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Erectile Dysfunction and Cardiovascular Disease

      Cardiovascular disease and erectile dysfunction (ED) are closely interrelated disease processes. Erectile dysfunction reportedly affects 10 million to 20 million men in the United States and more than 100 million men worldwide. Each year, about 500,000 persons in the United States survive a myocardial infarction, and an estimated 11 million have existing cardiovascular disease, making the issue of sexual function and cardiac disease relevant to many patients. We explore the relationship between ED and the presence of cardiovascular disease in the general population. We also review the prevalence and pathophysiological associations of ED and cardiovascular disease. The risks of sexual activity for patients with cardiovascular disease are discussed, as are prevention and treatment strategies for ED in this patient population.
      cGMP (cyclic guanosine monophosphate), ECG (electrocardiography), ED (erectile dysfunction), FDA (Food and Drug Administration), HDL (high-density lipoprotein), MET (metabolic equivalent), MMAS (Massachusetts Male Aging Study), NO (nitric oxide), PBI (penile brachial index), PDE-5 (phosphodiesterase type 5), PSV (peak systolic velocity)
      Erectile dysfunction (ED) is the inability to achieve or maintain an erection that is adequate for intercourse.
      • Muller JE
      Sexual activity as a trigger for cardiovascular events: what is the risk?.
      Erectile dysfunction is a common physiological disorder. According to estimates from the National Institutes of Health, ED affects 10 million to 20 million men in the United States; another 10 million men are affected by partial ED, defined as present but diminished erectile function.
      • NIH Consensus Development Panel on Impotence
      NIH Consensus Conference: impotence.
      Worldwide, more than 100 million men are believed to have ED.
      • Zusman RM
      • Morales A
      • Glasser DB
      • Osterloh IH
      Overall cardiovascular profile of sildenafil citrate.
      Between 1987 and 1989, the Massachusetts Male Aging Study (MMAS), a community-based random sample observational study of 1709 men, used self-administered sexual activity questionnaires to gather information about noninstitutionalized men aged 40 to 70 years in cities near Boston.
      • Feldman HA
      • Goldstein I
      • Hatzichristou DG
      • Krane RJ
      • McKinlay JB
      Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study.
      During a 9-year follow-up study of 513 of these men who had no ED at the first study, the risk of new-onset ED was analyzed.
      • Feldman HA
      • Johannes CB
      • Derby CA
      • et al.
      Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts Male Aging Study.
      The MMAS found the total prevalence of minimal to severe ED to be 52% and estimated that more than 617,000 new cases were expected to occur annually in the United States.
      • Feldman HA
      • Goldstein I
      • Hatzichristou DG
      • Krane RJ
      • McKinlay JB
      Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study.
      • Kloner RA
      Erectile dysfunction and cardiovascular risk factors.
      A 1985 study found that ED accounted for 400,000 outpatient visits and 30,000 hospital admissions per year in the United States, with a direct total cost of $146 million.
      • Feldman HA
      • Goldstein I
      • Hatzichristou DG
      • Krane RJ
      • McKinlay JB
      Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study.
      By 1996, fueled by the availability of the new oral agent sildenafil, the number of outpatient visits for ED as estimated by the National Ambulatory Medical Care Survey had increased to 1.3 million per year.
      • Feldman HA
      • Johannes CB
      • Derby CA
      • et al.
      Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts Male Aging Study.
      Aside from the economic costs, ED can have severe psychological effects, resulting in poor self-image, decreased self-esteem, depression, and mental stress, and negative effects on personal relationships.
      • NIH Consensus Development Panel on Impotence
      NIH Consensus Conference: impotence.
      Penile erectile function is the result of a complex interplay between vascular, neurologic, hormonal, and psychological factors.
      • Virag R
      • Bouilly P
      • Frydman D
      Is impotence an arterial disorder? a study of arterial risk factors in 440 impotent men.
      Attainment and maintenance of a firm erection requires good arterial inflow of blood and efficient trapping of venous outflow. Therefore, disease processes that affect the function of the arterial and venous systems would be expected to negatively affect erectile function. Unfortunately, cardiovascular disease is also prevalent in the male population and is especially evident with increasing age. The interplay of cardiovascular health and sexual function includes the risk of cardiac events precipitated by the physical exertion of sexual activity and by some medications, such as sildenafil, on the cardiovascular system. An estimated 500,000 patients survive a myocardial infarction each year in the United States, and an estimated 11 million patients have existing cardiovascular disease, making the issue of sexual function and cardiac disease relevant to many patients.
      • Muller JE
      • Mittleman A
      • Maclure M
      • Sherwood JB
      • Tofler GH
      • Determinants of Myocardial Infarction Onset Study Investigators
      Triggering myocardial infarction by sexual activity: low absolute risk and prevention by regular physical exertion.

      NORMAL ERECTILE FUNCTION

      In the absence of sexual stimulation, the penis is kept in a flaccid state by a baseline sympathetic tone originating in the interomediolateral gray matter of the thoracolumbar spinal cord.
      • Andersson K
      • Stief C
      Penile erection and cardiac risk: pathophysiologic and pharmacologic mechanisms.
      Penile sympathetic stimulation flows through several pathways, including the sympathetic chain ganglia, which also supply such structures as the heart and vascular system. Sympathetic tone precipitates release of norepinephrine from penile adrenergic nerves, resulting in tonic contraction of cavernosal smooth muscle and its vasculature, thereby keeping the penis flaccid.
      • Andersson K
      • Stief C
      Penile erection and cardiac risk: pathophysiologic and pharmacologic mechanisms.
      Norepinephrine also likely inhibits the release of nitric oxide (NO), thereby further inhibiting stimulation of erections.
      Sexual stimulation results in an increase in parasympathetic activity that overrides the basal sympathetic tone.
      • Andersson K
      • Stief C
      Penile erection and cardiac risk: pathophysiologic and pharmacologic mechanisms.
      Erections result from relaxation of the corpora cavernosa, which is mediated either by increasing intracellular cyclic guanosine monophosphate (cGMP) or cyclic adenosine monophosphate or by inhibition of their degradation. Increased parasympathetic tone results in a decrease in norepinephrine release and an increase in the release of acetylcholine; subsequently, NO synthase activity increases, which releases NO from both endothelial cells and nonadrenergic, noncholinergic neurons.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      Increased NO levels stimulate guanylate cyclase, which elevates intracellular levels of cGMP.
      • Andersson K
      • Stief C
      Penile erection and cardiac risk: pathophysiologic and pharmacologic mechanisms.
      Increased cGMP levels cause intracellular calcium levels to decrease, resulting in relaxation of the corporeal smooth muscle, active dilatation of the penile arteries, arterioles, and sinusoids, and finally, increased arterial inflow and passive compression of penile venous outflow.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      • Nehra A
      Intracavernosal therapy: when oral agents fail.
      • Rampin O
      • Giuliano F
      Central control of the cardiovascular and erection systems: possible mechanisms and interactions.
      Erectile function relies on the arterial blood supply from the internal pudendal arteries, which are branches of the hypogastric arterial system (Figure 1). Substantial increases in internal pudendal arterial flow result in pressures within the penis that are comparable to systemic arterial levels.
      • Rampin O
      • Giuliano F
      Central control of the cardiovascular and erection systems: possible mechanisms and interactions.
      Withdrawal of sexual stimulation causes a return of sympathetic tone and degradation of cGMP, predominantly by phosphodiesterase type 5 (PDE-5) within the trabecular smooth muscle.
      • Nehra A
      Intracavernosal therapy: when oral agents fail.
      Figure thumbnail gr1
      Figure 1Penile arterial supply (top) and venous drainage (middle), longitudinal views. Bottom, Transverse and longitudinal views of venous return. From Lue TF. Physiology of penile erection and pathophysiology of erectile dysfunction and priapism. In: Walsh PC, Retik AB, Vaughan ED Jr, Wein AJ, eds. Campbell's Urology. Vol 2. 7th ed. Philadelphia, Pa: WB Saunders Co; 1998:1157-1179. With permission from Elsevier.

