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Keywords:

  • Penile Doppler Parameters;
  • Cardiovascular Risk;
  • Flaccid Acceleration;
  • Sexual Dysfunction;
  • Residual Risk

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Aim
  5. Methods
  6. Main Outcome Measures
  7. Main Outcome Measures
  8. Results
  9. Discussion
  10. Conclusions
  11. Statement of Authorship
  12. References

Introduction

Conventional cardiovascular (CV) risk factors identify only half of subjects with incident major adverse CV events (MACE). Hence new markers are needed in high CV risk subjects, as those with erectile dysfunction (ED). A role for dynamic peak systolic velocity (D-PSV) at penile color Doppler ultrasound (PCDU) has been suggested, but it is operator dependent and time consuming. Flaccid penile acceleration (FPA) is a PCDU parameter that reflects PSV, the systolic rise time (SRT), and end diastolic velocity (EDV), arithmetically defined as (PSV−EDV)/SRT.

Aim

The study aims to verify, in a large series of ED patients, whether FPA has a role in predicting MACE.

Methods

A selected series of 1,903 patients (aged 54.6 ± 11.7) with a suspected organic component for ED was retrospectively studied from January 2000 until July 2012. A subset of this sample (n = 622) was enrolled in a longitudinal study that ended in December 2007.

Main Outcome Measures

Several clinical, biochemical, and instrumental (PCDU) parameters were studied.

Results

Decreased FPA levels were associated with worse metabolic profile and sexual symptoms. In addition, FPA was positively associated with both total and calculated free testosterone. In the longitudinal study, unadjusted incidence of MACE was significantly associated with lower baseline FPA. When FPA was introduced in a multivariate model, along with D-PSV, after adjusting for age and Chronic Disease Score, lower FPA, but not D-PSV, was associated with incident MACE in lower-risk—i.e., younger (HR = 0.48 [0.23–0.99]), nonhypertensive (HR = 0.59 [0.38–0.92]), nonobese (HR = 0.68 [0.49–0.96]), or nondiabetic (HR = 0.67 [0.49–0.96] subjects; all P < 0.05—but not in higher-risk ones. FPA demonstrated a threshold effect in predicting MACE at a value <1.17 m/s2 which showed a threefold increase in incidence of MACE in apparently lower-risk individuals.

Conclusions

FPA is an easily obtained PCDU parameter and capable of identifying adverse metabolic and CV profiles, particularly in apparently lower-risk individuals with ED. Rastrelli G, Corona G, Lotti F, Aversa A, Bartolini M, Mancini M, Mannucci E, and Maggi M. Flaccid penile acceleration as a marker of cardiovascular risk in men without classical risk factors. J Sex Med 2014;11:173–186.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Aim
  5. Methods
  6. Main Outcome Measures
  7. Main Outcome Measures
  8. Results
  9. Discussion
  10. Conclusions
  11. Statement of Authorship
  12. References

An adequate cavernosal blood inflow is the fuel of penile erection, a necessary step for allowing successful male fertility and sexuality. The penile architecture can be easily visualized by the combined application of Doppler effect to B-mode sonography, introduced by Lue et al. [1,2], that firstly evaluated penile blood flows in flaccid condition and after intracavernous injection of papaverine both in healthy volunteers and in subjects with erectile dysfunction (ED). Since then, the use of penile color Doppler ultrasound (PCDU) has became more and more relevant and nowadays is considered as the gold standard for studying penile vasculature, giving information on diameter of the penile (cavernous) artery, peak systolic velocity (PSV), degree of arterial dilatation, and waveform shape. PSV, measured 5–20 minutes after the injection of a vasodilating agent (dynamic PCDU; D-PCDU), such as prostaglandin E1 (PGE1; 10 μg), is the usual parameter for the evaluation of penile circulation [3–5]. Dynamic PSV (D-PSV) of the cavernosal arteries has been demonstrated to discriminate accurately normal from abnormal cavernosography [3,6]. In particular, a D-PSV <25 cm/s has a sensitivity and specificity ≥95% for detecting impaired cavernosal blood flow at angiography, whereas a D-PSV ≥35 cm/s is associated with normal vasculature [3,6]. Besides PSV, the following parameters, commonly used in vascular diagnostics for blood-flow quantification, can describe the waveform derived from D-PCDU: acceleration time or systolic rise time (SRT), end-diastolic velocity (EDV), and resistive index (RI) [3,7]. All these parameters give insights on different aspects of penile hemodynamics. Whereas PSV reflects the greatest flow velocity detectable in the cavernosal artery throughout the systole, SRT is the time measured from the start of the systolic peak velocity to the maximum value, whereas EDV and RI provide information on penile veno-occlusive mechanisms. Despite these evidence-based advantages and the relatively low invasiveness, D-PCDU is not routinely used for the evaluation of ED, primarily because it is time consuming [7] and it carries the risk of priapism [7]. In addition, D-PCDU is operator dependent [7], and it may result in an incorrect diagnosis because of anxiety and its related sympathetic stimulation [8,9] or as a consequence of the high prevalence of arterial anatomical variants [10]. Hence, standardization of D-PCDU is cumbersome and the major urological societies [11,12] and The International Society of Sexual Medicine (ISSM) [7] do not recommend its routine use in the screening of ED, limiting its application to cases in which information on vascular supply is needed as, for example, in the choice of surgical treatment. In contrast, a growing amount of evidence has shown that ED is an early marker of cardiovascular (CV) disease (CVD) ([13,14], see for review ref. [15]). Hence, recognizing an arteriogenic component of ED is pivotal for identifying patients that can benefit from changing lifestyle, both for their sexual and CV health [16]. Hence, finding a simple parameter that can give insight into penile vascular health without carrying the inconvenience of priapism and with limited costs in terms of time and money is an ideal goal for both sexual and CV medicine.

