REVIEW ARTICLE
Erectile dysfunction in patients
with
cardiovascular disease
A.J.M. Oude Ophuis, A.A.B. Lycklama a Nijeholt
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. (NethHeartJ2006;14:139-46.)
Keywords: cardiovascular diseases, risk factors, endothelium, sex, men, prognosis rectile dysfunction (ED), defined by the World Health Organisation as the inability to achieve and/or maintain an erection satisfactory for sexual intercourse, is a very common but frequently ignored condition.' The Massachusetts Male Aging Study showed symptoms of erectile dysfunction in 52% of 1290 males between 40 and 70 years of age.2 Erectile dysfunction is highly prevalent, the incidence is agerelated, it is a progressive condition and it is significantly undertreated. In 1995 it was estimated that 152 A.J.M. Oude Ophuis Department of Cardiology, Canisius-Wilhelmina Hospital, Nimegen, the Netherlands A.A.B. Lycklama a Nijeholt Department of Urology, Leiden University Medical Centre, Leiden, the Netherlands
Correspondence to: A.J.M. Oude Ophuis Department of Cardiology, Canisius-Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ Nijmegen, the Netherlands E-mail: [email protected]
Netherlands Heart Journal, Volume 14, Number 4, April 2006
million males worldwide suffered from ED. Due to an increase in life expectancy it is estimated that by the year 2025, 322 million males will suffer from ED worldwide, showing the importance of this widespread medical condition.3 An age-stratified sample of men >40 years in Boxmeer, the Netherlands showed that ED was a common disorder within the population. To the question regarding problems in getting an erection 13% of all men answered affirmatively. The prevalence was higher among older age groups but they regarded ED as less of a problem than the younger age groups.4 Normal erectile function is dependent on a finetuned interaction of multiple organ systems, including psychosocial, endocrine, neurological, genitourinary and cardiovascular systems. Impairment of normal erectile function may occur with malfunctioning of any of these systems. The aetiology of ED is organic in the majority ofpatients, arteriovascular abnormalities being the most common cause. Because the penis is essentially a vascular organ that requires the two corpora cavernosa to fill with and retain blood, the relation between cardiovascular disease and ED has become a new area of focus and research.5 Many of the well-established risk factors for cardiovascular disease such as smoking, diabetes, hypertension and lipid abnormalities are also risk factors for ED.26 Erectile dysfunction is not uncommon among men who have cardiovascular disease. It is postulated that ED with an arteriovascular aetiology can predate and be an indicator of potential coronary artery disease.7'8 This article is intended to increase awareness in cardiologists of ED and its cardiovascular implications and is not intended to be all-inclusive. The impact of sexual activity on the cardiovascular system Among the first authors to report on the cardiovascular response during intercourse were Littler et al. in 1974. He reported a significant rise in blood pressure during sexual arousal due to sympathetic activity and peripheral vasoconstriction (systolic increased by up to 139
Erectile dysfunction in patients with cardiovascular disease
100 mmHg, diastolic by up to 48 mmHg) and a significant increase in heart rate (up to 87 beats/min).9 After orgasm is reached, lower values of blood pressure and heart rate are attained than before intercourse. Bohlen and co-workers published on cardiovascular strain during four sexual activities.'0 Non-intercourse sexual activities gave rise to the least amount ofcardiovascular strain, whereas intercourse (man-on-top) with a new partner gave rise to maximal cardiovascular strain. Measurement of exhaled gases during sexual activity with the usual partner has demonstrated relatively low workloads ranging from two to six metabolic equivalent tasks (METs) depending on the position during intercourse."' The cardiac workload during intercourse has been equated to completing stage I on the Bruce protocol, or a workload offour to six METs, in relation to the physiological responses to sexual activity, induding a rise in systolic blood pressure to up to 180 mmHg and an increase in heart rate to up to 130 beats/min.'2 It is important to realise that cardiac workload varies between individuals and with different sexual activities, taking into account the additional cardiac workload related to emotional stress.'3 The patient's description of his functional capacity may be helpful in assessing whether sexual activity is likely to provoke clinically important cardiac symptoms.'4 The cardiac workloads for sexual activity are generally analogous to ironing (2-4 METs), walking a mile in 20 minutes (3-4 METs), or playing golf (3-5 METs)."5"16 Once men who have coronary artery disease and ED are allowed to engage in sexual activities, the risk of sexual activity precipitating a cardiac event becomes a potential concern. Among men who have suffered myocardial infarction, approximately 25% report cessation of sexual activities and 50% report decreased sexual activity. Patients with angina pectoris show less dramatic statistics. Following coronary artery bypass grafting, 36% of patients report less frequent sexual activity and nearly 10% report an increased frequency.17 Although many men and their partners are concerned about resuming sexual activity following myocardial infarction, recent data do not endorse this overrated concern. In patients without a cardiac history the baseline risk of acute myocardial infarction in the first two hours after sexual intercourse is increased by 2.5. For patients with a history of myocardial infarction the baseline risk was increased by 2.9. It seems that the relative cardiovascular risk for sexual activities in patients with a previous myocardial infarction is slightly higher than in healthy subjects.'8 In addition, it is suggested that regular exercise reduces or eliminates the risk of myocardial infarction during or immediately after sexual activity.'9 It is important that patients who develop significant anginal symptoms or ischaemia during exertion or exercise testing and patients with unstable angina or advanced heart failure should undergo cardiac evaluation and treatment before resuming sexual activity.