      ASSOCIATION OF CARDIOVASCULAR RISK FACTORS AND ED

      The relationship between cardiovascular disease and ED is well documented.
      • Chung WS
      • Shim BS
      • Park YY
      Hemodynamic insult by vascular risk factors and pharmacologic erection in men with erectile dysfunction: Doppler sonography study.
      Risk factors for cardiovascular disease include diabetes mellitus, obesity, physical inactivity, hyperlipidemia, tobacco use, and hypertension. Often, the relative risk of each of these factors in the development of ED is difficult to assess because many patients with ED and cardiovascular disease have more than 1 risk factor. Another important consideration is the effect of cardiac disease itself on erectile function. A history of a prior myocardial infarction was not found to be a significant independent risk factor for ED in a study comparing sexual function in 50 patients who had a prior myocardial infarction with a control group of 50 patients.
      • Dhabuwala CB
      • Kumar A
      • Pierce JM
      Myocardial infarction and its influence on male sexual function.
      When matched for age, hypertension, diabetes, and tobacco use, no significant difference was noted in the presence of ED (42% in the myocardial infarction group vs 48% in the control group). However, the presence of severe congestive heart failure has been associated with increased ED. A study of 80 patients with New York Heart Association class III/IV congestive heart failure found that 40% of these patients had complete ED, and another 40% had either mild or moderate ED.
      • Taylor Jr, HA
      Sexual activity and the cardiovascular patient: guidelines.
      The common associations between cardiovascular disease and ED have led some researchers to explore whether onset of ED can be an effective predictor of the presence of cardiovascular disease. A study of 40 patients with cardiac disease found an association between sexual dysfunction and the presence of cardiovascular disease, as well as a correlation between the severity of ED and the number of coronary arteries with extensive atherosclerosis.
      • Greenstein A
      • Chen J
      • Miller H
      • Matzkin H
      • Villa Y
      • Braf Z
      Does severity of ischemic coronary disease correlate with erectile function?.
      In another study, 60 patients underwent stress exercise cardiovascular testing and Doppler ultrasonography for measurement of their cavernosal artery peak systolic velocity (PSV).
      • Kawanishi Y
      • Lee KS
      • Kimura K
      • et al.
      Screening of ischemic heart disease with cavernous artery blood flow in erectile dysfunctional patients.
      This study found that the mean PSV was a better predictor of the presence of cardiovascular disease than stratification by standard cardiac risk factors such as diabetes mellitus, hypertension, obesity, and smoking. The researchers recommended that persons with no history of prior perineal trauma and with a PSV lower than 35 mL/s should undergo exercise testing before receiving treatment of ED because these patients had a 42% risk of having ischemic heart disease. However, other investigators questioned the utility of using penile arterial flow to predict the presence of ischemic heart disease.
      • Chiu AW
      • Chen KK
      • Chen MT
      • Chang LS
      • Chang MS
      Penile brachial index in impotent patients with coronary artery disease.
      They evaluated 40 patients with coronary artery disease who underwent coronary artery catheterization and whose penile brachial index (PBI) was measured by Doppler ultrasonography. Although a positive correlation was noted between the PBI and the severity of coronary artery obstruction, the relationship was not strong. Also, the degree of PBI abnormality did not effectively stratify the patients according to the severity of their coronary artery blockage. This study concluded that the PBI used alone would not be an effective predictor of ischemic heart disease.

      Diabetes Mellitus

      Diabetes mellitus is associated with both decreased erectile function and increased cardiovascular risk. The MMAS found that the age-adjusted probability of complete impotence was 3 times higher in patients with diabetes mellitus than in those without the disease.
      • Kloner RA
      Erectile dysfunction and cardiovascular risk factors.
      A survey of 1128 male patients showed that the 317 patients who had diabetes mellitus had a higher incidence of ED than their age-matched nondiabetic counterparts.
      • Newman HF
      • Marcus H
      Erectile dysfunction in diabetes and hypertension.
      A survey of 541 diabetic patients between the ages of 20 and 59 years found that 35% had ED.
      • McCulloch DK
      • Campbell IW
      • Wu FC
      • Prescott RJ
      • Clarke BF
      The prevalence of diabetic impotence.
      In a study of 365 diabetic patients, 75% had ED by age 65 years.
      • Klein R
      • Klein BE
      • Lee KE
      • Moss SE
      • Cruickshanks KJ
      Prevalence of self-reported erectile dysfunction in people with long-term IDDM.
      Incidence increased notably with age in this patient cohort: only 1.1% of diabetic men aged 21 to 30 years had ED compared with 47.1% of all diabetic patients older than 43 years. Diabetic patients often have other cardiovascular risk factors that may play a role in the development of ED. However, in an analysis of the PBI in 441 patients with ED and various cardiovascular risk factors (diabetes mellitus, hypertension, hyperlipidemia, tobacco use), diabetes was the only risk factor that was significantly and independently associated with a decrease in the PBI.
      • Virag R
      • Bouilly P
      • Frydman D
      Is impotence an arterial disorder? a study of arterial risk factors in 440 impotent men.
      Diabetes mellitus impairs both sensory and vascular function.
      • Feldman HA
      • Goldstein I
      • Hatzichristou DG
      • Krane RJ
      • McKinlay JB
      Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study.
      • Whitehead ED
      • Klyde BJ
      Diabetes-related impotence in the elderly.
      Diabetes was found to play a major role in vasculogenic impotence in a study of 265 patients with ED who underwent color duplex ultrasonography of the cavernosal arteries after intracavernosal injection of prostaglandin E1.
      • Chung WS
      • Shim BS
      • Park YY
      Hemodynamic insult by vascular risk factors and pharmacologic erection in men with erectile dysfunction: Doppler sonography study.
      Patients with vascular risk factors (diabetes mellitus, hypertension, heart disease, and hyperlipidemia) had significantly decreased peak systolic velocities and increased end-diastolic velocities. Patients with diabetes mellitus had increased end-diastolic velocities and decreased resistive indices, indicating a disorder of venous trapping during erections. Another study examined corpora cavernosal tissue removed at penile prosthesis placement in 21 diabetic men and 42 nondiabetic controls.
      • Saenz de Tejada I
      • Goldstein I
      • Azadzoi K
      • Krane RJ
      • Cohen RA
      Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence.
      Subsequent in vitro electrical stimulation of these tissue samples showed decreased neurogenic and endothelium-dependent smooth muscle relaxation in the tissue from the patients with diabetes. These effects persisted even after controlling for smoking and hypertension. Other studies have shown a heightened smooth muscle tone in patients with diabetes mellitus.
      • Christ GJ
      • Stone B
      • Melman A
      Age-dependent alterations in the efficacy of phenylephrine-induced contractions in vascular smooth muscle isolated from the corpus cavernosum of impotent men.
      Gonadal dysfunction has been suggested as contributing to the development of ED in diabetic patients.
      • Whitehead ED
      • Klyde BJ
      Diabetes-related impotence in the elderly.
      Onset of ED with diabetes mellitus has been correlated with the presence of proliferative retinopathy and symptomatic autonomic neuropathy, as shown by a loss of vibratory sensation.
      • Kloner RA
      Erectile dysfunction and cardiovascular risk factors.
      • McCulloch DK
      • Campbell IW
      • Wu FC
      • Prescott RJ
      • Clarke BF
      The prevalence of diabetic impotence.
      Additionally, the presence of nephropathy has been correlated with onset of ED, as has the length of time the patient has had diabetes; most of these patients experience ED within 10 years of being diagnosed as having insulin-dependent or non–insulin-dependent diabetes mellitus.
      • Feldman HA
      • Goldstein I
      • Hatzichristou DG
      • Krane RJ
      • McKinlay JB
      Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study.
      • McCulloch DK
      • Campbell IW
      • Wu FC
      • Prescott RJ
      • Clarke BF
      The prevalence of diabetic impotence.
      Glycemia, as measured by glycosylated hemoglobin, also has been associated with the risk of developing ED in diabetic patients.
      • Klein R
      • Klein BE
      • Lee KE
      • Moss SE
      • Cruickshanks KJ
      Prevalence of self-reported erectile dysfunction in people with long-term IDDM.

      Obesity and Physical Inactivity

      The relationship between obesity and ED has been difficult to ascertain because of the intimate association between obesity and diabetes mellitus.
      • Feldman HA
      • Johannes CB
      • Derby CA
      • et al.
      Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts Male Aging Study.
      The MMAS 9-year follow-up study has shown that a body mass index of 28 kg/m2 or higher was an independent predictor for ED, with an adjusted odds ratio of 1.96.
      • Feldman HA
      • Johannes CB
      • Derby CA
      • et al.
      Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts Male Aging Study.
      Central obesity is inversely related to levels of circulating androgens, which may contribute independently to the development of ED. Physical inactivity also is closely related to these issues of obesity and overall cardiovascular health.

      Hyperlipidemia

      Hyperlipidemia has been implicated in the development of ED by several different mechanisms. Hyperlipidemia is associated with development of atherosclerotic blood vessel disease, thus contributing to vasculogenic impotence. Penile vascular changes have been noted in impotent patients with elevated serum lipids.
      • Virag R
      • Bouilly P
      • Frydman D
      Is impotence an arterial disorder? a study of arterial risk factors in 440 impotent men.
      In a prospective review of 3250 men aged 26 to 83 years without ED at their first examination, total cholesterol and high-density lipoprotein (HDL) cholesterol levels were found to be strongly predictive of onset of ED after controlling for age, diabetes mellitus, stress level, cardiovascular disease, and prostate disease.
      • Wei M
      • Macera CA
      • Davis DR
      • Hornung CA
      • Nankin HR
      • Blair SN
      Total cholesterol and high density lipoprotein cholesterol as important predictors of erectile dysfunction.
      The risk of ED was 1.83 times higher in men with a total cholesterol level greater than 240 mg/dL as opposed to less than 180 mg/dL. Also, an HDL cholesterol level greater than 60 mg/dL was found to be protective against the development of ED. In the MMAS, HDL cholesterol levels were noted to have an inverse relationship with the presence of ED.
      • Feldman HA
      • Goldstein I
      • Hatzichristou DG
      • Krane RJ
      • McKinlay JB
      Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study.
      The 9-year follow-up MMAS study also found that self-reported increased cholesterol and unsaturated fat intake correlated positively with the development of ED.
      • Feldman HA
      • Johannes CB
      • Derby CA
      • et al.
      Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts Male Aging Study.

