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International Journal of Impotence Research (2009) 21, 327–335
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REVIEW
How to save a life during a clinic visit for erectile dysfunction
by modifying cardiovascular risk factors
BG Schwartz1,2 and RA Kloner1,2
1
Heart Institute, Good Samaritan Hospital, Los Angeles, CA, USA and 2Department of Internal Medicine, Division of
Cardiovascular Medicine, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA
Erectile dysfunction (ED) is an early marker for systemic atherosclerosis and is a predictor for
coronary artery disease and cardiac events. The aim of this paper is to convey the importance of
addressing cardiovascular risk factors in patients with ED and to inform urologists as well as other
physicians who are not specialized in cardiology how to carry out a basic cardiovascular
evaluation, including history, physical examination and objective data. We review the evidence and
pathophysiology linking ED to cardiovascular disease, and then describe how to carry out a basic
cardiovascular evaluation. We present data from the literature showing that appropriate use of
lifestyle modifications and medical therapy has a positive effect on mortality, on numerous
cardiovascular end points and on ED. Suggestions of when to refer the ED patient to an internist or
cardiologist are provided. Identifying and treating cardiovascular risk factors may not only benefit
the patient’s ED, but it might also save the patient’s life.
International Journal of Impotence Research (2009) 21, 327–335; doi:10.1038/ijir.2009.38;
published online 20 August 2009
Keywords: history; physical examination; diagnostic testing; modification of reversible causes;
vascular physiology of genital arousal; risk factors
Introduction
Erectile dysfunction (ED) affects 30 million men in
the United States. As many as 57% of these men are
o55 years.1 ED is now recognized as an early marker
for cardiovascular disease; therefore, the patient
presenting with ED should undergo a cardiovascular
evaluation. This paper briefly reviews the evidence
linking ED with cardiovascular disease, and then
describes the underlying pathophysiology. A basic
approach to cardiovascular evaluation is presented,
including history, physical examination and objective data. Evidence supporting a beneficial effect of
physical activity and weight loss on ED is reviewed,
as is evidence supporting medical therapy for
cardiovascular risk factors. Identifying and treating
cardiovascular risk factors may not only benefit the
patient’s ED, but it might also save the patient’s life.
Correspondence: Dr RA Kloner, Heart Institute, Good
Samaritan Hospital, 1225 Wilshire Blvd., Los Angeles, CA
90017-2395, USA.
E-mail: [email protected]
Received 27 June 2009; revised 24 July 2009; accepted 24
July 2009; published online 20 August 2009
Evidence that ED is an early marker
of vascular disease
The evidence linking ED with vascular disease
is reviewed elsewhere.2–5 Briefly, a large epidemiological study6 and a prospective study7 reported that
ED shares numerous risk factors with vascular
disease, including smoking, hypertension, diabetes,
dyslipidemia, obesity and metabolic syndrome. A
longitudinal survey8 described the coronary artery
disease (CAD) incidence densities per 1000 personyears for men without vs with ED: 0.94 vs 48.52 (40–
49 years), 5.09 vs 27.15 (50–59 years), 10.72 vs 23.97
(60–69 years) and 23.30 vs 29.63 (X70 years).
Although ED had a marked association with CAD
in men o60 years, the association seemed to have
little prognostic importance in older men. Similarly,
the association between ED and diabetes mellitus
is strongest for men aged 46–55 years, and this
association decreases with older age,1 which emphasizes the point that ED is a stronger marker for
vascular disease in men o60 years. Kaiser et al.9
investigated vascular parameters in 30 patients with
ED and found evidence of penile vascular disease,
endothelial dysfunction and impaired endothelialindependent vasodilatation. An accompanying editorial stated that ED is a marker for vascular disease
Modifying cardiovascular risk in erectile dysfunction
BG Schwartz and RA Kloner
328
and should alert the physician to the possibility of
systemic vascular problems in the future.10 Morley
et al.11 discovered that patients with ED and an
abnormal penile brachial pressure index (PBPI)
(o0.65), compared with those with PBPI 40.65,
had significantly more myocardial infarctions and
cerebrovascular accidents. Vlachopoulos et al.12
investigated the prevalence of CAD in men whose
only complaint was ED and found angiographically
silent CAD in 19% (9 of 47), which emphasizes the
importance of risk reduction in this high-risk
population. Similarly, Pritzker13 evaluated 50
asymptomatic (cardiac) men who had ED for cardiac
ischemia. All 20 patients who underwent coronary
angiography had demonstrable disease, and the
investigators concluded that men with ED and
without cardiac symptoms have a high prevalence
of cardiac risk factors and CAD. They likened male
sexual function to the penile stress test as a ‘window
to the hearts of man.’
