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CARDIOLOGY ASPRESENTEDINTHEROUNDSOF
Rounds THEDIVISIONOFCARDIOLOGY,
ST. MICHAEL’S HOSPITAL,
UNIVERSITY OF TORONTO
Endothelial dysfunction/Erectile dysfunction:
Common mechanisms, common management
Division of Cardiology
Endothelial dysfunction, considered by many to be at the root of atherosclerotic vascular
disease, shares many common risk factors with erectile dysfunction. In addition, they fre-
quently occur in the same patients. A common mechanism that may explain the coexistence
of these two seemingly disparate conditions is a decrease in the bioavailability of nitric oxide
(NO), a small unstable molecule that mediates many of the normal functions of the endothe-
lium. NO is also responsible for neurally-induced vasomotor changes at the level of the
corpora cavernosa that underlie penile erection. A state of increased oxidative stress not only
renders NO inactive, but also, through the reaction of oxygen-free radicals with NO, may
lead to the formation of potentially toxic products. Therefore, addressing common risk fac-
tors is important because it may reduce cardiovascular events and improve erectile function.
In addition, control of risk factors may increase the possibility of safely resuming sexual activ-
ity in the patient with coronary artery disease (CAD), although this has yet to be proven in
properly designed randomized trials. Most cardiac patients, when appropriately risk-stratified
and managed, can resume sexual activity safely, while many who also exhibit erectile
dysfunction are eligible for first-line therapeutic modalities, including phosphodiesterase-5
inhibitors such as sildenafil. This issue of Cardiology Rounds examines the research linking
endothelial with erectile dysfunction and discusses patient management.
In October 1998, some of the major national and international media outlets announced that the Nobel Prize for Physiology and Medicine had been awarded to three American St. Michael’s Hospital
researchers for “the discovery of the Viagra principle.” By the following day, some local and sec- ondary media organizations had transformed this news to “Viagra discoveries win Nobel Prize Room 9-004, Queen WingToronto, Ont. M5B 1W8 for Medicine.” It should have come as no surprise that the link between the Nobel Prize- winning discoveries of Furchgott, Ignarro, and Murad and sildenafil, the novel therapy for erectiledysfunction, was so quickly established by the media, given the great interest of the media and The opinions expressed are only those of the Divisional members. This publication is the public following the release of sildenafil. However, the Nobel-winning discoveries – start- made possible through unrestricted grants. ing with the description by Furchgott of an endothelium-derived relaxing factor (EDRF) – wereactually related to a simple molecule called nitric oxide (NO). NO, besides being the biologicprinciple responsible for EDRF activity, is also, among many other functions, the physiologicalmediator of penile erection.1-5 The search for catchy headlines notwithstanding, the media, perhaps inadvertently, were right in establishing a link between endothelial dysfunction and erectile dysfunction. Furchgottdiscovered the former condition when he observed that arteries denuded of endothelium con- Leading with InnovationServing with Compassion tracted in response to acetylcholine, while normal arteries dilated. Endothelial dysfunction iscaused by a decrease in the bioavailability of endothelial NO and erectile dysfunction is very often also caused by a decrease in NO of endothelial or neural origin. Therefore, both conditions A teaching hospital affiliated with the University of Toronto share the same mechanisms and in many cases, the same risk factors. It is reasonable to postulatethat addressing common mechanisms and modifying common risk factors may be indicated inthe management of patients with erectile dysfunction.