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Erectile dysfunction equivalent to endothelial dysfunction? The discovery of nitric oxide with its regulating properties of vascular tone played a pivotal role in the understanding ofvascular physiology and opened unprecedented avenues for research in the development of many cardiovascular drugs.20'2' Nitric oxide released by vascular endothelial cells induces smooth muscle cell relaxation and inhibits vascular smooth muscle proliferation. Nitric oxide exerts many of its effects by activation of soluble guanyl cyclase, resulting in increased production of cyclic guanosine monophosphate (cGMP), which results in lower intracellular calcium levels and therefore, vasodilatation.22 Nitric oxide is widely recognised as the most important factor involved in corpus cavernosal smooth muscle relaxation, and hence in erection.23 A correlation between erectile dysfimction and endothelial dysfunction in type II diabetic men is established, involving a defective nitric oxide activity, linked to reduced nitric oxide availability.24 The concentration ofintracellular cGMP is regulated by the rates of production and elimination of cGMP. The rate of production is controlled through the nitric oxide-guanyl cyclase activity. The rate of elimination depends on the activity of phophodiesterase enzymes (PDE) responsible for the breakdown of cyclic nucleotides cAMP and cGMP. Four phosphodiesterase isoforms have been identified in human penile tissue (types 2, 3, 4, and 5); PDE-5 is the most important form of PDE in cavernosal smooth muscle.25'26 Inhibition of this enzyme by a PDE-5 inhibitor such as sildenafil (Viagra) enhances nitric oxide-induced vasorelaxation by increasing vascular smooth muscle cGMP concentration.27'28 Sildenafil has been shown to be an effective oral treatment for erectile dysfunction in men, including men with diabetes.29 In a brachial artery flowmediated dilatation study (FMD, a marker of endotheial function), the favourable short- and long-term effect ofsildenafil on FMD was recently demonstrated.30 The beneficial effect of prolonged sildenafil therapy may have implications for management of erectile dysfunction as well as cardiovascular disease, especially in patients with diabetes. Just recently Halcox et al. studied the effects of the phophodiesterase inhibitor sildenafil on coronary and peripheral vascular function, platelet activation, and myocardial ischaemia.3' The authors concluded that sildenafil dilates epicardial coronary arteries, improves endothelial dysfunction and inhibits platelet activation in patients with coronary artery disease. The concept of endothelial dysfunction leading to erectile dysfunction and eventually to coronary heart disease was heavily advocated during the International Summit on Sexual Medicine and Cardiology, Paris 2002. A clear relation between erectile dysfunction and cardiovascular disease such as hypertension, coronary artery disease and myocardial infarction is well documented.32'33 Cardiovascular disease is clearly underdiagnosed and ignored in men with erectile dysNetherlands Heart Journal, Volume 14, Number 4, April 2006
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Erectile dysfunction in patients with cardiovascular disease
Table 1. Patient's attitudes toward discussions about sexuality (Bedell, et al.).4
64 Should physicians talk with their patients about sexual functioning? Is your doctor comfortable talking about sexual functioning? Are you comfortable talking about sexual functioning? 6 Does your concern about confidentially of the medical record influence your willingness to discuss sexuality with your doctor? Should a healthcare professional other than a physician ask questions about sexuality? Do you feel your physician has adequately informed you about your sexual functioning?
function.34 Montorsi et al. reported on 200 consecutive patients admitted with an acute coronary syndrome. In 70% ofthese patients erectile dysfunction was present before the clinical manifestation of coronary heart disease.35'36 'The Penile Stress test: a window to the hearts of men' was the appealing title of an abstract presented at the American Heart Association by Pritzker et al. who reported on the presence of significant coronary heart disease in 40% of patients with ED.37 Recently, data were presented linking ED to other atherosclerotic diseases by showing a correlation between total coronary artery plaque burden as assessed angiographically and objective measures of ED.38 All of the above underlines the importance of knowledge and awareness of erectile dysfunction as a potential marker for endothelial dysfunction by the cardiologist. Recognition of ED by the cardiologist Sexual function is widely considered to be of importance in quality of life. This function is frequently altered in patients with coronary artery disease.2 17 3941 As mentioned earlier, ED may be among the first manifestations ofdisease because the erectile function heavily depends on both the arterial system perfusing the penis as well as on the delicate endothelial system within the smooth musculature of the cavernous bodies. Because the arterial system must enlarge considerably in diameter to enable penile tumescence, these vessels may be more sensitive to atherosclerotic occlusion than the coronary circulation or other vasculature. The assessment oferectile status may indeed give clues to clinically silent yet progressive coronary, peripheral or cerebrovascular disease as well as to underdiagnosed hypertension, diabetes, or other endocrine disorders.37 Patients with multivessel coronary disease may have greater difficulty achieving an erection than those with single-vessel disease.32 On top of the intrinsic effects of cardiovascular disease, drugs used to treat heart disease such as P-blocking agents and thiazide diuretics have been associated with the development of ED. Because of the growing awareness of ED among patients, media and physicians and the changing face of treatment approaches, cardiologists are more
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Women
Men
28 42
81 52 73 9
10 23 18 3
frequently consulted by their patients and fellow physicians. Some cardiologists believe that discussions about sexuality fall outside the realm oftheir responsibility, or they may think that these discussions are embarrassing for patients and themselves. Open and frank discussions about sexuality between physicians and patients are a prerequisite for addressing treatable causes ofsexual dysfunction.42'43 In a study addressing cardiologist's discussions on sexuality with patients it was mentioned that a considerable portion of patients would like their cardiologist to take a full sexual history (81% in males) and that they would be comfortable with these discussions.44 However, the majority of patients believed that they were inadequately informed about sexual functioning. Male patients believed that physicians were comfortable about discussing sexuality but noted that detailed questioning occurred only rarely (table 1). Physicians should initiate the discussion on ED by being direct, forthright, and nonjudgemental.45 An example of an introductory question on sexual function could be: 'Some men may have sexual difficulties after myocardial infarction, bypass surgery or from cardiac medication'. In addition, the more routine use of a sexual function questionnaire for men aged >40 years can be an easy springboard for discussion. The Sexual Health Inventory for Men (SHIM) is a valid and reliable instrument that takes only a few minutes for the patient to complete (table 2)."6 Initiatives such as specialised Male Cardiovascular Health Clinics with a multidisciplinary team consisting of a cardiologist, urologist and cardiac sexual advice nurse to help cardiac patients with sexual problems have recently been instituted and have shown very favourable results.47 Several factors influence sexuality in the elderly, among them the overall health status of both the patient and the partner and use ofmedications.4849 An important element in cardiac rehabilitation of patients with coronary heart disease is counselling about sexual activity; however, counselling occurs only infrequently. Cardiac rehabilitation programmes are the key to helping cardiac patients to resume their sexual activities.
