ISSN: 2047-2919 ANDROLOGY

REVIEW ARTICLE

Correspondence:
Gabriele Fragasso, Heart Failure Clinic, Ospedale Erectile dysfunction in heart failure
San Raffaele via Olgettina 60, Milano 20132 Italy.
E-mail: gabriele.fragasso@hsr.it patients: a critical reappraisal
Keywords: L. Alberti,* C. Torlasco,* L. Lauretta,* M. Loffi,* F. Maranta,* A. Salonia,†
beta-blockers, erectile dysfunction, heart failure, A. Margonato,* F. Montorsi† and G. Fragasso*
medical therapy
*Heart Failure Clinic, Ospedale San Raffaele, Milano, Italy and †Urology Department, Ospedale San
Raffaele, Milano, Italy
Received: 31-Jul-2012
Revised: 15-Nov-2012
Accepted: 19-Nov-2012

doi: 10.1111/j.2047-2927.2012.00048.x

SUMMARY
Heart failure (HF) is a complex clinical syndrome with a constantly increasing incidence and prevalence in western countries. Total
absence of sexual activity is registered in 30% of HF patients. Moreover, HF-induced reduction in exercise tolerance, side effects of
HF medications and the coexistence of shared risk factors between HF and sexual dysfunction may further aggravate the sexual
health of HF patients. The purpose of this review is to examine the pathophysiological mechanisms behind the association of erectile
dysfunction (ED) and HF, the potential therapeutic approaches and the eventual indications for sexual activity in HF patients. Med-
line and Cochrane Library search was performed from January 1970 through October 2012 to retrieve relevant papers outlining the
association between ED and HF. Many evidences have outlined a tight association between ED and HF pathophysiological stand-
point. Shared risk factors, common pathogenic traits and epidemiologic association represent some of the links between these condi-
tions. Erectile dysfunction has been recognized as an earlier predictor of cardiovascular events; moreover, HF itself may cause and/
or worsen ED because of its particular feature and co-morbidities. Furthermore, some cardiovascular drugs may contribute to
impaired erectile function. In stable patients with stable HF, sexual activity is generally not contraindicated but it should be encour-
aged, as a form of moderate-intensity physical exertion. An effective treatment of ED in HF patients should be founded on the correc-
tion of reversible risk factors, on the choice of cardiovascular drugs with the lowest effect upon patient’s erectile function, and on the
use of phosphodiesterase-5-inhibitors. Physicians should be aware of the close relation between HF and ED and of the related clini-
cal and therapeutic implications, in order to improve patients quality of life and clinical outcome.

INTRODUCTION Among the different aspects contributing to the definition of

Heart failure (HF) is a complex clinical syndrome that may
result from any structural or functional cardiac disorder impair-
ing the ability of the heart to fill with or eject blood. Incidence
and prevalence of HF are constantly increasing, due to improved
management of coronary disease and increased life length
expectancy. In western countries, HF prevalence ranges between
1 and 2%, and it is expected to double in the next 30 years (Rosa-
mond et al., 2008). The Framingham study demonstrated a
direct correlation between age and incidence of HF, along with a
greater prevalence in men than in women (Cowie et al., 1999).
Heart failure is secondary to ischaemic heart disease and idio-
pathic dilated cardiomyopathy in 60% and in 20% of patients,
respectively. Valvular defects, hypertension and other causes
account for the remaining cases. Typical HF manifestations
include peripheral venous congestion, reduction in exercise tol-
erance and dyspnoea, which systematically lead to quality of life
(QoL) impairment.
QoL, sexual activity has certainly a place of paramount impor-
tance. Many studies (Schwarz et al., 2006, 2008; Hebert et al.,
2008, 2009) have demonstrated the strong impact of HF on sex-
ual health, depending both on psychological and physical fac-
tors. Patients concern about the potential risk inherent to sexual
activity leads to total absence of sexual activity in 30% of HF
patients (Bocchi et al., 2002). Moreover, HF-induced reduction
in exercise tolerance, side effects of HF medications and the
coexistence of shared risk factors (Drory et al., 1998, 2000; Feld-
man et al., 2000) between HF and sexual dysfunction may fur-
ther aggravate the sexual health of HF patients. In fact, ED and
HF share several risk factors and pathogenetic mechanisms
(Jackson et al., 2010).
We sought to review the pathophysiological mechanisms
behind the association of ED and HF, the potential therapeutic
approaches and the eventual indications and contraindications
for sexual activity in HF patients. Literature search was