Nitric oxide: a key biologic mediator
disease, or stroke. The patients were evaluated with a fast- Nitric oxide is a volatile gas formed during the con- ing lipid profile and penile Doppler ultrasound to assess version of L-arginine to L-citrulline by an enzyme called blood flow. Patients were divided into two groups: normal nitric oxide synthase. Three isoforms of NO synthase are cholesterol (total cholesterol <5.2 mmol/L) comprising 40% of patients, or abnormal cholesterol (60% of • Endothelial NO synthase (eNOS) is expressed main- patients). In the abnormal cholesterol group, 91% had ly, but not exclusively, in endothelial cells and this expres- Doppler evidence of penile arterial disease, a finding that sion is a hallmark of endothelial health.
was also present in 83% of the patients in the normal cho- • Brain or neuronal NO synthase (bNOS) is expressed lesterol group. However, nearly 90% of the patients with in central and peripheral nervous tissues, including cav- abnormal Doppler studies and normal total cholesterol val- ues had LDL cholesterol levels that were above the rec- • Inducible NO synthase (iNOS); expression can be ommended target of 2.5 mmol/L for patients with CAD.8 induced in macrophages and other cell types in response to Another study evaluated the relationship between the severity of CAD and impairment of erectile function in 40 NO is a rather unstable and short-lived molecule that men, aged 40-73, who were undergoing coronary angiog- acts locally, near the cells that produce it. After its secre- raphy to evaluate symptoms of ischemic heart disease. The tion, it can follow one of three directions. First, it can act patients completed a standardized questionnaire on sexual on guanylyl cyclase located in a target cell to generate function and their cardiovascular risk factors were docu- cGMP, and if the target cell is a vascular smooth muscle mented. Men with 2- or 3-vessel CAD had significantly cell, this leads to vasodilatation. Second, it can be exposed fewer erections during a 30-day period and also scored to hemoglobin and be inactivated. Third, it can react with lower on an index of erection firmness than men with sin- oxygen-free radicals such as superoxide, leading not only gle-vessel disease. This study also confirmed that diabetic to its inactivation, but also to the formation of potentially patients scored significantly worse on both parameters The levels of cardiovascular risk factors present in men Oxidative stress – A common element of endothelial
seeking treatment for erectile dysfunction were the subject dysfunction and some forms of erectile dysfunction
of another study. The investigator evaluated the results of An enhanced state of oxidative stress is present in all cardiovascular stress testing, risk profile analysis, and coro- common cardiovascular risk factors associated with nary angiography (not performed in all subjects) in 50 endothelial dysfunction, such as diabetes mellitus, hyper- asymptomatic men with erectile dysfunction of presumed lipidemia, hypertension, or smoking. Indeed, the produc- vascular origin. Multiple risk factors were present in 80% tion of superoxide is increased in these conditions and of the subjects, including smoking in 80% and a total cho- leads to inactivation of NO and the production of peroxy- lesterol level >5.2 mmol/L in 70%. Graded exercise testing nitrite. Experimental studies have demonstrated that was positive in 28/50 patients and following this test, coro- cardiovascular risk factors enhance the production of nary angiography was performed in 20 of them, revealing superoxide in the same endothelial cells where NO is severe left main or 3-vessel disease in 6, 2-vessel disease in being produced, leading to an immediate decrease in NO 7, and single-vessel disease in 7. This study demonstrates bioavailability, even if normal amounts are produced.6,7 the high prevalence of cardiac risk factors and significant Therefore, the amount of biologically-active NO is a func- CAD in men presenting with no symptoms other than tion of the state of oxidative stress in the endothelium, as erectile dysfunction.10 This finding is likely explained by much as of the total amount of NO synthesized by eNOS the common mechanism underlying both endothelial dys- and, in the case of penile erection, also by bNOS.
function and erectile dysfunction of vascular origin, name-ly the decreased availability of NO.
