Review

Pharmacologic Therapy for Erectile Dysfunction and its Interaction With the Cardiovascular System

Journal of Cardiovascular Pharmacology and Therapeutics 2014, Vol 19(1) 53-64 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248413504034 cpt.sagepub.com

Nikolaos Ioakeimidis, MD, PhD1 and John B. Kostis, MD2

Abstract Phosphodiesterase (PDE) enzymes are widely distributed throughout the body, having numerous effects and functions. The PDE type 5 (PDE5) inhibitors are widely used to treat erectile dysfunction (ED). Recent, intense preclinical and clinical research with PDE5 inhibitors has shed light on new mechanisms and has revealed a number of pleiotropic effects on the cardiovascular (CV) system. To date, PDE5 inhibition has been shown to be effective for the treatment of idiopathic pulmonary arterial hypertension, and both sildenafil and tadalafil are approved for this indication. However, current or future PDE5 inhibitors have the potential of becoming clinically useful in a variety of CV conditions such as heart failure, coronary artery disease, and hypertension. The present review discusses recent findings regarding pharmacologic treatment of ED and its interaction with the CV system and highlights current and future clinical applications beyond ED. Keywords erectile dysfunction, PDE5 inhibitors, cardiovascular disease

Introduction Erectile dysfunction (ED) is common, affecting almost 40% of men more than 40 years of age and increases in frequency with age.1 ED and cardiovascular (CV) disease (CVD) share common risk factors including age, hypercholesterolemia, hypertension, insulin resistance and diabetes, smoking, obesity, metabolic syndrome, sedentary lifestyle, and depression.2-4 ED is highly prevalent in patients with vascular diseases, such as coronary artery disease (CAD), cerebrovascular, and peripheral arterial disease,5-9 although there is an increased risk of CV events in patients with preexisting ED,10-14 implying an intimate nexus between the 2 conditions. Sexual function in men is frequently evaluated by the International Index of Erectile Function, a validated self-administered questionnaire that has been psychometrically sound and linguistically validated in 10 languages. It evaluates on a scale of 1 to 5, five factors of sexual function including erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction.8 From a pathophysiological standpoint, this can be explained on the following basis: (1) the endothelium has an essential role in the physiology of penile erection, (2) endothelial dysfunction and its related processes in ED are most likely not confined to the penis but they are rather widespread, and (3) endothelial dysfunction often underlies CVD.5-7 Besides correcting unhealthy lifestyle and risk factors whenever possible and providing sexual education and counseling, a first-line treatment strategy for ED usually includes a phosphodiesterase type 5 (PDE5) inhibitor either administered

on demand or on a daily basis. Although PDE5 inhibitors were originally developed in the wake of the discovery of the nitric oxide (NO)/soluble guanylate cyclase pathway with a view to be used in CV conditions such as angina, thanks to the abundant presence of the PDE5 isoenzyme in the corpora cavernosa, their development was rapidly redirected to the exploding field of ED. However, the attention is now reverting to the possible use of PDE5 as therapeutic agents for CVD. The aim of this review is to summarize the existing knowledge on pharmacologic therapy for ED and its interaction with the CV system and to discuss the evidence for supporting potential future indications.

Physiology of Erection Erection involves sinusoidal relaxation, arterial dilatation, and venous compression in the penis.2 Because the penis is a richly vascularized organ, penile erections are, in large part, 1

First Department of Cardiology, Cardiovascular Diseases and Sexual Health Unit, Athens Medical School, Hippokration Hospital, Athens, Greece 2 Cardiovascular Institute, Robert Wood Johnson Medical School, New Brunswick, NJ, USA Manuscript submitted: May 9, 2013; accepted: July 19, 2013. Corresponding Author: John B. Kostis, Cardiovascular Institute, Robert Wood Johnson Medical School, New Brunswick, NJ, USA. Email: [email protected]

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a vascular event. The endothelium of penile vasculature plays an important role in modulating vascular tone and blood flow into the penis in response to humoral, neural, and mechanical stimuli.15 Endothelial cells lining the internal surface of penile arteries and sinusoids of the cavernosal tissue affect the tone of adjacent smooth muscle cells through the release of relaxing factors (such as NO, prostanglandin-E2, and C-type natriuretic peptide) and vasoconstrictive agents (such as endothelin-1 and angiotensin-II).16 The NO pathway is of critical importance in the normal induction and maintenance of erections. The NOdependent relaxation of the cavernosal smooth muscles leads to compression of the subtunical small veins, occluding local venous return, and resulting in an erection. Penile detumescence is due to a reduction in arterial blood inflow and a collapse of lacunar spaces. Decompression of the drainage venules from the cavernous bodies occurs, allowing venous drainage of the lacunar spaces and relief of the erection.15,16