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Erectile dysfunction in patients with cardiovascular disease
Table 2. Sexual health inventory for men. Sexual health inventory for men Patient's name: ............................................ Dat o e f evaluation
Sexual health is an important part of an individual's overall physical and emotional well-being. Erectile dysfunction, also known as impotence, is one of the very common medical conditions affecting sexual health. Fortunately, there are many different treatment options for erectile dysfunction. This questionnaire is designed to help you and your doctor identify if you may be experiencing erectile dysfunction. If you are, you may choose to discuss treatment options with your doctor. Each question has several possible responses. Circle the number of the response that best describes your own situation. Please be sure that you select one and only one response for each question. Over the past 6 months: 1. How do you rate your confidence that you could get and keep an erection? - Very low = 1 - Low = 2 - Moderate = 3 - High = 4 - Very high = 5 2. When you had erections with sexual stimulation, how often were your erections hard enough for penetration (entering your partner)? - No sexual activity = 0 - Almost never or never = I - A few times (much less than half the time) = 2 - Sometimes (about half the time) = 3 - Most times (much more than half the time) = 4 - Almost always or always = 5 3. During sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner? - Did not attempt intercourse = 0 - Almost never or never = 1 - A few times (much less than half the time) = 2 - Sometimes (about half the time) = 3 - Most times (much more than half the time) = 4 - Almost always of always = 5 4. During sexual intercourse, how difficult was it to maintain your erection to completion of intercourse? - Did not attempt intercourse = 0 - Extremely difficult = 1 - Very difficult = 2 - Difficult = 3 - Slightly difficult = 4 - Not difficult = 5 5. When you attempted sexual intercourse, how often was it satisfactory for you? - Did not attempt intercourse = 0 - Almost never of never = 1 - A few times (much less than half the time) = 2 - Sometimes (about half the time) = 3 - Most times (much more than half the time) = 4 - Almost always of always = 5 Add the numbers corresponding to questions 1-5. If your score is 21 or less, you may be showing signs of erectile dysfunction and may want to speak with your doctor.
Score: ....................................
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Erectile dysfunction in patients with cardiovascular disease
Table 3. Management algorithm according to graded risk. Grading risk
Cardiovascular status on presentation
Management recommendations*
Low risk
Controlled hypertension Asymptomatic, 3 risk factors for CAD excluding age and gender
Specialised evaluation recommended (e.g. exercise test for angina, echo for murmur) Patient to be placed in high- or low-risk category, depending on outcome of testing
High risk
Severe or unstable or refractory angina Uncontrolled hypertension (SBP >180 mmHg) CHF (NYHA IlIl and IV) Recent Ml or CVA (i.e. within last 14 days) High risk of arrhythmias Hypertrophic cardiomyopathy Moderate/severe valvular disease
ED treatment can be initiated but exercise testing recommended to stratify risk Refer for specialised cardiac evaluation and management Treatment for ED to be deferred until cardiac condition established and/or specialist evaluation completed
CAD=coronary artery disease, Ml=myocardial infarction, CVA=cerebral vascular accident, CHF=congestive heart failure, LVD=left ventricular dysfunction, SBP=systolic blood pressure, ED=erectile dysfunction, TIA=transient ischaemic attack. *Management recommendations for erectile dysfunction for primary care physicians. From Jackson G, et al.50
Patients with cardiovascular disease and assessment for the treatment of ED All patients with ED should undergo adequate medical assessment. It is important to establish a baseline measure of the type of activities and level of physical exertion a patient normally undertakes. The risk of a cardiac event in a patient with cardiovascular disease is higher than in a patient without cardiovascular disease; therefore, cardiovascular risk assessment should focus on the risk of further cardiovascular events at a return
evaluated and treated by their cardiologist before instituting treatment for ED.
primary care; otherwise exercise testing
Cardiovascular drug-induced ED There are a number of drugs that are suspected of contributing to ED in cardiovascular patients. Reports have indicated an incidence range of 5 to 43% with propranolol and 4 to 32% with thiazide diuretics.5' There is not much evidence to confirm the effectiveness of changing drug therapy to reverse ED. However, if a relation in time exists between the start oftherapy and onset of symptoms it is conceivable to stop or safely change medication and evaluate the effect on improvement of ED after two to four weeks. However, physicians should realise that the development of ED might be due to the condition being treated, rather than the drugs used.50
guide management when cardiovascular risk is in doubt. If a patient can perform stage I of the Bruce protocol without significant ST-segment changes, arrhythmia or drop in systolic blood pressure, the patient is not at risk during normal sexual activity. Patients falling into the high-risk category should be
Current treatment options for ED in the cardiovascular patient Currently, the range of therapy for managing ED in the general population includes oral PDE-5 inhibitors such as sildenafil citrate, sublingual apomorphine,
to sexual activity. Cardiovascular status has been split into three categories defining patients at low, intermediate or high risk. A practical framework for assessing the potential level of cardiovascular risk following a return to sexual activity is shown in table 3.5° Most of the patients with low or intermediate risk can be managed
in
can
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Erectile dysfunction in patients with cardiovascular disease
Figure M. Mechanism ofaction ofsitdenafil. NO(S)=nitric oxide (synthase), GCGguanyl cyclase, GTP-guanosine triphosphate, cGMP-cyclic guanosine monophosphate, PDG-phophodiesterase enzymes.