© 2013 American Society of Andrology and European Academy of Andrology Andrology, 2013, 1, 177–191 177
L. Alberti et al.
performed to retrieve relevant papers outlining the association
between ED and HF. Medline and Cochrane library was
searched from January 1970 through October 2012, using the fol-
lowing keywords: ‘heart failure’, ‘cardiovascular diseases’, ‘erec-
tile dysfunction’, ‘sexual dysfunction’, ‘endothelial dysfunction’.
The reference lists of the identified publications were reviewed
for additional references.
Erectile dysfunction and heart failure
A significant association between ED and cardiovascular dis-
eases (CVD) has been confirmed in many studies, meta-analysis,
reviews and consensus conferences (Kostis et al., 2005; Rastogi
et al., 2005; Jackson et al., 2010). In this context, published data
evidence an increased prevalence of ED, and sexual dysfunction
as a whole, in cardiovascular patients, and, vice versa, an
increased prevalence of CVD in patients with ED (Guo et al.,
2010); overall, men with ED share numerous comorbid condi-
tions with those subjects with cardiovascular disorders (Lau-
mann et al., 1999). Rosen et al. (2004), for instance, showed a
significantly higher prevalence of hypertension, angina, high
cholesterol, diabetes and depression in men with ED as com-
pared with men with normal erectile function. This association
correlates with an increased prevalence of ED in cardiovascular
patients. Indeed, patients experiencing acute coronary syn-
dromes or undergoing cardiac revascularization often report a
decrease in their sexual activity due to impaired erectile function
and decreased libido (Lai et al., 2011). Psychological factors also
play a significant role, since patients may be afraid of triggering
new cardiovascular events during sexual activity. At present, ED
has even been proposed as an early predictor of coronary artery
disease (CAD) (Thompson et al., 2005; Riedner et al., 2011); in
this context, a number of data evidence how ED could anticipate
CAD manifestation up to 3 years in advance (Montorsi et al.,
2006; Hodges et al., 2007). Among the different CVD manifesta-
tions, a particular correlation between HF and ED has been also
highlighted. Overall, a growing body of evidence shows that
patients with cardiovascular risk factors complaining of ED
should also undergo a comprehensive cardiological evaluation.
Montorsi et al. found that cardiovascular symptoms were pre-
ceded by ED in almost 70% of patients, preceding angina and
cardiovascular events of 2–3 and of 3–5 years, respectively (Mon-
torsi et al., 2003). Schouten et al. (2008) evaluated 7945 men
aged 50–70. They showed that ED is prospectively associated
with CVD, with a hazard ratio [HR] of 1.6 (95% CI: 1.2–2.3) for
reduced erectile rigidity and 2.6 (95% confidence interval (CI):
1.3–5.2) for severely reduced erectile rigidity. Baumha €kel &
Bo€ hm (2007) showed that left ventricular dysfunction is an inde-
pendent risk factor for ED, unrelated to severity of HF symptoms
(p = 0.001). In addition, ED manifestation preceded cardiovas-
cular events by 3 years. The ONTARGET/TRANSCEND trial
demonstrated that ED could be a potent independent predictor
of all-cause death (HR 1.84, 95% CI: HR 1.21–2.81, p = 0.005)
and of the composite end point of cardiovascular death, myocar-
dial infarction, stroke and HF in men with cardiovascular dis-
eases (HR 1.42, 95% CI: 1.04–1.94, p = 0.029) (Bo € hm et al., 2010).
A recent cohort study by Apostolo et al. has shown a strong cor-
relation between ED and HF. Indeed, investigators found an ED
prevalence of 69.3% in patient with HF. Moreover, in the sub-
group of patients with ischaemic HF, ED prevalence raised up to
81.1% (Apostolo et al., 2009). These data appear even stronger
178 Andrology, 2013, 1, 177–191
ANDROLOGY
when compared with prevalence of ED in the general popula-
tion: the Second Princeton Consensus Conference actually esti-
mated an ED prevalence of 50% in 60 year old men (Kostis et al.,
2005). In the same study, evaluating 101 HF patients, multivari-
ate regression has established a link between diabetes mellitus,
anaemia and ED among HF patients. No association between
ED and left ventricular ejection fraction, natriuretic peptide lev-
els or chronic renal failure has been proven.
Erectile dysfunction and heart failure risk factors
Erectile dysfunction and Heart failure are tightly associated
to the same risk factors (Table 1) (Laumann et al., 1999; Fung
et al., 2004). These include both not modifiable conditions,
such as ageing (Bacon et al., 2003) and modifiable conditions,
such as obesity, altered lipid profile, hypertension and diabe-
tes mellitus (Grover et al., 2006). Recreational habits, for
instance cigarette smoking, yield a strong unfavourable impact
on both conditions, as evidenced by the FAMHES trial (Wu
et al., 2011). This study evaluated 2 686 men, aged 20–79, with
a 1-year follow-up. Data adjusted for age, alcohol drinking,
physical activity, hypertension, diabetes, dyslipidemia and
obesity, showed a significantly increased risk of ED in smokers
(namely, more than 20 cigarettes die) than in non-smokers
(odds ratio = 1.23; 95% CI: 1.03–1.49; p = 0.02). Consistently
with these findings, improving cardiac risk factors profile in
mid-life may decrease the risk of ED as well as CVD in old
age (Fung et al., 2004).
Endothelial dysfunction has been suggested as the potential
common pathophysiological mechanism underlying ED, CVDs,
diabetes and metabolic syndrome (Vlachopoulos et al., 2008). At
present, there is a general agreement on the fundamental role of
endothelial dysfunction in the development and progression of
cardiovascular and metabolic diseases (Davignon & Ganz, 2004),
and the role of endothelium in penile erectile function has also
been extensively discussed (Solomon et al., 2003; Costa & Virag,
2009; Averbeck et al., 2012).
Erection physiology: the case for endothelial dysfunction
The acquisition and maintenance of penile erection is primar-
ily a vascular phenomenon, triggered by neural signals and facil-
itated by the presence of appropriate hormonal and
psychological conditions. Nitric oxide (NO) plays a fundamental
role in maximizing arterial blood flow and penile engorgement
by acting as a local neurotransmitter, facilitating the relaxation
of intracavernosal trabeculae (Gratzke et al., 2010). High levels
of intrapenile NO are necessary for normal erectile function.
Nitric oxide is synthesized in the endothelial cells from citrulline
and oxygen by the nitric oxide synthase (NOS) enzyme. In
patients with endothelial dysfunction, this process becomes
inefficient (Wu et al., 2011). In fact, endothelium is an active bio-
logical tissue, which constantly secretes metabolic factors. Any
injuring condition, like atherosclerosis or metabolic unbalances,
leads to a reduction in endothelial function (Piatti et al., 2000,
2003a,b), which is characterized by an impaired synthesis and
an increased NO degradation, and to an increased permeability
of the endothelium to plasma constituents. Clearly, endothelial
dysfunction reduces penile erection, because of the physiopath-
ological mechanisms discussed above (Costa & Virag, 2009) and
on this ground, many authors have recently focused on the need
to consider endothelial function assessment as a fundamental
© 2013 American Society of Andrology and European Academy of Andrology
ERECTILE DYSFUNCTION IN HEART FAILURE PATIENTS ANDROLOGY
Table 1 Common risk factors, markers and associate conditions for cardiovascular disease and erectile dysfunction

Risk factors Pathophysiology References

Age Impaired endothelial NO bioavailability Laumann et al. (1999), Walsh (2009), Hannan et al.
Impaired microvascular function (age-associated changes in microvessel (2010)
function are uncertain but may involve alterations in NO,
prostanoid, endothelium-derived hyperpolarizing factor and endothelin-1 pathways)
Associated CAD risk factors
Hypertension Left ventricular hypertrophy Burchardt et al. (2000), Giuliano et al. (2004),
Heart failure Hannan et al. (2011)
Myocardial ischaemia
Endothelial dysfunction
Atherosclerosis
Aneurysm formation
Dyslipidaemia Impaired endothelial function Fung et al. (2004), Solomon et al. (2006), Jackson et al.
Atheromatous lesion formation (2010), Huang et al. (2010), Raman et al. (2011)
Diabetes Impaired endothelial function Pyorala et al. (1998), Piatti et al. (2000), Desouza et al.
mellitus type Atherogenesis (2002), Potenza et al. (2009), Batty et al. (2010)
II Abnormalities in apoprotein and lipoprotein particle distribution
Glycosylation and advanced glycation end-products (AGE) in plasma and
arterial wall
‘Glycoxidation’ and oxidation
Procoagulant state
Insulin-resistance and hyperinsulinemia
Hormone-, growth-factor- and cytokine-enhanced smooth muscle cell
proliferation and foam cell formation
Peripheral neuropathy
Smoking Impaired endothelial function Bocchi et al. (2002), Rosen et al. (2004)
Arterial stiffness
Overweight Imbalance between endothelium-derived vasoactive factors favoring Bocchi et al. (2002), Piatti et al. (2003a,b),
vasoconstriction Corona et al. (2010a,b), Toque et al. (2011),
Endothelial inflammation Barton et al. (2012)
Sedentary Loss in central arterial compliance Derby et al. (2000), Hamburg et al. (2007),
lifestyle Metabolic dysfunction (increased plasma triglyceride levels, decreased levels of high- Jackson et al. (2010), Nualnim et al. (2011)
density lipoprotein -HDL- cholesterol, and decreased insulin sensitivity; reduction of
lipoprotein lipase –LPL- activity)
Impaired reactive hyperaemia (ameasure of peripheral vascular function)
Influence of mood
Depression Reduced adherence to medical prescription (medications and life style modifications) Bandini et al. (2010), Serrano et al. (2011)
Greater platelet activation and aggregation
Endothelial dysfunction
Impaired autonomic dysfunction (lower heart rate variability)
Psychogenic
Alcohol Alcoholic cardiomyopathy Klatsky et al. (1977), Diamond (1989),
Hypertension Jackson et al. (2006a,b), Kam et al. (2010)
Changes in heart rate variability (HRV) (acute consumption) HRV is defined as
fluctuations in inter-beat interval length which reflect the heart’s response to extra-
cardiac factors that affect heart rateHRV allows simultaneous assessment of both
sympathetic and parasympathetic activity and the interplay between them
Inhibition of hypothalamo-pituitary-testes axis
Impaired serum testosterone level
Decline of smooth muscle, choline acetyltransferase and NO synthase in the penis