Classification of ED Diagnosis and Testing. Erectile dysfunction is defined as the inability to attain or maintain a penile erection sufficient for satisfactory sexual performance. Cases of ED may be classified as predominantly organic in nature, predominantly psychogenic, or mixed. Usual organic etiologies are vasculogenic, hormonal, and neurogenic.2,17,18 Due to the relationship of vasculogenic ED with CVD, it is important to distinguish men with predominantly vasculogenic ED from those with predominantly psychogenic ED or nonvasculogenic organic ED. Organic ED has a gradual onset, a constant disease course, and is associated with poor noncoital erections.18 Of note, a psychogenic component may coexist in cases of organic origin. The most common organic etiology of ED is vasculogenic. Coexistence of vascular disease, advancing age, the presence of CVD risk factors, and metabolic disorders increase the likelihood that ED is of vasculogenic etiology. Prostatectomy is a common cause of organic ED. Psychogenic ED tends to be acute, situational, and of varying disease course and is associated with rigid noncoital erections. The etiology of predominantly psychogenic ED is multifactorial, and components may include psychiatric disorders (especially depression), interpersonal problems with the sexual partner, or misconceptions about normal sexual activity.18 Identifying and treating patients with psychogenic causes of ED, such as depression that may also increase CVD risk, is also important.19

Erectile Dysfunction ¼ Endothelial Dysfunction Not all ED is due to endothelial dysfunction. Corporeal venous leakage, prostatectomy, and other urological as well as psychological conditions account for a significant proportion of patients with ED.20 However, in many patients vasculogenic ED may be the consequence of a derangement of the normal NO-mediated endothelial vasodilation and the complex interplay between endothelial dysfunction, subclinical inflammation, and testosterone deficiency, which often lead to the

development of atherosclerotic plaque.16,17,21,22 In vasculogenic ED, dysfunctional endothelial cells lining the penile arterial system and the corpus cavernosum produce less NO. Hence, PDE5 isoenzyme, abundant in perivascular smooth muscle cells, degrades faster the reduced quantities of cyclic guanosine monophosphate (cGMP), thus limiting the duration of vasodilation and having negative impact on obtaining and sustaining an erection (Figure 1).17,21 Inflammation plays an important pathophysiological role in both ED and systemic arterial dysfunction.20 The dysfunctional endothelium sets the stage for both initiation and progression of atherosclerotic lesions in the penile and systemic vasculature by promoting inflammation within the vessel wall through enhanced production of cytokines and expression of cellular adhesion molecules. Increasing attention is focused also on the effect of testosterone on arterial function. Appropriate testosterone levels have been demonstrated to be necessary for maintenance of intrapenile NO synthase levels. Testosterone deficiency and ED appear to be interrelated at the pathophysiologic level through associations with endothelial dysfunction.23

Physiology of the Types of PDEs and Cross-Talk Phosphodiesterases are a heterogenous group of hydrolytic enzymes whose principal biological activity is to modulate intracellular levels of cyclic nucleotides such as cGMP and cyclic adenosine monophosphate.24 Of the 11 families of PDEs consisting of more than 50 isoenzymes identified to date, 6 (PDE 1, 2, 3, 4, 5, and 11) have been proven to be of pharmacological importance (Table 1).25 Since the distribution and functional significance of PDE isoenzymes varies in different tissues, isoenzyme selective inhibitors have the potential to exert specific effects on the target tissue.24 Undoubtedly, the major interest of research was focused on PDE5 isoenzyme because of its specificity in catalyzing the hydrolysis of cGMP.24,26 Since cGMP is catabolized by the PDE5 isoenzyme, its inhibition will result in an increase in the intracellular levels of cGMP and prolong the duration of its action. Preferential expression of PDE5 in the corpus cavernosum and the cGMP-mediated relaxation of the cavernous smooth muscle during sexual stimulation have made inhibition of this enzyme by sildenafil, vardenafil, or tadalafil, a clinical benefit in the management of ED.15,27 Apart from corpus cavernosum, PDE5 isoform is expressed in various other tissues, such as the arterial and venous vasculature, myocardial, skeletal, visceral, and tracheobronchial muscles, brain, retina, and platelets, and there is ‘‘cross-talk’’ between the PDEs expressed in the heart (Figures 1 and 2).25,26,28

Pharmacology of PDE Inhibitors The vascular tone, systemic vasodilation, and circulation are principally regulated through the endothelial production of NO from the systemic arteries and veins. After its production, NO diffuses into the adjacent smooth muscle cells and

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Figure 1. Molecular mechanisms of smooth muscle relaxation by the cGMP pathway. Adapted with permission from Sa´enz de Tejada15 and Abrams D et al.28 cGMP indicates cyclic guanosine monophosphate; GC, guanylate cyclase; GMP, guanosine monophosphate; GTP, guanosine-50 -triphosphate; IP3, inositol triphosphate; PKA, protein kinase A; PKG, protein kinase G; PLB, phospholipase B; PLC, phospholipase C; NO, nitric oxide.