The aforementioned studies and others14–18 comprise an abundance of evidence indicating ED is an
early marker for vascular disease. Conversely, ED is
highly prevalent in cardiac patients. Kloner et al.19
investigated sexual function in 76 men with chronic
stable CAD and reported that 75% had ED or a
recent history of ED. Similarly, 75% of patients with
CAD at the Tel-Aviv Sourasky Medical Center had
ED.20 Not only is ED an early marker for vascular
disease, but once CAD becomes evident, atherosclerosis has already begun to impair penile blood
flow and erectile function in the majority of
patients, as will be discussed in the next section.
Endothelial cells have an integral role in penile
erection and endothelial dysfunction and may also
explain the frequent occurrence of ED before overt
CAD.9,22 Endothelial cells modulate vascular tone
and blood flow and are crucial to physiological
flow-mediated dilation9,24,25 and penile erection.9,16,26 In contrast, while most conduit arteries
dilate B15% during flow-mediated dilation, cavernosal and helicine arteries must dilate up to 80% to
sustain an erection. Moreover, to maintain an
erection, endothelial-dependent dilation of trabecular smooth muscle and engorgement of the sinusoidal system with blood is necessary to compress the
venous system and prevent venous outflow. In
contrast, endothelial cells have little role in venous
circulation in most other vascular beds. Thus,
compared with most vascular processes, penile
erection relies heavily on endothelial function for
more substantial arterial dilation and for venous
compression.9 As endothelial dysfunction occurs
early in the process of atherosclerosis,9,24,25,27 penile
erection may be affected before the development of
overt CAD.
Basic cardiovascular evaluation
Pathophysiology behind ED as an early
marker of vascular disease
As ED is an early marker for systemic atherosclerosis5,6,9,10,16–18 and is a predictor for CAD and cardiac
events,8,11,13–15 all patients presenting with ED
should be questioned about their cardiovascular
health.2–5,28 When a patient presents with ED,
especially a younger patient, the clinician has the
opportunity to identify modifiable risk factors at an
early stage. This section describes the essential
elements of a basic cardiovascular evaluation,
including history, physical examination and objective data.
It is now evident that ED is an early warning sign for
cardiovascular disease in many patients. This
phenomenon results from the effects of atherosclerosis and endothelial dysfunction on the physiology of penile erection.21,22 Penile erection is a
neurovascular event that involves dilation of the
arteries and arterioles that supply the erectile tissue
which culminates in a several fold increase in penile
blood flow. Atherosclerosis affects the vasculature
throughout the entire body.3 All vascular beds are
affected; however, clinical manifestations present at
different times. When a lumen obstruction reaches
50–75% it begins to limit flow.3 Therefore, differing
arterial lumen sizes may account for varying clinical
presentations. ED may present before manifestations
of CAD in some patients because the penile arteries
are smaller than the epicardial coronary arteries
(typically 0.5–2 mm vs 3–4 mm in diameter).2,5,9,23
In this way, the smaller penile arteries can be
regarded as ‘the tip of the iceberg’,3 so that ED is a
harbinger of systemic atherosclerosis.
History
Patients should be asked about major symptoms
associated with cardiac disease, including chest
discomfort, dyspnea, fatigue, orthopnea, edema,
palpitations and syncope. The differential diagnosis
of chest pain can be divided into three broad
categories: CAD, cardiac non-CAD and non-cardiac
(Figure 1). When evaluating chest discomfort,
eliciting the etiology can be facilitated by assessing
the following factors: location, radiation, precipitating and alleviating factors, duration and associated
symptoms. Typical angina is substernal, exertional,
and is described as ‘pain’ or a sensation of
‘pressure’, ‘squeezing’, ‘burning’, ‘aching’, ‘discomfort’ or ‘tightness’. Angina typically lasts for a few to
several minutes. Pain that lasts only a few seconds
or that is fleeting is usually not angina. Conversely,
pain that is constant and described by the patient as
‘there all the time’ is unlikely to be angina. Angina
International Journal of Impotence Research
Modifying cardiovascular risk in erectile dysfunction
BG Schwartz and RA Kloner
CHEST PAIN
CARDIAC
CORONARY
ARTERY DISEASE
NON-CORONARY
ARTERY DISEASE
Chronic stable angina
Unstabel angina
Myocardial infarction
Pericarditis
Pulmonary
hypertension
Pulmonary embolism
Mitral valve prolapse
Aortic dissection
Myocarditis
NON-CARDIAC
Musculoskeletal
(including
costochondritis)
Esophageal disease
(GERD, motility
disorders, etc.)