Figure lB. Mechanism of action of concurrent use of sildenafil and nitrates. NO=nitric oxide, GC=guanyl cyclase, GTP=guanosine
triphosphate, cGMPcyclicguanosine monophosphate. intracavernosal injection or transurethral alprostadil, vacuum constriction devices and penile implants. However, in cardiac patients on warfarin, injections and vacuum devices are not indicated because of increased risk of haematoma or bleeding PDE-5 inhibitors (sildenafil) and the heart A balance in the rates of production and elimination regulates the concentration of intracellular cGMP necessary for smooth muscle cell relaxation and maintaining an erection (figure IA). The rate of production is controlled through the nitric oxideguanylate cyclase activity. The rate of elimination 144
depends on the activity ofphosphodiesterase enzymes. The predominant isoform in human penile tissue is PDE type 5. The most widely used PDE-5 inhibitor is sildenafil, an orally active, potent and selective inhibitor of cGMP-specific phosphodiesterase type 5. It enhances the relaxant effect of nitric oxide released in response to sexual stimulation by increasing cGMP concentrations in the corporal smooth muscle. A metaanalysis of nine double-blind, placebo-controlled studies determined the efficacy ofsildenafil in patients with ED and ichaemic heart disease who were not taking nitrates.52 The concomitant use of nitrates and sildenafil leads to profound and prolonged blood Netherlands Heart Journal, Volume 14, Number 4, April 2006
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Erectile dysfunction in patients with cardiovascular disease
pressure drop (up to 30 mmHg) and is contraindicated for that reason (figure 1B). It is important for cardiologists to instruct their patients what to do if they have angina during sexual activity after using sildenafil. The habituous intake of nitroglycerin sublingually by cardiac patients should be prohibited and patients should be instructed to visit the emergency department, notfying physicians about the use of a PDE-5 inhibitor. In these cases calcium antagonists given intravenously could be administered. Oral nitrates can be discontinued in the presence of continuing [-blockade and/or calcium antagonist therapy in stable coronary disease patients with ED to allow for the safe use of PDE-5 inhibitors.53 In contrast to an unwanted synergistic effect ofthe combined use with nitrates, sildenafil has shown many advantageous influences on the heart. During coronary angiography, it has been shown that sildenafil increased epicardial diameters after the administration of acetylcholine in patients with coronary artery disease as well as in patients with normal endothelial fimction compared with placebo.54 The same study suggested a reduction in platelet GP IIb/IIIa-receptor activation by sildenafil. Another study looked at the effect on coronary blood flow in patients with severe coronary artery disease (CAD). Average peak velocity, coronary artery diameter and coronary blood flow showed no significant changes with sildenafil administration in stenosed or non-stenosed arteries.55 Halcox et al. assessed endothelial function by FMD. In patients with and without CAD, hyperaemic vasodilation lasted significantly longer following sildenafil administration compared with the pre-sildenafil control group.54 Another relevant clinical study evaluated whether sildenafil affected the ischaemic threshold in men who experienced exercise-induced angina. Sildenafil significantly increased the time to onset of limiting angina and increased exercise duration compared with placebo.56 Furthermore, a neutral effect of PDE-5 inhibition on exercise echocardiography was observed.57 Also in the field of heart failure favourable reports have been published. In a double-blind, twoway crossover study 24 males with chronic heart failure (CHF) were randomised to placebo or sildenafil 50 mg.58 Sildenafil was a well-tolerated and effective treatment in CHF patients with ED. The improvement in exercise capacity, in particular in heart rate, suggests that sildenafil might decrease myocardial oxygen consumption during sexual activity. Others have reported safe and effective treatment with sildenafil for ED in men with New York Heart Association classes II and III chronic heart failure and reliefofdepressive symptoms, explaining an improvement in the perception of quality of life.59 Ever since the introduction of sildenafil seven years ago, the incidence of MI and mortality has been a matter of discussion. The pooled data from 80 studies of patients treated with sildenafil between 1993 and
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2000 were analysed. These data indicate that sildenafil was not associated with short-term risk for myocardial infarction and are consistent with the growing body of evidence that sildenafil use is not associated with an increased risk for cardiovascular events.60 Recently, more PDE-5 inhibitors have been registered for the treatment ofED, such as vardenafil and tadalafil. The main pharmacokinetic difference is in the onset and duration ofthese drugs. Large safety and efficacy studies concerning the recent developed PDE-5 inhibitors are still lacking. Conclusions and recommendations The management ofED remains primarily within the domain of urologists, psychologists and family practitioners. However, the association of ED with vascular disease does involve other medical specialists, including cardiologists, in the management of ED. ED is a common disease and its prevalence will grow considerably in the coming years. Growing evidence showing endothelial dysfunction to be the common denominator for cardiovascular disease and ED explains the high incidence of ED in patients with cardiovascular disease. Suggestions that ED predates coronary artery disease provides a tool to cardiovascular risk management in these patients. Modifying risk factors is the key in treating ED and preventive cardiovascular medicine. Management of ED in cardiovascular patients can be performed safely following the guidelines of the Princeton panel. Cardiologists should pay more attention to ED. It occurs more in their patients than they are aware of. Possibly a significant role can be played in the future by cardiac rehabilitation programmes. Drug therapy for ED is still evolving. Good knowledge ofpharmacokinetic actions and interactions is important for cardiologists in order to advise and instruct their patients in the best possible way. U References 1
2 3 4
5 6 7 8
9
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36 Montorsi P, Ravagnani PM, Briganti A, Salonia A, Deho F, et al. Association between erectile dysfunction and coronary disease; A case report study. JSex Med 2005;2:575-82. 37 Pritzker MR The penile stress test: a window to the hearts of man. 72nd Scientific Sessions of the American Heart Association; 7-10 November 1999; Atlanta GA. Abstract 104561. 38 Solomon H, Man JW, Wierzbicki AS, Jackson G. Relation of erectile dysfunction to angiographic coronary artery disease. Am JCardiol2003;91:230-1. 39 Thienhaus OJ. Practical overview of sexual function and advancing age. Geriatrics 1988;43:63-7. 40 Goldstein I, Lue TF, Padma Nathan H, et al. Oral sildenafil in the treatment oferectile dysfunction. NEnglJMed 1998;338:1397404. 41 Westin L, Carlsson R, Israelsson B, et al. Quality oflife in patients with ischemic heart disease: a prospective controlled study. JIntern Med 1997;242:239-47. 42 Rosen RC, Riley A, Wagner G, et al. The International Index of erectile dysfunction: a multidimensional scale for assessment of erectile dysfunction. Urology 1997;49:822-30. 43 Benet AE, Melman A. The epidemiology of erectile dysfunction. Urol Clin North Am 1995;22:699-709. 44 Bedell SA, Duperval M, Goldberg R. Cardiologist's discussions about sexuality with patients with chronic coronary artery disease. Am HeartJ2002;144:239-42. 45 Levine LA, Mloner RA. Importance of asking questions about erectile dysfunction. Am HeartJ2000;86:1210-3. 46 Rosen RC, Cappelleri JC, Smith MD, Lipsky J, Pena BN. Development and evaluation of an abridged, 5-item version of the international index of erectile function as a diagnostic tool for erectile dysfunction. IntJImpotRes 1999;11:319-26. 47 Swinburne C. Affairs of the heart. Nursing Standard2002;16:189. 48 Diokno AC, Brown MB, Hergoz AR. Sexual function in the elderly. Arch Intern Med 1990;150:197-200. 49 Papadoulos C. Cardiovascular drugs and sexuality: a cardiologist's review. Arch Intern Med 1980;140:1341-5. 50 Jackson G, Betteridge J, Dean J, et al. A systematic approach to erectile dysfunction in the cardiovascular patient: A consensus statement update 2002. IntJ Clin Pract 2002;56:663-71. 51 Smith PJ, Talbert RL. Sexual dysfunction with antihypertensive and antipsychotic agents. Clin Pharm 1986;5:373-84. 52 Conti CR, Pepine CJ, Sweeney M. Efficacy and safety of sildenafil citrate in the treatment of erectile dysfunction in patients with ischemic heart disease. Am J Cardiol 1999;83:29c-34c. 53 Jackson G, Martin E, McGing E, CooperA. Successful withdrawal of oral long-acting nitrates to facilitate phosphodiesterase type 5 inhibitor use in stable coronary disease patients with erectile dysfunction. JSex Med 2005;2:513-6. 54 Halcox JP, Nour KR, Zalos G, Mincemoyer RA, Waclawiw M, Rivera CE, et al. The effect of sildenafil on human vascular function, platelet activation and myocardial ischemia. JAm Coll Cardiol 2002;40:1232-40. 55 Herrmann HC, Chang G, Klugherz BD, Mahoney PD. Hemodynamic effects ofsildenafil in men with severe coronary artery disease.