      Tobacco Use

      Cigarette smoking is an established risk factor in the development of atherosclerotic vascular changes and thus would be expected to play a role in the development of vasculogenic ED. The MMAS 9-year follow-up study found that the risk of developing moderate or complete ED in smokers was nearly doubled (odds ratio, 1.97) compared with that in matched nonsmokers.
      • Feldman HA
      • Johannes CB
      • Derby CA
      • et al.
      Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts Male Aging Study.
      After adjusting for age, vascular disease, psychiatric disease, hormonal factors, and marital status, a study of 4462 US Army veterans aged 31 to 49 years found an odds ratio of 1.8 for the risk of developing ED in men who smoked.
      • Mannino DM
      • Klevens RM
      • Flanders WD
      Cigarette smoking: an independent risk factor for impotence?.
      Interestingly, this study found no association between erectile function and the number of years or packs per day of cigarette use. In contrast, a study of 314 current smokers with ED found that the number of cigarettes smoked inversely correlated with penile rigidity as measured by nocturnal penile tumescence.
      • Hirshkowitz M
      • Karacan I
      • Howell JW
      • Arcasoy MO
      • Williams RL
      Nocturnal penile tumescence in cigarette smokers with erectile dysfunction.
      Also, cigar smoking and passive exposure to cigarette smoke have been shown to significantly predict onset of ED.
      • Feldman HA
      • Johannes CB
      • Derby CA
      • et al.
      Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts Male Aging Study.
      Adverse penile vascular changes associated with cigarette smoking have been shown in several studies.
      • Chung WS
      • Shim BS
      • Park YY
      Hemodynamic insult by vascular risk factors and pharmacologic erection in men with erectile dysfunction: Doppler sonography study.
      After controlling for age, trauma, hypertension, and diabetes mellitus, a study of 97 young patients with ED who underwent selective pudendal angiography showed a significant relationship between lifetime cigarette smoking and the degree of internal pudendal and common penile arterial atherosclerosis.
      • Rosen MP
      • Greenfield AJ
      • Walker TG
      • et al.
      Cigarette smoking: an independent risk factor for atherosclerosis in the hypogastric-cavernous arterial bed of men with arteriogenic impotence.
      Tobacco use was associated with altered penile arterial flow changes in 440 patients with ED as measured by duplex ultrasonography.
      • Virag R
      • Bouilly P
      • Frydman D
      Is impotence an arterial disorder? a study of arterial risk factors in 440 impotent men.
      Other candidate mechanisms linking ED and cigarette smoking include hypercoagulability and increased platelet aggregation, increased release of free fatty acids and catecholamines, changes in NO synthetic pathways, and a possible direct toxic effect on vascular endothelium.
      • Chung WS
      • Shim BS
      • Park YY
      Hemodynamic insult by vascular risk factors and pharmacologic erection in men with erectile dysfunction: Doppler sonography study.
      • Xie Y
      • Garban H
      • Ng C
      • Rajfer J
      • Gonzalez-Cadavid NF
      Effect of long-term passive smoking on erectile function and penile nitric oxide synthase in the rat.

      Hypertension

      The relationship between hypertension and erectile function, often complicated by the effects of antihypertensive medications, has not been established definitively.
      • Feldman HA
      • Johannes CB
      • Derby CA
      • et al.
      Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts Male Aging Study.
      Possible etiologies for ED secondary to hypertension include vascular damage due to hypertensive changes as well as hormonal abnormalities such as elevated prolactin levels.
      • Jaffe A
      • Chen Y
      • Kisch ES
      • Fischel B
      • Alon M
      • Stern N
      Erectile dysfunction in hypertensive subjects: assessment of potential determinants.
      A study of 24 patients with ED and untreated essential hypertension showed decreased levels of free and total serum testosterone compared with normal controls.
      • Hughes GS
      • Mathur RS
      • Margolius HS
      Sex steroid hormones are altered in essential hypertension.
      These hormonal findings were supported by a study of 1132 men aged 30 to 79 years that found an inverse relationship between blood pressure and serum testosterone levels.
      • Khaw KT
      • Barrett-Connor E
      Blood pressure and endogenous testosterone in men: an inverse relationship.
      The MMAS 9-year follow-up study found that hypertension was an independent, although modest, predictor of ED.
      • Feldman HA
      • Johannes CB
      • Derby CA
      • et al.
      Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts Male Aging Study.
      Sleep studies in 175 patients with hypertension and erectile problems showed significantly lower penile rigidity measured by strain gauge plethysmography compared with 110 normotensive male controls with similar subjective erectile problems.
      • Hirshkowitz M
      • Karacan I
      • Gurakar A
      • Williams RL
      Hypertension, erectile dysfunction, and occult sleep apnea.
      In comparison, a study of 132 patients evaluated by penile duplex ultrasonography after intracorporeal papaverine injection found that hypertension alone was not an independent risk factor for vasculogenic ED.
      • Shabsigh R
      • Fishman IJ
      • Schum C
      • Dunn JK
      Cigarette smoking and other vascular risk factors in vasculogenic impotence.
      A study of 1128 patients aged 16 to 80 years found only a “meagre” relationship between hypertension and ED.
      • Newman HF
      • Marcus H
      Erectile dysfunction in diabetes and hypertension.
      After controlling for diabetes mellitus, tobacco use, and hyperlipidemia, hypertension was not found to be an independent predictor of vasculogenic ED in 440 impotent men as measured by the PBI.
      • Virag R
      • Bouilly P
      • Frydman D
      Is impotence an arterial disorder? a study of arterial risk factors in 440 impotent men.
      Another study evaluated 32 hypertensive men with ED and 78 normotensive men with ED with regard to age, body mass index, hormonal profile, penile arterial flow, risk factors for arterial disease, psychiatric disease, and neurologic disease measured by pudendal nerve conduction studies.
      • Jaffe A
      • Chen Y
      • Kisch ES
      • Fischel B
      • Alon M
      • Stern N
      Erectile dysfunction in hypertensive subjects: assessment of potential determinants.
      This study found that, although hypertensive patients had more coronary artery disease, no direct evidence supported an association between hypertension and arteriogenic impotence, as measured by the PBI, peak systolic velocity, and resistive index, in patients with mild to moderate hypertension.