The two EDs (endothelial and erectile
dysfunction): Common presentations
Mechanism of penile erection
Erectile dysfunction is occasionally the presenting Neural impulses resulting from sexual stimulation lead symptom in patients who have a variety of diseases char- to the release of NO by bNOS located in nonadrenergic, acterized by endothelial dysfunction, (eg, diabetes melli- noncholinergic cavernous nerves. Similarly, cholinergic tus, CAD, arterial hypertension, and hyperlipidemia). As nerves release acetylcholine that acts on the surface recep- an example of this association, a recent study assessed the tors of the endothelial cells, leading to activation of eNOS incidence of lipid abnormalities and penile arterial insuffi- and, in the healthy endothelium, a release of significant ciency in men presenting with erectile dysfunction and no levels of bioactive NO.11 In the presence of an increased other known vascular abnormalities. This study included state of oxidative stress, much of the NO would be inacti- 57 men presenting to a clinic over a 3-month period with vated; otherwise, it diffuses to the trabecular smooth erectile dysfunction and no history of heart disease, muscle cells surrounding the sinusoidal spaces and acts on diabetes, hypertension, hyperlipidemia, peripheral vascular guanylyl cyclase. The cGMP thus generated mediates Figure 1: Mechanism of action of sildenafil12
Figure 2: Sildenafil – Improvement in erections
NO-cGMP mechanism of penile erection and the
Efficacy in sub-populations
NO-enhancing effect of the PDE5 inhibitor sildenafil
Sildenafil
1. Hulting C et al. Int J Impot Res 1998;10(3):532.
NO= nitric oxide. cGMP = cyclic guanosine monophosphate. PDE5 = phosphodiesterase 2. Price D. Int J Impot Res 1998;10(3):534.
4. Conti CR et al. Am J Cardiol 1999;83:3C-12C.
type 5. GTP = guanosine triphosphate. NANC = nonadrenergic-noncholinergic neurons.
and in those requiring frequent doses of sublingual nitrates relaxation of the smooth muscle, allowing an inflow of for symptomatic relief of angina pectoris.14 blood into the sinusoidal spaces and engorgement of the Sildenafil has been shown to improve erections signif- penis. Release of norepinephrine from the adrenergic icantly in patients with ischemic heart disease and in those nerves, coupled with the endothelial release of endothelin with risk factors like hypertension and diabetes. It is also (a potent vasoconstrictor whose synthesis is increased in helpful in the management of erectile dysfunction due to endothelial dysfunction), induce smooth muscle cell con- nonvascular causes such as depression, spinal cord injury, traction and hinder penile erection. These mechanisms or following radical prostatectomy (Figure 2). Due to the
provide the common link between the two EDs, erectile potentially disastrous interactions with nitrates and the additive effects with antihypertensive agents, reasonableconcerns have been raised regarding the use of sildenafil in Development of phosphodiesterase inhibitors and
the cardiovascular patient. However, in 53 clinical trials treatment of erectile dysfunction
with sildenafil that included over 6000 patients, no excess Phosphodiesterases are enzymes that catabolize cyclic incidence of myocardial infarction (MI) or death was nucleotides such as cGMP. Because of the vasodilatory observed.15 Similarly, in a prescription event-monitoring effects of cGMP, phosphodiesterase inhibitors were felt to study of more than 5000 men conducted in the United be a good target for development of inhibitors that, by Kingdom, there was no increased incidence of MI, enhancing cGMP levels, would be of potential benefit for the ischemic heart disease, death or total mortality, compared treatment of hypertension and angina pectoris. Sildenafil, the first phosphodiesterase inhibitor approved for the treat- Sexual activity in patients with CAD
ment of erectile dysfunction, exhibits high affinity for thephosphodiesterase-5 (PDE-5) isoform that is abundant in Sexual activity can be associated with a transient the corpus cavernosum, but is also present in platelets, skele- increase of 50-60 bpm in heart rate and 50-60 mm Hg in tal muscle, and visceral and vascular smooth muscle cells. systolic blood pressure. The risk of non-fatal MI transiently Sildenafil was originally developed as a cardiovascular doubles following sexual activity, but the absolute risk is drug of potential antianginal and antihypertensive efficacy.