Markers Pathophysiology References

Testosterone deficiency
Markers of endothelial dysfunction
Induces metabolic syndrome Stellato et al. (2000), Laaksonen et al. (2005),
Veno-occlusive dysfunction Corona et al. (2010a,b)
Impaired endothelial function and inflammation Libby et al. (1995), Reape & Groot (1999),
Ferri et al. (1999), Bocchio et al. (2004),
Hansson et al. (2006), Zouaoui Boudjeltia et al. (2007)

Associated Pathophysiology References

conditions

Metabolic Abdominal obesity: adiponectin has both vascular and metabolic actions, Bocchi et al. (2002), Esposito et al. (2005),
syndrome and may contribute importantly to the connection between metabolism Kupelian et al. (2006), Vlachopoulos et al. (2007),
and vascular dysfunction Suetomi et al. (2008), Pohjantahti-Maaroos &
Hyperlipidemia (see above) Palomaki (2011)
Glucose intolerance (see above)
Hypertension(see above)
Insulin restistance is associated with impaired endothelium-dependent
vasodilation and, specifically, with impaired insulin-stimulated
vasodilation

(continued)

© 2013 American Society of Andrology and European Academy of Andrology Andrology, 2013, 1, 177–191 179
L. Alberti et al.
Table 1 (continued)
Associated Pathophysiology
conditions
Chronic Atherosclerotic disease initiation and progression
Inflammation Atherothrombosis
Prediction of future clinical events: Acute coronary syndrome, following revascularization
procedures
Obstructive sleep Oxidative stress-induced endothelial dysfunction
apnoea (OSA) OSA causes pulmonary vasoconstriction, bradycardia, and decreased cardiac output, with
regional cerebral and myocardial vasodilation to preserve oxygen delivery to these critical
organs
Cardiac contractility and diastolic relaxation may be directly impaired by cyclic
hypoxaemia in OSA
Sympathetic activation
Insulin resistanceHypertension
Severe OSA itself may contribute directly to LV diastolic dysfunction
step in evaluating ED (Tamler & Bar-Chama, 2008). The macro-
scopic effects of endothelial dysfunction could be evidenced by
decreased arterial dilation in response to different stimuli, such
as adenosine or acetylcholine infusion or shear stress. In
particular, in normal vessels shear stress induces the so called
‘flow-mediated vasodilation’ (FMD), which can be measured by
echo Doppler imaging of the brachial artery before and after an
ischaemic stimuli. The ischaemia-induced vasodilation is an
index of vasomotor function and permits to estimate endothelial
function.
Role of endothelial dysfunction in heart failure
Heart failure is a complex syndrome associated to several met-
abolic imbalances (e.g. increased production of oxygen free radi-
cals, increased rest energy expenditure, altered glucose
tolerance). Additionally, peripheral blood supply reduction con-
tributes to worsen all pathological conditions mentioned above
and vice versa, leading to a vicious circle of HF progression and
impairment of the patient general conditions. Reduction in NO
availability due to impaired endothelial NOS activity and subse-
quent impairment in vascular dilation causes a decrease in
blood flow and oxygen supply, favouring free oxygen radical pro-
duction. This inflammatory substrate favours myocardial fibrosis
and progressive loss of contractile function, leading to left ven-
tricular remodelling and dilation (Torre-Amione et al., 1996).
Endothelial dysfunction is also linked with atherosclerosis devel-
opment and progression, facilitating cholesterol deposition in
the intimal wall. The endothelial lesion is not confined to coro-
nary vessels, but it generally involves the whole organism. In
fact, in presence of impaired endothelial function, inflammation
blood markers, such as TNF-alfa, interleukin-1, -6 and -18, are
consistently raised. These markers are released from endothe-
lium, circulating monocytes and platelets but also from lungs,
liver and the failing heart itself (Yndestad et al., 2006). The
response to medical treatment may depend on different effects
on the inflammatory state (Alfieri et al., 2008; Fragasso et al.,
2013).
Metabolic syndrome is defined as the contemporary presence
of raised triglycerides, reduced HDL cholesterol, raised blood
pressure and raised fasting plasma glucose. Metabolic syn-
drome, as shown by Rosen et al. (2004), is highly prevalent in
patients with ED and in patients with HF. As for other vascular
conditions, endothelial dysfunction is one of the pathophysio-
logical mainstays of metabolic syndrome (Piatti et al., 2000). The
180 Andrology, 2013, 1, 177–191
ANDROLOGY
References
Osman et al. (2006), Urbonaviciene et al. (2012)
Somers et al. (1995), Atkeson et al. (2009), Lavie
(2009), Budweiser et al. (2009), Szymanski et al.
(2011)
clinical implications of the pathophysiological components of
the metabolic syndrome on erectile and cardiac function have
been previously discussed across the manuscript.
Causes of erectile dysfunction in heart failure patients
Many factors contribute to the onset and progression of ED,
and most of them are predominant in HF patients. Moreover,
those factors are strongly connected, so usually they co-exist
and potentiate each other. Causes of ED in HF patients include
endothelial dysfunction, atherosclerosis, exercise tolerance
reduction, cardiac drugs, psychogenic factors and HF related
hypogonadism.
• Endothelial dysfunction. This pathological condition is
strongly associated with HF and may reduce NO production
and vascular dilation, which are fundamental steps through-
out the penile erection process (Piatti et al., 2000; Costa &
Virag, 2009).
• Atherosclerosis, which emerges as one of the main cause of
HF by determining myocardial ischaemia and necrosis, but it
may also induce penis blood flow impairment (Hodges et al.,
2007).
• Exercise tolerance impairment. Depending on the severity of
heart function, HF patients experience various degrees of
reduction in exercise tolerance, ranging from limitation on
physical exertion to limitation on basic activities of daily liv-
ing. Therefore, although the physical effort related to sexual
activity is relatively modest (Thorson, 2003), some HF
patients, especially those in NYHA class III–IV, cannot afford
it. Energy expenditure of sexual intercourse will be discussed
across the manuscript, along with the correlation between HF
stage and prevalence and severity of ED.
• Cardiac pharmacological treatment: due to their intrinsic
multiple vascular, metabolic and neuro-humoral effects,
many cardiovascular drugs are known to exert a negative
effect upon erectile function (Grimm et al., 1997; Karavitakis
et al., 2011). Different and specific effects of CV drugs will be
further discussed.
• Anabolic deficiency: metabolic imbalance is a typical feature
of HF patients and leads to increase catabolism and cardiac
cachexia. Anabolic hormones, including insulin-like growth
factor-1 (IGF-1), dehydroepiandrosterone sulphate (DHEA-S)
and total testosterone (TT), enhance exercise tolerance in
healthy men. Reduction of those hormones leads to reduction
in exercise capacity. Many studies demonstrate the increased
© 2013 American Society of Andrology and European Academy of Andrology
ERECTILE DYSFUNCTION IN HEART FAILURE PATIENTS
prevalence of anabolic deficiency in HF. Jankowska et al.
evaluated 208 HF patients and found TT and DHEA-S levels
inversely related to NYHA class, regardless of HF aetiology (all
p < 0.01) (Jankowska et al., 2009). Moreover, anabolic defi-