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56 Fox KM, Thadani U, Nash SD, et al. Sildenafil does not reduce exercise tolerance in men with erectile dysfunction and chronic stable angina. EurHeartJ2003;24:2206-12. 57 Arruda-Olson AM, Mahoney DW, Nehra A, Leckel M, Pellika PA. Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease. JAMA 2002;287:71925. 58 Bocchi E, Guimaraes G, Mocelin A, Bacal F, Bellotti G, et al. Sildenafil effects on exercise, neurohumoral activation, and erectile dysfunction in congestive heart failure. Circulation 2002;106: 1097-103. 59 Webster LJ, Michelakis, Davis T, Archer SL. Use of sildenafil for safe improvement of erectile function and quality oflife in men with New York Heart Association Classes II and III congestive heart failure. 60 Mittleman MA, MacLure M, Glasser DB. Evaluation of acute risk for myocardial infarction in men treated with sildenafil citrate. Am J Cardiol 2005;96:443-6.
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Erectile dysfunction in patients
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A.J.M. Oude Ophuis, A.A.B. Lycklama a Nijeholt
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. (NethHeartJ2006;14:139-46.)
Keywords: cardiovascular diseases, risk factors, endothelium, sex, men, prognosis rectile dysfunction (ED), defined by the World Health Organisation as the inability to achieve and/or maintain an erection satisfactory for sexual intercourse, is a very common but frequently ignored condition.' The Massachusetts Male Aging Study showed symptoms of erectile dysfunction in 52% of 1290 males between 40 and 70 years of age.2 Erectile dysfunction is highly prevalent, the incidence is agerelated, it is a progressive condition and it is significantly undertreated. In 1995 it was estimated that 152 A.J.M. Oude Ophuis Department of Cardiology, Canisius-Wilhelmina Hospital, Nimegen, the Netherlands A.A.B. Lycklama a Nijeholt Department of Urology, Leiden University Medical Centre, Leiden, the Netherlands
Correspondence to: A.J.M. Oude Ophuis Department of Cardiology, Canisius-Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ Nijmegen, the Netherlands E-mail: [email protected]
Netherlands Heart Journal, Volume 14, Number 4, April 2006
million males worldwide suffered from ED. Due to an increase in life expectancy it is estimated that by the year 2025, 322 million males will suffer from ED worldwide, showing the importance of this widespread medical condition.3 An age-stratified sample of men >40 years in Boxmeer, the Netherlands showed that ED was a common disorder within the population. To the question regarding problems in getting an erection 13% of all men answered affirmatively. The prevalence was higher among older age groups but they regarded ED as less of a problem than the younger age groups.4 Normal erectile function is dependent on a finetuned interaction of multiple organ systems, including psychosocial, endocrine, neurological, genitourinary and cardiovascular systems. Impairment of normal erectile function may occur with malfunctioning of any of these systems. The aetiology of ED is organic in the majority ofpatients, arteriovascular abnormalities being the most common cause. Because the penis is essentially a vascular organ that requires the two corpora cavernosa to fill with and retain blood, the relation between cardiovascular disease and ED has become a new area of focus and research.5 Many of the well-established risk factors for cardiovascular disease such as smoking, diabetes, hypertension and lipid abnormalities are also risk factors for ED.26 Erectile dysfunction is not uncommon among men who have cardiovascular disease. It is postulated that ED with an arteriovascular aetiology can predate and be an indicator of potential coronary artery disease.7'8 This article is intended to increase awareness in cardiologists of ED and its cardiovascular implications and is not intended to be all-inclusive. The impact of sexual activity on the cardiovascular system Among the first authors to report on the cardiovascular response during intercourse were Littler et al. in 1974. He reported a significant rise in blood pressure during sexual arousal due to sympathetic activity and peripheral vasoconstriction (systolic increased by up to 139
Erectile dysfunction in patients with cardiovascular disease
100 mmHg, diastolic by up to 48 mmHg) and a significant increase in heart rate (up to 87 beats/min).9 After orgasm is reached, lower values of blood pressure and heart rate are attained than before intercourse. Bohlen and co-workers published on cardiovascular strain during four sexual activities.'0 Non-intercourse sexual activities gave rise to the least amount ofcardiovascular strain, whereas intercourse (man-on-top) with a new partner gave rise to maximal cardiovascular strain. Measurement of exhaled gases during sexual activity with the usual partner has demonstrated relatively low workloads ranging from two to six metabolic equivalent tasks (METs) depending on the position during intercourse."' The cardiac workload during intercourse has been equated to completing stage I on the Bruce protocol, or a workload offour to six METs, in relation to the physiological responses to sexual activity, induding a rise in systolic blood pressure to up to 180 mmHg and an increase in heart rate to up to 130 beats/min.'2 It is important to realise that cardiac workload varies between individuals and with different sexual activities, taking into account the additional cardiac workload related to emotional stress.'3 The patient's description of his functional capacity may be helpful in assessing whether sexual activity is likely to provoke clinically important cardiac symptoms.'4 The cardiac workloads for sexual activity are generally analogous to ironing (2-4 METs), walking a mile in 20 minutes (3-4 METs), or playing golf (3-5 METs)."5"16 Once men who have coronary artery disease and ED are allowed to engage in sexual activities, the risk of sexual activity precipitating a cardiac event becomes a potential concern. Among men who have suffered myocardial infarction, approximately 25% report cessation of sexual activities and 50% report decreased sexual activity. Patients with angina pectoris show less dramatic statistics. Following coronary artery bypass grafting, 36% of patients report less frequent sexual activity and nearly 10% report an increased frequency.17 Although many men and their partners are concerned about resuming sexual activity following myocardial infarction, recent data do not endorse this overrated concern. In patients without a cardiac history the baseline risk of acute myocardial infarction in the first two hours after sexual intercourse is increased by 2.5. For patients with a history of myocardial infarction the baseline risk was increased by 2.9. It seems that the relative cardiovascular risk for sexual activities in patients with a previous myocardial infarction is slightly higher than in healthy subjects.'8 In addition, it is suggested that regular exercise reduces or eliminates the risk of myocardial infarction during or immediately after sexual activity.'9 It is important that patients who develop significant anginal symptoms or ischaemia during exertion or exercise testing and patients with unstable angina or advanced heart failure should undergo cardiac evaluation and treatment before resuming sexual activity.
