Erectile dysfunction The cardiovascular connection

Cardiology Review® Online, September 2004, Volume 21, Issue 9

From the Heart Institute, Good Samaritan Hospital, and the Division of Cardiovascular Medicine, Keck School of Medicine, University of Southern California, Los Angeles

Erectile dysfunction and risk factors If a patient went to see his health care worker some 15 years ago about the problem of impotence (now referred to as erectile dysfunction [ED]), in many cases, he may have been told that it was primarily a psychological problem. Indeed, psychogenic difficulties, such as anxiety, depression, and problems in relationships, may contribute to ED. In men older than 40 to 50 years, however, the etiology is more likely to be organic in nature. Common organic causes include vascular (endothelial dysfunction, frank atherosclerosis), neurogenic (cerebrovascular event, spinal cord injury, multiple sclerosis, neuropathy), or endocrine (diabetes [which also includes elements of vascular and neurogenic ED], hyperthyroidism, hypothyroidism, hyperprolactinemia), trauma, structural abnormalities (such as Peyronie’s disease), or causes related to such drugs as thiazide diuretics, beta blocking agents, centrally acting antihypertensive medicines, selective serotonin reuptake inhibitor—type antidepressants, alcohol, nicotine, and others.1

Because an erection is a vascular event involving vasodilation of vascular structures in the corpus cavernosum of the penis, endothelial function must be intact. Factors that injure the endothelium and lead to endothelial dysfunction may contribute to ED. Thus, hypertension, diabetes, smoking, lipid abnormalities (especially low high-density lipoprotein [HDL] cholesterol and high total cholesterol), lack of physical activity, and obesity, which are known risk factors for coronary artery disease (CAD), are also risk factors for ED.2,3 Therefore, patients with these risk factors should be questioned about their sexual health. Conversely, patients who present with ED should be questioned about cardiovascular risk factors. A recent study found that men who presented with ED were more likely to have endothelial dysfunction.4 Furthermore, they were more likely to have cardiovascular risk factors and an exercise stress test that was positive for ischemia.5 Pritzker coined the term penile stress test to make the point that ED may be an early warning that a man may have vascular disease.5

How common is ED once vascular disease occurs? In a recent study, my colleagues and I queried men with stable angina pectoris about their sexual health with a five-question survey called the Sexual Health Inventory for Men.6 This questionnaire focused on two key issues—the ability to attain an erection and the ability to maintain an erection through successful completion of intercourse. Answers to questions were scored from 0 to 5 and then added. Scores of 21 or less suggested ED. Of the 76 men, 75% had ED according to their questionnaires, and ED was severe in 25% of these men. Therefore, ED is common in the CAD patient.

ED is also common in patients with diabetes. In one study, the prevalence of ED was greater than 75% in diabetic men older than 60 years.7 Diabetes can induce ED both by accelerating vascular disease and via a diabetic neuropathy. Loss of sensation on the neurologic examination correlated with the development of ED in diabetic men. The incidence

of ED is also high in patients with hypertension.8

Age, of course, is another factor associated with ED. In the Massachusetts Male Aging Study (MMAS), 52% of men between the ages of 40 and 70 years had some degree of ED.2 At age 40, 5% had complete ED, meaning they were never able to achieve an erection satisfactory for sexual activity. By age 70, 15% had complete ED. Moderate degrees of ED also increased with age, whereas mild ED did not appear to be affected by age. After correction for age, heart disease, hypertension, diabetes, and low HDL cholesterol correlated closest with development of ED. In a follow-up study of MMAS, smoking and passive exposure to smoke also predicted ED.9

Unfortunately, there is a paucity of data that examine whether control of these cardiovascular risk factors will reverse ED.10 Some, but not all, studies suggest that smoking

cessation will help. Unfortunately, even passive smoking may worsen ED.9 HMG-CoA reductase inhibitors (statins) were shown to improve spontaneous nocturnal erections in another analysis.11 There is a lack of data on whether tight control of hypertension or diabetes will help. One study suggested that better control of some risk factors may improve response to oral therapy with sildenafil.12

Oral pharmacologic therapy

Oral pharmacologic therapy for ED in the form of the phosphodiesterase-5 (PDE-5) inhibitors is effective not only in a general population, but also in men with ED who have vascular disease, including ischemic heart disease13 and hypertension.14 The PDE-5 inhibitor sildenafil improved ED in 72% of men with chronic ischemic heart disease and in about the same percentage

of men with hypertension, most of whom were on antihypertensive medicines. In a general population of men with ED, sildenafil improved ED in 82% at the 100-mg dose. Efficacy rates were somewhat lower in men with diabetes. Vardenafil and tadalafil also have been shown to be effective in men with ED, including those with ED of a vascular basis. Their efficacy in diabetic men also tends to be somewhat lower than their efficacy in nondiabetic men.15

