Erectile Dysfunction and Cardiovascular Disease
Case Presentation
A 67-year-old man visits his primary care physician with the chief complaint of erectile dysfunction (ED). He has a two-year history of inability to achieve and maintain an erection adequate for vaginal penetration. He has a decrease in the frequency of nocturnal and early morning erections. He has tried sildenafil 50 mg on several occasions without any improvement in his sexual performance. He also reports lethargy, a decrease in his libido, and falling asleep after meals. He has a history of borderline hypertension and elevated total cholesterol. He is a smoker, approximately one-and-a-half packs per day for the past 30 years. He consumes three to four cocktails each evening. He is a stockbroker and admits to having a moderate amount of stress. He has a very sedentary lifestyle. He is married and describes his marriage as “rocky.” He has mild shortness of breath on exertion. He denies angina or use of nitroglycerin. He has moderate lower urinary tract symptoms with a decrease in the force and caliber of his urinary stream, hesitancy of urination, post-micturition dribbling, and nocturia times three.
On physical examination, his height is 68 inches and his weight is 225 pounds. His body mass index is 34.2. The blood pressure is 185/100 mm Hg with a few premature ventricular contractions. On auscultation of the heart, a 4th heart sound was heard. The aortic component of the 2nd heart sound was accentuated. A soft ejection systolic murmur was heard at the base of the heart. The chest has an increase in anteroposterior diameter with occasional rhonchi. The digital rectal exam reveals a moderately enlarged benign prostate with no masses in the rectal ampulla. The extremities reveal decreased peripheral pulses in the dorsalis pedis and posterior tibilias.
Laboratory tests show that the urinalysis is normal. Blood urea nitrogen is 22 mg/dL, and creatinine is 1.7 mg/dL. Total cholesterol is 250 mg/dL, and high-density lipoprotein (HDL) is 30 mg/dL, with a cholesterol/HDL ratio of 8.33. The random glucose is 225 mg/dL. Total serum testosterone is 225 ng/dL, and the prolactin level was normal. Prostate-specific antigen (PSA) is 4.5 ng/dL, and free/total PSA is 26%. Chest x-ray reveals mild cardiomegaly with a prominent left ventricle and evidence of mild emphysema. Resting electrocardiogram (ECG) demonstrates prominent QRS complexes with secondary ST-T changes. A nuclear stress test was performed; the patient developed chest discomfort and shortness of breath after 5 minutes, and the test was stopped. This test was positive for stress-induced ischemia, which demonstrated shortness of breath after 5 minutes. An angiogram revealed 80% narrowing of the left anterior descending artery. Angioplasty was accomplished with placement of a stent in the left anterior descending artery.
The patient was diagnosed with coronary artery disease (CAD), hypertension, obesity, diabetes mellitus, androgen deficiency, dyslipidemia, and benign prostatic hyperplasia (BPH). He also has two other comorbid conditions contributing to his ED, including a sedentary lifestyle and smoking. Alcohol may also be a factor that diminishes his sexual performance. Treatment included metoprolol 50 mg twice daily for high blood pressure, glipizide 5 mg/day for diabetes, and simvastatin 20 mg at bedtime for hypercholesterolemia. For BPH, he was placed on finasteride 5 mg/day and alfuzosin 10 mg/day. For androgen deficiency, he was given testosterone supplements with a topical gel applied each day. He was advised to begin exercise, weight reduction, and smoking cessation programs.