We previously demonstrated, in a large population of ED subjects, that D-PSV lower than 25 cm/s was associated with a doubled risk of forthcoming major adverse CV event (MACE) [13], but we also found that PSV in the flaccid state can provide additional information on penile and overall CV status [13,17–19]. In particular, flaccid PSV <13 cm/s was capable of detecting subjects with inducible myocardial ischemia [17], and of predicting incident MACE [13]. Also, SRT has demonstrated its usefulness in reflecting vessel health, in fact its increase has previously been shown to reflect proximal arterial disease in the lower limbs [20,21]. Oates et al. [22] showed that SRT after pharmacological stimulation is a good discriminant of penile arteriopathy, as confirmed by pudendal arteriography (data confirmed also by other authors [23–25]). Acceleration is a dimension that recapitulates all the previously mentioned Doppler parameters, because it reflects both PSV and the time elapsed to reach it. It is calculated as ([PSV − EDV]/SRT, m/s2) and represents the slope of the tangent of the systolic rise waveform [7]. Moreover, acceleration is not affected by other parameters such as heart rate which can affect the SRT. In earlier studies, waveform acceleration was even superior to D-PSV in detecting arteriography-documented penile abnormalities [26].

Aim

  1. Top of page
  2. Abstract
  3. Introduction
  4. Aim
  5. Methods
  6. Main Outcome Measures
  7. Main Outcome Measures
  8. Results
  9. Discussion
  10. Conclusions
  11. Statement of Authorship
  12. References

The aim of this study is to evaluate the clinical correlates of flaccid penile acceleration (FPA) in a large series of patients consulting for ED and with a suspected organic component for ED, and to verify the role of this parameter—relatively costless and simple to obtain—in predicting MACE in a subset of the previous cohort, longitudinally studied.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Aim
  5. Methods
  6. Main Outcome Measures
  7. Main Outcome Measures
  8. Results
  9. Discussion
  10. Conclusions
  11. Statement of Authorship
  12. References

Cross-Sectional Study

A selected series of 1,903 male patients attended our Outpatient Clinic for ED for the first time between January 2000 and July 2012. All patients enrolled underwent the usual diagnostic protocol applied to newly referred subjects at our Outpatient Clinic for sexual dysfunction, in agreement with the Italian Consensus on Clinical and Metabolic Evaluation of Subjects with ED [27,28]. In particular, according to the Italian Consensus, PCDU was performed, after specific first-line evaluation, in subjects with a suspected organic component of ED [27,28]. The presence of at least one of the following criteria has been considered for suspecting an organic component of ED: metabolic syndrome (defined as below), diabetes mellitus (DM), hypertension, family or personal history of CVD, pathological score on Structured Interview on Erectile Dysfunction (SIEDY) Scale 1 score (i.e., ≥4, see below), hypogonadism (total testosterone <12 nmol/L), or presence of more than three risk factors for CVD (3rd Princenton Consensus Panel; [29]). Figure 1 summarizes the inclusion/exclusion criteria leading to the study sample (N = 1,903). The sociodemographic and clinical characteristics of the sample are summarized in Table 1.

figure

Figure 1. Exclusion criteria for selecting from the entire population of subjects consulting for erectile dysfunction (ED), only those patients with a suspected organic component for erectile dysfunction. W/O = without; CVD = cardiovascular disease; SIEDY = Structured Interview on Erectile Dysfunction

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Table 1. Characteristics of the sample for cross-sectional study
CharacteristicsN = 1,903
  1. Data are expressed as mean ± standard deviation when normally distributed, median [quartiles] when not normally distributed, and as percentages when categorical.

