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ORIGINAL RESEARCH & REVIEWS
Longitudinal Risk of Developing Cardiovascular Diseases in Patients
With Erectile Dysfunction—Which Patients Deserve More Attention?
Edoardo Pozzi, MD,
1,2
Paolo Capogrosso, MD,
1
Luca Boeri, MD,
1,3
Federico Belladelli, MD,
1,2
Andrea Baudo, MD,
1,2
Nicolò Schifano, MD,
1,2
Costantino Abbate,
1
Federico Dehò, MD,
1
Francesco Montorsi, MD,
1,2
and
Andrea Salonia, MD, PhD
1,2
ABSTRACT
Background: Erectile dysfunction (ED) is widely considered as an early manifestation of cardiovascular diseases
(CVDs), sharing similar risk factors.
Aim: Assess rates and predictors of developing CVD and/or hypertension (HTN) over a long-term follow-up
period using user-friendly and clinically reliable tools in men presenting with ED but without CVD/HTN or
known vascular risk factors at baseline.
Methods: Data from 108 patients presenting between 2005 and 2011 with ED were analyzed. All patients were
free from CVD and/or HTN (CVD/HTN) at baseline. Patients completed the International Index of Erectile
Function (IIEF) at baseline and were followed up every 6 months with clinical assessment or phone interview.
Kaplan-Meier analyses estimated the probability of developing CVD/HTN over time. Cox-regression models
tested the association between patient baseline characteristics (for example, age, Charlson Comorbidity Index,
baseline IIEF-EF, ED severity, alcohol intake, smoking), response to phosphodiesterase type-5 inhibitors
(PDE5is), and the risk of developing CVD/HTN.
Results: Of all, 43 (40%) patients showed IIEF-EF scores suggestive of severe ED; 37 (39%) and 59 (61%) were
nonresponders and responders to PDE5i, respectively. Median (interquartile range) age was 51 (41, 61) years.
Median (interquartile range) follow-up was 95 (86-106) months. Overall, the estimated risk of developing CVD/
HTN was 15% (95% confidence interval [CI]: 9-27) at 10-year assessment. Men with baseline severe ED had a
higher risk of developing CVD/HTN (34%; 95% CI: 17-59, P¼.03) at 10 years than patients with mild to
moderate ED (5% [95% CI: 2-14]). At the Cox regression analysis, severe ED (Hazard ratio [HR], 4.62; 95%
CI: 1.43, 8.89; P¼.01) and baseline IIEF-EF score (HR, 0.92; 95% CI: 0.86, 0.99; P¼.02) were associated to
the risk of CVD/HTN overtime. Conversely, age and nonresponders to PDE5is (HR, 0.92; 95% CI: 0.32, 2.68;
P¼.9) were not associated to a risk of CVD/HTN over time.
Clinical Implications: The use of an easy and user-friendly tool, as the IIEF-EF domain score, would allow to
reliably assess which men with ED at first presentation may deserve a different, more specific and detailed
cardiologic investigation to prevent inauspicious CV events.
Strengths & Limitations: A single-center-based, observational longitudinal study, raising the possibility of
selection biases are the main limits.
Conclusions: Patients with severe ED and lower baseline IIEF-EF but no vascular risk factors at first presen-
tation have more than 30% risk of developing CVD/HTN in 10-year time. Those patients may benefit from
medical preventive strategies to lowering the risk of CV events and HTN. Pozzi E, Capogrosso P, Boeri L, et al.
Longitudinal Risk of Developing Cardiovascular Diseases in Patients With Erectile Dysfunction—Which
Patients Deserve More Attention?. J Sex Med 2020;XX:XXXeXXX.
Copyright 2020, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Erectile Dysfunction; Cardiovascular Disease; Hypertension; International Index Erectile Function;
Sexual Dysfunction
Received September 5, 2019. Accepted March 26, 2020.
