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Clinical Science

Association Between Erectile Dysfunction and Carotid Subclinical Atherosclerosis in HIV-Infected Patients

Bernal, Enrique MD, PhD*; Torres, Marcos MD; Alcaraz, Antonia MD*; Alcaraz, Maria Jose MD*; Rosa, Vicente de la MD*; Valero, Salvador MD*; Muñoz, Angeles MD*; Onteniente, María MD; Vicente, Tomas MD§; Cano, Alfredo MD*

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: April 1, 2019 - Volume 80 - Issue 4 - p 429-435
doi: 10.1097/QAI.0000000000001932
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Abstract

INTRODUCTION

Erectile dysfunction (ED) is classically defined as the inability to achieve and maintain a penile erection sufficient to complete satisfactory sexual activity.1 In HIV-infected patients, prevalence of ED ranges widely from 7% to 74%,2 in whom it frequently has a negative impact on quality of life and social welfare.

ED, atherosclerosis, and cardiovascular disease (CVD) share common risk factors including obesity, hypertension, metabolic syndrome, diabetes mellitus, and smoking. ED and CVD also have common underlying pathological mechanisms, including endothelial dysfunction, inflammation, and atherosclerosis.3–5 Moreover, there is growing evidence that ED may represent an early harbinger for more generalized vascular disease and a powerful predictor of future coronary artery disease risk and mortality.6 In this regard, ED may represent a sensitive clinical marker of endothelial and vascular health throughout the body.

CVD is highly prevalent in HIV-infected patients, and we hypothesized that presence of ED in these patients might also represent an early manifestation of subclinical atherosclerosis (SCA) and, as such, an early marker of cardiovascular risk. We therefore sought to investigate the extent of the association between ED and SCA in HIV-infected patients.

MATERIAL AND METHODS

Study Design, Participants, Setting, and Eligibility

This cross-sectional 6-month observational study was developed in a sample of men attending a university-based HIV clinic in Murcia. Subjects were recruited if they were male, age >18 years, and documented HIV infection. Concomitant pathologies or treatments were not exclusion criteria. The study conformed to the Declaration of Helsinki principles and the Good Clinical Practice Guidelines, and was approved by the local ethics committee (“Comité Ético de Investigación Clínica del Hospital General Universitario Reina Sofía de Murcia”). All patients gave their written informed consent to participate in the study.

Clinical and Laboratory Measurements

Medical records were carefully reviewed, and all subjects underwent a physical examination. Information on gender, age, body mass index, smoking status, family history of CVD, and treatment with antiretroviral drugs was recorded. The presence of arterial hypertension, hypercholesterolemia, and hypertriglyceridemia was defined according to the Adult Treatment Panel III criteria. Dyslipidemia was considered if total cholesterol level was ≥200 mg/dL, low-density lipoprotein (LDL) cholesterol level was ≥130 mg/dL, or high-density lipoprotein (HDL) cholesterol level was <40 mg/dL. A sample of fasting venous blood was obtained to determine concentrations of glucose, high-sensitivity C-reactive protein (hsCRP), creatinine, total cholesterol, D-Dimer, HDL cholesterol, and triglycerides using standard enzymatic methods. LDL cholesterol concentrations were calculated using the Friedewald equation. Plasma viral load was measured using the Cobas TaqMan HIV-1 assay (Roche Diagnostics Systems, Branchburg, NJ). CD4 and CD8 T-cell counts were determined by using flow cytometry (Beckman-Coulter, Münster, Germany).

ED Evaluation

ED was evaluated using the International Index of Erectile Function (IIEF-5) in its validated Spanish version.7 The IIEF-5 is a brief, five-item version of the IIEF. Scores are interpreted as follows: severe ED (5–7 points), moderate (8–11 points), mild to moderate (12–16 points), mild (17–21 points), and normal (22–25 points). To simplify analyzes, ED was grouped into 2 degrees of severity (no ED or mild ED and moderate–severe ED).

cIMT Measurements

Carotid measurements were performed during the baseline visit. For the determination of carotid intima–media thickness (cIMT), B-mode high-resolution ultrasound was used following a standard procedure previously described.8 All measurements were performed by the same researcher, who was unaware of the group to which the patients belonged. It was considered SCA if IMT was higher than 0.8 mm in common carotid, higher than 1 mm in bulb carotid, or there was a plaque in the carotid artery.