Lung disease
Pleural disease
Gall bladder or biliary
disease
Anxiety
Figure 1 A suggested differential diagnosis and method for
categorizing patients with chest pain, based on the opinion of the
authors. GERD, gastroesophageal reflux disease.
may be associated with dyspnea, diaphoresis,
nausea or vomiting. Although angina is typically
precipitated by exertion, it is generally relieved by
rest or by nitroglycerin. Typical chest pain is more
likely to be indicative of CAD, however, atypical
presentations are not uncommon. A greater risk of
coronary disease is also associated with a higher
number of cardiac risk factors, as discussed below.
Pain that is sharp, pleuritic, positional or reproducible with palpation is less likely to be angina
(likelihood ratios (LRs) 0.2–0.3), whereas exertional
pain or discomfort that radiates to one or both
shoulders is more likely angina (LRs 2.3–4.7).29
Pleuritic pain often indicates pulmonary or pleural
disease, but also results from pulmonary embolism
and pericarditis.29,30
Chest pain due to CAD may manifest as stable
angina, unstable angina or acute myocardial infarction. Stable angina is generally unchanged in
frequency over time and represents chronic CAD.
Unstable angina often results from erosion of an
atherosclerotic plaque and may occur suddenly.
Unstable angina may be new angina or angina
occurring more frequently and severely with less
activity, or angina at rest. Myocardial infarction
entails prolonged ischemia usually due to rupture of
a plaque with superimposed thrombus preventing
distal blood flow and causing myocyte cell death.
Unstable angina and myocardial infarction require
emergent treatment, whereas stable angina can be
routinely relieved with nitroglycerin. Traditionally,
the duration of stable angina is considered to be
2–10 min, whereas unstable angina can last a few
minutes or up to 30 min, and pain longer than
30 min is either acute myocardial infarction or nonischemic in etiology. Again, pain that lasts for only
few seconds or pain that is constant is unlikely to be
angina.29,30
Palpitations, an awareness of one’s own heart
beat, may be described using a variety of terms,
such as ‘flutters’, ‘skips’ or ‘pounding’, and may
indicate an arrhythmia. Palpitations may be associated with other symptoms and it is worth asking
if the patient noted dyspnea, dizziness, chest pain,
diaphoresis or syncope as well. Cardiac syncope
classically has a sudden onset and resolves
quickly, restoring full consciousness. In contrast, a
prodrome typically precedes neurogenic syncope,
which often shows signs of seizure or a prolonged
postictal state. Orthostatic syncope results from
dehydration, blood loss or extreme vasodilation
(which can occur with certain antihypertensive
medicines). Orthostatic syncope occurs when
sitting up or standing from a laying position (often
when the shift in posture is rapid or sudden),
and is suggested by orthostatic hypotension, a
X20 mm Hg drop in systolic blood pressure or a
X10 mm Hg drop in diastolic blood pressure within
3 min of standing.30
Heart failure usually manifests as dyspnea,
orthopnea, fatigue, edema and exercise limitation.
Orthopnea is a discomfort in breathing that is
brought on or aggravated by lying flat. Paroxysmal
nocturnal dyspnea is common in heart failure,
usually occurs 2–4 h after onset of sleep (as fluid
shifts into the lungs), compels the patient to sit
upright or stand, and subsides gradually over
several minutes. Lower extremity edema worsens
as the day progresses. The extent of exercise
limitation should be assessed by the New York
Heart Association (NYHA) Functional Classification
(Table 1), because in patients with heart failure, the
NYHA class is a strong and independent predictor
of mortality.30
A vascular disorder may manifest as limb pain,
edema, skin discoloration, peripheral ulcerations or
claudication (a cramping pain in the legs brought on
by exertion and relieved by rest).30
In addition to symptoms, the clinician should
inquire about the presence of modifiable cardiovascular risk factors, including diabetes mellitus,
hypertension, dyslipidemia, smoking, physical inactivity and obesity. The clinician should also note
non-modifiable risk factors, such as male gender,
age (male 445 years, female 455 years), and family
history of premature CAD (CAD in male first-degree
relative o55 years, CAD in female first-degree
relative o65 years). Patients should also be asked
about their medications. Treatment of ED with
phosphodiesterase-5 (PDE5) inhibitors is contraindicated with organic nitrates (nitroglycerin, isosorbide mononitrate, and so on). Organic nitrates
increase the production of cyclic GMP and PDE5
inhibitors prevent the breakdown of cyclic GMP, the
substance that promotes relaxation of vascular
smooth muscle cells leading to an erection. Combining organic nitrates with PDE5 inhibitors has the
potential for systemic vasodilation and frank hypotension.31 In contrast, sildenafil has proven to be
safe and effective for ED in patients with heart
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Modifying cardiovascular risk in erectile dysfunction
BG Schwartz and RA Kloner
330
Table 1 New York Heart Association Functional Classification
Class
Symptoms in patients with cardiac disease
I
Physical activity not limited. Regular physical activity
does not cause excessive fatigue, palpitation, dyspnea
or angina.