Table 1. Tissue Distribution and Specificity of Various Isoforms of PDE.a Isoforms of PDE

Tissue Distribution

Specificity for

PDE PDE PDE PDE PDE PDE PDE PDE

Vascular smooth muscle, cardiomyocytes, brain Vascular smooth muscle, cardiomyocytes, brain, corpus cavernosum Vascular smooth muscle, cardiomyocytes, corpus cavernosum, platelets Vascular smooth muscle, cardiomyocytes Corpus cavernosum, vascular smooth muscle, skeletal muscle, platelets Retina Various Skeletal muscle, heart, vascular smooth muscle

cAMP, cGMP cAMP, cGMP cAMP cAMP cGMP cGMP cAMP or cGMP cAMP, cGMP

1 2 3 4 5 6 7-10 11

Abbreviations: PDE, phosphodiesterase; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate. a Adapted with permission from Reffelmann and Kloner.25

enhances the production of cGMP, which, in turn, increases the production of NO and leads to both vascular smooth muscle relaxation and an increase in systemic vasodilation. Since cGMP is catabolized by the PDE5 enzyme, its inhibition by the PDE5 inhibitors will result in an increase in the intracellular levels of cGMP and prolongation of the duration of its action.15,27,29

The chemical structures of the 3 PDE5 inhibitors approved by the US Food and Drug Administration (US FDA) are depicted in Figure 3. All PDE5 inhibitors are rapidly absorbed after oral administration and are reported as effective within 30 minutes from administration. The chemical structures of sildenafil and vardenafil are very similar, their half-lives are approximately 4 hours, and their action is dissipated 24 hours later. In

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Figure 3. Molecular structures of PDE5 inhibitors sildenafil, vardenafil, and tadalafil. Adapted with permission from Rosen RC and Kostis JB.27 PDE5 indicates phosphodiesterase type 5. Figure 2. Regulatory network interconnecting cardiac phosphodiesterases. Arrows indicate activation; blunt-ends indicate inhibition or cyclic nucleotide hydrolysis. Adapted with permission from Zaccolo M, Movsesian MA.26 Ca2þ indicates Ca2þ calcium ion; CaM, calmodulin; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; PDE, phosphodiesterase; PKA, protein kinase A; PKG, protein kinase G.

contrast, the chemical structure of tadalafil is different, wherein its half-life is longer (approximately 17.5 hours) and its action is dissipated 48 hours later.27,29,30 The actions of PDE5 inhibitors could have clinical implications in patients with ED and CAD receiving nitrates, which are also NO donors and could lead to significant vasodilation and lowering of blood pressure.31 In addition, they could have interactions with other drugs taken by patients with CAD, hypertension, heart failure, and diabetes.31-33 These drug interactions are important to be known by physicians managing these patients. Although PDE5 inhibitors were initially approved as on-demand therapy, in 2008, tadalafil was also approved for everyday use in 2.5 mg or 5 mg doses.

Efficacy and Effectiveness of PDE Inhibitors in Treating ED Clinical studies demonstrate that the 3 PDE5 inhibitors are similarly effective at improving the erectile function domain scores of patients with organic, psychogenic, and mixed etiology of ED.27,33 PDE5 inhibitors are the first-line therapy for ED of organic etiology unless there is a specific contraindication to their use. This class of agents is widely used because of its effectiveness and safety. The efficacy and safety of PDE5 inhibitors in improving erectile function in patients with clinical CVD or CV risk factors have been established in numerous randomized controlled clinical trials.34 As tadalafil and vardenafil were more recently licensed than sildenafil, there are fewer published clinical trials specific for tadalafil and vardenafil in patients with CVDs. The clinical efficacy of PDE5 inhibitor therapy in the general ED population has been extensively evaluated in clinical

trials and is well documented.35 Further, efficacy of the 3 currently available PDE5 inhibitors has been evaluated extensively in patients with ED and concomitant hypertension, dyslipidemia, diabetes, or known CVD.33,36 Overall, these studies have shown similar efficacy for the 3 agents, resulting in significant improvement of erectile function in patients with any of these comorbid conditions. However, diabetic patients are one of the most difficult to treat subgroup.33,36 Findings from several studies have shown that chronic or daily use of PDE5 inhibitors in ED can significantly improve endothelial dysfunction. Tadalafil 5 mg is the only PDE5 inhibitor clinically approved for daily use in the treatment of ED. Potential benefits of daily use of PDE5 inhibitors include salvage of on-demand PDE5 inhibitor nonresponders, apparent disease modification, and development of a more natural sexual function.36-38 Sildenafil has been proven to be effective across all efficacy measures, regardless of ED duration.37 Similar data have not been published for tadalafil or vardenafil. In a study by Matic and McCabe, men who had experienced ED for different lengths of time did not differ in their preference for or satisfaction with PDE5 inhibitors with longer or shorter duration of action.39

Adverse Effects of PDE Inhibitors Adverse events are dose related, mild in nature, and selflimited by continuous use.37 The drop-out rate due to adverse events is similar to placebo (2% for sildenafil vs 2.3% for placebo).33 The most common side effects are facial flushing and headache, which are mild to moderate in severity and are short lived.27,33 Tadalafil can cause myalgia and pain at different body sites. The PDE5 inhibitor-related priapism has been reported in a few instances. Although nonarteritic ischemic optic neuropathy has been reported after PDE5, a direct link could not be established. However, minor visual adverse effects occur in 3% to 11% of patients receiving these medications and they are transient and reversible.40 Patients using PDE5 inhibitors should be also warned about a possible link

