Interplay between ED and cardiovascular disease

Erectile dysfunction (ED) affects as many as 30 million men in the United States. Its risk factors are similar to those for atherosclerotic heart disease. Physicians should ask male patients–particularly those with cardiovascular disease–about ED and men with confirmed ED about cardiovascular risk factors. Oral sildenafil is an effective therapy for both organic and psychogenic ED; it is contraindicated in patients taking organic nitrates.

Until just a few years ago, patients rarely discussed and physicians rarely asked about sexual health. Men in particular often were embarrassed to discuss erectile dysfunction (ED), seeing it as a failure of their manhood; indeed, some had difficulty even admitting that they had the disorder. Other men feared that their physician might be embarrassed if the issue was raised. Such attitudes have eased considerably since the advent of an oral agent for the treatment of ED and the subsequent dissemination of information about ED in the media. Even so, many men and their physicians still hesitate to broach the subject. This review underscores the importance of discussing ED with male patients–the disorder is often associated with cardiovascular disease. The interplay between ED and cardiovascular disease must be taken into account in both diagnosis and treatment.

Scope of the Problem

The landmark Massachusetts Male Aging Study, which included more than 1,200 noninstitutionalized men aged 40 to 70 years, found that 52% of men complained of impotence. ED was complete (i.e., patient never able to achieve an erection satisfactory for sexual activity) in 10% of the men, moderate in 25%, and minimal in 17%. This study, reported by H.A. Feldman and colleagues in 1994, served as a wake-up call about the prevalence of impotence in the United States. Based on the Massachusetts data, it is estimated that ED affects more than 25 million U. S. men aged 40 to 70 and millions more who are older than 70.

Other studies have corroborated the Massachusetts findings: ED is common in the United States and its prevalence increases with age. M. Jønler and colleagues surveyed men in a prostate cancer screening program in three U.S. cities. Of 1,517 who responded to a self-administered questionnaire, 129 (8.5%) reported having had no sexually stimulated erections during the past year. Of 1,388 who did have erections, 12.4% had them less than one in five times when sexually stimulated and 19.7% less than half the time.

A more recent report from the Massachusetts Male Aging Study concluded that 617,715 new cases of ED can be expected to occur each year in the United States among white men aged 40 to 70. The authors, C. B. Johannes, and colleagues, based their conclusions on an 8.8-year follow-up of 847 subjects who did not have ED at baseline. In this group, 194 new cases of ED were detected during 7,475 man-years of follow-up. The annual risk of ED was 26 cases per 1,000 men. The annual incidence increased with age: 12.4 cases per 1,000 men aged 40 to 49, 29.8 cases per 1,000 men aged 50 to 59, and 46.4 cases per 1,000 men aged 60 to 69. Thus, the risk of ED approximately quadrupled between ages 40 and 70.

In another study, M. Wei and colleagues reported that ED developed in 71 of 3,250 men aged 26 to 83 who did not have ED at baseline and were followed for six to 48 months. These investigators estimated the annual incidence to be 2.4 cases per 1,000 men aged 44 and under, 5.5 cases per 1,000 men aged 45 to 54, 15.9 cases per 1,000 men aged 55 to 64, and 52.3 cases per 1,000 men aged 65 and over.

Physiology of Erection

It has been said that the penis is a vascular organ. Indeed, for an erection to occur sufficient blood must flow into the penis. The penile anatomy pertinent to erection includes three cylinders: the corpus spongiosum (which contains the urethra) and the two corpora cavernosa (the erectile bodies). The corpora cavernosa consists of sinusoidal tissue that is surrounded by a tough fibroelastic covering, a central artery that runs through the sinusoidal tissue, and veins underneath the fibroelastic covering that drain the erectile bodies. During the flaccid state, smooth muscles lining the central arteries and sinusoids of the corpora cavernosa are tonically contracted. Thus, in an unaroused state, vascular resistance in the penis is high.

With sexual stimulation, nitric oxide is released into the corpora cavernosa from nonadrenergic-noncholinergic autonomic nerves and the vascular endothelium. Nitric oxide stimulates the enzyme guanylate cyclase to produce cyclic guanosine monophosphate (cGMP), which ultimately causes relaxation of vascular smooth muscle in the arteries, arterioles, and sinusoids of the corpora cavernosa, which then fill with blood much like a sponge fills with water. As blood enters the corpora cavernosa, the veins under the fibroelastic covering are compressed, and blood is trapped in the penis.

