Serum low density lipoprotein cholesterol / high density lipoprotein cholesterol ratio predicts lower urinary tract dysfunction related dyslipidemia

Abstract

Objectives: To investigate the effect of dyslipidemia on the lower urinary tract function by examining the LDL-C/HDL-C ratio in patients without bladder outlet obstruction (BOO).

Methods: Patients who underwent urodynamic study before robot-assisted radical prostatectomy were included.　Exclusion criteria were diabetes mellitus (HbA1c > 6.2%) and BOO (Schäfer nomogram obstruction III - V).　The association between the preoperative LDL-C/HDL-C ratio and urodynamic findings were analyzed.　Patients were divided into two groups based on Schäfer nomogram: weak contraction group (W−, W+, N−) and strong contraction group (N+, ST) to assess the relationship between the LDL-C/HDL-C ratio and bladder contraction.

Results: A total of 52 patients entered the study.　The LDL-C/HDL-C ratio was 2.4 ± 0.8.　The preoperative international prostate symptom score was mild (6.7 ± 5.6).　Voided volume was significantly positively associated with the LDL-C/HDL-C ratio (P=0.041).　The LDL-C/HDL-C ratio was significantly less in the strong contraction group than in the weak contraction group (P=0.047).　Receiver operating characteristic (ROC) analysis showed a cut-off value of 2.15 for the LDL-C/HDL-C ratio in predicting weak bladder contraction.

Conclusions: Dyslipidemia-induced lower urinary tract dysfunction (LUTD) showed less bladder contractility with larger voided volume.　The LDL-C/HDL-C ratio ≥ 2.15 may be a useful marker of dyslipidemia-induced LUTD.

Introduction

Lower urinary tract symptoms (LUTS), such as increased daytime frequency, nocturia, incontinence and slow stream, are common in both sexes in later life and affect quality of life (QOL)^1,2).　Lower urinary tract dysfunction (LUTD) including smaller voided volume, detrusor overactivity and decreased detrusor contraction, contributes to the onset of LUTS.　The cause of LUTD is multifactorial and involves many pathophysiological mechanisms.　Some studies suggested that dyslipidemia is associated with LUTS³⁾.　Martin et al. assessed changes in LUTS over a five-year period in men aged 35-80 years and concluded that lower high-density lipoprotein cholesterol (HDL-C) predicted the progression of voiding LUTS³⁾.　Several basic studies have also demonstrated that dyslipidemia contributes to LUTD^4,5).　In addition, Watanabe Heritable Hyperlipidemic rabbits have shown detrusor overactivity with decreased detrusor contraction⁴⁾.　The hyperlipidemic rats developed bladder overactivity with smaller voided volumes and a shortened micturition interval⁵⁾.　However, there has been little clinical evidence showing an association between dyslipidemia and LUTD.

Recently, the low-density lipoprotein cholesterol (LDL-C)/HDL-C ratio has been used to assess dyslipidemia.　The LDL-C/HDL-C ratio more accurately predicts cardiovascular disease (CVD) risk than LDL-C or HDL-C levels^6,7).　However, it is not clear whether the LDL-C/HDL-C ratio can predict the progression of LUTD associated with dyslipidemia.

The aim of this study is to investigate the effect of dyslipidemia on the lower urinary tract function by evaluating association between the LDL-C/HDL-C ratio and the urodynamic findings of the patients without bladder outlet obstruction and discuss whether the LDL-C/HDL-C ratio predicts lower LUTD related dyslipidemia.

Patients and Methods

Patients

This prospective observational study included patients who underwent urodynamic study (UDS) before robot-assisted radical prostatectomy (RARP) at Fukushima Medical University Hospital (Fukushima, Japan) from February 2013 to April 2014.　To eliminate the effects of diabetic neuropathy and bladder outlet obstruction, exclusion criteria were defined as HbA1c > 6.2% and Schäfer nomogram obstruction III - V, which was defined with maximum flow rate (Qmax) and detrusor pressure at Qmax (PdetQmax)⁸⁾.　In our institution, during the early period after the introduction of RARP, we performed a UDS to accurately evaluate lower urinary tract function for patients who were concerned about postoperative LUTD at their request.