Physical activity slightly limited. Comfortable at rest.
Regular physical activity causes fatigue, palpitation,
dyspnea or angina.
Physical activity markedly limited. Comfortable at rest.
Less than regular physical activity causes fatigue,
palpitation, dyspnea or angina.
Unable to do any physical activity without symptoms.
Symptoms may be present at rest. Discomfort is
increased if any physical activity is undertaken.
II
III
IV
Adapted from Fang and O’Gara.30
failure, and may even benefit patients with heart
failure and secondary pulmonary hypertension.32
The safety of PDE5 inhibitors in patients with aortic
stenosis or hypertrophic obstructive cardiomyopathy has not been evaluated.
Physical examination
General appearance is important and may alert the
physician to serious disease if the patient is
diaphoretic, dyspneic, emaciated or cyanotic. Waist
circumference and body mass index should be
measured routinely in men with ED. Vital signs,
including pulse rate, blood pressure, respiratory rate
and oxygen saturation, are important indicators of
cardiovascular health. The normal range is generally
considered a pulse rate of 60–100 beats per min,
blood pressure o140/90 mm Hg, respiratory rate 12–
20 breaths per min and oxygen saturation 494%.
Hypotension is ill defined with different values
reported for various clinical situations, but a blood
pressure o90/60 mm Hg should elicit concern. Vital
signs significantly outside the normal range may
necessitate urgent intervention, especially in a
symptomatic patient. Mild abnormalities must also
be addressed, albeit less urgently. The first response
to abnormal vital signs is to repeat the vital signs,
which may normalize after the patient has been
sitting, relaxed for several minutes. The asymptomatic patient with hypertension in clinic usually
represents chronic hypertension; however, a systolic
blood pressure 4180 mm Hg or a diastolic blood
pressure 4120 mm Hg defines hypertensive urgency
and must be treated immediately.
The extremities are examined. Yellow staining of
the fingertips suggests smoking; and clubbing, loss
of the normal o1651 angle between the nail bed and
the fold (cuticle) usually indicates lung disease or
cyanotic heart disease. Lower extremity ulcers often
result from diabetes mellitus (located at points of
increased pressure) or venous insufficiency (usually
International Journal of Impotence Research
medial). Bilateral lower extremity edema occurs in
many volume-overloaded states, including heart
failure, renal failure and hepatic failure, or from
dihydropyridine calcium channel blockers (for example, nifedipine, felodipine and amlodipine) secondary to vasodilation of arterioles. Unilateral leg
swelling can reflect venous thrombosis, lymphatic
obstruction or previous surgery.
The peripheral arterial pulses are palpated and are
examined for symmetry and strength, including the
radial, femoral and dorsalis pedis. Listen for bruits
over the femoral arteries, carotid arteries and abdomen (aorta and renal arteries). Stenotic atheromatous lesions may manifest as weak or asymmetrical
peripheral pulses or bruits. Varicose veins in
the lower extremities may be associated with a
varicocele.33 The jugular veins are assessed with
the patient reclined at 301 from supine position.
In this position, a general rule is the level of
the clavicle represents 5 cm from the heart and the
angle of the mandible corresponds to 12 cm,
although values range widely between patients.
Right-sided heart failure (and a few other conditions) causes jugular venous distension, venous
pulsations (double pulsations) 46 cm (8 mm Hg)
from the heart.30,34
The lungs are auscultated. Rales (a fine crackly
sound), often confined to the bases, suggest congestive heart failure, whereas distant lung sounds
with rhonchi (a coarse rattling sound somewhat like
snoring) often result from chronic obstructive
pulmonary disease. Distant lung sounds confined
to the bases usually indicate pleural effusions, but
may also result from mass lesions.