Following ejaculation, detumescence normally occurs with the release of catecholamines and the breakdown of cGMP. In vascular smooth muscle cells, cGMP is metabolized by the enzyme phosphodiesterase (PDE). Of the numerous PDE isoforms, PDE-5 is found in high concentrations in the penis. A frequent underlying cause of ED is a lack of cGMP; the PDE-5 inhibitors (e.g., sildenafil) prevent the breakdown of cGMP by blocking PDE-5.

Physicians should be aware that PDE-5 is present elsewhere in the body (e.g., in the smooth muscle cells of systemic arteries and veins, gastrointestinal tract, platelets). Thus, inhibition of PDE-5 by any agent may have a hemodynamic effect, including a reduction in systemic vascular resistance and mild decreases in arterial pressure.

ED Causes and Risk Factors

The etiology of ED may be organic, psychogenic, or a combination of the two (Table 1). For many years, it was assumed that most cases were secondary to psychogenic factors. However, our understanding of ED has changed. As F. E. Kaiser and colleagues noted in 1988, “atherosclerotic disease is the cause of approximately 40% of erectile dysfunction in men older than 50 years.”

Table 1. Causes of Erectile Dysfunction
ORGANIC
Drugs
 Alcohol
Anticholinergics
Antidepressants
Antihypertensives (e.g., thiazide diuretics, reserpine,
  beta-blockers, methyldopa, hydralazine)
Cancer chemotherapeutics
Cardiac agents (e.g., clofibrate, gemfibrozil, digoxin)
Hormones
H2-receptor antagonists
Tranquilizers
Endocrine Abnormalities
 Hypogonadism
Hypothyroidism, hyperthyroidism
Pituitary tumor, hyperprolactinemia
Neurogenic
 Cerebrovascular accidents
Multiple sclerosis
Nerve damage after prostate surgery
Neuropathies (e.g., diabetic, alcoholic)
Spinal cord injuries
Renal Failure, Dialysis
Structural Abnormalities
 Peyronie’s disease
Priapism
Trauma
Vascular
 Atherosclerosis and associated risk factors (e.g., smoking,
  diabetes, lipid abnormalities, hypertension)
Vascular surgery
Venous leak (veins do not collapse fully during erection
  and blood drains from penis)
PSYCHOGENIC
Anxiety
Depression

Indeed, in men with lipid abnormalities, ED can occur before significant vascular stenosis develops in the penile arteries. High cholesterol levels most likely alter endothelial function and prevent normal vasodilation of the penile vasculature. In a study by K. M. Azadzoi and colleagues, male rabbits were fed either a high-cholesterol or standard diet, and erections were induced by injecting papaverine or phentolamine into the corpora cavernosa. Erections were maintained in rabbits fed standard rabbit chow, but in those who received high-cholesterol chow, loss of erection occurred both in animals with penile arterial stenoses and in animals with hypercholesterolemia but no significant stenoses.

Because vascular disease is a prominent cause of ED, risk factors that cause cardiovascular disease are also risk factors for ED. Hence, the following should be considered risk factors for ED: smoking, diabetes, low high-density lipoprotein (HDL) levels, high low-density lipoprotein (LDL) and total cholesterol levels, hypertension, sedentary lifestyle, and obesity.

When R. Virag and colleagues looked for potential risk factors in 440 men with ED, they found that smoking, diabetes, and hyperlipidemia were more common (and had a cumulative effect) among men with ED than in men without the disorder. In the original Massachusetts Male Aging Study, men with heart disease, diabetes, or hypertension were four times more likely to have ED in later life than men without these risk factors. A low HDL level also was a risk factor. In men with treated heart disease, the probability of complete ED was 21% in nonsmokers and 56% in smokers.

The follow-up Massachusetts Male Aging Study included 513 men aged 40 to 70 who, in addition to being free of ED at baseline, did not have diabetes or heart disease. In men who smoked cigarettes at baseline, the likelihood of moderate or complete ED had nearly doubled (24% vs 14%) eight years later. Cigar smoking and passive exposure to cigarette smoke also predicted ED, as did obesity, and a composite coronary risk score (which was based on the Framingham Heart Study and included age, systolic blood pressure, serum cholesterol level, and cigarette smoking).