  2. CVD = cardiovascular diseases; BMI = body mass index; HDL = high-density lipoprotein; HbA1c = glycated hemoglobin; NHLB/AHA = National Heart, Lung, and Blood Institute; American Heart Association

Age (years)54.6 ± 11.7
Marital status (%) 
Not stable relationship9.7
Stable relationship90.3
Education (%) 
None/primary school15.5
Secondary school32.9
Secondary higher34.0
University17.6
Morbidities (%) 
Current smoker29.4
Alcohol intake >4 drink daily19.7
Hypertension35.0
Diabetes mellitus27.3
CVD16.3
Clinical and laboratory parameters 
BMI (kg/m2)27.2 ± 4.3
Waist circumference (cm)99.4 ± 11.0
Systolic blood pressure (mm Hg)140 [130–140]
Diastolic blood pressure (mm Hg)80 [80–90]
Pulse pressure (mm Hg)54.0 ± 13.1
Glycemia (mg/dL)110.5 ± 41.8
HbA1c (%)7.1 ± 1.7
Total cholesterol (mg/dL)205.2 ± 41.0
Triglycerides (mg/dL)125 [89–179]
HDL cholesterol (mg/dL)47.6 ± 12.1
Total testosterone (nmol/L)14.7 ± 6.2
Calculated free testosterone285.8 ± 118.6
Prolactin (mU/L)152 [108–221]
Thyroid-stimulating hormone (mU/L)1.4 [1.0–2.0]
ANDROTEST score8.3 ± 3.4
Penile color doppler ultrasound 
Flaccid peak systolic velocity (cm/s)16.3 ± 5.7
Flaccid penile acceleration (m/s2)2.7 ± 1.3
Dynamic peak systolic velocity (cm/s)49.1 ± 19.0
NHLB/AHA defined metabolic syndrome (%)47.2

Patients were interviewed before any specific diagnostic procedures and prior to the beginning of any treatment, using ANDROTEST [30] and SIEDY ([31]). ANDROTEST is a 12-item structured interview previously validated for the screening of hypogonadism in patients with ED [30].

SIEDY is a 13-item interview made up of three scales, which identify and quantify components concurring with sexual dysfunctions [31]. Scale 1 deals with organic disorders and it is made up of questions 4, 13, and 15, concerning medical history, morning/nocturnal erection, and volume of the ejaculate, respectively. A score higher than 4 on SIEDY Scale 1 predicted organic component of ED with an accuracy of about 70% [31]. Scale 2 deals with disturbances in the patient's relationship with his primary partner and consists of questions 7, 8, 9, and 10, concerning reported presence of primary partner's disease, primary partner's climax and desire, and menopausal symptoms, respectively [32–34]. Scale 3 deals with psychological traits and it is made up of questions 2, 3, 6, 11, 12, and 14, concerning presence of life stressors, conflict in primary relationship and within the family, extramarital affairs, and patient's hypoactive sexual desire, respectively [35–37]. Scores higher than 3 in both SIEDY Scales 2 and 3 are indicative of relational or intrapsychic problems [33,35]. The characteristics of ED were assessed using SIEDY Appendix A, as previously described (the appendix appears in ref. [31]). In particular, ED was evaluated using question 1C of SIEDY appendix A (difficulties in achieving an erection sufficient for penetration scoring 0 = <25% of cases, 1 = 25–50%, 2 = 50–75%, and 3 = >75% of cases; see ref. [31]). Severe ED was codified as a dummy variable scoring 0 = difficulties in achieving an erection sufficient for penetration ≤75% of cases and 1 = difficulties in achieving an erection sufficient for penetration >75% of cases [31]. Sleep-related erections were specifically evaluated using question #13 of SIEDY (“Does it ever happen to you to wake up with an erection?”) rating 0 = yes, regularly, 1 = less frequently than in the past, 2 = only occasionally, and 3 = never as previously reported [38]. Frequency of sexual intercourse was assessed using a standard question (“During the last three months how many sexual attempts per month did you have?”), rating 0 = never; 1 = 1–2 times per month, 2 = 3–7 times per month, and 3 = ≥8 times per month as previously reported [32]. Perceived partner's orgasmic function was investigated by question #9 of SIEDY (Does your partner reach climax?), rating 0 = always, 1 = most of the times, 2 = sometimes, 3 = never [31]. Patients were asked to report any kind of drugs used. Chronic Disease Score (CDS), an index of concomitant morbidities, was calculated as previously described [39]. The score is an aggregate comorbidity measure based on current medication used and originally validated for use as a predictor of physician-rated disease status, self-rated health status, hospitalization, and mortality [39].

Main Outcome Measures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Aim
  5. Methods
  6. Main Outcome Measures
  7. Main Outcome Measures
  8. Results
  9. Discussion
  10. Conclusions
  11. Statement of Authorship
  12. References

All patients underwent a complete physical examination, including measurement of waist circumference and blood pressure (mean of three measurements 5 minutes apart, in sitting position, with a standard sphygmomanometer). Pulse pressure (PP) was calculated as the difference between systolic and diastolic blood pressure, as previously reported [40] Height and weight were used to calculate body mass index (BMI; kg/m2).

Blood samples were drawn in the morning, after an overnight fast, for determination of total testosterone (T), prolactin and thyroid stimulating hormone (TSH) (modular E170 platform electrochemiluminescence immunoassay; Roche Diagnostics, Mannheim, Germany), blood glucose (by glucose oxidase method; Aeroset Abbott, Rome, Italy), glycated hemoglobin (HbA1c, with high-pressure liquid chromatography method, with upper limit of the normal range of 5.9%; Menarini Diagnostics, Florence, Italy), and triglycerides (by automated enzymatic colorimetric method; Aeroset Abbott). Levels of calculated free T (cFT) were derived using Vermuelen formula as previously described [41]. A diagnosis of DM was made at enrollment (newly diagnosed DM), on the basis of a fasting glycemia above the threshold of 126 mg/dL or HbA1c above 6.5%. Hypertension was defined as blood pressure ≥130/85 mm Hg or treatment. Hypertriglyceridemia was defined as triglyceride levels ≥150 mg/dL or treatment, whereas high-density lipoprotein levels were considered as low when <40 mg/dL or treatment. Metabolic syndrome (MetS) was defined according to the National Heart, Lung, and Blood Institute/American Heart Association definition [42].