Finally, the clinician examines the heart. With the
patient reclined at 301 from the supine position, the
cardiac point of maximal impulse (PMI), usually
located in the mid-clavicular line at the fifth
intercostal space, is palpated. Standing on the
patient’s right with the patient in the left lateral
decubitus position may facilitate palpation in obese
or muscular patients. Leftward and downward
displacement of the PMI results from an enlarged
heart, as may occur with valvular disease, dilated
cardiomyopathy or previous myocardial infarction.
A diffuse and sustained PMI may reflect systolic
dysfunction and a dyskinetic apex may reflect a
recent myocardial infarction. The heart sounds are
auscultated in several locations, including the
second intercostal space at both parasternal borders
and the fifth intercostal space at the left parasternal
border and left midclavicular line, and the apex.
Murmurs usually reflect valvular pathology. Murmurs
are described in terms of intensity (grade I is very
faint, grade II is soft, grade III is loud and grades IV–
VI are associated with a thrill), timing (early-, mid-,
late-, or holosystolic or diastolic), location on the
chest wall where the murmur is loudest, and
whether the murmur radiates to another area
(axillary or carotids). A cardiac thrill is a palpable
Modifying cardiovascular risk in erectile dysfunction
BG Schwartz and RA Kloner
vibration that accompanies a cardiac murmur and
indicates severe pathology. A pathological fourth heart
sound (heard just before S1) is common in patients
who have CAD or hypertension, whereas a pathological third heart sound (heard just after S2) suggests
volume overload or congestive heart failure.30
Objective data
The clinician might investigate a variety of objective
data in response to abnormalities in the cardiovascular history and physical examination. In all
patients presenting with ED, ordering a fasting
glucose, hemoglobin A1C, lipid panel, creatinine,
serum testosterone35 and electrocardiogram are
considered. The electrocardiogram is invaluable in
detecting and diagnosing nearly all types of heart
disease, including rhythm abnormalities, structural
abnormalities, and the extent and severity of
myocardial ischemia. Depending on the clinical
scenario, additional workup may be indicated.
Chest X-rays should be obtained for all patients
with cardiac symptoms to assess the heart and
chamber size, great vessels, pulmonary vascular
redistribution, pulmonary edema, calcification
(valves, aorta, vessels) or other pathology. A chest
X-ray should also be obtained for patients with
respiratory complaints or an abnormal lung examination and most pleural effusions should be
aspirated for analysis, except in the patient with
bilateral pleural effusions and evidence of congestive heart failure. The possibility of a deep venous
thrombosis should be investigated with a lowerextremity Doppler ultrasound for patients with
unilateral leg edema without a clear cause. If cardiac
syncope or an arrhythmia is suspected but not
apparent on electrocardiogram, 24-h electrocardiographic recording or an event monitor may be
useful. Evidence suggestive of heart failure or
valvular pathology should prompt an echocardiogram, which noninvasively evaluates structural,
functional or hemodynamic abnormalities of the
heart and great vessels.
Concern for myocardial ischemia should be
further evaluated with a cardiac stress test and in
some cases a coronary angiogram. Different types of
cardiac stress tests use different ‘stressors’ and
different ‘evaluators’. Exercise is the preferred
‘stressor’ and should be used in all patients capable
of attaining a sufficient level of exercise, X85% of
maximum heart rate (220–age). In addition to
estimating the likelihood and extent of CAD,
exercise stress testing determines functional capacity, estimates prognosis and predicts the effectiveness of therapies. For patients who are unable to
exercise, pharmacological ‘stressors’ are used. Adenosine and dipyridamole dilate the normal coronary
resistance vessels and increase blood flow to
vascular distributions supplied by normal coronary
arteries. Stenotic vessels, however, show limited or
no dilation to adenosine or dipyridamole resulting
in relatively low or diminished blood flow to the
vascular beds supplied by stenotic coronary arteries.