      CARDIOVASCULAR MEDICATIONS AND ED

      Medications used in the treatment of cardiovascular disease, especially antihypertensive medications, have been implicated frequently in the development of sexual dysfunction. A study of 5485 patients in the Hypertension Detection and Follow-up Program found that, during a 5-year period, 8.3% of male hypertensive patients stopped taking their antihypertensive medications secondary to sexual adverse effects.
      • Curb JD
      • Borhani NO
      • Blaszkowski TP
      • Zimbaldi N
      • Fotiu S
      • Williams W
      Long-term surveillance for adverse effects of antihypertensive drugs.
      Almost every class of antihyper-tensive medication has been implicated in causing ED; however, most of these studies, published as case reports or patient surveys, have been relatively subjective and uncontrolled.
      • Feldman HA
      • Goldstein I
      • Hatzichristou DG
      • Krane RJ
      • McKinlay JB
      Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study.
      • Wein AJ
      • Van Arsdalen KN
      Drug-induced male sexual dysfunction.
      To implicate a medication as a cause of ED, a study must show a reproducible dose-related effect that stops after the medication is discontinued.
      • Wein AJ
      • Van Arsdalen KN
      Drug-induced male sexual dysfunction.
      Unfortunately, few such studies exist.
      The mechanisms of action by which antihypertensive medications cause ED are currently unknown. Some investigators have theorized that antihypertensive medications affect erectile function by decreasing blood pressure, which reduces the perfusion pressure needed to maintain sufficient blood flow for erections through atherosclerotic penile arteries.
      • Benet AE
      • Melman A
      The epidemiology of erectile dysfunction.
      However, other studies have noted that, when blood pressure levels are monitored after initiation of antihypertensive therapy, changes in blood pressure level are not correlated with sexual function.
      • Rosen RC
      • Kostis JB
      • Jekelis A
      • Taska LS
      Sexual sequelae of antihypertensive drugs: treatment effects on self-report and physiological measures in middle-aged male hypertensives.
      Also, if lower blood pressure level was the primary etiology of ED, all classes of antihypertensive agents should be expected to have relatively similar effects on erectile function because of their efficacy in lowering pressure, which has not been seen.
      • Kloner RA
      Erectile dysfunction and cardiovascular risk factors.
      Other investigators have suggested these medications may exert a hormonal effect. β-Blockers have been associated with decreased free and total testosterone levels in placebo-controlled trials.
      • Rosen RC
      • Weiner DN
      Cardiovascular disease and sleep-related erections.
      Digoxin and some diuretics such as spironolactone have been associated with decreased levels of circulating androgens.
      • Wein AJ
      • Van Arsdalen KN
      Drug-induced male sexual dysfunction.
      • Horowitz JD
      • Goble AJ
      Drugs and impaired male sexual function.
      • Neri A
      • Aygen M
      • Zukerman Z
      • Bahary C
      Subjective assessment of sexual dysfunction of patients on long-term administration of digoxin.
      β-Blockers often have been cited as one of the medications most frequently associated with onset of ED.
      • Kloner RA
      Erectile dysfunction and cardiovascular risk factors.
      Different classes of β-blockers have been postulated to have differential effects on erectile function, with the nonselective β-blockers (eg, propranolol) having more deleterious effects than the more cardioselective medications (eg, atenolol, metoprolol).
      • Weiss RJ
      Effects of antihypertensive agents on sexual function.
      A dose-related phenomenon with propranolol use was suggested by another study, which showed that patients receiving propranolol dosages exceeding 120 mg/d developed ED at a higher rate than patients who received lower dosages of the same medication.
      • Warren SC
      • Warren SG
      Propranolol and sexual impotence [letter].
      In comparison, a randomized placebo-controlled trial of 65 patients given either placebo or 95 mg/d of sustained-release metoprolol for 4 months after percutaneous coronary angioplasty found no significant difference in sexual function between the 2 groups.
      • Franzen D
      • Metha A
      • Seifert N
      • Braun M
      • Hopp HW
      Effects of beta-blockers on sexual performance in men with coronary heart disease: a prospective, randomized and double blinded study.
      Centrally acting antihypertensive agents such as clonidine and methyldopa also affect sexual function.
      • Kloner RA
      Erectile dysfunction and cardiovascular risk factors.
      • Rosen RC
      • Weiner DN
      Cardiovascular disease and sleep-related erections.
      These medications cause intracavernosal pressure changes in animal models, and human studies have noted deleterious effects on erectile function, decreased libido, and ejaculatory problems.
      • Weiss RJ
      Effects of antihypertensive agents on sexual function.
      • Srilatha B
      • Adaikan PG
      • Arulkumaran S
      • Ng SC
      Sexual dysfunction related to antihypertensive agents: results from the animal model.
      Drugs that cause sexual dysfunction: an update.
      Postulated mechanisms of effect on sexual function with these centrally acting medications have included increased prolactin levels and a direct effect on α2-adrenergic receptors in the central nervous system.
      • Wein AJ
      • Van Arsdalen KN
      Drug-induced male sexual dysfunction.
      • Mroczek WJ
      • Davidov M
      • Finnerty Jr, FA
      Prolonged treatment with clonidine: comparative antihypertensive effects alone and with a diuretic agent.
      Diuretics, especially thiazides, have been identified traditionally as common causes of new-onset ED.
      • Kloner RA
      Erectile dysfunction and cardiovascular risk factors.
      • Bansal S
      Sexual dysfunction in hypertensive men: a critical review of the literature.
      • McCarron DA
      Diuretic therapy for mild hypertension: the “real” cost of treatment.
      However, there has been disagreement regarding the effects of diuretics on erectile function; many studies found that only rarely have these medications been implicated convincingly as the cause of a patient's ED.
      • Wein AJ
      • Van Arsdalen KN
      Drug-induced male sexual dysfunction.
      An exception is spironolactone, which exerts an antiandrogen effect and can cause gynecomastia and ED in a small percentage of patients.
      • Wein AJ
      • Van Arsdalen KN
      Drug-induced male sexual dysfunction.
      • Horowitz JD
      • Goble AJ
      Drugs and impaired male sexual function.
      α-Blocking agents have been implicated as a cause of ED in some studies, whereas other studies have reported minimal effects on erectile function.
      • Weiss RJ
      Effects of antihypertensive agents on sexual function.
      • Meinhardt W
      • Kropman RF
      • Vermeij P
      • Nijeholt AA
      • Zwartendijk J
      The influence of medication on erectile function.
      • DeBusk R
      • Drory Y
      • Goldstein I
      • et al.
      Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel.
      However, α-blockers are a well-known cause of retrograde ejaculation secondary to a reversible relaxation of bladder neck smooth muscle.
      • Meinhardt W
      • Kropman RF
      • Vermeij P
      • Nijeholt AA
      • Zwartendijk J
      The influence of medication on erectile function.
      Digoxin also has been associated with increased rates of ED, decreased libido, and decreased sexual frequency.
      • Wein AJ
      • Van Arsdalen KN
      Drug-induced male sexual dysfunction.
      • Neri A
      • Aygen M
      • Zukerman Z
      • Bahary C
      Subjective assessment of sexual dysfunction of patients on long-term administration of digoxin.
      The 2 classes of medications least associated with ED are calcium channel blockers and angiotensin-converting enzyme inhibitors.
      Drugs that cause sexual dysfunction: an update.
      • DeBusk R
      • Drory Y
      • Goldstein I
      • et al.
      Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel.
      Although some case studies have reported a relationship between calcium channel blockers and ED, most studies suggest that this effect is minimal and that any relationship is likely secondary to a decrease in blood pressure with consequent reflex sympathetic activation.
      • Weiss RJ
      Effects of antihypertensive agents on sexual function.
      • Meinhardt W
      • Kropman RF
      • Vermeij P
      • Nijeholt AA
      • Zwartendijk J
      The influence of medication on erectile function.
      • King BD
      • Pitchon R
      • Stern EH
      • Schweitzer P
      • Schneider RR
      • Weiner I
      Impotence during therapy with verapamil.
      Angiotensin-converting enzyme inhibitors also have low rates of secondary ED associated with their use in both animal and human studies.
      • Srilatha B
      • Adaikan PG
      • Arulkumaran S
      • Ng SC
      Sexual dysfunction related to antihypertensive agents: results from the animal model.
      Drugs that cause sexual dysfunction: an update.
      • Meinhardt W
      • Kropman RF
      • Vermeij P
      • Nijeholt AA
      • Zwartendijk J
      The influence of medication on erectile function.
      Other medications used often by patients with cardiovascular disease may affect erectile function. Lipid-lowering agents have been reported to cause ED.
      • Bruckert E
      • Giral P
      • Heshmati HM
      • Turpin G
      Men treated with hypolipidaemic drugs complain more frequently of erectile dysfunction.
      However, a double-blind, placebo-controlled study of 22 middle-aged men with hypercholesterolemia treated for 6 weeks with pravastatin or lovastatin showed improved erectile function with both medications.
      • Kostis JB
      • Rosen RC
      • Wilson AC
      Central nervous system effects of HMG CoA reductase inhibitors: lovastatin and pravastatin on sleep and cognitive performance in patients with hypercholesterolemia.
      In study patients taking these medications compared with controls, significant decreases in total cholesterol and low-density lipoprotein cholesterol levels were found, as well as significant increases in length of maximal tumescence per nocturnal penile tumescence testing at 2 weeks. Hypoglycemia secondary to the use of insulin or hypoglycemic agents may result in ED or orgasmic dysfunction.
      • Feldman HA
      • Goldstein I
      • Hatzichristou DG
      • Krane RJ
      • McKinlay JB
      Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study.
      Antidepressant medications, especially tricyclics, also have been associated with increased ED.
      Drugs that cause sexual dysfunction: an update.

      TREATMENT OF ED

      Overview

      The ability to achieve an erection can often be enhanced by pharmacotherapy or surgery in patients with cardiovascular disease. Studies show that up to 90% of healthy men aged 70 to 90 years are interested in sexual activity.
      • Taylor Jr, HA
      Sexual activity and the cardiovascular patient: guidelines.
      Erectile dysfunction secondary to cardiovascular disease often responds well to the standard ED treatments developed over the past few decades. Penile prosthesis implantation was developed in the 1970s, followed by intracavernosal injections of vasoactive agents, including papaverine, phentolamine, and prostaglandin E1, introduced in the 1980s.
      • Nehra A
      Intracavernosal therapy: when oral agents fail.
      • Altwein JE
      • Keuler FU
      Oral treatment of erectile dysfunction with apomorphine SL.
      Another treatment option is mechanical vacuum erection devices. In 1997, transurethral insertion of prostaglandin E1 was made available.
      • Nehra A
      Intracavernosal therapy: when oral agents fail.
      Early oral agents include the α-blocker yohimbine, which is primarily effective only for psychogenic impotence.
      • Altwein JE
      • Keuler FU
      Oral treatment of erectile dysfunction with apomorphine SL.
      Apomorphine is another oral agent that works by activation of central dopamine receptors.
      • Altwein JE
      • Keuler FU
      Oral treatment of erectile dysfunction with apomorphine SL.
      Apomorphine does not appear to have any notable cardiovascular adverse effects and has been used successfully in Europe. However, apomorphine use has been associated with other unpleasant adverse effects such as nausea and emesis, and the drug has not been approved by the US Food and Drug Administration (FDA) for use in the United States.

      Oral PDE-5 Inhibitors

      Oral PDE-5 inhibitors revolutionized the treatment of ED when sildenafil was released after receiving US FDA approval in March 1998.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      Since then, several other oral PDE-5 inhibitors have been developed, including vardenafil and tadalafil, which generated considerable interest in both the scientific and lay communities. There was also much concern about their safety, especially in men with cardiovascular disease. Compared with the 2 newer PDE-5 inhibitors vardenafil and tadalafil, sildenafil has been available for a much longer time; therefore, the vast majority of published cardiovascular safety studies have been performed on this medication. Recommended starting and maximum doses of oral PDE-5 inhibitors are shown in Table 1.
      Table 1Recommended Starting and Maximum Doses of Oral PDE-5 Inhibitors
      PDE-5 = phosphodiesterase type 5.
      PDE-5 inhibitorRecommended starting dose
      Recommended starting doses may be decreased in patients with certain medical comorbidities.
      (mg)
      Maximum recommended dose (mg)
      Sildenafil50100
      Vardenafil1020
      Tadalafil1020
      * PDE-5 = phosphodiesterase type 5.
      Recommended starting doses may be decreased in patients with certain medical comorbidities.