ciency is independently associated with increased mortality
and hospitalization in men with HF (Wehr et al., 2011). Obvi-
ously, very important clinical manifestations of anabolic defi-
ciency and hypogonadism are ED and reduced libido. These
data suggest that anabolic deficiency may exert a twofold neg-
ative effect on sexual function, reducing exercise tolerance
and decreasing penile function and libido.
• Psychogenic factors are very relevant in both conditions. HF
patients often suffer from depression, a condition known to
decrease libido and impair erectile function. Major depression
is associated to a decrease in pleasure, concentration, sex
drive, sleep and appetite. Gottlieb et al. (2004) demonstrated
a linear correlation between the extent of depression and the
severity of functional limitation in 155 HF patients. Depres-
sion, associated to concern about cardiac health may induce
performance anxiety, which increases sympathetic tone and
arteriolar constriction, finally decreasing penis blood flow.
Cardiac drugs and erectile dysfunction
Many cardiac drugs may be implicated in the development of
ED. A major role has been suggested for thiazide diuretics, beta
blockers and lipid-lowering drugs.
Thiazide diuretics
Thiazide diuretics are commonly used to unload HF patients,
in association with loop diuretics, especially when the latter do
not achieve the desired diuretic effect. These drugs are also often
prescribed among hypertensive patients, especially after the JNC
VII, which indicated them as the first line therapy for uncompli-
cated hypertension (Chobanian et al., 2003). However, they have
been associated to ED in a number of studies. In the Treatment
of Mild Hypertension Study (TOMHS) (Grimm et al., 1997) a
higher incidence of ED has been reported at 2 years in patients
treated with chlorthalidone compared with the placebo group.
These results probably depend on the vascular and metabolic
abnormalities caused by these drugs, including endothelial dys-
function and increased vascular oxidative stress (Zhou et al.,
2008), hyperlipidemia (Lithell, 1991), insulin resistance (Ferrari
et al., 1991), new onset diabetes mellitus (Eriksson et al., 2008;
Gupta et al., 2008), and stimulation of the sympathetic (Grassi
et al., 2003) and renin–angiotensin–aldosterone (RAAS) systems
Burnier & Brunner (1992). In the ALLHAT study a higher inci-
dence of type 2 diabetes was observed in the thiazide-treated
group compared with the other treatment groups (Whelton
et al., 2005).
Beta blockers
Beta blockers (BB) are a mainstay of HF therapy, with a thera-
peutic efficacy which does not only rely on heart rate reduction
alone (Fragasso et al., 2008). Conversely, their role in contribut-
ing to ED is still controversial. Indeed, BB have been suspected
to be an important cause of ED (Croog et al., 1986), depending
on their adverse metabolic effects and on increased peripheral
vascular resistance and arteriolar tone, but a systematic review
of randomized, controlled trials found only a small increase in
risk of sexual dysfunction with beta blocker therapy (5 per 1 000
© 2013 American Society of Andrology and European Academy of Andrology
ANDROLOGY
patients treated) (Ko et al., 2002). The key of the problem lies in
the different effects exerted by different BB, depending on their
pharmacologic and ancillary properties profile. First and second
generation BB (e.g. propranolol and atenolol) are well-known to
reduce sexual function. The link between early generation BB
and ED could be found in some central nervous system effects
(for those hydrophilic molecules passing the hematoencephalic
membrane) and in worsening endothelial function, eventually
contributing to arteriolar vasoconstriction. Additionally, first
generations BB have been consistently shown to adversely affect
lipid metabolism (Eliasson et al., 1981). In contrast, third gener-
ation BB have been shown to be devoid of detrimental effects on
erectile function and metabolic parameters. In this context,
many studies have focused on nebivolol, a third generation
selective b1-blocker, lacking of intrinsic sympathomimetic activ-
ity, which has a unique haemodynamic profile. Indeed nebivolol
is the only BB able to modulate endothelial NO system (Dessy
et al., 2005), by increasing the availability of endothelial NO.
This effect results in coronary and systemic vasodilation and,
thereby, in peripheral resistance reduction and counteraction of
endothelial dysfunction. This effect of restoring endothelial
function has recently been tested on penile function, outlining
that treatment with nebivolol may significantly potentiate erec-
tile response both in diabetic and non-diabetic rats, regardless
of its effects on blood pressure. It also improved response to sil-
denafil in diabetic rats, completely reversing ED after sildenafil
administration (Angulo et al., 2010). In a study evaluating 48
hypertensive patients nebivolol, as compared with metoprolol,
played a significantly greater beneficial effect on erectile func-
tion. Nebivolol administration also correlated with an increase
in orgasmic function, sexual desire and intercourse satisfaction,
while none of these effects was observed with metoprolol (Brixi-
us et al., 2007). Furthermore, Doumas et al. evaluated 44 hyper-
tensive men treated with atenolol, metoprolol or bisoprolol. 29
(65.9%) of these patients suffered from baseline ED. After at least
6-months BB treatment, all patients were switched to nebivolol.
After 3 months, 20 out of 29 (69%) patients reported a significant
improvement in erectile function and in 11 out of these 20, erec-
tile function was even normalized (Doumas et al., 2006). Blood
pressure control was as satisfactory as with other BB in all
patients. These data confirm the optimal profile of nebivolol in
the context of ED. Moreover, results of the SENIORS study
showed efficacy and safety of nebivolol in the setting of chronic
HF in patients older than 70 (Flather et al., 2005), and nebivolol
is currently registered in most European countries (but not in
the USA) for HF therapy. On this basis nebivolol can be consid-
ered as an efficient option in patients older than 70 that experi-
enced ED. However, since no data from randomized controlled
trials have pointed out the safety and efficacy of nebivolol in the
settings of HF in patients younger than 70, further studies are
needed to better focus this issue.
Lipid-lowering drugs
Considering that HF is mostly a consequence of ischaemic
heart disease, lipid lowering drugs, in particular statins, emerge
as a mandatory therapy in most patients with HF. Hyperlipid-
emia is also considered a significant risk factor for ED, being the
only active risk factor in up to 42% of patients (Dog ru et al.,
2008). Saltzman et al. (2004) demonstrated that atorvastatin
alone could lead to an improvement in erectile function in men
Andrology, 2013, 1, 177–191 181
L. Alberti et al.
with hypercholesterolaemia as the only risk factor for ED. This
study does not clarify if the improvement in erectile function
was directly related to reduction in cholesterol levels and/or to
the pleiotropic, non-lipidic effects of statins. Studies in rats and
diabetic mice show that atorvastatin or rosuvastatin can amelio-
rate endothelial function in corpora cavernosa and also amelio-
rate sildenafil responsiveness (Miner & Billups, 2008). Results in
humans are still controversial. A placebo-controlled randomized