Discussion
This case represents an example of how ED can be a harbinger of other comorbid conditions. A normal erection requires the complex integration between the central nervous system and the smooth muscle cells of the corporal bodies of the penis. With sexual stimulation there is a release of nitric oxide from the noradrenergic noncholinergic cavernous nerves, which increases cyclic guanosine monophosphate (cGMP) that mediates the vasodilatory process, allowing more blood to enter the corporal bodies and resulting in tumescence and rigidity of the penis adequate for vaginal penetration. The etiology of ED is usually multifactorial, as in this case. In most men over the age of 50 there are risk factors such as obesity, smoking, diabetes, hypertension, or hypercholesterolemia that result in oxidative stress leading to endothelial dysfunction and ultimately to erectile dysfunction. The atherosclerotic process, which may begin in the small penile arteries, reduces the blood flow into the penis and also impairs the local nitric oxide generation from the smooth muscle cells within the corporal bodies of the penis.1 Both of these pathologic mechanisms result in ED. Cardiovascular disease and ED share many of the same risk factors, and they commonly coexist. The prevalence of ED in cardiovascular patients is higher than in the general population. In men with a history of heart disease or previous myocardial infarction (MI), the incidence of sexual dysfunction ranges from 39-64%.2
The most common condition associated with ED is undoubtedly hypertension; 68% of men with hypertension have ED.3 Dyslipidemia is also strongly associated with ED. In men presenting with ED, 56% were found to have a positive stress test, and 20% of these on angiography were shown to have significant underlying coronary occlusions.4
Because of the coexistence of ED and CAD, it is imperative that all men over the age of 50 who present with ED be evaluated for cardiovascular disease, especially in men with concomitant risk factors such as smoking, hypertension, diabetes mellitus, hypercholesterolemia, and obesity. It is recommended that a new patient with ED receive a thorough history, lipid profile, 12-lead ECG, and exercise tolerance to identify men with subclinical CAD.5 Treating ED and resumption of normal sexual activity is important to most men with CAD. Their concept of themselves as a man is threatened, their relationship with their partner, family, and friends can be impaired, and their productivity in the workplace can also be affected. Untreated ED can lead to depression. There are now guidelines for the assessment and management of ED in the cardiovascular patient.6 These guidelines suggest that patients can be stratified into low, medium, or high risk, depending on the activity of the cardiovascular disease. The low-risk category includes patients in whom sexual activity poses no significant cardiac risk; these patients generally can initiate ED therapy without the need for additional cardiovascular evaluation or treatment. Low-risk patients may be treated for ED by their primary care physician; the full armamentarium of ED therapies is available to these patients, although a reevaluation at 6- to 12-month intervals is recommended. High-risk patients are those with cardiovascular disease that requires specialized consultation, evaluation, and priority cardiovascular management. These patients should defer sexual activity and treatment for sexual dysfunction until the cardiac condition has been fully evaluated, treated, and stabilized. The indeterminate- (or intermediate-) risk category is for patients who do not fall into the low- or high-risk groups. These patients should have a cardiac evaluation to permit restratification into either the high- or low-risk category prior to resumption of sexual activity and/or treatment for sexual dysfunction.7
Organic nitrates are frequently prescribed to manage the symptoms of angina pectoris. However, the coadministration of nitrates and PDE5 inhibitors significantly increases the risk of potentially life-threatening hypotension and is contraindicated.8-10 The time interval for nitrate administration during a medical emergency to patients who have taken either sildenafil or vardenafil has not been definitively determined. However, administration of nitrates may be considered if at least 24 hours has elapsed since the ingestion of sildenafil, based on the pharmacokinetic profile of a 100-mg oral dose of sildenafil in healthy volunteers.11 Tadalafil has been specifically studied to determine the time course of nitrate interaction.3,5 A total of 150 male subjects received daily doses of placebo or tadalafil 20 mg for 7 consecutive days. On day 7 and beyond, after the last dose of placebo or tadalafil, subjects received repeated doses of sublingual nitroglycerin (SL NTG). Subjects were crossed over to the alternate treatment after a washout period of 10-21 days. The hemodynamic interaction between tadalafil and SL NTG lasted 24 hours, but was not seen at 48 or more hours. In a patient who has received tadalafil when nitrate administration is deemed medically necessary, at least 48 hours should elapse after the last dose of tadalafil before nitrate administration is considered.12 Similar to other PDE5 inhibitors, tadalafil should not be administered in combination with organic nitrates.10 In emergency situations, other therapies apart from nitrates can be considered, including morphine, aspirin, or other thrombolytic medications, beta blockers, and calcium-channel blockers.13 In patients with documented hypogonadism, testosterone augmentation should be prescribed in place of or in addition to a PDE5 inhibitor.14
Addressing other risk factors for ED, such as removing the patient from medications that cause ED; treating sleep disorders and other potentially exacerbating conditions; reducing stress; counseling the patient to limit or quit smoking, alcohol, and recreational drug use; and educating the patient and his partner about the factors that can exacerbate ED, may help to improve treatment outcomes with PDE5 inhibitors.15 Clinicians often limit their examination of a patient with ED to a general medical history. However, a broader context including organic and psychogenic aspects of ED, which includes examining patients’ health status, the quality of the patient-partner relationship, the length of sexual abstinence, and the individual’s life stressors, should be considered. In order to achieve best results in the treatment of ED, proper follow-up is essential. A follow-up visit in the first 1-6 months of treatment can help to determine the efficacy of treatment and to determine whether any adjustments or additional measures are necessary.16
Conclusion
ED and CAD are often coexisting conditions, and ED may antedate a serious cardiovascular event such as an MI. Therefore, it is good medicine to take a sexual history in all men over age 45, and those who present with ED should undergo a more extensive cardiovascular evaluation.