This heterogeneity in myocardial blood flow caused
by exercise or pharmacological ‘stressors’ can be
measured with various ‘evaluators’. All stress tests
should use electrocardiography to assess for myocardial ischemia, which manifests as ST segment
displacement. Electrocardiography is often sufficient as an ‘evaluator’ in patients with low or
intermediate likelihood of CAD. However, since
electrocardiography stress testing alone has a sensitivity of 68% and a specificity of 77% for detecting
CAD,36 an additional ‘evaluator’ is often indicated for
high-risk patients. For patients with ST segment
abnormalities at baseline, electrocardiography is
less interpretable and must be supplemented by
radionuclide myocardial perfusion imaging. In
addition, perfusion imaging is often indicated for
patients with a high probability of CAD, previous
myocardial infarction, or intermediate electrocardiographic stress test results. Radionuclide myocardial perfusion imaging uses intravenous tracers
(thallium, sestamibi) preferentially extracted from
the blood by viable myocytes to illustrate areas of
normal coronary blood flow, and inversely, tissue
with limited or no blood flow. Although nuclear
imaging consists of increased risk, time and cost
relative to electrocardiography, nuclear testing more
accurately determines the location and extent of
coronary disease with increased sensitivity and
specificity for detecting CAD, and can assess
myocardial viability. By comparing stress and rest
images, stress echocardiography can be used to
determine whether exertional symptoms result from
CAD, valvular disease or diastolic dysfunction.
Echocardiography as an ‘evaluator’ is usually combined with the ‘stressor’ exercise or dobutamine, an
adrenergic agonist that increases cardiac contractility, heart rate and oxygen demand, which stimulates
increased
myocardial
blood
flow.
Multidetector computed tomography (which includes computed tomography angiography) represents a relatively new, relatively noninvasive
method of assessing the coronary arteries and
has the capacity to identify the presence of
early CAD (o50% lumen obstruction).37 Multidetector computed tomography reports a coronary
calcium score, which incorporates the size and
density of all calcium deposits in atherosclerotic
plaques throughout the coronary vasculature and
predicts cardiac events. Using multidetector computed tomography, Jackson and Padley23 reported an
elevated coronary calcium score (450) in 11 out of
20 men with ED and without cardiac symptoms;
only two of them had an abnormal exercise electrocardiography stress test. Coronary angiography is
the ‘gold standard’ in evaluating CAD and an
experienced interventionalist can deploy various
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Modifying cardiovascular risk in erectile dysfunction
BG Schwartz and RA Kloner
332
therapies directed at diseased vessels. When noninvasive methods are insufficient, cardiac catheterization is recommended to define the presence or
severity of a suspected cardiac lesion.
Life-saving interventions
Once the clinician has identified cardiovascular
risk factors, achieving treatment goals will drastically reduce patients’ cardiovascular morbidity
and mortality. Hypertension, diabetes mellitus and
dyslipidemia should be controlled with lifestyle
modifications and, if necessary, with medications.
Smoking cessation, diet and exercise are fundamental to good cardiovascular health, reduce major
cardiovascular events and should be recommended
to all patients with cardiac risk factors. In addition
to controlling cardiovascular risk factors, some
evidence supports a beneficial effect of physical
activity and weight loss on ED. Numerous
large multicenter controlled trials demonstrate the
markedly positive effect of medical therapy on a
number of cardiovascular end points including
mortality.
Lifestyle modifications
Cigarette smoking increases the risk of death from
CAD (relative risk ¼ 1.57).38,39 and the incidence of
ED.6,15,19,40 Compared with persistent smokers, after
1 year of cessation the risk of death from CAD is
reduced (relative risk ¼ 0.63), and is further reduced
at 10 years (relative risk ¼ 0.38).39
Obesity is a risk factor for cardiovascular disease
and for ED.7,22,41 Derby et al.40 evaluated the impact
of lifestyle changes on ED through a longitudinal
cohort study and concluded that physical activity
initiated in midlife may reduce the risk of ED.
In a related study, Esposito et al.42 conducted a
randomized, single-blind trial of 110 obese men
aged 35–55 years, with ED and without diabetes
mellitus, hypertension or hyperlipidemia. The 55
men in the intervention group received detailed
advice about how to achieve weight loss through
diet and exercise and showed improvement compared with the control group after 2 years: greater
decrease in body mass index (5.7 vs 0.7, Po0.001),
more physical activity (195 vs 84 min per week,
Po0.001), significant improvement in ED by
improved mean score on questions 1–5 of the
International Index of Erectile Function (IIEF) test
(13.9–17.0, Po0.001), and more men no longer met
ED criteria with a score X22 on questions 1–5 of the
IIEF test (17 vs 3 men, P ¼ 0.001). In multivariate
analysis, changes in body mass index (P ¼ 0.02) and
physical activity (P ¼ 0.02) were independently
associated with changes in the IIEF score (questions
1–5). It was concluded that about one-third of obese
International Journal of Impotence Research
men with ED at baseline were able to improve sexual
function through lifestyle changes.
Medical therapy
When lifestyle modifications are insufficient to
control disease, medical therapy for diabetes, hypertension and dyslipidemia markedly and significantly affect an array of cardiovascular end points.