trial in 12 men who were non-responders to sildenafil suggested
that atorvastatin improved sexual function and the response to
sildenafil (Herrmann et al., 2006). A larger trial in 131 men also
showed that atorvastin can ameliorate responsiveness to silde-
nafil, especially in those patients who have moderate to severe
ED. None of these patients regained normal, unassisted erectile
function (Dadkhah et al., 2010).
On the other hand, other studies have shown the occurrence
of ED with statins and fibrate therapy (Bruckert et al., 1996; de
Graaf et al., 2004). ED associated with simvastatin usage has also
been reported by the French Pharmacovigilance System Data-
base (Do et al., 2009). In addition, Solomon et al. (2006) reported
that statin therapy in patients at high-risk for CVD may lead to
further deterioration of ED. Therefore, the risk of ED induced by
statins should also be considered in some cases.
In conclusion, statins effects on ED are potentially positive but
still not fully understood. Further investigations are needed to
determine if statin administration by itself could ameliorate
erectile function and phosphodiesterase type 5 inhibitors
(PDE5Is) responsiveness in treated patients, as well.
SEXUAL ACTIVITY IN HEART FAILURE
Cardiac patients are often concerned about potential trigger-
ing of myocardial events during sexual intercourse and, as a con-
sequence, they might have sex less frequently or they may
abstain at all. Additionally, their physicians often do not have
adequate knowledge of the issue and sometimes they do suggest
to reduce sexual activity, by default. Actually, moderate physical
exercise is not contraindicated in stable HF, but it is indeed rec-
ommended. In fact, the reduction in exercise tolerance experi-
enced by many HF patients leads to a progressive reduction in
daily activities. Restriction of activity promotes physical decon-
ditioning, which may adversely affect clinical status and contrib-
ute to the exercise intolerance of patients with HF, creating a
vicious circle of deconditioning and exercise intolerance. In
addition, low left ventricular ejection fraction typical of HF plays
a key role in the reduction of exercise capacity and, as a conse-
quence, of sexual activity in patients with HF.
Table 2 New York Heart Association functional classification of heart failure
NYHA Severity based on symptoms and physical activity
Class
NYHA I No limitation of physical activity. Ordinary physical activity does not
cause undue fatigue, palpitation, or dyspnoea
NYAH II Slight limitation of physical activity. Comfortable at rest, but ordinary
physical activity results in fatigue, palpitation, or dyspnoea
NYAH III Marked limitation of physical activity. Comfortable at rest, but less
than ordinary activity results in fatigue, palpitation, or dyspnoea
NYAH IV Unable to carry on any physical activity without discomfort.
Symptoms at rest. If any physical activity is undertaken, discomfort is
increased
182 Andrology, 2013, 1, 177–191
ANDROLOGY
Functional impairment in HF is mainly characterized by fati-
gue, dyspnoea and development of peripheral oedema. Since
symptoms severity is directly correlated with heart function
impairment, the most widely used clinical classification of HF is
the New York Heart Association (NYHA) classification, which
defines four functional classes (Table 2).
A direct correlation between HF severity and ED has been also
demonstrated. Apostolo et al. showed a direct correlation
between NYHA HF classification and prevalence and severity of
ED, assessed by the International Index of Erectile Function
(IIEF): the rate of patients with normal or mildly impaired erec-
tile function decreased from 70 to 50%, 10% and to almost 0% in
NYHA I, NYHA II, and NYHA IV, respectively (Apostolo et al.,
2009). On the other side, the prevalence of moderate to severe
ED increased from 25% in NYHA to 90% in NYHA IV patients.
According to these data, cardiopulmonary testing was performed
in all study patients and showed a reverse correlation between
ED severity and peak oxygen consumption (VO2) (the maximal
oxygen uptake during exercise, with a normal value of  20 mL/
min/kg). Peak VO2 is known to have a strong linear correlation
with both cardiac output and muscular blood flow (Reddy et al.,
1988) and it is a predictor of cardiovascular events. Peak VO2 is
reduced in HF, with an inverse relation with NYHA class, averag-
ing around 10 mL/min/kg in the most severe cases. Assuming
that sexual activity requires, during the orgasmic phase, a VO2
between 10 and 14 mL/min/kg, investigators found that in 10/
29 patients with peakVO2 between 10 and 14 mL/min/kg there
was a normal or slightly reduced sexual performance, while none
of the individuals with peakVO2 <10 mL/min/kg reported a nor-
mal sexual function (Apostolo et al., 2009). Interestingly enough,
regardless of the presence of HF, level of sexual function appears
to have a significant link with the 6 min walking test (6MWT)
(Jaarsma et al., 1996). In the 6MWT the patient is asked to walk
for six minutes at the maximum speed on a pre-measured dis-
tance, usually a hospital corridor. Global distance is then mea-
sured and provides an estimate of exercise capacity. Peripheral
oxygen saturation is also measured and at the end of the test a
questionnaire is administered to evaluate physical exertion
capacity.
In this context, many studies in HF patients have demon-
strated the safety and efficacy of physical exercise on symptoms
reduction and QoL improvement. There is general agreement on
the beneficial effects exerted by aerobic exercise training in HF
patients, as outlined by ACC/AHA guidelines (Jessup et al.,
2009). In fact, regular physical exercise increases peak VO2 (Be-
lardinelli et al., 1996), improves muscle energetic metabolism
and gas exchange, reduces fatigue, reduces sympathetic tone
and increases vagal tone at rest, thereby restoring autonomic
cardiovascular control towards normal (Roveda et al., 2003).
Moreover, physical exercise reduces neurohumoral activity, low-
ering resting levels of aldosterone, vasopressin and natriuretic
peptide, reduces inflammatory cytokines and improves endothe-
lial function (Braith et al., 1999; Adamopoulos et al., 2002). Aero-
bic exercise also improves hemodynamic, since it lowers
peripheral vascular resistance (Hambrecht et al., 2000a,b) and
improves left ventricle ejection fraction (Haykowsky et al., 2007).
Consistently with those evidences, exercise training has been
shown to reduce hospitalization and improve survival in HF
patients. The HF-ACTION (The Heart Failure: A Controlled Trial
Investigating Outcomes of Exercise Training) trial was designed
© 2013 American Society of Andrology and European Academy of Andrology
ERECTILE DYSFUNCTION IN HEART FAILURE PATIENTS
to evaluate the efficacy and safety of exercise training in HF
patients. A cohort of 2331 NYHA class II to IV patients was ran-
domly assigned to conventional therapy or conventional therapy
plus aerobic exercise, with the specific end points to assess all
cause mortality and hospitalizations. After adjusting for HF aeti-
ology, the results did not show significant differences, but the
analysis demonstrated a relevant decrease in primary end points
with the exercise training programme, after stratification for
baseline major prognostic factors (Flynn et al., 2009).
Sexual intercourse could be considered a modest exertion,