Statistical Analyses

A descriptive analysis of patients' characteristics was conducted using frequency tables for categorical variables, and mean and SD for continuous variables. Differences in categorical variables between patients with and without SCA were assessed through the χ2 test or the Fisher test, and t student tests for continuous variables. Binary logistic regression was used to evaluate the independent variables associated with ED. Multivariable models were adjusted for age, transmission group (homosexual/bisexual, injecting drug use, heterosexual, and other/unknown), Framingham risk score, and variables that were significant in univariate analysis. Wald tests were used to derive P values.

Significance levels were placed at P < 0.05. All statistical analyses were performed using SPSS package version 24.

RESULTS

A total of 139 HIV-infected male patients were included in the study. The basal characteristics are described in Table 1. Mainly, the median age was 45.22 years (SD, 10.47 years), median CD4+ count was 728 cells/mL (358), and 73.2% had HIV viral load lower than 50 copies/mL. One hundred thirty (94.9%) patients were on antiretroviral therapy (ART), 24.8% was on PI-based regimens, 30.7% was with nonnucleoside reverse transcriptase inhibitor–based regimens, and 38.7% with IIS-based regimen. Seventeen (12.3%) patients were hypertensive, 3.6% had type 2 diabetes, 31.4% were dyslipidemic, and 53.2% were smokers. The mean Framingham risk score was 7.77 (6.78), and 22% had Framingham risk score higher than 10%. The mean time on ART was 2.21 (2.58) years. In 34 patients (24.5%), cIMT was higher than 0.8 mm, and 53 (38.1) patients had carotid SCA.

TABLE 1-a
TABLE 1-a:
Basal Characteristics of 139 HIV-Infected Patients
TABLE 1-b
TABLE 1-b:
Basal Characteristics of 139 HIV-Infected Patients

According to the IIEF-5, prevalence of all degrees of ED was 61.2%. ED was mild in 49 (35.3%) men, mild to moderate in 22 (15.8%), moderate in 4 (2.8%), and severe in 10 (7.2%) patients.

Table 2 summarizes the clinical and HIV-related parameters distributed by SCA.

TABLE 2-a
TABLE 2-a:
Patients' Characteristics Distributed by SCA
TABLE 2-b
TABLE 2-b:
Patients' Characteristics Distributed by SCA

Variables associated with SCA in the univariate analysis were as follows: hepatitis C virus antibodies, lipodystrophy or lipoatrophy, glomerular filtration rate, glucose level, age, Framingham risk score, and ED. To simplify analyzes, ED was grouped into 2 degrees of severity (no ED or mild ED and moderate–severe ED).

In multivariate regression analysis, where variables of univariate analysis with statistical significance were included and considering 2 degrees of severity in ED, variables independently associated with SCA were as follows: older age [odds ratio (OR) = 1.22, confidence interval (CI) 95%: 1.1 to 1.35; P < 0.001] and moderate–severe ED (OR = 4.68, CI 95%: 1.18 to 18.5; P = 0.028) (Table 3). Neither mild ED nor no ED was associated with SCA.

TABLE 3
TABLE 3:
Variables Associated With Carotid SCA

Subsequently, we analyzed only the patients who had a low cardiovascular risk (Framingham risk score lower than 10%) and observed that 32 (29.35%) of 109 patients had SCA, and there were 24 (22%) with moderate–severe ED. In the multivariate regression analysis, adjusted for cardiovascular risk factors (age, smoke, hypertension, and dyslipidemia) and hepatitis C virus antibodies, variables independently associated with SCA were as follows: age (OR = 1.27, 95% CI: 1.13 to 1.42; <0.001), moderate–severe ED (OR = 3.87, CI 95%: 1.12 to 13.3, P = 0.031), and hypertension (OR = 8.54, CI 95%: 1.027 to 71.05, P = 0.047).

There was an inverse correlation between ED rating and global cIMT (r = −0.295, P = 0.01), left cIMT (r = −0.192, P = 0.024), and bulb cIMT (r = −0.267, P = 0.002) (Figure 1).