All patients also underwent a PCDU examination performed in the flaccid state and 20 minutes after a PGE1 (10 μg) intracavernous injection (dynamic evaluation), as previously described [17]. We decided to use the same protocol for PCDU in all patients studied in order to make the results fully comparable. The following parameters were considered: flaccid PSV and penile acceleration and, after PGE1 stimulation, dynamic PSV [17]. PCDU procedure was performed as recommended in “Standard Practice in Sexual Medicine” produced by the ISSM Standards Committee [7] and the Third International Consultation on Sexual Medicine [4].

Longitudinal Study

All patients attending the clinic between 2000 and 2007 (N = 622) were enrolled in a longitudinal study, the characteristics of which have been previously described [5,13] and are summarized in Table 2.

Table 2. Characteristics of the sample for longitudinal study
Characteristicsn = 622
  1. Data are expressed as mean ± standard deviation when normally distributed, median [quartiles] when not normally distributed, and as percentages when categorical.

  2. CVD = cardiovascular diseases; BMI = body mass index; HDL = high density lipoprotein; HbA1c = glycated hemoglobin; NHLB/AHA = National Heart, Lung, and Blood Institute; American Heart Association

Age (years)56.0 ± 10.8
Marital status (%) 
Not stable relationship19.9
Stable relationship80.1
Education (%) 
None/primary school19.7
Secondary school29.5
Secondary higher32.8
University18.0
Morbidities (%) 
Current smoker32.4
Alcohol intake >4 drink daily14.4
Hypertension38.9
Diabetes mellitus20.9
CVD17.3
Clinical and laboratory parameters 
BMI (kg/m2)27.1 ± 3.9
Waist circumference (cm)99.2 ± 10.1
Systolic blood pressure (mm Hg)140 [130–160]
Diastolic blood pressure (mm Hg)85 [80–95]
Pulse pressure (mm Hg)56.6 ± 14.2
Glycemia (mg/dL)111.6 ± 42.0
HbA1c (%)7.3 ± 1.7
Total cholesterol (mg/dL)207.7 ± 42.2
Triglycerides (mg/dL)128 [91–189]
HDL cholesterol (mg/dL)48.9 ± 12.2
Total testosterone (nmol/L)15.3 ± 6.1
Calculated free testosterone294.8 ± 115.9
Prolactin (mU/L)154 [115–212]
Thyroid-stimulating hormone (mU/L)1.4 [1.0–2.0]
ANDROTEST score8.5 ± 3.1
Penile color doppler ultrasound 
Flaccid peak systolic velocity (cm/s)15.1 ± 5.5
Flaccid penile acceleration (m/s2)2.7 ± 1.3
Dynamic peak systolic velocity (cm/s)51.2 ± 20.5
NHLB/AHA defined metabolic syndrome (%)49.9

Main Outcome Measures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Aim
  5. Methods
  6. Main Outcome Measures
  7. Main Outcome Measures
  8. Results
  9. Discussion
  10. Conclusions
  11. Statement of Authorship
  12. References

CV events were identified through the regional hospital discharge system and the City of Florence Registry Office. Information on mortality up to December 31, 2007, including causes of death, was obtained from the City of Florence Registry Office, which contains complete and updated records of all persons living within city boundaries. For those who had moved away, queries were sent to the Registry Office of the new city of residence. Collection of new data from 2008 up to now is ongoing. Nonfatal cases of MACE requiring hospitalization were identified through the regional hospital discharge system. Following the International Classification of Diseases, fatal and nonfatal MACE were coded as 410–414 (ischemic heart disease), 420–429 (other heart diseases), or 798–799 (sudden death) from cardiac diseases, as 430–434 or 436–438 for cerebrovascular disease, and 440 for peripheral arterial disease. The data set of the regional hospital discharge system, which is used for administrative (reimbursement) purposes, contains complete data on all hospital admissions of subjects residing within the borders of the local health district. Compilation in the register of causes of death is completed for any deceased subjects. Therefore, these sources of data allow a complete retrieval of information on all subjects, with no loss at follow-up.

