Relationship between Autonomic Nervous System Activity and Lower ...

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Objectives: Lower urinary tract symptoms (LUTS) are common, but their etiology and mechanism remain unclear. We believe that changes in autonomic nervous ...

LUTS (2009) 1, 25–28

Relationship between Autonomic Nervous System Activity and Lower Urinary Tract Symptoms: An Analysis of Heart Rate Variability in Men with Lower Urinary Tract Symptoms Il Han KIM,1 Jong Bo CHOI,1∗ Se Joong KIM,1 Young Soo KIM,1 Joon Chul KIM,2 and Jeong Gu LEE3 1 Department of

Urology, Ajou University School of Medicine, Suwon, 2 Department of Urology, Catholic University School of Medicine, Seoul, and 3 Department of Urology, Korea University School of Medicine, Seoul, Korea

Objectives: Lower urinary tract symptoms (LUTS) are common, but their etiology and mechanism remain unclear. We believe that changes in autonomic nervous system (ANS) activity may be contributory because the lower urinary tract is regulated through the sympathetic and parasympathetic nervous systems. Heart rate variability (HRV) is a tool by which autonomic nervous function can be measured; therefore, we measured and compared parameters of heart rate variability between men with LUTS and asymptomatic subjects. Methods: We studied 35 men with LUTS (mean age 50.5 ± 14.9 years) and 110 asymptomatic male volunteers who had requested a health check up (mean age 49.5 ± 5.19 years) from July 2006 to June 2008. HRV is known to be a useful tool for evaluating ANS activity, and we measured and compared HRV in the resting state. Results: The standard deviation of the N-N interval (SDNN) and total power (TP) for patients with LUTS revealed no significant differences from those in the control group. On frequency domain analysis, there was evidence of decreased high frequency (HF) in patients with LUTS (P < 0.05), but there were no significant differences in other parameters, such as heart rate, square root of the mean squared differences of successive N-N intervals (RMSSD), very low frequency (VLF), low frequency (LF), or LF/HF ratio. Conclusion: Patients with LUTS exhibited different HRV parameters compared with asymptomatic controls. Their decreased HF indicated that they may have had an imbalance in the autonomic nervous system. Key words autonomic nervous system, heart rate, prostate hyperplasia 1. INTRODUCTION

In men, lower urinary tract symptoms (LUTS), defined by the International Continence Society as storage, voiding and post-micturition symptoms, have traditionally been associated with benign prostatic hyperplasia.1 LUTS is a common disease, but its etiology and mechanism are still unclear. This condition can be bothersome, leading to anxiety and even morbidity.2 Worldwide, the severity and/or frequency of LUTS are most commonly quantified using the International Prostate Symptom Score (IPSS), which is essentially a clinical measure. The IPSS is a widely accepted, quantitative, objective assessment of the severity of the seven symptoms and of the total severity of LUTS.2 In contrast, heart rate variability (HRV) can be used to assess sympathetic and parasympathetic activity. This tool has recently been validated, and is now widely used in cardiology.3 – 5 It provides qualitative, quantitative, and non-invasive analysis of global autonomic function. We believe autonomic nervous dysfunction may be one of the causative factors of LUTS because the lower urinary tract is controlled through the sympathetic and parasympathetic nervous systems. Heart rate variability © 2009 Blackwell Publishing Asia Pty Ltd

(HRV) is a valid tool for estimating autonomic nervous system function; therefore, we measured and compared parameters of HRV between men with LUTS and asymptomatic groups. 2. METHODS

We studied 35 men with LUTS (mean age 50.5 ± 14.9 years) and 110 asymptomatic male volunteers who had requested a health checkup (mean age 49.5 ± 5.19 years). None of the patients had a history of coronary heart disease, diabetes mellitus, heart failure or cardiac arrhythmia. None of the patients or controls had any evidence of clinically significant dehydration. Patient selection was based on subjective symptoms using

∗ Correspondence: Jong Bo Choi, MD, PhD, Department of Urology,

Ajou University School of Medicine, San-5, Wonchon-dong, Yeongtong-gu, Suwon 442-721, Korea . Tel: +82-31-219-5273; Fax: +82-31-219-5276. Email: [email protected] Received 16 January 2009; revised 3 March 2009; accepted 17 March 2009. DOI: 10.1111/j.1757-5672.2009.00002.x

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Il Han Kim et al.