FIGURE 1
FIGURE 1:
Patients distributed by ED severity and SCA. Results represented as percent. When the effect of each of the groups on the presence of SCA was analyzed, there were no statistical differences between mild ED and no ED (P = 0.293), neither between moderate ED and severe ED (P = 0.293). There were statistical differences between no ED or mild ED and moderate or severe ED (P < 0.001).

Furthermore, is it interesting to note that 31% of patients with moderate–severe ED had carotid plaque compared with 13.9% of patients with mild ED or no ED, P = 0.021.

Patients with moderate–severe ED compared with mild or no ED were more likely to be hypertensive (25.7% vs. 7.8%, P = 0.013), have hepatitis C virus antibodies (41.2% vs. 17.5%; P = 0.009), have higher D-dimer levels (437 ± 711 vs. 244 ± 145 mg/dL, P = 0.030), have higher Framingham risk score (10.81 ± 9.73% vs. 7.11 ± 6.33%, P = 0.01), be older (52.25 ± 9.24 vs. 42.74 ± 9.77 years; P < 0.001), and have lower CD4 cell count (620.29 ± 307.71 vs. 764.89 ± 368.86 cells/mL; P = 0.039). We did not find any difference between patients with mild ED and those with no ED of the parameters analyzed, and neither between patients with moderate and severe ED.

In the multivariate analysis, which included hypertension, dyslipidemia, smoking, age, Framingham risk score, hepatitis C virus, D-dimer level, and CD4 cell count, the variables that maintained their independence and were related to ED were as follows: age (OR = 1.107, 95% CI: 1.041 to 1.17; P < 0.001) and hepatitis C virus antibodies (OR = 5.12, 95% CI: 1.54 to 17; P = 0.0008).

We found no relationship between the degree of fibrosis, genotype, and whether or not they had received treatment with ED.

Figure 2 shows patients distributed by age and by the presence of SCA and ED. Figure 3 represents patients distributed by SCA and ED.

FIGURE 2
FIGURE 2:
Patients distributed by age, SCA, and ED. Results represented as percent.
FIGURE 3
FIGURE 3:
Correlation between carotid IMT and ED score (IIEF).

DISCUSSION

In our study, ED in HIV-infected patients was frequent, and moderate–severe degree was independently associated with the presence of SCA in the carotid artery.

ED in HIV-infected patients is not infrequent,9 especially mild ED, and is more prevalent than in general population regardless of age.10 In our study, prevalence of ED was 61.2%, with mild ED (35.4%) being very frequent compared with severe ED, which only appeared in 7.2% of the study population.

The exact mechanism underlying the positive association between HIV and ED remains poorly understood. Traditional factors that contribute to the increase in ED risk have to be considered, such as age, hypertension, diabetes, CVD, impaired endothelial function, metabolic syndrome, depression and anxiety, illicit drug use (particularly intravenous use), alcohol abuse, medication (especially antidepressants), and recreational drugs, because their frequency is significantly higher in HIV-infected population.11,12 In addition, there are other factors, such as primary or secondary hypogonadism, that are more frequent in HIV-infected patients,13 and the combination of depression and anxiety.14 On the other hand, ART and, particularly, the use of protease inhibitors have been associated with a worsening of erectile function.15 In our study, in addition to age, we observed that the presence of HCV antibodies was associated with an increased risk of ED. Although it is not clear, chronic HCV liver disease has been associated with a greater likelihood of ED, probably not only because of the presence of associated hypogonadism but also because of an increased cardiovascular risk, especially through insulin resistance or endothelial dysfunction.16,17

The association between atherosclerosis and ED has already been described previously in general population.18 It has also been related to the degree of severity of ED and the extent of coronary atherosclerosis.19,20 However, the association between ED and the occurrence of cardiovascular events it is more interesting.6,21 In this sense, ED increases the risk of 44% of cardiovascular events, 62% of MI, and 25% of global mortality compared with patients without ED,21 and its appearance precedes the cardiovascular event between 2 and 3 years,19 thus constituting a strong risk marker and cardiovascular death.

