Photoplethysmography-Derived Flow-Mediated Dilation as a Non-Invasive Marker of Endothelial Function in Erectile Dysfunction

1. Introduction

Erectile dysfunction (ED) is the inability to achieve or maintain an erection sufficient for sexual satisfaction. It is a significant health concern that affects millions of men and their partners worldwide [1]. While ED itself poses substantial quality-of-life issues, its strong association with cardiovascular diseases (CVD) underscores its broader clinical significance. Recent studies indicate that endothelial dysfunction is a key pathological mechanism underlying this relationship. Since the endothelium and nitric oxide (NO) play central roles in both erectile function and cardiovascular regulation, it is unsurprising that endothelial dysfunction contributes to the pathophysiology of both ED and CVD.

Erection is a complex process involving vascular, neurological, and hormonal pathways. Any disruption in this intricate system can result in ED. Among its various etiologies, vascular causes are the most prevalent, accounting for approximately 60% of cases [2]. Other contributing factors include neurological disorders, hormonal imbalances, psychological conditions, unhealthy lifestyle habits, medication side effects, and chronic diseases [3]. The prevalence of ED varies across studies, but it is estimated to affect 30–50% of men over 40 years old [2,4]. Furthermore, ED is not uncommon in younger men; one study reported that one in four ED patients is under the age of 40 [5].

ED is increasingly recognized as a precursor to various comorbid conditions, particularly CVD. It has been linked to hypertension, diabetes, metabolic syndrome, obesity, and chronic obstructive pulmonary disease [6]. This suggests that ED is not merely a localized dysfunction but a marker of systemic vascular health [7]. Given the crucial role of endothelial function in vascular homeostasis, its assessment in ED patients can provide valuable insights into both erectile and cardiovascular health.

Endothelial function is typically evaluated using Flow-Mediated Dilation (FMD), which is considered the gold standard for non-invasive endothelial function assessment [8]. This technique involves transient occlusion of the brachial artery followed by Doppler ultrasound measurement of the NO-mediated vasodilation response. However, despite its extensive use, FMD has significant limitations, including the need for expensive equipment, specialized software, and an experienced operator, making it less feasible for routine clinical practice.

Given these challenges, alternative methods have been developed to improve the practicality and accessibility of endothelial function assessment. One such method is Peripheral Arterial Tonometry (PAT), which utilizes the Endo-PAT device (Itamar Medical, Caesarea, Israel) [9]. PAT has been widely used for cardiovascular risk stratification and prognostication in coronary artery disease and other conditions [10,11,12,13].

More recently, Photoplethysmography Flow-Mediated Dilation (PPG-FMD) has emerged as a promising alternative. Compared to FMD and PAT, PPG-FMD is more accessible, operator-independent, and cost-effective. While still a relatively new technique, it has shown strong correlation with the gold standard USG-FMD method in different patient populations [14,15]. Its applications have been explored in various clinical contexts, including gestational hypertension [16] and coronary artery disease [14,17], with promising results.

Despite its increasing clinical use, PPG-FMD has not yet been systematically evaluated in ED patients. The present study aimed to assess endothelial function using the PPG-FMD method in patients diagnosed with ED who do not have coronary artery disease (CAD). Additionally, the study aimed to evaluate the effectiveness of PPG-FMD in differentiating between vascular and non-vascular causes of ED.

2. Materials and Methods

2.1. Study Population and Design

The study was conducted at the Urology Outpatient Clinic of Alanya Alaaddin Keykubat University Training and Research Hospital. The study was approved by the Ethics Committee of Akdeniz University, Faculty of Medicine (protocol code: 39; date of approval: January 11, 2017). Patients presenting to the outpatient clinic who volunteered to participate were evaluated by an experienced urologist, diagnosed, and subsequently enrolled in the study. All participants were male. The present study is a clinic-based observational cross-sectional comparative study involving three groups. Patients with known coronary artery disease (CAD) were excluded from the study.

