coronary artery disease. Tadalafil, a long-acting inhibitor of the enzyme phosphodiesterase-5 (PDE5), is used for the treatment of ED; there are no previous data regarding tadalafil in the setting of coronary artery occlusion (CAO). Sprague-Dawley male rats were treated with tadalafil or vehicle (10 mg/kg, by gastric gavage), 2 h before a 30 min CAO. Heart rate was comparable between tadalafil and control groups. Tadalafil reduced mean arterial pressure (P=0.009), systolic (P=0.035) and diastolic (P=0.009) blood pressures during ischemia/reperfusion. Tadalafil significantly reduced IS (42+/-2%) versus controls (54+/-3%) (P=0.006). For the first time, we showed that the PDE5 inhibitor, tadalafil, was well tolerated and cardioprotective in the setting of an experimental myocardial infarction, by substantially reducing ischemic cell death.

Erectile dysfunction and hypertension.

Recent analyses suggest that about 67-68% of men with hypertension have some degree of erectile dysfunction (ED). With about 25 million men in the US with hypertension, substantial numbers of hypertension-related ED exist that tend to be of a more severe nature than the general population. Men with ED are also more likely to have hypertension. Thiazide diuretic and beta-blocker therapy may contribute to ED. Phosphodiesterase-5 (PDE5) inhibitors are effective therapy in men with ED owing to hypertension who are taking antihypertensive medicines including those on multiple antihypertensive medicines. The addition of PDE5 inhibitors to usual common antihypertensive medicines (diuretics, beta blockers, calcium blockers, angiotensin converting enzyme inhibitors and angiotensin receptor blockers) results in either no or small additive reductions in blood pressure (BP) and no increase in serious clinical adverse events. There are however precautions regarding the use of PDE5 inhibitors in patients taking alpha blockers for either hypertension or benign prostatic hypertrophy, as some patients may develop orthostatic hypotension. Organic nitrates remain an absolute contraindication for PDE5 inhibitors because synergistic and symptomatic reductions in BP may occur in some patients with this drug combination.

Preconditioning and the human heart.

Brief episodes of ischemia prior to coronary occlusion protect the heart during sustained coronary ischemia and is known as ischemic preconditioning. During acute myocardial infarction it is associated with smaller infarction size, less cardiac arrhythmias, and better left ventricular function. Brief balloon inflation in the cardiac catheterization laboratory during coronary intervention enables the operator to have further prolonged balloon inflations with lesser degrees of ischemia. Brief ischemia prior to coronary bypass surgery results in smaller perioperative infarctions and lesser degrees of postoperative arrhythmias. Preconditioning mimetic drugs may have a promising future in simulating ischemic preconditioning.

Efficacy of tadalafil in the treatment of erectile dysfunction in hypertensive men on concomitant thiazide diuretic therapy.

Many men with erectile dysfunction (ED) have hypertension as a comorbid condition. Recent guidelines recommend thiazide diuretics as first-line therapy for hypertension. We analyzed data from 14 randomized, double-blind, placebo-controlled trials (N=2501) to evaluate the efficacy of tadalafil 20 mg for the treatment of ED in men on thiazides. Of the 2501 patients, 163 were on concomitant thiazides (116 tadalafil/47 placebo) and 159 (98%) were reported to have hypertension. The primary efficacy measures were mean change from baseline in the international index of erectile function (IIEF) erectile function (EF) domain and the proportion of 'yes' responses to sexual encounter profile (SEP) Questions 2 and 3. The tadalafil group showed a significantly (P<0.001) greater mean baseline to endpoint improvement on all efficacy outcome measures compared to placebo-treated patients regardless of concomitant thiazide use. More importantly, the responses to tadalafil were similar regardless of concomitant thiazide use. Additionally, responses to tadalafil were comparable between thiazide and nonthiazide users regardless of baseline ED severity (P>0.05).

Erectile dysfunction in patients with coronary artery disease.

Recent studies suggest that erectile dysfunction (ED) may be an early marker of endothelial dysfunction and coronary artery disease (CAD). Conversely, patients with CAD commonly have ED. The phosphodiesterase 5 (PDE5) inhibitors are very effective for the treatment of ED in patients with CAD. Numerous studies show that this class of drugs is in general safe in patients with stable CAD and these agents do not exacerbate ischemia in men with CAD undergoing exercise stress testing. Analysis of placebo-controlled trials did not show an increase in cardiovascular events among men receiving PDE5 inhibitors, and post-marketing surveillance studies with sildenafil did not observe an increase in cardiovascular events compared to expected age-matched rates. Organic nitrates remain a contraindication for PDE5 inhibitors and alpha blockers have precautions/contraindications depending upon specific drugs. The Princeton Consensus Guidelines (soon to be updated) suggest a logical approach to the patient with CAD seeking therapy for sexual dysfunction.

A case of erectile dysfunction and risk factors for coronary artery disease.

The hypothetical case of a man with erectile dysfunction and multiple cardiovascular risk factors is presented to illustrate the use of the second Princeton Consensus Conference Guidelines. Methods to optimize efficacy of the phosphodiesterase inhibitors are described. The overall cardiovascular safety of the phosphodiesterase inhibitors and their interaction with organic nitrates and alpha blockers are discussed.

Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 2.

In experimental studies in the dog, total proximal coronary artery occlusions of up to 15 minutes result in reversible injury, meaning that the myocytes survive this insult. The 15 minutes of ischemia, however, induce numerous changes in the myocardium, including certain monuments to the brief episode of ischemia that may persist for days. One of these monuments is stunned myocardium, which represents "prolonged postischemic contractile dysfunction of myocardium salvaged by reperfusion." The mechanism of stunning involves generation of oxygen radicals as well as alteration in calcium homeostasis and possibly alteration in contractile protein structure. Stunning has been observed in several clinical scenarios, including after percutaneous transluminal coronary angioplasty, unstable angina, stress-induced ischemia, after thrombolysis, and after cardiopulmonary bypass. Oxygen radical scavengers and calcium channel blockers have been shown to enhance function of stunned myocardium in experimental studies, and in a few clinical studies, calcium channel blockers have been shown to ameliorate stunning. Although brief periods of ischemia can contribute to prolonged left ventricular dysfunction and even heart failure, they paradoxically play a cardioprotective role. Episodes of ischemia as short as 5 minutes, followed by reperfusion, protect the heart from a subsequent longer coronary artery occlusion by markedly reducing the amount of necrosis that results from the test episode of ischemia. This phenomenon, called ischemic preconditioning, has been observed in virtually every species in which it has been studied and is a powerful cardioprotective effect. The mechanism of ischemic preconditioning involves both triggers and mediators and involves complex second messenger pathways that appear to involve such components as adenosine, adenosine receptors, the epsilon isoform of protein kinase C, the ATP-dependent potassium channels, as well as others, including a paradoxical protective role of oxygen radicals. Both an early and a late phase of preconditioning have been described, and the mechanisms underlying their induction are under investigation. That preconditioning may occur in humans is suggested by the observations that repetitive balloon inflations in the coronary artery are associated with progressively less chest pain, ST-segment elevation, lactate production, the protective effects of preinfarction angina, the anginal "warm-up phenomenon," and studies performed on human cardiac biopsies that show metabolic properties suggesting preconditioning. Development of pharmacological agents that stimulate second messenger pathways thought to be involved in preconditioning, but without causing ischemia, could result in novel approaches to treating ischemia. Hence, on one hand, brief episodes of ischemia can have a negative effect on the heart: stunning; and on the other hand, they have a protective effect: preconditioning. The future challenge is how to minimize the stunning phenomenon and maximize the preconditioning phenomenon in clinical practice.

Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 1.

In experimental studies in the dog, total proximal coronary artery occlusions of up to 15 minutes result in reversible injury, meaning that the myocytes survive this insult. The 15 minutes of ischemia, however, induce numerous changes in the myocardium, including certain monuments to the brief episode of ischemia that may persist for days. One of these monuments is stunned myocardium, which represents "prolonged postischemic contractile dysfunction of myocardium salvaged by reperfusion." The mechanism of stunning involves generation of oxygen radicals as well as alteration in calcium homeostasis and possibly alteration in contractile protein structure. Stunning has been observed in several clinical scenarios, including after percutaneous transluminal coronary angioplasty, unstable angina, stress-induced ischemia, after thrombolysis, and after cardiopulmonary bypass. Oxygen radical scavengers and calcium channel blockers have been shown to enhance function of stunned myocardium in experimental studies, and in a few clinical studies, calcium channel blockers have been shown to ameliorate stunning. Although brief periods of ischemia can contribute to prolonged left ventricular dysfunction and even heart failure, they paradoxically play a cardioprotective role. Episodes of ischemia as short as 5 minutes, followed by reperfusion, protect the heart from a subsequent longer coronary artery occlusion by markedly reducing the amount of necrosis that results from the test episode of ischemia. This phenomenon, called ischemic preconditioning, has been observed in virtually every species in which it has been studied and is a powerful cardioprotective effect. The mechanism of ischemic preconditioning involves both triggers and mediators and involves complex second messenger pathways that appear to involve such components as adenosine, adenosine receptors, the epsilon isoform of protein kinase C, the ATP-dependent potassium channels, as well as others, including a paradoxical protective role of oxygen radicals. Both an early and a late phase of preconditioning have been described, and the mechanisms underlying their induction are under investigation. That preconditioning may occur in humans is suggested by the observations that repetitive balloon inflations in the coronary artery are associated with progressively less chest pain, ST-segment elevation, lactate production, the protective effects of preinfarction angina, the anginal "warm-up phenomenon," and studies performed on human cardiac biopsies that show metabolic properties suggesting preconditioning. Development of pharmacological agents that stimulate second messenger pathways thought to be involved in preconditioning, but without causing ischemia, could result in novel approaches to treating ischemia. Hence, on one hand, brief episodes of ischemia can have a negative effect on the heart: stunning; and on the other hand, they have a protective effect: preconditioning. The future challenge is how to minimize the stunning phenomenon and maximize the preconditioning phenomenon in clinical practice.