      Sildenafil.

      Sildenafil was the first oral agent deemed safe and effective for treatment of ED, thereby offering impotent men a less invasive and therefore more attractive treatment option.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      Originally evaluated as a mild preload reducer and antianginal agent in its early phases of development, sildenafil's effect on male and female genitalia became quickly apparent.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      Sildenafil is a selective inhibitor of PDE-5 and has a half-life of approximately 4 hours.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      Phosphodiesterase type 5 is found predominantly in the smooth muscle of the corpora cavernosa but can be found in smaller quantities in platelets and other vascular smooth muscle.
      • Wallis RM
      • Corbin JD
      • Francis SH
      • Ellis P
      Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro.
      Phosphodiesterase type 5 is primarily responsible for the breakdown of cGMP in cavernosal tissues. The inhibition of PDE-5 by sildenafil therefore causes continued activation of the NO-cGMP pathway in the cavernosal tissue, thereby improving erectile function.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      Sildenafil is taken orally 1 hour before anticipated sexual intercourse and enhances the normal response to sexual stimulation; however, it has no effect on erections in the absence of stimulation.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      Sildenafil is absorbed rapidly, and peak plasma levels of 127 to 560 ng/mL are seen in a fasting state approximately 1 hour (range, 0.5-2 hours) after ingestion.
      • Zusman RM
      • Morales A
      • Glasser DB
      • Osterloh IH
      Overall cardiovascular profile of sildenafil citrate.
      Ninety-six percent of sildenafil is bound by plasma proteins and is metabolized by the liver.
      • Zusman RM
      • Morales A
      • Glasser DB
      • Osterloh IH
      Overall cardiovascular profile of sildenafil citrate.
      The efficacy of sildenafil in the treatment of ED has been established in more than 21 randomized placebocontrolled trials.
      • Kirby M
      • Jackson G
      • Betteridge J
      • Friedli K
      Is erectile dysfunction a marker for cardiovascular disease?.
      Treatment-related improvements in erections with sildenafil range between 70% and 90%, as opposed to 10% to 30% improvement with placebo.
      • Kirby M
      • Jackson G
      • Betteridge J
      • Friedli K
      Is erectile dysfunction a marker for cardiovascular disease?.
      In a double-blind, placebo-controlled study, sildenafil was effective in patients with diabetes mellitus.
      • Rendell MS
      • Rajfer J
      • Wicker PA
      • Smith MD
      • Sildenafil Diabetes Study Group
      Sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized controlled trial.
      Sildenafil also has good efficacy in patients with ischemic heart disease, as shown by a retrospective subanalysis of data from 11 double-blind, placebo-controlled studies involving 3672 patients with ED and ischemic heart disease who were not taking nitrates.
      • Kloner RA
      Cardiovascular risk and sildenafil.
      • Webb DJ
      • Freestone S
      • Allen MJ
      • Muirhead GJ
      Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist.
      Sildenafil has a relatively good safety profile with tolerable adverse effects and a low (<3%) incidence of adverse effects that lead to discontinuation of the medication.
      • Zusman RM
      • Morales A
      • Glasser DB
      • Osterloh IH
      Overall cardiovascular profile of sildenafil citrate.
      Most adverse effects are mild and are related primarily to vasodilation (headache, flushing, nasal congestion), gastrointestinal disturbances (dyspepsia), or retinal effects such as vision changes.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      Vision changes are described most frequently as an increased perception of bright lights, a blue-green tinge to observed colors, or blurred vision. Sildenafil has no direct effect on platelet function but potentiates the inhibitory effect of sodium nitroprusside on adenosine diphosphate–induced platelet aggregation ex vivo.
      • Wallis RM
      • Corbin JD
      • Francis SH
      • Ellis P
      Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro.
      Sildenafil has no effect on bleeding time or prothrombin time when used either alone or in patients taking aspirin or warfarin.
      • Nehra A
      • Colreavy F
      • Khandheria BK
      • Chandrasekaran K
      Sildenafil citrate, a selective phosphodiesterase type 5 inhibitor: urologic and cardiovascular implications.
      Rates of cardiac and noncardiovascular adverse effects related to sildenafil were similar in patients with a history of cardiovascular disease.
      • Kloner RA
      Cardiovascular risk and sildenafil.
      • Webb DJ
      • Freestone S
      • Allen MJ
      • Muirhead GJ
      Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist.
      Sildenafil should be used with caution in patients with liver dysfunction or renal impairment, as well as in patients taking any medications that inhibit the P-450 pathway such as cimetidine or erythromycin.
      • Zusman RM
      • Morales A
      • Glasser DB
      • Osterloh IH
      Overall cardiovascular profile of sildenafil citrate.
      Between March and November 1998, 6 million prescriptions for sildenafil were filled for approximately 3 million men.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      During this period, 130 deaths were reported to the US FDA; 41 of these men died or had cardiac arrest within 4 to 5 hours after taking sildenafil, and 27 died or had cardiac arrest either during or immediately after sexual activity. The average age of these men was 64 years. Of the 77 men in this group who died of documented cardiovascular-related events, 41 died of definite or suspected myocardial infarction, 27 died after cardiac arrest, and 6 had symptoms of cardiac disease at the time of death. Sixteen of the men had taken nitroglycerin or organic nitrates in association with sildenafil; another 3 had nitroglycerin in their possession at the time of death. In 48 men, the cause of death was unknown, and another 3 died of cerebrovascular accidents. Overall, it was concluded that sildenafil was not associated with an excess of cardiovascular death.
      The cardiovascular adverse effects of sildenafil use have been studied extensively. Phosphodiesterase type 5, although located primarily in the genitalia, also can be found throughout the systemic vasculature, although other PDEs predominate there
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      ; PDE-3 plays the primary role in the regulation of cardiac contractility.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      Sildenafil has a 4000-fold increased selectivity for PDE-5 over PDE-3, has negligible effects on heart rate, and has only a modest effect on blood pressure level in healthy persons, with an average systolic pressure decrease of 10 mm Hg with a single dose of 100 mg.
      • Zusman RM
      • Morales A
      • Glasser DB
      • Osterloh IH
      Overall cardiovascular profile of sildenafil citrate.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      • Wallis RM
      • Corbin JD
      • Francis SH
      • Ellis P
      Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro.
      The maximum decrease in blood pressure level was noted at 1 hour after the oral dose was taken and was correlated with peak plasma levels. The blood pressure level in these patients returned to baseline within 4 hours.
      • Wallis RM
      • Corbin JD
      • Francis SH
      • Ellis P
      Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro.
      In an open-label study, 8 patients monitored with a Swan-Ganz catheter were given a total of 40 mg of sildenafil in 4 intravenous transfusions (the equivalent of 1 to 3 times the plasma concentration after an oral dose of 100 mg).
      • Jackson G
      • Benjamin N
      • Jackson N
      • Allen MJ
      Effects of sildenafil citrate on human hemodynamics.
      Their mean resting systolic and diastolic blood pressure levels decreased by 6% and 11%, respectively, compared with baseline. These patients also experienced a mild decrease in mean resting right atrial pressure, pulmonary artery pressure, pulmonary artery occlusion pressure, and cardiac output. However, the hemodynamic response to exercise was preserved. Phase 2 and 3 trials showed no difference in the rate of adverse events between sildenafil and placebo in patients being treated with antihypertensive medications. The effects of sildenafil on blood pressure level were similar in patients who were taking antihypertensive medications compared with those who were not. In healthy volunteers, no consistent or significant doserelated electrocardiographic (ECG) changes were noted at 1 and 2 hours after doses of sildenafil ranging from 1.25 to 200 mg.
      • Zusman RM
      • Morales A
      • Glasser DB
      • Osterloh IH
      Overall cardiovascular profile of sildenafil citrate.
      No data suggested adverse interactions between sildenafil and other drugs commonly used in the treatment of coronary artery disease, such as aspirin, heparin, or narcotics.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      Phase 2 and 3 trials reported minimal associated cardiac adverse effects, which occurred in 3% of patients taking sildenafil and in 3.5% of patients receiving placebos.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      Rates of severe cardiovascular adverse effects were also similar at 1.7 per 1000 person-years of treatment with sildenafil compared with 1.0 events per 1000 personyears with placebo treatment.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      Open-label trials showed a myocardial infarction rate of only 1.0 event per 1000 person-years of treatment with sildenafil.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      In conclusion, sildenafil, when used alone, seems to produce minimal decreases in blood pressure level, which are well tolerated in healthy patients and in those with stable ischemic coronary disease.
      • Zusman RM
      • Morales A
      • Glasser DB
      • Osterloh IH
      Overall cardiovascular profile of sildenafil citrate.
      The cardiovascular effects of sildenafil during exercise in patients with known or probable cardiovascular disease were studied in a randomized placebo-controlled trial of 105 men with a mean age of 66 years.
      • Arruda-Olson AM
      • Mahoney DW
      • Nehra A
      • Leckel M
      • Pellikka PA
      Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease: a randomized crossover trial.
      All these men had ED and twice underwent symptom-limited supine bicycle exercise echocardiography 1 hour after taking either sildenafil (50 mg or 100 mg) or placebo. This study found no significant changes in resting heart rate, diastolic blood pressure level, or wall motion score index, and the exercise capacity of the 2 groups was similar. Both groups had similar numbers of patients who experienced dyspnea and/or chest pain, had a positive exercise echocardiographic test, and had exercise-induced wall motion abnormalities. Sildenafil caused a mean decrease of 7 mm Hg in the resting systolic blood pressure level compared with the placebo group. In conclusion, this study showed that in patients with stable coronary artery disease, sildenafil caused no change in symptoms, exercise endurance, or presence/extent of exercise-induced ischemia as measured by exercise echocardiography.
      The use of nitroglycerin or other NO-donor medications represents an absolute contraindication to sildenafil use or other PDE-5 inhibitors for ED.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      • Ishikura F
      • Beppu S
      • Hamada T
      • Khandheria BK
      • Seward JB
      • Nehra A
      Effects of sildenafil citrate (Viagra) combined with nitrate on the heart.
      Nitroglycerin is a vasodilator that is commonly used as an antianginal agent because of its ability to improve the imbalance between myocardial oxygen supply and demand.
      • Stamler JS
      • Loh E
      • Roddy MA
      • Currie KE
      • Creager MA
      Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans.
      Nitroglycerin and other NO donors work through the same NO-cGMP pathway that sildenafil affects, thereby decreasing vascular resistance and blood pressure level.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      When used in combination with NO-donor medications such as nitroglycerin, the modest blood pressure effects of sildenafil are potentiated, resulting in a significant decrease in systolic (21-55 mm Hg) and diastolic (up to 26 mm Hg) blood pressure levels, as well as vasodilatory symptoms such as headache, light-headedness, and nausea.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      The use of any NO-donor medications should be avoided for 24 hours after the last dose of sildenafil and even longer if there is a suspected prolonged half-life secondary to such conditions as renal insufficiency.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      Nitrates have only modest antianginal effects and offer no prognostic benefit for mild recurrent angina or unstable angina. Therefore, such anginal symptoms occurring after sildenafil use should be treated with other nonnitrate antianginal agents such as β-blockers.
      • Taylor Jr, HA
      Sexual activity and the cardiovascular patient: guidelines.
      • Jackson G
      Sexual intercourse and stable angina pectoris.
      Patients who experience myocardial infarction after sildenafil use should receive standard treatment, except for nitrate use.
      • Taylor Jr, HA
      Sexual activity and the cardiovascular patient: guidelines.
      Management of severe hypotension associated with sildenafil ingestion while receiving nitrate therapy is shown in Table 2.
      Table 2Management of Severe Hypotension in Patients Receiving Nitrate Therapy After Sildenafil Ingestion
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      • 1.
        Immediately stop nitrate therapy
      • 2.
        Tilt head 30°-40° lower than body (Trendelenburg position)
      • 3.
        Initiate aggressive fluid therapy
      • 4.
        Judiciously use intravenous α-adrenergic agonists (eg, phenylephrine)
      • 5.
        Consider use of α- and β-adrenergic agonists (eg, norepinephrine) to control blood pressure level; note that this could worsen cardiac ischemia
      • 6.
        Use intra-aortic balloon counterpulsation if necessary
      Current American College of Cardiology/American Heart Association guidelines quote an absolute contraindication to sildenafil use in the setting of chronic nitrate treatment or the use of short-acting nitrate medications.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      Another contraindication is the use of recreational drugs (“poppers”) that contain amyl nitrate. The guidelines also caution use in patients who have a high risk of cardiovascular effects, including patients with active coronary artery disease who are not taking nitrates, patients with congestive heart failure with a borderline low blood pressure level and low blood volume, or those with complicated multidrug antihypertensive regimens.
      Recent revised labeling for sildenafil states that there is a lack of controlled data for its use in patients with resting hypotension (<90/50 mm Hg) or hypertension (>170/110 mm Hg); a history of myocardial infarction, cerebrovascular accident, or life-threatening arrhythmia within the past 6 months; coronary artery disease or cardiac failure causing unstable angina; or retinitis pigmentosa and possible genetic disorders of retinal PDEs.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      Overall, sildenafil appears to be relatively safe and effective for treatment of ED in men with stable cardiovascular disease who are not taking NO-donor medications. In a study of 105 men with ED and known or likely coronary artery disease, patients underwent symptom-limited supine bicycle echocardiography 2 times after receiving either sildenafil or placebo.
      • Arruda-Olson AM
      • Mahoney DW
      • Nehra A
      • Leckel M
      • Pellikka PA
      Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease: a randomized crossover trial.
      This study concluded that patients who have stable coronary artery disease who can exercise to 4.5 metabolic equivalents (METs) with a negative or mildly positive stress test and without angina or hypotension can safely take sildenafil. Physicians who prescribe sildenafil should counsel their patients that, if they have chest pain or other cardiac symptoms with sexual intercourse, they should not take nitrates and should immediately call their physician.
      • Jackson G
      Sexual intercourse and stable angina pectoris.
      Similar counseling should be given with the newer agents of the PDE-5 inhibitor class.