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between PDE5 inhibitor use, especially sildenafil, and transient hearing impairment. A strong body of clinical data shows that all 3 agents (sildenafil, tadalafil, and vardenafil) do not increase the risk of nonfatal myocardial infarction, stroke, or CV deaths.34 These drugs do not exacerbate ischemia or worsen exercise tolerance in patients with known CAD who achieve levels of exercise comparable or greater than that achieved during sexual intercourse.41,42 Furthermore, the safety profile of sildenafil in men with ED and diabetes mellitus, arterial hypertension, or CV conditions is similar to that in men with ED without these conditions.33 The safety of sildenafil has not been studied in men with recent history of stroke or myocardial infarction, and its use is therefore currently contraindicated in men with these conditions. Existing data cannot give straight answers on the safety of PDE5 inhibitors in patients with obstructive sleep apnea. Interactions with CV drugs have been minimal with the exception of nitrates and other NO donors (such as nicorandil), where coadministration may result in severe vasodilation and hypotension.31 Since nitrates are often overused in clinical practice, the option of their discontinuation should be considered in order to allow PDE5 therapy. Treatment-emergent adverse events have been shown to be similar in patients who are taking antihypertensive agents and those who are not, and no clinically relevant changes in blood pressure were observed even in patients taking 2 or more antihypertensive agents.32 To avoid hypotension, low starting doses of PDE5 inhibitors are preferred in patients on a-blocker treatment, and likewise, low starting doses of a-blockers are encouraged in patients taking PDE5 inhibitors.32 No direct effect of PDE5 inhibitors on cardiac repolarization (QT interval or dispersion) is reported. However, precautions may be warranted when using these drugs in patients with congenital QT prolongation, class Ia, III antiarrhythmics (vardenafil), and in patients with heart failure.43

Effects of PDE Inhibitors on the CV System Although currently their only additional indication, beyond ED, is idiopathic pulmonary hypertension (PAH; for sildenafil and tadalafil), PDE5 show potential to be of benefit in several other conditions, such as CAD and heart failure with left ventricular systolic function.43,44 The PDE5 inhibitors are an exciting class of drugs with pleiotropic effects since PDE5 isoenzymes are expressed throughout the human body, including the pulmonary and systemic vasculature and hypertrophied myocardium.25,26,28 Indeed, accumulating data show that the therapeutic potential extends to the myocardium, the coronary and peripheral arteries, subclinical inflammation, oxidative stress, thrombosis, neurological recovery, and pathways of fibrosis (Table 2). Mechanisms of benefit of PDE5 inhibitors include pulmonary and systemic vasodilation, increased myocardial contractility, reduced large artery stiffness and wave reflections, improved endothelial function and reduced apoptosis, fibrosis, and hypertrophy through mechanisms involving

NO, cGMP, protein kinase G, and r-kinase inhibition.43,44 It should be stressed that although the currently available agents show many similar modes of action, an effect proven for an agent does not necessarily apply to the others. Furthermore, extrapolations of experimental evidence to clinical settings should be made with caution. A very important issue is whether treatment of ED per se (and not of its risk factors and comorbidities) will have an impact on CV risk. Although this applies to all therapeutic modalities of ED, it is particularly pertinent for PDE5 inhibitors, since they represent the mainstay of ED therapy. Data are limited to date. Gazzaruso et al12 showed a trend of PDE5 inhibitors to reduce CV morbidity and mortality in diabetic patients with silent CAD and ED, while Frantzen et al showed that 2 years after the introduction of sildenafil, the relative risk of the incidence of CVD among men with ED compared with healthy men significantly decreased from 1.7 to 1.1.50

Use of ED in the Early Identification of Men at Risk of CV Events Erectile dysfunction carries an independent risk of CV events. A considerable number of studies has examined the ability of ED to predict the risk of future fatal and nonfatal CV events (myocardial infarction, stroke, and revascularization) and total mortality in the general population and in patients with high CV risk, in diabetic patients, and in patients with heart failure.10-13 In a meta-analysis of 14 prospective cohort studies involving 92 757 men followed for a mean period of 6.1 years, ED increased significantly and independent of traditional risk factors such as the risk of CV events, CV mortality, myocardial infarction, cerebrovascular events, and all-cause mortality by 44%, 19%, 62%, 39%, and 25%, respectively.14 This predictive capability also extends in men with known CVD: ED increased the risk of all-cause mortality by 90%. Of importance, the predictive ability of ED is higher in younger patients with ED despite the fact that probability of ED increases with age, most likely identifying a group of patients with early and aggressive vascular disease.14 Clinical implementation of ED as a biomarker relies on whether its addition on classical risk scores such as the Systematic COronary Risk Evaluation (SCORE) or the Framingham Risk Score (FRS) correctly reclassifies a meaningful percentage of patients into a higher or lower risk category. To this end, data are limited. Yet, in a population-based study of men 40 to 70 years of age, addition of ED status to FRS resulted in a reclassification of 6.2%, 95% confidence interval (CI) 4.6-7.8, of the men.10 The third Princeton Consensus panel defines CV risk as the risk of morbid events during a 3- to 5-year interval from the onset of ED.62 A man with organic ED should be considered at increased risk of CVD until recommended checks suggest otherwise. Office-based assessment of CV risk using conventional risk factor algorithms, such as FRS and SCORE, includes few data from patients younger than 40 years. These algorithms also lack some important risk factors (eg, family history, fasting glucose level, serum creatinine level [estimated glomerular