quite small. In individuals free of cardiac disease, weekly sex- However, the observation of interesting “side-effects” led to ual activity would only increase the annual risk of MI from its study in the management of erectile dysfunction where 1% to 1.01%. In subjects with a prior MI history, sexual activ- it was proven to be highly effective (Figure 1).12,13 Sildenafil
ity transiently doubles the risk from 10 in a million per hour is a modest vasodilator, similar to a weak nitrate, and it has
to 20 in a million per hour. Nevertheless, the absolute risk no direct cardiac effects given the absence of PDE-5 in the remains low since, in the clinically high-risk patient, weekly myocardium. By itself, sildenafil results in a modest 10/5 sexual activity increases the risk of MI from 10% to 10.2%.17 mm Hg reduction in blood pressure that is not dose-relat- In order to assess whether a cardiac patient is fit to ed within and beyond the recommended dose range. There resume sexual activity, it is crucial to obtain a history of the are additive blood-pressure lowering effects when com- activities that the patient is able to perform and correlate bined with other antihypertensive drugs and special caution them with the workload required for sexual intercourse.
must be exercised in patients taking multiple agents. A The workload can be expressed in metabolic equivalents or particularly striking synergistic effect is observed when METs. One MET is the amount of oxygen consumed at sildenafil is co-administered with nitrates, explained by the rest, which is 3.5 ml/kg/minute. Other activities can then induction of cGMP synthesis that is the mechanism of be measured against this standard. For instance, walking at action of these agents. Thus, sildenafil is absolutely con- 2 mph requires 2-3 METS, gardening or digging requires traindicated in patients on regular oral or topical nitrates 5-6 METS, swimming 9-10 METS, whereas sexual activity Table 1: Energy requirements of selected
Figure 3: Algorithm for sexual activity and
physical activities (in METs)
cardiac risk
Pashkow and Dafoe, Eds. Clinical Cardiac Rehabilitation, Appendix A. 1999.
with the usual partner requires only 3-5 METS. Sexualintercourse with an extramarital or much younger eral arterial disease or stroke. These patients must be partner is associated with significantly greater energy reclassified to the low- or high-risk categories based requirements and a higher risk of MI (Table 1). If nec-
on cardiac testing, including a graded exercise test essary, an exercise test can be obtained to determine and an echocardiogram. In some cases, a cardiology objectively the patient’s exercise tolerance and work- load achieved in METS. A patient who is able to • Patients in the high-risk category are those who achieve 6 METS on a treadmill (for instance, follow- have a cardiac condition sufficiently severe or unsta- ing the Bruce protocol) without any symptoms, ECG ble that sexual activity may constitute significant risk.
changes, arrhythmias, or hemodynamic instability, This category includes patients with unstable or can resume sexual activity safely, provided that there refractory angina, uncontrolled hypertension, NYHA are no other absolute contraindications. class III or IV heart failure, recent MI (within 2weeks), high-risk arrhythmias, hypertrophic obstruc- The management of erectile dysfunction in
tive or other cardiomyopathies, and moderate to patients with cardiovascular disease
severe valvular heart disease. These patients should Establishing whether a patient is eligible to have high priority for referral to a cardiovascular receive therapy with sildenafil requires a determina- specialist and the initiation of sexual activity should tion of the patient’s risk. The Princeton Consensus be deferred until the cardiac condition is stabilized or Panel in the United States suggests stratifying the managed appropriately and a specialist determines patients in low-risk, intermediate- or indeterminate- that it can be safely resumed (Figure 3).