TABLE 1. Basic characteristics of patients and controls (mean ± SD)

Age (years) Symptoms Micturition times/day Micturition times/night Total IPSS Voiding Sx (1, 3, 5, 6) Storage Sx (2, 4, 7) Uroflowmetry Qmax (mL/sec)

LUTS group (n = 35)

Control group (n = 110)

P-value

50.5 ± 14.9

49.5 ± 15.2

0.103

11.3 ± 3.8 2.1 ± 1.3 21 ± 6.7 13 ± 5.2 8 ± 3.1

7.5 ± 1.6 0.9 ± 0.7 6 ± 1.8 4 ± 2.3 2 ± 2.5

0.001 0.013 0.000 0.000 0.000

11.3 ± 5.4

16.9 ± 4.0

0.001

IPSS, international prostate symptom score; LUTS, lower urinary tract symptoms; Sx, symptoms.

the IPSS and a 3-day voiding diary; patients who had lower urinary tract symptoms (IPSS ≥8) and had urinary daytime frequency greater than eight occasions or nocturia greater than two occasions in their voiding diary. We excluded patients with neurologic disease, diabetes, hypertension or other disease which can affect autonomic nervous system activity. None of the control subjects had voiding difficulty, urgency, incontinence, frequency, or nocturia (defined as needing to urinate more than once nightly). Both the asymptomatic controls and the LUTS patients underwent complete blood count; serum electrolyte, glucose, urea, creatinine, and liver enzyme measurements; urinalysis; and uroflowmetry. Patients were restricted in their consumption of tea and coffee, cigarette smoking and use of beta-receptor agonists or antagonists before the study. We used a system developed in-house for HRV acquisition and signal processing. We ultrasonographically confirmed that each subject’s bladder contained at least 100 mL of urine before testing. We assumed that some amount of urine in the bladder is more physiological than emptiness. After 30 min of rest, each patient and control subject underwent electrocardiographic signal recording for 5 min while in a seated position (SA−3000P, Medicore, Seoul, Korea). With the subjects breathing normally, we calculated the mean heart rate, standard deviation of the N-N interval (SDNN), and the square root of the mean squared differences of successive N-N intervals (RMSSD). We also determined the resting sympathetic and parasympathetic heartbeat rate modulation by means of frequency domain methods, including total power (TP), very low frequency (VLF), low frequency (LF), high frequency (HF), and LF/HF ratio. These measures of HRV in the patients with LUTS were compared with those in

the asymptomatic controls using the independent sample t-test. Statistical calculations were performed using SPSS version 12 (SPSS, Chicago, IL, USA). The null hypothesis was rejected if P < 0.05. 3. RESULTS 3.1. Patient characteristics

The mean age of patients with LUTS was 50.5 ± 14.9 years, and that of asymptomatic controls was 49.5 ± 15.2 years (P = 0.103). The IPSS of patients with LUTS was 21.0 ± 6.7, and that of asymptomatic controls was 6.0 ± 1.8 (P = 0.000). All of the patients’ laboratory results were within normal limits. There were no significant differences in age between patients and controls (Table 1). 3.2. Analysis of time domain and frequency domain

On time domain analysis, the mean SDNN and RMSSD of the patients with LUTS were not significantly lower than those of the asymptomatic controls (P > 0.05). On frequency domain analysis, the mean values of TP, LF, and VLF and the LF/HF ratio were not significantly different between the groups. However, the mean value of HF in men with LUTS was lower than in the control subjects (P = 0.015, Table 2). 4. DISCUSSION

Lower urinary tract symptoms (LUTS) are common in older men; they can be bothersome, leading to anxiety and even morbidity.2 The overall prevalence of LUTS is high, and it increases with age, as does its severity.6 LUTS exhibit no marked cultural variations. LUTS, commonly divided into storage, voiding, and postmicturition symptoms, have historically been linked to benign prostatic hyperplasia (BPH) in men. However, not all cases of LUTS are prostate-related, and the evidence for a direct link among benign prostate enlargement, bladder outlet obstruction, and LUTS is weak. Current interest in LUTS has focused on additional mechanisms and sites of origin, particularly with respect to the pathogenesis of storage symptoms.7 The lower urinary tract is generally under the control of the autonomic nervous system, is innervated by three sets of peripheral nerves (the parasympathetic, sympathetic, and somatic nervous systems), and contains afferent and efferent motor axons.8,9 Heart rate variability depends on the influence of sympathetic and vagal activity on the sinus node, and

TABLE 2. Parameters of heart rate variability for patients and controls (mean ± SD)

LUTS group Control group P-value

SDNN (msec)

RMSSD (msec)

HR (bpm)

TP (msec2 )

VLF (msec2 )

LF (msec2 )

HF (msec2 )

LF/HF ratio

28 ± 2.3 34 ± 1.1 0.57

21 ± 2.4 24 ± 1.0 0.332

71 ± 3.4 72 ± 1.2 0.338

652 ± 133.3 933 ± 65.1 0.080

379 ± 97.6 505 ± 35.8 0.220

178 ± 30.9 247 ± 20.0 0.131

98 ± 16.9 181 ± 15.5 0.015

2.5 ± 0.4 2.2 ± 0.2 0.481

HF, high frequency; HR, heart rate; LF, low frequency; LUTS, lower urinary tract symptoms; RMSSD, square root of the mean squared differences of successive N-N intervals; SDNN, standard deviation of the N-N interval; TD, total power; VLF, very low frequency.