since it averages 2–3 metabolic equivalents (METs) in the pre-
orgasm phase and 3–4 METs during orgasm. The MET is a unit
of resting oxygen uptake, equivalent to 3.5 mL O2 uptake/kg/
min. As an example, 2 METs is the energy expenditure for walk-
ing at 3 km/h on ground level; walking at 5 Km/h correspond to
3 METs. Compared with higher-intensity physical exertion, such
as cycling at 16 Km/h (6–7 METs) or running on the treadmill
(13 METs), the exertion of sexual activity is relatively modest
(Thorson, 2003). Furthermore, studies performed in the ‘real-life’
setting showed a peak heart rate of 117 beats per minute (bpm)
during sexual intercourse, which was lower than the heart rate
during normal daily activities (mean 129 bpm) (Hellerstein &
Friedman, 1970). The clinical implication of these observations
is that sexual intercourse is associated with a modest increase in
myocardial oxygen demand with a peak lasting only a brief per-
iod of time.
Clearly, physical exertion is not indicated in every HF patient.
The Second Princeton Consensus Conference has developed rec-
ommendations for the management of sexual dysfunction in HF
patients (Kostis et al., 2005). These guidelines suggest a prior
stratification in low-risk (NYHA I), intermediate risk (NYHA II)
and high risk (NYHA III–IV) patients. Low-risk patients have no
limitation on their sexual activity and do not need further inves-
tigations. High-risk patients should be assessed for their cardiac
condition before having sexual activity because also mild exer-
cise might decompensate their cardiac status. Intermediate risk
patients should be further stratified by exercise testing, echocar-
diography and 6MWT in high- or low- risk.
Assuming that sexual intercourse is not contraindicated in
patients with stable HF, there is still the problem of the highest
prevalence of sexual dysfunction in chronic heart failure (CHF)
patients to deal with. The management of ED in HF patients
should pass across three steps (i) the correction of all modifiable
risk factors, (ii) the choice of HF drugs with the best sexual pro-
file, and (iii) the use of PDE5is.
Correction of risk factors
Even though some factors like age or family history could not
be modified, an important component of the treatment of sexual
dysfunction is the correction of reversible causes, leading to res-
toration of endothelial function.
There is general agreement on the statement that the severity
of ED significantly correlates with the level of exposure to smok-
ing. Cigarette smoking has been correlated to ED independently
from the increase in cardiovascular risk (Chew et al., 2009).
Mannino et al. (1994) examined 4 462 US Army Vietnam-era vet-
erans aged 31–49 years: of those, 1162 never smoked, while 1 292
were former smokers and 2008 current smokers. Reported preva-
lence of ED was 3.7% among current smokers, 2.0% among for-
mer smokers, and 2.2% among those men who never smoked
© 2013 American Society of Andrology and European Academy of Andrology
ANDROLOGY
(p = 0.005). Pourmand et al. (2004) studied 118 former smokers
and 163 active smokers, demonstrating that quitting the smoking
habit could prevent ED progression and, in 25% of cases, lead to
an improvement in ED. Chew et al. (2009) found that former
smokers and ever smokers have significantly higher odds of ED
as compared with those who never smoked. The mechanism
behind this association probably depends on the cigarette smok-
ing-dependent increased prevalence of arterial constriction, with
reduction in oxygen supply and increased free oxygen radical
production. Cigarette smoking can also induce impairment of
endothelial function and reduced NO bioavailability (Tostes
et al., 2008). Patterns of ED in former smokers suggest that there
may be a latent interval between active smoking and symptom-
atic ED, involving a process initially triggered by smoking: in fact,
odds of ED in former smokers were significantly higher 6–
10 years following cessation of smoking than <6 or >10 years
(Chew et al., 2009). Another study in 40 smokers with ED under-
going penile colour Duplex ultrasound at baseline and after 24–
36 h after smoking cessation demonstrated a significant improve-
ment in end-diastolic velocity and a trend towards an increase in
peak systolic velocity trough the penile artery (Sighinolfi et al.,
2007), confirming the short term detrimental effects of smoking.
Many studies in rats have demonstrated how regular exercise
training could improve ED, either associated to co-morbidities
(e.g. diabetes mellitus) or not. Investigators attribute these
results to an improvement in vascular response and to the re-
establishment of a better balance between NO production and
NO inactivation. Specifically, a trial has shown an increase in the
expression of penile endothelial (eNOS) and neuronal NOS
(nNOS) in old and young trained rats, compared with old and
young non-trained rats (Ozbek et al., 2010). A small prospective
study on 22 hypertensive men showed an improvement in erec-
tile function after 8 weeks of daily exercise training compared
with a sedentary population (Lamina et al., 2009). As previously
discussed, lowering blood lipid levels usually yields a positive
effect on ED in both the general population and in HF patients.
Even if lipid lowering drugs (HGM-CoA reductase inhibitor and
fibrate) have been associated to ED (Bruckert et al., 1996; de
Graaf et al., 2004), two recent studies demonstrated that statin
administration improves response to sildenafil in hypercholeste-
rolaemic men with ED who were not initially responsive to silde-
nafil (Dadkhah et al., 2010) and that atorvastatin administration
may ameliorate response to sildenafil in experimental diabetes
(Morelli et al., 2009). Therefore, where indicated, statins can be
safely administered in patients with ED. Finally, Khoo et al.
(2010) have recently demonstrated an improvement in sexual
function associated to a 10% reduction in body weight, both in
diabetic and non-diabetic obese patients. In fact, a significant
association between weight loss and increase in insulin sensitiv-
ity and plasma testosterone levels have been established.
Hypertension is a well-described risk factor for ED. The preva-
lence of ED is significantly greater among men with hypertension
than in the general population. In the Massachusetts Male Ageing
Study, the age-adjusted prevalence of complete ED was 15% in
patients with treated hypertension and was associated with the
duration and severity of hypertension (Feldman et al., 1994).
Pharmacological treatment of heart failure in patients with ED
Many cardiovascular drugs, such as BBs, angiotensin convert-
ing enzyme (ACE) inihibitors/angiotensin receptors blockers
Andrology, 2013, 1, 177–191 183
L. Alberti et al.
(ARBs), aldosterone antagonists and statins, have been shown to
exert a significant impact upon the prognosis in HF patients
(Jessup et al., 2009). This clearly means that withdrawing any of
them may be difficult. However, as discussed above, different
drugs of the same class can exert slightly different effects on
metabolic and vascular function. When using drugs potentially
responsible for ED, like BB, clinicians should carefully choose
the best molecule to administer for any single patient. As previ-
ously outlined, newly developed BB, such as nebivolol, should
be preferred.
Other commonly adopted HF drugs, such as ACE-inhibitors
and ARBs, yield positive effects on vascular function and, usually,