PDE-5 inhibitors prevent the breakdown of cyclic guanosine monophosphate, the substance that ultimately causes smooth muscle cell relaxation in the vasculature of the corpus cavernosum of the penis. Because the enzyme PDE-5 is present not only in the vasculature of the penis, but also in systemic arteries and veins, PDE-5 inhibitors are mild vasodilators. Because they dilate ar-teries and veins, they are associated with small reductions in arterial pressure. In general, these small reductions are not considered clinically significant. The vasodilator effect can account for some of the nuisance adverse effects of these agents, including flushing, headache, and nasal stuffiness.15

The PDE-5 inhibitors are not aphrodisiacs. Patients must be instructed that sexual stimulation is needed for these agents to be effective. Sildenafil and vardenafil have

a relatively short half-life of about

4 hours, whereas tadalafil has a long half-life of 17.5 hours. Sildenafil and vardenafil have some interaction with food, and fatty meals may delay the onset of their action. Tadalafil does not have a food interaction.

All three PDE-5 inhibitors are contraindicated in patients taking organic nitrates, including all nitroglycerin preparations and long-acting nitrates, such as isosorbide mononitrate and isosorbide dinitrate.16 It is important for cardiologists to realize that the contraindication holds for patients taking intermittent nitrates, such as sublingual nitroglycerin tablets or sprays, as well as regularly dosed nitrates. In general, the PDE-5 inhibitors are safe to use in patients taking the usual antihypertensive agents in whom they are associated with no or small additive decreases in blood pressure.

In general, the PDE-5 inhibitors are safe to use in patients taking the usual antihypertensive agents in whom they are associated with no or small additive decreases in blood pressure. In general, the adverse effect profile of the PDE-5 inhibitors is not worsened when patients take antihypertensive medicines—even in those taking multiple antihypertensive agents. Alpha blocking agents, however, appear to be an exception. A 25-mg dose of sildenafil may be administered with alpha blockers at any time, but it is recommended that doses of 50 or 100 mg not be administered within a 4-hour window of alpha blocker therapy because some patients have developed orthostatic hypotension when given more than 25 mg sildenafil simultaneously with doxazosin. Vardenafil is absolutely contraindicated with alpha blockers, as some patients taking

terazosin or tamsulosin have developed orthostatic hypotension when taking this combination. Tadalafil is contraindicated with alpha blockers, except for a 0.4-mg dose of tamsulosin, because some patients who received tadalafil plus doxazosin developed orthostatic hypotension. Vardenafil carries a warning that it should not be given to patients with congenital QT prolongation or patients taking type 1A antiarrhythmics, such as quinidine or procainamide, or type 3 antiarrhythmics, such as sotalol or amiodarone. Neither sildenafil nor tadalafil carries a QT interval warning. The PDE-5 inhibitors have not been associated with documented cases of torsades de pointes. In addition, studies assessing rates of myocardial infarction (MI) or death did not suggest an increase in these events in men taking PDE-5 inhibitors as part of double-blind, placebo-controlled, or open-label studies.16 In postmarketing surveillance studies of sildenafil, there was no evidence of an increase in MI or death compared with what would be expected in an age-matched population.17,18 Similar postmarketing surveillance data on vardenafil and tadalafil are not yet available.

In general, the PDE-5 inhibitors are safe in most stable cardiac patients. They do not exacerbate ischemia when given to patients with CAD undergoing exercise testing; however, treatment for sexual dysfunction in unstable cardiac patients, in general, should be withheld until their cardiac condition is stabilized and should be approached as outlined in the Princeton consensus document.19 Furthermore, any vasodilators, including PDE-5 inhibitors, should be used with great caution in patients who could deteriorate hemodynamically as a result of vasodilator therapy, such as those with left ventricular outflow obstruction or aortic stenosis, hypotensive patients, and patients with congestive heart failure with low blood volume. Additional guidelines regarding the safety of sildenafil and the cardiac patient were issued by the Ameri-can College of Cardiology and the American Heart Association.20

Conclusions

Investigational studies are exploring the potential cardiac applications of PDE-5 inhibitors.21 In many studies, sildenafil was shown to reduce pulmonary artery pressure and pulmonary vascular resistance in patients with primary and secondary pulmonary hypertension. It was also shown to improve endothelial function measured by flow-mediated vasodilation of the brachial artery in patients with endothelial dysfunction associated with congestive heart failure or diabetes. Early studies suggest that sildenafil may improve hemodynamics and exercise tolerance in patients with congestive heart failure. These agents may be explored as possible adjunctive therapies for patients with hypertension. n