© 2009 Blackwell Publishing Asia Pty Ltd

Autonomic dysfunction in Men with LUTS

variation and variability reflect spontaneous changes in autonomic activity. HRV is a new, important tool for studying autonomic control of the heart and autonomic dysfunction, and it represents one of the most promising of such markers.10,11 Apparent easy derivation of this measure has popularized its use. As many commercial devices now provide automated measurement of HRV, cardiologists have been provided with a simple tool for conducting both research and clinical studies.10,12 The clinical relevance of HRV was first appreciated in 1965, when Hon and Lee noted that fetal distress manifested itself as alterations in interbeat intervals before any appreciable change occurred in the heart rate itself.13 The clinical importance of HRV became apparent in the late 1980s when HRV was confirmed to be a strong, independent predictor of mortality following acute myocardial infarction.14 – 16 Most investigators have suggested that HF and RMSSD are predominantly a response to changes in parasympathetic tone, whereas LF and SDNN are dually influenced by cholinergic and adrenergic activities, as well as by other physiologic inputs. The values of TP are similar to those of SDNN; they affect control of the autonomic nervous system. Efferent vagal activity is a major contributor to the HF component, as is seen in clinical and experimental observations of autonomic maneuvers, such as electrical vagal stimulation, muscarinic receptor blockade, and vagotomy.17 – 19 More controversial is the interpretation of the LF component, which is considered by some19 – 22 to be a marker of sympathetic modulation (especially when expressed in normalized units) and considered by others17,23 to be a parameter that includes both sympathetic and vagal influences. Our data indicated that the mean value of HF was decreased in patients with LUTS compared to control patients. The decreased values indicate a decreased ability to control the parasympathetic systems. This study was limited in that LUTS are not specific and can be changed by factors unrelated to prostatic conditions, including diet, fluid intake, alcohol intake, and anticholinergic effects of commonly used over-thecounter medications.6 We attempted to restrict such effects by asking that patients not consume anything that could affect the autonomic nervous system before HRV recording. Furthermore, the physiological explanation of the VLF component is much less well defined, and the existence of a specific physiological process contributing to these heart period changes is questionable.10 In order to standardize physiological and clinical studies, some investigators10 have suggested that short-term recordings of 5 min be made under physiologically stable conditions processed by frequency-domain methods, and/or have suggested that nominal 24-h recordings be processed using time-domain methods. Experience shows that a substantial part of the long-term HRV value is attributable to day–night differences. Thus, long-term recordings need to be analyzed using timedomain methods. We conducted a short study because 24-h electrocardiographic recording would have limited © 2009 Blackwell Publishing Asia Pty Ltd

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our ability to compare the HRV results obtained during varying activities, such as exercise, sleep, and deep breathing. We believe that subjects in this study were slightly younger than average patients with LUTS. This age difference may result from the exclusion of men with diseases such as diabetes and hypertension, which can affect the autonomic nervous system in our study. Older men had a higher prevalence of disease, and they more commonly took medications that could affect the nervous system; such patients should be excluded from analysis. In the present study, we detected reductions of HF in the HRV values in patients with LUTS. Our findings suggest that the autonomic nervous system is altered in patients with LUTS, and this alteration may play a role in disturbed bladder function. The present study showed results similar to those noted in a study of women with OAB. Choi et al. reported that the values of SDNN, RMSSD, TP, VLF, and HF in female OAB patients were lower than those in normal, healthy women.9 Therefore, we cautiously suggest that decreased parasympathetic nervous system activity is related to LUTS, because most investigators believe that HF is reflected in parasympathetic activity. In vivo studies of HRV in a large population are required to clarify these possible alterations in the autonomic nervous system. 5. CONCLUSION

Men with LUTS exhibited decreased values of HF in HRV. These decreased values indicate that these patients may have autonomic nervous system imbalances, particularly decreased parasympathetic activity. However in vivo study is required to confirm the causal relationship between the autonomic nervous system and LUTS. The data presented here may help to further define the characteristic of LUTS. Acknowledgements

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