Study design

The UDS was performed before RARP.　The association between the LDL-C/HDL-C ratio and urodynamic findings was analyzed.　According to Schäfer nomogram contraction, which was defined with Qmax and PdetQmax as well as Schäfer nomogram obstruction⁹⁾, patients were divided into two groups, weak contraction (contraction Weak−, Weak+, Normal−) group and strong contraction group (contraction Normal+, Strong) to evaluate the association between the LDL-C/HDL-C ratio and bladder contraction.　The international prostate symptom score (IPSS) and QOL index questionnaire were also assessed prior to RARP.　The study was carried out in accordance with the Guidelines for the Care and Use of the Declaration of Helsinki and protocols approved by the ethical Committee of Fukushima Medical University (#2565).

Urodynamic study

The UDS was carried out with Solar System (Medical Measurement Systems, USA) according to the Good Urodynamic Practice Guidelines of the International Continence Society (ICS)¹⁰⁾.　Pressure flow study was performed using a 6-Fr double-lumen trans urethral catheter with normal saline solution (37°C) at a filling rate of 50 mL/min, and abdominal pressure was monitored using a 10-Fr intrarectal balloon catheter.　The volume at first desire to void (FDV) and strong desire to void (SDV), bladder compliance and the presence of detrusor overactivity (DO) were assessed during bladder filling.　After patients were asked to void at capacity, voided volume (VV), Qmax, PdetQmax and postvoid residual urine volume (PVR) were measured.　The other definitions of parameters used in the UDS conformed to the standards recommended by the ICS¹¹⁾.

The international prostate symptom score and QOL index questionnaire

The IPSS questionnaire has seven questions, which are used to evaluate LUTS in male patients.　The patients are given five options for the seven questions and each option indicates severity of that symptom.　The total score ranges from 0 to 35.　LUTS are classified as mild to severe depending on the IPSS total score.　Patients having a total score from 0 to 7 are classified as having mild symptoms, scores from 8 to 19 are classified as moderate symptoms, and symptom scores from 20 to 35 are classified as severe symptoms.　Quality of life index (QOL) such as feelings if current symptoms lasted for life, were rated on a scale ranging from 0 (delighted) to 6 (terrible)¹²⁾.

Statistical analysis

All values were expressed as mean ± standard deviation.　A two-sided Mann-Whitney U test was used for the categorical variable and a Pearson correlation test was used for continuous variables.　P-values of <0.05 were considered to be statistically significant.　Cut-off values of the LDL-C/HDL-C ratio as a predictor of LUTD were determined using receiver operating characteristic (ROC) analysis.　All data were analyzed using SPSS statistical package version 24.0 (SPSS Inc., Chicago, IL, USA).

Results

A total of 52 patients (66.5 ± 5.4 years) entered the study.　The patients’ characteristics are shown in Table 1.　The LDL-C/HDL-C ratio of patients was 2.4 ± 0.8.　Their IPSS and QOL index were mild (IPSS: 6.7 ± 5.6 score, QOL index: 2.7 ± 1.4 score).　Table 2 shows the correlation between the LDL-C/HDL-C ratio and urodynamic findings.　VV (P=0.041, C.C=0.329) and bladder compliance (P=0.049, C.C=0.318) were significantly positively associated with the LDL-C/HDL-C ratio.　Qmax, the volume at FDV, the volume at SDV and PVR were not significantly associated with the LDL-C/HDL-C ratio.　The LDL-C/HDL-C ratio was significantly less in the strong contraction group than in the weak contraction group (strong contraction group vs weak contraction group: 1.9 ± 0.5 vs 2.5 ± 0.8, P=0.047).　There was no significant difference in the LDL-C/HDL-C ratio between the negative and positive measures of DO (Table 3).　ROC analysis showed a cut-off value of 2.15 for the LDL-C/HDL-C ratio to predict weak bladder contraction (sensitivity, 64.9%; specificity, 72.7%; area under the curve, 0.71) (Fig. 1).

Table 1.

Patients’ characteristics

BMI: body mass index

LDL-C: low density lipoprotein cholesterol

HDH-C: high density lipoprotein cholesterol

IPSS: International prostate symptom score

Continuous data are presented as mean ± standard deviation (range) and discrete data as numbers of patients (%)

Table 2.

Correlation between LDL-C/HDL-C ratio and urodynamic findings using Pearson correlation analysis

SD: standard deviation, LDL-C: low density lipoprotein cholesterol,

HDL-C: high density lipoprotein cholesterol, C.C: correlation coefficient

*Denotes statistical significance at p<0.05 level

Table 3.

