Greater Endothelial Dysfunction and Arterial Stiffness in Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome-A Possible Link to Cardiovascular Disease

Daniel A Shoskes, Donna Prots, Jeffrey Karns, Joi Horhn, Aaron C. Shoskes

<sup>All from the Glickman Urological and Kidney Institute, Cleveland Clinic

Running Head: Endothelial Dysfunction in CP/CPPS</sup>

Keywords: Prostatitis, Chronic Pelvic Pain Syndrome, Endothelial Dysfunction

Correspondence: Glickman Urological and Kidney Institute, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

Abstract

Introduction:  Men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) have higher self reported rates of cardiac disease than controls. Peripheral arterial tone abnormalities correlate with cardiac disease and mortality. We wished to study vascular dysfunction in men with CP/CPPS and controls.

Methods:  Twenty one men with CP/CPPS and 14 asymptomatic controls were tested with an Endo-PAT2000 machine which assessed the Augmentation Index(AI), a measure of arterial stiffness and Reactive Hyperemia Index(RHI), a measure of endothelial vasodilation. Symptoms were measured with the NIH Chronic Prostatitis Symptom Index (CPSI) and patient phenotype characterized by the UPOINT system. Statistical significance was set at p<0.05

Results: Ages were similar in the CP/CPPS group (22-63 years, median 40) and controls (19-57, median 40). Patients had median symptom duration of 24 months (range 3-440), mean CPSI score of 24.7+/-5.1 and mean UPOINT domains of 2.9+/-1.1 (range 1-5). AI was significantly higher (greater arterial stiffness) in CPPS patients vs Controls (5.0%+/-2.3 vs -6.0%+/-3.0, p=0.006). RHI was significantly lower (more endothelial dysfunction) in CPPS patients (1.76+/-1.2 vs 2.21+/-1.7, p=0.03). There was no correlation between symptom duration, severity or phenotype (number or type of UPOINT domains) and RHI or AI

Conclusions: Men with CP/CPPS have evidence for increased arterial stiffness and vascular endothelial dysfunction. This is the first mechanistic correlation found that links the higher incidence of self reported cardiac disease in these patients. Noninvasive Endo-PAT testing may allow stratification of CP/CPPS patients by vascular dysfunction, which may require specific treatment, or at least further assessment of cardiac risk.

 

Introduction

    Category III prostatitis, also known as chronic pelvic pain syndrome (CPPS) is a common syndrome affecting adult men of all ages. If is likely multifactorial and includes patients with varied clinical phenotypes1. Clinical associations in men with CPPS were examined in a large multicenter case-control study of 463 patients and 121 asymptomatic controls and surprisingly it was observed that patients had a significantly higher prevalence of self reported "cardiovascular disease" (11% vs 2% in controls, p=0.004) 2. This was surprising given a typical mean age of presentation in the early 40's and lack of other associated cardiac risk factors such as diabetes and obesity. Since the publication of this observation, no other study has examined either association or causality between CPPS and cardiovascular disease.

    A primary mechanism for cardiovascular disease is vascular endothelial cell dysfunction which is implicated in both cardiomyopathy3 and coronary artery disease4. Endothelial cell dysfunction can be measured by assessing peripheral arterial tone and it's response to nitric oxide mediated relaxation induced by ischemia-reperfusion and sheer stress. The EndoPAT-2000 (Itamar Medical, Caesarea Israel) is a device that non-invasively measures vascular endothelial cell function and arterial stiffness by measuring the peripheral arterial tone of the index finger before and after temporary occlusion of flow with a blood pressure cuff5. We hypothesized that CPPS patients without active cardiovascular disease may be at increased risk to develop these conditions and that therefore they may exhibit endothelial cell dysfunction. We therefore studied CPPS patients with the EndoPAT device and compared their findings with asymptomatic controls.