      Vardenafil.

      The US FDA recently approved a second oral selective PDE-5 inhibitor for ED called vardenafil.
      Vardenafil (levitra) for erectile dysfunction.
      • Young JM
      Vardenafil.
      The time to peak serum concentration of vardenafil is 0.75 hour, comparable to that of sildenafil (1.16 hours).
      • Young JM
      Vardenafil.
      Vardenafil is metabolized by the liver and excreted mainly in the feces with an excretion half-life of 4.7 hours, only slightly longer than that of sildenafil (approximately 4 hours).
      Vardenafil (levitra) for erectile dysfunction.
      • Young JM
      Vardenafil.
      Vardenafil has been shown to be significantly more effective than placebo in the treatment of ED secondary to diabetes mellitus and after radical retropubic prostatectomy.
      • Goldstein I
      • Young JM
      • Fischer J
      • Bangerter K
      • Segerson T
      • Taylor T
      • Vardenafil Diabetes Study Group
      Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes: a multicenter double-blind placebo-controlled fixed-dose study.
      • Brock G
      • Nehra A
      • Lipschultz LI
      • et al.
      Safety and efficacy of vardenafil for the treatment of men with erectile dysfunction after radical retropubic prostatectomy.
      Several double-blind, placebo-controlled studies have shown vardenafil to be more effective than placebo in the treatment of ED secondary to a wide range of other etiologies as well.
      • Hellstrom WJ
      • Gittelman M
      • Karlin G
      • Vardenafil Study Group
      • et al.
      Sustained efficacy and tolerability of vardenafil, a highly potent selective phosphodiesterase type 5 inhibitor, in men with erectile dysfunction: results of a randomized, double-blind, 26-week placebo-controlled pivotal trial.
      • Porst H
      • Young JM
      • Schmidt AC
      • Buvat J
      • International Vardenafil Study Group
      Efficacy and tolerability of vardenafil for treatment of erectile dysfunction in patient subgroups.
      Several differences distinguish vardenafil from sildenafil. Unlike sildenafil, vardenafil can be taken after eating a moderately fatty meal and after consumption of alcohol, neither of which affects its pharmacokinetics.
      • Young JM
      Vardenafil.
      • Rajagopalan P
      • Mazzu A
      • Xia C
      • Dawkins R
      • Sundaresan P
      Effect of high-fat breakfast and moderate-fat evening meal on the pharmacokinetics of vardenafil, an oral phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction.
      Although both drugs share adverse-effect profiles of increased incidence of headaches, flushing, rhinitis, and dyspepsia, vardenafil use does not appear to be associated with any visual changes.
      • Young JM
      Vardenafil.
      Similar to sildenafil, vardenafil produces a slight hypotensive effect with an average maximal decrease in blood pressure level of 5 to 10 mm Hg.
      • Gresser U
      • Gleiter CH
      Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil—review of the literature.
      Like sildenafil, vardenafil may potentiate the hypotensive effects of nitrates; therefore, their combined use is contraindicated.
      Vardenafil (levitra) for erectile dysfunction.
      Unlike sildenafil, vardenafil has been associated with a slight prolongation of the QT interval and thus should not be used by patients with a congenital QT prolongation or by any patient currently taking antiarrhythmic medications.
      Vardenafil (levitra) for erectile dysfunction.
      Vardenafil also has been associated with an increased hypotensive effect of α-adrenergic blocking medications; therefore, their combined use is contraindicated.
      Vardenafil (levitra) for erectile dysfunction.
      This is important because many men with ED have concomitant benign prostatic enlargement with bladder outlet obstruction for which they are taking α-blockers.
      Vardenafil does not affect the pharmacokinetics of digoxin.
      • Young JM
      Vardenafil.
      Only 1 published study has investigated the effect of vardenafil on cardiac function.
      • Thadani U
      • Smith W
      • Nash S
      • et al.
      The effect of vardenafil, a potent and highly selective phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction, on the cardiovascular response to exercise in patients with coronary artery disease.
      This was a doubleblind, single-dose crossover study involving 41 men with stable coronary artery disease characterized by reproducible stable exertional angina. After taking either 10 mg of vardenafil or placebo, these men underwent treadmill exercise tolerance testing to 5 to 10 METs. Compared with placebo, vardenafil use did not result in a change in exercise treadmill time or time to first awareness of angina but significantly increased the time to ischemic threshold. At peak exercise levels, vardenafil did not cause a change in either heart rate or blood pressure level. This study concluded that 10 mg of vardenafil did not impair the ability of men with stable coronary artery disease to exercise at levels consistent with the exertion associated with sexual intercourse.