Statistical Analysis

Data were expressed as mean ± standard deviation (SD) when normally distributed and as median (quartiles) for parameters with nonnormal distribution, unless otherwise specified. Unpaired two-sided Student's t-tests were used for comparison of means of normally distributed parameters. For continuous variables, correlations were assessed using Pearson's or Spearman's method whenever appropriate. Stepwise multiple linear or logistic analyses were used for multivariate analyses whenever appropriate. Kaplan–Meier analysis of survival was performed with definition of hazard ratios (HR) and 95% confidence intervals, and a stepwise Cox regression was carried out for multivariate analysis adjusting all data for age and CDS. All analyses were carried out with SPSS 20.0.1 statistical package (IBM Corporation, Armonk, NY, USA) and a P < 0.05 was considered statistically significant. HR, which is the outcome of Cox regression analysis, provides an estimate of risk, which is easy to understand for clinicians. The choice of Cox regression for multivariate analysis was motivated by the robustness and widely demonstrated validity of this statistical approach.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Aim
  5. Methods
  6. Main Outcome Measures
  7. Main Outcome Measures
  8. Results
  9. Discussion
  10. Conclusions
  11. Statement of Authorship
  12. References

Cross-Sectional Study

Table 3 shows that a higher age, obesity, as well as DM, hypertriglyceridemia, hypertension, or a personal history of CVD are associated with a lower FPA. FPA progressively decreased from nondiabetic patients to those with a prediabetic state or overt diabetes (Figure 2, panel A). In diabetic subjects, HbA1c was also negatively associated with FPA (Figure 2, panel B). In addition, in the whole sample, acceleration showed a negative relationship with PP (Figure 2, panel C). Accordingly, FPA demonstrated a stepwise decrease as a function of an increasing number of MetS components (Figure 2, panel D). All of these findings were confirmed after adjusting for age, smoking, alcohol consumption, and BMI (Figure 2).

figure

Figure 2. Associations between flaccid penile acceleration and metabolic parameters i.e. Glycemic status (Panel A), HbA1c (Panel B), pulse pressure (Panel C), MetS components (Panel D). Data are expressed as mean (95% confidence interval). Insets represent the age-, smoking-, alcohol drinking-, and body mass index-adjusted data using flaccid penile acceleration as continuous variable. DM = diabetes mellitus; HbA1c = glycated hemoglobin; NHLB/AHA = National Heart, Lung, and Blood Institute; American Heart Association, MetS = metabolic syndrome

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Table 3. Mean values of flaccid acceleration according to the absence or presence of several risk factors
 NoYesP
Age ≥55 years3.04 ± 1.332.42 ± 1.22<0.0001
Family history of diabetes mellitus2.74 ± 1.302.56 ± 1.300.005
Diabetes mellitus2.82 ± 1.352.32 ± 1.10<0.0001
Cardiovascular diseases2.80 ± 1.292.14 ± 1.20<0.0001
Body mass index ≥30 kg/m22.71 ± 1.332.56 ± 1.160.032
Blood pressure ≥130/85 or treatment3.18 ± 1.362.58 ± 1.28<0.0001
Triglycerides ≥150 mg/dL or treatment2.79 ± 1.312.54 ± 1.27<0.0001

Concerning sexual symptoms, FPA decreased as a function of severity of the impairment in both sexual intercourse-related and spontaneous erections (Figure 3, panels A and B) and it showed a positive relationship with frequency of intercourse (Figure 3, panel C) and a negative association with partner's orgasmic dysfunction, as referred by the patient (Wald = 23.758; P < 0.0001).

figure

Figure 3. Associations between flaccid penile acceleration and sexual parameters (i.e. sex- and sleep-related erections [Panel A and B] and frequency of intercourse [Panel C]) and androgenic status (i.e. ANDROTEST score [Panel D], total and calculated free testosterone [Panel E and F]). Data are expressed as mean (95% confidence interval). Insets represent the age-, smoking-, alcohol drinking-, and body mass index-adjusted data using flaccid penile acceleration as continuous variable.

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When hormonal parameters were evaluated, FPA was positively associated with both total T and cFT (Figure 3, panels E and F). Accordingly, FPA decreased as a function of ANDROTEST score (the higher the score, the higher the hypogonadal symptoms) (Figure 3, panel D); again, those findings were confirmed after adjusting for the above-specified confounders (Figure 3). Conversely, no association between FPA and both prolactin and TSH levels was observed (not shown). Figure 4 shows the positive relationship between FPA and both flaccid and dynamic PSV, which was confirmed at multivariate analysis adjusted for the aforementioned confounders and cFT (Adj. r = 0.647 and 0.372; both P < 0.0001).

figure

Figure 4. Relationship between flaccid penile acceleration and flaccid (Panel A) and dynamic (Panel B) peak systolic velocity. Insets represent the age-, smoking-, alcohol drinking-, and body mass index-adjusted data using all the data as continuous variables.

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Longitudinal Study

During a mean follow-up of 4.1 ± 2.6 years, 126 MACE, 14 of which were fatal, were observed, with a yearly rate of 2.67%. The median time to MACE was 4 (2–7) years. Of those cases, 77 were ischemic heart diseases, 36 were cerebral (stroke or transient ischemic attack), and 13 were peripheral artery diseases. Furthermore, 66 (4.1%) patients died during follow-up from non-CV (N = 54) or unspecified causes (N = 12).

