Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia and Cardiovascular Diseases in Japan ― What Is the Next Step? ―
論文ID: CJ-21-0688
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論文ID: CJ-21-0688
The frequency of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) and erectile dysfunction (ED) increases with age, and the number of men with these symptoms is climbing in Japan as the population continues to age. The pathogenesis of LUTS/BPH and ED remains unclear because of the multiple factors involved. However, risk factors for cardiovascular disease (CVD), including obesity and diabetes mellitus, have been also identified as risk factors for LUTS/BPH and ED, and their association with CVD has been reported mainly in Europe and the USA.1 However, this association has not been examined much in Japan.
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In this issue of the Journal, Tanaka et al2 present a cross-sectional study on LUTS in Japanese community-dwelling men during their health examinations, reporting that moderate-to-severe LUTS were associated significantly with coronary artery disease and stroke. Although the causal relationship is unclear, this study did clarify the association between LUTS/BPH and CVD, even in Japan, where the incidence of obesity is lower than in Western countries. The proportions of patients with moderate or severe LUTS were 38.4% and 6.5%, respectively, among men in the general population aged 55–75 years (mean age, 67 years).
According to a patient survey in 2017 by the Japanese Ministry of Health, Labor, and Welfare, the number of patients with BPH was estimated to be 473,000,3 but the actual number of patients may be much higher. According to a 2021 population estimate, 23.35 million men aged ≥55 years old were living in Japan. If the percentage of those with severe LUTS (6.5%) were applied to this figure, the number of men with LUTS would be 1.5 million, and if those with moderate symptoms were added, the number would be 10.5 million. Therefore, a more detailed study of the association between urological disease and CVD may be important for prevention.
Two points must be addressed in future research on the relationship between urological disease and CVD. The first is to elucidate the pathophysiology involved. As Tanaka et al point out,2 although stroke and heart failure may affect urological disease, LUTS/BPH may be an important predictor of CVD. Previous epidemiological studies have reported that CVD risk factors such as obesity and diabetes also are associated with BPH.4,5 Prospective studies have shown that men who are obese or have a greater abdominal circumference have a higher risk for developing LUTS/BPH than do men without these health issues.6,7 Furthermore, a systematic review and a meta-analysis for LUTS and cardiovascular events has shown that the presence of moderate-to-severe LUTS was associated with an increased incidence of major adverse cardiac events as compared with the rest of the sample (odds ratio, 1.68; 95% confidence interval, 1.13–2.50; P=0.01).1
BPH is characterized by an enlarged prostate gland and increased smooth muscle tone, which leads to urinary symptoms. The prostate and prostatic urethra are surrounded by adipose tissue, which is thought to play a paracrine role in prostate growth and reactivity by releasing growth factors and anti-inflammatory, antioxidant, contractile, and anticontractile substances.5 As shown in the Figure, the prostatic microenvironment, including angiogenesis, proliferation, and inflammation, can be influenced by substances present in the systemic circulatory system or released from the periprostatic adipose tissue.5 Microscopic evaluation of local atherosclerosis in prostatic arteries removed during prostatectomy has shown a dose-response relationship between the degree of atherosclerosis and prostatic enlargement, which may be mediated by chronic inflammation and oxidative stress, such as lectin-like oxidized low-density lipoprotein receptor-1 and macrophages.8,9 Therefore, a detailed study of the relationships among perivascular adipose tissue, systemic adipose tissue including prostate and periprostatic fat, and LUTS/BPH will enable an approach to CVD prevention that also includes a urological perspective.
(A) General schematic showing the organs of the lower urinary tract. (B) Substances present in the systemic circulation and/or released from periprostatic adipose tissue (PPAT) that may interfere in the prostatic microenvironment such as angiogenesis, proliferation and inflammation. IL, interleukin; MCP-1, monocyte chemoattractant protein-1; NOX, NADPH oxidase; TNF, tumor necrosis factor. (Reprinted from Passos GR, et al.5)
A second point to be considered is the treatment of LUTS/BPH. A treatment that can alleviate symptoms and also prevent CVD would be ground-breaking. One medication that can be expected to have this effect is the phosphodiesterase type 5 (PDF5) inhibitor, a typical treatment for ED. The pathophysiological mechanisms of ED and LUTS/BPH are similar, and tadalafil, a PDF5 inhibitor, is now available in Japan for the clinical treatment of urinary dysfunction associated with BPH. PDF5 inhibitors are known to have pharmacological effects on the lower urinary tract, including inhibition of bladder outlet obstruction and improvement of bladder blood flow, as well as providing vascular endothelial protection and anti-inflammatory and antioxidant effects.10 Therefore, they also can have a protective effect on the cardiovascular system.
In an observational study of 5,956 men with type 2 diabetes aged 40–89 years in the UK, those who had taken a PDF5 inhibitor at baseline had a 31% lower risk of death during a mean observation period of 7.5 years as compared with those who had not.11 These associations were similar after adjusting for confounding factors such as age, serum lipids, renal function, smoking history, and medication use, and also were similar when the analysis was limited to those men with a history of myocardial infarction. Therefore, future interventional studies of PDF5 inhibitors on cardiovascular events are warranted to clarify the causal relationship.
The associations of LUTS/BPH and ED with CVD are still unclear in many respects, including pathophysiology and causality. However, the prevalence of LUTS/BPH and ED is high, and their attribution to CVD also is high. Further studies, including interventional trials, are necessary to determine a new approach from a urological perspective to prevent CVD.
Conflicts of interest: none.