1
Division of Experimental Oncology/Unit of Urology, URI, IRCCS Ospedale
San Raffaele, Milan, Italy;
2
Unit of Urology, Università Vita-Salute San Raffaele, Milan, Italy;
3
Dipartimento di Urologia, U.O.C. Urologia, Fondazione IRCCS Ca’Granda
Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
Copyright ª2020, International Society for Sexual Medicine. Published by
Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jsxm.2020.03.012
J Sex Med 2020;-:1e61
INTRODUCTION
The association between erectile dysfunction (ED) and onset
of cardiovascular diseases (CVD) has been extensively demon-
strated in several studies over the last decades.
1e4
In this context,
common risk factors (eg, diabetes mellitus [DM], smoking,
obesity, hypercholesterolemia, hypertension [HTN]) and path-
ophysiological mechanisms have been found to be shared among
the 2 conditions.
5
Recently, ED has been even added as an in-
dependent clinical risk factor able to help doctors to identify
patients at most risk of heart disease and stroke.
6
Of relevance,
vasculogenic ED, widely considered the most common type
among organic variants of ED, has been demonstrated to
significantly increase the risk of further CV events.
5
Over time, different hypotheses have been postulated to
explain this relationship. Of those, endothelial dysfunction
(EDy) together with artery size hypothesis would easily explain
why ED usually precedes CVD onset.
7e9
Accordingly, it has
been demonstrated that symptoms of ED can precede even by 3
to 5 years the onset of a CV event, thus allowing and making
cardiovascular prevention fundamental in terms of overall men’s
health.
4,5,10,11
The time-span between the onset of ED and a
potential life-threatening CV event emerged to become crucial to
identify patients that are at sufficient risk of developing CVD
and that would benefit further cardiological investigations.
1,12
In this context, some studies found a correlation between the
severity of ED and the probability of developing CVD. Schouten
et al,
13
for instance, assessed ED severity using a single question on
erectile rigidity; the group found that patients with reduced penile
rigidity had higher probability of experiencing coronary artery
disease (CAD) than those with normal penile rigidity. Banks et al
14
found that risk of developing CVD was directly proportional to ED
severity in men with or without a history of cardiovascular events at
baseline. Moreover, ED has been found to be highly prevalent in
patients with HTN (and vice versa) because of increased vessel
rigidity, EDy, and systemic vascular alterations.
14e16
Overall, published data would support the concept that pre-
ventive strategies toward a number of CVD may be developed also
through a personalized approach in terms of cardiovascular risk
factors modification. To this aim, the identification of a clinically
relevant and effective predictive symptom, such as ED, could allow
earlier and effective cardiovascular prevention. Therefore, the goal
of the present study was to depict those patients at higher risk of
further developing CVD and/or HTN over time, after an initial
diagnosis of ED. In this context, we sought to follow up a cohort of
patients seeking first medical help for ED as their primary
compliant and without any known CVD/HTN at baseline, to
depict whether ED per se could act as a reliable and effective
preventive clinical marker in the everyday clinical setting.
METHODS
Data from a cohort of 120 patients presenting for ED as their
primary complaint at a single outpatient clinic between 2005 and
2011 entered this analysis. All patients were assessed with a
comprehensive medical history. Health significant comorbidities
were scored with the Charlson Comorbidity Index (CCI)
17
(CCI
was categorized as 0 or 1). For the specific purpose of the study,
all selected patients were free from CVD/HTN (any type) at first
outpatient-clinic assessment; conversely, patients with a previous
diagnosis of either any cardiovascular comorbid condition or HTN
were excluded from the analyses to avoid unnecessary selection
bias. CVD were defined as follows: acute myocardial infarction
and/or surgical treatment of CAD; angina; cerebrovascular acci-
dents (ie, stroke, transient ischemic attack); congestive heart fail-
ure; aortic aneurysm; and, nonfatal cardiac arrhythmias, defined as
a minimum of an arrhythmia requiring treatment. HTN was
defined as office systolic blood pressure values 130 mmHg and/
or diastolic blood pressure values 90 mmHg. Patients were also
comprehensively assessed in terms of sociodemographic charac-
teristics, thus including recreational habits (ie, smoking history,
alcohol use) and regular physical exercise (defined as at least
2 hours/week) at the time of first assessment. Smoking habits were
assessed as pack-year history and then categorized into 2 groups as
follows: no smokers (never smoked); ex-smokers/active smokers.