Diabetes mellitus is considered a CAD equivalent
and its management, beginning with diet and weight
loss, is essential to improving cardiovascular health.
Two separate fasting plasma glucose levels of 126 mg
per 100 ml or higher is diagnostic of diabetes
mellitus. An elevated hemoglobin A1C (normal range
4–6%) is not considered diagnostic, but is highly
suggestive of diabetes mellitus.43 The degree of
hyperglycemia, as measured by hemoglobin A1C,
correlates with increased incidences of CAD and
peripheral arterial disease.44 Moreover, hemoglobin
A1C independently predicts the presence of ED and
the degree of ED among patients with diabetes
mellitus.27 Improved glucose control protects
against microvascular complications.45,46 Early initiation of intensive glucose control reduces the risk
of macrovascular events and death;46 however,
delayed initiation of intensive glucose control does
not reduce macrovascular events45 and even increased mortality in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.47 Again,
this underscores the importance of early detection
and initiation of therapy for diabetes and other
cardiovascular risk factors. Diabetes therapy should
target a hemoglobin A1C of p7%, with a lower target
for selected patients for primary prevention of
macrovascular disease.45
Low-density lipoprotein (LDL) cholesterol is the
primary target of cholesterol lowering therapy and
LDL goals vary depending on the number of cardiac
risk factors, which include smoking, hypertension
(blood pressure X140/90 mm Hg or on antihypertensive medication), low high-density lipoprotein
cholesterol (o40 mg per 100 ml), age (men X45
years, women X55 years) and family history of
premature CAD (CAD in male first-degree relative
o55 years, CAD in female first-degree relative o65
years). LDL treatment goals are o70 mg per 100 ml
for patients with CAD and a history of an acute
coronary syndrome;48 o100 mg per 100 ml for
patients with CAD, systemic atherosclerosis or
diabetes mellitus; o130 mg per 100 ml for patients
with X2 cardiac risk factors; and o160 mg per
100 ml for patients with 0–1 cardiac risk factor.49
The use of statins lowers LDL levels by 30–40% that
translates to a similar reduction in risk for major
coronary events of 30–40% over 5 years.49
Case reports50 and an observational study51
implicated statins as a cause of ED. However, these
reports lacked control patients and the nature of ED
introduced potential bias as patients are eager to
Modifying cardiovascular risk in erectile dysfunction
BG Schwartz and RA Kloner
blame external factors.52 A different observational
study53 suggested that atorvastatin improves ED,
whereas Castro et al.54 showed that atorvastatin
enhanced the effects of sildenafil through an
endothelium-dependent nitric oxide mechanism.
Randomized controlled trials50,52 have not shown a
significant difference between statins and placebo in
relation to ED. Although the affect of statins on ED
is unknown, if a patient reports ED in relation to
statin therapy, it is reasonable to prescribe a different
class of lipid-lowering drug or a different statin.50
Regarding cardiovascular disease, two large randomized trials, the Anglo-Scandinavian Cardiac
Outcome Trial (ASCOT) and the Collaborative
Atorvastatin Diabetes Study (CARDS), were designed
to evaluate statin therapy as primary prevention in
patients who were not considered dyslipidemic, but
had hypertension or diabetes, respectively. Each trial
was stopped early because of a highly significant
reduction in major cardiovascular and cerebrovascular events in the statin group. These trials likely
included a significant number of men with ED,
which emphasizes the importance of cardiovascular
risk reduction in this high-risk group.5
The benefits of lowering blood pressure in
patients with hypertension have been shown in
numerous large-scale studies.55–57 Treatment with
any commonly used antihypertensive reduces the
risk of total major cardiovascular events, stroke,
CAD, heart failure, cardiovascular death and total
mortality; and a greater reduction in blood pressure
is directly associated with greater reductions in risks
of stroke, CAD, major cardiovascular events, cardiovascular death and total mortality.55–57 Another
large-scale analysis of cohort studies and randomized trials reported that a 5 mm Hg reduction in
blood pressure, from any baseline blood pressure
level, reduces the risk of stroke by 34% and
ischemic heart disease by 21%.58 Blood pressure
goals are o140/90 mm Hg for patients with few
other risk factors, o130/80 mm Hg for patients with
diabetes mellitus or chronic kidney disease and
o120/80 mm Hg for high-risk patients with a history
of cardiovascular events.