      Tadalafil.

      Tadalafil is another selective PDE-5 inhibitor that was recently approved by the US FDA.
      • Gresser U
      • Gleiter CH
      Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil—review of the literature.
      • Porst H
      IC351 (tadalafil, Cialis): update on clinical experience.
      • Holmes S
      Tadalafil: a new treatment for erectile dysfunction.
      The time to peak serum concentrations for tadalafil is 2 hours, considerably longer than that of sildenafil.
      • Young JM
      Vardenafil.
      The relative excretion half-life of tadalafil is even longer, at 17.5 hours.
      • Young JM
      Vardenafil.
      In some elderly men, tadalafil could be detected in the bloodstream 6 days after oral ingestion.
      • Gresser U
      • Gleiter CH
      Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil—review of the literature.
      This prolonged excretion half-life produces enhanced erections up to 36 hours after oral dosing, thereby potentially allowing for more spontaneous engagement of intercourse. The efficacy of tadalafil in the treatment of ED has been proved in randomized double-blind, placebo-controlled trials.
      • Porst H
      • Padma-Nathan H
      • Giuliano F
      • Anglin G
      • Varanese L
      • Rosen R
      Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial.
      Adverse-effect profiles of headaches, flushing, rhinitis, and dyspepsia, without visual changes, mimic those of vardenafil.
      • Gresser U
      • Gleiter CH
      Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil—review of the literature.
      As with vardenafil, food intake does not seem to affect the pharmacokinetics of tadalafil.
      • Gresser U
      • Gleiter CH
      Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil—review of the literature.
      As with sildenafil, use of nitrate or NO-donor medications is contraindicated while taking tadalafil because of the potential for marked hypotensive interactions.
      • Gresser U
      • Gleiter CH
      Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil—review of the literature.

      SEXUAL FUNCTION AND THE RISK OF A CARDIAC EVENT

      Although most patients can be treated effectively for ED, the issue is whether resumption of sexual activity is safe in patients with cardiac disease.
      • Taylor Jr, HA
      Sexual activity and the cardiovascular patient: guidelines.
      Theoretically, the risk of a cardiac event during sexual activity should be increased. Sexual activity is associated with an elevated heart rate, blood pressure level, and myocardial oxygen demand, and this increase in hemodynamic stress may result in myocardial ischemia.
      • Kimmel SE
      Sex and myocardial infarction: an epidemiologic perspective.
      Hemodynamic stress also may cause rupture of a vulnerable atherosclerotic plaque resulting in angina, myocardial infarction, or sudden cardiac death.
      • Muller JE
      Triggering of cardiac events by sexual activity: findings from a case-crossover analysis.
      The significant sympathetic discharge associated with sexual intercourse may contribute to the development of arrythmias in susceptible patients.
      • Drory Y
      • Fisman EZ
      • Shapira Y
      • Pines A
      Ventricular arrhythmias during sexual activity in patients with coronary artery disease.
      Because of this perceived increase in risk, many couples are concerned about resuming sexual activity in the setting of cardiac disease. A study that monitored male patients after coronary artery bypass grafting found that 17% of patients and 35% of their partners were afraid of resuming sexual activity.
      • Muller JE
      Sexual activity as a trigger for cardiovascular events: what is the risk?.
      More than 11 million people in the United States have cardiovascular disease, and each year, about 500,000 survive a myocardial infarction. These patients often seek counseling on their relative risk of resuming sexual activity. In the past, it was often assumed that if a patient could climb 2 flights of stairs without symptoms, it was safe for the patient to engage in sexual activity.
      • Hellerstein HK
      • Friedman EH
      Sexual activity and the postcoronary patient.
      • Tardif GS
      Sexual activity after a myocardial infarction.
      More recently, researchers have recognized that climbing stairs does not correlate closely with sexual activity in terms of autonomic, psychological, and emotional patterns of stress on the body.
      • Muller JE
      Sexual activity as a trigger for cardiovascular events: what is the risk?.
      Early work in this field, performed by Masters and Johnson in 1966, involved evaluation of young patients in a laboratory setting and found that heart rates and systolic blood pressure levels during sexual activity approached levels seen during maximal exercise.
      • Stein RA
      Cardiovascular response to sexual activity.
      However, subsequent studies of older patients who had sexual intercourse in their home and were monitored with ambulatory ECG reported significantly lower heart rates and blood pressure levels.
      • Stein RA
      Cardiovascular response to sexual activity.
      Cardiologists use METs of oxygen consumption to compare the energy expenditure of different forms of activity.
      • DeBusk R
      • Drory Y
      • Goldstein I
      • et al.
      Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel.
      • DeBusk RF
      Evaluating the cardiovascular tolerance for sex.
      One MET is equal to a resting state, or 3.5 mL/kg per minute. The relative MET values of sexual activity compared with other forms of activity are shown in Table 3. In general, sexual activity is similar to mild or moderate activity for most patients either with or without coronary artery disease.
      • DeBusk R
      • Drory Y
      • Goldstein I
      • et al.
      Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel.
      However, some researchers have questioned whether the strain of sexual activity can be compared accurately with standard types of physical activity and whether sexual activity is more closely related to episodes of anger or fear.
      • DeBusk RF
      Evaluating the cardiovascular tolerance for sex.
      Other studies have proposed that the strain involved with intercourse in older patients is less associated with physical exertion and more closely related to sexual arousal.
      • DeBusk R
      • Drory Y
      • Goldstein I
      • et al.
      Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel.
      Masturbation has been noted to be associated with increased heart rates in several studies.
      • Stein RA
      Cardiovascular response to sexual activity.
      • Bohlen JG
      • Held JP
      • Sanderson MO
      • Patterson RP
      Heart rate, rate-pressure product, and oxygen uptake during four sexual activities.
      Typically, the response to sexual activity is no more than an increase in heart rate to 130 beats/min and an increase in systolic blood pressure level to 170 mm Hg.
      • DeBusk R
      • Drory Y
      • Goldstein I
      • et al.
      Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel.
      Overall, sexual intercourse does not lead to an extremely exaggerated heart rate or blood pressure level when performed in a familiar setting with one's usual partner.
      • Hellerstein HK
      • Friedman EH
      Sexual activity and the postcoronary patient.
      Sexual intercourse is interpreted by the body as just one of many activities that it typically encounters during normal daily life.
      • Hellerstein HK
      • Friedman EH
      Sexual activity and the postcoronary patient.
      Table 3Metabolic Equivalent (MET) Values for Various Physical Activities
      • Wallis RM
      • Corbin JD
      • Francis SH
      • Ellis P
      Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro.
      • Muller JE
      Triggering of cardiac events by sexual activity: findings from a case-crossover analysis.
      METActivity
      2Walking 2 mph
      3Walking 3 mph
      2–3Sexual activity preorgasm
      3–4Sexual activity with orgasm
      5–6Upper range of sexual activity in younger patients
      6–7Cycling 10 mph
      13Walking 4.2 mph
      15.5Peak exercise capacity in healthy young man
      Sexual intercourse is an infrequent cause of myocardial infarction. In a study of 1774 patients after myocardial infarction, only 1.5% of these events occurred within 2 hours of sexual intercourse, and sexual activity was considered a direct contributing factor in 0.9%.
      • Muller JE
      • Mittleman A
      • Maclure M
      • Sherwood JB
      • Tofler GH
      • Determinants of Myocardial Infarction Onset Study Investigators
      Triggering myocardial infarction by sexual activity: low absolute risk and prevention by regular physical exertion.
      In the general population, the estimated relative risk of experiencing a myocardial infarction within 2 hours after sexual intercourse is approximately 2.5 times higher than the baseline infarction risk of that individual, which itself is extremely low
      • Muller JE
      • Mittleman A
      • Maclure M
      • Sherwood JB
      • Tofler GH
      • Determinants of Myocardial Infarction Onset Study Investigators
      Triggering myocardial infarction by sexual activity: low absolute risk and prevention by regular physical exertion.
      ; this compares with an increased odds ratio of myocardial infarction of 2.3 with anger and 5.9 with heavy physical exertion.
      • Kimmel SE
      Sex and myocardial infarction: an epidemiologic perspective.
      The Framingham Heart Study found a baseline risk of myocardial infarction in a healthy 50-year-old nonsmoking man to be approximately 1% per year, or 1 chance per million per hour.
      • Anderson KM
      • Odell PM
      • Wilson PW
      • Kannel WB
      Cardiovascular disease risk profiles.
      After sexual intercourse, this risk increases approximately 2-fold, to 2 chances per million per hour, but only for the 2 hours after intercourse. For low-risk patients with no history of cardiovascular disease and an annual myocardial infarction risk of 1% per year, the risk increases to 1.01% with weekly sexual activity.
      • Muller JE
      • Mittleman A
      • Maclure M
      • Sherwood JB
      • Tofler GH
      • Determinants of Myocardial Infarction Onset Study Investigators
      Triggering myocardial infarction by sexual activity: low absolute risk and prevention by regular physical exertion.
      In high-risk patients with an annual myocardial infarction risk of 10%, this risk would increase to only 10.1% per year with weekly sexual activity.
      • Kimmel SE
      Sex and myocardial infarction: an epidemiologic perspective.
      Patients with an implanted pacemaker appear to have no increased risk with sexual activity.
      • DeBusk R
      • Drory Y
      • Goldstein I
      • et al.
      Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel.
      However, patients with hypertrophic obstructive cardiomyopathy and idiopathic hypertrophic subaortic stenosis are at increased risk of syncope and sudden death after exercise.
      • DeBusk R
      • Drory Y
      • Goldstein I
      • et al.
      Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel.
      The risk after sexual activity in these patients is unknown, although vasodilators should be avoided because they may increase the intraventricular gradient.
      • DeBusk R
      • Drory Y
      • Goldstein I
      • et al.
      Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel.
      Risk of arrythmias after sexual intercourse was evaluated in 82 patients with stable coronary artery disease who were monitored with ambulatory ECG after sexual intercourse.
      • Drory Y
      • Fisman EZ
      • Shapira Y
      • Pines A
      Ventricular arrhythmias during sexual activity in patients with coronary artery disease.
      Most patients with baseline rhythm disturbances experienced no exacerbation in their arrhythmias with sexual activity. If ventricular ectopic activity occurred during sexual activity, most of it was noted to be similar to that seen with normal daily activity.
      Stable angina pectoris has been defined as predictable chest pain for a given level of exercise that has been present for at least several weeks with no indication of increasing severity.
      • Jackson G
      The use of sildenafil in heart disease [editorial].
      These symptoms are caused by an imbalance between myocardial oxygen supply and demand, secondary to coronary artery disease.
      • Jackson G
      The use of sildenafil in heart disease [editorial].
      The annual cardiovascular mortality risk for patients with stable angina pectoris is approximately 2% to 3%, and the annual nonfatal myocardial infarction rate is an additional 2% to 3%.
      • Jackson G
      The use of sildenafil in heart disease [editorial].
      Stable angina has been associated with slightly lower rates of sexual intercourse.
      • Taylor Jr, HA
      Sexual activity and the cardiovascular patient: guidelines.
      However, if optimally treated with β-blockers, lipid-lowering agents, and aspirin, these patients have no significantly increased cardiovascular risk associated with sexual activity, although they should receive appropriate risk information.
      • Jackson G
      The use of sildenafil in heart disease [editorial].
      Sildenafil can be administered safely to these patients if they are taking no oral, topical, or sublingual nitrates.
      • Jackson G
      The use of sildenafil in heart disease [editorial].