Similarly, alcohol consumption was categorized as abstainers (no
alcohol consumption) or drinkers (any amount per week).
Measured body mass index, defined as weight in kilograms by
height in square meters, was obtained for every patient. All patients
completed the International Index of Erectile Function (IIEF)
18
at
baseline. We used the IIEF-EF to more specifically segregate ED
severity to further stratify those patients at greater risk of having
future CV events, with a potentially superior and more tailored
CVD prevention strategy. Severity of ED was interpreted ac-
cording to Cappelleri’s criteria, with severe ED defined for IIEF-
EF <11.
18
Patients’response to initial phosphodiesterase type 5
inhibitors (PDE5is) trials (any type) was also assessed. For the
specific purposes of the study, patients without any reported IIEF-
EF improvement after PDE5i therapy (any) were categorized as
nonresponders.
Hence, the cohort of patients has been longitudinally followed
up every 6 months with either outpatient clinical assessments or
dedicated phone interviews. Overall, 12 patients (10%) have
been lost to follow-up and were eventually excluded; a conve-
nience sample of 108 ED patients (90%) was included in the
final analysis. Of 108, 99 patients (91.7%) attended the follow-
up outpatient clinic in person, whereas 9 (8.3%) only answered
to the phone call updating the physicians with their clinical data.
Data collection followed the principles outlined in the
Declaration of Helsinki. All patients signed an informed consent
agreeing to share their own anonymous information for other
future studies. The study was approved by the local ethic com-
mittee (IRCCS OSR Prot. 2014 ePazienti Ambulatoriali).
Statistical Analysis
Univariate Cox proportional hazards regression models iden-
tified the association between patient baseline characteristics
J Sex Med 2020;-:1e6
2Pozzi et al
(eg, age, CCI, baseline IIEF-EF, recreational habits), PDE5is
response, and the risk of developing CVD/HTN over time.
Kaplan-Meier analysis was used to estimate the probability of
developing CVD/HTN over time of the whole cohort and in
patients with nonsevere (IIEF-EF 11) vs severe ED (IIEF-
EF <11) at baseline assessment. Statistical analyses were con-
ducted using Stata 14.0 (StataCorp, College Station, TX), with a
2-sided significance level set at P<.05.
RESULTS
Table 1 shows patients’characteristics. Median (IQR) age at
first presentation was 51 (41-61) years. Median (IQR) follow-up
duration was 95 (86-106) months. Of all, 74% of the whole
cohort was free of comorbidities at first assessment; 26% had
CCI 1 (neurologic disease, COPD, type 1 DM, type 2 DM,
chronic kidney diseases, solid tumors, and peripheral vascular
disease).
Table 2 depicts IIEF-EF scores at baseline. Overall, 43 (40%)
patients had IIEF-EF scores suggestive for severe ED.
Overall, the estimated risk of developing CVD/HTN was
15% (95% CI: 9-27) at 10-year assessment.
Table 3 reports univariate cox regression hazard models pre-
dicting the risk of developing CVD/HTN over time. Severe ED
(HR, 4.62; 95% CI: 1.43, 8.89; P¼.01) and baseline IIEF-EF
score (HR, 0.92; 95% CI: 0.86, 0.99; P¼.02) were associated
to higher risk of CVD/HTN overtime. No further univariable
association has been observed.