The specific contribution of FPA and D-PSV (as continuous variables) to incident MACE in this longitudinal cohort of ED subjects was verified by introducing both parameters into a Cox regression model, together with age and CDS. FPA, but not D-PSV, was associated with incident CV events (FPA HR = 0.718 [0.538–0.959] for each m/s2 increment; P = 0.025; D-PSV HR = 0.997 [0.982–1.014] for each cm/s increment; P = 0.756). To further verify the ability of impaired FPA in detecting a higher incidence of MACE, we designed an iterative series of Cox models, introducing, in a step-by-step fashion, as further covariates, other known CV risk factors. Results are reported in Table 4. Stepwise addition of traditional CV risk factors, such as lifestyle (smoking and drinking habit, BMI), hypertension, and DM substantially confirmed the ability of lower FPA levels, but not D-PSV, in predicting incident MACE. These results were confirmed after excluding those subjects reporting severe ED, as shown in Table 4. Figure 5 graphically represents HR for FPA and D-PSV—after adjusting for each other, plus lifestyle (BMI, smoking and drinking behaviors), age, and CDS—in subjects with and without traditional high CV risk conditions (hypertension, morbid obesity, and DM) or according to the median age of the cohort population. In youngest subjects and in those considered at “lower-risk,” but not in their at “higher-risk” counterpart, only lower FPA levels, but not D-PSV, was able to specifically predict incident MACE. The specific associations of FPA and D-PSV with incident MACE were confirmed even after excluding those subjects with severe ED (HR = 0.514 [0.312–0.848], P = 0.009; HR = 0.583 [0.370–0.920], P = 0.020; HR = 0.649 [0.443–0.951], P = 0.027; for each m/s2 increment of FPA in nonhypertensive, nondiabetic, nonobese, respectively). The significant association of lower FPA levels with MACE in the “lower-risk,” but not in “higher-risk” (not shown) group and the lack of association of D-PSV with incident events both in “lower-” and “higher-risk” groups (not shown) were also confirmed in this subset of ED subjects.

figure

Figure 5. Hazard ratio and 95% confidence interval (log scale) for incident major cardiovascular events as a function of flaccid penile acceleration (Panel A and C) and dynamic peak systolic velocity (D-Peak Systolic Velocity) (Panel B and D) according to the presence (Panel C and D)/absence (Panel A and B) of several risky conditions and to the median age of the population. Data are derived from a Cox regression analyses, after adjusting for age, Chronic Disease Score, smoking and drinking behavior, and body mass index.

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Table 4. Hazard ratio (HR) and 95% confidence interval (CI) for MACE as a function of flaccid penile acceleration (FPA) and dynamic peak systolic velocity (D-PSV) as derived from different Cox regression models with stepwise introduction of further confounding factors
 Overall populationAfter excluding subjects with ED
LifestyleBMIHypertensionDMFPAD-PSVFPAD-PSV
HR95% CIPHR95% CIPHR95% CIPHR95% CIP
  1. All the Cox regression models are also adjusted for age and Chronic Disease Score.

  2. BMI = body mass index; DM = diabetes mellitus

0.7180.538–0.9590.0250.9970.982–1.0140.7560.6550.473–0.9060.0111.0010.985–1.0180.894
+0.7230.537–0.9740.0330.9970.981–1.0140.7420.6610.475–0.9210.0141.0000.983–1.0170.964
++0.7280.530–1.0000.0500.9980.981–1.0160.8510.6620.462–0.9480.0241.0010.983–1.0200.885
+++0.7310.534–1.0010.0510.9980.981–1.0160.9530.6670.468–0.9510.0251.0010.983–1.0200.880
++++0.7370.538–1.0100.0580.9980.981–1.0160.8410.6680.469–0.9530.0261.0010.983–1.0200.886

The introduction of flaccid PSV in a fully adjusted Cox regression model, confirmed the association of FPA, but not of dynamic or flaccid PSV, with incident MACE only in the “lower-risk” group (HR = 0.545 [0.319–0.931], HR = 0.583 [0.361–0.942], HR = 0.579 [0.377–0.888] for nonhypertensive, nondiabetic, and nonobese subjects, respectively, all P < 0.05).

Figure 6 (panel A) shows the annual incidence of MACE in the entire cohort, categorized in deciles of FPA. Being in the lowest FPA decile (0.4–1.17 m/s2) doubles the risk of incident annual events, as compared with the other deciles. Figure 6 (panel B) shows unadjusted incidence of MACE, depicted as Kaplan–Meier curve, associated with this threshold of FPA (<1.17 m/s2) at study entry (P for trend <0.001).

figure

Figure 6. Panel A: annual incidence of MACE in the whole population, according to deciles of flaccid penile acceleration. Lower and upper limits for the first decile are 0.4 and 1.17 m/s2. Panel B shows unadjusted incidence of MACE, associated with baseline flaccid penile acceleration <1.17 m/s2. MACE = major adverse cardiovascular event