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Table 2. Effects and Clinical Significance of PDE5 Inhibition on the Cardiovascular System. Variable 1. Cardiac function Cardiac contraction43-49

Clinical Implications/Potential Therapeutic Applications

Potential Mechanisms Inhibition of acute b-adrenergic stimulation. Suppression and reversal of pressure overloadinduced ventricular hypertrophy

Cardioprotection12,25,26,28,43,44,50 Mainly increase in cGMP levels (with activation of PKG and subsequent opening of the mitochondrial KATP channels); increased expression of eNOS, iNOS, activation of ERK, PKC, and opening of the mitochondrial KATP channels 2. Arteries Coronary vasculature43,51 Vasodilation, increase in coronary blood supply Blood Pressure32,35,52,53,54 Pulmonary vasculature48,55,56

Peripheral vasculature53,48

3. Subclinical inflammation20,43,57 4. Oxidative stress43 5. Platelets58,59

6. Angiogenesis60,61

Potential benefits for disorders which are complicated by hypertrophy (eg, essential hypertension), or in which neurohormonal activation is enhanced (eg, heart failure) Preconditioning-like cardioprotective effect against ischemia/reperfusion injury, potential use in acute ischemic events, coronary artery bypass surgery

Potential benefit in patients with diffuse coronary microvessel disease and vasospastic angina Potential benefits in essential hypertension

Mild blood pressure lowering effect and clinically insignificant heart rate changes Improvement in hemodynamic parameters and Enhancement of vasodilatory and antiproliferative clinical variables in patients with pulmonary arterial cGMP-mediated effects; reduction of plasma levels hypertension, either idiopathic or secondary; in endothelin-1; inhibition (tadalafil) of the hypoxiaindication for sildenafil for the treatment of the induced cytokine expression (TNF-a, IL-1b) first, potential for the second. Reversal of endothelial dysfunction; increase in the Favorable effects in patients with heart failure, coronary artery disease, and in patients with number of circulating endothelial progenitor cells; increased cardiovascular risk; reduction of decrease in large artery stiffness and wave microalbuminuria in patients with type 2 diabetes reflections from peripheral sites Reduction of markers/mediators in increased Beneficial effects in patients with risk factors and inflammatory activation increased subclinical inflammatory state Inhibition of superoxide formation Beneficial effects in conditions with increased vascular oxidative stress Biphasic effect on platelet response; increase in the Adjunctive use as antiplatelets agents in patients with coronary artery disease threshold for activation of the platelet glycoprotein IIb/IIIa receptor; inhibition of aggregation Via protein kinase G-dependent pathway Angiogenesis in peripheral arterial disease

Abbreviations: PDE5, phosphodiesterase type 5; cGMP, cyclic guanosine monophosphate; PKG, protein kinase G; KATP, adenosine triphosphate-sensitive potassium; eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; ERK, extracellular signal-regulated kinase; PKC, protein kinase C; TNF-a, tumor necrosis factor a; IL-1b, interleukin 1b.

filtration rate], urinary albumin to creatinine ratio, and, potentially, testosterone level) that should be considered when estimating CV risk in patients with ED. Therefore, although the consensus panel recommends the FRS as a starting point for estimating the likelihood of subclinical atherosclerosis in men with ED, the presence of ED per se, especially in men aged 30 to 60 years, should alert the physician to the possibility of increased CV risk independent of the FRS.62

Use of PDE Inhibitors in Patients With CVD Hypertension. The links between hypertension and ED are increasingly recognized, and the 2009 reappraisal of European guidelines include relevant statements.52 ED is almost twice as frequent in hypertensive as normotensive individuals and appears to be of worse severity. Regarding pathophysiology, hypertension appears to cause ED per se through a multitude

of mechanisms that include prolonged exposure to elevated levels of systemic blood pressure, endothelial dysfunction, and circulation of vasoactive substance (with a pivotal role of angiotensin II) that lead to structural and functional alterations in the penile vasculature.63 Several lines of evidence indicate that antihypertensive drugs can indeed deteriorate sexual function, but this effect appears mainly with older generation drugs (b-blockers, diuretics) while newer agents (nebivolol, angiotensin receptor blockers) might even improve sexual function.31,32 There is clear evidence that PDE5 inhibitors are efficacious in men where the ED is a consequence of hypertension and antihypertensive medications.32,35 Antihypertensive medications do not seem to have any clinically relevant impact on the effectiveness of the PDE5 inhibitors or vice versa. The PDE5 inhibitors are equally effective, regardless of the type of antihypertensive agent; comparable improvements in erectile function were