they do not exert negative effects on ED. The Trial on Reversing
ENdothelial Dysfunction (TREND) demonstrated that quinalapril
improves endothelial function in normotensive patients without
CAD, severe hyperlipidemia or evidence of HF (Mancini et al.,
1996). Investigators attributed these results to the reduction in
the vasospastic effect and free radical generation by angiotensin
II and to enhancement of endothelial NO production. Moreover,
in a pilot study enalapril showed a positive effect on cavernosal
perfusion and erectile function in middle aged patients with
atherosclerotic ED (mean age 60  6.8 years) (Speel et al., 2005).
In a cross-over study, Fogari et al. (2001) treated 160 hyperten-
sive men without prior sexual dysfunction with carvedilol or val-
sartan; patients were divided in two groups and assumed placebo
for 4 weeks, then carvedilol 50 mg/die or valsartan 80 mg/die for
16 weeks and then, after additional 4 weeks placebo step,
switched to the other drug for 16 weeks. The results of this latter
trial showed a worsening in erectile function during the carvedi-
lol phase, which was not confirmed during the valsartan period.
The results were confirmed by the switch off and showed a full
recovery of erectile function during valsartan assumption.
Moreover, a study evaluating 3 502 hypertensive patients treated
with valsartan 80–160 mg/die showed an improvement in erec-
tile function, orgasmic function and overall satisfaction both in
the whole group and in the subgroup of patients previously
treated with a different antihypertensive drug (Dusing, 2003).
Regarding the use of aldosterone blocking agents, a negative
effect of spironolactone on erectile function has been demon-
strated (Loriaux et al. 1976), probably due to the affinity of spir-
onolactone for progesteron receptors. Other drugs of the same
class, e.g. eplerenone, which has higher specificity for aldoste-
rone receptors, have been demonstrated to exert no negative
effect on sexual function. The Eplerenone Post-Acute Myocardial
Infarction Heart Failure Efficacy and Survival Study (EPHESUS)
(Pitt et al., 2003), was a randomized controlled study evaluating
6 642 HF patients, which showed an equivalence of eplerenone
to placebo with respect to the incidence of gynaecomastia and
ED. Therefore, when aldosterone antagonism is needed, the new
agent eplerenone should be preferred.
Diuretics are very frequently used in HF treatment, although
their effect on prognosis is not clear (Jessup et al., 2009). As dis-
cussed above, diuretics, especially thiazides, may impair erectile
function, probably by worsening metabolic balance (alteration
in glucose homeostasis, increasing in LDL and total cholesterol,
hypeuricemia) (Ferrari et al., 1991; Lithell, 1991; Eriksson et al.,
2008; Gupta et al., 2008; Zhou et al., 2008). Further studies are
needed to evaluate the effect of other classes of diuretics, such
as loop diuretics, on erectile function. However, while studies on
other diuretic agents are lacking, the administration of thiazide
184 Andrology, 2013, 1, 177–191
ANDROLOGY
diuretics should be avoided in HF patients with sexual
dysfunction.
Pharmacological treatment of erectile dysfunction in patients
with HF
It has been estimated that over 300 millions of people world-
wide will use sildenafil or other phosphodiesterases inhibitors
(PDE5i) by 2025 (Ayta et al., 1999), most of them having cardio-
vascular co-morbidities. PDE5is have been demonstrated to be
safe in men with CVD. Risk profile is similar in patients with and
without CAD and sildenafil has been shown to be safe even in
patients with multi-antihypertensive drug regimens regardless
of the classes, although some precautions should be taken in
order to minimize drugs-interaction risks (Jackson et al., 2006a,
b). The main contraindication to PDE5is is the contemporary
use of nitrates that can lead to severe hypotension as a conse-
quence of excessive cGMP accumulation and vasodilation. For
this reason guidelines recommend a 24-h time interval between
the administration of any NO donor and sildenafil (and vice
versa) (Cheitlin et al., 1999); for tadalafil and vardenafil interval
should be equal to 48 h. Sildenafil should also be used with cau-
tion and started at the lowest dose in patients taking a-blockers
to avoid symptomatic hypotension. Similar care should also be
taken for mixed a/b-blockers, such as carvedilol and labetalol.
Phophodiesterase type 5 and its isoforms 1, 3 and 4 are
expressed in the pulmonary arterial vasculature and they are
involved in the regulatory system of pulmonary arterial resis-
tance (Rabe et al., 1993). In details PDE5 seems to be overex-
pressed in pulmonary hypertensive lung, making PDE5
inhibition an ideal pharmacological target for pulmonary vascu-
lar disease (Rhodes et al., 2009). In fact, there are several studies
demonstrating safety and efficacy of sildenafil, alone or in com-
bination with iloprost and endothelin receptors antagonists, in
the treatment of idiopathic pulmonary hypertension. Adminis-
tration of sildenafil in patients with symptomatic pulmonary
arterial hypertension improves exercise capacity, WHO func-
tional class, and hemodynamics (Wilkens et al., 2001; Gali e
et al., 2005). Orally administered sildenafil (commercially
termed as Revatio®) is approved for primary pulmonary arterial
hypertension at the dosage of 20 mg three times a day.
Secondary pulmonary hypertension is a common finding in
patients with congestive HF and it is present in up to 78% of
patients. These patients have reduced exercise tolerance and
poor prognosis compared with patient without pulmonary
hypertension (Ghio et al., 2001). Pulmonary artery pressure
(PAP) and right ventricular function are important prognostic
factors for patients with left ventricle systolic dysfunction. The
effects of PDE5is on pulmonary hemodynamics of HF patients
suggest an activity similar to that reported for idiopathic PAH. In
patients with left ventricular dysfunction and secondary PAH,
50 mg of sildenafil did not affect systemic blood pressure but
improved cardiac output by balanced pulmonary and systemic
vasodilation (Lepore et al., 2005). Sildenafil has also been shown
to improve stress capacity and quality of life in patients with HF
and pulmonary hypertension (Lewis et al., 2007). These effects
appear operative even in more advanced HF patients. In this
context, Freitas et al. (2009) analysed the acute effects of 100 mg
sublingual sildenafil in patients with HF and pulmonary hyper-
tension awaiting a heart transplantation. They observed that sil-
denafil is an effective and safe alternative as a vasodilator during
© 2013 American Society of Andrology and European Academy of Andrology
ERECTILE DYSFUNCTION IN HEART FAILURE PATIENTS
the PAH reversibility test in patients with heart failure and await-
ing a heart transplant.
On this basis, usefulness of PDE5 inhibition in HF has grown
rapidly. Further evidence has come from the demonstration of a
variety of actions in addition to the effects on pulmonary hemo-
dynamics. Many in vitro and animal studies have provided the
interesting demonstration that chronic PDE5-inhibition is effec-
tive in the control of important cellular and molecular pathways
involved in the morphological and functional changes leading to
maladaptive left ventricular remodelling and HF. It appears that
sildenafil may exert a direct antyhypertrophic effect on myocytes