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Erectile dysfunction equivalent to endothelial dysfunction? The discovery of nitric oxide with its regulating properties of vascular tone played a pivotal role in the understanding ofvascular physiology and opened unprecedented avenues for research in the development of many cardiovascular drugs.20'2' Nitric oxide released by vascular endothelial cells induces smooth muscle cell relaxation and inhibits vascular smooth muscle proliferation. Nitric oxide exerts many of its effects by activation of soluble guanyl cyclase, resulting in increased production of cyclic guanosine monophosphate (cGMP), which results in lower intracellular calcium levels and therefore, vasodilatation.22 Nitric oxide is widely recognised as the most important factor involved in corpus cavernosal smooth muscle relaxation, and hence in erection.23 A correlation between erectile dysfimction and endothelial dysfunction in type II diabetic men is established, involving a defective nitric oxide activity, linked to reduced nitric oxide availability.24 The concentration ofintracellular cGMP is regulated by the rates of production and elimination of cGMP. The rate of production is controlled through the nitric oxide-guanyl cyclase activity. The rate of elimination depends on the activity of phophodiesterase enzymes (PDE) responsible for the breakdown of cyclic nucleotides cAMP and cGMP. Four phosphodiesterase isoforms have been identified in human penile tissue (types 2, 3, 4, and 5); PDE-5 is the most important form of PDE in cavernosal smooth muscle.25'26 Inhibition of this enzyme by a PDE-5 inhibitor such as sildenafil (Viagra) enhances nitric oxide-induced vasorelaxation by increasing vascular smooth muscle cGMP concentration.27'28 Sildenafil has been shown to be an effective oral treatment for erectile dysfunction in men, including men with diabetes.29 In a brachial artery flowmediated dilatation study (FMD, a marker of endotheial function), the favourable short- and long-term effect ofsildenafil on FMD was recently demonstrated.30 The beneficial effect of prolonged sildenafil therapy may have implications for management of erectile dysfunction as well as cardiovascular disease, especially in patients with diabetes. Just recently Halcox et al. studied the effects of the phophodiesterase inhibitor sildenafil on coronary and peripheral vascular function, platelet activation, and myocardial ischaemia.3' The authors concluded that sildenafil dilates epicardial coronary arteries, improves endothelial dysfunction and inhibits platelet activation in patients with coronary artery disease. The concept of endothelial dysfunction leading to erectile dysfunction and eventually to coronary heart disease was heavily advocated during the International Summit on Sexual Medicine and Cardiology, Paris 2002. A clear relation between erectile dysfunction and cardiovascular disease such as hypertension, coronary artery disease and myocardial infarction is well documented.32'33 Cardiovascular disease is clearly underdiagnosed and ignored in men with erectile dysNetherlands Heart Journal, Volume 14, Number 4, April 2006
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Table 1. Patient's attitudes toward discussions about sexuality (Bedell, et al.).4
64 Should physicians talk with their patients about sexual functioning? Is your doctor comfortable talking about sexual functioning? Are you comfortable talking about sexual functioning? 6 Does your concern about confidentially of the medical record influence your willingness to discuss sexuality with your doctor? Should a healthcare professional other than a physician ask questions about sexuality? Do you feel your physician has adequately informed you about your sexual functioning?
function.34 Montorsi et al. reported on 200 consecutive patients admitted with an acute coronary syndrome. In 70% ofthese patients erectile dysfunction was present before the clinical manifestation of coronary heart disease.35'36 'The Penile Stress test: a window to the hearts of men' was the appealing title of an abstract presented at the American Heart Association by Pritzker et al. who reported on the presence of significant coronary heart disease in 40% of patients with ED.37 Recently, data were presented linking ED to other atherosclerotic diseases by showing a correlation between total coronary artery plaque burden as assessed angiographically and objective measures of ED.38 All of the above underlines the importance of knowledge and awareness of erectile dysfunction as a potential marker for endothelial dysfunction by the cardiologist. Recognition of ED by the cardiologist Sexual function is widely considered to be of importance in quality of life. This function is frequently altered in patients with coronary artery disease.2 17 3941 As mentioned earlier, ED may be among the first manifestations ofdisease because the erectile function heavily depends on both the arterial system perfusing the penis as well as on the delicate endothelial system within the smooth musculature of the cavernous bodies. Because the arterial system must enlarge considerably in diameter to enable penile tumescence, these vessels may be more sensitive to atherosclerotic occlusion than the coronary circulation or other vasculature. The assessment oferectile status may indeed give clues to clinically silent yet progressive coronary, peripheral or cerebrovascular disease as well as to underdiagnosed hypertension, diabetes, or other endocrine disorders.37 Patients with multivessel coronary disease may have greater difficulty achieving an erection than those with single-vessel disease.32 On top of the intrinsic effects of cardiovascular disease, drugs used to treat heart disease such as P-blocking agents and thiazide diuretics have been associated with the development of ED. Because of the growing awareness of ED among patients, media and physicians and the changing face of treatment approaches, cardiologists are more
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Women
Men
28 42
81 52 73 9
10 23 18 3
frequently consulted by their patients and fellow physicians. Some cardiologists believe that discussions about sexuality fall outside the realm oftheir responsibility, or they may think that these discussions are embarrassing for patients and themselves. Open and frank discussions about sexuality between physicians and patients are a prerequisite for addressing treatable causes ofsexual dysfunction.42'43 In a study addressing cardiologist's discussions on sexuality with patients it was mentioned that a considerable portion of patients would like their cardiologist to take a full sexual history (81% in males) and that they would be comfortable with these discussions.44 However, the majority of patients believed that they were inadequately informed about sexual functioning. Male patients believed that physicians were comfortable about discussing sexuality but noted that detailed questioning occurred only rarely (table 1). Physicians should initiate the discussion on ED by being direct, forthright, and nonjudgemental.45 An example of an introductory question on sexual function could be: 'Some men may have sexual difficulties after myocardial infarction, bypass surgery or from cardiac medication'. In addition, the more routine use of a sexual function questionnaire for men aged >40 years can be an easy springboard for discussion. The Sexual Health Inventory for Men (SHIM) is a valid and reliable instrument that takes only a few minutes for the patient to complete (table 2)."6 Initiatives such as specialised Male Cardiovascular Health Clinics with a multidisciplinary team consisting of a cardiologist, urologist and cardiac sexual advice nurse to help cardiac patients with sexual problems have recently been instituted and have shown very favourable results.47 Several factors influence sexuality in the elderly, among them the overall health status of both the patient and the partner and use ofmedications.4849 An important element in cardiac rehabilitation of patients with coronary heart disease is counselling about sexual activity; however, counselling occurs only infrequently. Cardiac rehabilitation programmes are the key to helping cardiac patients to resume their sexual activities.