      PREVENTION AND RISK ASSESSMENT

      Cardiovascular tolerance for sex is based on “functional reserve,” which corresponds to how closely the cardiovascular response to sex (in terms of heart rate, blood pressure level, and oxygen consumption) approaches the patient's peak response to exercise.
      • DeBusk RF
      Evaluating the cardiovascular tolerance for sex.
      It has been postulated that regular exercise can decrease or possibly eliminate the small risk of myocardial infarction associated with sexual intercourse in most patients.
      • Muller JE
      • Mittleman A
      • Maclure M
      • Sherwood JB
      • Tofler GH
      • Determinants of Myocardial Infarction Onset Study Investigators
      Triggering myocardial infarction by sexual activity: low absolute risk and prevention by regular physical exertion.
      Regular exercise can significantly decrease the patient's risk of having a myocardial infarction during sexual intercourse by increasing the patient's functional reserve, decreasing the heart rate, and increasing the stroke volume.
      • Muller JE
      • Mittleman A
      • Maclure M
      • Sherwood JB
      • Tofler GH
      • Determinants of Myocardial Infarction Onset Study Investigators
      Triggering myocardial infarction by sexual activity: low absolute risk and prevention by regular physical exertion.
      • Stein RA
      Cardiovascular response to sexual activity.
      Of 1774 patients with a history of myocardial infarction, only 2 who had experienced a myocardial infarction after sexual intercourse were able to exercise to at least 6 METs without symptoms.
      • Muller JE
      • Mittleman A
      • Maclure M
      • Sherwood JB
      • Tofler GH
      • Determinants of Myocardial Infarction Onset Study Investigators
      Triggering myocardial infarction by sexual activity: low absolute risk and prevention by regular physical exertion.
      The risk of myocardial infarction with sexual activity has been estimated to be less than 3% in high-risk patients with prior cardiovascular disease if they can exercise to more than 7 METs without symptoms.
      • Moss AJ
      • Benhorin J
      Prognosis and management after a first myocardial infarction.
      If the safety of resuming sexual activity is a concern, the patient can undergo exercise ECG with the patient's partner observing.
      • Jackson G
      The use of sildenafil in heart disease [editorial].
      Also, risk can be minimized by avoiding heavy meals and alcohol before sexual activity and by limiting intercourse to a familiar partner and setting.
      • Kloner RA
      • Zusman RM
      Cardiovascular effects of sildenafil citrate and recommendations for its use.
      • Taylor Jr, HA
      Sexual activity and the cardiovascular patient: guidelines.
      Avoiding sexual activity between 6 AM and noon may be recommended to higher-risk patients because this is the time of peak incidence of most arrhythmias, myocardial ischemia, sudden cardiac death, and cerebrovascular accidents.
      • Muller JE
      Sexual activity as a trigger for cardiovascular events: what is the risk?.
      Coital position has not been shown to play a role in increased cardiovascular risk; similar peak heart rates and blood pressure levels are evident with either the man or the woman in the superior position during intercourse.
      • Nemec ED
      • Mansfield L
      • Kennedy JW
      Heart rate and blood pressure responses during sexual activity in normal males.
      Aspirin and β-blocker use have been suggested to decrease the risk of cardiovascular events with sexual activity, although their benefit has not been proved definitively.
      • Kimmel SE
      Sex and myocardial infarction: an epidemiologic perspective.
      Patients with prior cardiac events should be encouraged to enroll in cardiac rehabilitation programs before restarting sexual activity.
      • Muller JE
      Triggering of cardiac events by sexual activity: findings from a case-crossover analysis.
      Sedentary patients with a history of cardiac disease and patients with unstable angina or advanced congestive heart failure should undergo a full medical evaluation before resuming sexual activity.
      • Muller JE
      Triggering of cardiac events by sexual activity: findings from a case-crossover analysis.
      The Princeton Consensus Panel provided guidelines (Table 4) for physicians regarding patients who are being evaluated for their level of risk in resuming sexual activity.
      • DeBusk R
      • Drory Y
      • Goldstein I
      • et al.
      Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel.
      The cardiologist should provide the final recommendations regarding the patient's ability to safely resume sexual intercourse.
      Table 4Princeton Consensus Panel Guidelines
      • Wallis RM
      • Corbin JD
      • Francis SH
      • Ellis P
      Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro.
      • Low-risk category
        • Patients can be safely encouraged to initiate or resume sexual activity and to receive treatment for sexual dysfunction. An exception is the use of sildenafil in any patients receiving nitrate therapy
          • No cardiac symptoms and <3 cardiovascular risk factors
          • Controlled hypertension
          • Mild, stable angina
          • Successful coronary revascularization (assessed by postoperative exercise stress testing)
          • History of uncomplicated myocardial infarction (>6–8 wk previously) with negative postinfarction stress test results to 4–5 metabolic equivalents
          • Mild valvular disease, including mild mitral and selected aortic valve abnormalities; subacute bacterial endocarditis prophylaxis not needed if erectile dysfunction treatment is used
      • Intermediate-risk category
        • Patients need further cardiologic evaluation before restratification into the low- or high-risk category
          • Moderate angina
          • Recent myocardial infarction (<6 wk previously)
          • Left ventricular dysfunction and/or class II congestive heart failure (slight limitations, such as dyspnea with walking, secondary to cardiac disease)
          • Nonsustained low-risk arrhythmias
          • ≥3 risk factors for coronary artery disease
      • High-risk category
        • Patients should be stabilized by specific treatment for their cardiac condition before they resume sexual activity or receive treatment for sexual dysfunction
          • Unstable or refractory angina
          • Uncontrolled hypertension
          • Class III or IV congestive heart failure (marked limitation of activity to breathlessness at rest)
          • Recent myocardial infarction (<2 wk previously)
          • High-risk arrhythmia (may be evaluated with Holter monitoring during sexual activity in selected patients)
          • Obstructive cardiomyopathy
          • Moderate to severe vascular disease

      CONCLUSIONS

      Cardiovascular disease and ED represent 2 common disease processes that are often intimately associated with one another. These common pathophysiological links necessitate a solid scientific and clinical understanding of these 2 disorders and a team effort between the cardiologist and urologist to provide effective management strategies for these patients.

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