Erectile dysfunction is more prevalent in patients
with untreated hypertension than in normotensive
controls.59 Although no study has shown that
lowering blood pressure benefits ED, one study of
101 hypertensive outpatients showed that impotent
patients had higher systolic blood pressures and a
higher World Health Organization hypertension
stage than potent hypertensives.60 Contrary to
improving ED symptoms, several antihypertensive
agents have been implicated in causing sexual side
effects, including thiazide diuretics, b-blockers,
spironolactone and clonidine, although direct supporting evidence is limited and conflicting.59 The
high prevalence of ED associated with hypertension
and with antihypertensive medications underscores
the importance of inquiring about sexual function
before initiating therapy. Sexual side effects are
frequently cited by patients as the reason for
discontinuing medications. If a patient reports that
sexual function worsens after initiation of an
antihypertensive medication, the medication should
be discontinued and replaced with an agent with
a different mechanism. If sexual function returns,
the medication can be assumed to have caused
the dysfunction. Angiotensin-converting enzyme
inhibitors, angiotensin II receptor antagonists and
calcium channel blockers are suggested to have less
deteriorating effects on erectile function.59–61
In addition, the metabolic syndrome predicts ED,
the severity of ED7 and cardiovascular disease.62
The metabolic syndrome (syndrome X) consists of a
constellation of risk factors commonly clustered
together. According to the Adult Treatment Panel III,
the diagnosis of metabolic syndrome is made when
3 of 5 criteria are met: (i) waist circumference
4102 cm for men (488 cm for women), (ii) triglycerides X150 mg per 100 ml, (iii) high-density lipoprotein o40 mg per 100 ml for men (o50 mg per
100 ml for women), (iv) blood pressure X130/85 mm Hg
and (v) fasting glucose X110 mg per 100 ml. Obesity
is the primary target of therapy for metabolic
syndrome, therefore clinicians should encourage
weight loss through diet and exercise. Also, blood
pressure should be controlled as previously discussed, and statins should be prescribed to reduce
the risk for cardiovascular events for patients with
the metabolic syndrome. If the patient also meets
criteria for diabetes, then glucose should be controlled with medications.
333
Referrals
In some patients, referral to an internist or cardiologist may be indicated if the patient is not already
followed by someone. A general internist is capable
of managing most clinic patients and will consult a
cardiologist when necessary. Table 2 presents general principles to guide appropriate referrals and
represents the opinion of the authors.
Summary
Erectile dysfunction is an early marker for systemic
atherosclerosis and predicts CAD and cardiac
events; thus, all patients presenting with ED should
undergo a basic cardiovascular evaluation. Patients
with ED should be encouraged to adopt a healthy
lifestyle, including smoking cessation, and weight
loss through diet and exercise. Identifying and
modifying cardiovascular risk factors is a simple
way to make a major impact on morbidity and
mortality in the high-risk population with ED. These
lifestyle changes may not only improve the patient’s
sex life, but it may also save their life.
International Journal of Impotence Research
Modifying cardiovascular risk in erectile dysfunction
BG Schwartz and RA Kloner
334
Table 2 Referral guidelines for a patient with cardiac disease
Referral
History
Examination
Objective data
Optional
Asymptomatic
p1 cardiac risk factor responsive
to lifestyle changes
No abnormality
p1 cardiac risk factor responsive to lifestyle
changes
General
internist
Cardiac risk factor(s) not responsive to
lifestyle changes
X2 cardiac risk factors
Mild stable angina
Atypical chest pain
NYHA class I or II CHF
Claudication or ulcerations
Clubbing or ulcers
Cardiac risk factor(s) not responsive to
Edema or JVD
lifestyle changes
Distant lung sounds, rales X2 cardiac risk factors
or rhonchi
Abnormal X-ray
Displaced PMI
Mildly abnormal EKG
Murmur
Mildly abnormal echocardiogram
Fourth heart sound
Cardiologist
Known CAD
Moderate or severe stable angina
Unstable angina (emergent)
Ongoing angina (emergent)
NYHA class III or IV CHF (emergent)
Orthopnea or paroxysmal nocturnal dyspnea
Palpitations or syncope
Cardiac thrill or
prominent murmur
Third heart sound
EKG suggesting previous myocardial
infarction (Q waves)
EKG suggesting ongoing ischemia (emergent)
Severely abnormal echocardiogram
Abnormal cardiac stress test
Abbreviations: CAD, coronary artery disease; CHF, congestive heart failure; EKG, electrocardiogram; JVD, jugular venous distension;
NYHA, New York Heart Association; PMI, point of maximal impulse.
Based on the opinions of the authors.
Conflicts of interest
The authors declare no conflict of interest.
12
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