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Table 2. Sexual health inventory for men. Sexual health inventory for men Patient's name: ............................................ Dat o e f evaluation
Sexual health is an important part of an individual's overall physical and emotional well-being. Erectile dysfunction, also known as impotence, is one of the very common medical conditions affecting sexual health. Fortunately, there are many different treatment options for erectile dysfunction. This questionnaire is designed to help you and your doctor identify if you may be experiencing erectile dysfunction. If you are, you may choose to discuss treatment options with your doctor. Each question has several possible responses. Circle the number of the response that best describes your own situation. Please be sure that you select one and only one response for each question. Over the past 6 months: 1. How do you rate your confidence that you could get and keep an erection? - Very low = 1 - Low = 2 - Moderate = 3 - High = 4 - Very high = 5 2. When you had erections with sexual stimulation, how often were your erections hard enough for penetration (entering your partner)? - No sexual activity = 0 - Almost never or never = I - A few times (much less than half the time) = 2 - Sometimes (about half the time) = 3 - Most times (much more than half the time) = 4 - Almost always or always = 5 3. During sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner? - Did not attempt intercourse = 0 - Almost never or never = 1 - A few times (much less than half the time) = 2 - Sometimes (about half the time) = 3 - Most times (much more than half the time) = 4 - Almost always of always = 5 4. During sexual intercourse, how difficult was it to maintain your erection to completion of intercourse? - Did not attempt intercourse = 0 - Extremely difficult = 1 - Very difficult = 2 - Difficult = 3 - Slightly difficult = 4 - Not difficult = 5 5. When you attempted sexual intercourse, how often was it satisfactory for you? - Did not attempt intercourse = 0 - Almost never of never = 1 - A few times (much less than half the time) = 2 - Sometimes (about half the time) = 3 - Most times (much more than half the time) = 4 - Almost always of always = 5 Add the numbers corresponding to questions 1-5. If your score is 21 or less, you may be showing signs of erectile dysfunction and may want to speak with your doctor.
Score: ....................................
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Table 3. Management algorithm according to graded risk. Grading risk
Cardiovascular status on presentation
Management recommendations*
Low risk
Controlled hypertension Asymptomatic, 3 risk factors for CAD excluding age and gender
Specialised evaluation recommended (e.g. exercise test for angina, echo for murmur) Patient to be placed in high- or low-risk category, depending on outcome of testing
High risk
Severe or unstable or refractory angina Uncontrolled hypertension (SBP >180 mmHg) CHF (NYHA IlIl and IV) Recent Ml or CVA (i.e. within last 14 days) High risk of arrhythmias Hypertrophic cardiomyopathy Moderate/severe valvular disease
ED treatment can be initiated but exercise testing recommended to stratify risk Refer for specialised cardiac evaluation and management Treatment for ED to be deferred until cardiac condition established and/or specialist evaluation completed
CAD=coronary artery disease, Ml=myocardial infarction, CVA=cerebral vascular accident, CHF=congestive heart failure, LVD=left ventricular dysfunction, SBP=systolic blood pressure, ED=erectile dysfunction, TIA=transient ischaemic attack. *Management recommendations for erectile dysfunction for primary care physicians. From Jackson G, et al.50
Patients with cardiovascular disease and assessment for the treatment of ED All patients with ED should undergo adequate medical assessment. It is important to establish a baseline measure of the type of activities and level of physical exertion a patient normally undertakes. The risk of a cardiac event in a patient with cardiovascular disease is higher than in a patient without cardiovascular disease; therefore, cardiovascular risk assessment should focus on the risk of further cardiovascular events at a return
evaluated and treated by their cardiologist before instituting treatment for ED.
primary care; otherwise exercise testing
Cardiovascular drug-induced ED There are a number of drugs that are suspected of contributing to ED in cardiovascular patients. Reports have indicated an incidence range of 5 to 43% with propranolol and 4 to 32% with thiazide diuretics.5' There is not much evidence to confirm the effectiveness of changing drug therapy to reverse ED. However, if a relation in time exists between the start oftherapy and onset of symptoms it is conceivable to stop or safely change medication and evaluate the effect on improvement of ED after two to four weeks. However, physicians should realise that the development of ED might be due to the condition being treated, rather than the drugs used.50
guide management when cardiovascular risk is in doubt. If a patient can perform stage I of the Bruce protocol without significant ST-segment changes, arrhythmia or drop in systolic blood pressure, the patient is not at risk during normal sexual activity. Patients falling into the high-risk category should be
Current treatment options for ED in the cardiovascular patient Currently, the range of therapy for managing ED in the general population includes oral PDE-5 inhibitors such as sildenafil citrate, sublingual apomorphine,
to sexual activity. Cardiovascular status has been split into three categories defining patients at low, intermediate or high risk. A practical framework for assessing the potential level of cardiovascular risk following a return to sexual activity is shown in table 3.5° Most of the patients with low or intermediate risk can be managed
in
can
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Erectile dysfunction in patients with cardiovascular disease
Figure M. Mechanism ofaction ofsitdenafil. NO(S)=nitric oxide (synthase), GCGguanyl cyclase, GTP-guanosine triphosphate, cGMP-cyclic guanosine monophosphate, PDG-phophodiesterase enzymes.