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Then we introduced in a Cox regression model, as dummy variables, both impaired D-PSV (<25 cm/s) and impaired FPA (<1.17 m/s2), adjusting for the aforementioned confounding factors, and we evaluated the HR for incident MACE according to the presence/absence of several traditional risk factors (hypertension, DM, morbid obesity) or to median age. Results confirm the ability of FPA < 1.17 m/s2 in predicting forthcoming CV events in “lower-risk” individuals (HR = 2.738 [1.210–6.195]; HR = 3.619 [1.517–8.633]; HR = 2.768 [1.397–5.484] for subjects without hypertension, DM, and with BMI < 35 kg/m2, respectively; all P < 0.05), without any significant effect in the “higher-risk” groups (data not shown). After excluding those subjects reporting severe ED, we confirmed the ability of FPA <1.17 m/s2 in predicting MACE (HR = 4.524 [1.772–11.553]; P = 0.002 in younger subjects and HR = 4.027 [1.579–10.269]; HR = 4.524 [1.772–11.553]; HR = 3.522 [1.636–7.584], all P < 0.01 for subjects without hypertension, DM, and with BMI < 35 kg/m2, respectively). No significant relationship was observed in the “higher-risk” group (data not shown).

When flaccid PSV was introduced in a multivariate Cox model, impaired FPA (<1.17 m/s2) was significantly associated with incident MACE in nondiabetic and nonobese subjects (HR = 4.054 [1.541–10.662]; HR = 2.802 [1.313–5.981], respectively; both P < 0.01), whereas a nonsignificant trend was observed in nonhypertensive subjects (HR = 2.266 [0.949–5.407], P = 0.065).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Aim
  5. Methods
  6. Main Outcome Measures
  7. Main Outcome Measures
  8. Results
  9. Discussion
  10. Conclusions
  11. Statement of Authorship
  12. References

FPA is a sonographic dimension that recapitulates both SRT and PSV within a single integrative number (PSV − EDV)/SRT), which graphically corresponds to the slope of the tangent line of spontaneous cavernous waveform at PSV, reflecting vascular stiffness. Accordingly, FPA is tightly related to flaccid and dynamic PSV. However, in contrast to dynamic PSV, FPA does not require PGE1-induced erection and is therefore devoid of painful or potentially serious (priapism) adverse side effects. Finally, it is relatively inexpensive and easy to perform.

In the cross-sectional study, FPA was negatively related to increased glycemia and DM, pulse pressure and metabolic syndrome components, therefore representing a marker of metabolically healthy penile (cavernosal) vessels. Accordingly, subjects with conventional CV risk factors have lower FPA values. Because FPA is a marker of healthy cavernosal vessels, it is positively associated with spontaneous and intercourse-related erections and with an increased frequency of sexual acts. In addition, lower FPA values were observed in the presence of hypogonadal symptoms (as measured by ANDROTEST) or signs (low total and free testosterone). The relevance of androgenic regulation of penile vasculature has been reviewed elsewhere [43]. All these data are not surprising and in line with the Italian Consensus on Clinical and Metabolic evaluation of subjects with ED, which suggests to perform PCDU in patients at high hormonal, metabolic, and CV risk [27,28].

The most important finding of this study is that FPA is capable of predicting MACE in subjects that, based on traditional risk factors, would be classified as “lower-risk.” It is important to note that in the general population, the majority of CV events occur in subjects who would be classified as “lower-risk” by using conventional parameters [44,45]. Searching for new parameters capable of identifying this “residual CV risk” is clinically relevant [46–48]. FPA could be considered one of the potential markers in patients undergoing PCDU for ED of this residual risk [45].

It is well known that ED is a marker of CV risk, even in a short window of time [14]. In the specific “higher-risk” population of patients seeking medical care for ED, parameters derived from the assessment of ED itself can be used to further characterize CV risk, beyond traditional risk factors. We speculate that an early atherosclerotic plaque could not impair cavernosal PSV, especially when challenge with vasodilatory drugs is performed and the arterial bed is fully stretched; by contrast, arterial stiffness at baseline may be more sensitive than pharmaco-stimulated PSV, as previously demonstrated by Aversa et al. [49] with peripheral arterial tonometry at fingertip level. In fact, when both FPA and dynamic or flaccid PSV at PCDU were simultaneously introduced into iterative multivariate Cox regression models of increasing complexity, along with other traditional risk factors, as further additive covariates, adjusting for CDS and age, only FPA—but not dynamic or flaccid PSV—was predictive of forthcoming MACE in youngest subjects and in those conventionally considered at “lower-risk” on the basis of traditional CV risk factors. This suggests that FPA may be considered a new surrogate marker of arterial stiffness in men with ED, predicting CV events in young and at “lower-risk” ED subjects. Interestingly, in the Olmsted study ED had relatively little impact on the development of incident cardiac events in the oldest men, but it resulted in a nearly 50-fold increase in the 10-year incidence of heart disease in men aged 40 to 49 years [50]. This observation further suggests the possibility that ED in young men may indeed be an early manifestation of a progressive systemic vasculopathy, preceding the development of coronary disease by decades.