(Takimoto et al., 2005). Furthermore, sildenafil yields a protec-
tive influence on myocytes apoptosis (Das et al., 2005) can
reduce ischaemia-reperfusion damage (Salloum et al., 2008).
Guazzi et al. (2011) have demonstrated than 50 mg of sildenafil
three times a day can sinergically act with ACE-inhibitors and
BBs, modulating diastolic function and remodelling of left
chambers. Webster et al. (2004) observed that sildenafil can
improve QoL, ED and associated depression in patient with
chronic stable HF. These evidences of safety and efficacy of sil-
denafil in patient with HF and ED are encouraging but they need
to be confirmed by large randomized controlled trials (Cooper
et al., 2012).
Potential additional treatments for HF and ED
Other substances could be effective in treating HF and ED.
Considering endothelial dysfunction as a primary pathogenetic
factor in both conditions as comprehensively discussed in this
review, all drugs able to improve this important regulator of vas-
cular function could, at least theoretically, be beneficial. Among
the others, oral arginine administration could play a role. L-Argi-
nine has been shown to successfully restore endothelium-
dependent vascular responses in the coronary (Drexler et al.,
1991) and peripheral (Creager et al., 1992) arteries of hypercho-
lesterolaemic patients, in patients with microvascular angina
pectoris (Egashira et al., 1996; Piatti et al., 2003a,b), congestive
heart failure (Koifman et al., 1995; Rector et al., 1996), critical
limb ischaemia (Bode-Bo € ger et al., 1996) and CAD associated to
reduced monocyte adhesion to endothelial cells (Adams et al.,
1997). Furthermore, recent findings revealed that arginine-rich
medical food, coupled with therapy, improves vascular function,
exercise capacity and QoL in patients with stable angina (Max-
well et al., 2002). Additionally, L-arginine administration has
been shown to reverse the hemodynamic and rheological
changes caused by acute hyperglycaemia (Giugliano et al.,
1997). According to this evidence, L-arginine supplementation
could also improve endothelial-dependent vasodilatation in
patients with microvascular dysfunction, where endothelial dys-
function has been shown to play a major role (Drexler et al.,
1991). A study has also evidenced beneficial effects of medium
long-term oral administration of L-arginine on blood pressure
control and endothelial function in patients with hypertension
and microvascular angina (Palloshi et al., 2004). Anecdotical evi-
dence suggests that arginine could be an effective adjunctive
treatment also in HF patients (Hambrecht et al., 2000a,b). By
inference, oral arginine could be successfully employed in ED,
alone or in combination with 5PDEi, even if clinical evidence of
this is still poor (Gentile et al., 2009).
Capsaicin, a natural product of capsicum species (chili pepper
– capsicum frutescens), induces reflex coronary vasodilatation
© 2013 American Society of Andrology and European Academy of Andrology
ANDROLOGY
by stimulation of vagal C fibres. In experimental studies, capsai-
cin administration has been shown to evoke the release of calci-
tonin gene-related peptide (CGRP) (White et al., 1993), a
principal transmitter in sensory nerves (Kawasaki et al., 1988),
which also acts as one of the most potent endogenous vasodila-
tors yet discovered (Brain et al., 1985). Several endogenous
agents and conditions activate cardiac C-fibre afferents, with
subsequent local release of CGRP (Hua & Yaksh, 1993). During
myocardial ischaemia, C-fibre afferents not only convey the sen-
sation of pain, but there is also a local efferent release of CGRP
in the heart (Kallner, 1998). After being released, CGRP causes
coronary vasodilatation and attenuates the development of
myocyte death (Franco-Cereceda & Liska, 2000), probably
through a preconditionig mechanism (Li & Peng, 2002). In ani-
mal studies, capsaicin-induced increase in coronary flow and
heart rate (Oroszi et al., 1999) and hypotensive effects (Chen
et al., 1996) have been shown to be dependent on interplay
between CGRP and NO. The results of a preliminary study (Frag-
asso et al., 2004) have indicated that transdermal administration
of capsaicin can improve the ischaemic threshold in a signifi-
cant proportion of patients with CAD. This improvement is
likely depending on an increased availability of NO, as evi-
denced by the observed augmentation of NO levels at 6 h from
capsaicin patches application. CGRP levels did not change in
patients showing improved exercise during capsaicin treatment.
Rate-pressure product (RPP) was similar between placebo and
capsaicin, since the latter determined a decrease of blood pres-
sure balanced by an increase in heart rate, indicating a potential
beneficial effect also in patients with HF. On this basis, capsai-
cine could also play a role in ED. The erectile response to intra-
urethral infusion of capsaicin has suggested the activation of a
reflex arc between urethra and corpora cavernosa (Lazzeri et al.,
1994). Further studies are necessary to clarify if this arc is inte-
grated at central nervous system level or it is locally triggered,
and if it may have pathophysiologic implications. In summary,
whether the popular belief that chilli peppers containing capsai-
cine could improve erectile function in humans needs focused
studies.
Finally, despite cardiac transplantation and implantation of
left ventricular assistance devices has improved survival and
overall QoL in patients with terminal heart failure, their effects
on sexual activity is not clearly defined, depending probably by
the individual emotional response to such invasive therapies
(Basile et al., 2001; Marcuccilli et al., 2011). Nevertheless, in
these patients physical activity is usually encouraged and, as a
consequence, sexual activity is not contraindicated.
SUMMARY AND CONCLUSION
Heart failure and erectile dysfunction are two clinical condi-
tions characterized by a constantly increasing prevalence and by
a deep impact on patients QoL. Likewise, growing evidences
have outlined a tight association between the two conditions,
from the pathophysiological standpoint. Shared risk factors,
common pathogenic traits and epidemiologic association repre-
sent some of the links between these conditions. Erectile dys-
function has been recognized as an earlier predictor of
cardiovascular events and cardiovascular death; moreover, HF
itself may cause and/or worsen ED because of its particular fea-
ture and co-morbidities, ranging from impaired exercise toler-
ance to psychogenic factors and neurohumoral, metabolic and
Andrology, 2013, 1, 177–191 185
L. Alberti et al.
vascular modification. Furthermore, some cardiovascular drugs
may contribute to impaired erectile function.
In stable patients with stable HF, sexual activity is generally
not contraindicated; in contrast, it should be encouraged, as a
form of moderate-intensity physical exertion. An effective treat-
ment of ED in HF patients is possible and should be founded on
the correction of reversible risk factors, on the choice of cardio-
vascular drugs with either low or even none effect upon patient’s
erectile function, and on the use of PDE5is. Physicians should be
aware of the close relation between HF and ED and of the related
clinical and therapeutic implications, in order to improve
patients QoL and clinical outcome as well.
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