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observed in the presence of b-blockers, diuretics, calcium channel blockers, or angiotensin-converting enzyme inhibitors.37,63 Of clinical significance is that men with hypertension having ED are more likely to comply with their antihypertensive medication when under PDE5 inhibitors.38 It should be noted, however, that initiation of PDE5 inhibitors in patients with hypertension should follow adequate blood pressure stabilization and is therefore contraindicated in patients with untreated, poorly controlled, accelerated, or malignant hypertension; these patients are considered ‘‘high risk’’ for CV events and should be evaluated by a cardiologist before taking PDE5 inhibitors.62 By virtue of their arterial effects, PDE5 inhibitors are an appealing class of agents for the treatment of hypertension.53,54 However, despite the small acute blood pressure-lowering effect reported in treated patients with hypertension, their potential as antihypertensive agents has not been thoroughly explored. The addition of PDE5 inhibitors to usual common antihypertensive drugs results in either no or small additive reductions in blood pressure.43 Active mid-term treatment with sildenafil reduced ambulatory and clinic blood pressure to a similar extent as that observed with other classes of antihypertensive drugs. An incremental antihypertensive effect of a single dose of tadalafil has been demonstrated in patients with uncontrolled hypertension on multiple agents.43 However, at this stage, the use of PDE5 inhibitors cannot be advocated as antihypertensive agents. Other long-lasting PDE5 inhibitors currently under development may prove to be more efficacious in this setting. Coronary Artery Disease. ED is frequent in patients with diagnosed CAD,8,9 and PDE5 inhibitors are widely used in such patients. PDE5 inhibitors are effective and well-tolerated therapies for the treatment of ED in patients with CAD.34 A favorable response to sildenafil in patients with CAD who were receiving b-blockers and/or angiotensin-converting enzyme inhibitors and/or calcium channel blockers has been observed.41,42 Safety issues were raised soon after the introduction of sildenafil. However, a strong body of clinical data shows that not only sildenafil, which is the most extensively studied drug, but all 3 agents do not increase the risk of nonfatal myocardial infarction, stroke, or CV deaths. These drugs do not exacerbate ischemia or worsen exercise tolerance in patients with known CAD who achieve levels of exercise comparable or greater than that achieved during sexual intercourse.64-67 It is now well recognized that even in patients with severe CAD, sildenafil does not adversely affect coronary artery diameter, coronary blood flow, or coronary vascular resistance, while it even increases coronary flow reserve.43 In patients with high risk of cardiac disease, the diagnostic workup and initiation of treatment for sexual dysfunction should be deferred until the cardiac problem has been corrected or stabilized.62 Thus, despite their safe profile, PDE5 inhibitors should not be used in patients with unstable angina, recent myocardial infarction (6-8 weeks) have been classified as

intermediate risk. These patients may need additional cardiac workup (such as an exercise stress test) and can then be reclassified to low risk or high risk before therapy for ED.62 Nitrates in combination with PDE5 inhibitors cause a profound and unpredictable decline in blood pressure and are contraindicated. Nevertheless, studies show dissipation of the interaction effect before 24 hours, while patients with CAD taking sildenafil tolerate the intravenous infusion of nitrates if a careful titration is employed. However, the 24-hour period between nitrate use and short-acting PDE5 inhibitor administration (up to 48 hours for the long-acting tadalafil) appears prudent until additional data including information on outliers and patients with CAD are available. The PDE5 inhibitors have potential as CV drugs in patients with vasospastic angina or diffuse coronary microvessel disease and in patients undergoing coronary artery bypass grafting.43,51 Because PDE5 isoenzyme is expressed in coronary arteries, its inhibition has been hypothesized to augment coronary blood flow. Recent experimental and clinical evidence suggests that coronary circulation and hemodynamics are not unfavorably altered after treatment with PDE5 inhibitors; on the contrary, epicardial coronary diameter may increase and coronary blood supply may show improvement. The PDE5 inhibition may aid coronary blood flow by decreasing large artery stiffness and reducing amplitude and delaying arrival of wave reflections from peripheral sites. A considerable body of experimental studies with PDE5 inhibitors has demonstrated decreased infarct size after ischemia/reperfusion in animal models, providing evidence for cardioprotective effects. Finally, although their potency is modest compared with other agents that specifically target platelet adhesion/aggregation, their adjunctive use as antiplatelet agents could be also considered.58 Heart Failure. A significant proportion (ranging from approximately 60% to 90%) of patients with heart failure report ED and marked decrease in sexual interest, with ultimately onefourth reporting cessation of sexual activity altogether.45 In these patients, ED deteriorates further the poor quality of life and aggravates depression.68 Although heart failure and ED share common predisposing risk factors, heart failure by itself can cause ED or decrease engagement to sexual activity.45,68 Neurohumoral activation, medications (b-blockers, thiazides, and spironolactone), limited exercise capacity, and depression are responsible. Evaluation of functional capacity is the mainstay for the management of ED in patients with heart failure. However, it should be kept in mind that in men with heart failure, sexual activity may affect the heart differently from physical activity of similar metabolic equivalents (METs) due to differences in psychological anticipation and sympathetic activation. The current Princeton III recommendations classified patients with New York Heart Association (NYHA) class II as low risk rather than intermediate risk as in previous Princeton recommendations. Patients with NYHA class III have been moved from high to intermediate risk.62 Yet, PDE5 inhibitors are not given in patients with heart failure. The reason for this is the fear of complications from