As represented in Figure 1, those patients with severe ED at
baseline had a higher risk of developing CVD/HTN (estimated
risk of developing CVD/HTN: [34%; 95% CI: 17-59, P¼.03])
at 10 years than patients with mild and moderate ED (estimated
risk of developing CVD/HTN: 5% [95% CI: 2-14]). The esti-
mated risk of CVD/HTN in nonsevere and severe ED groups,
according to Kaplan-Meier analysis, is depicted in Table 4.
DISCUSSION
Potential user-friendly and easy to be clinically collected pre-
dictors of CVD and/or HTN have been analyzed over a long-
term follow-up in a cohort of patients presenting with ED and
no history of CVD/HTN at the time of their first assessment.
The aim was to identify those patients at actual higher risk of
developing future CV events to offer them more specific and
comprehensive cardiological primary prevention strategies. Our
findings suggest that baseline IIEF-EF score (ie, ED severity at
presentation) acts as a predictor of CVD/HTN development
over time; in particular, severe ED at baseline (eg, IIEF-EF <11)
emerged to be associated with almost 30% risk of CVD/HTN
over time. Conversely, age and being nonresponder to PDE5i as
afirst-line treatment did not emerge as predictors of future
development of CVD/HTN.
Over the last decades, several studies have been carried out to
assess and confirm the association between ED and CVD.
19
Among the first, Montorsi et al clearly demonstrated the link
between the 2 conditions.
1,5,9,20
Indeed, of the historical cohort
of 300 consecutive patients presenting for acute chest pain and
angiographically documented CAD, almost 70% had reported
that ED onset had preceded the CV event itself.
1
Clinically
speaking, of paramount importance was the mean time interval
of 38.8 months between the onset of ED and CAD, and even
more relevant the complete absence of significant differences in
terms of risk factors distribution and clinical and angiographic
characteristics between patients with the onset of ED before vs
after CAD diagnosis.
1
All these results sound even more
appealing at the light of our current findings, where ED severity
Table 1. Clinical characteristics of the entire cohort (N ¼108)
Age, years; median (IQR) 51 (41, 61)
Charlson Comorbidity Index, N (%)
080(74)
1 28 (26)
Body mass index, median (IQR) 24.9 (23.2, 26.9)
Smoking history, N (%)
Never smoked 76 (70)
Current/ex-smoker 32 (30)
Alcohol use, N (%)
No 21 (19)
Yes 87 (81)
Regular physical activity, N (%)
No 62 (58)
Yes 45 (42)
Type 1 diabetes mellitus, N (%)
No 105 (97)
Yes 3 (2.8)
Type 2 diabetes mellitus, N (%)
No 98 (91)
Yes 10 (9.3)
Newly developed HTN, N (%)
0 96 (91)
1 9 (8.6)
Newly developed CVD, N (%)
No 102 (94)
Yes 6 (5.6)
CVD ¼cardiovascular disease; HTN ¼hypertension; IQR ¼interquartile
range.
Table 2. Baseline erectile function severity according to IIEF-EF
domain scores
Baseline IIEF-EF, median (IQR) N (%)
ED severity
Severe 43 (40)
Moderate 18 (17)
Mild to moderate 17 (16)
Mild 30 (28)
IIEF-EF ¼International Index of Erectile FunctioneErectile Function; IQR ¼
interquartile range; ED ¼erectile dysfunction.
J Sex Med 2020;-:1e6
Long-Term Erectile Dysfunction Outcomes 3
per se emerged as a stand-alone predictor associated with the
long-term development of CVD and/or HTN.
Thereafter, a number of evidences had confirmed ED as a
vascular disorder and a warning sign of future CVD.
5,21,22
For
instance, using the placebo group cohort of the Prostate Cancer
Prevention Trial, Thompson et al
23
showed that among those
men without ED at study entry, as many as 57% reported
incident ED after 5 years; incident ED emerged to be associated
with a 1.25 HR for subsequent CVD during study follow-up.
The authors also found that the association was in the range of
risk associated with smoking or a family history of acute
myocardial infarction.