Materials and Methods

    Patients with a diagnosis of CPPS were recruited from a specialty prostatitis clinic and consented for an IRB approved study of endothelial cell function assessment. CPPS was diagnosed clinically and required symptoms for at least 3 of the prior 6 months and no evidence of current urinary tract infection. Patients with a history of active cardiac disease or diabetes were excluded from the analysis. Symptom severity was measured by the NIH Chronic Prostatitis Symptom Index (CPSI) 6 and disease phenotype classified by the UPOINT system7. Controls were recruited by advertisement in the clinic for adult men without current or prior symptoms or diagnosis of CPPS. Most of the controls were either medical staff or patients presenting for a vasectomy consult.

    Subjects were tested with an EndoPAT-2000 machine according to manufacturers instructions. Most men were assessed on the day of their initial evaluation but for those assessed later, none had begun specific therapy for their CPPS. Briefly, men sat in a quiet room with a device on both index fingers that measures arterial tone. A blood pressure cuff on the left arm occluded arterial blood flow for 5 minutes and then released. The software then calculated the Augmentation Index(AI), a measure of arterial stiffness and Reactive Hyperemia Index (RHI), a measure of nitric oxide mediated endothelial vasodilation. Both elevated AI and diminished RHI suggest vascular and endothelial disease.

    All parameters except symptom duration met the D'Agostino test for normality and therefore statistics whose assumptions include parametric data were used with significance set at p<0.05. Correlations between continuous variables were analyzed with the Pearson product-moment correlation coefficient. Continuous variables between patients and controls were compared with an unpaired student's t test. In 4 patients, a repeat measure was obtainable at least 3 months after treatment and these values were compared with a paired student's t test. Statistical analyses were performed with Prism 4 for Macintosh (Graphpad software).

Results

    There were 21 CPPS patients and 14 asymptomatic controls who met all criteria. Ages were similar in the CPPS group (22-63 years, median 40, mean 39+/-2.6) and controls (19-57, median 40, mean 44+/-2.3, p=0.12). Patients had median symptom duration of 24 months (range 3-440), mean CPSI score of 24.7+/-5.1 (range 18-37) and mean number of positive UPOINT domains of 2.9+/-1.1 (range 1-5). Unlike our prior published phenotype studies, the 21 patients had nobody with Infection and a relatively high incidence of pelvic floor spasm (17/21=81%). Other domain prevalences were Urinary at 12/21 (57%), Psychosocial at 10/21 (50%), Organ Specific at 17/21 (81%), and Neurologic/Systemic at 6/21 (29%).

    As seen in figure 1, both markers of vascular disease were worse in the CPPS patients than in the controls. AI was significantly higher (greater arterial stiffness) in CPPS patients vs controls (5.0%+/-2.3 vs -6.0%+/-3.0, p=0.006). RHI was significantly lower (more endothelial dysfunction) in CPPS patients (1.76+/-1.2 vs 2.21+/-1.7, p=0.03). Patient age had a negative correlation to RHI (Spearman R -0.48, p=0.03) but no correlation with AI (Spearman R -0.02, p=0.92). There was no correlation between AI or RHI with total symptom duration, CPSI total score or number of UPOINT domains. We then compared the AI and RHI between those patients with and without each individual UPOINT domain. None of the domains individually resulted in a statistically significant change in RHI or AI. Of note, there was a large difference in mean AI between those with and without the Neurologic/Systemic domain but given the small numbers (6 of 21 patients had the N domain) and large standard deviation, this difference was not statistically significant (no N domain: AI 1.6%+/-2.6, yes N domain AI 8.3%+/-3.7, p=0.11).

    Only 4 of the patients were able to be restudied more than 3 months after starting treatment. As seen in figure 2, while there was no change in RHI, there was significant improvement in AI following therapy (2.5% +/- 2.3 vs -8.5 +/- 1.7, p=0.039). Interestingly, AI improved in 3 of the 4 patients and what those 3 patients had in common was therapy that included pelvic floor physical therapy and oral quercetin. The patient whose AI worsened was treated with pregabalin and an alpha blocker, although his symptoms significantly improved.