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these drugs due to the lack of experience from large, long-term, placebo-controlled clinical trials regarding the safety of these drugs in such patients.69 However, several small, short-term studies have demonstrated a beneficial effect of PDE5 inhibitors on erectile function and satisfaction with sexual performance in patients who have mild to moderate heart failure (NYHA class II and III).46 The PDE5 inhibitors also decreased depressive symptoms and increased quality of life. The nature and frequency of reported adverse events are comparable to those reported in previous clinical trials of sildenafil in other populations with CVD and are consistent with the known pharmacologic activity of sildenafil. Intriguing new evidence points toward improvement in heart failure symptoms and in the underlying pathophysiology during chronic treatment with sildenafil. Indeed, in a recent clinical study, prolonged use of sildenafil heightened ventilatory efficiency and exercise performance, tempered the peripheral stimulus to hyperventilation, and improved the NOmediated vasodilation in patients with chronic systolic heart failure.47 Furthermore, long-term treatment (12 weeks) with sildenafil improved peak oxygen consumption, 6-minute walk distance, and right ventricular ejection fraction in patients with systolic heart failure complicated by secondary PAH.48 The potential effects on diastolic heart failure are an appealing target for further investigation. However, according to findings of a recent study in heart failure with preserved ejection fraction, PDE5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status.49 Reduction in systemic and pulmonary vascular resistance, both hallmarks of heart failure, is of paramount importance. Mechanisms related to the beneficial effects of sildenafil in this context include improvement in endothelial function as well as reduction in large artery stiffness and wave reflections. Furthermore, this agent improves tissue oxygenation during exercise and gas diffusion at the lung level and protects the alveoli from exercise-induced edema formation.43 Interesting experimental data suggest direct myocardial effects of PDE5 inhibition that may counteract b-adrenergic, hypertrophic, and proapoptotic signaling, 3 critical pathways in the development of left ventricle dysfunction. Inotropic effects of sildenafil were shown in human and animal hypertrophied right ventricle models; however, whether this is present in failing right ventricles remains to be determined.43,44

Use of PDE Inhibitors in CVDs (In The Absence of ED) Pulmonary Hypertension. The treatment of idiopathic pulmonary arterial hypertension is the only non-ED currently approved indication of PDE5 inhibitors (specifically for sildenafil and tadalafil).70,71 Sildenafil has been shown to be beneficial in patients with pulmonary arterial hypertension, either idiopathic or secondary. It significantly enhances exercise capacity by improving pulmonary hemodynamics and reducing right ventricular afterload.72 It also reduces right ventricular mass as determined by magnetic resonance imaging.73 Interestingly,

sildenafil might have the very desirable combination of primary inotropic, antihypertrophic, and afterload-reducing effects on the right ventricle without significantly affecting systemic hemodynamics.43 Thus, this agent appears very attractive for the treatment of pulmonary arterial hypertension involving the right ventricle. Despite their classification as PDE5 inhibitors, all 3 agents are however not equally efficacious in the treatment of PAH. Reduction in mean pulmonary artery pressure, in the pulmonary-to-systemic vascular resistance ratio, and in right ventricle afterload, as well as an increase in cardiac index, has been reported with all 3 PDE5 inhibitors.72 However, only sildenafil caused a significant improvement in arterial oxygenation. The etiology of these agent-specific characteristics is currently not known, but it may be related to the different selectivities of the 3 PDE5 inhibitors with respect to other PDE isoforms. These agents may also differ in their binding capacity to PDE5 during hypoxia.72 Based on the Sildenafil Use in PAH (SUPER) 1, a large, randomized, controlled, multinational trial study, in which sildenafil significantly improved exercise capacity, functional class, and hemodynamic parameters and was well-tolerated, sildenafil 20 mg 3 times a day was approved by the US FDA and the European Agency for the Evaluation of Medicinal Products in 2005 for improving exercise tolerance in patients with pulmonary arterial hypertension. However, the best dose regimen and the effect on survival remain to be determined.70 Based on the results of the Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) study, the US FDA granted approval for use of tadalafil in the 40-mg dose for increasing exercise capacity in patients with World Health Organization (WHO) class 1 PAH.71 Tadalafil 40 mg was well tolerated and improved exercise capacity as measured by 6-minute walk distance, time to clinical worsening, and quality-of-life measures in patients with pulmonary arterial hypertension, but WHO functional class was unaffected by treatment. Interestingly, the results were not so prominent in the bosentan-treated patients compared with treatment- naivepatients, suggesting, according to the authors, that there might be a ‘‘ceiling’’ reached that limits additional improvements in patients on background therapy. To date, available clinical data on the effects of vardenafil on pulmonary vasculature are limited. Vardenafil has shown to be a safe and effective treatment of pulmonary arterial hypertension and acts in synergy with inhaled NO. Congenital Heart Disease. Increased pulmonary vascular resistance complicating congenital heart disease may be caused by decreased endogenous pulmonary endothelial NO production. A recent study suggested that the relative deficiency of circulating endothelial progenitor cells and endothelial dysfunction in patients with pulmonary arterial hypertension with Eisenmenger syndrome might contribute to the pulmonary vascular pathology, while chronic pharmacological augmentation with PDE5 inhibitors could offer a novel therapeutic strategy. In patients with Eisenmenger syndrome, sildenafil improves symptoms and functional capacity; it also increases arterial