2.2. Measures

Erectile function of all participants was evaluated using the self-reported International Index of Erectile Function (IIEF) under the supervision of a urologist. Current biochemical analysis results were collected from laboratory records. Subsequently, participants were directed to a separate room within the outpatient clinic and informed about the study protocol. Following a 15-minute rest period, demographic data were collected, anthropometric measurements were taken, and endothelial function was assessed.

The PPG-FMD method was employed for the measurement of endothelial function. Briefly, PPG-FMD is a non-invasive approach that measures the microvascular dilation response in the upper extremity during reactive hyperemia. Endothelial function was represented by the Dilation Index (DI), which indicates the percentage maximum change in blood volume in the arterial bed compared to baseline. After obtaining the PPG-FMD result curves and determining the maximum dilation response as the Dilation Index, the time elapsed from the beginning of reperfusion to reach this response (in seconds) was recorded as Tmax, and the area under the curve (AUC) of the portion of the curve above zero was calculated and recorded (Figure 1). Finally, the average slope of the curve from the beginning of reperfusion to the maximum dilation response was calculated and recorded as DIslope. Details of the PPG-FMD methodology have been described previously [18].

2.3. Data analysis

Statistical analyses were performed using GraphPad Prism. The normality of data distribution was assessed using the Shapiro-Wilk test. For comparisons across groups, one-way analysis of variance (ANOVA) with Tukey’s post-hoc test was applied for normally distributed continuous variables, and the chi-square test was used for categorical variables. A p-value of less than 0.05 was considered statistically significant. All continuous variables are expressed as mean ± standard error of the mean (SEM), and categorical variables are expressed as number (percentage).

3. Results

3.1. Participants

The study included 24 patients with vascular ED, 18 patients with non-vascular ED, and 30 healthy controls. The demographic and clinical characteristics of the study groups are summarized in Table 1.

Significant differences were observed among the groups in terms of IIEF scores (p < 0.001). Pairwise comparisons revealed that both the vascular and non-vascular ED groups had significantly lower IIEF scores than the control group.

The Framingham Risk Score (FRS) was highest in the vascular ED group (7.7 ± 0.7), lowest in the non-vascular ED group (2.5 ± 1.0), and intermediate in the control group (5.6 ± 0.9). The difference among groups was statistically significant (p = 0.003), and pairwise comparisons showed that only the vascular ED vs. non-vascular ED difference reached statistical significance.

3.2. Demographics and laboratory values

The demographic characteristics and laboratory values of the study groups are presented in Table 1 and Table 2, respectively. While age, BMI, waist circumference, pulse rate, and blood pressure values were similar among the groups (p > 0.05 for all), significant differences were observed in FRS and IIEF scores (p < 0.05, Table 1).

In the biochemical analyses (Table 2), fasting glucose, hemoglobin, HbA1c, HDL, and LDL levels differed significantly among the groups (p = 0.025, p = 0.017, p = 0.022, p < 0.001, and p = 0.005, respectively). LDL levels were highest in the vascular ED group, whereas HDL levels were lowest. Additionally, the non-vascular ED group exhibited significantly lower hemoglobin levels compared to the control group.

3.3. Endothelial function assessment

Systemic endothelial function was assessed using the PPG-FMD method. Vascular ED patients exhibited significantly lower endothelial function compared to both the non-vascular ED and control groups (Figure 2a, p < 0.001), whereas no significant difference was observed between the non-vascular ED and control groups.

The mean PPG-Dilation Index (PPG-DI) values were 47.1% ± 4.2 in the vascular ED group, 113.6% ± 5.3 in the non-vascular ED group, and 97.7% ± 4.5 in the control group (p < 0.001 for both pairwise comparisons).

3.4. Additional endothelial function parameters

In addition to PPG-DI, several other endothelial function parameters were analyzed (Figure 2). The Tmax parameter, representing the time required to reach maximum dilation, was 92.5 ± 11.9 s in the vascular ED group, 67.0 ± 10.2 s in the non-vascular ED group, and 74.4 ± 9.6 s in the control group. Although the vascular ED group exhibited a longer time to reach maximum dilation, the difference among groups was not statistically significant (p = 0.297).