In this context, different theories have been tested to deeply
understand the linkage between the 2 conditions. In this regard,
common risk factors for atherosclerosis were found to be highly
prevalent in patients with ED.
22,24e26
Moreover, vasculogenic
ED was demonstrated to share pathophysiological mechanisms
with other common systemic vascular diseases. Among those,
EDy with deficient nitric oxide pathway achieved great interest
over the last 2 decades; indeed, EDy leads to malfunctional
endothelium-dependent vasodilatation owing to structural
vascular abnormalities, penile artery atherosclerosis, and flow-
limiting stenosis.
19
In addition to this, artery sized hypothesis
had been proposed to find a rational explanation of why symp-
toms of ED can precede by even 3 to 5 years the onset of a CV
event. The theory stated that common risk factors shared be-
tween ED and CVD gradually and uniformly affect all vascular
beds leading to EDy, intima thickening, and eventually flow-
limiting stenosis; chronologically, penile arteries are first to be
affected in respect to coronary vessels which explains why ED
precedes CVD.
9,27
Although the association between ED and
CVD is well known and extensively discussed, only few studies
have investigated which patients—mostly among men with
ED—are actually at a higher risk of harboring a silent cardio-
logical disorder.
28,29
Historically, Greenstein et al, for instance,
identified a correlation between prevalence of multivessel
involvement at coronary angiography and ED severity
30
; patients
with severe ED (as defined with a single question upon penile
rigidity) had higher probability of experiencing CAD than those
with normal penile rigidity. Likewise, Banks et al found that
among men without previously diagnosed CVD, those with se-
vere ED were more likely to develop ischemic heart disease (risk
1.60), heart failure (risk 8.00), peripheral vascular disease (risk
1.92), and other causes of CVD (risk 1.26) in respect to men
without ED at presentation.
14
As a major flaw, this group did
not use the IIEF-EF domain to attempt and standardize ED
severity assessment.
14
This approach has been extensively fol-
lowed throughout times.
31
More recently, studies have shown
that ED is not only correlated with CV events but can be also
considered as a proxy of general health status.
32,33
Our current data come together and therefore confirm the
latter broad number of studies that have widely analyzed both the
pathophysiological and the clinical correlations between ED and
Table 3. Univariate cox regression analysis predicting risk of
developing CVD/HTN over time
Characteristics
Hazard
ratio (HR) 95% CI Pvalue
Age 1.02 0.98, 1.06 .4
CCI 0 vs CCI 1 1.73 0.57, 5.19 .3
Smoking 0.69 0.19, 2.47 .6
Alcohol use 0.56 0.18, 1.80 .3
Regular physical
activity
0.50 0.16, 1.59 .2
Total testosterone 1.02 0.78, 1.33 .8
Dyslipidaemia 0.51 0.12, 2.18 .3
Baseline IIEF-EF 0.92 0.86, 0.99 .02
Severe ED 4.62 1.43, 14.89 .01
PDE5i responder vs
nonresponder
0.92 0.32, 2.68 .9
CCI ¼Charlson comorbidity index; CI ¼confidence interval; CVD ¼
cardiovascular disease; ED ¼erectile dysfunction; HTN ¼hypertension;
IIEF-EF ¼International Index of Erectile FunctioneErectile Function;
PDE5i ¼phosphodiesterase type 5 inhibitors.
Bold values indicate statistically significant Pvalue .05.
Figure 1. Kaplan-Meier estimates. Figure 1 is available in color
online at www.jsm.jsexmed.org.
Table 4. Estimated risk of CVD/HTN among patients with
nonsevere and severe ED, according to Kaplan-Meier analysis
(median follow-up ¼95 [86-106] mo)
Time KM estimate, 95% CI
Nonsevere ED
12 mos 2% (0, 11)
48 mos 2% (0, 11)
84 mos 5% (2, 14)
120 mos 5% (2, 14)
Severe ED
12 mos 2% (0, 15)
48 mos 12% (5, 26)
84 mos 19% (10, 34)
120 mos 34% (17, 59)
CI ¼confidence interval; CVD ¼cardiovascular disease; ED ¼erectile
dysfunction; HTN ¼hypertension; KM ¼Kaplan Meier.