• The low-risk category includes subjects with no Sildenafil in the cardiovascular patient: Position
significant cardiac risk associated with sexual activity of the Heart and Stroke Foundation of Canada
(ie, asymptomatic individuals or those with <3 cardiac and the Canadian Cardiovascular Society
risk factors). Also in the low-risk group are patients These two organizations have jointly stated that with controlled hypertension, mild stable angina, prior the majority of cardiovascular patients can be treated successful coronary revascularization, uncomplicated with sildenafil except those already taking any form of prior MI, mild valvular disease, and NYHA class I nitrates. Patients for whom nitrate therapy is essential heart failure patients. Patients in the low-risk cate- must be considered for other forms of therapy for gory require no special cardiac testing or evaluation erectile dysfunction. Patients who are receiving prior to resuming sexual activity or initiating therapy multiple, concomitant, antihypertensive therapy must for erectile dysfunction. All the first-line treatment be assessed carefully to ensure that there is no modalities, including sildenafil, can be considered in symptomatic hypotension. Of great interest is the recommendation that etiological and risk factors • Individuals at intermediate- or indeterminate- contributing to both cardiovascular disease and erec- risk include those with ≥3 cardiac risk factors, moder- tile dysfunction be diagnosed and treated.19 This may ate stable angina, recent MI (>2, but <6 weeks), prove to be remarkable foresight by the authors of the NYHA class II heart failure, or significant manifesta- recommendations. Although the hypothesis that treat- tions of noncoronary vascular disease such as periph- ing endothelial dysfunction also improves erectile CARDIOLOGY Rounds
Figure 4: Decision tree for treating patients with cardiovascular disease and ED with sildenafil19
Diagnose and treat etiological and risk factors contributing to both diseases
Should patient be considered for sildenafil treatment?
Patients in whom nitrate therapymay be needed:A) Acute coronary syndromesB) Ischemia provoked within 3 function has yet to be studied in randomized con- with sildenafil, but it is important to emphasize that trolled trials, the biological plausibility is strong. As close monitoring of these patients must be continued discussed above, treating the risk factors or etiologies or intensified after initiation of therapy (Figure 4). of endothelial dysfunction would lead to a reductionin oxidative stress and an increase in the bioavailabil- Conclusion
ity of NO leading, theoretically, to an increase in the In summary, NO bioavailability is at the center of efficacy of an agent like sildenafil. At the very least, both erectile and endothelial function and this could treatment of risk factors for endothelial dysfunction explain why erectile dysfunction and cardiovascular with agents such as statins or ACE inhibitors, would disease share so many common risk factors. Patients, reduce the risk of coronary events and possibly make whose presenting complaint is erectile dysfunction, the initiation of therapy for erectile dysfunction and may have previously unrecognized risk factors for the resumption of sexual activity safer.
atherosclerotic vascular disease such as hyperlipi- In the Canadian recommendations, patients who demia, hypertension, or diabetes. Treatment of the should not be considered for sildenafil treatment are underlying conditions common to both disorders those for whom nitrate therapy is prescribed and should be instituted in the appropriate patients in used. As well, sildenafil should be avoided in patients order to improve endothelial function and NO for whom nitrate therapy may be needed, such as bioavailability. Sexual activity usually implies a mild patients with acute coronary syndromes, ischemia to moderate level of energy expenditure that could be provoked within 3 minutes of exercise on the Bruce safely achieved by many cardiac patients. It is impor- protocol, and patients who develop angina during tant to stratify patients by risk and address correctable intercourse. A potential exception, and one that has to causes of structural heart disease or optimize medical be considered with great caution, are patients taking therapy before the resumption of sexual activity. Most nitrates only very sporadically. A rule-of-thumb in cardiac patients thus stratified and treated may be eli- these patients is that sildenafil should not be used gible for treatment of erectile dysfunction with a PDE within 24 hours of any nitrate therapy and, converse- inhibitor such as sildenafil or other first-line therapies.
ly, nitrates should be avoided completely within a In patients who require therapy with nitrates or 24-hour period of any dose of sildenafil. Patients with multiple antihypertensive agents, other therapeutic symptomatic hypotension of any etiology are not Patients, who may be considered for treatment References
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those with asymptomatic hypotension, aortic stenosis 2. Ignarro LJ, Byrns RE, Buga GM, Wood KS. Endothelium-derived or left ventricular outflow obstruction, or heart failure relaxing factor from pulmonary artery and vein possesses pharmaco-logic and chemical properties identical to those of nitric oxide radi- patients. All other cardiovascular patients are consid- cal. Circ Res 1987;61 (6):866-879.