Figure lB. Mechanism of action of concurrent use of sildenafil and nitrates. NO=nitric oxide, GC=guanyl cyclase, GTP=guanosine
triphosphate, cGMPcyclicguanosine monophosphate. intracavernosal injection or transurethral alprostadil, vacuum constriction devices and penile implants. However, in cardiac patients on warfarin, injections and vacuum devices are not indicated because of increased risk of haematoma or bleeding PDE-5 inhibitors (sildenafil) and the heart A balance in the rates of production and elimination regulates the concentration of intracellular cGMP necessary for smooth muscle cell relaxation and maintaining an erection (figure IA). The rate of production is controlled through the nitric oxideguanylate cyclase activity. The rate of elimination 144
depends on the activity ofphosphodiesterase enzymes. The predominant isoform in human penile tissue is PDE type 5. The most widely used PDE-5 inhibitor is sildenafil, an orally active, potent and selective inhibitor of cGMP-specific phosphodiesterase type 5. It enhances the relaxant effect of nitric oxide released in response to sexual stimulation by increasing cGMP concentrations in the corporal smooth muscle. A metaanalysis of nine double-blind, placebo-controlled studies determined the efficacy ofsildenafil in patients with ED and ichaemic heart disease who were not taking nitrates.52 The concomitant use of nitrates and sildenafil leads to profound and prolonged blood Netherlands Heart Journal, Volume 14, Number 4, April 2006
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pressure drop (up to 30 mmHg) and is contraindicated for that reason (figure 1B). It is important for cardiologists to instruct their patients what to do if they have angina during sexual activity after using sildenafil. The habituous intake of nitroglycerin sublingually by cardiac patients should be prohibited and patients should be instructed to visit the emergency department, notfying physicians about the use of a PDE-5 inhibitor. In these cases calcium antagonists given intravenously could be administered. Oral nitrates can be discontinued in the presence of continuing [-blockade and/or calcium antagonist therapy in stable coronary disease patients with ED to allow for the safe use of PDE-5 inhibitors.53 In contrast to an unwanted synergistic effect ofthe combined use with nitrates, sildenafil has shown many advantageous influences on the heart. During coronary angiography, it has been shown that sildenafil increased epicardial diameters after the administration of acetylcholine in patients with coronary artery disease as well as in patients with normal endothelial fimction compared with placebo.54 The same study suggested a reduction in platelet GP IIb/IIIa-receptor activation by sildenafil. Another study looked at the effect on coronary blood flow in patients with severe coronary artery disease (CAD). Average peak velocity, coronary artery diameter and coronary blood flow showed no significant changes with sildenafil administration in stenosed or non-stenosed arteries.55 Halcox et al. assessed endothelial function by FMD. In patients with and without CAD, hyperaemic vasodilation lasted significantly longer following sildenafil administration compared with the pre-sildenafil control group.54 Another relevant clinical study evaluated whether sildenafil affected the ischaemic threshold in men who experienced exercise-induced angina. Sildenafil significantly increased the time to onset of limiting angina and increased exercise duration compared with placebo.56 Furthermore, a neutral effect of PDE-5 inhibition on exercise echocardiography was observed.57 Also in the field of heart failure favourable reports have been published. In a double-blind, twoway crossover study 24 males with chronic heart failure (CHF) were randomised to placebo or sildenafil 50 mg.58 Sildenafil was a well-tolerated and effective treatment in CHF patients with ED. The improvement in exercise capacity, in particular in heart rate, suggests that sildenafil might decrease myocardial oxygen consumption during sexual activity. Others have reported safe and effective treatment with sildenafil for ED in men with New York Heart Association classes II and III chronic heart failure and reliefofdepressive symptoms, explaining an improvement in the perception of quality of life.59 Ever since the introduction of sildenafil seven years ago, the incidence of MI and mortality has been a matter of discussion. The pooled data from 80 studies of patients treated with sildenafil between 1993 and
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2000 were analysed. These data indicate that sildenafil was not associated with short-term risk for myocardial infarction and are consistent with the growing body of evidence that sildenafil use is not associated with an increased risk for cardiovascular events.60 Recently, more PDE-5 inhibitors have been registered for the treatment ofED, such as vardenafil and tadalafil. The main pharmacokinetic difference is in the onset and duration ofthese drugs. Large safety and efficacy studies concerning the recent developed PDE-5 inhibitors are still lacking. Conclusions and recommendations The management ofED remains primarily within the domain of urologists, psychologists and family practitioners. However, the association of ED with vascular disease does involve other medical specialists, including cardiologists, in the management of ED. ED is a common disease and its prevalence will grow considerably in the coming years. Growing evidence showing endothelial dysfunction to be the common denominator for cardiovascular disease and ED explains the high incidence of ED in patients with cardiovascular disease. Suggestions that ED predates coronary artery disease provides a tool to cardiovascular risk management in these patients. Modifying risk factors is the key in treating ED and preventive cardiovascular medicine. Management of ED in cardiovascular patients can be performed safely following the guidelines of the Princeton panel. Cardiologists should pay more attention to ED. It occurs more in their patients than they are aware of. Possibly a significant role can be played in the future by cardiac rehabilitation programmes. Drug therapy for ED is still evolving. Good knowledge ofpharmacokinetic actions and interactions is important for cardiologists in order to advise and instruct their patients in the best possible way. U References 1
2 3 4
5 6 7 8
9
Lewis RW. Epidemiology of erectile dysfunction. Urol Clin North Am 2001;28:209-16. Feldman HA, Goldstein I, Hatzchristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results ofthe Massachusetts Male Aging Study. J Urol 1994;151:54-61. Ayta IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJUInt 1999;84:50-6. Meuleman EJ, Donkers LH, Robertson C, Keech M, Boyle P, et al. Erectile dysfunction: prevalence and effect on the quality Boxmeer study. Ned Tijdschr Geneeskd 2001;145:576-81. Shabsigh R, et al. Sildenafil Citrate, three years later. Pharma Libri Publishers INC, Montreal Canada; 2001. Fung MM, Bettencourt R, Barrett-Connor E. Heart disease risk factors. Predict Erectile Dysfunction 25 years later. JAm Coll Car-
diol 2004;43:1405-11. Montorsi F. Personal communication during 17th Congress ofthe European Association of Urology. Birmingham UK 2002. Meuleman EJ, Kingma JH. Medicamenteuze behandefing van erectiestoomissen bij cardiovasculair belaste patienten. Ned Tijd-
schr Geneeskd 2001;145:167-71. Littler WA, Honour AJ, Sleight P. Direct arterial pressure, heart rate and electrocardiogram during human coitus. J Reprod Fertil 1974;40:321-31.
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