In Wei’s study, the risk of ED was 1.83 times greater in men with total cholesterol levels greater than 240 mg/dL than in men with levels of less than 180 mg/dL. An HDL level of greater than 60 mg/dL protects against ED. These patterns are, of course, similar to the relationships between total cholesterol and HDL levels and coronary artery disease.

Diabetic sequelae that facilitate the development of ED include peripheral neuropathy and acceleration of vascular disease and atherosclerosis. R. Klein and colleagues found that about 75% of diabetic men had ED by the age of 60. Loss of vibratory sense was predictive of ED, suggesting that ED has a neurogenic component in patients with diabetes.

Several studies have implicated hypertension (and antihypertensive drugs) as a risk factor for ED. In the original Massachusetts Male Aging Study, the age-adjusted probability of complete ED was 15% in men treated for hypertension, compared with 9.6% in the total study population. Another trial that suggested that antihypertensive agents may have an etiologic role in ED was a U.K. study of 302 men reported by C. J. Bulpitt and colleagues. ED was present in 6.9% of 30 men without hypertension, in 17.1% of 43 men with untreated hypertension, and in 24.6% of 229 men with treated hypertension. This study and others suggest that antihypertensive agents may add to the risk posed by hypertension.

Studies that have compared various antihypertensive agents indicate that thiazide diuretics have the highest association with ED. Beta-blockers and centrally acting agents also have been associated with ED; to a lesser extent, so have angiotensin-converting enzyme inhibitors and calcium channel blockers. In contrast, a recent study by R. Fogari and colleagues found that ED improved in hypertensive men treated with the angiotensin II-receptor antagonist valsartan.

Why do some antihypertensive agents seem to exacerbate ED? One theory is that they may reduce the driving pressure within the vasculature needed for an erection. However, only about 80 mm Hg of pressure is required in the corpora cavernosa for an erection, so unless an antihypertensive drug causes hypotension, this theory seems unlikely. Moreover, if it were simply a question of absolute blood pressure, then all antihypertensives should exacerbate ED to about the same degree, but this does not appear to be the case. Other factors (e.g., ion shifts across smooth muscle cells) may play a role.

Of course, once a patient has atherosclerotic heart disease, it is likely that atherosclerosis also will be present in other vascular beds. So it is not surprising that heart disease has been associated with ED. For example, 57% of 30 patients (mean age, 51 years) followed by M. J. Gundle and colleagues reported sexual dysfunction, mainly ED, one to two years after coronary artery bypass surgery. Of 131 men (aged 31-86 years) who were hospitalized for acute myocardial infarction, 64% had ED, reported A. J. Wabrek and R.C. Burchell. In the original Massachusetts Male Aging Study, the age-adjusted probability of complete ED was 39% in patients treated for heart disease, compared with 9.6% in the total sample.

Thus, once heart disease develops–especially coronary artery disease and myocardial infarction–ED may occur. On the other hand, once ED is diagnosed, there is an increased probability that the patient also has risk factors for coronary artery disease. Therefore, physicians need to question patients who present with ED about cardiac risk factors. If smoking, lipid abnormalities, hypertension, or diabetes are identified and treated appropriately, the patient’s life may be saved.

It is also important to question patients with cardiovascular risk factors about ED. One useful tool for addressing the issue is the abridged version of the International Index of Erectile Function (IIEF-5) (Table 2). This five-item questionnaire (also known as the Sexual Health Inventory for Men, or SHIM) takes about five minutes to complete and can be taken home if the patient is uncomfortable filling it out in the physician’s office. A score of 21 or less suggests that ED is likely. We have found the questionnaire to be a useful way to break the ice when broaching the issue of ED.

Table 2. The Abridged International Index of Erectile Function
During 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?
Never or
Almost 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
Always or
Almost Always



5
3.During sexual
intercourse, how often
were you able to
maintain your erection
after you had penetrated
(entered) your partner?
Never or
Almost 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
Always or
Almost Always



5
4.During sexual
intercourse, how
difficult was it to
maintain your erection
to completion of
intercourse?
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?
Never or
Almost 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
Always or
Almost Always


5

Score can range from 5 to 25; a score of 21 or less suggests erectile dysfunction.