Discussion

    CPPS is a syndrome of diverse phenotypes and etiologies. One technique to generate hypotheses as to pathophysiology or associated conditions is with a case-control study. In a large multicenter NIH sponsored study, several differences were found in the self reported incidence between CPPS patients and controls for history of nonspecific urethritis, neurologic disease, psychiatric conditions and hematologic or infectious diseases2. While none of these associations was unexpected or surprising, the one novel observation was an increased incidence of cardiovascular disease in CPPS patients. This was especially surprising given the typically young age of these men and a relative absence of other cardiovascular risk factors such as obesity and diabetes.

    If indeed patients with CPPS are at increased risk to develop cardiovascular disease, whether by direct effect or by association, then one could hypothesize that CPPS patients without active cardiovascular disease could be at increased risk to develop it in the future and that such risk could be assessed with biomarkers.  Indeed, such a relationship between urologic disease incidence and subsequent cardiac risk has already been established for erectile dysfunction8. A validated measure of cardiovascular risk is Peripheral Arterial Tone (PAT) 9 which can reflect changes in the vascular endothelial response as well as the autonomic nervous system. The Endo-PAT2000 is an FDA approved device that measures PAT in the finger before and after temporary brachial artery occlusion and normalized to the non-occluded contralateral side10. This yields a reactive hyperemia index (RHI), a measure of endothelial cell relaxation and an Augmentation Index (AI), a measure of arterial stiffness. Both RHI and AI can lead to atherosclerosis and abnormalities as measured by the Endo-PAT2000 have been associated with pulmonary hypertension11 and an increased rate of subsequent cardiac events12. This technique has also been used to assess cardiovascular effects of elevated triglycerides 13 and job stress 14. Interestingly, endothelial cell dysfunction has also been found in complex regional pain syndromes15 which have recently been linked to chronic pelvic pain16.

    In our study, we compared a population of CPPS patients with asymptomatic controls and found clinically and statistically significant changes in both RHI and AI in the CPPS group that indicate endothelial cell dysfunction and increased arterial stiffness. This novel observation may be related to increased autonomic vascular tone associated with pain induced chronic stress17. These changes may also contribute to the pathophysiology of chronic pelvic pain. Chronic skeletal muscle spasm is a feature of many men with CPPS18 and inability of the vascular endothelium to relax in response to this spasm may exacerbate ischemia and produce pain19. Alternatively, these vascular changes may be unrelated to the symptoms of CPPS but may simply be a method to stratify which CPPS patients are at truly increased risk for cardiac disease. Interestingly, while numbers were small, there was no apparent association between the Endo-PAT values and the patient's UPOINT clinical phenotype, and in particular no association with the psychosocial or muscle tenderness domains. This raises the possibility that abnormalities in PAT may have value as an independent biomarker in CPPS.

    Finally, while we only had four patients with repeated measures before and after multimodal therapy⁷, AI improved significantly in 3 of those 4 patients and these 3 patients all received pelvic floor physical therapy²⁰ and quercetin ²¹. By relieving pelvic floor spasm, the physical therapy may have directly improved local arterial blood flow, although it is unclear how this might effect vascular tone systemically. Quercetin is a potent antioxidant with demonstrated vasodilatory effects²² and dietary intake improves cardiac risk factors23 and is associated with lower cardiac mortality²⁴.

    In conclusion, we demonstrated deleterious changes in peripheral vascular tone in men with CPPS compared with asymptomatic controls. While preliminary, this novel finding can generate hypotheses as to the link between CPPS, risk of cardiac disease, relationship to complex regional pain syndromes and autonomic dysfunction. Further data, especially on patients following treatment can answer whether this is a modifiable risk factor that could be targeted for therapy or biomarker for cardiovascular risk stratification.

 

References