Correlation between LDL-C/HDL-C ratio and urodynamic findings using Mann-Whitney U test

LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol,

n: number of patients (%), SD: standard deviation, *Denotes statistical significance at p<0.05 level

Fig. 1.

Receiver operating characteristic curve (ROC) analysis showed a cut-off value of 2.15 for the LDL-C/HDL-C ratio predicting weak bladder contraction.

Discussion

In this study, we demonstrated that male patients with reduced bladder contraction have elevated LDL-C/HDL-C ratio.　The LDL-C/HDL-C ratio reflects the degree of dyslipidemia more sensitively than LDL-C or HDL-C alone^6,7).　It is well known that an elevated LDL-C concentration in plasma is atherogenic and an increased HDL-C level is cardioprotective.　The elevated LDL-C/HDL-C ratio is associated with progression of atherosclerosis⁶⁾.　Dyslipidemia causes atherosclerosis, which in turn leads to a variety of diseases including LUTS.　The correlation between LUTS and CVD, which is related to atherosclerosis, is well established.　CVD has been proposed as a potential risk factor for both LUTS progression and severity¹³⁾.　Ponholzer et al. also reported that vascular risk factors, such as dyslipidemia, play a role in the development of LUTS in both sexes¹⁴⁾.　Recently, the association between LUTD and atherosclerosis has been reported, as well as the association between LUTS and atherosclerosis.　The male patients with atherosclerosis evaluated by measurement of intima-media thickness of the carotid artery showed decreased Qmax and reduced VV as compared with the male patients without atherosclerosis¹⁵⁾.　Previously, we have demonstrated that pelvic arterial occlusion related with atherosclerosis impaired bladder muscle strip contractility by using a rat model of chronic bladder ischemia^16,17).　The elevated LDL-C/HDL-C ratio induced weak bladder contraction in male patients through chronic ischemia by atherosclerosis.

Our results showed that elevated LDL-C/HDL-C ratio increased VV and bladder compliance with little PVR although bladder contraction was weak.　We consider that the reason for the increased VV and bladder compliance is that their dyslipidemia-induced LUTD was in a compensated state.　Our previous basic study indicated that progressive LUTD by atherosclerosis increased VV without increased PVR in the early stages of detrusor underactivity, because of reduced afferent sensory input from the bladder and maintained detrusor contractility¹⁸⁾.　Some basic studies have indicated increased bladder compliance and bladder hypocontractility in compensated bladder function by using diabetic rats¹⁹⁾.　Our study was targeted at preoperative RARP patients, not patients with severe LUTS or LUTD.　As a result, patients with dyslipidemia-induced LUTD in the compensatory phase might be included in the study.　Mild IPSS and little PVR in these patients support our considerations.　Our results suggest that dyslipidemia first causes a larger bladder capacity with good compliance but less contractility.

We suggested that the optimal cut-off value for LDL-C/HDL-C ratio to predict impaired bladder contraction was 2.15.　Some studies reported that the predictive cut-off value of LDL-C/HDL-C ratio in CVD was 2.5^7,20).　While those studies use a cut-off value for the onset of CVD, our study calculates a cut-off value for the compensatory phase of LUTD.　Therefore, it is suspected that the cut-off value to predict LUTD in our study was lower than the cut-off value for the onset of CVD.　Using the cut-off values in this study, treatment of dyslipidemia could be initiated before LUTD becomes more critical, which may prevent the severity of LUTD.

There are several limitations that need to be addressed.　First, the number of patients in our study was comparatively small due to the single-institution design.　Further multicenter studies with a larger number of patients are needed to clarify the underlying mechanisms of dyslipidemia-induced LUTD.　Second, this study included patients in the compensatory phase of LUTD, so the overall details of dyslipidemia-induced LUTD are not yet clear.　Future studies should include patients with severe LUTD caused by dyslipidemia to elucidate the full extent of dyslipidemia-induced LUTD.　Third, our study did not directly evaluate the association between atherosclerosis and LUTD, nor between atherosclerosis and dyslipidemia.　Future evaluation of these associations is needed to elucidate the detailed pathogenesis of LUTD caused by dyslipidemia.

Conclusion

Bladders have less contractility, but a larger capacity with good compliance at a compensated stage of dyslipidemia related LUTD.　The LDL-C/HDL-C ratio ≥ 2.15 may be a useful marker of hyperlipidemia-induced LUTD.