J Sex Med 2020;-:1e6
4Pozzi et al
CVD, along with the simultaneous presence of common risk
factors, and the relevant possibility that ED anticipates, even well
in advance, the subsequent development of CVD and/or HTN.
What is clinically important of these new observations at a
relatively long-term follow-up is the fact that the use of a vali-
dated questionnaire (ie, IIEF), the most known and widely
investigated instrument in this setting, may allow to understand
which ED men deserve a different, more specific and detailed
cardiologic investigation, so as to implement strategies to prevent
even inauspicious events, or at least to reduce their risk and
severity.
5
Even more relevant, this long-term prediction could be
obtained with a user-friendly, easy, poorly inquisitive, but suf-
ficiently reliable, approach.
5,28
In this sense, further studies are
needed to corroborate our longitudinal long-term findings and to
investigate also the relationship between ED severity and the
development of other specific comorbidities. This will give
physicians proper tools to offer more personalized and tailored
medical assessment in terms of prevention and screening strate-
gies to patients presenting with ED as their primary complaint.
Our study is certainly not devoid of limitations. First, despite the
fact that we analyzed a homogeneous, same-ethnicity cohort of men
presenting with ED as their primary compliant, this was a single-
center-based observational longitudinal study, raising the possibil-
ity of selection biases. In this context, in spite of the merit of being
homogeneous for patients enrollment and meticulous in terms of
the longitudinal evaluation of the enrolled patients themselves, the
absence of age as a predictive factor may suggest that a single-center
analysis could not derive final conclusions; indeed, with larger
numbers and a longer follow-up period, we cannot exclude age to
become a significant predictor for CVD/HTN.
34
Thereof, larger
cohort studies across different centers and populations are needed to
validate our findings. Second, our study did not prospectively
include and follow up over time a control group of healthy men
without ED and CVD at baseline. Third, a multivariate analysis was
not performed because the number of events did not allow to
include all covariates in a single model. Nevertheless, our results
indicate that an accurate investigation of the presence of severe ED
at the baseline may be important in the everyday diagnostic workup
of men with sexual function impairment.
CONCLUSIONS
Findings from this longitudinal observational cohort study
showed that severe ED per se was associated with a risk not less
than 17% of developing CVD and/or HTN in 10-year time in
men without any known CVD at baseline. The IIEF-EF domain
may act as a user-friendly and clinically effective tool to develop
preventive strategies to lowering the risk of CV events and HTN
in the everyday clinical practice even in this subset of relatively
healthy men at baseline.
Corresponding Author: Andrea Salonia, MD, PhD, University
Vita-Salute San Raffaele, Division of Experimental Oncology/
Unit of Urology, URI-Urological Research Institute, IRCCS
Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy.
Tel: þ39 02 26435506; Fax: þ39 02 26432969; E-mail: sal-
onia.andrea@hsr.it
Conflict of Interest: The authors report no conflicts of interest.
Funding: None.
STATEMENT OF AUTHORSHIP
Category 1
(a) Conception and Design
Edoardo Pozzi; Paolo Capogrosso; Andrea Salonia
(b) Acquisition of Data
Edoardo Pozzi; Luca Boeri; Federico Belladelli; Andrea Baudo;
Nicolò Schifano; Federico Dehò; Costantino Abbate
(c) Analysis and Interpretation of Data
Paolo Capogrosso; Andrea Salonia; Edoardo Pozzi
Category 2
(a) Drafting the Article
Edoardo Pozzi; Andrea Salonia; Paolo Capogrosso
(b) Revising It for Intellectual Content
Andrea Salonia; Paolo Capogrosso; Francesco Montorsi
Category 3
(a) Final Approval of the Completed Article
Andrea Salonia; Francesco Montorsi
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