The area under the curve (AUC), which reflects the magnitude and duration of the dilation response, was significantly lower in the vascular ED group (3329%×s ± 489) compared to both the non-vascular ED (13342%×s ± 1151) and control groups (9830%×s ± 1127) (p < 0.001).

The DIslope parameter, indicating the rate of vasodilation during the reperfusion period, was 1.68%×s⁻¹ ± 0.27 in the vascular ED group, 2.84%×s⁻¹ ± 0.71 in the non-vascular ED group, and 3.02%×s⁻¹ ± 0.64 in the control group. Although vascular ED patients had a lower slope value, suggesting a slower dilation response, the difference was not statistically significant (p = 0.156).

Figure 3 presents PPG-FMD result curves from individual participants. Vascular ED patients (Figure 3a,b) exhibited delayed and weaker vasodilation responses compared to non-vascular ED and control participants (Figure 3c,d). In non-vascular ED and control groups, dilation occurred rapidly after reperfusion onset, with a sustained positive dilation response. In contrast, vascular ED patients showed a delayed transition to positive dilation, and the vasodilation response was markedly shorter in duration, suggesting impaired endothelial function.

Figure 4 displays the average PPG-FMD result curves for five randomly selected participants from each study group. The vascular ED group demonstrated a slower and reduced vasodilation response, whereas the non-vascular ED and control groups exhibited a more rapid and prolonged dilation pattern. The vascular ED curve dropped below baseline after three minutes, whereas in the other groups, it remained positive beyond four minutes, further emphasizing differences in the vasodilation response.

4. Discussion

Our findings align with the well-established relationship between erectile dysfunction (ED) and cardiovascular disease (CVD), further emphasizing the role of endothelial dysfunction as a shared pathological mechanism. Given that ED and CVD share common risk factors such as aging, smoking, diabetes, and hypertension, endothelial impairment in ED patients may serve as an early marker of systemic vascular dysfunction. The artery size hypothesis suggests that the smaller penile arteries are more susceptible to vascular narrowing before larger arteries, such as coronary vessels, exhibit symptoms. This may explain why ED often precedes major cardiovascular events, highlighting the importance of early endothelial function assessment in these patients.

Previous studies have shown that approximately two-thirds of men diagnosed with coronary artery disease (CAD) experienced ED prior to CAD symptoms [19]. Additionally, younger ED patients appear to have a higher predisposition to future cardiovascular disease compared to older individuals with ED [20]. These findings underscore the necessity of early screening and risk assessment in ED patients, particularly those with a vascular etiology, as endothelial dysfunction may be a critical predictor of future cardiovascular events.

Endothelial function plays a fundamental role in vascular homeostasis, primarily through the release of nitric oxide (NO), which mediates vasodilation in response to increased blood flow demands. Reduced NO bioavailability leads to a diminished and shorter-lasting vasodilation response, contributing to both erectile and cardiovascular dysfunction. This mechanism is essential for erectile function and cardiovascular regulation. Given its key role in vascular health, endothelial dysfunction is increasingly recognized as a major contributor to various vascular diseases. Although endothelial function measurement is not yet a routine clinical tool, accumulating evidence supports its use in assessing disease progression and prognosis.

In our study, PPG-FMD successfully detected endothelial dysfunction in vascular ED patients, showing significantly lower endothelial function compared to the non-vascular ED and control groups. These results reinforce the idea that systemic endothelial impairment is a hallmark of vascular ED and suggest that PPG-FMD may serve as a useful tool in differentiating between vascular and non-vascular ED etiologies.

Assessing endothelial function in ED patients provides two key benefits. First, it helps differentiate between vascular and non-vascular ED, allowing for more precise diagnostic and treatment strategies. Second, it enables the early identification of cardiovascular risk factors, facilitating timely intervention and risk modification to prevent future cardiovascular events. Given the strong link between ED, endothelial dysfunction, and cardiovascular disease, incorporating endothelial function assessments into routine evaluation could provide significant diagnostic and prognostic advantages.