References

• 1.  Irwin DE, Milsom I, Hunskaar S, et al: Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study.　Eur Urol 50: 1306-1314; discussion 1314-1315, 2006.
• 2.  Chapple CR, Wein AJ, Abrams P, et al: Lower urinary tract symptoms revisited: a broader clinical perspective.　Eur Urol 54: 563-569, 2008.
• 3.  Martin S, Lange K, Haren MT, et al: Risk factors for progression or improvement of lower urinary tract symptoms in a prospective cohort of men.　J Urol 191: 130-137, 2014.
• 4.  Yoshida M, Masunaga K, Nagata T, et al: The effects of chronic hyperlipidemia on bladder function in myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits.　Neurourol Urodyn 29: 1350-1354, 2010.
• 5.  Rahman NU, Phonsombat S, Bochinski D, et al: An animal model to study lower urinary tract symptoms and erectile dysfunction: the hyperlipidaemic rat.　BJU Int 100: 658-663, 2007.
• 6.  Noike H, Hitsumoto T, Sakurai T, et al: [Relationships between intravascular ultrasonographic findings and coronary risk factors in patients with normal coronary angiography].　J Cardiol 45: 1-10, 2005.
• 7.  Sun T, Chen M, Shen H, et al: Predictive value of LDL/HDL ratio in coronary atherosclerotic heart disease.　BMC Cardiovasc Disord 22: 273, 2022.
• 8.  Cicione A, Lombardo R, Nacchia A, et al: Post-voided residual urine ratio as a predictor of bladder outlet obstruction in men with lower urinary tract symptoms: development of a clinical nomogram.　World J Urol 41: 521-527, 2023.
• 9.  Tanabe T, Ishizuka O, Ichino M, et al: Analysis of the Pressure-Flow Study in Weak Detrusor Patients with Benign Prostatic Hypertrophy.　Low Urin Tract Symptoms 3: 109-112, 2011.
• 10.  Schafer W, Abrams P, Liao L, et al: Good urodynamic practices: uroflowmetry, filling cystometry, and pressure-flow studies.　Neurourol Urodyn 21: 261-274, 2002.
• 11.  Lee KH, Kuo HC: Recovery of Voiding Efficiency and Bladder Function in Male Patients With Non-neurogenic Detrusor Underactivity After Transurethral Bladder Outlet Surgery.　Urology 123: 235-241, 2019.
• 12.  Taneja Y, Ram P, Kumar S, et al: Comparison of Visual Prostate Symptom Score and International Prostate Symptom Score in the evaluation of men with benign prostatic hyperplasia: A prospective study from an Indian population.　Prostate Int 5: 158-161, 2017.
• 13.  Gacci M, Corona G, Sebastianelli A, et al: Male Lower Urinary Tract Symptoms and Cardiovascular Events: A Systematic Review and Meta-analysis.　Eur Urol 70: 788-796, 2016.
• 14.  Ponholzer A, Temml C, Wehrberger C, et al: The association between vascular risk factors and lower urinary tract symptoms in both sexes.　Eur Urol 50: 581-586, 2006.
• 15.  Takahashi N, Shishido K, Sato Y, et al: The Association between Severity of Atherosclerosis and Lower Urinary Tract Function in Male Patients with Lower Urinary Tract Symptoms.　Low Urin Tract Symptoms 4: 9-13, 2012.
• 16.  Akaihata H, Hata J, Tanji R, et al: Tetrahydrobiopterin prevents chronic ischemia-related lower urinary tract dysfunction through the maintenance of nitric oxide bioavailability.　Sci Rep 10: 19844, 2020.
• 17.  Akaihata H, Nomiya M, Matsuoka K, et al: Protective Effect of a Rho-kinase Inhibitor on Bladder Dysfunction in a Rat Model of Chronic Bladder Ischemia.　Urology 111: 238 e7-238 e12, 2018.
• 18.  Nomiya M, Yamaguchi O, Akaihata H, et al: Progressive vascular damage may lead to bladder underactivity in rats.　J Urol 191: 1462-1469, 2014.
• 19.  Daneshgari F, Liu G, Imrey PB: Time dependent changes in diabetic cystopathy in rats include compensated and decompensated bladder function.　J Urol 176: 380-386, 2006.
• 20.  Bray PF, Larson JC, Lacroix AZ, et al: Usefulness of baseline lipids and C-reactive protein in women receiving menopausal hormone therapy as predictors of treatment-related coronary events.　Am J Cardiol 101: 1599-1605, 2008.