ered eligible for treatment for erectile dysfunction CARDIOLOGY Rounds
3. Rajfer J, Aronson WJ, Bush PA, Dorey FJ, Ignarro LJ. Nitric oxide as a medi- functional class IV. Subjects had primary PHT (8), pulmonary arteri- ator of relaxation of the corpus cavernosum in response to nonadrenergic, al hypertension (2) or secondary PHT (2). Hemodynamics and serum noncholinergic neurotransmission. N Engl J Med 1992;326(2):90-94.
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Results: The decrease in pulmonary vascular resistance was similar
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pressure (+17±7 versus -9±8%, P<0.001). Systemic arterial pressure Curr Opin Lipidol 200112(4):383-389.
was similar amongst groups and did not decrease with treatment.
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combination elevated cGMP more (P<0.05).
9. Greenstein A, Chen J, Miller H, Matzkin H, Villa Y, Braf Z. Does severity Conclusion: A single oral dose of sildenafil is as effective and selec-
of ischemic coronary disease correlate with erectile function? Int J Impot Res tive a pulmonary vasodilator as INO. Sildenafil may be superior to INO in that it causes greater increase in cardiac output and does not 10. Pritzker MR. Circulation 1999;100(suppl1);I-711. increase wedge pressure. Future studies are indicated to establish 11. Lue TF. Erectile dysfunction. N Engl J Med 2000;342(24):1802-1813.
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Upcoming Scientific Meetings
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Int J Clin Pract Suppl 1999;102:3-5.
Hypertension
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18. DeBusk R, Drory Y, Goldstein I, et al. Management of sexual dysfunction Canadian Cardiovascular Congress 2002
in patients with cardiovascular disease: recommendations of The Princeton Consensus Panel. Am J Cardiol 2000;86(2):175-181.
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Email: [email protected]: www.cardiocongress.org Abstract of Interest
13-20 November, 2002
American Heart Association Scientific Sessions 2002
Oral sildenafil is an effective and specific
pulmonary vasodilator in patients with
pulmonary arterial hypertension
MICHELAKIS ED, TYMCHAK W, LIEN D, DASILVA L, HASHIMOTO K, ARCHER SL. EDMONTON, ALBERTA Background: The prognosis of patients with severe pulmonary hyper-
tension (PHT) is poor. To determine prognosis and guide chronic
therapy, an acute trial of a selective pulmonary vasodilator, usually
inhaled nitric oxide (INO), is performed during cardiac catheteriza-
tion. We hypothesized that oral sildenafil, a phosphodiesterase V
Change of address notices and requests for subscriptions are inhibitor, is a safe and effective alternative to INO.
to be sent by mail to P.O. Box 310, Station H, Montreal,Quebec H3G 2K8 or by fax to (514) 932-5114 or by e-mail Methods: We studied 12 consecutive patients (mean±SEM, 43±2
to [email protected]. Undeliverable copies are to be years, 8 female) referred during one year, for consideration of heart- lung transplantation or as a guide to medical therapy. All but one were This publication is made possible by an educational grant from Novartis Pharmaceuticals Canada Inc.
2002 Division of Cardiology, St. Michael’s Hospital, University of Toronto, which is solely responsible for the contents. The opinions expressed in this publication do not necessarily reflect those of the publisher or sponsor, but rather are those of the authoring institution based on the available scientific literature. Publisher: SNELL Medical Communication Inc. in cooperation with the
Division of Cardiology, St. Michael’s Hospital, University of Toronto. All rights reserved. The administration of any therapies discussed or referred to in Cardiology Rounds should always be consistent with the recognized prescribing information in Canada. SNELL Medical Communication Inc. is committed to the development of superior Continuing Medical Education.

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