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saturation and reduces systolic and mean pulmonary artery pressures and pulmonary vascular resistance. Improvement in pulmonary blood flow is of the same magnitude as in patients with idiopathic PAH.55,56 Interestingly, long-term sildenafil therapy (3-4 months) improved survival according to findings of a recent study.74 Preliminary evaluation of tadalafil has shown beneficial effects of this agent on hemodynamics, tolerability, and efficacy over a 12-week period.75 Finally, in patients with large atrial septal defects, sildenafil improves pulmonary arterial hemodynamics and right ventricular function and relieves symptoms associated with severe pulmonary arterial hypertension.76

Individualized Global Risk and Global Management of Each Patient The first and extremely important objective of the most recent, third Princeton Consensus recommendations focuses on the evaluation and management of CV risk in men with ED and no known CVD.62 For patients with ED with no known CVD, the panel recommends at first evaluation of (1) patient history, including age and CV risk factors, (2) physical examination noting blood pressure, waist circumference, body mass index (BMI), cardiac auscultation, and evaluation of peripheral vascular function including fundal arterial changes, carotid bruits, and palpation of femoral and pedal pulses, (3) ED severity and duration, (4) resting electrocardiogram, (5) fasting plasma glucose level, (6) serum creatinine level (estimated glomerular filtration rate) and albumin-to-creatinine ratio, and (7) lipid profile. After the initial evaluation, the next step to estimate CV risk associated with sexual activity is to evaluate exercise ability.62,77,78 Sexual activity is equivalent to walking 1 mile on the flat in 20 minutes or briskly climbing 2 flights of stairs in 10 seconds. Patients who can generally perform exercise of modest intensity without symptoms are classified as low risk, while patients unable to perform this level of exercise (such as patients with uncontrolled hypertension) are classified as high risk. Further evaluation using exercise stress test is required for patients at indeterminate risk. These patients are restratified to low or high risk based on the results of stress test (4 minutes of the standard Bruce treadmill protocol ¼ 5-6 METs) without symptoms. The documented interval between the onset of ED and symptomatic CAD allows for timely risk factor intervention.79 Modification of lifestyle factors in men with ED is the first step in preventing future CV events. In obese men (BMI > 30 kg/m2) with ED, reduced calorie intake and increased physical activity can significantly reduce weight, decrease the concentrations of inflammatory markers (eg, C-reactive protein), and improve erectile function. Similar results have been observed in men with the metabolic syndrome and comorbid ED.80 In men undertaking or maintaining an active lifestyle, the incidence of ED is significantly lower than in men with a sedentary lifestyle. Unfortunately, there is limited evidence that once ED has occurred, it can be reversed by initiation of an active lifestyle, although for overall health benefit this is recommended.80,81 Established CV risk factors such as hypertension, diabetes, and

hyperlipidemia should be managed with appropriate medical therapy. However, treatment should be tailored to the individual patient, as certain drugs used in the treatment of CVD may be associated with the development of ED or exacerbation of existing ED.30 In general, unless ED developed within 4 weeks of initiating drug therapy, there is little evidence to support switching the suspect drug to alleviate the symptoms of ED. Furthermore, ED may be a result of the underlying CV pathology rather than the drugs used for its treatment. Conversely, in men with ED and hypertension, angiotensin II receptor blockers may improve sexual function and may be the drug of first choice in sexually active men, especially as the potential for adverse effects is low.31,32 In a number of studies involving men with ED and hypercholesterolemia, treatment with a statin has been reported to significantly reduce low-density lipoprotein cholesterol concentrations and also to improve erectile function.22 Among men with type 2 diabetes, ED, and silent CAD, treatment with statins and PDE inhibitors has been reported to be associated with a significant reduction in major adverse cardiac events.12 We recommend the treatment to a target LDL cholesterol of 2 mmol/L (80 mg/dL) or less. Testosterone therapy should be reserved for patients who (1) are symptomatic (ED or reduced libido) from testosterone deficiency and (2) have biochemical evidence of low testosterone defined as total testosterone