This study not only identify FPA as a new tool able to detect an otherwise undetectable residual risk, but also provides a threshold (1.17 m/s2) to categorize ED subjects as at “higher-” or “lower-risk” of forthcoming CV events. This threshold, if confirmed in further studies, might have an immediate clinical relevance. In fact, identifying young individuals or those at residual risk of incident vascular events might open new possibilities of lifestyle or pharmacotherapeutic intervention: the residual risk of incident vascular events or the progression of established vascular damage might be slowed or even halted by some form of current evidence-based recommended care. However, it is difficult to communicate and to convince young people or “lower-risk” individuals with ED that lifestyle change is needed for modifying their risk profile. On the other hand, clinicians are often led to classify young subjects with ED as “psychogenic,” and therefore treating them with symptomatic medicaments, overlooking important aspects of their general health, even those that could be specifically corrected [51]. In all the available calculator risk engines, age is the most important factor in determining the absolute burden for CVD, and, by definition, youngest subjects are almost automatically categorized as at “lower-risk,” irrespective to their real risk level. Even the effect of classical CV risk factors is often buffered by the age-smoothing effect universally present in the chart risk algorithms. Hence, we need to identify new risk markers, useful in reclassifying correctly those conventionally considered at “lower-risk” as being above a chosen intervention threshold. We previously developed the concept that “impotent patients are lucky” [52]. Unsatisfying sexual activity, because of impotence, represents a meaningful, straightforward motivation for consulting healthcare professionals, which can screen for the presence of unfavorable associated conditions. An unexpected advantage is that in young individuals, because of ED with a suspected organic pathogenetic component, PCDU investigation is a well-accepted routine procedure; in particular, flaccid parameters can be collected with an inexpensive and noninvasive approach. Visualizing, computing, and communicating about pathological penile circulation might help in breaking considerable barriers existing to lifestyle modification, including change in diet, quitting smoking, and physical activity, or to proceed for preventive pharmacotherapy.

Several limitations should be recognized. First of all, these results were taken from patients consulting an Italian Andrology Clinic for sexual dysfunction, who could have different characteristics from those consulting general practitioners or other specialists, not seeking medical care, or without ED. In addition. they were obtained in a relatively “higher-risk” population (ED subjects) that, after the first line examination, give rise to the suspicion of a relevant organic component in the determinism of their sexual problems. Hence, these results cannot be extended to the general population or to all the ED subjects. Another limitation is that we did not measure the dynamic acceleration, but we have only this parameter in the flaccid state. Additional limits of flaccid PCDU are its intrinsic operator dependency and its inability to detect venous abnormalities, which can be studied in a more complex setting after PGE1 stimulation, if clinically indicated [6]. In this study, four different operators (G.C., F.L., M.M., M.B.) performed PCDU and provided data. However, all the operators were trained by the same radiologist (M.B.). Finally, it has to be considered that the identification of nonfatal MACE through registers raises the possibility of misclassification of some cases.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Aim
  5. Methods
  6. Main Outcome Measures
  7. Main Outcome Measures
  8. Results
  9. Discussion
  10. Conclusions
  11. Statement of Authorship
  12. References

Flaccid penile acceleration is a reliable and quick measurement (operative time: a few minutes) of the PCDU procedure; it is relatively inexpensive and devoid of side effects. It essentially recapitulates three different PCDU parameters (PSV, SRT, and EDV). Abnormal (<1.17 m/s2) FPA identifies adverse metabolic and CV risk profiles, even in relatively “lower-risk” individuals, such as younger subjects. The World Health Organization strategy to decrease the worldwide epidemic of CVD (http://www.who.int/cardiovascular_diseases/en/), is based on prevention and reduction of risk factors. We believe that investigating ED and penile arteries at rest might represent a useful strategy in reducing male CVDs. From the penis to the heart there is only half a meter; maybe measuring flaccid penile acceleration can shorten this distance.

Conflict of Interest: The authors report no conflicts of interest.

Statement of Authorship

  1. Top of page
  2. Abstract
  3. Introduction
  4. Aim
  5. Methods
  6. Main Outcome Measures
  7. Main Outcome Measures
  8. Results
  9. Discussion
  10. Conclusions
  11. Statement of Authorship
  12. References

Category 1

  • (a)
    Conception and Design
    Giulia Rastrelli; Giovanni Corona; Mario Maggi
  • (b)
    Acquisition of Data
    Giulia Rastrelli; Giovanni Corona; Francesco Lotti
  • (c)
    Analysis and Interpretation of Data
    Giulia Rastrelli; Giovanni Corona; Edoardo Mannucci; Mario Maggi

Category 2

  • (a)
    Drafting the Article
    Giulia Rastrelli; Giovanni Corona; Edoardo Mannucci; Mario Maggi
  • (b)
    Revising It for Intellectual Content
    Giulia Rastrelli; Giovanni Corona; Antonio Aversa; Marco Bartolini; Mario Mancini; Mario Maggi; Edoardo Mannucci

Category 3

  • (a)
    Final Approval of the Completed Article
    Giulia Rastrelli; Giovanni Corona; Antonio Aversa; Marco Bartolini; Mario Maggi; Mario Mancini; Edoardo Mannucci

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  2. Abstract
  3. Introduction
  4. Aim
  5. Methods
  6. Main Outcome Measures
  7. Main Outcome Measures
  8. Results
  9. Discussion
  10. Conclusions
  11. Statement of Authorship
  12. References
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