Several studies have investigated endothelial function in ED patients, primarily using USG-FMD and PAT methods. Kaya et al. found that ED patients had significantly lower USG-FMD results than controls (6.0% vs. 12.3%), reinforcing the role of endothelial dysfunction in ED [21]. Similarly, Yavuzgil et al. demonstrated a clear distinction in endothelial function between ED patients, individuals with cardiovascular risk factors but no ED, and healthy controls (3.2%, 6.0%, and 10.2%, respectively) [22]. These findings suggest that measuring endothelial function in ED patients may provide insights into undiagnosed vascular disease and cardiovascular risk.

Studies utilizing PAT measurements in ED patients have yielded inconsistent results. While some studies found significant differences between ED and control groups [23,24], others, such as Mehta et al., reported no significant difference between general ED and post-prostatectomy ED patients (RHI: 1.97 vs. 2.08, p = 0.074) [25]. Similarly, Wu et al. observed a positive correlation between systemic and local penile endothelial function (r = 0.640, p < 0.001), suggesting that systemic endothelial assessments could be used to evaluate both ED and cardiovascular risk [26].

Our study is the first to utilize PPG-FMD for systemic endothelial function assessment in ED patients. Unlike PAT, which relies on pneumatic finger sensors, PPG-FMD detects vascular volume changes using LED and photodiode technology, providing a continuous, real-time assessment of endothelial responses. This may explain why PPG-FMD detected significant differences between vascular and non-vascular ED groups, whereas PAT-based studies have shown inconsistent results.

A major advantage of PPG-FMD is its ability to provide continuous measurement of dilation responses during each cardiac cycle. Unlike traditional FMD, which captures dilation at discrete time points, PPG-FMD offers real-time tracking of vascular responses, allowing for a more precise determination of peak dilation. Additionally, PPG-FMD does not require ECG synchronization, simplifying the assessment process and enhancing accuracy.

Beyond a single maximum dilation value, PPG-FMD provides multiple vascular parameters, including rate of dilation, time to peak dilation (Tmax), and total dilation response over time (AUC). These additional measures offer a more comprehensive evaluation of endothelial function, capturing physiological variations that may be overlooked with traditional methods.

Endothelial dysfunction is a multifaceted process, involving reduced NO synthesis, diminished NO sensitivity, and increased PDE-mediated NO degradation [27]. These mechanisms not only affect the magnitude of vasodilation but also its timing and duration. Given this complexity, PPG-FMD’s ability to analyze multiple parameters makes it a promising tool for both research and clinical applications.

Taken together, the continuous, operator-independent nature of PPG-FMD and its ability to track dynamic endothelial responses position it as a promising alternative to conventional endothelial function measurement techniques. While our findings support its clinical potential, further studies with larger cohorts and direct comparisons to USG-FMD and PAT are needed to establish its diagnostic accuracy and clinical applicability.

This study has several limitations. The small sample size and exclusion of ED patients with CAD may limit the generalizability of our findings. Additionally, the cross-sectional design prevents establishing a causal relationship between endothelial dysfunction and ED. Selection from a single outpatient clinic introduces potential selection bias, and the absence of Penile Doppler Ultrasonography may have affected the differentiation between vascular and non-vascular ED. Finally, uncontrolled factors such as medication use and lifestyle variables could have influenced endothelial function outcomes.

5. Conclusions

This study demonstrated that vascular ED patients exhibit significantly impaired endothelial function as assessed by PPG-FMD, reinforcing the role of endothelial dysfunction in its pathophysiology. In contrast, non-vascular ED patients had endothelial function comparable to controls, suggesting that psychogenic, neurogenic, or hormonal etiologies may predominate in this group.

These findings highlight the potential utility of PPG-FMD as a non-invasive tool for endothelial function assessment in ED evaluation. Future research should focus on validating PPG-FMD against established methods in larger cohorts and exploring its clinical utility in both ED diagnosis and cardiovascular risk stratification.