Our study is the first one to relate the presence of ED to SCA in HIV-infected patients. We observed that there was an important relationship between both the processes. The IIEF score was inversely and significantly associated with the burden of carotid arteriosclerosis, especially at the bulb level. Thus, we found a very important relationship between the degree of severity of ED and the possibility of having SCA.

Atherosclerosis is a complex process whose pathogenesis shares mechanisms similar to ED.22 Although normal erectile function is a neurovascular event modulated by hormonal and psychological factors, endothelial integrity plays a major role in physiology of penile erections.23 Endothelial dysfunction plays a major role in pathogenesis of ED and atherosclerosis.24 There are multiple factors that have influenced on the deterioration of endothelial function, but the most important ones are classic cardiovascular risk factors such as diabetes, dyslipidemia, hypertension, smoking, and age. In our study, the most important factor, related to both, was age. When analyzing the variables associated with SCA, cardiovascular risk factors were the most important ones. Therefore, patients with atherosclerosis had higher scores on the Framingham risk score. Other associated factors were dyslipidemia (although at the limit of statistical significance), having antibodies for hepatitis C, renal failure, high glucose level, and high D-dimer level. Although these variables did not maintain their independence in the multivariate analysis, all of them have been previously associated with an increased risk of atherosclerosis and cardiovascular risk in other studies, both in general population and in patients with HIV.25 If we analyze patients with moderate–severe ED, they also had a higher cardiovascular risk because they were older, had hypertension more frequently, had positive serology to hepatitis C virus antibodies, and had a higher Framingham risk score.

Despite that cardiovascular risk factors were more frequent in patients with ED and atherosclerosis, the fact that ED in HIV-infected patients was associated with SCA independently of vascular risk factors implies that other associated mechanisms may exist. In this regard, it has been observed that low androgen levels have been shown to be associated with ED, metabolic syndrome, diabetes, and CVD.26 Endothelial cells and smooth muscle cells are the main targets for androgen effects in penile and CV systems, and hypogonadism is associated with an increased risk of atherosclerotic vascular remodeling.26 Androgens can reduce the expression of inflammatory markers in these tissues, and low testosterone levels have a proinflammatory and proapoptotic effect on endothelial cells.26 However, in our study, we did not find any association between free testosterone levels with ED and SCA. Another mechanism that may be involved is the state of persistent inflammation that exists in HIV-infected patients, despite the control of viral replication with ART.27 Low-grade subclinical inflammation affects the endothelial function and could lead to a prothrombotic status. Several studies reported that ED onset and severity are associated with an increased expression of markers of inflammation.24,28 Inflammatory markers and mediators (ie, CRP, intercellular adhesion molecule-1, interleukin [IL]-6, IL-10, IL-1b, and tumor necrosis factor-a), and endothelial/prothrombotic factors (ie, von Willebrand factor, tissue plasminogen activator, plasminogen activator inhibitor 1, and fibrinogen) have been shown to be expressed at higher levels in patients with ED.24,28 In our study, we observed that patients with ED had higher levels of D-dimer and lower levels of CD4 T lymphocytes. Low levels of CD4 T lymphocytes have been associated with the severity of atherosclerosis associated with HIV-infected patients.29 On the other hand, in the SMART study, D-dimer level together with other inflammatory markers was higher in the patients who interrupted the treatment and was associated with an increased risk of cardiovascular events and death from any cause.30 HIV-associated immune activation is characterized by an increase in proinflammatory mediators, dysfunctional T regulatory cells, and a pattern of T-cell–senescent phenotypes similar to those seen in the elderly. These changes predispose HIV-infected persons to atherosclerosis, CVD, and ED.31

In conclusion, and despite the limitations of our study, mainly concerning the number of patients that hinder the significance of our results and its cross-sectional nature that makes difficult causality assignment of observed associations, our results show that ED is common in HIV-infected patients and that moderate–severe degree is very significantly associated with SCA regardless of cardiovascular risk factors and age. Although more studies are needed to verify these results and to confirm the long-term consequences, their presence should alert the clinician to adopt appropriate measures to prevent the development of cardiovascular events, especially lifestyle measures, control of cardiovascular risk factors, and use of an antiretroviral treatment with a less atherogenic profile.

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Keywords:

erectile dysfunction; subclinical atherosclerosis; cardiovascular risk

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