Treatment

Common therapies for ED include sexual counseling, sildenafil, intraurethral alprostadil suppositories, intracavernosal injections of alprostadil, vacuum erection devices, and penile prostheses. Physicians should assess the patient’s cardiovascular health before prescribing ED therapy. Sexual activity has been likened to moderate physical exertion (e.g., golfing, cleaning windows, painting, a room) that increases oxygen demand and stresses the heart in some patients, particularly men with coronary artery disease or its risk factors who have been physically and sexually inactive for a long time.

During sexual intercourse, heart rate increases to 120 to 130 beats per minute and systolic blood pressure to 150 to 180 mm Hg. Diastolic blood pressure increases by about 10 mm Hg, and the patient expends four to six METs (metabolic equivalents of the task). If a patient can achieve these levels on an exercise stress test without the occurrence of chest pain, ST-segment depression, a reversible thallium defect, or echocardiographic wall motion abnormality, the risk of ischemia during sexual activity is low. However, no test will rule out the possibility of a cardiac event during sexual activity. Although the relative risk of myocardial infarction within the first two hours of sexual intercourse is 2.5, the good news is that the absolute hourly risk is only about one in a million.

Sildenafil is a highly effective oral agent for the treatment of organic and psychogenic ED. Overall, it improves erections in 74% of men taking 50 mg before sexual activity and in 82% of men taking 100 mg, compared with 24% of men taking placebo. It is effective in more than 70% of men who also have vascular disease or hypertension. Efficacy rates are somewhat lower in diabetic men and in men with nerve disruption after radical prostate surgery.

Dosing guidelines suggest that sildenafil be taken one hour before sexual activity and not more than once a day. The most common side effects (headache, flushing, nasal congestion) are related to the drug’s vasodilatory effects. Dyspepsia, vision changes, and dizziness are less common. Because sildenafil blocks PED-5, it causes small decreases in systolic and diastolic arterial pressures of about 8 and 5 mm Hg, respectively (see Figure 1).

Clinical trials have shown that the incidence of side effects was not increased when sildenafil was administered to men who were taking one or more antihypertensive agents. Moreover, the drug has not been associated with an increased incidence of cardiac events, compared with placebo. While some men have died after taking sildenafil, the number of those deaths was well within the expected rate according to age group.

Sildenafil is contraindicated in patients taking organic nitrates (e.g., nitroglycerin, isosorbide mononitrate, isosorbide dinitrate). Organic nitrates are nitric oxide donors and therefore cause increased cGMP production. Patients taking both an organic nitrate and sildenafil may experience marked increases in cGMP, followed by vasodilation and a synergistic decrease in blood pressure.

Patients with angina who present to the emergency department should be asked if they have ever taken sildenafil, particularly within the last 24 hours. If they have, they should receive nonnitrate antianginal agents (e.g., beta-blockers or calcium channel blockers). A consensus statement of the American College of Cardiology and American Heart Association suggested that nitrates not be administered for 24 hours after sildenafil is taken. The recent Princeton Consensus Conference established other guidelines for the use of sildenafil in cardiovascular patients.

New Oral Agents. At least two other PDE-5 inhibitors are being developed for the treatment of ED. Another agent under study is the centrally acting apomorphine; however, it may cause syncope in some patients.

Lifestyle Changes

Few studies have examined whether lifestyle changes can modify the risk of ED. With the advent of oral therapy for ED, it will be even more difficult to resolve this issue. One of the best studies on the subject was that of C. A. Derby and colleagues who followed for nine years 593 men from the Massachusetts Male Aging Study who did not have ED at baseline. ED was most likely to develop in men who were obese at baseline, regardless of their weight nine years later. ED was also more likely to occur in men who remained sedentary than in those who remained physically active or initiated physical activity. Somewhat surprising was the finding that smoking cessation or reduced alcohol consumption did not affect the incidence of ED. The authors postulated that midlife changes simply may be too late to reverse the effects of smoking, obesity, and alcohol consumption.

Conclusion

ED is a common disorder in the United States. Many of its risk factors are the same as those for atherosclerotic heart disease. Thus, patients with heart disease in particular should be asked about ED and patients with ED about their cardiovascular risk factors. Sildenafil is an effective oral therapy for ED but is contraindicated in patients taking organic nitrates.

Categorized in:

Erectile Dysfunction,

Last Update: 26 March 2024